Sunday, May 22, 2016

Placebo Effect and The Choice of Placebo

Recently, NPR had a discussion about the influence of Placebo effect on consumer product purchases.  While the concept of the placebo effect comes from clinical trials in medical contexts, the placebo effect also have impact in non-medical research fields. For example, just by telling the people it is a brand name product (even though it is not), it affects the results of using the product.

Placebo effect is also called the placebo response. It is a remarkable phenomenon in which a placebo -- a fake treatment, an inactive substance like sugar, distilled water, or saline solution -- can sometimes improve a patient's condition simply because the person has the expectation that it will be helpful. Expectation to plays a potent role in the placebo effect. The more a person believes they are going to benefit from a treatment, the more likely it is that they will experience a benefit.”

Placebos have to be identical in all respects to the active drug, except that the active drug is absent. This means for oral placebos that they are not distinguishable by color, size, shape, taste, or texture. For oral therapy there are several modes of application available: capsules, tablets, or liquids. Since many active drugs have a distinctive taste, the use of capsules is most often feasible.

Sometimes, it is not so easy to make the placebo that are not distinguishable from the active drug. For example, liquids containing therapeutic protein generate foam but the placebo using buffer solutions do not. The treatment can be differentiated by observing the foam by shaking the test products. In this case, the ideal placebo will contain also an inactive protein in low concentrations such as human albumin. Some clinicians are very clever in breaking the code; they not only shake or identify the drugs by taste and smell but even photometers were used to determine differences between active drug and placebo. For such reasons it is sometimes very difficult to guarantee blinding.

While majority of the placebos used in the clinical trials are true inactive substance (at least we think so), there are times that the placebos may not be true inactive substance. This is especially true in the clinical trials using the protein therapies, for example, the therapeutic proteins derived from human plasma.

Table below listed several randomized, placebo controlled clinical trials using the therapeutic proteins derived from human plasma. Various concentrations of albumin (also protein) were used as the placebo assuming that the low dose of albumin has no therapeutic effect.

Experimental Treatment
Choice of Placebo
Biological: 0.25% human albumin solution (Placebo)
Biological: Placebo solution: Human Albumin 0.25% - 4 mL/kg
Biological: Placebo solution: Human Albumin 0.25% - 2 mL/kg
2% human albumin administered by weekly SC infusions during the SC treatment period of the study
Albumin (Human) 20%, United States Pharmacopeia (USP)
Placebo will be supplied as 20% or 25% Albumin and diluted with glucose 5% to a final concentration of 0.1%

If the results of these clinical trials are positive (statistically significant), people will not question the use of albumin as the placebo. If the results of these clinical trials are negative (not statistically significant) or the placebo group perform much better than expected, people may question the adequacy of the use of albumin as the placebo. This happened in one of the clinical trials in relapse-remitting multiple sclerosis (RRMS).  

Prior to the clinical trial below, previous studies had shown that the benefit of IGIV in treating the RRMS. The expected response rate in placebo group is about 50%.

Randomized, Double-Blind, Placebo-Controlled Study to Compare the Effects of Different Dose Regimens of IGIV Chromatography (IGIV-C), 10% Treatment on Relapses in Patients With Relapsing Remitting Multiple Sclerosis
The study results were published in Fazekas et al (2009) “Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial”. For the primary efficacy endpoint, after 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%). Surprisingly, the response rate in placebo group is much higher than expected and than what was assumed when the study was designed. This prompted the discussion of the potential therapeutic effect of albumin used as the placebo. The article by Hommes et alIVIG trials in MS. Is albumin a placebo?” argued that albumin may have properties that make it unsuitable as placebo.

Since using the albumin as the placebo may have therapeutic effects, something other than albumin (for example, saline with Polysorbate) may be an option as the placebo in clinical trials with these therapeutic proteins. Polysorbete is added to mimic the foam created by the therapeutic protein.  However, the blinding may still remain as a concern when saline is used as the placebo because of the difference in foaming. In clinical trials using the therapeutic proteins, we need to balance the risks of potential unblinding of using Saline as placebo versus potential placebo effect of using albumin as placebo. 

For blinded studies, we always assume that the blinding is maintained during the course of the study. However, this can be wrong in many trials where the investigators and/or patients can tell which treatment group the patients are on by the distinguishable features between the actual product and the placebo, by the different adverse event profiles, and others. It is important to assess the potential unblinding by asking the investigators or patients to guess the treatment assignments – a practice seems to be reasonable, but pretty much nobody wants to do. If the assessment indicates the potential unblinding or high percentages of guess-it-right, there is no easy way to mitigate the impact and make it difficult to interpret the results from the clinical trial.

After the study, it is a good practice to compare the results from placebo group back to the original assumptions. During the design stage of the clinical trial, we usually make assumptions about the response rate or mean/standard deviation in placebo group. After the study, it will be interesting to compare the actual results from the placebo group with the assumptions in the protocol sample size calculation section. I see the situations where the final results are way different from the assumptions in the protocol sample size calculation – in this case, we must have some further investigation what goes wrong and why this happens. 

Monday, May 02, 2016

Dose Cohort Expansion Study - A Never Ending Phase I Study Design

Clinical trials are conducted in a series of steps, called phases - each phase is designed to answer a separate research question. In Phase I studies, Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase I trials are usually conducted in healthy volunteers, however, phase I trials are often conducted in patients for 1) Trials in life-threatening diseases (such as cancer, AIDS); 2) clinical trials with human plasma derived products; 3) clinical trials with some biological products; 3) clinical trials with gene-therapy

Many phase I studies are designed as a dose escalation study. In previous articles, I have discussed the Phase I Dose Escalation Study Design: "3 + 3 Design" and Alternative phase I dose escalation study designs: CRM, BLRM, mTPI, and PGDE. The purpose of these dose escalation studies is to find the maximum tolerable dose (MTD). However, the efficacy signal can also be detected/assessed.

In a recent issue in New England Journal of Medicine, Prowell et al published an article titled “Seamless Oncology-Drug Development” and discussed the suddenly popular study design so called ‘dose cohort expansion study’. The study on pembrolizumab or MK-3475 or Keytruda (a programmed cell death 1 receptor) by Merck was mentioned as the example.  

The study was initially designed as a typical dose escalation study with a title “Phase I Study of Single Agent MK-3475 in Patients With Solid Tumors. The anticipated number of subjects was 32. “When impressive response rates and durations of response were observed early in the trial, particularly in patients with metastatic melanoma or non–small-cell lung cancer, the sample size was rapidly increased. Cohorts were added to assess efficacy in these two patient populations and to evaluate alternative dosing regimens and candidate predictive biomarkers — a move that resulted in the enrollment of more than 1200 patients in the trial”

This phase I study is still active, but not recruiting participants at this point. The latest description on is so much different from the original study design. The official title of the study has been revised to “Phase I Study of Single Agent MK-3475 in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma”. The change history documented on indicated 60 updates. One of the FDA review documents stated that the protocol was amended 50 times and counting.

While the protocol is still staged as a phase I study, many of the sub-studies have been added to this phase I study protocol. The study design is way beyond the initial dose escalation. The purpose of the study has been shifted to demonstrate the efficacy with an appropriate dose level. Within some added cohorts, the control group was added and subjects were randomly assigned. Essentially this is a combined phase I/II studies with multiple sub-studies. If it is designed in traditional phased clinical trial approach, this one study will have to be split into multiple phase I and phase II studies.

With portion of the results from this phase I study, Merck has obtained the approval from FDA initially for Advanced Melanoma, and last October for Non-small cell lung carcinoma. FDA review documents for its approval for advanced Melanoma have been posted on FDA’s website and the review documents for its approval for non-small cell lung carcinoma should be posted soon.

Cohort expansion design has now been used by many other study sponsors. We can easily see these studies with cohort expansion design from the website. In cohort expansion study, the decision on which cohort to add and how many subjects to expand depends on the results from the previous cohorts. However, it is very different from the adaptive design where the adaptation rules are pre-specified. In cohort expansion study, the changes to the study design are all post-hoc.

Cohort expansion study can be replaced with multiple phase I and phase II studies. However, keeping the study under the same protocol (but with many protocol amendments) will probably still save time and budget in study conduct, patient recruitment, IRB/EC submissions, and regulatory submissions. In a very competitive environment for oncology drug development, the time has the ultimate importance. 

Cohort expansion design becomes a viable approach in drug development perhaps due to following special circumstances:

Further reading:

Sunday, May 01, 2016

Free SAS e-learning courses in Programming 1 and Statistics 1

Great news to new SAS learners! SAS have made their introductory e-learning courses available to everyone at no cost. Don’t miss this chance to learn – or brush up on – programming and statistics basics.
  • Programming 1: This course will teach you the basics of writing SAS programs. You'll learn how to navigate SAS, create and combine SAS data sets, create reports and more.
  • Statistics 1: This introductory course is for SAS users who perform statistical analyses using SAS/STAT® software. You'll learn about ANOVA and linear regression and get a brief introduction to logistic regression.
These e-learning courses are the same material SAS teach on-site and via Live Web. 

To access the free version of the e-learning courses, use the following web link. You will need to enter your SAS profile account user name and password. if you don't have a SAS profile, you can create one for free. 

In addition, if you don't have a SAS software, you can get a SAS University Version for free. 
Als try SAS new video portal loaded with tons of free SAS tutorials
SAS user guides for all SAS products are always free on the web. 
Youtube also has many videos for SAS tutorials

Monday, April 25, 2016

Communications Between DMC (Data Monitoring Committees) and Regulatory Authorities

In the recent issue of, Karl Swedberg, M.D., Ph.D et al wrote an article “Challenges to Data Monitoring Committees When Regulatory Authorities Intervene”. also published the corresponding Regulatory authority response and the Sponsor Novartis Response.

The ATMOSPHERE study was a large clinical trial sponsored by Novartis to evaluate the efficacy and safety of both aliskiren monotherapy and aliskiren/enalapril combination therapy as compared to enalapril monotherapy, on morbidity and mortality in patients with chronic heart failure. While the ATMOSPHERE study was ongoing, there were external information from other clinical trials indicating the risk of medicinal products containing aliskiren. While the ATMOSPHERE study DMC insisted that they had been very aware of the study results from other trials and paid much attention to the risk of Aliskiren in their assessment of safety in ATMOSPHERE, the German regulatory authority seemed not to trust the assessment by DMC and requested DMC to provide the unblinded data for their review. DMC declined the request from German regulatory authority. German regulatory authority then contacted the study sponsor to force the discontinuation of a subset of subjects of using aliskiren – essentially altered the study.

Conflict between DMC and the regulatory authorities is rarely a topic because usually there should be no communications between the DMC and the regulatory authorities. For an ongoing blinded study, DMC is the only party who is empowered to review the unblinded information to assess the safety issue and evaluate the benefit-risk balance. While DMC is independent, the DMC members are selected by the sponsor and report the recommendations to the sponsor, not the regulatory authorities. The sponsor then may have obligations to communicate with the regulatory authorities about any issues that are raised by the DMC committee.

There is not too much guidance in this area. However, in FDA’s guidance for clinical trial spsonsors “Establishment and Operation of Clinical Trial Data Monitoring Committees” does have a section discussing “SPONSOR INTERACTION WITH FDA REGARDING USE AND OPERATION OF DMCs”

There are many situations, several mentioned earlier, in which sponsor consultation with FDA on matters regarding a DMC is advisable.  
7.1. Planning the DMC In planning a clinical trial, a sponsor makes several decisions regarding use, types of membership, and operations of a DMC. Many of these can be critical to the success of the trial in meeting regulatory requirements. This guidance document is intended to provide general FDA guidance regarding those decisions, but each set of circumstances can raise unique considerations. Issues regarding use of DMCs are appropriate topics for FDA-sponsor meetings (in person or by telephone) at the sponsor’s request.
7.2. Accessing Interim Data As discussed above, accessing interim data by the sponsor carries many risks, not all of which may be fully appreciated by the sponsor. We recommend that sponsors contact FDA before initiating communication with the DMC regarding access to interim data from a trial likely to be an important part of a regulatory submission. While FDA permission is not required, a discussion regarding the potential risks and implications of that action and of methods to limit the risks may contribute to informed decision making.
7.2.1. DMC Recommendations to Terminate the Study In almost all cases, a DMC is advisory to the sponsor; the sponsor decides whether to accept recommendations to discontinue a trial. FDA will rarely, if ever, tell a sponsor which decision to make. For trials that may be terminated early because a substantial benefit has been observed, however, consideration may still need to be given to the adequacy of data with regard to other issues such as safety, duration of benefit, outcomes in important subgroups and important secondary endpoints. We recommend that sponsors of trials that could potentially be terminated early for efficacy reasons discuss these issues with FDA prior to implementing the trial, when the statistical monitoring plan and early stopping boundaries are being developed. In these settings, consultation with FDA may provide the sponsor with important information regarding the regulatory and scientific implications of a decision and may lead to better decisions. Sponsors are encouraged to revisit these issues with FDA when considering DMC recommendations for early termination if new issues have arisen and/or if the regulatory implications of early termination were not adequately clarified at the outset of the trial.
For trials that may be terminated because of safety concerns, timely communication with FDA is often required (see, e.g., 21 CFR 312.56(d) (drugs); 21 CFR 812.150 (devices)). In such cases, we recommend that the sponsor initiate discussion as soon as possible about the appropriate course of action, for the trial in question as well as any other use of the investigational product.
We strongly recommend that sponsors initiate discussion with FDA prior to early termination of any trial implemented specifically to investigate a potential safety concern.
7.2.2. FDA Interaction with DMCs In rare cases, we may wish to interact with a DMC of an ongoing trial to ensure that specific issues of urgent concern to FDA are fully considered by the DMC or to address questions to the DMC regarding the consistency of the safety data in the ongoing trial to that in the earlier trials, to optimize regulatory decision-making. An example might be a situation in which FDA is considering a marketing application in which a safety issue is of some concern, and the sponsor has a second trial of the investigational agent ongoing. In such a situation, we might wish to be sure that the DMC for the ongoing trial is aware of the existing safety data contained in the application and is taking those data into consideration in evaluating the interim safety data from the ongoing trial. In such a case, we could request that the sponsor arrange for FDA to communicate with, or even meet with, the DMC (see 21 CFR 312.41(a); 21 CFR 812.150(b)(10)), and care should be taken to minimize the possibility of jeopardizing the integrity of the ongoing trial.
The takeaway messages from FDA guidance are:
  • FDA may request the sponsor to establish a DMC for a specific study
  • Direct Interaction between FDA and DMCs is rare
  • It is advisable to communicate with FDA if DMC has recommended the study termination especially the early study stopping due to overwhelming efficacy

EMA’s “GUIDELINE ON DATA MONITORING COMMITTEES” did not specifically mention the direct communication between the DMC and the regulatory authorities. It did say that “the use of an independent DMC gives more credibility to the process” for clinical trials. This implies that the independent DMC is more trustful than study sponsor to make the objective assessment of the benefit-risk balance. 

Usually, regulatory authorities are more concerned about the necessity of the DMC for clinical trials and the potential unblinding issue during the study or the potential study integrity issue in the DMC operation process when a DMC is established. 

In terms of The ATMOSPHERE study, the final results are negative. "In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril."

Friday, April 15, 2016

Race for the first drug approval by FDA for treating Duchenne Muscular Dystrophy (DMD)

Duchenne muscular dystrophy (DMD) is an inherited disorder that involves muscle weakness, which quickly gets worse. Duchenne muscular dystrophy is caused by a defective gene for dystrophin (a protein in the muscles). However, it often occurs in people without a known family history of the condition. Because of the way the disease is inherited, it usually affects boys. Duchenne muscular dystrophy occurs in about 1 out of every 3,600 male infants. DMD is a rare disease and is an orphan disease indication for the drug development.

In June 2015, FDA issued its draft guidance for industry “Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment” which delineated the details about FDA’s thinking about the drug development for treating Duchenne Muscular Dystrophy.
FDA recognized that Duchenne Muscular Dystrophy is life-threatening and severely debilitating disease with unmet medical need (no FDA-approved drug up to this date). The statutory standards for effectiveness apply to drugs for dystrophinopathies just as they do for all other drugs. FDA has long stressed, however, that it is appropriate to exercise flexibility in applying the statutory standards to drugs for serious diseases with important unmet needs, while preserving appropriate guarantees for safety and effectiveness.
Several companies are racing to developing and getting FDA approval for the first drug for treating DMD. Here are some updates on the progression of DMD drug development by these companies: 2014 updates and 2015 updates. Three companies are in the front: BioMarin Pharmaceutical, PTC Therapeutics, and Sarepta Therapeutics. So far, there are more disappointing news for these companies.

FDA usually organizes advisory committee meetings when they face the challenges in deciding whether or not approve a drug. While FDA does not need to follow the advisory committee's suggestion, the voting results from the advisory committee usually put a great weight on FDA's decision. In DMD situation, the designated FDA advisory committee is Peripheral and Central Nervous System Drugs Advisory Committee (PCNS in short). FDA organized an PCNS meeting
before rejecting Biomarin’s NDA for NDA 206031 Drisapersen. FDA’s briefing documents indicated FDA’s concerns about approving Drisapersen. The meeting minutes indicated that the majority of the advisory committee members were not convinced by the efficacy of the Drisapersen and were concerned about the risk of safety issues outweighing the benefits.

FDA is now planning to have an advisory committee for Sarepta‘s Eteplirsen. FDA’s briefing document did not sound encouraging. FDA officials said they “concluded that the standard of substantial evidence of effectiveness has not been met” and that the drug “is not ready for approval in its present form.” The meeting was originally scheduled for Jan 22, 2016, but was delayed/rescheduled for a late date (TBD) due to the winter storm in DC area.

FDA did not hold the advisory committee meeting for PTC therapeutics’ rolling NDA submission. PTC’s Translarna was approved by EMA for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older. See Translarna’s EMA approval information and Translarna’s Summary of Product Characteristics. Luckily, the PTC's translarna also got the endorsement from UK's NICE. NICE is usually not nice in terms of the drug's cost-benefit assessment. 

Now that FDA has rejected PTC’s Translarna and Biomarin’s Drisapersen, Sarepta’s Eteplirsen becomes the only choice to be approved by FDA as the first drug for treating DMD. FDA’s assessment as delineated in their briefing book do not look promising. The patient communities and medical experts in the field are starting to put the pressures on FDA to approve the drug.

Sometimes the medical experts can have biases toward the drug approval. If you are working on something for so long, you will be more likely to see the benefit of the treatment and tend to make judgment in favor of the drug approval even though the evidence and the clinical trial results are not strong. In the interview, one DMD expert Dr Kunkel said he believes the Sarepta’s drug's promises far outweigh the risk – completely different from FDA’s assessment.
“My feeling is, it can’t hurt to be approved, in the sense that it’s got such a safety profile, it looks like its efficacious, and it’s making protein,” said Kunkel, who agreed to serve on a new scientific advisory board for Sarepta last year. “That, to me, would predict it to have an effect. And it would be a travesty not to let patients have it.”
It is always interesting to see how flexible FDA will be willing to lower the requirements for approving a drug for treating life-threatening and severely debilitating orphan disease. It is also interesting to see how FDA will withstand the pressures from the patient advocate group and the medical experts.

Last August, we saw that FDA approved the Addyi as the first female Viagra for treating acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women under the pressure of being accused of sexist. The Addyi's approval process demonstrated that while not often, FDA could be influenced by outside groups to approve a drug even though they felt the risks outweighed the benefits. 

Friday, April 01, 2016

Submitting Individual Patient or Subject's Case Report Forms to FDA

When submitting the NDA (new drug application) or BLA (biological license application) to FDA, as part of the CTD (common technical document) or eCTD module 5 (Clinical Study Report), individual subject's case report forms (CRFs) need to be submitted for some patients.  For each individual subject, there will be multiple pages of case report forms. The term 'CRF case book' may be used to refer to all CRF pages for an individual subject. Individual subject's case report forms are those with patient data (versus the blank CRFs when we discuss the CDISC and SDTM define documents). 

For Which Subjects, Will Their Case Report Forms Need to be Submitted?

According to US 21 CFR 314.50 (Content and Format of an Application), individual subject's CRFs are needed for subjects who died or who did not complete the study due to an AE. 

(b) The applicant shall, under section 505(i) of the act, update periodically its pending application with new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling and, if applicable, any Medication Guide required under part 208 of this chapter. These ‘‘safety update reports’’ are required to include the same kinds of information (from clinical studies, animal studies, and other sources) and are required to be submitted in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition, the reports are required to include the case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event (unless this requirement is waived). The applicant shall submit these reports (1) 4 months after the initial submission; (2) in a resubmission following receipt of a complete response letter; and (3) at other times as requested by FDA. Prior to the submission of the first such report, applicants are encouraged to consult with FDA regarding further details on its form and content.

According to FDA’s internal “Reviewer Guidance Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review”, the individual subject's CRFs for patients with SAEs will also be needed for safety review.

Before beginning the safety review, the reviewer should identify and assemble (or locate electronically) all available materials for the review. These materials include:
  • The applicant’s Integrated Summary/Analysis of Safety (ISS)
  • Adverse event tables in the NDA/BLA submission7
  • Case report forms (CRFs) for patients who experienced serious adverse events or who dropped out of a study because of an adverse event.

 The reviewer should request these CRFs if the applicant does not include them in the submission (although they are required under 21 CFR 314.50). If the number of cases is very large (e.g., for dropouts) and many of the events are similar, it may be reasonable to request only a sample of CRFs.8 Note that, in some cases, dropouts attributed to other reasons will upon review be associated with an adverse event.

To be on the safe side and avoid the additional requests from FDA, individual subject's CRFs should be provided for all subjects who:
  •           Died during the study
  •           Discontinued from the study due to an AE
  •           Had SAE during the study

How Should the Individual Subject’s CRFs be Prepared for Submission?

FDA guidance “Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications” has some specific requirements for individual subject’s CRFs. In old days, we had to send individual subject’s case report forms to a specialty company for scanning and bookmarking – manual bookmarking was a tedious task. Nowadays, the popular EDC systems can generate individual subject’s case report form for submission.
         3. Case report forms
You should provide an individual subject’s complete CRF as a single PDF file. If a paper CRF was used in the clinical trial, the electronic CRF should be a scanned image of the paper CRF including all original entries with all modifications, addenda, corrections, comments, annotations, and any extemporaneous additions. If electronic data capture was used in the clinical trial, you should submit a PDF-generated form or other PDF representation of the information (e.g., subject profile). You should use the subject’s unique identifier as the title of the document and the file name. These names are used to assist reviewers in finding the CRF for an individual subject. Each CRF must have bookmarks as part of the comprehensive table of contents required under 21CFR314.50(b). We recommend bookmarks for each CRF domain and study visit to help the reviewer navigate the CRFs. For addenda and corrections, making a hypertext link from the amended item to the corrected page or addendum is a useful way to avoid confusion. Bookmarks for these items should be displayed at the bottom of the hierarchy.
Furthermore, PDF files for individual subject’s CRFs should follow the requirements specified in FDA guidance “Providing Regulatory Submissions in Electronic Format — General Considerations”. For example, there are requirements for page size and margin, font size, embedded fonts, ……

Is the Requirement for submitting Individual Subject’s CRFs for all FDA Submissions?

No. The requirements above are only applicable to FDA CDER and CBER divisions. CDRH for device division does not have a requirement. As a matter of fact, the above mentioned FDA guidance is only for CDER and CBER divisions, does not include CDRH.

FDA guidance “Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications” (again sponsored by CDER and CBER, but not CDRH) specified that the following submissions should follow the eCTD specifications including the individual subject’s CRFs.
  •  Certain investigational new drug applications (INDs)
  •  New drug applications (NDAs)
  •  Abbreviated new drug applications (ANDAs)
  •  Certain biologics license applications (BLAs)

Thursday, March 24, 2016

Protocol Template for Clinical Trials

For any clinical trial, the study protocol is the most critical document and is the blue print of the entire study. There are clinical studies with very high quality of the study protocol. There are also clinical studies with sub-optimal quality of the study protocol. It would be nice if there is a protocol template so that all clinical trial protocols are written in a consistent way no matter whether the clinical trial sponsors are industry, academic, or government agencies.  

Usually, people follow the ICH E6 (Good Clinical Practice) as the guidance for developing the clinical study protocol. ICH E6 has a specific section about "Clinical Trial Protocol and Protocol Amendment(s)". The outline of the clinical trial protocol is listed as below in ICE E6:
1 General Information
2 Background Information
3 Trial Objectives and Purpose
4 Trial Design
5 Selection and Withdrawal of Subjects
6 Treatment of Subjects
7 Assessment of Efficacy
8 Assessment of Safety
9 Statistics
10 Direct Access to Source Data/Documents
11 Quality Control and Quality Assurance
12 Ethics
13 Data Handling and Record Keeping
14 Financing and Insurance
15 Publication Policy
16 Supplements
Another way people write the clinical study protocol is to follow the ICH E3 (Structure and Contents of Clinical Study Report). The idea is that the section 7 to 9 of the study report will describe the study protocol and delineate how the clinical study is conducted. Following the ICH E3, the clinical study protocol can be organized according to the outline below:
9.3.1 Inclusion Criteria
9.3.2 Exclusion Criteria
9.3.3 Removal of Patients from Therapy or Assessment
9.4.1 Treatments Administered
9.4.2 Identity of Investigational Product(s)
9.4.3 Method of Assigning Patients to Treatment Groups
9.4.4 Selection of Doses in the Study
9.4.5 Selection and Timing of Dose for each Patient
9.4.6 Blinding
9.4.7 Prior and Concomitant Therapy
9.4.8 Treatment Compliance
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart
9.5.2 Appropriateness of Measurements
9.5.3 Primary Efficacy Variable(s)
9.5.4 Drug Concentration Measurements
9.7.1 Statistical and Analytical Plans
9.7.2 Determination of Sample Size
It will be desirable to have a protocol template so that all clinical trial protocols are written in a consistent way. While there is no universal protocol template across the industry, academic, and governmental agencies, for efficiency and consistency, there should be a protocol template within each company or organization.

In an effort to increase the efficiency of clinical trial protocol reviews, the National Institutes of Health (NIH) has released a draft protocol template developed in collaboration with the US Food and Drug Administration (FDA). As indicated in the preface of the draft protocol template,
"This Clinical Trial Protocol Template is a suggested format for Phase 2 or 3 clinical trials supported by the National Institutes of Health (NIH) that are being conducted under a Food and Drug Administration (FDA) Investigational New Drug Application (IND) or Investigational Device Exemption (IDE). Investigators for such trials are strongly encouraged to use this template when developing protocols for NIH supported clinical trial(s). However, others may also find this template beneficial for other clinical trials not named here.
This template is provided to aid the investigator in writing a comprehensive clinical trial protocol that meets the standard outlined in the International Conference on Harmonisation (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (ICH-E6). In order to facilitate review by NIH and FDA, investigators should retain the sections in the order provided."
In the meantime, FDA is also make the collaborative efforts to develop so-called the common protocol template developed by TransCelerate Biopharma to help ensure consistency for the medical product development community. CDISC is also making efforts to develop or modelize the clinical study protocol - The protocol representation model (PRM). The common protocol template and PRM (once developed and accepted by clinical research community) can also help with the downstream activities: standardized study protocol -> standardized data collection / case report forms -> standardized data structure -> standardized software -> standardized data presentations.