Don’t Do It Alone: The Need for Independent Insight and the Role of Outside Expert Committees

Independent Expert Committees provide crucial validation on clinical data as additional support for regulatory submissions and commercial strategy. Partnering with outside experts can lead to better-defined data gathering, earlier risk signal detection and, ultimately, a value-enhanced, streamlined approach to leveraging the intelligence gathered from clinical trials.

Without the insights that expert committees provide, sponsors risk missed signals, conflicts of interest and delays, and squandered resources. Trials that should proceed may quickly drag, and trials that should be halted continue for too long. The financial and human cost can be massive.

Most sponsors already understand this, of course. Data Monitoring Committees (DMCs) and, to a lesser extent, Endpoint Adjudication Committees (EACs), are already important parts of many clinical trials. Where sponsors often fall short, however, is optimizing the use of these experts and keeping these committees at arm’s length.

 

The Need for Outside Expertise

Sponsors often don’t realize how much work is involved in creating these committees—building the technology, creating an effective charter, defining criteria for the endpoints being monitored, finding the experts, etc. As a result, many sponsors may try to manage expert committees in-house. But most lack the internal people, processes and technology to do this effectively, so they end up diverting resources from the clinical trial startup to operationalize all the elements needed for adequate oversight.

Handing it off to the study CRO isn’t the preferred option either. You wouldn’t want the CRO that’s managing the operational aspect of your trial also responsible for providing an independent perspective. A sponsor and CRO in the throes of the clinical trial may not see the signals the same way an outside expert would.

And then, there’s the issue of bias—actual or perceived. Sponsors and CROs are committed to the scientific integrity of clinical trials and the research process. But we cannot ignore the inherent conflict of interest between taking difficult—and often costly—actions to do what is right for a trial, and taking the actions that will propel the drug to the next milestone.

Independent data monitoring committees and endpoint adjudication committees mitigate bias, be it from the investigator, provider, sponsor or CRO. Independent oversight committees also reduce the perception of bias for situations when optics do matter. Sponsors need an arms-length relationship with committees and committee members.

 

Understanding Committees

DMCs and EACs include independent medical physicians—and perhaps a statistician—who review study data. Both committee types require charters that define their review process and responsibilities. Each has a different purpose. The DMC focuses on monitoring aggregate data trends to advise on study continuation, while the EAC looks at patient-level events to provide an expert assessment on them.

The Data Monitoring Committee goes by a variety of names, including data safety monitoring board and data safety board. All clinical trials require safety monitoring, but not all require a DMC.

The DMC experts sit arm’s length from a clinical trial and look at the overall trial or clinical program data as it’s unfolding. Unlike the sponsors and study CROs, the DMC has access to unblinded data that is reviewed for early indicators of safety problems with the drug.

According to FDA Guidance, here are examples of when a DMC is needed:

• The study is being performed in a potentially fragile or vulnerable population, such as children, pregnant women, the very elderly, the terminally ill or those with diminished mental capacity.
• When the therapeutic being studied has a known toxicity—e.g., the drug is known to cause blood problems—the DMC should include a hematologist. 
• A particular safety concern has been identified—e.g., if the procedure for administering the treatment is particularly invasive.
• The therapeutic is a new molecular entity.
• The trial is long, and investigators may leave and new ones join. The DMC provides a stable view of the safety of the compound.
• It’s a large, multi-center trial.
• The study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion.
• The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint.

 

The Endpoint Adjudication Committee—also called a Clinical Endpoint Committee—adjudicates identified patient events to better classify clinical endpoints. The panel of independent adjudicators reviews blinded clinical trial information to give an expert opinion on patient-level safety or efficacy events of interest according to predefined rules.

We’ve all been in situations—in the family, classroom or at work—where several people appear to be ill with the same thing. One person’s doctor says it’s a cold. Another person’s doctor calls it the flu. One calls it a viral syndrome and another attributes it to allergies. Yet everyone has the same symptoms. An independent EAC creates standard definitions for endpoints. So, returning to that cold/flu/allergy example: The EAC develops precise definitions for “cold” and “flu.” Then it looks at the trial data to classify patients very specifically. This brings precision to the study endpoints, making regulators happy and potentially reducing study size.

EACs are especially important for certain therapeutic areas, where the endpoint is subjective and/or differs from the overall study’s therapeutic area. For instance, a cardiac event may be evaluated in a diabetes trial to assess whether the cause was drug-related or not. The same concept applies in many therapeutic areas where clinical trial investigators may have a different specialty than a clinical event of interest. Those events can be evaluated by the independent, blinded Endpoint Adjudication Committee’s medical experts. EACs can be comprised of experts in multiple specialties to properly evaluate an event. For instance, Cardiologists and Neurologists may both be included within an EAC that will adjudicate stroke.

Here are examples when an EAC is important:

• The study has complex and/or subjective endpoints.
• The study cannot be blinded—such as most device trials.
• The study has high enrollment and/or long duration.
• The study is global, with cultural differences across sites.
• Endpoints of interest fall outside the therapeutic expertise of the investigator.

 

A Regulatory Edge

Regulators in the US, Europe, Japan and Australia, already require very rigorous and transparent standards in order to accept information. The FDA recently expressed a desire to partner with industry to streamline safety committees, and it has increased mention of independent expert committees in recent guidance. Deployed correctly, expert committees bolster regulatory strategy prior to submission, which speeds the process and lowers cost-to-market while helping ensure optimized reimbursement.

In addition, several publications about Expert Committees with regulatory authorship have come out of private-public efforts, such as the Cardiac Safety Research Consortium and Clinical Trials Transformation Initiative. These publications articulate current thinking on Endpoint Adjudication/Data Monitoring Committee best practices for both drug and device studies.

 

A Customized Early-Warning System

Deploying independent expert committees is about far more than simply checking a regulatory box.

Committees that are consistently monitoring data and adjudicating endpoints can help sponsors identify issues early. Consider it an early-warning system: Maybe the trial needs to be stopped; if that’s the case, you want to find out sooner rather than later to avoid harm to patients and additional investment. More often, expert committees detect early problem trends that allow a trial to be modified and continue for a better chance at success.

In addition, expert committees may be able to share insights for future development and identify additional labeling to pursue. One simple labeling change can make a tremendous difference in commercial revenue—far more than the cost of external review.

 

Guidance Across the Lifecycle

Earlier is better. Scientific review should begin during the pre-study phase, and have medical expertise woven into every aspect of the study. Our experience shows—and common sense dictates—that planning your committees at the onset of clinical trial design, rather than during trial conduct, provides better insights and value. The later you bring in the expertise, the less useful it may be for a strategy that is already underway.

You want access to these insights throughout the lifecycle of the trial. This allows you to detect signals during the trial’s course that help decide whether, and how, to keep moving forward.

The value doesn’t end when the trial ends.

Although independent expert committees more commonly focus on prospective review of clinical trial data, companies are gaining valuable, competitive advantage producing insights from the retrospective review of data from select trials. Thoughtful deployment of committees in the post-marketing phase has enabled companies to organize, define and gain insightful expertise to bridge from clinical trial to commercialization—and beyond.