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."

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