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."
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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