Experts, FDA officials discuss future of clinical trials

Officials from the US Food and Drug Administration (FDA) and participants from the JAMA Summit on clinical trials recently highlighted the relationship between the randomized controlled trial (RCT), the downsides of RCTs, and the gap that exists in implementing trial results in clinical practice.

The paper, published as a special communication in JAMA, was a key focus of the first JAMA Summit, a two-day meeting where stakeholders discussed how to better integrate clinical trials with clinical practice.

“Traditionally, clinical trialists and clinicians have worked independently, and, as the authors of the Special Communication underscore, their separate missions, incentives, and infrastructures have been siloed. The result is inefficiency in the performance of trials and limitations in their scope and impact,” Gregory Curfman, executive editor for JAMA, wrote in an editor’s note accompanying the paper.

Derek Angus, of the University of Pittsburgh School of Medicine, and colleagues said that RCTs “grew dramatically in importance” over the last half century but pointed to problems with the design and conduct of RCTs as well as the issue of trial results not translating over to clinical practice.

The authors noted that there is substantial clinical uncertainty in some areas despite the 40,000 RCTs registered every year on ClinicalTrials.gov and said treatment guidelines released by the US Preventative Services Task Force and by medical societies often are based in expert opinion and reference few high quality RCTs in their recommendations.

“Much of the problem arises because of the mismatch between narrowly defined RCTs and the broader context of clinical practice,” they said. “Even when therapies are used in the same populations studied in registration trials, new questions arise for which RCTs are lacking.”

When RCTs enroll participants that do not resemble the larger patient population for a condition, the results can be too narrow, with background care instructions contained in the RCT but not integrated into clinical practice, and outcomes may not match up with what patients and society view as important, they explained. On the other side, RCTs can provide broad answers that may help patients in aggregate but be harmful to certain patient populations.

“Additional RCTs or meta-analyses may improve prediction of who is most likely to benefit or be harmed, but patients and their clinicians are often left asking ‘This drug may work on average, but will it work for me or my patient?’” they added.

On the clinical side, there is a disconnect between clinical trial results and implementation in clinical practice, such as when physicians prescribe inappropriate therapies or fail to prescribe therapies that would improve outcomes. “Even when strong RCT evidence exists, it is frequently not followed in practice, leading to poor quality of care rife with both overuse and underuse,” the authors said.

The siloed nature of both clinical trial ecosystems and health care delivery means that clinicians are not implementing RCT results, and RCTs are not answering questions that would lead to improvements in the clinical setting.

“To meet societal goals, RCTs must be relevant and responsive to those receiving care, delivering care, or organizing the delivery of care,” Angus and colleagues wrote. “To be relevant and responsive, RCTs must address the correct questions and be timely, safe, and efficient. They must also be embedded in care in ways that ensure care changes in response to meaningful trial results.”

The authors proposed four areas of improvement, in ethical and regulatory oversight, study design, data infrastructure, and incentive alignment across both clinical trial and health care delivery ecosystems. Since ethical review in the US is decentralized, there is inconsistency in what is being labeled as research, they noted. “One solution is to broaden what counts as human participant research, capturing all activities intended to generate knowledge under uncertainty but, at the same time, make protection requirements fit for purpose, ensuring that each specific activity is not unduly burdened by requirements that are neither necessary nor helpful,” they said.

A patient and community-focused overhaul to study design is also needed. “If RCTs are to become more relevant and responsive to patients’ needs, patients and communities must be engaged in trial selection, framing, and design,” the authors explained. This includes looking to other industries, which employ A/B testing, and observing what novel study designs have been successful, such as the adaptive platform trials seen in the RECOVERY and REMAP-CAP COVID-19 clinical trials that let researchers add study questions as study amendments, rather than conducting a whole new trial.

Digital data collection is already occurring in clinical settings but does not always contain the level of data needed for an RCT and there is currently no standard for data collection or auditing for accuracy. While some organizations are leading standardization efforts in this area, standardization is not required, and uptake of standards has been slow.

Angus and colleagues said aligning the incentives of stakeholders who work in clinical trials and in clinical practice requires addressing the needs of each group with separate strategies. “One path to ensure greater relevance would be for health care systems, insurers, and patient groups to advocate for legislation that increases the proportion of RCTs whose funding or regulatory approval is conditional on proof of relevance to patients and other end-users, either through direct engagement or demonstration of post-research implementation of findings,” they said.

Engaging patients in RCTs may require creating financial incentives for hospitals and clinicians to participate in RCTs through the Merit-based Incentive Payment System or Hospital Value-Based Purchasing Program.

“[B]uilding trust and awareness that integration of research and practice yields better care may motivate patients to seek care at learning health care systems, further motivating health care system leaders to support RCT engagement,” Angus and colleagues said.

Pragmatic clinical research

In a related viewpoint opinion paper, FDA officials Ali Abbasi, Lesley Curtis, and FDA Commissioner Robert Califf, said that pragmatic clinical research is a good “middle ground” between RCTs and observational studies to answer clinical questions after market approval and “deserves much more attention and emphasis.”

“Such research holds special promise when embedded in health care systems, where it can help investigators avoid some of the most critical drawbacks of ‘traditional’ clinical trials, such as substantial, sometimes prohibitive costs, as well as the loss of diverse representation that can arise from conducting trials in environments that are unrepresentative of all clinical practice settings and patient populations,” they said.

The authors said FDA is interested in pragmatic clinical research in the areas of answering clinical questions in post-market studies, evaluating gene editing for rare diseases, and in chronic diseases such as diabetes, obesity, and Alzheimer’s disease.

“Pragmatic clinical research can inform regulatory decisions while also supporting patients, clinicians, health systems, and payers in assessing the comparative effectiveness of treatments and making determinations about the relative value of different interventions,” they said.

JAMA Angus et al

Experts, FDA officials discuss future of clinical trials

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