tag:blogger.com,1999:blog-156543012024-03-27T19:53:05.427-04:00On Biostatistics and Clinical TrialsCQ's web blog on the issues in biostatistics and clinical trials.Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.comBlogger521125tag:blogger.com,1999:blog-15654301.post-65166630847354968392024-02-22T22:00:00.002-05:002024-02-22T22:00:00.464-05:00Advancing Psychedelic Clinical Study Design - Virtual Public Meeting Organized by Reagan-Udall Foundation Over the past decade, psychedelic compounds like psilocybin and ecstasy have emerged as potentially life-changing treatments for mental illnesses, including major depressive disorder and posttraumatic stress disorder. These psychedelic products may be synthetic compounds or extracts from natural products (such as magic mushroom). They usually have hallucinations effects and belongs to the substance control products. <div><br /></div><div>Academics and pharmaceutical/biotech companies are now interested in developing the psychedelic products for therapeutic uses in treating diseases like major depression, PTSD, Pakington's disease,...</div><div><br /></div><div>In order to obtain the regulatory approval, various phases of clinical trials need to be conducted. The clinical trial designs for psychedelic drugs are more complicated than typical drugs because of its known side effects and the nature of the substance-controlled products. </div><div><br /></div><div>Reagan-Udall Foundation recently organized a virtual public meeting to discuss "advancing psychedelic clinical study design". During this public meeting, attendees discussed the experience of scientists working with psychedelics in FDA-authorized clinical studies and drug development, considerations for psychedelics in clinical trial designs, and perspectives and current research in psychedelic clinical trials. FDA presenters provided an overview of its newly issued guidance "<a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/psychedelic-drugs-considerations-clinical-investigations" target="_blank">Psychedelic Drugs: Considerations for Clinical Investigations</a>."</div><div><br /></div><div>Video recording of this virtual public meeting is available on Reagan-Udall Foundation website: </div><div><h3 class="text-align-center" style="background-color: white; box-sizing: border-box; color: #4a4a4a; font-family: Gotham, sans-serif; font-size: 1.5em; font-weight: 500; line-height: 1.2; margin-bottom: 10px; margin-top: 20px; padding: 0px; text-align: center;"><a href="https://reaganudall.org/news-and-events/events/advancing-psychedelic-clinical-study-design" target="_blank">Advancing Psychedelic Clinical Study Design<br style="box-sizing: border-box;" /><em style="box-sizing: border-box;">Virtual Public Meeting</em></a></h3></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-45658269798482579672024-01-15T23:30:00.002-05:002024-01-15T23:30:00.185-05:00Terminal events as intercurrent events in clinical trials<p>ICH E9 "<a href="https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf" target="_blank">Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials</a>" contained discussions about intercurrent events and strategies for handling intercurrent events. Intercurrent events were defined as: </p><p style="text-align: left;"></p><blockquote>Events occurring after treatment initiation that affect either the interpretation or the existence
of the measurements associated with the clinical question of interest. It is necessary to address
intercurrent events when describing the clinical question of interest in order to precisely define
the treatment effect that is to be estimated.</blockquote><p></p><p>The terminal events are one kind of intercurrent event. <a href="https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf" target="_blank">ICH E9 Addendum</a> did not provide the formal definition for 'terminal events', but gave examples of the terminal events: </p><p></p><blockquote>Examples of intercurrent
events that would affect the existence of the measurements include terminal events such as
death and leg amputation (when assessing symptoms of diabetic foot ulcers), when these events
are not part of the variable itself.</blockquote><p></p><p>In a paper by Siegel et al "<a href="https://arxiv.org/ftp/arxiv/papers/2203/2203.02182.pdf" target="_blank">The role of occlusion: potential extension of the ICH E9 (R1) Addendum on Estimands and Sensitivity Analysis for Time-to-Event oncology studies</a>", the terminal events were described as the following: </p><p></p><blockquote>The estimands guidance also introduces the concept of a terminal event. Terminal events prevent the possibility of subsequent measurement. "For terminal events such as death, the variable cannot be measured after the intercurrent event, but neither should these data generally be regarded as missing." There are two examples given in the guidance, death and leg amputation. These examples clarify that terminal events physically prevent subsequent measurement, for any estimand in any study. </blockquote><p></p><p></p><blockquote>Terminality is an objective property of an event which renders further observation physically impossible. If an event is terminal, it is impossible to devise a study that can look beyond it. Indeed there is no meaningful clinical question regarding the treatment effect that manifests after a terminal event. </blockquote><p>Terminal events can be defined as events that make the outcome measures impossible and the events are not part of the outcome such as death and ankle amputation in a trial assessing ankle function). Sometimes, the outcome measure after the terminal events may still be possible, but the measures after the terminal events are not meaningful. For example, in clinical trials of pulmonary diseases with spirometry measure as the primary outcome, lung transplantation will be a terminal event. After the lung transplantation, the spirometry measure can still be performed, but the spirometry measure is a reflection of the transplanted lungs, not the intended measure of the clinical trial endpoint. </p>Terminal events should be separated as fatal (death, mortality) and non-fatal terminal events (may be called 'terminal events excluding mortality'). While they are all considered intercurrent events, the strategies for handling the fatal and non-fatal terminal events need to be different. <p class="MsoNormal"><b>Strategies for Handling the Fatal Terminal Events</b></p><p class="MsoNormal"><o:p>Treatment policy strategy can not be used for handling fatal terminal events (death events). <a href="https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf" target="_blank">ICH E9 Addendum</a> mentioned the following: </o:p></p><p class="MsoNormal"><o:p></o:p></p><p class="MsoNormal"></p><p></p><p></p><blockquote>In general, the treatment policy strategy cannot be implemented for intercurrent events that are terminal events, since values for the variable after the intercurrent event do not exist. For example, an estimand based on this strategy cannot be constructed with respect to a variable that cannot be measured due to death.</blockquote><p class="MsoNormal">Composite strategies (or composite variable strategies) are particularly useful for handling fatal terminal
events (deaths). The occurrence of the fatal terminal intercurrent event is informative about the
effect of the treatment and so it is incorporated in the endpoint. In practice, the outcomes after the fatal terminal intercurrent event can not be observed, but need to be assumed to have the worst values. </p><p class="MsoNormal">With the composite
strategy, the terminal intercurrent events will be assigned a failed value. A failed value may be:</p><ul style="margin-top: 0in; text-align: left;" type="disc">
<ul style="margin-top: 0in;" type="circle">
<li class="MsoListParagraph" style="margin-left: 0in; mso-list: l0 level2 lfo1;">Worse possible measure (for example, 0 for 6MWD and 0 for FEV1 or FVC measures)</li><li class="MsoListParagraph" style="margin-left: 0in; mso-list: l0 level2 lfo1;">Worst observed value across all subjects at the endpoint visit</li><li class="MsoListParagraph" style="margin-left: 0in; mso-list: l0 level2 lfo1;">Trimmed means (trimmed
means and quantiles were mentioned in <a href="https://database.ich.org/sites/default/files/E9%28R1%29%20Training%20Material%20-%20PDF_0.pdf">ICH
E9 addendum training materials</a>)<o:p></o:p></li>
<li class="MsoListParagraph" style="margin-left: 0in; mso-list: l0 level2 lfo1; text-autospace: none;">The worst change (from
baseline) of all subjects plus a random error. The error can be randomly
drawn from a normal distribution with a mean of 0 and a variance equal to
the residual variance estimated from the mixed model for all observed
values of change from baseline</li></ul></ul>In FDA's guidance, "<a href="https://www.fda.gov/media/130964/download" target="_blank">Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment Guidance for Industry</a>", deaths were integrated into the functional measure by the ALS Functional Rating Scale-Revised (ALSFRS-R). The guidance said:<div><blockquote>Functional endpoints can be confounded by loss of data because of patient deaths. To address
this, FDA recommends sponsors use an analysis method that combines survival and function into
a single overall measure, such as the joint rank test.</blockquote>In pivotal clinical trials in ALS, the joint rank test is almost the default method for analyzing the primary efficacy endpoint of the ALSFRS-R. The Joint Rank statistic ranks study participants in each treatment group, first by survival and then by ALSFRS-R score. The Joint Rank can increase power relative to analysis of either ALSFRS-R or survival analysis alone in some circumstances, for example when mortality rates are high<span style="background-color: white; color: #212121; font-family: Cambria, "Cambria Math", stixgeneral, "Times New Roman", Times, serif; font-size: 20px;">. </span> </div><div><br /></div>Joint Rank test was described and used in the NEJM paper by Miller et al "<a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2204705#:~:text=The%20joint%20rank%20test%20was,of%20data%20owing%20to%20deaths." target="_blank">Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS</a>".<div><span class="title_default" style="background: transparent; border: 0px; box-sizing: inherit; font-family: inherit; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; font-variation-settings: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline: 0px; padding: 0px; touch-action: inherit; vertical-align: baseline;"><br /></span></div><div><p class="MsoNormal"><o:p><b>Strategies for Handling the Non-Fatal Terminal Events</b></o:p></p><p class="MsoNormal">It is acceptable to use hypothetical strategy to handle the non-fatal terminal intercurrent events. "Hypothetical strategies: A scenario is envisaged in which the intercurrent event would not occur: the value of the
variable to reflect the clinical question of interest is the value which the variable would have
taken in the hypothetical scenario defined." </p><p class="MsoNormal">The value of the variable to reflect the clinical question of interest is the
value which the variable would have taken in the hypothetical scenario
defined. The value to be considered would have been the one
collected if patients had not had the non-fatal terminal event. Outcomes after the non-fatal terminal events do not need to be measured. If the outcomes after the non-fatal terminal events are measured (for example, the spirometry measure after lung transplantation), the measures can be disregarded and not used in the analyses. The outcomes after the non-fatal terminal events cannot be observed, can be left as missing values, and usually need to be implicitly
or explicitly predicted/imputed.</p><p></p></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-37564785527402930992024-01-12T07:00:00.011-05:002024-01-12T07:00:00.142-05:00Post-Marketing Requirement (PMR) versus Post-Marketing Commitment (PMC)Following the NDA or BLA approval, the sponsors may be required to conduct post-marketing studies. The phrase <a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/postmarket-requirements-and-commitments" target="_blank">post marketing requirements and commitments</a> refers to studies and clinical trials that sponsors conduct after approval to gather additional information about a product's safety, efficacy, or optimal use. Some of the studies and clinical trials may be required; others may be studies or clinical trials a sponsor has committed to conduct.<p class="MsoPlainText">Post-approval studies can be classified by FDA as a
postmarketing requirement (PMR) or a postmarketing commitment (PMC).<span style="mso-spacerun: yes;"> </span></p><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><p class="MsoPlainText" style="text-align: left;">A PMR is a study or clinical trial that an applicant (or sponsor) is
required by statute or regulation to conduct postapproval. A PMC is a study or clinical trial that an applicant (or sponsor) agrees in writing to conduct postapproval, but that is
not required by statute or regulation. PMRs and PMCs can be issued upon approval of a drug or
postapproval, if warranted.</p></blockquote><p class="MsoPlainText">As a result, failure to
conduct a PMR would be a violation of the Federal Food, Drug, and Cosmetic Act
(FDCA) and/or implementing regulations, subject to enforcement action.<span style="mso-spacerun: yes;"> </span>Potential enforcement actions can include an
FDA Warning Letter, charges under section 505(o)(1) of the FDCA, misbranding
charges under section 502(z), or civil monetary penalties.<span style="mso-spacerun: yes;"> </span>In contrast, failure to conduct a PMC would
not be a violation of the FDCA or regulations, and therefore not subject to
enforcement action.</p><p class="MsoPlainText">The table below compares the features of the PMR versus PMC:</p><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><table style="--tw-border-spacing-x: 0px; --tw-border-spacing-y: 0px; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: inherit; border-image: initial; border-spacing: var(--tw-border-spacing-x) var(--tw-border-spacing-y); border-style: solid; border-width: 0px; color: #374151; font-family: Söhne, ui-sans-serif, system-ui, -apple-system, "Segoe UI", Roboto, Ubuntu, Cantarell, "Noto Sans", sans-serif, "Helvetica Neue", Arial, "Apple Color Emoji", "Segoe UI Emoji", "Segoe UI Symbol", "Noto Color Emoji"; font-size: 0.875em; line-height: 1.71429; margin-bottom: 0.25rem; margin-top: 0.25rem; table-layout: auto; text-indent: 0px; white-space-collapse: preserve; width: 613px;"><thead style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-th-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box;"><th style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; background-color: rgba(236, 236, 241, 0.2); border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-top-left-radius: 0.375rem; border-width: 1px 0px 1px 1px; box-sizing: border-box; color: var(--tw-prose-headings); padding: 0.25rem 0.75rem; vertical-align: bottom;">Feature</th><th style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; background-color: rgba(236, 236, 241, 0.2); border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 1px 0px 1px 1px; box-sizing: border-box; color: var(--tw-prose-headings); padding: 0.25rem 0.75rem; vertical-align: bottom;">Post-Marketing Requirements (PMR)</th><th style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; background-color: rgba(236, 236, 241, 0.2); border-top-right-radius: 0.375rem; border: 1px solid rgb(217, 217, 227); box-sizing: border-box; color: var(--tw-prose-headings); padding: 0.25rem 0.75rem; vertical-align: bottom;">Post-Marketing Commitments (PMC)</th></tr></thead><tbody style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box;"><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Definition</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Regulatory obligations imposed by authorities</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Voluntary commitments made by the sponsor</td></tr><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Purpose</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Gather additional data on safety, efficacy, etc.</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Obtain more information post-approval</td></tr><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Enforcement</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Mandatory; non-compliance may lead to penalties</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Voluntary, but sponsors are expected to fulfill</td></tr><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Imposition</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Imposed by health regulatory agencies</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Made voluntarily by the sponsor during approval</td></tr><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Consequences of Non-compliance</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Regulatory actions, fines, or product withdrawal</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Regulatory actions; may impact marketing authorization</td></tr><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Flexibility</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Typically less flexible; regulatory mandates</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Voluntary, but commitment should be honored</td></tr><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px 0px 1px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Origin</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">External (regulatory agency)</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Internal (sponsor during regulatory approval)</td></tr><tr style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-color: var(--tw-prose-td-borders); border-image: initial; border-left-color: rgb(217, 217, 227); border-right-color: rgb(217, 217, 227); border-style: solid; border-top-color: rgb(217, 217, 227); border-width: 0px; box-sizing: border-box;"><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-left-radius: 0.375rem; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;"><span color="var(--tw-prose-bold)" style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border: 0px solid rgb(217, 217, 227); box-sizing: border-box; font-weight: 600;">Examples</span></td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Post-approval safety studies, surveillance</td><td style="--tw-border-spacing-x: 0; --tw-border-spacing-y: 0; --tw-ring-color: rgba(69,89,164,.5); --tw-ring-offset-color: #fff; --tw-ring-offset-shadow: 0 0 transparent; --tw-ring-offset-width: 0px; --tw-ring-shadow: 0 0 transparent; --tw-rotate: 0; --tw-scale-x: 1; --tw-scale-y: 1; --tw-scroll-snap-strictness: proximity; --tw-shadow-colored: 0 0 transparent; --tw-shadow: 0 0 transparent; --tw-skew-x: 0; --tw-skew-y: 0; --tw-translate-x: 0; --tw-translate-y: 0; border-bottom-right-radius: 0.375rem; border-color: rgb(217, 217, 227); border-image: initial; border-style: solid; border-width: 0px 1px 1px; box-sizing: border-box; padding: 0.25rem 0.75rem; vertical-align: baseline;">Additional clinical trials, long-term safety studies</td></tr></tbody></table></blockquote><div><br /></div>According to FDA's guidance "<a href="https://www.fda.gov/media/131980/download#:~:text=Section%20505(o)(3)%20of%20the%20Act%20authorizes%20FDA,aware%20of%20new%20safety%20information.">Guidance for Industry Postmarketing Studies and Clinical Trials — Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act</a>", PMR may be required in the following situations:<div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEj8G3acJ8Q-G0iW5IwRIf_1i7lnGo2gr1TuWkAewr6Fl1qg3yi0JQdmj-EU5kJHeq0mHWozBmCmp0okgH9gmIeBYnk6kNSM9bF18BWzxVTDuGriPxXxsX4lplDQ7FoNeBc-ScwS3cSqgi-y2PXSJeyr9ypoCl87-P27KkiNOyOilMywPnOlHQ" style="margin-left: 1em; margin-right: 1em;"><br /><img alt="" data-original-height="141" data-original-width="629" height="139" src="https://blogger.googleusercontent.com/img/a/AVvXsEj8G3acJ8Q-G0iW5IwRIf_1i7lnGo2gr1TuWkAewr6Fl1qg3yi0JQdmj-EU5kJHeq0mHWozBmCmp0okgH9gmIeBYnk6kNSM9bF18BWzxVTDuGriPxXxsX4lplDQ7FoNeBc-ScwS3cSqgi-y2PXSJeyr9ypoCl87-P27KkiNOyOilMywPnOlHQ=w618-h139" width="618" /></a></div>PMC may be required in the following situations: </div><blockquote>These PMCs were generally agreed upon by FDA and the applicant. Prior to the passage of FDAAA, FDA required postmarketing studies or clinical trials only in the situations described below: </blockquote><blockquote>• Subpart H and subpart E <u>accelerated approvals for products approved under 505(b)</u> of the Act or section 351 of the PHS Act, respectively, which require postmarketing studies to demonstrate clinical benefit (21 CFR 314.510 and 601.41, respectively); </blockquote><blockquote>• <u>Deferred pediatric studies, where studies are required under section 505B</u> of the Act (21 CFR 314.55(b) and 601.27(b)); 6 and </blockquote><blockquote>• Subpart I and subpart H <u>Animal Efficacy Rule approvals</u>, where studies to demonstrate safety and efficacy in humans are required at the time of use (21 CFR 314.610(b)(1) and 601.91(b)(1), respectively). 7</blockquote><b>Is the confirmatory trial after the accelerated approval PMR or PMC? </b><div><b><br /></b></div>As a condition of accelerated approval, the applicant should conduct confirmatory trials to verify the clinical benefit of the drug or demonstrate an effect on irreversible morbidity or mortality. If these trials completed post-approval verify the clinical benefit of an indication granted accelerated approval, the indication is granted traditional approval.<div><br /></div><div>Per regulatory guidance, the confirmatory trial after the accelerated approval can be PMC, not PMR. However, without the results from the confirmatory trial to verify the clinical benefit, the approval will remain as 'conditional' and benefits will remain on the surrogate endpoint or biomarkers. A traditional approval (or full approval) can be obtained after the confirmatory trial verifies the benefit of clinical benefit. A drug with full approval will have advantages in the marketing and reimbursement positions. </div><div><br /></div>Searching the FDA's <a href="https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm" target="_blank">Postmarket Requirements and Commitments Database</a>, almost all confirmatory trials after accelerated approval are PMRs, not PMCs. <div><br /><b>Is Post-Approval Pregnancy Study PMR or PMC?</b><div><br /></div>TheFDAlawblog.com had a blog article "<a href="https://www.thefdalawblog.com/2024/01/why-are-post-approval-pregnancy-studies-post-marking-requirements-rather-than-post-marketing-commitments/" target="_blank">Why are Post-Approval Pregnancy Studies Post-Marketing Requirements Rather Than Post-Marketing Commitments?</a>". It said the following: <div><blockquote>"Notably, of the 99 postmarketing pregnancy studies in the 10-year period, all but one were PMRs. The only example of a pregnancy PMC is for Paxlovid, for treatment of COVID-19, which is a distinguishable example because the sponsor committed to this study while the drug was still under an Emergency Use Authorization (EUA), not an NDA."</blockquote><p>In general, the post-approval pregnancy's studies are PMR, not PMC.</p><p><b>What are examples of the PMR versus PMC?</b></p><p>Large pharmaceutical companies posted their PMRs and PMCs only for the purpose of transparency. For example, here are the lists of PMRs and PMCs for Amgen and Janssen. These PMRs and PMCs provide great examples what kind of studies they are. </p></div></div><p></p><ul style="text-align: left;"><li><a href="https://www.clearlyamgen.amgen.com/-/media/Themes/Amgen/clearlyamgen-amgen-com/clearlyamgen-amgen-com/documents/ciapmcpmr.pdf" target="_blank">Amgen United States Clinical Postmarketing Commitments/Requirements</a></li><li><a href="https://www.janssen.com/us/sites/www_janssen_com_usa/files/us_pmc_list_july_2023.pdf" target="_blank">Janssen Pharmaceutical CompaniesU.S. Post-Marketing Requirements and Commitments </a></li></ul><p></p>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-39117942055863402472024-01-01T23:40:00.003-05:002024-01-01T23:40:00.144-05:00Exposure adjusted event rate (EAER) and exposure adjusted incidence rate (EAIR)In clinical trials, analyses of the adverse events (AEs) including serious adverse events, mortality, and adverse event of special interests (AESI) are the center piece of the safety analyses. The default approach is to calculate the incidence of AEs (the number of subjects with one specific type of AE divided by the number of patients in the specific group). The presentation of the AE profiles is usually based on the incidence of AEs. For example, in an example table below, the incidence of AEs was presented for each preferred term by treatment group. The numerator is the number of subjects with one specific AE (preferred term) and the denominator is the total number of subjects in each treatment groups (109 for Drug-X group and 110 for Placebo group). <div><br /></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhXLZD8thNAISa0cQdxpJXAN6qERuWP38kNVN9-oF11bW-5Czku9O4acnMhQb_7ukog4QQOdVt5lqFIgcEXGvK5yqzlh8p-uov9Z44et9Q92YWPWWsS1FzyWamTSGCvGpxM-V8TsDTfcOAIoey-aWF2uKSINj7KGZDdMsEHh18p_hFIZlYVQA" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="168" data-original-width="633" height="165" src="https://blogger.googleusercontent.com/img/a/AVvXsEhXLZD8thNAISa0cQdxpJXAN6qERuWP38kNVN9-oF11bW-5Czku9O4acnMhQb_7ukog4QQOdVt5lqFIgcEXGvK5yqzlh8p-uov9Z44et9Q92YWPWWsS1FzyWamTSGCvGpxM-V8TsDTfcOAIoey-aWF2uKSINj7KGZDdMsEHh18p_hFIZlYVQA=w621-h165" width="621" /></a></div><br />Comparing the incidence of AEs between treatment groups is valid and fair if the length of exposure is balanced between two treatment groups. If the treatment exposure in one group is significantly longer than another group, the incidence of AEs may give a biased comparison. </div><div><br /></div><div>Ii the average duration of exposure differs significantly between treatment groups within a trial or between trials included in an analysis due to differential drop-out rates or study design, such incidence of AEs will need some adjustment to make the comparison meaningful. In the situation that the treatment exposures between treatment groups are not balanced, the exposure adjusted event rate (EAER) or exposure adjusted incidence rate (EAIR) may be calculated where the denominator for the calculation is the exposure duration expressed in person-time such as person-year or patient-year.</div><div><br /></div><div>In FDA CDER's MAPP "Good Review Practice: Clinical Review Template", it mentioned the following: </div><blockquote><div>"An analysis of the overall rate of serious events and the rate of specific serious events for each treatment group in critical subgroups (e.g., demographic, disease severity, excretory function, concomitant therapy) and by dose. The median duration of exposure should be examined across treatment groups. <u>If there is a substantial difference in exposure across treatment groups, incidence rates should be calculated using person-time exposure in the denominator, rather than number of subjects in the denominator</u>,...by treatment group"</div></blockquote><p></p><blockquote>"<u>Analyses should be corrected for differences in drug exposure using person-time in the denominator to calculate mortality rates</u>. If person-time exposure is not included in the submission (ideally, it should be requested at the pre-NDA/pre-BLA meeting), it should be requested as soon as the need is recognized..."</blockquote><p></p><div>When the incidence rate of AEs (or exposure adjusted incidence rate) needs to be calculated, the denominator is for sure the person-time, but the numerator for the calculation can be confusing. Should the numerator be the number of events or the number of subjects with at least one event? </div><div><br /></div><div>If the event can occur only once for each subject, the number of events and the number of subjects with at least one event will be the same (each subject can die only once!). Therefore, the exposure adjusted mortality rate will be same no matter which numerator is used. </div><div><br /></div><div>If the same subject experience multiple occurrences of the same AE during the study period, the incidence of AEs will be different depending on which numerator is used in calculation. In a previous post, <a href="https://onbiostatistics.blogspot.com/2011/03/incidence-rate-ir-how-could-this-be.html">Incidence Rate (IR) – How could this be wrongly calculated?</a>, I stated that the number of events should be used as the numerator for incidence rate calculation and criticized the use of the number of subjects with events as the numerator. In most situations, it is better and more accurate to count more than one event to the numerator if the subject experience multiple occurrences of the same event during the study period. </div><div><br /></div><div>In FDA guidance "<a href="https://www.fda.gov/media/124333/download" target="_blank">Safety, Efficacy, and PharmacokineticStudies to Support Marketing ofImmune Globulin Intravenous(Human) as Replacement Therapy forPrimary Humoral Immunodeficiency</a>", the serious bacterial infection is the primary interest. The serious bacterial infection can occur more than one in a specific patient. The guidance said the following: </div><div></div><blockquote><div>"We recommend that you provide in the BLA descriptive statistics for
<u>the number of serious infection episodes per person-year</u> during the
period of study observation. Additional information important to our
review includes a frequency table giving the number of subjects with
0, 1, 2… serious infections, a description of each serious infection, and
summary statistics for the length of observation of each subject."</div></blockquote><blockquote><div>"Based on our
examination of historical data, we believe that a statistical
demonstration of a serious infection rate per person-year less than 1.0
is adequate to provide substantial evidence of efficacy. You may test
the null hypothesis that the serious infection rate is greater than or
equal to 1.0 per person-year at the 0.01 level of significance or,
equivalently, the upper one-sided 99% confidence limit would be less
than 1.0."</div></blockquote><div></div><div>MACE (Major Adverse Cardiac Event) is the most frequently used endpoint in cardiovascular outcome studies. Incidence rate for MACE should be calculated with number of events as the numerator and the person-year as the denominator. This can be exemplified in <a href="https://www.fda.gov/media/162521/download" target="_blank">FDA's Briefing Document for Cardiovascular and Renal Drugs Advisory Committee Meeting </a>for GSK's drug Daprodustat for for the treatment of anemia due to chronic kidney
disease (CKD). The same patient can have more than one MACE event (from the non-fatal events to fatal event). </div><div><br /></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjdToxC_4cZR_6t12HyipHdJ6OAAbtTYXWsEAxZNM4gvLGv6sncUpx9OhKMB8sdDNxwHCVMuKEYKse6rd6yFNtokZpWpSH24sm7iE7RmbgggxvWD3a5_WZT7crxVF9kV4fK6hMjd95Ppq-plmothHCcYli2_O2By8iJAawYFsjsUo631N63tg" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="389" data-original-width="644" height="390" src="https://blogger.googleusercontent.com/img/a/AVvXsEjdToxC_4cZR_6t12HyipHdJ6OAAbtTYXWsEAxZNM4gvLGv6sncUpx9OhKMB8sdDNxwHCVMuKEYKse6rd6yFNtokZpWpSH24sm7iE7RmbgggxvWD3a5_WZT7crxVF9kV4fK6hMjd95Ppq-plmothHCcYli2_O2By8iJAawYFsjsUo631N63tg=w647-h390" width="647" /></a></div><br />However, in practice, the number of subjects has often been used as the numerator in incidence rate calculation. It turned out both the number of events and the number of subjects can be used in the calculation depending on how the denominator of exposure (person-time) is calculated. </div><div><br /></div><div>PSUSE published a document "<a href="https://phuse.s3.eu-central-1.amazonaws.com/Deliverables/Safety+Analytics/Analysis+and+Displays+Associated+with+Safety+Topics+of+Interest-+Focus+on+Phase+II+to+IV+Clinical+Trials.pdf" target="_blank">Analysis and Displays Associated with Safety Topics of Interest: Focus on Phase II to IV Clinical Trials</a>". In the document, two different terms were proposed: exposure adjusted event rate (EAER) and exposure adjusted incidence rate (EAIR). EAER is calculated using the number of events as the numerator and EAIR is calculated using the number of subjects as the numerator.</div><div><blockquote><b>Exposure-adjusted event rate (EAER)</b>: The number of events
(if a patient has more than one occurrence of the same event, all
occurrences are counted) divided by the total time exposed.
This is sometimes referred to as person-time absolute rate.
Total time exposed is calculated as the sum of each patient’s
time in the interval, whether or not the patient experienced the
event. The time unit used can be changed (e.g. if the original
units are events per person-year, this can easily be converted
to events per 100 person-years by multiplying by 100). The
exposure time should be based on the same time interval in
which any events that occur would be counted.</blockquote></div><div><blockquote><b>Exposure-adjusted incidence rate (EAIR):</b> The number of
patients with an event divided by the total time at risk for the
event. Total time at risk will be calculated as the sum of
time from the first dose (or randomisation) to first event for patients who experienced the event and the time during the
entire assessment interval for patients who do not experience
the event. This is sometimes referred to as the incidence rate or
person-time incidence rate . As noted above, we believe
the addition of “exposure-adjusted” or “person-time” is beneficial
for clarity.</blockquote></div><div>Notice that for EAIR calculation, the exposure duration (the person-time) is from the first dose to the first event, not the entire exposure duration (from the first dose to the last dose). </div><div><br /></div><div>In practice, EAER and EAIR were not specifically distinguished, the numerator and the denominator may be mismatched with the intended use. The numerator can be either the number of events or the number of subjects as long as the exposure or person-time is correctly calculated. </div><div><br /></div><div>For recurrent events or composite events where the same patient can have more than one event, if the exposure (denominator, person-time) is calculated for the entire duration, the numerator should be the number of events so that all events (not the first event) are counted in the calculation. If the exposure (denominator, person-time) is calculated from the first dose to the occurrence of the first event (or the entire exposure duration if the subject does not have any event), the numerator should then be the number of subjects. For example, in a paper "<a href="https://aacrjournals.org/cancerres/article/83/5_Supplement/P3-07-08/718226/Abstract-P3-07-08-Exposure-adjusted-incidence" target="_blank">Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in HR+/HER2- metastatic breast cancer (MBC)</a>", how the denominator of exposure time is calculation was explicitly spelled out. </div><blockquote>Time-at-risk EAIR considers patient’ exposure of a specific AE in quantifying the risk of AE, defined as the number of pts who experienced at least 1 specific AE, divided by the total exposure time (patient-year of exposure [PYE]) in each arm. For patients who experienced specific AEs, exposure time was calculated from first dose date up to the first AE onset, and for patients who did not, from first dose up to data cutoff (if still on study treatment) or up to last dose (if discontinued study treatment). </blockquote><div>In some cases, both EAER and EAIR may be calculate, for example, in <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761037orig1s000medr.pdf" target="_blank">FDA's clinical review for NDA 211675Orig1s000</a>, both EAER and EAIR were calculated. In <a href="https://classic.clinicaltrials.gov/ProvidedDocs/06/NCT02963506/SAP_001.pdf" target="_blank">a statistical analysis plan by </a></div><div><a href="https://classic.clinicaltrials.gov/ProvidedDocs/06/NCT02963506/SAP_001.pdf" target="_blank">UCB</a>, the details about the calculations of both EAER and ERIR were provided. </div><div><br /></div><div>Whether or not the EAER or EAIR is calculated may or may not change the conclusion of the safety assessment, however, it is worth noting the differences in the numerator and denominator used in the calculations. </div><div><br /></div><div>In summary, the AE analyses can be adjusted for the exposure duration. If the numerator is the number of events, the denominator should be the total exposure duration or person time (from the first dose to the last dose) and the calculated parameter is "Exposure adjusted event rate (EAER)". If the numerator is the number of subjects, the denominator should be the exposure duration or person time where the exposure duration is calculated from the first dose to the time of the first event for subjects with event(s) and from the first dose to the last dose for subjects who do not have any event. The calculated parameter is "exposure adjusted incidence rate (EAIR). </div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-68960049461785749702023-12-15T08:00:00.000-05:002023-12-15T08:00:00.151-05:00Randomized start design (RSD), delayed start design, randomized withdrawal design to assess disease modification effect<p>In the latest <a href="https://www.globalcvctforum.com/" target="_blank">Global CardioVascular Clinical Trialists (CVCT) Workshop</a>", one of the topics was "How to assess the disease modification in pulmonary arterial hypertension". the academic and industry representatives discussed the definition of disease modification and if the various individual drugs met the criteria as disease modifiers. </p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhu-lm1aosN-LyCT_wXwMLiaI8O8JLdfd_hYDAYzKmiFBHN_NoDSE2pMS4dSPWsI6vesiStIWSKSPOPq7GxSniQTyc6X-lRTWNorWJ5dWicMy_CCRKFMFKrI84h32eRcQ_rx3QqvAGWpDgVsr4TheWYLaizYl4Ix7rbm1xogcCwYrJachZkHw" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1012" data-original-width="714" height="546" src="https://blogger.googleusercontent.com/img/a/AVvXsEhu-lm1aosN-LyCT_wXwMLiaI8O8JLdfd_hYDAYzKmiFBHN_NoDSE2pMS4dSPWsI6vesiStIWSKSPOPq7GxSniQTyc6X-lRTWNorWJ5dWicMy_CCRKFMFKrI84h32eRcQ_rx3QqvAGWpDgVsr4TheWYLaizYl4Ix7rbm1xogcCwYrJachZkHw=w385-h546" width="385" /></a></div><p>Disease modification requires that the intervention have an impact of the underlying pathology and pathophysiology of the disease. For regulatory purposes, a disease modifying effect is when an intervention delays the underlying pathological processes and is accompanied by improvement in clinical signs and symptoms of the disease. The opposite of the disease modifying effect is symptomatic improvement which is defined as "may improve symptoms but does not affect the long-term survival or outcome in the disease, for example, use of diuretics in PAH". </p><div><div>For a drug to be defined as a disease modification therapy (DMT), disease modifier, or disease-modifying agent (DMA), the following criteria need to be met: <div><ul style="text-align: left;"><li>a drug targeting the underlying pathophysiology</li><li>distinction should be made from the "symptomatic treatment" (do not affect underlying pathophysiology)</li><li>Can achieve the goal of remission (partial or complete)</li><li>endures sustained clinical benefit (referred to as DMA). </li></ul></div><div>The last criterion "endures sustained clinical benefit" is difficult to meet. The traditional randomized, controlled, parallel design will not be sufficient. Clinical trial designs like delayed start design and randomized withdrawal design are needed to assess the disease modification effect. </div><div><br /></div><div><b>Randomized Start Design or Delayed Start Design</b>: </div><div><br /></div><div>This design was discussed in previous posts: </div><a href="https://onbiostatistics.blogspot.com/2013/03/randomized-start-design-rsd.html" target="_blank"></a><ul style="text-align: left;"><a href="https://onbiostatistics.blogspot.com/2013/03/randomized-start-design-rsd.html" target="_blank"></a><li><a href="https://onbiostatistics.blogspot.com/2013/03/randomized-start-design-rsd.html" target="_blank"></a><a href="https://onbiostatistics.blogspot.com/2013/03/randomized-start-design-rsd.html" target="_blank">Randomized Start Design (RSD)</a></li><li><a href="https://onbiostatistics.blogspot.com/2016/01/demonstrating-disease-modifying-effect.html" target="_blank">Demonstrating the disease modifying effect through delayed start study design or delayed start analyses</a></li></ul></div><b>Randomized withdrawal design: </b></div><div><br /><div><div>The randomized withdrawal design was extensively discussed in FDA's guidance "<a href="https://www.fda.gov/media/121320/download" target="_blank">Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products</a>". The following paragraphs are extracted from the guidance. </div><div><br /></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEh-w5JZ73rPdmLqlKzhOdIh2QvVlTsFdJq1LqhSNvZJNCgy8wVb7-RYZvi5ntBdoCpkgGW7gFfxRLh2IX0q3zvtRGfeakRWIS1Vlf1AwCgeFjeGUz606uGC5k-nAex9Xqzb6Ubsqgk1Pw2Xfihjgc1p4DqIqzSMiGmEFQfZmTRHKXNgcbA24w" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="487" data-original-width="648" height="464" src="https://blogger.googleusercontent.com/img/a/AVvXsEh-w5JZ73rPdmLqlKzhOdIh2QvVlTsFdJq1LqhSNvZJNCgy8wVb7-RYZvi5ntBdoCpkgGW7gFfxRLh2IX0q3zvtRGfeakRWIS1Vlf1AwCgeFjeGUz606uGC5k-nAex9Xqzb6Ubsqgk1Pw2Xfihjgc1p4DqIqzSMiGmEFQfZmTRHKXNgcbA24w=w616-h464" width="616" /></a></div><br />The randomized withdrawal design was originally proposed as an approach to enrich the study and reduce the sample size. The randomized withdrawal design (if it is feasible to implement) can be used to evaluate the long-term disease-modifying effect. </div><div><br /></div><div>In practice, the randomized withdrawal design can be implemented after the RCT - the responders from both the experimental drug group and the placebo group are re-randomized to receive the experimental drug or placebo. This is exactly what we did in the ICE study ("<a href="https://pubmed.ncbi.nlm.nih.gov/18178525/" target="_blank">Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial</a>") where the study contained a RCT portion to assess the treatment response and a re-randomized withdrawal portion to assess the relapse after the study drug withdrawal. </div><div><br /></div><div>The delayed start design and randomized withdrawal design have been mentioned frequently as a way to assess the disease modification effect. </div><div><p class="MsoNormal">In FDA's guidance "<a href="https://www.fda.gov/files/drugs/published/Alzheimer%E2%80%99s-Disease---Developing-Drugs-for-Treatment-Guidance-for-Industy.pdf" target="_blank">Early Alzheimer’s Disease: Developing Drugs for Treatment</a>", the randomized-start or randomized-withdrawal trial design was suggested:</p><p class="MsoNormal"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEg2aeI4RaJoFAa8N3QLDVwcUkxTbXjlOETioHdR-phA1r8fjcGo46KnQFmdc1_xbnSWvYpr9Wt4LCOAPTb9PoWv5UNOWzssW4ayMnTTf6lCaFFUbm7can1L04Ne7G6WCR24CukMCP71gDadMNahYKUv5ymIIrD6ARD7js0bFXfsYXGSGVQulg" style="margin-left: 1em; margin-right: 1em; text-align: center;"><img alt="" data-original-height="152" data-original-width="695" height="138" src="https://blogger.googleusercontent.com/img/a/AVvXsEg2aeI4RaJoFAa8N3QLDVwcUkxTbXjlOETioHdR-phA1r8fjcGo46KnQFmdc1_xbnSWvYpr9Wt4LCOAPTb9PoWv5UNOWzssW4ayMnTTf6lCaFFUbm7can1L04Ne7G6WCR24CukMCP71gDadMNahYKUv5ymIIrD6ARD7js0bFXfsYXGSGVQulg=w635-h138" width="635" /></a></p><p class="MsoNormal">In the FDA’s webinar on “<a href="https://www.fda.gov/training-and-continuing-education/guidance-webinar-series/webinar-transcript-draft-guidance-industry-alzheimers-disease-developing-drugs-treatment-early-stage">Draft
Guidance For Industry On Alzheimer’s Disease: Developing Drugs For The
Treatment Of Early-Stage Disease</a>”, the FDA presenters discussed the randomized start design or withdrawal design: <o:p></o:p></p>
<p class="MsoNormal" style="margin-left: .5in;">“… If there is a significant
effective treatment that couldn't serve as the basis of approval, we do not
believe that that argument in and of itself does not demonstrate. This is where
biomarkers come in. We learned in the trial results, the effect on up Alzheimer
disease biomarker, it is still very and clear. Where the biomarker has been
altered but there is no clinical effect. The clinical outcome was the opposite
of what you want to see. The bottom line is that that understanding and how it
relates to the clinical outcome still needs a bit of work. We would not be
willing to accept the effect on the biomarker, as a basis for a circuit --
Sarah get approval. <span style="background: yellow; mso-highlight: yellow;">For
that to be the case, it would be a fundamental itself in the disease process</span>.
In addition to biomarkers there are other ways to show disease modification, <span style="background: yellow; mso-highlight: yellow;">a randomized start design, or
withdrawal design</span>. These are based on clinical endpoints. These are
difficult studies to design, and conduct, and interpret. We are open to use
these approaches to show modification, let me show you what I mean by
randomized start design. One would be on .8, the other will be on placebo, the
patients on group to will be switched over to active treatment, patients in
group 2 will be caught up to group 1, they will have a systematic effect of
treatment. Patients that were switched to never really caught up to the first
group, can argue for an effect on the disease, this is challenging to do, but
we are open to the approach. It is a devastating condition, and an epidemic make
-- particularly in late stages, the field is moving to conduct trials in early
stages of the illness. As I pointed out they will pose regulatory challenges.
We hope that's where our guidance will come in and suggest pathways forward.
Thank you. I will have Russell Katz, come up and talk for the rest of the
webinar.”<o:p></o:p></p>
<p class="MsoNormal">In one of the EMA presentations “<a href="https://www.ema.europa.eu/en/documents/presentation/presentation-scientific-and-regulatory-approaches-facilitating-disease-modifying-drug-development-and-registration-global-environment-thomas-blaettler_en.pdf">The
scientific and regulatory approaches to facilitating disease-modifying drug
development and registration in a global environment</a>”, the delayed start
design (or randomized start) and randomized withdrawal design were mentioned.</p></div></div></div><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><div><div><div><p class="MsoNormal" style="text-align: left;"> <a href="https://blogger.googleusercontent.com/img/a/AVvXsEhNKcA547OUMTnZOBsYD3kaMHQYaapbKwEWYKXJdiTx-ymArOfL-so6erVXYxxY5pQa8z49zSxAHMZOnmZbcp8PrFNJipAT50hqNzoeSjoalLuy8r3Y4xPBXGW10uRcqyfheQTZBLhuJmqIpEp1reJ7IGrrFSA1vx1i1MJ1a-r_5uN78z0wCA" style="margin-left: 1em; margin-right: 1em; text-align: center;"><img alt="" data-original-height="400" data-original-width="572" height="303" src="https://blogger.googleusercontent.com/img/a/AVvXsEhNKcA547OUMTnZOBsYD3kaMHQYaapbKwEWYKXJdiTx-ymArOfL-so6erVXYxxY5pQa8z49zSxAHMZOnmZbcp8PrFNJipAT50hqNzoeSjoalLuy8r3Y4xPBXGW10uRcqyfheQTZBLhuJmqIpEp1reJ7IGrrFSA1vx1i1MJ1a-r_5uN78z0wCA=w433-h303" width="433" /></a></p></div></div></div></blockquote><p></p><div class="separator" style="clear: both;">In 2011, there was <a href="https://wayback.archive-it.org/7993/20170403224053/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm235850.htm">an FDA a</a><a href="https://wayback.archive-it.org/7993/20170403224053/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm235850.htm">dvisory committee meeting</a> to discuss Teva's Parkinson's drug ((rasagiline mesylate)) for disease modification indication. Even though <a href="https://www.pharmatimes.com/news/fda_panel_votes_against_tevas_azilect_to_slow_parkinsons_980218">the disease modification claim was voted down</a>), the delayed start design was confirmed to be adequate to evaluate the disease modification effect. <span style="color: white; font-size: 22px; text-align: center;">Arterial Hypertension</span></div><p></p>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-68762356709681098652023-12-14T22:36:00.005-05:002023-12-31T09:30:14.837-05:00Defining 'disease modification effect', 'disease modification therapy (DMT)' or 'disease modifier'The concept of "disease modification," "disease modification therapy (DMT)," and "disease modifier" has been a focal point in the realm of drug development for chronic diseases. The distinction reaches a heightened significance when a drug under development qualifies as a true disease modifier. Disease modification is a default for acute diseases (for example, the acute infections) and for gene therapies, transplants, some surgeries. The focus of our discussion about the disease modification is mainly for chronic diseases. <br /><br />Disease modification entails interventions or treatments designed not solely to alleviate symptoms but also to actively influence the trajectory of the disease, effectively impeding or halting its progression.<br /><br />It's important to note that a unified definition for disease modification does not exist. The nuances of the term, as well as what qualifies as a disease modifier, can vary across different diseases. The understanding and criteria for disease modification may differ, reflecting the intricacies inherent to each specific medical condition.<div><br />In a review paper by Vollenhoven et al "<a href="https://lupus.bmj.com/content/9/1/e000634" target="_blank">Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria</a>", authors put together <a href="https://lupus.bmj.com/content/lupusscimed/9/1/e000634/DC1/embed/inline-supplementary-material-1.pdf?download=true" target="_blank">a table</a> summarizing various definitions for disease modification in different disease areas: <div><div class="separator" style="clear: both; text-align: center;"><br /><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh30dSSzTFlbqZCPIUfWgT2r51a-nmsN12BSRFKCV7ju4qv_Ow4bchI0-q_rjq12KChFW70XlRFfxQAmXxeyvzKUqrZ6WyNQLFf-YNH52DAK8SZJ0zAJ5Ujq153avWpyzk6RU12UDIIX3DJQAS574v_0ZDbzw6FKkxkbqFJOqbP910iygZjLA/s786/Annotation%202023-12-12%20214406.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="786" data-original-width="565" height="777" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh30dSSzTFlbqZCPIUfWgT2r51a-nmsN12BSRFKCV7ju4qv_Ow4bchI0-q_rjq12KChFW70XlRFfxQAmXxeyvzKUqrZ6WyNQLFf-YNH52DAK8SZJ0zAJ5Ujq153avWpyzk6RU12UDIIX3DJQAS574v_0ZDbzw6FKkxkbqFJOqbP910iygZjLA/w558-h777/Annotation%202023-12-12%20214406.jpg" width="558" /></a></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMLbmQU6b60Y2bt3JvAlHpsqRa3FiBvyg4-KMmj8PSZdR8mKs-9TsmcrStBLA90IrEcvcdLvz6HjR24SB89cd2sRS3KQczH8Q6dxBQe3Lh2pOc1zsN_aOhfP542-ikzcHEFTMsyWweJYparAWmYs7cGqFDjDPhil3gYNGmeQzlWWjMmsffBw/s757/Annotation%202023-12-12%20214318.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="757" data-original-width="563" height="736" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMLbmQU6b60Y2bt3JvAlHpsqRa3FiBvyg4-KMmj8PSZdR8mKs-9TsmcrStBLA90IrEcvcdLvz6HjR24SB89cd2sRS3KQczH8Q6dxBQe3Lh2pOc1zsN_aOhfP542-ikzcHEFTMsyWweJYparAWmYs7cGqFDjDPhil3gYNGmeQzlWWjMmsffBw/w547-h736/Annotation%202023-12-12%20214318.jpg" width="547" /></a></div><br /><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;">As we are doing the clinical trials, the spectrum of treatment response can be listed as the following: </div><div class="separator" style="clear: both;">Harm -> No Response -> Modest Response -> Strong Response -> <b>Disease Modifying</b> -> Cure. For most chronic diseases, the ultimate outcome of a 'cure' may not be achievable. A therapy with a disease modification effect will be desirable. </div><div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;">There was a proposal to classify the disease modification into five different levels: </div></div></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;">Level 1: Slowing decline</div></div></div></div></blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: left;">Level 2: Arrest decline</div></div></div></blockquote><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: left;"></div></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: left;">Level 3: Disease improvement</div></div></div></blockquote><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: left;"></div></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: left;">Level 4: Remission</div></div></div></blockquote><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: left;"></div></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: left;">Level 5: Cure</div></div></div></blockquote><div><div class="separator" style="clear: both;"><div class="separator" style="clear: both; text-align: left;"></div><div class="separator" style="clear: both;"><br /></div>In a review article for Alzheimer's disease, "<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925210/" target="_blank">Trial Designs Likely to Meet Valid Long-Term Alzheimer's Disease Progression Effects: Learning from the Past, Preparing for the Future</a>", the changes in the level of functioning across time were depicted as the following. 'Slowing progression' would be considered as 'disease modification'. <div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgH7Et0d0QqQI6b1Bu-T8CWsn8KtgKSySQoSoFbIqJE1QTB3R-I_1jeyCpBekC_962Wbg4rk4TT3ImEkPlIWOkRCw3eR7QZAQrHmUM5o_apBgDYPG7j4LY0bTuQPJGy3_78IStJRno-JP1ETdzOpm2aGqK7TwGZAuO0RzTD3yVWsd-INhLnlA" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="500" data-original-width="851" height="339" src="https://blogger.googleusercontent.com/img/a/AVvXsEgH7Et0d0QqQI6b1Bu-T8CWsn8KtgKSySQoSoFbIqJE1QTB3R-I_1jeyCpBekC_962Wbg4rk4TT3ImEkPlIWOkRCw3eR7QZAQrHmUM5o_apBgDYPG7j4LY0bTuQPJGy3_78IStJRno-JP1ETdzOpm2aGqK7TwGZAuO0RzTD3yVWsd-INhLnlA=w577-h339" width="577" /></a></div><br /><div style="text-align: left;">In a paper by Morató et al "<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409252/" target="_blank">Symptomatic and Disease-Modifying Therapy Pipeline for</a></div><div><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409252/" target="_blank">Alzheimer’s Disease: Towards a Personalized Polypharmacology</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409252/" target="_blank">Patient-Centered Approach</a>", the following was said about the disease modification therapy in Alzheimer's disease:</div><div style="text-align: left;"><blockquote><div>A disease-modifying treatment (DMT) is defined as an intervention that produces an enduring change in the clinical progression of AD by interfering with the underlying pathophysiological mechanisms of the disease process that lead to neuronal death. Consequently, a true DMT cannot be established conclusively based on clinical outcome data alone, such a clinical effect must be accompanied by strong supportive evidence from a biomarker program.</div></blockquote><div></div><div>In 2011, there was <a href="https://wayback.archive-it.org/7993/20170403224053/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm235850.htm" target="_blank">an FDA a</a><span style="text-align: center;"><a href="https://wayback.archive-it.org/7993/20170403224053/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm235850.htm" target="_blank">dvisory committee meeting</a> to discuss Teva's Parkingson's drug for disease modification indication. According to <a href="https://wayback.archive-it.org/7993/20170405225128/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM275474.pdf" target="_blank">the FDA briefing book</a>, to demonstrate the disease modification effect, three hypothesis tests are needed to analyze the data from the study with a delayed start design (even though <a href="https://www.pharmatimes.com/news/fda_panel_votes_against_tevas_azilect_to_slow_parkinsons_980218" target="_blank">the disease modification claim was voted down</a>): </span></div></div><div style="text-align: left;"></div><blockquote><div style="text-align: left;">The study was to be analyzed according to three hypotheses, in the following
order: </div><div style="text-align: left;"><ul style="text-align: left;"><li>Hypothesis 1-the contrast between the slope of drug and placebo
response at Week 36 (using data from weeks 12-36; Linear Mixed Model
with random intercept and slope) </li><li>Hypothesis 2-the contrast of scores between baseline and Week 72
(Repeated Measures) </li><li>Hypothesis 3-a non-inferiority analysis of the slopes of the ES and DS
patients from weeks 48-72 (Linear Mixed Model with random intercept and
slope) </li></ul></div><div style="text-align: left;">The first hypothesis was designed to determine that a difference between
treatments emerged in Phase 1, the second hypothesis was designed to
determine that there was a difference between ES and DS patients at the end of
the study, and the third hypothesis was to determine that an “absolute” difference
between the ES and DS patients persisted during Phase 2 (that is, even though a
difference between groups at the end of the study might have existed [what was
4
tested by Hypothesis 2], it was important to show that the two groups were not
approaching each other). </div></blockquote><div style="text-align: left;"></div></div>To delve into the realm of disease modification therapy research, it is imperative to establish a standardized definition for disease modification, particularly tailored to the nuances of a specific disease area. This foundational step serves as a compass guiding subsequent investigations. Following the definition, the identification of endpoints to measure the disease modification effect becomes paramount. Given the nuanced nature of disease modification effects, the conventional clinical trial designs may prove insufficient. Hence, a specialized approach involving clinical trial designs (such as delayed start design and randomized withdrawal design) with multiple hypothesis tests becomes a requisite. Such a methodological shift is essential to comprehensively capture and validate the nuanced impacts of disease modification therapies.</div></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-82145536811061851052023-12-10T23:00:00.004-05:002023-12-10T23:00:00.127-05:00Significant level versus p-valueSometimes, the significant level and p-value are getting mixed up and confusing to some non-statisticians. It is not surprising to receive a question or request for statistician to design a study to obtain a p-value of 0.05 or 0.01. While the significant level and p-value are closed related, ,they are used in different stage of the trial - significant level is used in the study design stage and p-value is used in the analysis stage.<p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhhwYYAd6mZKK_pcPfoNcDVDqvu5vNtBTSQnPIPvzH7MKbW3mcQTZoC4EZk2wTy8CWeo6oPVet5gADcbXq2vQ4VCAETaf70nT3tYMypAEfLcMCUQof03oupXsGe9KP9bb-_is-0qZoK34DtfFvPjccWUA2KxME-y6_ELrcLhJhVhc0OsiOkiw" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="411" data-original-width="784" height="288" src="https://blogger.googleusercontent.com/img/a/AVvXsEhhwYYAd6mZKK_pcPfoNcDVDqvu5vNtBTSQnPIPvzH7MKbW3mcQTZoC4EZk2wTy8CWeo6oPVet5gADcbXq2vQ4VCAETaf70nT3tYMypAEfLcMCUQof03oupXsGe9KP9bb-_is-0qZoK34DtfFvPjccWUA2KxME-y6_ELrcLhJhVhc0OsiOkiw=w549-h288" width="549" /></a></div><div><br /></div>A significant level is usually set at 0.05 at the study design stage. After the study, data is analyzed and p-value is calculated. The p-value is then compared to the pre-specified significant level to determine if the study results is statistically significant. <div><br /></div><div>If the significant level is set at 0.01 at the study design stage, which is temped for avoiding doing two pivotal studies, it will set the unnecessary high bar for declaring the successful trial in the analysis stage. </div><div><br /></div>"The significance level," "alpha" (α), and "Type I error rate" are essentially referring to the same concept in the context of hypothesis testing. These terms are often used interchangeably and are closely related. Here's a brief explanation of each:<br /><br /><b>Significance Level (Alpha, α):</b> The significance level is a pre-defined threshold (usually denoted as α) set by the researcher before conducting a statistical test. It represents the maximum acceptable probability of making a Type I error. Common choices for alpha include 0.05 (5%), 0.01 (1%), and others. It determines the level of stringency for the test, where a smaller alpha indicates a more stringent test.<div><br /></div><div>Significant level is just one of the parameters in calculating the sample size during the study design stage. Other parameters include the effect size (assumed treatment difference), the standard deviation, statistical power (type 2 error), and alpha adjustment due to multiplicity issue, interim analyses,...<br /><br /><b>Alpha (α):</b> Alpha is the symbol used to represent the significance level in statistical notation. When you see α, it's referring to the predetermined threshold for statistical significance.<br /><br /><b>Type I Error Rate</b>: The Type I error rate is the probability of making a Type I error, which occurs when you reject the null hypothesis when it is actually true. The significance level (alpha) directly relates to the Type I error rate because the significance level sets the limit for how often you are willing to accept such an error. The Type I error rate is typically equivalent to the significance level (alpha), assuming the test is properly conducted.<div><br /></div><div><b>P-value:</b> The p-value is calculated as part of the statistical analysis after the data has been collected. It measures the strength of the evidence against the null hypothesis based on the collected data. A smaller p-value indicates stronger evidence against the null hypothesis, and a larger p-value suggests weaker evidence.</div><div><div class="separator" style="clear: both; text-align: center;"><br /></div>The p-value measures the strength of evidence against a null hypothesis. The p-value is the probability under the assumption of no effect or no difference (null hypothesis) of obtaining a result equal to or more extreme than what was actually observed. The 'p' stands for probability and measures how likely it is what any observed value between 0 and 1. Values close to 0 indicate that the observed difference is unlikely to be due to chance, whereas a p value close to 1 suggests that it is highly likely that the difference observed is due to chance. If the p-value is low, it suggests evidence against the null hypothesis, and then alternative hypothesis (assumption of the effect or difference) will be accepted. </div><div><br /></div><div>The p-value indicates how incompatible the data are with a specified statistical model constructed under a set of assumptions, together with a null hypothesis. The smaller the p-value, the greater the statistical incompatibility of the data with the null hypothesis. When we get a p-value that is greater than the pre-specified significant level, we fail to reject the null hypothesis - it means that there is insufficient evidence to reject. <br /><br /><div>STAT national biotech reporter Damian Garde explains what p-value is:</div><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen="" class="BLOG_video_class" height="266" src="https://www.youtube.com/embed/Otm7EKfhpc8" width="320" youtube-src-id="Otm7EKfhpc8"></iframe></div><br />Even though hypothesis testing and p-value have been criticized (see a previous post "<a href="https://onbiostatistics.blogspot.com/2019/07/retire-statistical-significance.html" target="_blank">Retire Statistical Significance and p-value?</a>"), the p-value is still the primary indicator by the sponsor, regulator, medical community, and pretty much everybody to judge if a clinical trial is successful or not. <div>,</div><div>Regulatory approval of a medicinal product depends on more than just a p-value. The approval depends on the totality of the evidence, the magnitude of the treatment difference, clinical significance or clinical meaningfulness, the confidence interval of the estimate, the safety profile, whether the benefit outweighs the risk.</div><div><br /></div><div>We have seen the cases that the drug is approved even though the p-value was not statistically significant (i.e., did not reach the pre-specified significant level). See the previous post "<a href="https://onbiostatistics.blogspot.com/2023/10/drugs-approved-by-fda-despite-failed.html" target="_blank">Drugs Approved by FDA Despite Failed Trials or Minimal/Insufficient Data</a>". We also see the cases that the drug was not approved even though the p-value was statistically significant. See the article "<a href="https://www.pharmalive.com/fda-blocks-alnylams-bid-to-expand-onpattro-label/">FDA blocks Alnylam's bid to expand Onpattro label</a>" even though the study results were statistically significant and published in the NEJM "<a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2300757">Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis</a>".</div></div></div><div><br /></div><div>In the end, we can't retire the p-value. We relied on the p-value to measure how strong the evidence is. However, we should not be the slave of the p-value. </div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-2761069072142004612023-11-19T22:30:00.001-05:002023-11-19T22:30:00.142-05:00RCTs for Chinese Traditional Medicine and Botanical Drug Development In the latest issue of JAMA (Journal of American Medical Association), Yang et al published a paper "<a href="https://jamanetwork.com/journals/jama/article-abstract/2811016">Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction The CTS-AMI Randomized Clinical Trial</a>". The CTS-AMI randomized clinical trial is one of the first times that a traditional Chinese medicine has been tested in a large-scale, Western-style clinical trial.<div><br /></div><div>Historically, the efficacy and safety of Chinese Traditional Medicine are not based on randomized, controlled clinical trials and, therefore, questioned by many. In the era of evidence-based medicine, researchers in China started to adopt and conduct the RCTs for Chinese Traditional Medicine. These RCTs were published primarily in journals in Chinese. It is rare for the CTS-AMI RCT study to be published in the prominent English journal, JAMA. </div><div><br /></div>In an article "<a href="https://www.newsweek.com/traditional-chinese-medicine-proves-effective-modern-clinical-trial-1842799" target="_blank">Traditional Chinese Medicine Proves Effective in Modern Clinical Trial</a>", Dr Matthew Saybolt, a cardiologist with the Hackensack Meridian Jersey Shore University Medical Center commented on the study <div><blockquote>"I am not aware of any other large, well-run trials like this studying traditional Chinese medicine. This is a rarely run type of study, and I congratulate the authors for their work and publication in such a prestigious medical journal. The study was well conducted with a large sample size that was well powered to measure the outcomes.</blockquote><blockquote>In this trial, there is clearly a benefit to patients treated with this Chinese medicine compound compared to placebo<br /><br />A reduction in death, reinfarction or complications after a STEMI is a very exciting finding. We have for some time been trying to bend the curve and improve mortality and complications after STEMI. Any new therapy, if safe, that can accomplish this would be very appealing to patients and physicians alike."</blockquote><p>Saybolt said he also observed some weaknesses in the way the study was conducted, one of which was that the participants were entirely Chinese citizens and predominantly male.</p><blockquote>"Thus the findings may not be generalizable throughout the world or to women," he said. "Furthermore, the patients were less frequently—compared to the United States, for example—treated with traditional proven medicine after their myocardial infarctions. Therefore, the effect of the Chinese medicine may have been augmented by the lack of patient exposure to proven therapies.<br /><br />"However, there was equivalent low utilization of these traditional medications in both groups," he continued. "Furthermore, the study drug Chinese medicine compound was composed of multiple plant and insect products. Thus, we do not know which component or combination of components were the active ingredients and what is the correct dose."</blockquote><p>If Chinese Traditional Medicine Compound needs to be approved in the US or other countries, the RCTs need to be conducted in multi-national clinical trials with a broad patient population. Given that the Chinese traditional medicine Compound is extracted from herbals, the drug development program will need to follow regulatory guidance such as USFDA guidance for the industry "<a href="https://www.fda.gov/media/93113/download" target="_blank">Botanical Drug Development</a>". </p>Recent years, psilocybin, the primary psychoactive substance in 'magic mushrooms' has been tested in clinical trials to study its effect on major depression disorder, PTSD,... the drug development process for psilocybin (if extracted from magic mushroom) will need to follow the FDA guidance ""<a href="https://www.fda.gov/media/93113/download" target="_blank">Botanical Drug Development</a>"" and "<a href="extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.fda.gov/media/169694/download" target="_blank">Psychedelic Drugs: Considerations for Clinical Investigations</a> ".</div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-76138482081312980942023-11-13T00:00:00.003-05:002023-11-21T10:10:44.971-05:00Operationally seamless design versus inferentially seamless designBiotech company, Aerovate Therapeutics <a href="https://ir.aerovatetx.com/news-releases/news-release-details/aerovate-therapeutics-presents-novel-phase-2bphase-3-impahct">presented a Phase 2b/Phase 3 study</a> of their inhaled imatinib in the treatment of pulmonary arterial hypertension. The study is dubbed as IMPAHCT study and is posted on <a href="https://clinicaltrials.gov/study/NCT05036135">clinicaltrials.gov</a>. The study used a so-called 'operationally seamless design' to combine the phase 2 and phase 3 studies. <div><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div style="text-align: left;">“This operationally seamless approach to the Phase 2b/Phase 3 clinical trial design for AV-101, with continued enrollment and collection of multiple endpoints, underscores Aerovate’s commitment to making new treatment options available to patients with PAH as soon as possible without compromising safety and scientific rigor,”</div></blockquote><div><br /></div>Traditional clinical development program includes phased clinical trials including at least one phase 2 dose-finding study and at least one phase 3 confirmatory or pivotal study. A 'seamless design' is intended to combine the studies in different phases in the hope of expediting the clinical development. When adaptive clinical trial design was initially introduced, the 'seamless phase 2/3 study<div><ul style="text-align: left;"><li>Jeff Maca, et al, 2006 <a href="https://journals.sagepub.com/doi/10.1177/216847900604000412" target="_blank">Adaptive Seamless Phase II/III Designs— Background, Operational Aspects, and Examples</a>, Drug Information Journal</li><li>Chen, YJ, et al, 2015, <a href="https://journals.sagepub.com/doi/10.1177/1740774514552110" target="_blank">A Seamless Phase IIB/III Adaptive OutcomeTrial: Design Rationale and Implementation Challenges</a>, Clin Trials</li><li>Jenkins, M, et al, 2011, <a href="https://pubmed.ncbi.nlm.nih.gov/22328327/" target="_blank">An adaptive seamless phase II/III design for oncology trials with subpopulation selection using correlated survival endpoints</a>, Pharm
stat.<br /></li></ul></div><div>In FDA's final guidance "<a href="https://www.fda.gov/media/78495/download" target="_blank">Adaptive Designs for Clinical Trials of Drugs and Biologics</a>", the terms 'seamless design' or 'adaptive seamless design' was no longer used, instead, they were described under the 'Adaptations to Treatment Arm Selection' section. The term 'seamless' occurred only once throughout the guidance in the following sentence: </div><div><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div style="text-align: left;">In general, seamless designs
that incorporate both dose selection and confirmation of efficacy of a selected dose (based on
data from the entire trial) can be considered if the principles outlined in section III (Principles for Adaptive Designs) are followed.</div></blockquote><div><br /></div><div><b>Operationally Seamless (or simply Seamless Design)</b></div><div><br /></div><div>A "Seamless Design" combines two separate trials (individual Phase 2 and Phase 3 trials) into one trial. "Operationally seamless design" specifically refers to the strategic and efficient organization of various aspects of the clinical trial process to ensure smooth and effective operations. Clinical trials are complex endeavors involving multiple stages, from protocol development and participant recruitment to data collection, analysis, and reporting. Operationally seamless design in this context aims to optimize these processes for enhanced efficiency and effectiveness.</div><div><br />Key features of operationally seamless design in clinical trials may include:<br /><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div><u>Separate Statistical Analyses</u>: Statistical analyses for Phase 2 and Phase 3 trials are separated, not combined. The data from the Phase 2 study will not be included in the statistical analysis of the Phase 3 data - therefore, the issues with multiplicity adjustment, handling of the immature data during the interim analysis, ... may be avoided. </div><div><br /></div><div><u>Integrated Workflows:</u> Streamlining the various stages of the clinical trial, from patient recruitment to data collection and analysis, to minimize delays and improve overall trial efficiency.</div></blockquote><div style="text-align: left;"><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div style="text-align: left;"><u>Technology Integration:</u> Leveraging technology solutions for data management, patient tracking, and communication to enhance the overall efficiency of the trial. This may involve using electronic data capture (EDC) systems, remote monitoring tools, and other technologies.</div></blockquote><div style="text-align: left;"><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div style="text-align: left;"><u>Collaboration and Communication:</u> Fostering effective communication and collaboration among different stakeholders, including researchers, sponsors, regulatory bodies, and clinical sites, to ensure a cohesive and coordinated approach.</div></blockquote><div style="text-align: left;"><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div style="text-align: left;"><u>Patient-Centric Approaches:</u> Implementing strategies that prioritize the experience of trial participants, making it easier for them to participate and comply with the trial requirements. This might involve the use of telemedicine, remote monitoring, or other patient-centric technologies.</div></blockquote><div style="text-align: left;"><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div style="text-align: left;"><br /></div><div style="text-align: left;"><u>Regulatory Compliance:</u> Ensuring that the trial design and operations adhere to regulatory requirements, which helps in avoiding delays and ensuring the validity and reliability of the trial results.</div></blockquote></div><div style="text-align: left;"><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div style="text-align: left;"><u>Risk Management:</u> Proactively identifying and managing potential risks throughout the trial to mitigate issues that could impact the overall progress and success of the study.</div></blockquote><div style="text-align: left;"><br />In summary, operationally seamless design in clinical trials is about creating a well-integrated and efficient process from the planning stages through to the conclusion of the trial. This approach aims to improve the quality of clinical trial data, reduce operational costs, and accelerate the development of new treatments.</div><div style="text-align: left;"><br /></div><div style="text-align: left;">The IMPAHCT study mentioned above is a operationally seamless design and the study design is described as the following: </div><div><div class="separator" style="clear: both; text-align: center;"><br /></div><blockquote><div class="separator" style="clear: both; text-align: center;"><div style="text-align: justify;"><span style="text-align: left;">PART 1 (Phase 2b): Part 1, which is the Phase 2b portion of the trial, will assess the safety, tolerability, and efficacy of three twice-daily doses (10, 35, or 70 mg) of AV-101 against placebo and establish an optimal dose for Phase 3. The primary endpoint for this part is change in pulmonary vascular resistance (PVR) after 24 weeks compared to placebo. (note: it is said that approximately 200 patients (50 per arm) will be enrolled in this part of the study)</span></div><br style="text-align: left;" /><div style="text-align: justify;"><span style="text-align: left;">PART 2 (Intermediate, Phase 3): PART 2 begins immediately following enrollment of the last participant in the Phase 2b part of the trial and signifies the start of enrollment in the Phase 3 trial. Part two uses the same dosing as in the Phase 2b part of the trial with participants randomized across three AV-101 doses and placebo. Enrollment in part two will continue until the optimal AV-101 dose is selected based on results from the Phase 2b analysis.</span></div><br style="text-align: left;" /><div style="text-align: justify;"><span style="text-align: left;">PART 3 (Phase 3): This part of the trial will start once an optimal dose of AV-101 has been selected based on the Phase 2b results. All patients enrolling during this part of Phase 3 will be randomized to either the optimal dose of AV-101 or placebo. The primary endpoint for Phase 3 is change in six-minute walk distance (6MWD) at 24 weeks for the optimal dose of AV-101 compared to placebo.</span></div></div></blockquote><div class="separator" style="clear: both; text-align: center;"><div style="text-align: justify;"><span style="text-align: left;"></span></div></div><div class="separator" style="clear: both; text-align: center;"><span style="text-align: left;"><br /></span></div><div style="text-align: left;">In order to be operational seamless, the IMPAHCT employed a PART 2 (intermediate, Phase 3) portion of the study. During this stage, all patients for Phase 2b portion of the study have been enrolled, but are being followed up for reaching the endpoint (24 weeks) and for conducting the interim analyses. In PART 2 (intermediate, Phase 3) stage, patients are still randomized to one of three dose arms or placebo. The data collected from two active arms that are not selected for PART 3 will not be included in the final analyses and will be wasted. For example, if the 35 mg BID dose is selected as the optimal dose for PART 3, the final analyses will be comparing the 35 mg BID dose with the Placebo. The data from the 10 mg BID and 70 mg BID treatment arms will be wasted. Suppose it takes 28 weeks from the last patients randomized in Phase 2b to the sponsor establishing the optional dose for Phase 3, if additional 100 patients were enrolled into the PART 2 (Intermediate, Phase 3), 50 of these patients (not in the optimal dose or placebo) will be wasted. </div></div><div><br /></div><div>With the operationally seamless design, the efficiency is sacrificed for the speed. </div><div><br /></div><div><b><br /></b></div><div><b>Inferentially Seamless Design (Adaptive Seamless Design)</b></div><div><br />An adaptive seamless design makes use of information (data) from patients enrolled before and after adaptation (pulls together data collected in both the Phase 2 and Phase 3 trials) in the final analysis. </div><div>The primary purpose of using the adaptive seamless design is to combine both the dose selection and confirmation phases into one trial, so information from the learning stage (Phase 2) can be combined with the confirmatory analyses of Phase 3.</div><div><br />"Inferentially seamless design" refers to an approach that emphasizes the seamless integration of data and statistical methodologies to derive meaningful inferences and insights throughout the course of the trial. The goal is to enhance decision-making by continuously analyzing data, drawing inferences, and adapting the trial design based on emerging findings.<br /><br />Adaptive seamless design is one of the adaptive designs. The typical setting for adaptive seamless design (inferentially seamless design) is to start the study with multiple active dose groups. At the interim analysis at the end of Phase 2 or close to the end of Phase 2, the data monitoring committee will review the unblinded data accumulated so far to select an optimal dose for Phase 3 portion of the study. The phase 2 data from the selected dose group and the placebo group will be included in the final analyses and contribute to the inferential analyses. The appropriate statistical methods need to be applied. For example, Grifols is conducting a phase 2/3 study with adaptive seamless design "<a href="https://clinicaltrials.gov/study/NCT02176863" target="_blank">Study of the Efficacy and Safety of Immune Globulin Intravenous (Human) Flebogamma® 5% DIF in Patients With Post-polio Syndrome (FORCE)</a>" where a method proposed by Posch et al "<a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/sim.2389" target="_blank">Testing and estimation in flexible group sequential designs with adaptive treatment selection</a>" was used to combine the data from phase 2 and phase 3.</div><div><br /></div><div>The inferentially seamless design can be illustrated as the following (cited from the paper by Maca et al "<a href="https://journals.sagepub.com/doi/abs/10.1177/216847900604000412?journalCode=dijb" target="_blank">Adaptive Seamless Phase II/III Designs— Background, Operational Aspects, and Examples</a>"</div><div><br /></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEg7fkHVK9xNrxwrpoXep2Ad50Yf-eK_dOoQeijdzIp3GcALrUnhgIr2zkL8S1_h0O81j44BOsoMefzqA_mBj822rGF4jcz6QjFbcCA2yhRTrxS1JGhlVopBOJ_MjOkqdfmacfZNbom0bjXwlqkmbk3RpCbTzw_XAfpwZxRK56D5cy4LeZs3iw" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="439" data-original-width="724" height="313" src="https://blogger.googleusercontent.com/img/a/AVvXsEg7fkHVK9xNrxwrpoXep2Ad50Yf-eK_dOoQeijdzIp3GcALrUnhgIr2zkL8S1_h0O81j44BOsoMefzqA_mBj822rGF4jcz6QjFbcCA2yhRTrxS1JGhlVopBOJ_MjOkqdfmacfZNbom0bjXwlqkmbk3RpCbTzw_XAfpwZxRK56D5cy4LeZs3iw=w518-h313" width="518" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: left;"><br /></div></div><div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">Putting them side by side, here is the table to compare the operationally seamless design and the inferentially seamless design: </div></div><div style="text-align: left;"><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div style="text-align: left;"><br /></div><div style="text-align: left;"><table border="1" cellpadding="0" class="MsoNormalTable" style="background: rgb(247, 247, 248); border: 1pt solid windowtext; mso-border-alt: solid windowtext .25pt; mso-cellspacing: 1.5pt; mso-yfti-tbllook: 1184; width: 580px;">
<thead>
<tr style="mso-yfti-firstrow: yes; mso-yfti-irow: 0;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-right-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in; text-align: center;"><b><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Operationally
Seamless Design<o:p></o:p></span></b></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in; text-align: center;"><b><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Inferentially
Seamless Design<o:p></o:p></span></b></p>
</td>
</tr>
</thead>
<tbody><tr style="mso-yfti-irow: 1;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Integration of
processes and systems for smooth operation.<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Integration of data
and insights for seamless decision-making.<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 2;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Not an adaptive design - since the data from the phase 2 study is not included in the inferential analysis<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">One type of adaptive
designs - </span>Adaptations to Treatment Arm Selection</p>
</td>
</tr>
<tr style="mso-yfti-irow: 3;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Emphasizes operational
efficiency and workflow integration.<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Focuses on integrating
data and deriving meaningful insights.<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 4;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Data collected from the
phase 2 and phase 3 portions of the study is analyzed separately and separate
clinical study reports may be written<o:p></o:p></span></p>
</td>
<td rowspan="2" style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Data collected from
phase 2 the selected arms (the selected dose and the placebo arm) is combined
into the phase 3 portion of the study and contributed to the final
inferential analyses<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 5;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Data collected from the
phase 2 portion of the study is not included in the final inferential analyses<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 6;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .25pt; mso-border-left-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Overall sample size is
larger since the data from Phase 2 and the data from the unselected arms in Phase
3 will not be used in the final inferential analyses.<o:p></o:p></span></p>
</td>
<td style="border-bottom: none; border-left: 1pt solid rgb(217, 217, 227); border-right: 1pt solid rgb(217, 217, 227); border-top: none; mso-border-left-alt: solid #D9D9E3 .75pt; mso-border-right-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Overall sample size is
smaller since the data from some patients in the phase 2 portion of the study
are used in the final inferential analyses<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 7;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .25pt; mso-border-left-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">No pre-specified rules
for dropping the inferior arms or selecting the optimal dose arm for confirmatory
portion of the study<o:p></o:p></span></p>
</td>
<td style="border-top: none; border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: solid #D9D9E3 .75pt; mso-border-left-alt: solid #D9D9E3 .75pt; mso-border-right-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Pre-specified rules
for dropping the inferior arms or selecting the optimal arm for the
confirmatory portion of the study. <o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 8;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .25pt; mso-border-left-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Dose selection is at the
hand of the sponsor (the sponsor can unblind the phase 2 portion of the study
data upon the completion)<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Dose selection is
implemented through the data monitoring committee (only they can review the unblinded
data).</span><span style="color: #374151; font-size: 10.5pt;"> </span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 9;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .25pt; mso-border-left-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">No need to deal with
the multiplicity issue since the Phase 2 data is not used in the final
analyses<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Multiplicity issue needs
to be considered and alpha needs to be adjusted since the portion of the phase
2 data will be included in the final analyses<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 10; mso-yfti-lastrow: yes;">
<td colspan="2" style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span face=""Segoe UI",sans-serif" style="color: #374151; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><a href="https://onbiostatistics.blogspot.com/2014/01/overrunning-issue-in-adaptive-design.html" target="_blank">Overrunning issues</a> and
handling of immature data (i.e. incomplete data at the time of data cut for interim analysis for patients who haven't reached the study endpoint) need to be considered <o:p></o:p></span></p>
</td>
</tr>
</tbody></table></div></blockquote></div><div style="text-align: left;"><br /></div><br />Additional reading: <div><ul style="text-align: left;"><li>the blog article by Esha Senchaudhuri (2014) "<a href="https://www.cytel.com/blog/seamless-adaptive-designs-crofelemer-trial" target="_blank">Operationally Seamless & Inferentially Seamless Adaptive Designs</a>"</li><li>Bhatt and Mehta (2016) <a href="https://www.nejm.org/doi/pdf/10.1056/NEJMra1510061" target="_blank">Adaptive Designs for Clinical Trials</a></li><li><a href="https://ir.aerovatetx.com/news-releases/news-release-details/aerovate-therapeutics-announces-simultaneous-completion" target="_blank">Aerovate Therapeutics Announces Simultaneous Completion of Enrollment in Phase 2b Portion and Enrollment of First Patient into Phase 3 in the IMPAHCT Trial Evaluating AV-101 for the Treatment of Pulmonary Arterial Hypertension</a> - the press release said IMPAHCT is "a seamless <b>adaptive</b> Phase 2b/Phase 3 design", but it is not. It is an operationally seamless design, not adaptive since the Phase 2b data will not be used for the final analysis. </li></ul></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-44740698699822868852023-11-03T01:00:00.001-04:002023-11-03T01:00:00.134-04:00Walk Distance versus Timed Walk - endpoints for measuring patients' function in clinical trials<div>Drug development is now moved to the patient-focused era. <a href="https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-development" target="_blank">Patient-focused drug development (PFDD)</a> is a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation. With PFDD, the endpoint or outcome measure needs to be meaningful, it should reflect or describe how the patient feels, functions, and survives.</div><div><br /></div><div>Various tools can be used to measure functions. The most commonly used functional measure may be the measure of the walk distance or the walking speed.<div><span style="color: #1f1f1f; font-family: ElsevierGulliver, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px;"><br /></span></div><div><span style="color: #1f1f1f; font-family: ElsevierGulliver, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;"><b>Measuring the walk distance by fixing the time:</b> </span>six-minute walk test (6MWT) to measure the distance the patient can walk in six minutes (6MWD), two-minute walk test (2MWT) to measure the distance the patient can walk in two minutes (2MWD). 6MWD and 2MWD can provide a functional, therapeutic response and prognostic data that is valuable in the care of patients with respiratory, cardiac, and neurological diseases. It can also be used as the endpoint for clinical trials to evaluate the treatment differences.</div><div><br /></div><div>There is also a 10-minute walk test to measure fatigability and walking economy, but it is not commonly used as primary efficacy endpoint in clinical trials. </div><div><span style="background-color: white; color: #202124; font-family: ElsevierGulliver, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;"><br /></span></div><div><span style="background-color: white; color: #202124; font-family: ElsevierGulliver, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;"><b>Measuring the time/speed by fixing the distance:</b> </span>The 10-meter Walk Test is a performance measure used to assess walking speed in meters per second over a short distance. It can be employed to determine functional mobility, gait, and vestibular function. Timed 25 Foot Walk (T25FW) is a quantitative mobility and leg function performance test based on a timed 25-walk. The time to complete 25-foot walk can be used to calculate the walk speed (ft/s). </div><div><br /></div><div><br /></div><div><span style="background-color: white; color: #202124; font-family: "Google Sans", Roboto, arial, sans-serif; font-size: 20px;"><b>Examples/applications:</b></span></div><div><span style="background-color: white; color: #202124; font-family: "Google Sans", Roboto, arial, sans-serif; font-size: 20px;"><br /></span></div><b><span style="font-size: medium;">6MWT/6MWD</span></b></div><div><b><br /></b>The 6MWT is a sub-maximal exercise test used to assess exercise capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. There is a specific guideline developed by ATS (American Thoracic Society): <a href="https://www.atsjournals.org/doi/epdf/10.1164/ajrccm.166.1.at1102?role=tab">Guidelines for the Six-Minute Walk Test</a>.<div><br /></div><div>6MWT/6MWD was the primary efficacy outcome measure in pivotal studies in <a href="https://www.nejm.org/doi/full/10.1056/nejmoa1209655" target="_blank">pulmonary arterial hypertension (PAH) </a>and <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2008470" target="_blank">pulmonary hypertension associated with interstitial lung disease (PH-ILD)</a>.</div><div><br />Bridgebio had a pivotal study to assess the efficacy and safety of the acoramidis in treatment of <br />ATTRibute-CM (a heart disease) with two parts: 6MWD was the primary efficacy endpoint for part 1 of the study and <br /><br /><a href="https://bridgebio.com/news/bridgebio-pharma-reports-month-12-topline-results-from-phase-3-attribute-cm-study/">Part 1 of the study failed to demonstrate the treatment difference in 6MWD</a><br /><br /><a href="https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-announces-consistently-positive-results-phase-3">Part 2 of the study successfully demonstrate the treatment difference in win ratio in clinical events (deaths and cardiovascular related hospitalization)</a> <br /><br />Alnylam's pivotal study (APOLLO-B study) <a href="https://www.biopharmadive.com/news/alnylam-apollo-b-study-results-onpattro-ttr-cardiomyopathy/631301/">demonstrated the statistical significant difference in primary efficacy endpoint of 6MWD at week 52</a>. However, the magnitude of the treatment difference was merely 14.7 meters. The study results were published in <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2300757" target="_blank">New England Journal of Medicine</a> and <a href="https://investors.alnylam.com/press-release?id=27716" target="_blank">had a positive vote</a> in favor of the approval by the Advisory Committee, however, <a href="https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-declines-approve-expanded-use-alnylams-heart-disease-drug-2023-10-09/" target="_blank">FDA declined the approval</a>. <br /><p>6MWT/6MWD may also be used in neurology diseases, for example: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824082/pdf/mus0048-0343.pdf" target="_blank">The 6-minute walk test and other endpoints in Duchenne Muscular Dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study</a></p><p><b><br /></b></p><p><b><span style="font-size: medium;">2MWT/2MWD:</span></b></p>Both 6MWT and 2MWT are clinical assessments to evaluate a patient's functional capacity and endurance, particularly in individuals with cardiopulmonary or musculoskeletal conditions. Compared to 6MWT/6MWD, 2MWT/2MWD was less commonly used in clinical trials. However, 2MWT is a shorter, more focused test designed to quickly assess walking capacity and is often used in situations where a shorter test is preferred. 2MWT can be conducted in a smaller space, making it more suitable for clinics or confined settings. 2MWT is particularly useful for assessing functional capacity in situations where time constraints or physical limitations may necessitate a shorter test, and offers a quicker assessment of walking capacity and can be used for patients who may have difficulty completing a longer test.<p><a href="https://n.neurology.org/content/86/5/442" target="_blank">Two- and 6-minute walk tests assess walking capability equally in neuromuscular diseases<br /></a></p><p>Grifols conducted a pivotal study to assess the efficacy of IGIV in the treatment of post-polio syndrome and <a href="https://clinicaltrials.gov/study/NCT02176863" target="_blank">used 2MWT as the primary efficacy endpoint</a>. The study is still ongoing. </p>MedDay Pharmaceuticals SA conducted a phase 3 study "<a href="https://clinicaltrials.gov/study/NCT02961803" target="_blank">MD1003-AMN MD1003 in Adrenomyeloneuropathy</a>" with 2MWD as primary efficacy endpoint</div><div><br /></div><div>Adamas Pharmaceuticals conducted a phase 3 study "<a href="https://clinicaltrials.gov/study/NCT03436199" target="_blank">Safety and Efficacy of ADS-5102 in Multiple Sclerosis Patients With Walking Impairment</a>" where 2MWT used as the secondary endpoint (T25FW used as the primary endpoint)<br /><p><b><span style="font-size: medium;">The 10 Metre Walk Test</span></b></p></div><div><a href="https://neuropt.org/docs/default-source/cpgs/core-outcome-measures/10mwt-pocket-guide-proof8-(2)28db36a5390366a68a96ff00001fc240.pdf?sfvrsn=e4d85043_0_10" target="_blank">Instructions for conducting 10 Meter Walk Test</a> or <a href="https://www.neuropt.org/docs/default-source/cpgs/core-outcome-measures/core-measure-10-meter-walk-test-(10mwt)_final.pdf" target="_blank">Core Measure 10 meter walk test</a></div><div><br /></div><div><a href="https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-topline-results-embark-global-0" target="_blank">Sarepta Therapeutics recently released their confirmatory study results</a> of gene therapy for the treatment of DMD (Duchenne Muscular Disease) and 10-meter walk test was one of the secondary efficacy endpoints. The 10-meter walk test results are shown here. The treatment differences are expressed in time (seconds). While all treatment differences are statistically significant, the clinical meaningfulness needs to be vetted by the experts and the regulators. </div><div><span style="background-color: #f2f2f2; box-sizing: border-box; font-size: 18px; line-height: inherit;"><span face="CircularXXWeb, sans-serif"><b><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjiilcM2em7IcRZQn7K2AVuBINnDihfw9S3YvbZGw1I0_bUSultpS-XkF-P9p_GcWvGIdTY3ElSn6i4aI7vVWOyn7STWQ2NCByIKDa8LmXC9zcXaJ2vWmNyETO62Z7OYsbTBGeRwemHm7KYnYgi3JgNYSyFCbiZ0UDs2jZ6jzDZEoW1d3ucg/s467/Annotation%202023-11-02%20154205.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="190" data-original-width="467" height="174" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjiilcM2em7IcRZQn7K2AVuBINnDihfw9S3YvbZGw1I0_bUSultpS-XkF-P9p_GcWvGIdTY3ElSn6i4aI7vVWOyn7STWQ2NCByIKDa8LmXC9zcXaJ2vWmNyETO62Z7OYsbTBGeRwemHm7KYnYgi3JgNYSyFCbiZ0UDs2jZ6jzDZEoW1d3ucg/w428-h174/Annotation%202023-11-02%20154205.jpg" width="428" /></a></div><br /></b></span></span></div><span style="background-color: white;"><b><div style="font-size: 15px;"><span style="background-color: white; font-size: 15px;"><b><br /></b></span></div><span style="font-size: medium;">Timed 25 Foot Walk (T25FW)</span></b></span><br /><br />The T25FW is a quantitative mobility and leg function performance test based on a timed 25-walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task.<div><br /><p>The drug AMPYRA® (dalfampridine) was approved for improving walking in adult patients with multiple sclerosis (MS). <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022250s018lbl.pdf" target="_blank">The drug label</a> stated that the T25FW was the primary efficacy endpoints:</p><p></p><blockquote>The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed
25-foot Walk (T25FW), using a responder analysis. A responder was defined as a patient who showed faster
walking speed for at least three visits out of a possible four during the double-blind period than the maximum
value achieved in the five non-double-blind no treatment visits (four before the double-blind period and one
after). </blockquote><p>Acorda Therapeutics conducted phase 3 studies "<a href="https://clinicaltrials.gov/study/NCT00483652">Study of Fampridine-SR Tablets in Multiple Sclerosis Patients</a>" and "<a href="https://clinicaltrials.gov/study/NCT00127530">Study of Oral Fampridine-SR in Multiple Sclerosis</a>" where T25FW was used as the primary efficacy measure.</p>The paper by Cohen et al "<a href="https://pubmed.ncbi.nlm.nih.gov/34449295/" target="_blank">A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment</a>" stated the following:<br /><blockquote>Walking speed ft/s was used for T25FW since walking speed is more normally distributed as compared to walking time, and is therefore a preferred approach. A 20% change in T25FW is considered a meaningful change in patients with MS</blockquote></div><div><p><a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761053orig1s000medr.pdf" target="_blank">FDA medical review document on ocrelizumab</a> for treatment of RMS discussed the missing data imputation for T25FW. </p><p><a href="https://pubmed.ncbi.nlm.nih.gov/28206828/" target="_blank">Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis</a></p></div><div><a href="https://erj.ersjournals.com/content/25/1/96">The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis</a></div><div><p><br /></p><p>All four measures discussed above (6MWD, 2MWD, 10-meter walk test, T25FW) can be an acceptable endpoint for confirmatory trials. Which measure to use in a specific trial depends on the indication and the study population. The endpoint selection should be discussed with the review division of regulatory agencies such as FDA. </p></div></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-70098509745482028202023-10-20T13:50:00.002-04:002023-10-20T13:50:11.266-04:00Human Challenge Study Design in Action - a Dengue Fever vaccine trial<p>A human challenge study, also known as a controlled human infection model (CHIM), is a type of clinical research study in which healthy volunteers are intentionally exposed to a specific pathogen (such as a virus, bacterium, or parasite) under controlled conditions. The primary goal of these studies is to better understand the pathogen's behavior, the human immune response to it, and to test the effectiveness of potential treatments, vaccines, or preventive measures. Human challenge studies can provide valuable insights into disease progression, immunity, and treatment efficacy in a controlled and ethical manner.</p>These studies are typically conducted under strict ethical and safety guidelines to minimize the risk to participants. Participants are closely monitored, and their informed consent is obtained. Human challenge studies have been used to study a variety of diseases, including influenza, malaria, Dengue fever, and COVID-19, among others. They play a crucial role in advancing medical and scientific knowledge and can accelerate the development of treatments and vaccines.<div><br /></div>A human challenge study was mentioned as an alternative clinical trial design at the beginning of the COVID-19 pandemic when the world was desperate to find an effective and safe vaccine. I wrote an article about this: "<a href="https://onbiostatistics.blogspot.com/2020/05/human-challenge-study-design-for-covid.html">Human Challenge Study Design for Covid-19 Vaccine Clinical Trials?</a>"<div><br /></div><div>Just this morning, <a href="https://www.jnj.com/janssen-announces-promising-antiviral-activity-against-dengue-in-a-phase-2a-human-challenge-model" target="_blank">Janssen Announces Promising Antiviral Activity Against Dengue in a Phase 2a Human Challenge Model</a>. The results were from a phase 2a study titled "<a href="https://clinicaltrials.gov/study/NCT05048875" target="_blank">A Phase 2a, Randomized, Double-blind, Placebo Controlled Trial to Evaluate the Antiviral Activity, Safety, and Pharmacokinetics of Repeated Oral Doses of JNJ-64281802 Against Dengue Serotype 3 Infection in a Dengue Human Challenge Model in Healthy Adult Participants</a>" that was posted on clinicaltrials.gov. Unfortunately, the clinical trial registration did not contain any description of the 'Challenge' part (i.e., how the healthy volunteers are exposed to the infectious agents (in this case, the Dengue virus). We will just need to wait for the formal publication of the study to know the details. </div><div><br /></div>In a paper by Porter et al "<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195259/" target="_blank">A human Phase I/IIa malaria challenge trial of a polyprotein malaria vaccine</a>", the whole details about the human challenge study including the 'challenge' part were discussed. The 'sporozoite challenge' to the healthy volunteers was described below: <br /><div><br /></div><div> </div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEg364OT0OyBrsVKR2l7m0saBKla9SoeB-kuNvogpHRY7sIr1G23nDK61uxJQ-UKfu0Xg0WQKCybEQH8FSWRyQW27v8-Wfi_HRtYc1vg7E0Al4YQuSjxZ7yf-6a67P5hnOsqcsgy9sh6k-0zBPAznbtRasNAkQpnXI4WQu5K_38u-DTBz-jIqg" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="540" data-original-width="871" height="388" src="https://blogger.googleusercontent.com/img/a/AVvXsEg364OT0OyBrsVKR2l7m0saBKla9SoeB-kuNvogpHRY7sIr1G23nDK61uxJQ-UKfu0Xg0WQKCybEQH8FSWRyQW27v8-Wfi_HRtYc1vg7E0Al4YQuSjxZ7yf-6a67P5hnOsqcsgy9sh6k-0zBPAznbtRasNAkQpnXI4WQu5K_38u-DTBz-jIqg=w629-h388" width="629" /></a></div><br /></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-60821597735252832402023-10-13T03:30:00.001-04:002023-10-13T03:30:00.140-04:00Drugs Approved by FDA Despite Failed Trials or Minimal/Insufficient DataI have been trying to collect the cases of that drugs were approved by the FDA despite the failed trials or minimal/insufficient data. For drugs treating rare diseases or diseases with unmet medical needs, the FDA may apply flexibility in approving the drug with loosened criteria. <div><br /></div><div>For diseases with clearly unmet medical needs such as ALS (Amyotrophic Lateral Sclerosis) and Alzheimer's disease, FDA officials have recently emphasized the urgent need for new treatments and pledged to use maximum "regulatory flexibility" when reviewing the NDA/BLA packages. By applying the maximum "regulatory flexibility", FDA has approved some drugs which do not meet the agency's traditional approval standards. Some of the approvals are really controversial and make me wonder if there is any boundary for the maximum "regulatory flexibility". </div><div><br /></div>The following paper on BioSpace.com listed six drugs that earned FDA approval without substantial evidence of effectiveness.<br /><br /><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><a href="https://www.biospace.com/article/6-drugs-approved-despite-failed-trials-or-minimal-data-/"><b>6 Drugs Approved Despite Failed Trials or Minimal Data</b></a></blockquote></blockquote><ul style="text-align: left;"><li>Ipsen’s <a href="https://www.biospace.com/article/fda-approves-ipsen-s-palovarotene-for-ultra-rare-bone-disease/?keywords=Palovarotene">Sohonos</a> (palovarotene) for the ultra-rare genetic disease fibrodysplasia ossificans progressive (FOP) </li><li><a href="https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene" target="_blank">Sarepta’s Elevidys</a> as the first gene therapy for Duchenne muscular dystrophy (DMD)</li><li>Biogen's <a href="https://www.biospace.com/article/moment-of-truth-for-biogen-and-ionis-sod1-als-drug-/?keywords=tofersen">Qalsody</a> (tofersen) to treat patients with superoxide dismutase 1 (SOD1)-ALS, a rare subtype of the fatal neurodegenerative disease</li><li>Biogen and Eisai got the nod for <a href="https://www.biospace.com/article/biogen-s-big-day-fda-to-decide-on-alzheimer-s-drug-s-fate/">Aduhelm</a> (aducanumab) for Alzheimer's diease,</li><li>Jazz Pharmaceuticals and PharmaMar’s <a href="https://www.biospace.com/article/fda-greenlights-jazz-pharma-s-zepzelca-for-small-cell-lung-cancer/">Zepzelca</a> (lurbinectedin) for small cell lung cancer (SCLC) that had progressed on or after platinum-based chemotherapy</li><li><a href="https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-hallucinations-and-delusions-associated-parkinsons-disease" target="_blank">Acadia Pharmaceuticals’ Nuplazid</a> (pimavanserin) to treat hallucinations and delusions associated with psychosis in Parkinson’s disease.</li></ul>Some of the approvals gave the sponsors the false hope that an innovative drug could be approved by the FDA even if the study failed to demonstrate the effectiveness as long as the drug was for the treatment of diseases with urgent unmet medical needs. <a href="BrainStorm's ALS cell therapy resoundingly rejected by FDA advisers" target="_blank">A recent story about BrainStorm's ALS drug</a> is exactly the case about this. Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-77588944440387019532023-10-06T03:00:00.008-04:002023-10-09T21:30:38.113-04:00MCID (Minimum Clinical Important Difference) for 6MWD - how low can we go? I went back to watch <a href="https://www.youtube.com/live/dVwtnX8Pzy4?si=kispawYWRZvNg36_" target="_blank">the FDA CRDAC (Cardiovascular and Renal Drugs Advisory Committee) meeting</a> to discuss Alnylam's drug Patisiran for the treatment of ATTR-CM (Transthyretin Amyloidosis) - a rare form of heart disease. The meeting discussion was centered on the clinical meaningfulness of the efficacy measures in the primary efficacy endpoint of 6MWD (how many meters patients can walk in 6 minutes) and the secondary endpoint of KCCQ - a patient-reported quality of life measure. <div><br /></div><div><div>The sponsor, Alnylam, conducted a phase III study called "<a href="https://clinicaltrials.gov/study/NCT03997383">APOLLO-B: A Study to Evaluate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)</a>". The study results showed statistically significant differences in 6MWD and in KCCQ total score. However, the magnitude of the treatment differences was very small: 14.7 meters in 6MWD and 3.7 points in KCCQ at month 12.</div><div><br /></div><div>To judge if the treatment difference is clinically meaningful, people will compare the magnitude of the treatment differences from the study with the MCID (minimal clinically important difference). MCID. MCID is the smallest change in a treatment outcome that individual patients would identify as important and which would indicate a change in the patients' management. The MCID is a patient-centered concept that captures both the magnitude of the improvement and the value patients place on the change. In other words, the MCID is the smallest amount of change in the score of a scale recognized by the patient without considering the side effects and cost. </div><div><br />In <a href="https://www.fda.gov/media/171977/download" target="_blank">FDA's briefing book</a> for CRADAC meeting, FDA casted doubts about the Patisiram's efficacy: </div><div><blockquote>The 6MWT, a performance outcome (PerfO), is a practical simple test that measures the distance that a
patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD). It evaluates the
global and integrated responses of all the systems involved during exercise. The results of the APOLLO-B
trial showed a statistically significant but small treatment effect for the primary efficacy endpoint.
Subjects treated with patisiran experienced an average decrease in their 6MWD of 13 m at Month 12
from an average 6MWD of 361 m at baseline, while subjects in the placebo arm experienced an average
decrease in their 6MWD of 31 m at Month 12 from an average 6MWD of 375 m at baseline. The change
from baseline at Month 12 in 6MWT (Hodges-Lehmann [HL] estimate of median difference) for patisiran
vs. placebo was 14.7 m (95% confidence interval [CI] 0.7, 28.7; p-value 0.04). Literature has reported a
range of meaningful differences (22 to 90 m) reflective of the heterogeneity in cardiomyopathy patients
(<a href="https://pubmed.ncbi.nlm.nih.gov/22723290/" target="_blank">Mathai et al. 2012</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/22993497/" target="_blank">Shoemaker et al. 2012</a>).</blockquote></div><div><blockquote> The KCCQ, a patient-reported outcome (PRO) and a disease-specific measure for HF, is a 23-item self-administered questionnaire developed to measure the patient’s perception of their health status, which
includes heart failure symptoms, impact on physical and social function, and how heart failure impacts
their quality of life (QOL) within a 2-week recall period. The KCCQ-OSS has a 0-100 transformed score
range where higher scores reflect better health status (based on the Physical Limitation, Symptom
Frequency, Symptom Burden, Quality of Life and Social Limitations Domain Scores). In the APOLLO-B
trial,the treatment effect for the first secondary efficacy endpoint, change from baseline at Month 12 in
KCCQ-OSS was small (3.7 points on a 0 to 100 transformed score range; 95% CI 0.2, 7.2; p-value 0.04).
On average, subjects treated with patisiran had an increase in KCCQ-OSS of 0.3 points at Month 12 from
the average baseline score of 69.8 points, while subjects in the placebo arm had a decrease in KCCQ-OSS
of 3.4 points at Month 12 from the average baseline score of 70.3 points. </blockquote></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEi3nTYrG5Tuc8NxYyRwrP8naIoUheA34xX49sGkozA6XQELug50gzFV88cycubNpsgLCsezAselR3zU8po1_DSYv2QxmgPJEm1sBoZuRSWBpaFrtKAvrYczybdt4tnfobDRIP6_nRbVmhQ4axm3StnjFZ7_Iqa5nIXP8nQ8HBmmTnbkdTwaMA" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="326" data-original-width="877" height="255" src="https://blogger.googleusercontent.com/img/a/AVvXsEi3nTYrG5Tuc8NxYyRwrP8naIoUheA34xX49sGkozA6XQELug50gzFV88cycubNpsgLCsezAselR3zU8po1_DSYv2QxmgPJEm1sBoZuRSWBpaFrtKAvrYczybdt4tnfobDRIP6_nRbVmhQ4axm3StnjFZ7_Iqa5nIXP8nQ8HBmmTnbkdTwaMA=w686-h255" width="686" /></a></div><div><br /></div>Sponsor, Alnyam's <a href="https://www.fda.gov/media/171979/download" target="_blank">briefing book</a> and <a href="https://www.fda.gov/media/172043/download" target="_blank">presentation</a> spent a lot of effort to defend that the small, but statistically significant treatment differences are clinically meaningful. </div><div><br /><div class="separator" style="clear: both; text-align: center;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjHcK9N1upv13H5LzxEGZ_GYWZI-7O69GJTQIh21j-NbyDAIBA3vXFL8C2jRQjUDNplV49YCiUJSwPwghW-H7CTpgtkeSYSMKaF03ejx8uXnFf14bMvcqlEz0rfl4-779LArEPX8pIFdKblSescLOznfcbyXnv73rRZULWKqI7vc4jiwqbmkg" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="676" data-original-width="1246" height="347" src="https://blogger.googleusercontent.com/img/a/AVvXsEjHcK9N1upv13H5LzxEGZ_GYWZI-7O69GJTQIh21j-NbyDAIBA3vXFL8C2jRQjUDNplV49YCiUJSwPwghW-H7CTpgtkeSYSMKaF03ejx8uXnFf14bMvcqlEz0rfl4-779LArEPX8pIFdKblSescLOznfcbyXnv73rRZULWKqI7vc4jiwqbmkg=w639-h347" width="639" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div></div></div></div><div class="separator" style="clear: both; text-align: center;"><div class="separator" style="clear: both; text-align: left;">Sponsor attempted to derive an MCID using KCCQ category as an anchor based on the data from the study itself (APOLLO-B study). </div></div><div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: center;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgpT5FxoOS7Qs7WbGAAhCdH_ZDMVXELEUzySV6mxauw8K-t2DrJEwUz6yL9a1qouBOKC5KzxVNk54C3-WNp9GP_1p2nMJesiKwgB7x6wQ1LisDG8S64ieN3X0XLVRnlLIv5TbqrVv8NXyXYXKB-kUoIdb3-QYxzTZXNOwaIsRV8i63dgEJCbg" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="697" data-original-width="1187" height="311" src="https://blogger.googleusercontent.com/img/a/AVvXsEgpT5FxoOS7Qs7WbGAAhCdH_ZDMVXELEUzySV6mxauw8K-t2DrJEwUz6yL9a1qouBOKC5KzxVNk54C3-WNp9GP_1p2nMJesiKwgB7x6wQ1LisDG8S64ieN3X0XLVRnlLIv5TbqrVv8NXyXYXKB-kUoIdb3-QYxzTZXNOwaIsRV8i63dgEJCbg=w531-h311" width="531" /></a></div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">Not surprisingly, the MCID they generated were much smaller (MCID in the range of 7 - 8 meters) than the MCIDs reported in the literature. If the MCID is indeed in the range of 7 - 8 meters, the 14.7 meters (treatment difference observed in Apollo-B study) would be clinically meaningful. </div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEg7sCz11Iaj0a6gZIxiJ-ibIB0cg97OjRCtg-zfJ18J-25TuhP0o4xhAv_Do37GSbb-9F76WSQaT2iTOOPjvcqsTCqZBiylSV_hwAglhyxcyndrNQJgfR8whLINKPXLxbTJmGA4aZk6qRVzS3vs2bHyiIuYPAPH50-NYbwrTx7uYqHmhOiEcA" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="689" data-original-width="1142" height="328" src="https://blogger.googleusercontent.com/img/a/AVvXsEg7sCz11Iaj0a6gZIxiJ-ibIB0cg97OjRCtg-zfJ18J-25TuhP0o4xhAv_Do37GSbb-9F76WSQaT2iTOOPjvcqsTCqZBiylSV_hwAglhyxcyndrNQJgfR8whLINKPXLxbTJmGA4aZk6qRVzS3vs2bHyiIuYPAPH50-NYbwrTx7uYqHmhOiEcA=w545-h328" width="545" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div style="text-align: left;">During the FDA advisory committee meeting, most of the members were not convinced by sponsor's presentation to defend the clinical meaningfulness of small treatment difference in 6MWD (about 14 meter). However, majority of them (9-3) still voted in favor of the Patisiran's efficacy and the benefit-risk profile. </div></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div><p><a href="https://www.statnews.com/2023/09/13/heart-disease-patisiran-alnylam/" target="_blank">FDA panel endorses Alnylam's heart drug - after picking apart its supporting data </a></p></div><div><p><a href="https://www.hcplive.com/view/expert-perspective-fda-crdac-vote-on-patisiran-for-attr-cm-with-ahmad-masri-md-ms" target="_blank">Expert Perspective: FDA CRDAC Vote on Patisiran for ATTR-CM, with Ahmad Masri, MD</a></p></div></blockquote><div><p class="MsoNormal">Pfizer's tafamidis is the only approved drug for the treatment of ATTR-CM. <a href="https://www.fda.gov/media/126283/download" target="_blank">According to the product label</a>, the treatment difference in 6MWD was much larger - 76 meters with 95% confidence interval 58, 94 meters at month 30. </p><p class="MsoNormal">For the same 6MWD, the MCID may be different depending on the treating diseases, different patient population, whether patients receiving the background therapies,... However, a treatment difference of 14 meters is still not a convincing number to be clinical meaningful. Putting on the relative scale, the 14 meters in patients with baseline 6MWD 361 meter is less than 5%. It is difficult to convince people a treatment difference less than 5% is clinically meaningful. </p><p class="MsoNormal">I am particularlly interested in the MCID of 6MWD in lung diseases (especially the pulmonary arterial hypertension). </p>Anne E. Holland (2014) "<a href="https://erj.ersjournals.com/content/44/6/1428">An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease</a>" stated<br /><blockquote>“Available evidence suggests a minimal important difference (MID) of <b>30 m</b> for the 6MWD in adults with chronic respiratory disease.”</blockquote><a href="https://www.atsjournals.org/author/Moutchia%2C+Jude">Jude Moutchia</a> (2023) "<a href="https://www.atsjournals.org/doi/abs/10.1164/rccm.202208-1547OC">Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension</a>" found:<br /><blockquote>The minimal clinically important difference in the derivation sample was <b>33 meters</b> (95% confidence interval, 27–38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29–43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class.</blockquote><p>Here is a table containing some literatures with estimated MCID. The MCID was found to be in the range of 20 - 54 meters depending on the indication/disease. </p><table border="0" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="border-collapse: collapse; margin-left: 22.5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-table-layout-alt: fixed; mso-yfti-tbllook: 1184; width: 66%;">
<tbody><tr style="break-inside: avoid; height: 0.2in; mso-yfti-firstrow: yes; mso-yfti-irow: 0; page-break-inside: avoid;">
<td style="background: white; border-bottom: 1pt solid windowtext; border-left: none; border-right: none; border-top: 1pt solid windowtext; height: 0.2in; mso-background-themecolor: background1; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><b><span style="font-family: "Times New Roman", serif; font-size: 10pt;">Study/Article<o:p></o:p></span></b></p>
</td>
<td style="background: white; border-bottom: 1pt solid windowtext; border-left: none; border-right: none; border-top: 1pt solid windowtext; height: 0.2in; mso-background-themecolor: background1; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><b><span style="font-family: "Times New Roman", serif; font-size: 10pt;">Indication/Disease<o:p></o:p></span></b></p>
</td>
<td style="background: white; border-bottom: 1pt solid windowtext; border-left: none; border-right: none; border-top: 1pt solid windowtext; height: 0.2in; mso-background-themecolor: background1; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><b><span style="font-family: "Times New Roman", serif; font-size: 10pt;">MCID Range<o:p></o:p></span></b></p>
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<td style="background: white; border-bottom: 1pt solid windowtext; border-left: none; border-right: none; border-top: 1pt solid windowtext; height: 0.2in; mso-background-themecolor: background1; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><b><span style="font-family: "Times New Roman", serif; font-size: 10pt;">MCID Midpoint<o:p></o:p></span></b></p>
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</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 1; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420183/pdf/chest_147_5_1316.pdf">Chan
(2015)</a> <o:p></o:p></span></p>
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<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">ARF<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">20 – 30<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">25<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 2; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://www.atsjournals.org/doi/epdf/10.1164/rccm.201007-1179OC?role=tab">du
Bois (2011)</a><o:p></o:p></span></p>
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<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">IPF<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">24 – 45<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">35<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 3; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://www.sciencedirect.com/science/article/pii/S0012369209600787?casa_token=sf3s2a45bM4AAAAA:TnaAuGjo1QUcF6AWjVth3FDc7pZ3FsJ2u1Kc9gq0EYQ13GT6yAb40nEs8YOVXjmYEiPiqwPulQ">Gilbert
(2009)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">PAH<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">41<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">41<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 4; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://pubmed.ncbi.nlm.nih.gov/25749346/">Granger (2015)</a><o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">Lung
Cancer<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">22 – 42<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">32<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 5; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://www.resmedjournal.com/article/S0954-6111(09)00147-4/fulltext">Holland
(2009)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">DPLD/IPF<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">29 – 34<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">32<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 6; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://www.archives-pmr.org/article/S0003-9993(09)00900-9/fulltext">Holland
(2010)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">COPD<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">25<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">25<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 7; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://pubmed.ncbi.nlm.nih.gov/36629737/">Mathai (2012)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">PAH<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">33<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">33<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 8; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://pubmed.ncbi.nlm.nih.gov/25956020/">Nathan (2015)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">IPF<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">22 – 37<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">30<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 9; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://www.atsjournals.org/doi/epdf/10.1164/rccm.201209-1596OC?role=tab">Polkey
(2013)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">COPD<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">30<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">30<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 10; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://pubmed.ncbi.nlm.nih.gov/18550610/">Puhan (2008)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">COPD<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">35<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">35<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 11; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://pubmed.ncbi.nlm.nih.gov/20693247/">Puhan (2011)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">COPD<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">24 – 28<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">26<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 12; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://pubmed.ncbi.nlm.nih.gov/9105067/">Redelmeier (1997)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">CLD<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">54<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">54<o:p></o:p></span></p>
</td>
</tr>
<tr style="break-inside: avoid; height: 0.2in; mso-yfti-irow: 13; mso-yfti-lastrow: yes; page-break-inside: avoid;">
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;"><a href="https://pubmed.ncbi.nlm.nih.gov/19996335/">Swigris (2010)</a> <o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">IPF<o:p></o:p></span></p>
</td>
<td style="background: white; border-bottom: solid windowtext 1.0pt; border: none; height: 0.2in; mso-border-bottom-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 25%;" valign="bottom" width="25%">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="font-family: "Times New Roman", serif; font-size: 10pt;">28<o:p></o:p></span></p>
</td>
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</tbody></table><br /><b>Latest update: </b></div><div><br /></div><div>In the end, the FDA did not approve Patisiran for the treatment of ATTR-CM because the treatment difference in 6MWD was too small (way below the MCID) and not clinically meaningful even though the FDA advisory committee voted in favor of the Patisiran's benefit and there was no issue with the safety and the manufacturing. </div><br /><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><a href="https://www.biospace.com/article/releases/alnylam-announces-receipt-of-complete-response-letter-from-u-s-fda-for-supplemental-new-drug-application-for-patisiran-for-the-treatment-of-the-cardiomyopathy-of-attr-amyloidosis/" target="_blank">Alnylam Announces Receipt of Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Patisiran for the Treatment of the Cardiomyopathy of ATTR Amyloidosis</a></blockquote><br /> <blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><div><a href="https://www.pharmalive.com/fda-blocks-alnylams-bid-to-expand-onpattro-label/">FDA blocks Alnylam’s bid to expand Onpattro label - PharmaLive</a></div></blockquote><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><p style="text-align: left;"> "<span style="background-color: white; font-family: "open sans", Helvetica, Arial, sans-serif; font-size: 13px;">In its Complete Response Letter (CRL), the regulator said that Alnylam had not provided enough evidence of the therapy’s benefit in the proposed indication. At the same time, the FDA did not flag any problems with patisiran’s clinical safety, drug quality, manufacturing processes or study conduct.</span></p></blockquote><blockquote><p style="background-color: white; border: 0px rgb(115, 115, 115); box-sizing: border-box; font-family: "open sans", Helvetica, Arial, sans-serif; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-size: 13px; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variant-position: inherit; font-variation-settings: inherit; line-height: inherit; margin: 0.85em 0px; padding: 0px; vertical-align: baseline;">“The CRL indicated that the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis had not been established,” according to the company’s announcement. In light of the rejection, Alnylam will no long work toward an expanded label for Onpattro in the U.S."</p></blockquote><p style="background-color: white; border: 0px rgb(115, 115, 115); box-sizing: border-box; font-family: "open sans", Helvetica, Arial, sans-serif; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-size: 13px; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variant-position: inherit; font-variation-settings: inherit; line-height: inherit; margin: 0.85em 0px; padding: 0px; vertical-align: baseline;"></p>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-81850935270095471542023-08-15T03:00:00.001-04:002023-08-15T03:00:00.143-04:00Platform trials in action beyond oncology trialsOne of the complex innovative designs is the study with 'Master protocol' that has been getting popularity in recent years. Master protocol simply refers to the study of more than one drug with a single protocol. In clinical trials with Master protocol, the protocol document stands alone, without reference to specific drugs. Protocol amendments (or study-specific protocol) are used to provide details of each drug. Master protocols establish a trial network with infrastructure in place to streamline trial logistics and improve data quality, and facilitate data sharing and new data collection. Master protocols develop a common protocol for the network that incorporates innovative statistical approaches to study design and data analysis.<div><div class="separator" style="clear: both; text-align: center;"><br /></div><br />Platform trial is one type of Master protocol and refers to establishing the trial infrastructure and master protocol as a perpetuating effort, with drugs entering and leaving the platform.<br /><br />Two prominent references for master protocols and platform trials are the following: <br /><p> "<a href="https://www.nejm.org/doi/pdf/10.1056/NEJMra1510062?articleTools=true" target="_blank">Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both</a>" in 2017 by Woodcock and LaVange defines Master protocols include three type of trials: Umbrella, basket, and platform trials. </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjtsgJMtK8tVPdK69bUVkFkbskTxR9g3CMr7tVtrmCtb2B4V3RQ74IGSk9ImbAF-mNRxjX-JSNZE0NeNaLwPgTfvtYXle-Ux2j4m62g3mBytWTfJ1IcMhKMoX0i1wIJUHekmevD8NBYhvFy8Gx_MFUGWtw1LXMsx6i3c0P75nrZW5tvSTJu-A" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="182" data-original-width="364" height="228" src="https://blogger.googleusercontent.com/img/a/AVvXsEjtsgJMtK8tVPdK69bUVkFkbskTxR9g3CMr7tVtrmCtb2B4V3RQ74IGSk9ImbAF-mNRxjX-JSNZE0NeNaLwPgTfvtYXle-Ux2j4m62g3mBytWTfJ1IcMhKMoX0i1wIJUHekmevD8NBYhvFy8Gx_MFUGWtw1LXMsx6i3c0P75nrZW5tvSTJu-A=w455-h228" width="455" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: center;"><br /></div>FDA procedural guidance in 2022 "<a href="https://www.fda.gov/media/120721/download" target="_blank">Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics Guidance for Industry</a>" provided the definition for Master protocols:</div><div><blockquote>a master protocol is defined as a protocol designed with
multiple substudies, which may have different objectives and involve coordinated efforts to
evaluate one or more investigational drugs in one or more disease subtypes within the overall
trial structure.</blockquote></div><div><blockquote>A master protocol may be used to conduct the trial or trials for exploratory purposes or to
support a marketing application and can be structured to evaluate, in parallel, different drugs
compared with their respective controls or to a single common control. The sponsor can design
the master protocol with a fixed or adaptive design with the intent to modify the protocol to
incorporate or terminate individual substudies within the master protocol. <br /><p></p><p></p></blockquote><p>Master protocols can include basket trial, umbrella trial, and platform trial and these trials can be schematically displayed as the following: </p><p><b>Basket trial</b></p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjW3mqysK7SXM0k5pDTtXuhSma9DrDGLQ4lx8uoIcnVy8JPeiS7LbCZ7oImB0mZZIVvIspKJnSP1VKODreu0tnFbLRITAhfiFuT5ASiC8a5L86742o9sN_tnfC9ol3nozfF34AznyrvLZinZjrXiy-VdFgCN3aBoIqHkOXcTjLk1iL9oWtA3A" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="421" data-original-width="733" height="338" src="https://blogger.googleusercontent.com/img/a/AVvXsEjW3mqysK7SXM0k5pDTtXuhSma9DrDGLQ4lx8uoIcnVy8JPeiS7LbCZ7oImB0mZZIVvIspKJnSP1VKODreu0tnFbLRITAhfiFuT5ASiC8a5L86742o9sN_tnfC9ol3nozfF34AznyrvLZinZjrXiy-VdFgCN3aBoIqHkOXcTjLk1iL9oWtA3A=w587-h338" width="587" /></a></div><b>Umbrella Trial</b><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhMQas1ErbG8PO88Bs7Uf68GdeFaME2FSdiu6ggj3Wmd5Ol46f9y_t9w58LhE0I4JMph2DbU9t3qTBcsrDEw38lJaaqUHUAAMtNQtU3Trm18wyY9nfOWavhvNWTtN_NdAM-JX28qDm38k_MKsY4ZbHZNAQEDC5eMguAcblBOZuFHPJ9mByFEw" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="488" data-original-width="737" height="374" src="https://blogger.googleusercontent.com/img/a/AVvXsEhMQas1ErbG8PO88Bs7Uf68GdeFaME2FSdiu6ggj3Wmd5Ol46f9y_t9w58LhE0I4JMph2DbU9t3qTBcsrDEw38lJaaqUHUAAMtNQtU3Trm18wyY9nfOWavhvNWTtN_NdAM-JX28qDm38k_MKsY4ZbHZNAQEDC5eMguAcblBOZuFHPJ9mByFEw=w565-h374" width="565" /></a></div><b>Platform Trial:</b><br /><br /><a href="https://blogger.googleusercontent.com/img/a/AVvXsEi4x6NAr1dr9rRRDiFDZBeLWK1lQIIHbAivn_zSdZGEfBzREgj6C8IYeTjDPBb6INJUEVNM6bfsFbukegxFDhGBMOB2PY4oUd3XGMWXQrI4zjhysVQk6PC8xTuhQM5uUxi9jWZXeMw95bghehK3fTvAekcQH4zRAmfj45ySwN5tdSP7-gTEyw" style="margin-left: 1em; margin-right: 1em; text-align: center;"><img alt="" data-original-height="613" data-original-width="636" height="635" src="https://blogger.googleusercontent.com/img/a/AVvXsEi4x6NAr1dr9rRRDiFDZBeLWK1lQIIHbAivn_zSdZGEfBzREgj6C8IYeTjDPBb6INJUEVNM6bfsFbukegxFDhGBMOB2PY4oUd3XGMWXQrI4zjhysVQk6PC8xTuhQM5uUxi9jWZXeMw95bghehK3fTvAekcQH4zRAmfj45ySwN5tdSP7-gTEyw=w660-h635" width="660" /></a><br /><p></p><p>In a paper by Berry et al, "<a href="https://jamanetwork.com/journals/jama/article-abstract/2210902" target="_blank">The Platform Trial An Efficient Strategy for Evaluating Multiple Treatments</a>", the platform trial was compared to the traditional trial: </p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjTT0kasPh5ISYp0yyMSHCYqIQ98-YDuFfM44HePktK0zNstKHDUaLCW9aVPiJAoqFcnqEpPHr8iQq35SF5YKNGj54gyvLsPqm22sJFF4ldH76wIWXtF2UQo9GrE_k79lj2dQllcDfVQwsQnwGtAQ-ym1pYlQkEltFOu5IXIehR-8elxyfl8Q" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="308" data-original-width="904" height="225" src="https://blogger.googleusercontent.com/img/a/AVvXsEjTT0kasPh5ISYp0yyMSHCYqIQ98-YDuFfM44HePktK0zNstKHDUaLCW9aVPiJAoqFcnqEpPHr8iQq35SF5YKNGj54gyvLsPqm22sJFF4ldH76wIWXtF2UQo9GrE_k79lj2dQllcDfVQwsQnwGtAQ-ym1pYlQkEltFOu5IXIehR-8elxyfl8Q=w660-h225" width="660" /></a></div><br />While platform trial has its challenges, we see the implementation trials in action, beyond the oncology trials. Here are examples of platform trials in areas other than the oncology trials. <p></p><a href="https://classic.clinicaltrials.gov/ct2/show/NCT04297683" target="_blank">HEALEY ALS Platform Trial</a></div><blockquote>The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS. This trial is designed as a perpetual platform trial. This means that there is a single Master Protocol dictating the conduct of the trial.<br /><br />In this trial, multiple investigational products for ALS will be tested simultaneously or sequentially. Each investigational product will be tested in a regimen. Each regimen consists of a placebo-controlled trial, meaning that the active investigational product and matching placebo will be tested in each regimen.</blockquote><p></p><blockquote><p>The study website is here: <a href="https://www.massgeneral.org/neurology/als/research/platform-trial">https://www.massgeneral.org/neurology/als/research/platform-trial</a></p><p>The study master protocol can be accessed <a href="https://www.massgeneral.org/assets/mgh/pdf/neurology/als/healey-als-platform%20trial-master-protocol.pdf" target="_blank">here</a></p><p>Several testing drugs have been completed or graduated from the platform, please see <a href="https://www.massgeneral.org/neurology/als/news" target="_blank">the news releases</a></p></blockquote><p></p><a href="https://classic.clinicaltrials.gov/ct2/show/NCT04129931" target="_blank">PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study</a><br /><blockquote>PrecISE is an adaptive platform trial under master protocol with common biomarker screening where drugs enter when available and discontinue based on futility analysis. According to <a href="https://classic.clinicaltrials.gov/ct2/show/NCT04129931">clinicaltrials.gov</a>, 5 novel interventions are currently listed as the testing drug for study: Medium Chain Triglycerides (MCT), Clazakizumab, Broncho-Vaxom, Imatinib Mesylate, Cavosonstat; each active will be tested against its own control.</blockquote><blockquote>the study design was described in the paper by Israel et al "<a href="https://pubmed.ncbi.nlm.nih.gov/33667479/" target="_blank">PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment</a>"</blockquote><a href="https://www.remapcap.org/" target="_blank">REMAP-CAP</a>: A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia<blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><p style="text-align: left;">REMAP-CAP platform trial was originally designed for identifying the treatments for community-acquired pneumonia. After the Covid pandemic in 2020, REMAP-CAP has quickly implemented the Pandemic Appendix to the Core Protocol so that the platform can respond rapidly in the event of widespread disease resulting from the <a href="https://www.who.int/emergencies/diseases/novel-coronavirus-2019">novel 2019 coronavirus</a> (COVID-19).</p></blockquote><a href="https://www.nih.gov/research-training/medical-research-initiatives/activ" target="_blank">ACTIV (NIH) Accelerating Covid-19 Therapeutic Interventions and Vaccines<br /></a><blockquote><div>Working in an unprecedented time frame, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership developed and launched 9 master protocols between 14 April 2020 and 31 May 2021 to allow for the coordinated and efficient evaluation of multiple investigational therapeutic agents for COVID-19. The ACTIV master protocols were designed with a portfolio approach to serve the following patient populations with COVID-19: mild to moderately ill outpatients, moderately ill inpatients, and critically ill inpatients.</div></blockquote><p></p><blockquote>The study design was described in the paper by LaVange et al "<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244665/" target="_blank">Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics</a>"</blockquote><p></p><div></div><a href="https://trials.recovercovid.org/" target="_blank">RECOVER Clinical Trials - for Long Covid<br /></a><blockquote>Long COVID is defined as "a multifaceted disease that can affect nearly every organ system" and can manifest as new or worsening chronic health problems, including but not limited to heart disease, diabetes, kidney disease, hematologic issues, and mental and neurologic conditions. The signs, symptoms, and conditions continue or arise anew 4 weeks or more after the initial symptomatic or asymptomatic infection and may be relapsing and remitting.</blockquote>
<blockquote>NIH RECOVER trial is also using platform protocols/clinical trials to investigate treatments for long covid and master protocol is posted on the study website: <a href="https://nam10.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrials.recovercovid.org%2Fdesign&data=05%7C01%7C%7C7d17e27234494b957cf008db94fc81c8%7Ce069698f79b14b6c9d56230f444246d3%7C0%7C0%7C638267584451248425%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=7oU8yY3X6CrsIpXqL8t6Z%2FpkUJCCXI0Ppp1x%2FzqdYpg%3D&reserved=0">https://trials.recovercovid.org/design</a>. There will be multiple master protocols: <a href="https://clinicaltrials.gov/study/NCT05595369">RECOVER-VITAL</a>, <a href="https://clinicaltrials.gov/study/NCT05965752">RECOVER-NEURO</a>, RECOVER-AUTONOMIC (coming soon), RECOVER-SLEEP (coming soon) to investigate different</blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"> It is ironic that the RECOVER trial is started after NIH spent 2.5 years and $1 billion on long Covid research and failed to test meaningful long Covid treatments. See the article "<a href="https://www.statnews.com/2023/08/09/long-covid-nih-trials/" target="_blank">Underwhelming’: NIH trials fail to test meaningful long Covid treatments — after 2.5 years and $1 billion</a> "</blockquote><p>Clinicaltrialsarena.com has an featured article "<a href="https://www.clinicaltrialsarena.com/features/platform-trials-an-opportunity-for-rare-dystrophies-or-gene-therapies/" target="_blank">Platform trials: an opportunity for rare dystrophies or gene therapies?</a>". The article discussed the possibility of platform trials in rare diseases and gene therapies. PaVeGT platform trial was listed: </p><div><div><blockquote><a href="https://pave-gt.ncats.nih.gov/" target="_blank">PaVe-GT: Paving the Way for Rare Disease Gene Therapies<br /></a><br />PaVe-GT will develop and test AAV-9, with a different gene for each indication, using a single master protocol. The NCATS-led Platform Vector Gene Therapy (PaVe-GT) pilot project seeks to increase the efficiency of clinical trial startup by using the same gene delivery system and manufacturing methods for multiple rare disease gene therapies. We will make program results and regulatory documents publicly available, with the intention of benefiting future gene therapy clinical trials for very rare diseases.<br /></blockquote><p> In a paper by Collignon (2022) "<a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794160" target="_blank">An Economic Perspective on Platform Trials—The Gift and the Curse</a>", the following conclusion was made about the platform trial: </p><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;">"...sharing a common control group in a platform trial can be viewed as a gift and a curse, and choosing whether to implement a platform trial or a more standard development program is complex since it is contingent on numerous factors that are disease and context dependent. To make such a decision, a clear framework needs to be implemented. Decision-making in the pharmaceutical industry is becoming increasingly more quantitative, and in practice, both development approaches would be compared according to a series of standard metrics, including <blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;">(1) duration of the clinical program;</blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;">(2) cost and expected reward of the clinical program;</blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;">(3) flexibility of the clinical program (eg, reporting of the analyses corresponding to the different treatments while maintaining data and trial integrity, ability to add sites, and so forth); (4) probability of success for each treatment, for all treatments, or for at least 1 treatment, assuming all or some of the treatments have a certain efficacy;</blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;">(5) probability of (multiple) false-positive findings (eg, achieving statistical significance) for each treatment or for at least 1 treatment, assuming all or some of the treatments are comparator-like; and</blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;">(6) the extent to which a positive readout informs the success of potential subsequent trials and the ability to de-risk the next phase of development. </blockquote>Using these metrics, governance boards would then make their decisions on whether to progress developing a treatment according to a range of diverse considerations, such as portfolio opportunities and investment priorities."</blockquote><br /></div></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com2tag:blogger.com,1999:blog-15654301.post-33573437510726180002023-08-01T00:00:00.001-04:002023-08-01T00:00:00.148-04:00Mediation Analysis vs. Landmark Analysis for Clinical Trial DataMediation analysis and Landmark analysis are two valuable statistical tools in different contexts, providing insights into different aspects of data analysis. Both methods can be utilized to investigate if a surrogate endpoint or short-term measure can predict the long-term clinical endpoint or to investigate if short-term measures can be mediators for the long-term clinical endpoint. Both mediation analysis and landmark analysis are useful tools for post-hoc, exploratory analyses, but not the primary analysis method for the primary efficacy endpoint. <div><b><br /></b></div><b>Mediation analysis</b> is a statistical method used to explore and understand the mechanism or process through which an independent variable influences a dependent variable. It helps to determine whether the effect of an independent variable on a dependent variable is mediated (i.e., transmitted through) one or more intermediate variables, often referred to as mediators. <br /><br />In mediation analysis, the main focus is on understanding the causal chain of relationships between variables. It involves three key components: <br /><ul style="text-align: left;"><li>Independent variable (X): The variable that is hypothesized to influence the dependent variable directly or indirectly through one or more mediators. </li><li>Mediator (M): The variable(s) that mediates the relationship between the independent variable and the dependent variable. It explains how and why the independent variable affects the dependent variable.</li><li>Dependent variable (Y): The variable that is influenced by the independent variable either directly or indirectly through the mediators.</li></ul>The analysis aims to estimate the direct effect of the independent variable on the dependent variable and the indirect effect mediated through the mediator(s). Several statistical techniques can be used for mediation analysis, such as regression-based methods (e.g., ordinary least squares regression) or more advanced methods like structural equation modeling.<div><br /></div><div>In our published paper "<a href="https://www.sciencedirect.com/science/article/pii/S105324982202071X?via%3Dihub" target="_blank">Contemporary risk scores predict clinicalworsening in pulmonary arterial hypertension - Ananalysis of FREEDOM-EV</a>", mediation analysis was used to test the
hypothesis that improvements in risk score (a surrogate endpoint) contributed to reduced likelihood for clinical worsening (a long-term clinical endpoint). </div><div> <div>In a paper by Blette et al, "<a href="https://www.sciencedirect.com/science/article/abs/pii/S2213260023001558" target="_blank">Is low-risk status a surrogate outcome in pulmonary arterialhypertension? An analysis of three randomised trials </a>", the mediation analysis was used to investigate surrogacy. The author stated:</div><div><blockquote>"we performed a mediation analysis considering
each candidate surrogate as an intermediate outcome. To avoid inconsistent mediation (ie, when direct and
indirect effects cancel each other out, the direct effect is
even larger than the total effect, or other situations that
can result in a negative proportion mediated), we first
empirically tested four criteria to justify the mediation
analysis. Next, Cox proportional hazards
models were fit for the clinical worsening and survival
outcomes conditional on each candidate surrogate
separately, as well as treatment, corresponding baseline
risk score, and a fixed effect variable with three levels for trial membership (to allow for similarity within each
trial). Results from these models were combined with
parallel models that did not condition on the candidate
surrogates, but otherwise conditioned on the same set of
variables to perform the difference method for
mediation, estimating the total effect and direct effects
of treatment on clinical worsening and survival, as well
as the indirect effects through each candidate surrogate.
The proportion of the effect mediated through each
surrogate risk score was estimated, along with 95% CIs
via a bootstrap procedure."</blockquote>In a previous post, the mediation analysis was discussed. "<a href="https://onbiostatistics.blogspot.com/2022/08/mediation-analysis-and-sas-causalmed.html" target="_blank">Mediation analysis and SAS CAUSALMED procedure</a>"<p><b>Landmark analysis</b>, also known as landmark survival analysis,
is a statistical method commonly used in survival analysis to investigate the
impact of time-dependent variables on the occurrence of an event of interest.
It allows for the assessment of time-varying effects in longitudinal studies or
clinical trials where the values of variables may change over time.</p></div><div><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">In landmark analysis, the follow-up time is divided into
predefined intervals or "landmarks," and the analysis is performed
separately for each landmark. The key steps in landmark analysis are as
follows:<o:p></o:p></p>
<p class="MsoNormal"></p><ul style="text-align: left;"><li>Define landmarks: Choose specific time points of interest
during the follow-up period.</li><li>Create landmark cohorts: At each landmark, divide the study
population into subgroups based on the status of the time-dependent variable(s)
of interest.</li><li>Analyze survival outcomes: Estimate survival probabilities
or hazard rates for each subgroup defined by the landmark cohorts.</li><li>Compare survival outcomes: Compare the survival outcomes
between the different subgroups to assess the impact of the time-dependent
variable(s) on the event occurrence.</li></ul><o:p></o:p><p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">Landmark analysis allows researchers to capture time-varying
effects and observe how the relationship between variables changes over the
course of a<span face=""Segoe UI",sans-serif" style="color: black; font-size: 13.5pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"> </span>study. It is particularly useful when analyzing
data with time-dependent covariates, treatment interventions, or changes in
exposure levels over time.<o:p></o:p></p><div><div>In a paper by McLaughlin et al "<a href="https://www.jacc.org/doi/epdf/10.1016/j.jacc.2017.12.010" target="_blank">Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality</a>", the landmark analysis was used to assess the impact of morbidity events on the risk of subsequent mortality.</div></div><div><br /></div><div>In a paper by Eisenstein et al "<a href="https://jamanetwork.com/journals/jama/fullarticle/205037" target="_blank">Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation</a>" , landmark analyses were performed to explore the association of extended clopidogrel use and long-term clinical outcomes of patients receiving drug eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease.<br /></div><div><br /></div><div><div>The tutorial paper "<a href="https://www.ahajournals.org/doi/10.1161/CIRCOUTCOMES.110.957951" target="_blank">Landmark Analysis at the 25-Year Landmark Point</a>" by Dr Dafni is a good reference for Landmark analysis. </div></div><div><br /></div>Mediation analysis and Landmark analysis differ in their goals, focus, and types of data they analyze:<br /></div><div><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div><b>Goals:</b> Mediation analysis aims to understand the mechanism or process through which an independent variable influences a dependent variable, exploring direct and indirect effects. Landmark analysis, on the other hand, focuses on assessing time-varying effects and understanding how the occurrence of an event is influenced by time-dependent variables.</div></blockquote><div style="text-align: left;"><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div style="text-align: left;"><b>Focus</b>: Mediation analysis emphasizes identifying mediators that explain the relationship between an independent variable and a dependent variable. Landmark analysis focuses on investigating the impact of time-dependent variables on survival outcomes or event occurrences.</div></blockquote><div style="text-align: left;"><br /><br /></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><div style="text-align: left;"><b>Data:</b> Mediation analysis typically requires cross-sectional or longitudinal data with variables measured at different time points. It is applicable to both continuous and categorical variables. Landmark analysis is commonly used in survival analysis, analyzing time-to-event data, and requires longitudinal data with time-dependent variables.</div></blockquote><div style="text-align: left;"><br />Both mediation analysis and landmark analysis are valuable statistical tools in different contexts, providing insights into different aspects of data analysis. Here is a table to compare the mediation analysis and the landmark analysis generated by ChatGPT, but I added the last row for implementing the mediation and landmark analyses. </div><div style="text-align: left;"><br /></div></div><div style="text-align: left;"><table border="1" cellpadding="0" class="MsoNormalTable" style="border: 1pt solid windowtext; mso-border-alt: solid windowtext .25pt; mso-cellspacing: 1.5pt; mso-yfti-tbllook: 1184; width: 653px;">
<thead>
<tr style="mso-yfti-firstrow: yes; mso-yfti-irow: 0;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-right-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in; text-align: center;"><b><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Aspect<o:p></o:p></span></b></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-right-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in; text-align: center;"><b><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Mediation
Analysis<o:p></o:p></span></b></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in; text-align: center;"><b><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Landmark Analysis<o:p></o:p></span></b></p>
</td>
</tr>
</thead>
<tbody><tr style="mso-yfti-irow: 1;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Statistical Method<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Investigates relationships and
effects between variables<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Analyzes time-varying effects and
event occurrences<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 2;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Time Dependency<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Considers temporal aspect of data<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Accounts for time-varying effects
and changing values over time<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 3;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Causal Inference<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Aims to understand causal chain of
relationships<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Examines impact of time-dependent
variables on event outcomes<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 4;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Focus<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Identifying mediators that explain
relationships<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Assessing time-dependent variables
and event occurrences<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 5;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Variables<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Independent, mediator, and dependent
variables<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Time-dependent variables influencing
event occurrences<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 6;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Data Type<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Cross-sectional or longitudinal with
measured variables<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Longitudinal data with time-dependent
variables<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 7;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Analytical Steps<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Estimating direct and indirect
effects using regression<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Dividing follow-up into landmarks,
comparing survival outcomes<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 8;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .25pt; mso-border-left-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Research Questions<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .25pt; mso-border-left-alt: solid #D9D9E3 .75pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Mechanisms and processes of variable
influence<o:p></o:p></span></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .25pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .75pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Impact of time-dependent variables
on events or survival<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 9; mso-yfti-lastrow: yes;">
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;">Implementation</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><br /></p><p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><br /></p><p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><br /></p>
</td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-bottom-alt: .75pt; mso-border-color-alt: #D9D9E3; mso-border-left-alt: .75pt; mso-border-right-alt: .25pt; mso-border-style-alt: solid; mso-border-top-alt: .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">In SAS, P</span>rocedure CASUALMED allows you to estimate direct and indirect effects using different mediation models. It supports various regression-based mediation approaches, including Sobel, bootstrapping, and Bayesian estimation.</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;">In R, to conduct mediation analysis, the most commonly used package is "mediation." This package provides a comprehensive set of functions to estimate direct and indirect effects in mediation models. It supports various mediation methods, including the causal steps approach, bootstrapping, and structural equation modeling (SEM).</p></td>
<td style="border: 1pt solid rgb(217, 217, 227); mso-border-alt: solid #D9D9E3 .75pt; mso-border-top-alt: solid #D9D9E3 .25pt; padding: 0.75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; margin: 24pt 0in;"><span style="font-family: "Times New Roman",serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">In SAS, Procedures LIFETEST, PHREG, and LIFEREG can all be used. <o:p></o:p></span>You can divide the
follow-up time into landmark intervals and analyze survival outcomes for
different subgroups defined by the landmarks</p>In R, you can utilize the "survival" package, which is widely used for survival analysis. The "survival" package provides functions to handle time-to-event data, perform survival analysis, and estimate survival probabilities. You can divide the follow-up time into landmarks and analyze survival outcomes for different landmark cohorts.<br /><br />
</td>
</tr>
</tbody></table><br /></div><div style="text-align: left;">Personally, I prefer the mediation analysis to the landmark analysis. In the landmark analysis, the subjects who did not reach the landmark timepoint were excluded from the analysis and the analyses are performed on a subset of the overall population - sort of principle stratum. The endpoint measure at the landmark timepoint and whether or not the subjects reach the landmark timepoint itself is meaningful. Excluding it from the analysis is against the intention-to-treatment principle and may cause biases. </div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-46964197077378348662023-07-24T00:00:00.001-04:002023-07-24T00:00:00.129-04:00Win Ratio and its application in clinical trials The win ratio is a method for examining composite endpoints in clinical trials. <a href="https://academic.oup.com/eurheartj/article/33/2/176/439013" target="_blank">It was introduced in 2012 by Dr Pocock</a> and has since been widely adopted in cardiovascular trials. The win ratio accounts for relative priorities of the components and allows the components to be different types of outcomes. The win ratio is calculated by dividing the total number of winners by the total number of losers.<div><br /></div><div>The win ratio was motivated by the <a href="https://assets.researchsquare.com/files/rs-2856514/v1/d38a65af-507d-44d9-a46e-4ff08d68df05.pdf?c=1683707740" target="_blank">Finkelstein–Schoenfeld (FS) test</a>, with the aim of providing an estimate of the treatment effect (the win ratio) and confidence interval, in addition to a P-value. The general principle behind both the Finkelstein-Schoenfeld test and the win ratio is that they are both methods for examining composite endpoints in clinical trials. Win ratio can be considered as a popular name for the Finkelstein-Schoenfeld test. See my previous post "<a href="https://onbiostatistics.blogspot.com/2020/07/finkelstein-schoenfeld-method-win-ratio.html" target="_blank">Finkelstein-Schoenfeld Method, Win Ratio, and Hodges-Lehman Estimates - Statistical Methods Based on All Paired Comparisons</a>". In practice, we may see the terms "Win Ratio test" and "Finkelstein-Schoenfeld test" interchangeably. <br /><br /></div><div>Win Ratio is defined differently than hazard ratio in survival analysis, however, both Win Ratio and Hazard Ratio are important statistical measures used in clinical trials to assess treatment outcomes and compare different treatments. However, they have distinct interpretations and applications, making them suitable for different types of clinical trial data and research questions. Here are comparison table for Win Ratio and Hazard Ratio:<div><br /><table border="1" cellpadding="0" class="MsoNormalTable" style="background: #F7F7F8; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; mso-border-insideh: .25pt solid windowtext; mso-border-insidev: .25pt solid windowtext; mso-cellspacing: 1.5pt; mso-yfti-tbllook: 1184; width: 653px;">
<thead>
<tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; text-align: center;"><b><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Metric<o:p></o:p></span></b></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; text-align: center;"><b><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Win
Ratio<o:p></o:p></span></b></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt; text-align: center;"><b><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Hazard
Ratio<o:p></o:p></span></b></p>
</td>
</tr>
</thead>
<tbody><tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Definition<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Ratio of treatment
success in the experimental group to the control group<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Compares the risk of
an event occurring in the treatment group to the control group over time<o:p></o:p></span></p>
</td>
</tr>
<tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Clinical trial design<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Usually fixed-duration
studies<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Both fixed-duration
studies and event-driven studies<o:p></o:p></span></p>
</td>
</tr>
<tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Endpoint<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Composite endpoint,
all events are considered<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Composite endpoint,
usually time to the first event<o:p></o:p></span></p>
</td>
</tr>
<tr style="height: 158.0pt; mso-yfti-irow: 4;">
<td style="border: solid windowtext 1.0pt; height: 158.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Interpretation<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; height: 158.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Great than 1:
Experimental treatment has higher success rate than control group <o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Equal to 1: Both
groups have the same success rate<br> <o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Less than 1:
Experimental treatment has lower success rate than control group<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; height: 158.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Greater than 1: Higher
risk of event in treatment group<br> <o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Equal to 1: Equal risk
of event in both groups<br> <o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Less than 1: Lower
risk of event in treatment group<o:p></o:p></span></p>
</td>
</tr>
<tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Application<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Non-inferiority or
superiority trials to assess treatment efficacy<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Survival analysis with
time-to-event outcomes (e.g., overall survival, progression-free survival)<o:p></o:p></span></p>
</td>
</tr>
<tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Focus<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Treatment success
rates<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Risk of an event over
time<o:p></o:p></span></p>
</td>
</tr>
<tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Type of Data<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Binary or categorical
data<o:p></o:p></span></p>
</td>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .25pt; padding: .75pt .75pt .75pt .75pt;" valign="bottom">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 24.0pt; margin-left: 0in; margin-right: 0in; margin-top: 24.0pt;"><span style="color: #374151; font-family: "Segoe UI",sans-serif; font-size: 10.5pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">Time-to-event data<o:p></o:p></span></p>
</td>
</tr>
</tbody></table><br />For win-ratio and hazard ratio comparison, please see the article by Ferreira et al "<a href="https://www.sciencedirect.com/science/article/pii/S221317792030202X?via%3Dihub">Use of the Win Ratio in</a> <a href="https://www.sciencedirect.com/science/article/pii/S221317792030202X?via%3Dihub">Cardiovascular Trials</a>".</div><div><br />Win Ratio approach has been used to re-analyze the clinical trials with a composite endpoint (either the primary efficacy or secondary efficacy endpoint). There is a table in <a href="https://academic.oup.com/eurheartj/article/41/46/4391/5903165" target="_blank">Redfors et al 2020 paper</a> that summarized the re-analysis results using the Win Ratio approach. We recently published a paper in Annals of American Thoracic Society "<a href="https://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.202303-229RL" target="_blank">A Novel Approach to Clinical Change Endpoints: A Win Ratio Analysis of the INCREASE Trial</a>" where the Win Ratio approach was used to analyze the secondary efficacy endpoint of clinical worsening events. <br /><br /><div>Win Ratio approach has also been prespecified as the primary analysis method to analyze the clinical trials with composite endpoints. A table in <a href="https://academic.oup.com/eurheartj/article/41/46/4391/5903165" target="_blank">Redfors et al 2020 paper</a> summarized seven different trials including <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1805689" target="_blank">ATTR-ACT,</a> <a href="https://academic.oup.com/eurheartj/article/38/9/648/2726317" target="_blank">Chart-1</a>, and <a href="https://www.sciencedirect.com/science/article/pii/S0002870316301703" target="_blank">TAVR-UNLOAD</a> trials where the Win Ratio approach was listed as the primary analysis method.</div><br />This past week, Biotech company, Bridgebio Pharma announced <a href="https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-announces-consistently-positive-results-phase-3">their phase III study of acoramidis in transthyretin amyloid cardiomyopathy, or ATTR-CM</a>. One of the primary efficacy endpoint is a composite endpoint - a hierarchical combination of 1) all-cause mortality, 2) cumulative frequency of cardiovascular-related hospitalization, 3) change from baseline in NT-proBNP, and 4) change from baseline in 6MWT over a 30-month fixed treatment duration. <a href="https://clinicaltrials.gov/study/NCT03860935" target="_blank">According to clinicaltrials.gov</a>, the composite endpoint is analyzed using the following approach: </div><div><blockquote>Each subject will be compared to every other subject within a stratum over outcomes of all-cause mortality (death due to any cause), cumulative frequency of cardiovascular-related hospitalizations (number of times a subject is hospitalized for cardiovascular-related causes), change from baseline in NT-proBNP, and change from baseline in the total distance walked in 6 minutes (distance in meters).<br /><br />The hierarchical approach with the Finkelstein-Schoenfeld test will be applied and the test recognizes the greater importance of the mortality endpoint. Scores are transformed to -1, 0, +1. The alternative hypothesis is a subject in the acoramidis treatment group will have a greater score than a subject in the placebo group.</blockquote>In <a href="https://investor.bridgebio.com/node/11866/html" target="_blank">the company's presentation slides</a>, results for the primary endpoint and secondary endpoints are listed. The win ratio is listed as 1.8, which indicates 80% more wins in acoramidis treatment group than in the placebo group. </div><div><br /></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgtuchAXrMu1GALSKXCrvSBiRSTAYzSUprfs4bXPO3pqLUs7SiIOuN1ugtbeIxMLQ82TZ9NwyxhZ7vxxVgCRVL4XIWnIhKsTpiYVYUjASHqGtyXN3c0mo1AvdAVlrpi6Wlehfq20PINi3fXf8H-tO6j8ApZ2rfVX42FjFUaHRVWKpLH5mUGEw" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="611" data-original-width="1213" height="312" src="https://blogger.googleusercontent.com/img/a/AVvXsEgtuchAXrMu1GALSKXCrvSBiRSTAYzSUprfs4bXPO3pqLUs7SiIOuN1ugtbeIxMLQ82TZ9NwyxhZ7vxxVgCRVL4XIWnIhKsTpiYVYUjASHqGtyXN3c0mo1AvdAVlrpi6Wlehfq20PINi3fXf8H-tO6j8ApZ2rfVX42FjFUaHRVWKpLH5mUGEw=w620-h312" width="620" /></a></div><br /><br />The win ratio test requires a pairwise comparison (each subject in the treatment group is compared with each subject in the placebo (control) group). The number of pairs is the sample size (n) for the treatment group times the sample size (m) for the placebo group, i.e., n x m pairs. The win ratio test results are largely dependent on the rules or algorithms in determining the win/loss/tie for each individual pair. Therefore, the rules and algorithm need to be pre-specified. For the prospective clinical trials, these rules and algorithms need to be pre-specified in the statistical analysis plan (SAP) and the SAP needs to be submitted to FDA for review to avoid the potential biases or potential impression of biases. </div><div> </div><div><br /><b>References: </b><br /><ul style="text-align: left;"><li>Pocock et al (2012) <a href="https://academic.oup.com/eurheartj/article/33/2/176/439013" target="_blank">The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities</a>.</li><li>Redfors et al, 2020 <a href="https://academic.oup.com/eurheartj/article/41/46/4391/5903165" target="_blank">The win ratio approach for composite endpoints: practical guidance based on previous experience<br /></a></li><li>Ferreira et al (2020) <a href="https://academic.oup.com/eurheartj/article/41/46/4391/5903165" target="_blank">Use of the Win Ratio in Cardiovascular Trials</a></li><li>Maurer et al (2018) <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1805689" target="_blank">Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy</a></li></ul></div></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-22982265216054654922023-07-07T00:00:00.003-04:002023-07-07T00:00:00.149-04:00GCP violation and tampering with evidence<p>Last week, biotech company <a href="https://ir.bioxceltherapeutics.com/news-releases/news-release-details/bioxcel-therapeutics-announces-positive-topline-results" target="_blank">BioXcel reported positive efficacy results</a> of their investigational product Igalmi in the treatment of Alzheimer's Agitation, but the supposed good news was shadowed by data integrity issues. On the same day, the company revealed allegations that an investigator had failed to adhere to trial protocol and was alleged to have fabricated emails to cover their tracks. <br /><br />See the article "<a href="https://www.fiercepharma.com/pharma/bioxcells-potential-episodic-alzheimers-agitation-treatment-marred-missed-trial-protocols" target="_blank">Missed trial protocols, fabricated emails and failed endpoint mar BioXcel's Alzheimer's agitation readout</a>".</p><p>The company filed <a href="https://ir.bioxceltherapeutics.com/static-files/4b36488e-6235-47d6-b793-0bd03ba506fa" target="_blank">Form 8-K</a> and revealed the GCP violation issues. Here are the excerpts from <a href="https://ir.bioxceltherapeutics.com/static-files/4b36488e-6235-47d6-b793-0bd03ba506fa" target="_blank">the SEC filing</a>: </p><p> <b><u> Important Information Regarding TRANQUILITY II Phase 3 Clinical Trial </u></b></p><p></p><blockquote><p>In December 2022, the U.S. Food and Drug Administration (“FDA”) conducted an inspection of one of the clinical trial sites in the Phase 3
TRANQUILITY II clinical trial, where the principal investigator enrolled approximately 40% of the subjects participating in the trial. At the conclusion of
this inspection, the FDA issued an FDA Form 483 identifying three inspectional observations. These observations related to the principal investigator’s
failure to adhere to the informed consent form approved by the Institutional Review Board for a limited number of subjects whose records the FDA
reviewed, maintain adequate case histories for certain patients whose records the FDA reviewed, and adhere to the investigational plan in certain instances.
For example, the FDA cited the principal investigator’s delay in informing the sponsor’s medical monitor or pharmacovigilance safety vendor of a serious
adverse event (“SAE”) for one of the subjects, which report was made to the Company’s vendor outside of the 24 hour time period prescribed by the
clinical trial protocol. The principal investigator for this clinical site responded to the FDA observations within the time period requested. The FDA
inspection remains open, however, as the FDA has not issued an Establishment Inspection Report. </p><p>In May 2023, it came to the Company’s attention that this same principal investigator in the TRANQUILITY II clinical trial may <span style="color: #a64d79;"><u>have fabricated email
correspondence purporting to demonstrate that the investigator timely submitted to the Company’s pharmacovigilance safety vendor a report of an SAE
from a different subject than the one cited in the FDA Form 483, and purporting to show that the vendor had confirmed receipt.</u></span> Upon receipt of this
information, the Company promptly initiated an investigation and recently received confirmation that the principal investigator fabricated the email
correspondence related to the timing of the reporting of this SAE to the Company’s pharmacovigilance vendor to make it appear as though this SAE had
been timely reported to the pharmacovigilance vendor as required by the clinical trial protocol. The Company also confirmed that this SAE had been timely
entered into the electronic data capture system, even though the SAE had not been separately reported to the Company’s pharmacovigilance safety vendor
within the 24 hour timeframe required under the protocol. </p><p>In connection with this ongoing investigation, the Company was made aware that <span style="color: #a64d79;">the fabricated email correspondence was provided to the FDA by the
principal investigator’s employer</span> during the on-site inspection in December 2022. After unblinding of the data, the Company determined that the SAE that
was the subject of this fabricated correspondence between the principal investigator and the Company’s pharmacovigilance vendor occurred in a subject in
the placebo arm. This principal investigator has not participated in any other clinical trial sponsored or conducted by the Company. Moreover, the study
was designed such that trained study staff other than principal investigators were to conduct assessments of the primary efficacy measure.</p></blockquote><p></p><p>In this case, the fabrication of evidence to hide the late reporting of the SAE to the sponsor is far more serious than the late reporting of the SAE itself. The situation is similar to <a href="https://en.wikipedia.org/wiki/Tampering_with_evidence" target="_blank">tampering with evidence</a> and obstruction of justice in the criminal law. </p><p>ICH E6 Good Clinical Practice requires <a href="https://onbiostatistics.blogspot.com/2023/06/sae-reporting-from-non-serious-ae-to.html" target="_blank">the investigational site to report the serious adverse events</a> (SAEs) to the sponsor in a timely manner usually within 24 hours when the site staff become aware of the occurrence of an SAE. Failure to do so will be recorded as a major protocol deviation. </p><p>However, fabricating the evidence to conceal the protocol deviation (late reporting of the SAE) is no longer a GCP compliance issue, it is a scientific misconduct issue. </p>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com1tag:blogger.com,1999:blog-15654301.post-53675002371238084812023-06-26T00:00:00.052-04:002023-06-26T00:00:00.146-04:00Placebo Effect versus Nocebo Effect<div>In placebo-controlled clinical trials, a placebo refers to an inactive or inert substance or treatment that has no specific therapeutic effect on a person's health condition but is given or administered with the intention of maintaining the blinding of the study (i.e., the participants and/or investigators do not know if the active treatment or placebo is given). Placebo can be in the form of a pill (sugar pill), injection, or any other treatment method that resembles a real medical intervention. However, during the clinical trial, the placebo may have a therapeutic effect and have an impact on the outcome measures. </div><div><br /></div>The placebo effect is defined as a beneficial effect experienced by a clinical trial participant due to receiving a placebo (inactive substance) believing it to be an active treatment. The placebo effect has been discussed quite extensively in the literature. I posted several articles to discuss the placebo effect in placebo-controlled clinical trials. <a href="https://onbiostatistics.blogspot.com/2019/01/placebo-effect-honest-placebo-open.html"></a><ul style="text-align: left;"><a href="https://onbiostatistics.blogspot.com/2019/01/placebo-effect-honest-placebo-open.html"></a><li><a href="https://onbiostatistics.blogspot.com/2019/01/placebo-effect-honest-placebo-open.html"></a><a href="https://onbiostatistics.blogspot.com/2019/01/placebo-effect-honest-placebo-open.html">Placebo Effect, Honest Placebo, Open-label Placebo</a></li><li><a href="https://onbiostatistics.blogspot.com/2022/08/placebo-effect-and-its-impact-on.html">Placebo effect and its impact on the overall treatment effect</a></li><li><a href="https://onbiostatistics.blogspot.com/2016/05/placebo-effect-and-choice-of-placebo.html">Placebo Effect and The Choice of Placebo</a></li></ul><div>Now there is a term 'nocebo effect' (it is not a typo). In a newly released draft guidance by FDA "<a href="https://www.fda.gov/drugs/news-events-human-drugs/our-perspective-importance-physical-characteristics-generic-drugs" target="_blank">Psychedelic Drugs: Considerations for Clinical Investigations</a>", the 'nocebo effect' is specifically mentioned: </div><div><blockquote>An AWC study uses a design that permits a valid comparison with a control to
provide a quantitative assessment of a drug’s effect. In the context of psychedelic drug development, the use of a traditional placebo as a control can be problematic for assessing efficacy. <u>Subjects receiving an active drug experience functional unblinding because of the intense perceptual disturbances that can develop; those who receive a placebo in the context of high expectancy may experience a <span style="color: #cc0000;">nocebo effect</span> (i.e., worsening symptoms as a result of knowing they did not get active treatment).</u> However, an inactive control allows for better contextualization of any safety findings. Alternatives to an inert placebo (e.g., subperceptual doses of a psychedelic drug, other psychoactive drugs that mimic some aspects of the psychedelic experience) may be considered as well. </blockquote></div><div>The nocebo effect is defined as a negative effect experienced by a clinical trial participant due to receiving a placebo (inactive substance) believing it to be a harmful treatment. With the help of the ChatGPT, the following table compared the differences between the placebo effect and the nocebo effect. </div><div><br /></div><div><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr>
<td style="background: #BFBFBF; border: solid windowtext 1.0pt; mso-background-themecolor: background1; mso-background-themeshade: 191; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><b><span style="font-size: 12pt;">Aspect</span></b><b><span style="font-size: 12.0pt;"><o:p></o:p></span></b></p>
</td>
<td style="background: #BFBFBF; border-left: none; border: solid windowtext 1.0pt; mso-background-themecolor: background1; mso-background-themeshade: 191; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><b><span style="font-size: 12pt;">Placebo Effect </span></b><b><span style="font-size: 12.0pt;"><o:p></o:p></span></b></p>
</td>
<td style="background: #BFBFBF; border-left: none; border: solid windowtext 1.0pt; mso-background-themecolor: background1; mso-background-themeshade: 191; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><b><span style="font-size: 12pt;">Nocebo Effect</span></b><b><span style="font-size: 12.0pt;"><o:p></o:p></span></b></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Definition <o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">A positive
response to an inactive treatment, often due to the person's belief in the
treatment's effectiveness.<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">A negative
response to a treatment, often due to the person's belief that the treatment
will cause harm or have adverse effects.<o:p></o:p></p>
</td>
</tr>
<tr style="height: 48.1pt; mso-yfti-irow: 2;">
<td style="border-top: none; border: solid windowtext 1.0pt; height: 48.1pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Psychological
Mechanisms<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; height: 48.1pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Expectation
of improvement, conditioning, and the power of suggestion.<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; height: 48.1pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Expectation
of harm, conditioning, and the power of suggestion.<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Potential
Chemical Mechanisms<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Belief and
expectation trigger the release of endorphins, dopamine, and other
neurochemicals, leading to perceived improvement in symptoms.<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Belief and
expectation trigger the release of stress hormones (e.g., cortisol) and
activate the brain’s pain pathways, leading to perceived worsening of
symptoms.<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Common
Occurrences<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">In clinical
trials, as a control group receiving an inactive treatment (e.g., sugar
pill).<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">In clinical
trials, when participants experience side effects despite receiving an inactive
treatment, or when they're informed about potential side effects<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Impact on
Treatment<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Can lead to
an actual improvement in symptoms or a perceived improvement in well-being<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Can cause or
exacerbate symptoms, leading to a perceived worsening of health<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Importance in
Research<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Helps
determine the true efficacy of a treatment by comparing it to the placebo
group<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Highlights
the importance of considering participants' expectations and beliefs when
designing and interpreting clinical trials.<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Clinical Use<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Utilized in
clinical trials as a control to assess the effectiveness of new treatments.<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Considered a
challenge in clinical trials as it can lead to false negative outcomes or
increased reports of adverse effects.<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Impact on Clinical
Trial Outcome<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Making the outcome
measures in placebo group artificially better than what they should be.<o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Underestimating
the treatment difference. Lowering the statistical power.</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Making the
outcome measures in placebo group artificially worse than what they should
be. <o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">On the efficacy side, overestimate the
treatment difference. Increasing the statistical power.</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Ethical
Considerations<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">May be
considered deceptive if participants are not informed about the possibility
of receiving a placebo<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Raises
questions about the balance between informing participants of potential side
effects and avoiding the creation of negative expectations<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 116.75pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Examples<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 2.5in;" valign="top" width="240">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">- Feeling
relief from pain after taking a sugar pill, believing it to be a painkiller. <o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">-
Experiencing reduced anxiety after receiving a fake treatment, thinking it is
an anti-anxiety medication.<o:p></o:p></p>
</td>
<td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 170.75pt;" valign="top" width="228">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">- Developing
side effects (e.g., nausea, dizziness) after taking a harmless sugar pill,
convinced it is a potent medication. <o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">- Perceiving
worsening of symptoms despite receiving an inert substance, assuming it is a
harmful treatment.<o:p></o:p></p>
</td>
</tr>
</tbody></table></div><p>References: </p><ul style="text-align: left;"><li>Wartolowska, Colloca, and Amandzio (2023) <a href="https://www.frontiersin.org/articles/10.3389/fpsyg.2022.1111324/full" target="_blank">Editorial: The nocebo effect and its consequences for clinical trials and clinical practice</a></li><li>Colloca and Barsky (2020) <a href="https://www.nejm.org/doi/full/10.1056/NEJMra1907805" target="_blank">Placebo and Nocebo Effects</a></li><li>Colloca and Miller (2011) <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167012/pdf/nihms312016.pdf">The nocebo effect and its relevance for clinical practice</a></li><li>Ferreres, Banos, and Farre (2004)<a href="https://pubmed.ncbi.nlm.nih.gov/15104949/" target="_blank">Nocebo effect: the other side of placebo</a>.</li><li>Mitsikostas (2009) <a href="https://pubmed.ncbi.nlm.nih.gov/21216874/" target="_blank">Nocebo is the enemy, not placebo. A meta-analysis for the nocebo effect in headaches</a></li><li>Amanzio, Corazzini, Vase, & Benedetti (2016). <a href="https://pubmed.ncbi.nlm.nih.gov/19781854/" target="_blank">A systematic review of adverse events in placebo groups of anti-migraine clinical trials</a>. </li><li>Wolters, Peerdeman, and Evers (2019) <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614509/" target="_blank">Placebo and Nocebo Effects Across Symptoms: From Pain to Fatigue, Dyspnea, Nausea, and Itch</a></li><li>Hoffman, et al (2022) <a href="https://www.nature.com/articles/s41598-022-21434-7" target="_blank">Vaccine hesitancy prospectively predicts nocebo side-effects following COVID-19 vaccination</a></li></ul><div><br /></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-70903334542041401852023-06-21T05:00:00.001-04:002023-06-21T05:00:00.163-04:00SAE reporting - from non-serious AE to serious AE - one event or two events?<p>An adverse event is any undesirable experience associated
with the use of a medical product in a patient. The event is serious (therefore
serious adverse event (SAE)) and should be reported when the patient outcome
is:</p><p class="MsoNormal"><o:p></o:p></p>
<blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><p class="MsoNormal"><b>Death</b></p><p class="MsoNormal">Report if you suspect that the death was an outcome of the
adverse event, and include the date if known. </p><p class="MsoNormal"><b>Life-threatening</b></p><p class="MsoNormal">Report if suspected that the patient was at substantial risk
of dying at the time of the adverse event, or use or continued use of the
device or other medical product might have resulted in the death of the
patient.</p><p class="MsoNormal"><b>Hospitalization (initial or prolonged)</b></p><p class="MsoNormal">Report if admission to the hospital or prolongation of
hospitalization was a result of the adverse event.</p><p class="MsoNormal">Emergency room visits that do not result in admission to the
hospital should be evaluated for one of the other serious outcomes (e.g.,
life-threatening; required intervention to prevent permanent impairment or
damage; other serious medically important event).</p><p class="MsoNormal"><b>Disability or Permanent Damage</b></p><p class="MsoNormal">Report if the adverse event resulted in a substantial disruption
of a person's ability to conduct normal life functions, i.e., the adverse event
resulted in a significant, persistent or permanent change, impairment, damage
or disruption in the patient's body function/structure, physical activities
and/or quality of life.</p><p class="MsoNormal"><b>Congenital Anomaly/Birth Defect</b></p><p class="MsoNormal">Report if you suspect that exposure to a medical product
prior to conception or during pregnancy may have resulted in an adverse outcome
in the child.</p><p class="MsoNormal"><b>Required Intervention to Prevent Permanent Impairment or
Damage (Devices)</b></p><p class="MsoNormal">Report if you believe that medical or surgical intervention
was necessary to preclude permanent impairment of a body function, or prevent
permanent damage to a body structure, either situation suspected to be due to
the use of a medical product.</p><p class="MsoNormal"><b>Other Serious (Important Medical Events)</b></p><p class="MsoNormal">Report when the event does not fit the other outcomes, but
the event may jeopardize the patient and may require medical or surgical
intervention (treatment) to prevent one of the other outcomes. Examples include
allergic brochospasm (a serious problem with breathing) requiring treatment in
an emergency room, serious blood dyscrasias (blood disorders) or
seizures/convulsions that do not result in hospitalization. The development of
drug dependence or drug abuse would also be examples of important medical
events.</p></blockquote><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">In clinical trial setting, there are two layers of SAE
reporting: <o:p></o:p></p>
<p class="MsoNormal"><b>The investigational site reports the SAE to the trial
sponsor: </b><o:p></o:p></p><p class="MsoNormal">According to ICH E6 (Good Clinical Practice), the SAEs should be reported immediately to the sponsor when the site staff become aware of the occurrence of a SAE. 'Reported immediately' is generally interpreted as 'reported within 24 hours'. The clinical trial protocol typically includes a statement "Sites must report SAE information regardless of causality or expectedness to the Sponsor within 24 hours of awareness of an SAE." </p><p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEg9SssFJ1C8iUagqG0p51VocgGKLWDxfs-WHtwIrDbfFygtqVzYTfllowsvzClWyiYjh6W5ci44Qpfcm8FLsm12U22QuN5cZbpJipWSKeZH50j_svdMqTm0SgUHW1ZQjJZ0mPNbATQe4lRgPMru3jFUFuJyceXkOaH7uepqrvAxf2sKEWnxrQ" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="333" data-original-width="640" height="309" src="https://blogger.googleusercontent.com/img/a/AVvXsEg9SssFJ1C8iUagqG0p51VocgGKLWDxfs-WHtwIrDbfFygtqVzYTfllowsvzClWyiYjh6W5ci44Qpfcm8FLsm12U22QuN5cZbpJipWSKeZH50j_svdMqTm0SgUHW1ZQjJZ0mPNbATQe4lRgPMru3jFUFuJyceXkOaH7uepqrvAxf2sKEWnxrQ=w592-h309" width="592" /></a></div><br /><b>The sponsor or designee reports the SAEs and SUSAR to the regulatory authorities (FDA):</b><p></p>SAEs need to be reported to regulatory agencies and IRBs/ECs in narrative format (so called SAE narratives). According to 21CRF part 312.32 Safety Reporting, here are the requirements:<div><br /><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEifj3cVWxngWIyxKf_6RIUECRRe2drwOTcucVEY6xSS5RNjDXJs9gXb_zoEvRXZAwfYyLMMMYnJoBo2IilwkwhTGSeByz4J8vnN4fECWtBOCqwU0-pWBT-SAvMyxwMcILM6C_AbS7UO4Bg_SXZKiAFPWg5gd7NjlJUUCDOxNbSigeAXZ3VG8w" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="217" data-original-width="738" height="196" src="https://blogger.googleusercontent.com/img/a/AVvXsEifj3cVWxngWIyxKf_6RIUECRRe2drwOTcucVEY6xSS5RNjDXJs9gXb_zoEvRXZAwfYyLMMMYnJoBo2IilwkwhTGSeByz4J8vnN4fECWtBOCqwU0-pWBT-SAvMyxwMcILM6C_AbS7UO4Bg_SXZKiAFPWg5gd7NjlJUUCDOxNbSigeAXZ3VG8w=w667-h196" width="667" /></a></div><br /><div><div>SUSUR stands for serious and unexpected suspected adverse reaction. FDA guidance "<a href="https://www.fda.gov/files/drugs/published/Safety-Reporting-Requirements-for-INDs-%28Investigational-New-Drug-Applications%29-and-BA-BE-%28Bioavailability-Bioequivalence%29-Studies.pdf" target="_blank">Safety Reporting Requirements for INDs and BA/BE Studies</a>" provided the definition for SUSAR and specified the reporting requirement. <p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjtcvtj75zO26DtrCPU3Gg4UAN5Zr8wcQwq6xa7KcTiva79uATCGJ7qD0HRUgY1nC6QQCM1E1vaHfLF0k3mLPAMeA5culPkDTb5Qxx49ZQmaQ_vlDTUTavBFhoiey7XeJ4lKMoIO3kRDGHgDjTRQdlJwhkVZyyoBitjHlKWebQYxEuOe-6vYg" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="193" data-original-width="623" height="181" src="https://blogger.googleusercontent.com/img/a/AVvXsEjtcvtj75zO26DtrCPU3Gg4UAN5Zr8wcQwq6xa7KcTiva79uATCGJ7qD0HRUgY1nC6QQCM1E1vaHfLF0k3mLPAMeA5culPkDTb5Qxx49ZQmaQ_vlDTUTavBFhoiey7XeJ4lKMoIO3kRDGHgDjTRQdlJwhkVZyyoBitjHlKWebQYxEuOe-6vYg=w585-h181" width="585" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEg61aLT9_OMv36V90XHe3kP1XXGpxfFtkNS1XQrjee-OaFfqTtFIOzF65OuGwanHD4RGnj6xvef-CS1yr9Uq2KsPQFwZ8uV0IedF1UbEdn9JLKHyHOabIVEI3_PQvehTqDeAMRij_G8BBdHpYUx2YdXYac51S2qORnXgzWRSRES03eq_U80Pw" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="318" data-original-width="624" height="291" src="https://blogger.googleusercontent.com/img/a/AVvXsEg61aLT9_OMv36V90XHe3kP1XXGpxfFtkNS1XQrjee-OaFfqTtFIOzF65OuGwanHD4RGnj6xvef-CS1yr9Uq2KsPQFwZ8uV0IedF1UbEdn9JLKHyHOabIVEI3_PQvehTqDeAMRij_G8BBdHpYUx2YdXYac51S2qORnXgzWRSRES03eq_U80Pw=w569-h291" width="569" /></a></div><br />SUSAR determination and subsequent reporting are typically handled by the drug safety or pharmacovigilance group, which has access to treatment assignment information. When a SUSAR event is reported, the drug safety or pharmacovigilance group may unblind the individual subject to determine if they are in the active drug group or the placebo group. If the subject is in the placebo group, it will not be considered a SUSAR.<br /><br />SUSAR events that involve unexpected fatal or life-threatening suspected adverse reactions must be reported to the FDA within 7 days through the submission of a "7-day IND safety report." Here is what is said in <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32" target="_blank">21CFR part 312.32 IND Safety Reporting</a>:<div><br /></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEi7YyQTLp0gk3FCrI_YX-Uf1xC4cfi1c5qsmPXrR2X5zhmwyXTuZVNmSdaftxesl8drR12r-KSWZW6B8AlI7Vv79LjK0JEvAzujYo5gJFUDGUxEwRc5UTLW_v3SxNaiRbrCRNRYvVpjvZbnF689XnXhWR6rK9kzE8W4akjRWSGHX8OLu3Dj2A" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="70" data-original-width="748" height="62" src="https://blogger.googleusercontent.com/img/a/AVvXsEi7YyQTLp0gk3FCrI_YX-Uf1xC4cfi1c5qsmPXrR2X5zhmwyXTuZVNmSdaftxesl8drR12r-KSWZW6B8AlI7Vv79LjK0JEvAzujYo5gJFUDGUxEwRc5UTLW_v3SxNaiRbrCRNRYvVpjvZbnF689XnXhWR6rK9kzE8W4akjRWSGHX8OLu3Dj2A=w665-h62" width="665" /></a></div><br /><br /></div><div>In practice, it is common for adverse events to initially present as non-serious (not meeting the criteria for defining a serious adverse event), but with the event worsening, they may evolve into a serious adverse event. For example, a subject may experience an adverse event that eventually requires hospitalization, meeting the criteria for a serious adverse event.<br /><br />There is a common (but inappropriate) approach to handling this situation by splitting the event into two separate entries: one for the initial non-serious adverse event and another for the subsequent serious adverse event. Some sponsors provide instructions to record the non-serious adverse event with a stop date, mark the outcome as 'Not recovered/not resolved,' and create a new entry for the serious adverse event with the start date when the seriousness criteria are met. The stop date of the non-serious adverse event should be the same date or the day prior to the start date of the serious adverse event. While this approach aligns with SAE reporting and is considered conservative, it artificially divides the same episode into two separate events, which will cause the problem when writing the SAE narratives. We can not just write a SAE narrative without including the non-serious part - they are essentially the same event. <br /><div><br />In general, when an adverse event initially presents with non-serious symptoms and later progresses to meet the criteria for a serious adverse event (SAE), it is typically reported once as an SAE. This is because the serious adverse event designation takes precedence over the non-serious symptoms.<br /><br />It's important to note that the onset date of the SAE should be the date when the symptoms started, not the date when the SAE criteria are met. Reporting of SAEs should be based on the date when the SAE criteria are met and when the site staff becomes aware of the SAE.<br /><br />In situations where an adverse event starts as non-serious and progresses to serious, it is appropriate to report the event as an SAE.<div><br /></div><div>When an adverse event evolves into a serious condition, such as requiring hospitalization or meeting other predefined criteria for seriousness, it is considered a new phase or stage of the same event. Reporting it as an SAE captures the escalated severity and ensures appropriate attention, monitoring, and reporting to regulatory authorities.</div><br /><br />When an adverse event (AE) starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). In this situation, there are three potentially relevant dates: the "serious adverse event start date," "adverse event becomes serious," and "the site staff became aware of the serious adverse event." These terms are associated with the reporting and monitoring of adverse events in clinical trials or medical research. Here's a comparison of these terms:<br /><br /></div></div></div></div></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div><div><div><div><div><div><b>Serious Adverse Event Start Date:</b> The serious adverse event start date refers to the specific date when an adverse event initially occurred or began in a participant during a clinical trial or medical research study. It marks the beginning of the event's timeline and is often recorded to establish the temporal relationship between the event and the study procedures.</div></div></div></div></div></div></blockquote><div><div><div><div><div><div><br /></div></div></div></div></div></div><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><div><div><div><div><div><div style="text-align: left;"><b>Adverse Event Becomes Serious:</b> An adverse event refers to any unfavorable or undesirable medical occurrence experienced by a participant during a clinical trial or medical research study, regardless of its seriousness. When an adverse event becomes serious, it means that the event has worsened in intensity, severity, or clinical impact. The criteria for determining whether an adverse event is considered serious may vary, but they generally include outcomes such as death, life-threatening situations, hospitalization or prolonged hospital stay, significant disability, congenital anomalies, or other important medical events.</div></div></div></div></div></div></blockquote><div><div><div><div><div><div><br /></div></div></div></div></div></div><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><div><div><div><div><div><div style="text-align: left;"><b>The Site Staff Became Aware of the Serious Adverse Event:</b> This phrase signifies the point at which the staff at the clinical trial site or research facility becomes aware of the occurrence of a serious adverse event in a participant. It is crucial to promptly report and document the event to ensure participant safety and adhere to regulatory requirements. The site staff's awareness triggers subsequent actions such as assessment, documentation, reporting to the appropriate authorities, and potential modifications to the study protocol or participant management.</div></div></div></div></div></div></blockquote><div><div><div><div><div><div><br />In summary, when an adverse event starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). The serious adverse event start date marks the initial occurrence of the event, while the "adverse event becomes serious" indicates the worsening of its intensity or impact. The "site staff became aware of the serious adverse event" signifies the point when the research facility staff acknowledges the occurrence and initiates the necessary actions for reporting and participant safety.<br /><div></div></div></div></div></div></div></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com1tag:blogger.com,1999:blog-15654301.post-70895810023120932872023-06-17T17:00:00.002-04:002023-06-18T07:19:48.026-04:00Regulatory Education for Industry (REdI) Annual Conference 2023 - Slides and Recordings Early this month, FDA conducted 'Regulatory Education for Industry (REdl) Annual Conference 2023'. This annual conference provided opportunity for health care industry professionals to Learn directly from the FDA’s regulatory experts in medical product centers: drugs, devices, and biologics. The course from annual conference is designed to provide participants with a strong, basic foundation in the FDA’s regulatory requirements, and also create awareness of current activities.<div><ul style="text-align: left;"><li>The flyer about this conference: <a href="https://www.fda.gov/drugs/news-events-human-drugs/regulatory-education-industry-redi-annual-conference-2023-06052023">https://www.fda.gov/drugs/news-events-human-drugs/regulatory-education-industry-redi-annual-conference-2023-06052023</a></li><li>The agenda for the conference: <a href="https://sbiaevents.com/files2023/REdI-2023-Agenda.pdf">https://sbiaevents.com/files2023/REdI-2023-Agenda.pdf</a></li></ul><div><p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman";">All the FDA presentation can be watched on Youtube and the presentation slides are listed in the tables. </span></p><p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman";">There are two presentations by FDA statisticians: Dr Andrew Potter on "</span><a href="https://www.dropbox.com/s/29nys03uxu78hn2/D1S12-Potter.pdf?dl=0" target="_blank">Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials</a>" and Dr John Scott on "<a href="https://www.dropbox.com/s/sya50gonbeqfb62/D5S05-Scott.pdf?dl=0" target="_blank">FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program</a>".</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><b>Plenary +
Drugs Day 1:</b></p></div></div><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><div><div style="text-align: left;"><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/usos9dummbshysd/D1S02-Plenary.pdf?dl=0" target="_blank">User Fee Impact on FDA Programs</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Jeff Shuren,
Patrizia Cavazzoni, Peter Marks<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/3glx1cqyuuzsrt2/D1S03-Ricci-Maxfield.pdf?dl=0" target="_blank">Biosimilar Program Updates and What’s New Under BsUFA III</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Stacey Ricci
and Kimberly Maxfield<o:p></o:p></p>
</td>
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<tr>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/3glx1cqyuuzsrt2/D1S03-Ricci-Maxfield.pdf?dl=0" target="_blank">FDA Formal Meetings: What’s New under PDUFA, BsUFA, and OMUFA</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Elizabeth
Thompson<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/c4ksbkilt5s6meo/D1S07-Bernhardt.pdf?dl=0" target="_blank">Electronic Submission Gateway (ESG): The Road to Modernization</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Jessica
Bernhardt<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/lsbj8xyt1jtchyp/D1S08-Resnick.pdf?dl=0" target="_blank">ECTD v4.0 Implementation Update</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Jonathan
Resnick<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/7a72cg3j0zkp7zj/D1S09-Crandall.pdf?dl=0" target="_blank">eCTD: More than a Document</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Heather
Crandall<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/ex6ez05kq2iworl/D1S11-Wang.pdf?dl=0" target="_blank">CDER-CBER Data Standards Program</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Ray Wang<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/29nys03uxu78hn2/D1S12-Potter.pdf?dl=0" target="_blank">Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Andrew Potter<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/4scnp63jh7rvzwh/D1S13-Slack.pdf?dl=0" target="_blank">PDUFA VII Goals For Digital Health Technologies – A Technical Perspective</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Marry Ann
Slack<o:p></o:p></p>
</td>
</tr>
</tbody></table></div></div></blockquote><div><div>
<div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen="" class="BLOG_video_class" height="266" src="https://www.youtube.com/embed/5b8CUs_mlrs" width="320" youtube-src-id="5b8CUs_mlrs"></iframe></div><div class="separator" style="clear: both; text-align: center;"><br /></div><br /><p class="MsoNormal"><b>Drugs Day 2:</b> </p></div></div><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><div><div style="text-align: left;"><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/o434n4pt3ajs99u/D2S01-Lal.pdf?dl=0" target="_blank">Leveraging Small Business and Industry Assistance (SBIA) Resources</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Renu Lal</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/shod4alhwp0fmuv/D2S02-Schnupp.pdf?dl=0" target="_blank">Overview of FDA Split Real Time Application Review (STAR) Pilot Program</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">LaShawn Schnupp</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/ndlyvdrjd8l8hca/D2S03-Sterrett.pdf?dl=0" target="_blank">Use-Related Risk Analysis (URRA) and Human Factors (HF) Protocol Reviews: What to Submit for an Efficient Review</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Lolita
Sterrett</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/1o323vejxzjvkc4/D2S05-Kunkoski.pdf?dl=0" target="_blank">The Modernization of Clinical Trials through Digital Health Technologies (DHTs), Decentralized Clinical Trials (DCTs), and Point of Care Trials</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Elizabeth
Kunkoski</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/jntlufyrpy9ymys/D2S06-Smith.pdf?dl=0" target="_blank">PDUFA VII Real-World Evidence</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Kimberly A.
Smith</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/xs8enp8f4unl71f/D2S09-Weil.pdf?dl=0" target="_blank">
New PDUFA VII
Commitments: Pre-approval & Post-approval Postmarketing Requirements
(PMRs)</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Kathleen Weil</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
How CDER is
Accelerating Rare Disease Cures and the PDUFA VII Rare Disease Endpoints
Advancement Pilot Program<br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Kerry Jo Lee</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/73ur4bxf8z7gcs0/D2S11-Patel.pdf?dl=0" target="_blank">Chemistry, Manufacturing, and Controls Assessment for Expedited Programs</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Paresma Patel</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/gvdkfrbhgolgd8o/D2S13-Chin.pdf?dl=0" target="_blank">Best Practices for Drug Product Recalls</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Doris Chin</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
</tbody></table></div></div></blockquote><div style="text-align: left;"><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen="" class="BLOG_video_class" height="266" src="https://www.youtube.com/embed/giuVD6Yk7pk" width="320" youtube-src-id="giuVD6Yk7pk"></iframe></div><br /><p></p>
<p class="MsoNormal"><br /></p>
<p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman";"><b>Devices Day 1:</b></span></p></div><blockquote style="border: none; margin: 0 0 0 40px; padding: 0px;"><div style="text-align: left;"><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/7n2fs7vrtyem0ar/D3S01-Holter.pdf?dl=0" target="_blank">Medical Device Regulatory Framework: Where to Start?</a></p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Kendra Holter</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/nc5jpwiz363k2ct/D3S02-Goode.pdf?dl=0" target="_blank">Biocompatibility Basics</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Jennifer
Goode</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/5u6ty1og2ve2oe2/D3S03-Colburn.pdf?dl=0" target="_blank">Streamlining Conformity Assessment: Putting Standards to Work</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Scott A.
Colburn</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/mhjs38bo0lotihk/D3S04-Sprau.pdf?dl=0" target="_blank">Detangling the 510(k) Process</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Andrew Sprau</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/it5fo2ceii77lre/D3S06-Anderson.pdf?dl=0" target="_blank">CDRH Portal Overview and Feature Walkthrough</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Nelson
Anderson</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/ns3c9adqins2j6i/D3S07-Brookbank.pdf?dl=0" target="_blank">Reduced Medical Device User Fees: Small Business Determination (SBD) Program</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Jason
Brookbank</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/bcd8q4n7nka558o/D3S09-Bediakoh.pdf?dl=0" target="_blank">Managing Medical Device Nonconforming Product with Quality</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Ruth Bediakoh</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/jw919m2cenn9g7m/D3S10-Wilbon.pdf?dl=0" target="_blank">Handling Medical Device Compliant Files with Quality</a><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Tonya Wilbon</p><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"></td></tr><tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><br /><p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p></o:p></p>
</td>
</tr>
</tbody></table></div></blockquote><div><div><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen="" class="BLOG_video_class" height="266" src="https://www.youtube.com/embed/cjw_q6QL1W4" width="320" youtube-src-id="cjw_q6QL1W4"></iframe></div><span style="mso-fareast-font-family: "Times New Roman";"><br />
<br /><b>Devices
Day 2/Biologics Day 1:</b></span></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div><div><span style="mso-fareast-font-family: "Times New Roman";"><b><br /></b></span></div></div><div><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr>
<td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<a href="https://www.dropbox.com/s/74498ifhbmcm47a/D4S01-Gossman.pdf?dl=0" target="_blank">Addressing Regulatory Science Gaps in Artificial Intelligence (AI) / Machine Learning (ML)</a><br />
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Alexej
Gossmann<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<a href="https://www.dropbox.com/s/b2cyzu3lbfr9ukj/D4S02-Burk.pdf?dl=0" target="_blank">Radiation-Emitting Medical Device Update</a><br />
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Laurel Burk<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<a href="https://www.dropbox.com/s/vbxj7kpf5d6k2h1/D4S03-Montes.pdf?dl=0" target="_blank">CDRH Medical Device Import Overview</a><br />
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Yvette Montes<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<a href="https://www.dropbox.com/s/g91h9ayw0bfo2xm/D4S04-Chang.pdf?dl=0" target="_blank">All about the Form FDA 483 and the ORA Electronic Reading Room</a><br />
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">William Chang<o:p></o:p></p>
</td>
</tr>
<tr>
<td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/uaaxbilskyklopb/D4S07-Miller.pdf?dl=0" target="_blank">PDUFA VII Enhancements - Interaction with OTP</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Mara Miller<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/q2km1zlvvsa9gs7/D4S08-Hornatko-Munoz.pdf?dl=0" target="_blank">Overview of PREA, PSPs plus an Introduction to the Rare Pediatric Disease (RPD) Priority Review Voucher Program</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Adrienne
Hornatko-Munoz<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/pkbnrcowzit31y7/D4S09-Moreira.pdf?dl=0" target="_blank">Nonclinical Development for Cellular and Gene Therapy Products from the Perspective of CBER/FDA</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Ernesto F.
Moreira<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/ro96rvtdjj7pxfp/D4S10-Conway.pdf?dl=0" target="_blank">Nonclinical Considerations for the Development of Cell and Gene Therapy Products for IND Submissions</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Gregory
Conway<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/iribqq448x7jj2f/D4S11-Elenburg.pdf?dl=0" target="_blank">Clinical Readiness for IND Submissions</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Shelby
Elenburg<o:p></o:p></p>
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</tbody></table></div></blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;"><tbody><tr><td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534"><a href="https://www.dropbox.com/s/rujl8mlgq9dmybf/D4S11-Sherafat.pdf?dl=0" target="_blank">Design Considerations for Clinical Trials in Rare Diseases</a></td></tr></tbody></table><br /></blockquote><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;"><tbody><tr><td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 400.25pt;" valign="top" width="534">Rosa Sherafat</td></tr></tbody></table></blockquote><p> </p><div><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen="" class="BLOG_video_class" height="266" src="https://www.youtube.com/embed/s8aLxfjRHRw" width="320" youtube-src-id="s8aLxfjRHRw"></iframe></div><div class="separator" style="clear: both; text-align: center;"><span style="text-align: start;"><br /></span></div><div class="separator" style="clear: both; text-align: center;"><span style="text-align: start;"><br /></span></div><b>Biologics Day 2:</b></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div><div><table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/omaeqh2vbb7ggkq/D5S01-Vatsan.pdf?dl=0" target="_blank">CMC Development and Readiness Pilot (CDRP) Program</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Ramjay S.
Vatsan<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/ttrce5t4sqf0koi/D5S02-Seeto.pdf?dl=0" target="_blank">CMC Considerations for Tissue Engineered Product Development</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Wen (Arron)
J. Seeto<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/mubzrz42qycbvg2/D5S03-Klinker.pdf?dl=0" target="_blank">Identifying and Controlling Attributes Related to Potency for Cell and Gene Therapy Products</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Matthew Klinker<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/sya50gonbeqfb62/D5S05-Scott.pdf?dl=0" target="_blank">FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">John Scott<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/bpv4bt20euh760o/D5S06-Alimchandani.pdf?dl=0" target="_blank">Postmarketing Safety and Pharmacovigilance for Vaccines</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Meghna
Alimchandani<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/nzt6na87wl3t9l6/D5S07-Xu.pdf?dl=0" target="_blank">Expanded Access to Investigational Drugs for Treatment Use</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Lei Xu<o:p></o:p></p>
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<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><a href="https://www.dropbox.com/s/ng0s4s8r8mu2m2j/D5S08-Wang.pdf?dl=0" target="_blank">CBER Inspections of Facilities for Biological Products</a><o:p></o:p></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Wei Wang<o:p></o:p></p>
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</tbody></table></div></div><div><div><b><br /></b></div></div></blockquote><div><div><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen="" class="BLOG_video_class" height="266" src="https://www.youtube.com/embed/kxJ7lKdChVw" width="320" youtube-src-id="kxJ7lKdChVw"></iframe></div></div></div><div><br /></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-34537064525005713522023-06-02T00:00:00.000-04:002023-06-02T00:00:00.139-04:00Resubmission of NDA/BLA After CRL: Class 1 versus Class 2 resubmissionIf new drug application (NDA) or biological license application (BLA) is not approved by the FDA, the sponsor will receive a complete response letter (CRL). FDA's CRL letter will state something like "the application could not be approved at this time based on [issues and deficiencies]". Receiving a CRL is not the end of the world and the sponsor can address the issues and deficiencies and resubmit the NDA/BLA. Many NDA/BLAs were approved after the resubmission. <div><br /></div><div>It may take the sponsor months/years to address the issues and deficiencies before NDA/BLA can be resubmitted. However, once the NDA/BLA is resubmitted, the time leading to the PDUFA date is predicable. FDA's policy is to classify the resubmission into one of two classes: class 1 and class 2. <br /><div><br /><div>Resubmission was discussed in <a href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-D/section-314.110" target="_blank">21 CFR Part 314.110 "Complete response letter to the applicant": </a><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgUQbzYq6W7cV22mcqb7QIvZdJgN6HzpeMJqJdBEBD1IejFWKc2z_6wuJ5wQZk-v3X9zTHxbFtIfpyDeaq7T9JWvAyj8qwOM0C9E-iBblKyD9eOjjCweUDssVGy-pEMXvIH-jKS81GVu3M5-XY57nDRUfGIrgnYGZg4WWHPi-ubWmy5JnA" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="524" data-original-width="715" height="423" src="https://blogger.googleusercontent.com/img/a/AVvXsEgUQbzYq6W7cV22mcqb7QIvZdJgN6HzpeMJqJdBEBD1IejFWKc2z_6wuJ5wQZk-v3X9zTHxbFtIfpyDeaq7T9JWvAyj8qwOM0C9E-iBblKyD9eOjjCweUDssVGy-pEMXvIH-jKS81GVu3M5-XY57nDRUfGIrgnYGZg4WWHPi-ubWmy5JnA=w576-h423" width="576" /></a></div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">FDA has a MAPP (Manual of Policies and Procedures) specifically about the classification of the NDA/BLA resubmission "<a href="https://www.fda.gov/files/about%20fda/published/Classifying-Resubmissions-of-Original-NDAs--BLAs--and-Efficacy-Supplements-in-Response-to-Action-Letters.pdf" target="_blank">Classifying Resubmissions of Original NDAs, BLAs, and Efficacy Supplements in Response to Complete Response Letters</a>". The MAPP listed the items qualifying for class 1 and 2 resubmission.</div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEifOCTVNugP_FkdjyRWI5lVALG5S3gg1hH85MTJB9yfZzdXa3kkP2Mb8gurQB4XwXDJvHCLXAlr2Qpp1jdE3_xkGvbN_nnCSWh6EmXiiI5lfWN6LXXsbC3Mgt87S2_LUOmxwlFE9JoLUiMZnIt8ZSR_KTcCgQ5GHLjeuPRQ8VgS5hZgGoU" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="667" data-original-width="585" height="657" src="https://blogger.googleusercontent.com/img/a/AVvXsEifOCTVNugP_FkdjyRWI5lVALG5S3gg1hH85MTJB9yfZzdXa3kkP2Mb8gurQB4XwXDJvHCLXAlr2Qpp1jdE3_xkGvbN_nnCSWh6EmXiiI5lfWN6LXXsbC3Mgt87S2_LUOmxwlFE9JoLUiMZnIt8ZSR_KTcCgQ5GHLjeuPRQ8VgS5hZgGoU=w575-h657" width="575" /></a></div><div class="separator" style="clear: both; text-align: left;"><br /></div>The review time leading to the PDUFA date is 4 months longer for Class 2 than Class 1 resubmission. Four months seem to be short, but sometimes can be critical if there are competitive NDA/BLA submissions in the same therapeutic area. This is why there is a priority review designation and a priority review voucher program - both will shorten the FDA review time by 4 months. </div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">Here is an example of resubmission with Class 1 category and an example of resubmission with Class 2 category:<br /><br /><a href="https://www.sec.gov/Archives/edgar/data/1535955/000149315222003057/ex99-1.htm">LIPOCINE ANNOUNCES ITS PARTNER RECEIVED FDA ACCEPTANCE OF NDA RESUBMISSION FOR TLANDO®</a> <div><blockquote>"...announcing that the U.S. Food and Drug Administration (“FDA”) has accepted its New Drug Application (“NDA”) resubmission for TLANDO® (testosterone undecanoate). The FDA designated the NDA as a <u>Class 1 resubmission with a two-month review goal period</u> and set a target action date of March 28, 2022, under the Prescription Drug User Fee Act (PDUFA). Lipocine licensed the exclusive U.S. rights for TLANDO® to Antares Pharma."</blockquote><p><a href="https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-announces-fda-acceptance-and-six-month-review" target="_blank">Ardelyx Announces FDA Acceptance and Six-Month Review for Resubmission of its New Drug Application of XPHOZAH® (tenapanor)</a></p><blockquote>"...the U.S. Food and Drug Administration (FDA) has accepted its resubmission of a New Drug Application (NDA) for XPHOZAH® (tenapanor) for the control of serum phosphate in adult patients with chronic kidney disease on dialysis who have had an inadequate response or intolerance to a phosphate binder therapy. <u>The FDA has determined that the NDA is a class 2 review, which results in a six-month review period from the date of resubmission.</u>..."</blockquote></div></div><p></p><a href="https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-resubmits-new-drug-application-us-food-and-drug"></a></div></div></div>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-62351922538719001172023-05-29T23:30:00.003-04:002023-06-08T21:56:31.537-04:00Final FDA Guidance "Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products" - what we learned?<p>In May 2023, FDA published the final guidance for industry "<a href="https://www.fda.gov/media/148910/download" target="_blank">Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products</a>". This final version was based on the draft guidance with the same title that was released 4 years ago in April 2019 (see a previous post "<a href="https://onbiostatistics.blogspot.com/2019/05/fda-and-ema-guidance-on-adjusting-for.html" target="_blank">FDA and EMA Guidance on Adjusting for Covariates in Randomized Clinical Trials</a>".</p><p>FDA created guidance snapshot below:</p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEj9sKXFQXfXagAZ6ZxrEOWshGzsmcCn9pTgk4deFvmph-W_EsBD3BVtGbn_GYv0p00i9VFuSrz6MItvI90cxl1lUgLB1eu0T21kFeYeMFxVgHxb0MImXLQO_yETktJrgUAm5qypZa-GR4LfBYfyH--KKgSKIKI1qC2id9lzk7Br2xyKmII" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="808" data-original-width="691" height="718" src="https://blogger.googleusercontent.com/img/a/AVvXsEj9sKXFQXfXagAZ6ZxrEOWshGzsmcCn9pTgk4deFvmph-W_EsBD3BVtGbn_GYv0p00i9VFuSrz6MItvI90cxl1lUgLB1eu0T21kFeYeMFxVgHxb0MImXLQO_yETktJrgUAm5qypZa-GR4LfBYfyH--KKgSKIKI1qC2id9lzk7Br2xyKmII=w614-h718" width="614" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhHElOObtu0Bls_6LMDyN6gMm9SgTOhLf-hiD6qx4gyq3w2WrYu8wmr58tLDPMLwuUVvuCweM4Sfbhr6tVu-3q9k4xw8qOhduW4JUYAGO8BCzJQO3ByGIun6jgmNAs9w4fZs2YRpDTbPteCfKWFoB4Ao1wkLG58Np2nCnuIyCUFcfW1HVk" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="865" data-original-width="694" height="799" src="https://blogger.googleusercontent.com/img/a/AVvXsEhHElOObtu0Bls_6LMDyN6gMm9SgTOhLf-hiD6qx4gyq3w2WrYu8wmr58tLDPMLwuUVvuCweM4Sfbhr6tVu-3q9k4xw8qOhduW4JUYAGO8BCzJQO3ByGIun6jgmNAs9w4fZs2YRpDTbPteCfKWFoB4Ao1wkLG58Np2nCnuIyCUFcfW1HVk=w642-h799" width="642" /></a></div><br /><br /><p></p><p><br /></p><p>The final guidance provided the general guidelines on several issues related to the covariates or baseline covariates. </p><p></p><div class="separator" style="clear: both; text-align: center;"><div class="separator" style="clear: both; text-align: center;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEh8Ry-_m1qrsHPPAoyXBnmi0CkTsidKB3cEFtfUKYqGKE5kuAy1elyKImobRWnD5zc98rRclC_bN1AXJwHVvJLBGtXjUxEW4QIVBARcHVC0h_mVlZklug0fsJfiape7_YzyhNSs9R8ZDvfLkNMJRIO-sCkkNkm7-KZg4yH9jLD63ydHjsk" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="739" data-original-width="651" height="712" src="https://blogger.googleusercontent.com/img/a/AVvXsEh8Ry-_m1qrsHPPAoyXBnmi0CkTsidKB3cEFtfUKYqGKE5kuAy1elyKImobRWnD5zc98rRclC_bN1AXJwHVvJLBGtXjUxEW4QIVBARcHVC0h_mVlZklug0fsJfiape7_YzyhNSs9R8ZDvfLkNMJRIO-sCkkNkm7-KZg4yH9jLD63ydHjsk=w627-h712" width="627" /></a></div><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgvNFgZhdueyqXR9easoU5fAZr5fUw0t8X4-KT_fcScyQZSH8-PJQK8fWe-SEYb4Vks00iL0-PYam9d4Lp1R-584MgUGsGDSg9xemRaYOA1NTBpc5t3zc9JoOFAeqDI37mfIjzaOk6VugRaPST8L3IYzDfFfxtYCCBT0MdCO5khB9m2Vyk" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="365" data-original-width="635" height="362" src="https://blogger.googleusercontent.com/img/a/AVvXsEgvNFgZhdueyqXR9easoU5fAZr5fUw0t8X4-KT_fcScyQZSH8-PJQK8fWe-SEYb4Vks00iL0-PYam9d4Lp1R-584MgUGsGDSg9xemRaYOA1NTBpc5t3zc9JoOFAeqDI37mfIjzaOk6VugRaPST8L3IYzDfFfxtYCCBT0MdCO5khB9m2Vyk=w629-h362" width="629" /></a></div><br /><div style="text-align: left;">Both unadjusted analysis and analysis adjusted for baseline covariates are acceptable. However, if analysis is adjusted for baseline covariates, the details about the covariates need to be pre-specified in the statistical analysis plan before the study unblinding. Our experience is that the details about which baseline covariates to be included and whether the baseline covariates are continuous or categorized need to be pre-specified. </div><div style="text-align: left;"><br /></div><div style="text-align: left;">Usually, the analysis adjusted for baseline covariates leads to efficiency gain and is more powerful than the unadjusted analysis. </div><div style="text-align: left;"><br /></div><div style="text-align: left;">It is acceptable to calculate the sample size based on adjusted analysis, but perform the final analysis based on analysis adjusted for baseline covariates. In practice, the sample size calculation is commonly based on adjusted analysis regardless of the final analysis. For example, for a study to compare two group means, the sample size may be calculated based on t-test approach, but the analysis may be based on analysis of covariates where the adjustment for baseline covariates are used. </div><div style="text-align: left;"><br /></div><div style="text-align: left;">For studies with stratified randomization where the randomization is stratified by one or more baseline covariates (categorical), the stratification factors are usually included in the analysis model even though the treatment assignments are generally balanced within each stratum. </div><div style="text-align: left;"><br /></div><div><div style="text-align: left;">For studies with stratified randomization, it is not uncommon that incorrect stratification may occur where the treatment assignment is picked from the incorrect stratum. When this occurs, there will be two sets of the randomization stratification information (two different strata variables): strata as randomized versus actual strata. It is acceptable to use either strata variable as randomized (intention-to-treat principle) or actual strata variable (correct strata information for all patients). When mis-stratification occurs, there should be any attempt to go back to the randomization systems (such as IRT, IVR, IWR) to correct the stratification allocation. Once randomized, it is randomized. While the incorrect stratification is used for randomization, the correct stratification can be recorded on the case report form or EDC (electronic data capture). See a previous post "<a href="https://onbiostatistics.blogspot.com/2018/03/handling-randomization-errors-in.html" target="_blank">Handling Randomization Errors in Clinical Trials with Stratified Randomization</a>".</div></div><div style="text-align: left;"><br /></div><div style="text-align: left;">For studies with continuous outcome measures, the endpoint is usually the change from baseline to a specific visit. Baseline covariate is used in the change from baseline calculation. In the analysis adjusted for baseline covariate, the baseline covariate can still be included in the model even though it gives an impression that the baseline measure is used twice. </div></div><p></p><p>The guidance contains additional guidelines on linear models and non-linear models. For example, for linear models, the issue related to treatment group by covariate interactions is discussed: </p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjKHgext6IHkhrp-kvRb7X7n8rDZZN7m4nUtTrNJ__cz7Wegqu3rvGcAvLquFt-6NWPV6ui59kY4Uz-FYEZ8fIbdceiUZT5tZiq5cK3bbR0b0mJOTCBWQQMixxKm6tixtTN8CPFAeHdMajAjmHpYYXhRNX_zzsrjxgQXPq6BGICsCasJ5M" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="136" data-original-width="636" height="134" src="https://blogger.googleusercontent.com/img/a/AVvXsEjKHgext6IHkhrp-kvRb7X7n8rDZZN7m4nUtTrNJ__cz7Wegqu3rvGcAvLquFt-6NWPV6ui59kY4Uz-FYEZ8fIbdceiUZT5tZiq5cK3bbR0b0mJOTCBWQQMixxKm6tixtTN8CPFAeHdMajAjmHpYYXhRNX_zzsrjxgQXPq6BGICsCasJ5M=w633-h134" width="633" /></a></div><br /> For non-linear models, binary outcome (logistic regression), ordinal outcome (generalized linear model), count outcome (Poisson regression), or time-to-event outcome (Cox regression) are analyzed. The estimators like odds ratio and hazard ratio are called are non-collapsible effect measures. Non-collapsibility implies that the effect parameter is not the same for different sets of covariates that are conditioned on, even if these covariates are independent of the exposure. Even when all subgroup treatment effects are identical, this subgroup specific conditional treatment effect can differ from the unconditional treatment effect. <p></p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgkFcMhR_vCBYyTUzMUqyeyWl7wa_XUXBpCi47enY2NpO0Cpc76tLbcST5pzXuxDpCBbiSVvIiFrPXVyC9aSmfoMB9peQo_fPSIKmfCQwBdDeczdvm8b5p22lPXatNDduO_kcUXU9pTkpagryjRm1jrQ0fZpDEAw9dgPI3vZgq34HR28a0" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="63" data-original-width="613" height="60" src="https://blogger.googleusercontent.com/img/a/AVvXsEgkFcMhR_vCBYyTUzMUqyeyWl7wa_XUXBpCi47enY2NpO0Cpc76tLbcST5pzXuxDpCBbiSVvIiFrPXVyC9aSmfoMB9peQo_fPSIKmfCQwBdDeczdvm8b5p22lPXatNDduO_kcUXU9pTkpagryjRm1jrQ0fZpDEAw9dgPI3vZgq34HR28a0=w585-h60" width="585" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: left;">References: raps.org: <a href="https://www.raps.org/news-and-articles/news-articles/2023/5/fda-finalizes-guidance-on-adjusting-for-covariates?mkt_tok=MjU5LVdMVS04MDkAAAGMDbkVyNTKLuPV1n48yDC9GH2O8bJpY9KJwEjV8td91vvNUAu-PrHpwie9l5PFNbK74Y-0VXt8RhW_xxYNOLgT8XCoWBG10HlV7P3zxZNV" target="_blank">FDA finalizes guidance on adjusting for covariates in randomized trials</a></div><p></p>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com1tag:blogger.com,1999:blog-15654301.post-83637421855679024912023-05-21T23:30:00.000-04:002023-05-21T23:30:00.232-04:00Comparing assumptions for sample size estimation with the interim and final results<p>Sample size estimation is one of the critical aspects of the clinical trial design. The sample size estimation is usually based on the primary efficacy endpoint. If the primary efficacy endpoint measure is a continuous variable, the sample size estimation will need to be based on assumptions about the effect size (for example, the difference in means) and the common standard deviation If the primary efficacy endpoint measure is a rate and proportion, the sample size estimation will need to be based on the effect size (for example, the difference in responder rate) and the rate/proportion in the control group. </p><p>Sometimes, the sample size estimations can be grossly inaccurate primarily because the assumptions used for the sample size calculation deviate from the observed data. This is especially true in planning pivotal studies with no or insufficient early-phase clinical trial data. </p><p>It is important to check the assumptions for sample size estimation during the study and adjust the sample size when the observed data suggests the inaccuracy of these assumptions. The process is essentially the "Adaptations to the Sample Size" described in FDA's guidance "Adaptive Designs for Clinical Trials"</p><blockquote><p>"Accumulating outcome data can provide a useful basis for trial adaptations. The analysis of
outcome data without using treatment assignment is sometimes called <b>pooled analysis</b>. The most
widely used category of adaptive design based on pooled outcome data involves sample size
adaptations (sometimes called<b> blinded sample size re-estimation</b>). Sample size calculations in
clinical trials depend on several factors: the desired significance level, the desired power, the
assumed or targeted difference in outcome due to treatment assignment, and additional nuisance
parameters—values that are not of primary interest but may affect the statistical comparisons. In
trials with binary outcomes such as a response or an undesirable event, the probability of
response or event in the control group is commonly considered a nuisance parameter. In trials
with continuous outcomes such as symptom scores, the variance of the scores is a nuisance
parameter. By using accumulating information about nuisance parameters, sample sizes can be
adjusted according to prespecified algorithms to ensure the desired power is maintained. In some
cases, these techniques involve statistical modeling to estimate the value of the nuisance
parameter, because the parameter itself depends on knowledge of treatment assignment. These adaptations generally do not inflate the Type I error probability. However,
there is the potential for limited Type I error probability inflation in trials incorporating
hypothesis tests of non-inferiority or equivalence. Sponsors should
evaluate the extent of inflation in these scenarios." </p></blockquote><p></p><blockquote> "One adaptive approach is to prospectively plan modifications to the sample size based on interim
estimates of nuisance parameters from analyses that utilize treatment assignment information.
For example, there are techniques that estimate the variance of a continuous outcome
incorporating estimates of the variances on the individual treatment arms, or that estimate the
probability of a binary outcome on the control arm based on only data from that arm. These
approaches generally have no effect, or a limited effect, on the Type I error probability.
However, unlike adaptations based on non-comparative pooled interim estimates of nuisance
parameters, these adaptations involve treatment assignment information and,
therefore, require additional steps to maintain trial integrity.
</blockquote><blockquote>Another adaptive approach is to prospectively plan modifications to the sample size based on
comparative interim results (i.e., interim estimates of the treatment effect). This is often called
unblinded sample size adaptation or unblinded sample size re-estimation. Sample size
determination depends on many factors, such as the event rate in the control arm or the
variability of the primary outcome, the Type I error probability, the hypothesized treatment
effect size, and the desired power to detect this effect size. In section IV., we described potential
adaptations based on non-comparative interim results to address uncertainty at the design stage
in the variability of the outcome or the event rate on the control arm. In contrast, designs with
sample size adaptations based on comparative interim results might be used when there is
considerable uncertainty about the true treatment effect size. Similar to a group sequential trial, a
design with sample size adaptations based on comparative interim results can provide adequate
power under a range of plausible effect sizes, and therefore, can help ensure that a trial maintains
adequate power if the true magnitude of treatment effect is less than what was hypothesized, but
still clinically meaningful. Furthermore, the addition of prespecified rules for modifying the
sample size can provide efficiency advantages with respect to certain operating characteristics in
some settings."</blockquote><p>One thing that is often neglected is to compare the final results with the assumptions. When a clinical trial is concluded, it is always good to check how different the final results are from the assumptions. If the final results are positive (indicating the success of the trials), people tend to ignore the assumptions made during the trial planning stage. Only if the final results are negative (indicating the failure of the trials), do people tend to go back to the assumptions and claim that the trial failed due to inaccurate assumptions leading to the lack of statistical power. </p><p><b><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2204705" target="_blank">Biogen's Tofersen for SOD1-ALS</a></b></p><p>Biogen designed a Valor study as the pivotal study to investigate the effect of tofersen for the treatment of patients with Amyotrophic
Lateral Sclerosis (ALS) associated with mutations in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS) - a subset of general ALS population. The primary efficacy endpoint is the ALSFRS-R score and the sample size for the study was based on assumptions about the ALSFRS-R score. </p><blockquote>"We calculated that a sample size of 60 participants (2:1 randomization ratio) in the faster-progression primary analysis subgroup would provide 84% power to detect a between-group difference on the basis of the joint rank test (described below), <u>assuming a change in the ALSFRS-R score from baseline to week 28 of −4.8 in the tofersen group and −24.7 in the placebo group, with a standard deviation of 20.39</u> and survival of 90% in the tofersen group and 82% in the placebo group, at a two-sided alpha level of 0.05."</blockquote><p>The final results indicated that assumptions were so inaccurate. In the placebo group, the change from baseline to week 28 is -8.14 (versus assumed -24.7).</p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEiaMxNz_dXJOac0U55SNYmkKrDfWlbib5aD0IJLtBlctyPUJmSsecreiHydV_oqBJqilOZ2FNHhls7zKGXuJQIs0UUXe0dOio4Jg2p2YpfX-JApGkJRUf6ui1W5ijB69PjG-9h455s-2KCXpIUdxRLp_qFfXr-nAs3CqpEDw2s08MdHwpY" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="127" data-original-width="535" height="143" src="https://blogger.googleusercontent.com/img/a/AVvXsEiaMxNz_dXJOac0U55SNYmkKrDfWlbib5aD0IJLtBlctyPUJmSsecreiHydV_oqBJqilOZ2FNHhls7zKGXuJQIs0UUXe0dOio4Jg2p2YpfX-JApGkJRUf6ui1W5ijB69PjG-9h455s-2KCXpIUdxRLp_qFfXr-nAs3CqpEDw2s08MdHwpY=w603-h143" width="603" /></a></div><p></p><p>Usually, it is the sponsor's responsibility to ensure that the assumptions for sample size calculation are as accurate as possible. If inaccurate assumptions are used in sample size calculation that leads to the failure of the trial, the regulatory agency may request the sponsor to do additional trials (with more accurate assumptions). However, in Biogen's Tofersen Vilor trial, FDA came to the defense of Biogen why the trial failed in the primary efficacy endpoint in ALSFRS-R score so that they could potentially approve a drug based on the positive results in biomarker and discredit the fact that the study failed in clinical endpoint. In <a href="https://www.fda.gov/media/166326/download" target="_blank">FDA's briefing book for the advisory committee</a> to discuss the Tofersen in SOD1-ALS, the following was mentioned:</p><p></p><div class="separator" style="clear: both; text-align: left;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgx0Epe7M-vx44HLJ3MrdQqATj3YSX7HHqB9jzSsbAYi11UPoXVA6nhnnT9r81_4KTCPmnP0I9iV8ooX5IR9K_rX7x8P_BNEqUgtQr2HrJZrDFwO7lMtbWXhYnOte9W3QROEy5IlM6IB3nnIflspnWqwCzEf9hBrSOco09U1JKufs1GvmY" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="394" data-original-width="645" height="377" src="https://blogger.googleusercontent.com/img/a/AVvXsEgx0Epe7M-vx44HLJ3MrdQqATj3YSX7HHqB9jzSsbAYi11UPoXVA6nhnnT9r81_4KTCPmnP0I9iV8ooX5IR9K_rX7x8P_BNEqUgtQr2HrJZrDFwO7lMtbWXhYnOte9W3QROEy5IlM6IB3nnIflspnWqwCzEf9hBrSOco09U1JKufs1GvmY=w619-h377" width="619" /></a></div><div class="separator" style="clear: both; text-align: left;"><span style="text-align: left;">Comparing the assumptions for sample size estimation with the analysis results can be complicated by the fact that different statistical methods are used. Sample size estimation may be based on a two-sample t-test while the actual data will be analyzed using more complicated methods (analysis of covariance, mixed model repeated measures, random coefficient model, non-parametric methods,...). For studies with a time-to-event primary efficacy endpoint, the sample size calculation may be based on the log-rank test, and the statistical analyses may be based on the Cox regression where analyses are adjusted for multiple explanatory variables. </span></div><p></p><p></p>However, it is always good to compare the assumptions for the sample size estimation with the observed data (during the study or at the conclusion of the study). Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com1tag:blogger.com,1999:blog-15654301.post-78461653931532989512023-05-17T23:30:00.001-04:002023-05-17T23:30:00.153-04:00Another successful trial with randomized withdrawal design<p>Biotech company <a href="https://www.ptcbio.com/" target="_blank">PTC Therapeutics</a> announced today that their phase III study of Sepiapterin in PKU patients achieved the primary efficacy endpoint.</p><p style="text-align: center;"><a href="https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-aphenity-trial-achieved-primary" target="_blank">PTC Therapeutics Announces APHENITY Trial Achieved Primary Endpoint </a></p><p style="text-align: center;"><a href="https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-aphenity-trial-achieved-primary" target="_blank">with Sepiapterin in PKU Patients</a></p>PKU (Phenylketonuria) is a rare, inherited metabolic disease, which affects the brain. It is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine. If left untreated or poorly managed, phenylalanine – an essential amino acid found in all proteins and most foods – can build up to harmful levels in the body. This causes severe and irreversible disabilities, such as permanent intellectual disability, seizures, delayed development, memory loss, and behavioral and emotional problems. There are an estimated 58,000 people with phenylketonuria globally.<div><br /></div><div>The pivotal license trial is called <a href="https://clinicaltrials.gov/ct2/show/NCT05099640" target="_blank">APHENITY trial </a>and the randomized withdrawal design was used for the trial even though the randomized withdrawal design was not explicitly mentioned. According to PTC's new release, the APHENITY study is described as the following:</div><blockquote>APHENITY was a global double-blind, placebo-controlled, registration-directed study which enrolled 156 children and adults with PKU. Participants were randomized to receive sepiapterin or placebo for six weeks with the primary endpoint being reduction in blood phenylalanine levels. The trial consisted of two parts. Part 1 was a run-in phase, during which all screened subjects received sepiapterin for two weeks. Only those subjects who demonstrated a reduction in phenylalanine levels of 15% or more from baseline in Part 1 were randomized to receive either sepiapterin or placebo in Part 2 of the clinical trial. The primary analysis population consists of those who had greater than 30% reduction in phenylalanine levels from baseline during Part 1 of the trial. The primary outcome measure is the reduction of blood phenylalanine levels from baseline compared to Weeks 5 and 6 in patients from Part 2 of the clinical trial. All patients are eligible to enroll in an open label long term clinical trial designed to further evaluate the long-term safety and durable effect of sepiapterin.</blockquote><p>The study design (randomized withdrawal design) can be depicted in the following diagram: </p><div class="separator" style="clear: both; text-align: center;"><div class="separator" style="clear: both;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEiqWJbTYC81_EJbBZAkMN3a7EtLfDuYiXzhsreQd-y97zLjyCE8qrc4cwQ20vG2jV16bX20vYs9RDOpGDDRN9Q4zK1dLSIXL4vcLrxgdBBjZCyuoeGKsep8ETVPXBVpLA9vCDYZ0KTk2yVeiamho0pE20sOf87uNL8FaVYuRflnZIcKDn0" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="459" data-original-width="1004" height="291" src="https://blogger.googleusercontent.com/img/a/AVvXsEiqWJbTYC81_EJbBZAkMN3a7EtLfDuYiXzhsreQd-y97zLjyCE8qrc4cwQ20vG2jV16bX20vYs9RDOpGDDRN9Q4zK1dLSIXL4vcLrxgdBBjZCyuoeGKsep8ETVPXBVpLA9vCDYZ0KTk2yVeiamho0pE20sOf87uNL8FaVYuRflnZIcKDn0=w642-h291" width="642" /></a></div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">Through the APHENITY trial, it is demonstrated that the randomized withdrawal design can be successfully used in the pivotal study of the rare, inherited metabolic disease.</div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">Refer to the previous posts on randomized withdrawal design:</div><div style="text-align: left;"><ul style="text-align: left;"><li><a href="https://onbiostatistics.blogspot.com/2013/01/randomized-withdrawal-design.html">Randomized withdrawal design and randomized discontinuation trial</a></li><li><a href="https://onbiostatistics.blogspot.com/2018/09/randomized-withdrawal-design-examples.html" target="_blank">Randomized Withdrawal Design - Examples for Defining the Criteria for Run-in and Randomized Withdrawal Periods</a></li><li><a href="https://onbiostatistics.blogspot.com/2022/11/randomized-withdrawal-design-in-action.html" target="_blank">Randomized withdrawal design in action - Accord trial in Alzheimer's agitation</a></li></ul></div></div></div><p></p>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0tag:blogger.com,1999:blog-15654301.post-82307773560706253772023-05-01T05:00:00.002-04:002023-05-01T05:00:00.139-04:00Violin plot versus Box-Whisker Plot<p><span style="background-color: white; color: #090909; font-family: Helvetica, sans-serif; font-size: 14px;"><a href="https://en.wikipedia.org/wiki/Box_plot" target="_blank">A box and whisker plot</a> (Also called: box plot, box-whisker diagram) is defined as a graphical method of displaying variation in a set of data. In most cases, a histogram </span><span style="background-color: white; color: #090909; font-family: Helvetica, sans-serif; font-size: 14px;">provides a sufficient display, but a box and whisker plot can provide additional detail while allowing multiple sets of data to be displayed in the same graph. The box-whisker plot displays the following in the data set. </span></p><ol class="rte-ordered-list" style="background-color: white; box-sizing: border-box; color: #090909; counter-reset: ol-counter 0; font-family: Helvetica, sans-serif; font-size: 14px; list-style-type: none; margin: 1em 0px; padding: 1px 0px;"><li style="box-sizing: border-box; margin-left: 15px; padding-bottom: 1px; padding-left: 3em; padding-top: 1px; position: relative;"><span style="box-sizing: border-box; font-weight: bolder;">Minimum value:</span> The smallest value in the data set</li><li style="box-sizing: border-box; margin-left: 15px; padding-bottom: 1px; padding-left: 3em; padding-top: 1px; position: relative;"><span style="box-sizing: border-box; font-weight: bolder;">Second quartile:</span> The value below which the lower 25% of the data are contained</li><li style="box-sizing: border-box; margin-left: 15px; padding-bottom: 1px; padding-left: 3em; padding-top: 1px; position: relative;"><span style="box-sizing: border-box; font-weight: bolder;">Median value:</span> The middle number in a range of numbers</li><li style="box-sizing: border-box; margin-left: 15px; padding-bottom: 1px; padding-left: 3em; padding-top: 1px; position: relative;"><span style="box-sizing: border-box; font-weight: bolder;">Third quartile:</span> The value above which the upper 25% of the data are contained</li><li style="box-sizing: border-box; margin-left: 15px; padding-bottom: 1px; padding-left: 3em; padding-top: 1px; position: relative;"><span style="box-sizing: border-box; font-weight: bolder;">Maximum value:</span> The largest value in the data set</li></ol><p><span style="background-color: white; color: #090909; font-family: Helvetica, sans-serif; font-size: 14px;">The box-whisker plot can also indicate the mean value (the dot). The difference between the mean value and the median value can indicate how skewed the data is. </span></p><p><span style="background-color: white; color: #090909; font-family: Helvetica, sans-serif; font-size: 14px;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgXMvpzWnFH4We7DR9Wq7aECvilKX-xhHbziC_JbMlfoqh0VMHjEH2MsYiLHUSv-M1cSd92LMA3pH1bgbQrkQjOA1RyEYDAzuE5l_oGGmAU5h7e0yEYaiL7tSTpCK60XPMQZns_P06cntXoZH_RTf-ORdcV2iLC8AZYNoq_HylLZKuwP3k" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="594" data-original-width="733" height="283" src="https://blogger.googleusercontent.com/img/a/AVvXsEgXMvpzWnFH4We7DR9Wq7aECvilKX-xhHbziC_JbMlfoqh0VMHjEH2MsYiLHUSv-M1cSd92LMA3pH1bgbQrkQjOA1RyEYDAzuE5l_oGGmAU5h7e0yEYaiL7tSTpCK60XPMQZns_P06cntXoZH_RTf-ORdcV2iLC8AZYNoq_HylLZKuwP3k=w349-h283" width="349" /></a></div><br />The box and whisker plot can also include the outliers where outliers are defined as values below Q1 - 1.5 * IQR or values above Q3 + 1.5 IQR (Q1 is 25th percentile and Q3 is 75th percentile, IQR - Interquartile is the distance between 25th percentile and 75th percentile). <p></p><p><span style="background-color: white; color: #090909; font-family: Helvetica, sans-serif; font-size: 14px;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhtZNH9cwWcKe4L8fhScemZEeflHLziIwzkmpYSeXwskzkZHuX0JJxnr1KVEs_02RDMML7dcRl5FaR60uwFZuU5FkR-azjYIjInochJ3Eb5HppPfUCq4CyIcX68Me0AkvBsrSiah78-jfjP_HvQOx9Hkm-Y0yQi8LR7p6g5ZNRdsDWMEn4" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="514" data-original-width="670" height="293" src="https://blogger.googleusercontent.com/img/a/AVvXsEhtZNH9cwWcKe4L8fhScemZEeflHLziIwzkmpYSeXwskzkZHuX0JJxnr1KVEs_02RDMML7dcRl5FaR60uwFZuU5FkR-azjYIjInochJ3Eb5HppPfUCq4CyIcX68Me0AkvBsrSiah78-jfjP_HvQOx9Hkm-Y0yQi8LR7p6g5ZNRdsDWMEn4=w382-h293" width="382" /></a></div><br /><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;">Boxplot can include the only box with lower, upper quartile and median, but not include the min and max values. In a paper by White et al "Combination Therapy with Oral Treprostinil for Pulmonary
Arterial Hypertension
A Double-Blind Placebo-controlled Clinical Trial", the boxplots without min and max were used to present the NT-proBNP data (a measure with skewed distribution). </div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhqR35cvaVxgD9HLFjwARga0EJkxaC4fpQqyIbbNb5M-idGqdbXGkhXpSexuVDFIOtC32pt8A_BtJOt51uHuQI3Caxh8Dl7LdkfxdoBmUISTaPV_eDXbGoRoAkCHOt5xzAlvHQ2JA7PJ318dXLoaXkBrU826E7F23Eu-yiK_IssW1bSO_I" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="383" data-original-width="465" height="425" src="https://blogger.googleusercontent.com/img/a/AVvXsEhqR35cvaVxgD9HLFjwARga0EJkxaC4fpQqyIbbNb5M-idGqdbXGkhXpSexuVDFIOtC32pt8A_BtJOt51uHuQI3Caxh8Dl7LdkfxdoBmUISTaPV_eDXbGoRoAkCHOt5xzAlvHQ2JA7PJ318dXLoaXkBrU826E7F23Eu-yiK_IssW1bSO_I=w514-h425" width="514" /></a></div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;"><br /></div></div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;">Recently, I see several papers using violin plots to display the data distribution. According to Wikipedia:</div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;"><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;"></p><blockquote><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;">A <b>violin plot</b> is a statistical graphic for comparing probability distribution. It is similar to a box plot, with the addition of a rotated kernel density plot on each side.</p><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;">Violin plots are similar to box plots, except that they also show the probability density of the data at different values, usually smoothed by a kernel density estimator. Typically a violin plot will include all the data that is in a box plot: a marker for the median of the data; a box or marker indicating the interquartile range; and possibly all sample points, if the number of samples is not too high.</p><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;">A violin plot is more informative than a plain box plot. While a box plot only shows summary statistics such as mean/median and interquartile ranges, the violin plot shows the full distribution of the data. The difference is particularly useful when the data distribution is multimodal (more than one peak). In this case a violin plot shows the presence of different peaks, their position and relative amplitude.</p><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;">Like box plots, violin plots are used to represent comparison of a variable distribution (or sample distribution) across different "categories" (for example, temperature distribution compared between day and night, or distribution of car prices compared across different car makers).</p><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;">A violin plot can have multiple layers. For instance, the outer shape represents all possible results. The next layer inside might represent the values that occur 95% of the time. The next layer (if it exists) inside might represent the values that occur 50% of the time.</p><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;">Although more informative than box plots, they are less popular. Because of their unpopularity, they may be harder to understand for readers not familiar with them. In this case, a more accessible alternative is to plot a series of stacked histograms or kernel density distributions.</p></blockquote><p style="background-color: white; color: #202122; font-family: sans-serif; font-size: 14px; margin: 0.5em 0px;"></p></div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;">in a paper by Chen et al "<a href="https://onlinelibrary.wiley.com/doi/epdf/10.1111/1759-7714.13343" target="_blank">Efficacy of transcutaneous electrical acupoint stimulationcombined with general anesthesia for sedation andpostoperative analgesia in minimally invasive lung cancersurgery: A randomized, double-blind, placebo-controlled trial</a>", violin plots were used to display the distribution of the VAS measure. </div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhEqkBZSYnqPqdZfkFSpBe95IWT27rbknYo3OEsHgDp2nS5PAJd4eB1tm4rYfqFecrMQMjJOxsFjHHXnW8a-qJnOvIBOKXoPv_fPEISPPQq9QlkJiQN__elNuDAUPO-EDuI29rAjMMg6L6UROVnr2-Z8Z0GZCOmmmiairNDdER9Svpyd-M" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="372" data-original-width="399" height="392" src="https://blogger.googleusercontent.com/img/a/AVvXsEhEqkBZSYnqPqdZfkFSpBe95IWT27rbknYo3OEsHgDp2nS5PAJd4eB1tm4rYfqFecrMQMjJOxsFjHHXnW8a-qJnOvIBOKXoPv_fPEISPPQq9QlkJiQN__elNuDAUPO-EDuI29rAjMMg6L6UROVnr2-Z8Z0GZCOmmmiairNDdER9Svpyd-M=w420-h392" width="420" /></a></div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;"><br /></div>In a paper by Colli et al "<a href="https://watermark.silverchair.com/3767.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAArQwggKwBgkqhkiG9w0BBwagggKhMIICnQIBADCCApYGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMZ0gvPYcGFfgfPGOrAgEQgIICZ-NycnfGU_q-nfhRuxlaF3zNPHb35RoJwf0Sna96puR0N-Jw6UaDpgvueb4dxBlxMpebiVcJBzHqYqtDaTI0H0SDFpKT-kGuq7qc8ls8egSrs1TLdatX4lKxA1zujMR-ZQOrZo_OuRvDBtFucFIA_PdPZECAa7CuhgAu-NzD7aX6E3xu9T3T2bGyEunzIMqTt2nL3-gJSah8-w1VdaTZUAvM5DJBS-gLqmkcHz_jhdHh4GA4zgyv7GtlRcN4RA5wdjTwa4DMLYIZ9ZCjPSLCBKndGJIFvZ7yFrKf40MZ_ILXVgc3j1aQ4zfRtlbcDMMYLP8bnVjZoXBHjn94JLlefjt8raocg7bFFV9t-MzGJgoU5aAMqzUUj-KDDHtpouE77Q7DGBT8CmfmXxES5exVsh-YiXrHP0tCLW9XMQIKUfIj-o84nbShZO7y0D_S58re4oVhCxxVvMwzGr8OoyQDPrEhjRpPZDxRXkod0tIjK4hByPo-JoPabXl2s1zJZbr00lgM2Bhx9mHiXJj-AHryPKOAk1uVN37eL1bIJwmTM52SO160gRSGuILTTtaLxePKXmxs2kqShB0AMuIWVHuAc40p3SWBSDDDXjdqFrorE9VBu3L_AyuvVHUCAW-AXOYjAC3TNIUTHYuEx9bm3nU3vTXCkqYbQkLdD03VvF_aYuoh0UD7gNwbbyX3yjbaHPKClibLREV325dxjjRdF-qAyDZbR6fQPwttu7Q4ejdFkb-HkuwLGTgyg8GXGYHltECll4iaVt4fDZuRgVFeTtim2m_0uwdhURR3Cx-El4lwDWcLs0rgAG5fXA" target="_blank">Burden of Nonsynonymous Mutations amongTCGA Cancers and Candidate Immune CheckpointInhibitor Responses</a>", the violin plot was used to display the distribution for r the number of NsM (log10) across different tumor types. </div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;"><br /></div><div style="border: 0px; box-sizing: inherit; flex: 1 1 auto !important; font-feature-settings: inherit; font-kerning: inherit; font-optical-sizing: inherit; font-stretch: inherit; font-variant-alternates: inherit; font-variant-east-asian: inherit; font-variant-numeric: inherit; font-variation-settings: inherit; line-height: 1.3; margin-bottom: var(--su8) !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; overflow-wrap: break-word !important; padding: 0px; text-align: left; vertical-align: baseline;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjb4BmTmck-g2RsFnkhityRCRqthQ0YVkdMoCGORL_G5EU9wgaO4SBegAKNLbx_bphSAIOipgEC8RZI3_yEcFnj4IOXKiHyNRs_5GKKfdo-8WTyXYQRr7BLpGMhntGm2CL6il2pvVdMFpCvDckSU6Ke2dq3trFFulFOre7vdeYcDPRCsKc" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="305" data-original-width="654" height="302" src="https://blogger.googleusercontent.com/img/a/AVvXsEjb4BmTmck-g2RsFnkhityRCRqthQ0YVkdMoCGORL_G5EU9wgaO4SBegAKNLbx_bphSAIOipgEC8RZI3_yEcFnj4IOXKiHyNRs_5GKKfdo-8WTyXYQRr7BLpGMhntGm2CL6il2pvVdMFpCvDckSU6Ke2dq3trFFulFOre7vdeYcDPRCsKc=w651-h302" width="651" /></a></div><br />SAS has a procedure <a href="https://documentation.sas.com/doc/en/pgmsascdc/9.4_3.4/statug/statug_boxplot_syntax01.htm" target="_blank">Proc BOXPLOT</a> to generate the box-whisker plots and SAS codes are also provided for <a href="https://blogs.sas.com/content/graphicallyspeaking/2012/10/30/violin-plots/" target="_blank">generating the Violin plots</a>. Other data analysis software including R have packages to generate the box-whisker plot and violin plot. </div><p></p>Web blog from Dr. Denghttp://www.blogger.com/profile/11917138094035874938noreply@blogger.com0