On Biostatistics and Clinical Trials: January 2014

Sunday, January 26, 2014

FDA Guidance Webinar Series

FDA's Guidance Webinar series aims to foster collaboration and transparency in the development of guidance documents through direct outreach to affected stakeholders. The webinar series are free to the public and the past webinars are achieved for free access. These webinars are presented by senior FDA officers and the author/coauthor of the issued FDA guidance.

FDA's Guidance Webinar series

Since 2011, the following webinars have been conducted:

Overrunning Issue In Adaptive Design Clinical Trials

Adaptive designs have been more and more commonly used from early phase clinical trials to late phase pivotal clinical trials and from the limited therapeutic areas (such as oncology) to broad therapeutic areas. While adaptive design can have different forms (group sequential design, seamless phase II/III design, sample size re-estimation, futility design,…), it all requires formal interim analyses with results to be reviewed by the independent Data Monitoring Committee. The rule for adaptation is pre-specified and the decision for adaptation is based on the interim analysis results.

In the phased clinical trials, the period between the analysis of phase II data and recruitment of phase III patients, is called “white space”. During the “white space” period, the results from early phase studies are digested and the additional time is needed for the study start up including regulatory submissions. The common perception is that with adaptive design such as seamless phase II/III design, the ‘white space’ can be eliminated – that is why the term ‘seamless’ is used in the first place. However, with adaptive design, the ‘white space’ may be shortened, not be eliminated. In studies with adaptive designs, there is usually no break in patient enrollment between the phases or stages or no break while preparing for the interim analysis. This brings in another issue – overrunning issue.

During the period while waiting for the endpoint data available for interim analysis, If the treatment duration is too long, too many patients would be randomized during the transition period – so called ‘overrunning’, which could result in inefficiencies and losing the benefits of the adaptive design.

Recruitment rate relative to treatment data availability is the critical factor for overrunning. According to a paper by Judith Quinlan and Michael Krams (Implementing adaptive designs: logistical and operational considerations, the ideal ratio of recruitment / treatment duration is 4.

“As a rule of thumb we propose to establish whether the overall recruitment duration is at least four times the observational period required before the primary endpoint reads out in any one patient. For example, in a stroke trial where each patient is observed over a period of 3 months, an adaptive design could be considered if the trial is open for recruitment for 12 months or longer. This view may need to be modified, should there be a good early predictor of final outcome, allowing for the deployment of a longitudinal model. For example, in acute stroke it might be possible to use early measurements of the stroke scale to predict final outcome (Grieve and Krams, 2005). Should the early observation be a good predictor of the final outcome, we may consider using it in our assessment of weighing recruitment speed versus time needed before endpoint readout. To formally establish the “optimal” recruitment speed, we propose to conduct clinical trial simulations, mimicking the potential real life environment of the trial and exploring the impact of longitudinal models.”

The overrunning issue was not discussed in FDA’s guidance “Adaptive Design Clinical Trials for Drugs and Biologicals”, however, it is discussed in EMA guidance “Reflection Paper In Methodological Issues in Confirmatory Clinical Trials Planned With an Adaptive Design”. Section 4.1.3 of this guidance has specific discussions about the overrunning issue.

"4.1.3 Overrunning
In many clinical trials the primary endpoint is not observed immediately for each patient (e.g. survival or time to event data). Furthermore, in trials with a complex organisational structure, additional patients are likely to be randomised or some even followed to the primary endpoint before the results of a pre-planned interim analysis are known. If a trial is to be terminated as a result of an interim analysis it is always important to carry out an additional analysis including all of these further patients that did not contribute to the interim analysis. It may be that when this analysis is carried out, the null hypothesis can no longer be rejected and apparently decision making may depend on whether or not these so called overrunning patients are included or excluded from the analysis. In such a situation, it is accepted regulatory practice to base decision making on the final results of the trial (not the interim analysis). This is also in accordance with the intention to treat principle that all randomised patients should be analysed. Obviously, overrunning patients need to be treated and observed according to the protocol and due attention should be given to this at the planning stage of the trial.

A full discussion of the results of a trial should be based on estimates of the treatment effect rather than simply on P-values alone. If the estimate of the treatment effect including the overrunning patients is not very different from that excluding them, then a small increase in the P-value might not be regarded as a concern. An important reduction in the size of the point estimate might, in contrast, lead to reluctance to accept the overall result as “positive”, especially as, unless a trial is stopped very early, the proportion of overrunning patients will usually be sufficiently small such that the estimate of the treatment effect should not be substantially altered. In all cases, results including and excluding the overrunning patients should be presented and differences between these two analyses should be discussed.”

The overrunning issue is discussed in many adaptive clinical trial implementations. Here are some of them:

Introduction to Adaptive Designs by Werner Brannath
Pitfalls in Clinical Trials Using Adaptive Design by Thomas Zwingers
Monitoring Continuous Long-Term Outcomes in Adaptive Designs by Kirsten Wust & Meinhard Kieser
On the efﬁciency of adaptive designs for ﬂexible interim decisions in clinical trials by Werner Brannath et al

Friday, January 24, 2014

Archives of Webcast and Presentation Slides for Public Workshop on Complex Issues in Developing Drug and Biological Products for Rare Diseases

To meet the requirements by PDUFA V and FDASIA, FDA organized a public workshop on "Complex Issues in Developing Drug and Biological Products for Rare Diseases".

The webcast and presentation slides for this public workshop are accessible to the public for free.

To access the Webcase and presentation slides for this workshop, please follow the link below:

Complex Issues in Developing Drug and Biological Products for Rare Diseases

Free Webinar by FDA on the final guidance for industry Electronic Source Data in Clinical Investigations

On Wednesday, January 29, 2014, from 2:00PM - 3:00PM EST, FDA will present a webinar on the final guidance for industry Electronic Source Data in Clinical Investigations.

FINAL GUIDANCE: Electronic Source Data In Clinical Investigations (Procedural)
Federal Registration FR NOA

SUMMARY: The Food and Drug Administration (FDA) has announced the availability of a final guidance for industry titled “Electronic Source Data in Clinical Investigations.” This final guidance provides recommendations to sponsors, Contract Research Organizations (CROs), clinical investigators, and others involved in the capture, review, and retention of electronic source data in FDA-regulated clinical investigations. In an effort to streamline and modernize clinical investigations this guidance promotes capturing source data in electronic form, and it is intended to assist in ensuring the reliability, quality, integrity, and traceability of data from electronic source to electronic regulatory submission.

Guidance Webinar Online-Access Instructions: To access this webinar, follow the link provided below. Audio will broadcast from your computer speakers.

After following the link, enter as a guest and provide your FULL NAME and organization (i.e. "John Smith - FDA/CBER"). The host will then allow you to enter. If you experience technical difficulties email Jeffery.Rexrode@fda.hhs.gov for assistance. Closed captioning will be provided.
Questions/Comments can be submitted live via a Q/A chat window.

Webinar Access link: https://collaboration.fda.gov/guidancewebinars

SPEAKERS:
Leonard V. Sacks, MD
Associate Director
Office of Medical Policy
Center for Drug Evaluation and Research
Food and Drug Administration

Ron Fitzmartin, PhD, MBA
Office of Strategic Programs
Center for Drug Evaluation and Research
Food and Drug Administration

Jonathan S. Helfgott, MS
Associate Director for Risk Science (Acting)
Office of Scientific Investigations
Center for Drug Evaluation and Research
Food and Drug Administration

Wednesday, January 01, 2014

Artistic and Creative Way in Naming a New Drug

We all may have difficulties in remembering the drug names and wonder why many drug names are so awkward and difficult to read. For drug makers, finding a name is more art than science. For a new drug, the proprietary name or brand name needs to reflect certain features.

“Want to sound high-tech? Go for lots of Z's and X's, such as Xanax, Xalatan, Zyban and Zostrix.

Want to sound poetic? Try Lyrica, Truvada and Femara.

Want to suggest what it does? Flonase is an allergy medicine that aims to stop nasal flow. Lunesta, a sleeping drug, implies "luna," the Latin word for moon — a full night's sleep.

Then there's Viagra, the erectile-dysfunction drug made by Pfizer. It uses the prefix "vi" to suggest vigor and vitality. The word rhymes with Niagara, suggesting a mighty flow.”

On the other hand, the proprietary name for a new drug is closely regulated to avoid the similar names that may cause the medical errors. For example, in an article "This Is How Easy It Is to Pick Up the Wrong Prescription Drug", the similar drug names increases the chances for making mistakes in prescribing and in pharmacy. In US, FDA needs to approve the proprietary names of prescription drugs.

“New prescription drugs approved by FDA have both a scientific name, known as the generic (also called the established name), and a name given by the manufacturer, known as the proprietary name (also called the brand name or trade name). Before a drug is approved by FDA, the Agency will carefully review the proposed proprietary name.

It is important for safety reasons that the written proprietary name not look like that of another proprietary name nor sound like another proprietary name when spoken. If there is similarity between the proprietary name of a new prescription drug and the proprietary name of an existing drug, a mix-up could occur in ordering and a patient could receive one drug instead of the other. FDA’s Division of Medication Error Prevention and Analysis is responsible for proprietary name review prior to approval in the Center for Drug Evaluations and Research. If a company submits a name that is too similar to another name, FDA will require the company to select another name, for safety reasons, as part of the approval process. “

See the following links for more discussion:

Recently, the United Therapeutics is very creative in naming their new drug. They simply used their CEO’s name (backward) for their new drug in treating the pulmonary hypertension. The new drug name Orenitram is Martine Ro. backward. And that would be the name of Martine Rothblatt, United Therapeutics’ founder/CEO and one of the most captivating people in the biotechnology industry.