Communications Between DMC (Data Monitoring Committees) and Regulatory Authorities

In the recent issue of NEJM.org, Karl Swedberg, M.D., Ph.D et al wrote an article “Challenges to Data Monitoring Committees When Regulatory Authorities Intervene”. NEJM.org 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."

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.

• Jan 14, 2016 FDA rejects BioMarin's muscle wasting drug; Sarepta drug in focus
• On Feb 23, 2016, FDA rejected PTC’s application for Duchenne drug, rattling investors and parents
• PTC shares sink as FDA says application does not merit review 
• 01/15/16 Sarepta Plunges on Harsh FDA Eteplirsen Review Ahead of Next Week's Advisory Panel Meeting
• 02/23/2016 Hope for Sarepta Drug Approval Found in Obscure FDA Document
• 04/22/2016 Sarepta shares plunges as FDA questions muscular dystrophy drug
• 04/26/2016 FDA advisory committee vote against the Serepta DMD drug

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.

• CUREDUCHENNE urges regulators to approve Eteplirsen, stresses the importance of multiple drugs in the pipeline
• 36 Duchenne experts sign UCLA letter in support of approval of Sarepta’s drug
• FDA urged to approve Sarepta’s DMD drug by dozens of medical experts
• Duchenne pioneer says FDA rejection of Sarepta’s drug ‘would be a travesty’
• FDA Faces Sensitive Challenge With Review of DMD Drug
• Muscular dystrophy drug advocates plan to pack crucial meeting
• Sarepta shares sink as FDA staff stay sour on muscle 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. 

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)