Complete, Rapid Reporting of Clinical Trials: A Necessary Component of the Pandemic Response
With Deborah A. Zarin, MD, program director, Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard
Health professionals and the general public wake up every morning to a blast of information about the pandemic and possible treatments to either prevent infection or improve outcomes in those who are infected. While opinions and speculation abound, we need results from well-controlled randomized clinical trials adequately powered to enable reliable conclusions about the benefits and harms of treatment options. And — as with most things we’ve learned in this pandemic — the faster we have answers, the better.
For years, we have been involved in the development and evolution of ClinicalTrials.gov, a place where clinical trials are registered and the results can be recorded. A series of laws and policies require that most clinical trials (with certain exceptions) be registered at study initiation; in addition, in the U.S., certain trials are required to post their summary results within 1–3 years (depending on various factors) of study completion. These policies are designed to ensure that all studies report their results; standards and quality control processes are in place so that the reported results are complete and not misleading. There are penalties for lack of compliance, and although reporting has been imperfect, it is improving. There are now results for over 45,000 studies, about half of which do not have associated publications.
Rapid dissemination of results is especially critical during a pandemic. In an ideal world, each set of study results would be made available to inform future research, clinical or policy decisions. However, this can only happen if study results are reported accurately, completely and within a relevant timeframe. Results from studies of possible treatments for COVID-19 are especially critical, given the high stakes involved. Of 558 interventional clinical trials with at least one U.S. site assessing medical products for treatment or prevention of COVID-19 registered on ClinicalTrials.gov, 36 have been reported as completed or terminated (26 completed, 10 terminated) and results are only available in ClinicalTrials.gov for 3 (2 completed, 1 terminated). Pre-print servers and press releases accelerate the dissemination of results from some trials, but we know from decades of research that such relatively uncontrolled methods of study dissemination tend to be selective and potentially misleading. Full peer-reviewed publications of results are only linked in ClinicalTrials.gov for 28% of the completed or terminated COVID trials. Despite the promise of eventual widespread vaccination, hospitals are currently at (or past) capacity with COVID patients who need treatment now. The earliest COVID trial results would be “due” in ClinicalTrials.gov a year from now — clearly too late to help the millions of people who will need treatment while we are waiting.
As we make decisions about what treatments are recommended and how to plan for the next trials, access to complete and reliable results is critical. If only dramatic results are available, there is a risk of misunderstanding the total picture of evidence about a treatment. Furthermore, new research studies should be informed by the landscape of all relevant completed and ongoing trials as they occur. If not, multiple trials could be initiated that are addressing the same question, or that are addressing questions for which we already know the answer. This can cause harm by unnecessarily burdening those trial participants or create opportunity costs by not having participants recruited into potentially more valuable studies — an especially detrimental effect during a pandemic when patient volunteers are greatly needed for rapid recruitment into trials with large enough sample sizes and high-quality design to produce reliable results.
The requirement for trial registration has allowed us to track the explosion of COVID-19 clinical trials since the pandemic began.
Figure: Number of COVID-19 Studies Posted at ClinicalTrials.gov, by Funder Type
2,243 COVID-19 interventional clinical trials were registered on Clinical Trials.gov as of Dec 1, 2020; 558 were treatment or prevention trials with at least one US site. As Krumholz has reported, many of these studies are small and unlikely to yield definitive results when considered alone. In addition, the lack of upfront coordination hinders efforts to combine data from studies that use different outcome measures in different populations.
In contrast, the RECOVERY trial provides an excellent example of the power of coordination when more than 170 sites come together taking advantage of every opportunity for a trial participant to contribute. The program answered several critical therapeutic questions quickly and has moved on to testing additional therapies.
A simple search of ClinicalTrials.gov prior to study design and initiation could help to solve problems like trial duplication and inefficiency. Researchers and sponsors could use the search results to inform their choice of study question and avoid inventing a new study design or outcome measure when a “common” or “standard” is already evolving. Gaps in the research landscape could more readily be filled while avoiding unnecessary duplication of existing or completed research.
An issue of immediate importance that calls for active coordination is the use of therapeutic antibodies. EUAs have been granted for bamlanivimab and casirivimab + imdevimab because of definitive results in small trials showing a reduction in symptoms and need for hospitalization. However, multiple questions remain unanswered and the current use of therapeutic antibodies is suboptimal. Traditionally, industry would fund studies that are designed to support marketing applications or new indications, while, over time, the academic and clinical practice community would address issues necessary to inform clinical decision making. This system may or may not be “good enough” in normal times, but it is not producing the right array of clinical trials that are needed right now to address urgent clinical questions.
Table: SARS-CoV2 Interventional Monoclonal Antibody Studies with >/=1 U.S. site
Given the time frame in which we need to understand additional issues about dosing, comparative effectiveness and patient selection for therapeutic antibodies, there may be a need for more central control over the prioritization and conduct of trials in this arena.
There is a part of FDAAA that authorizes the Secretary of HHS to require results reporting within 30 days if it is “necessary to protect the public health” — the public health emergency that we are currently experiencing should satisfy this criterion. Of course, researchers and sponsors could simply choose to report their results rapidly. In fact, the NIH set a good example when NIAID posted results for the ACTT trial within 127 days of its completion — long before the results were due. And the NIH overall has encouraged grantees to report more quickly to ClinicalTrials.gov. The numbers, however, suggest that such voluntary action is rare. We urge HHS, the FDA and NIH to use this provision of FDAAA, as well as other tools available to them, to get study results into ClinicalTrials.gov as rapidly as possible; this will improve the ability of our clinical trials system to reliably and efficiently answer key questions essential to optimize treatment in the midst of this crisis.
There are multiple efforts underway examining the use of common platforms to optimize the design of protocols for therapies attempting to treat the same diseases or specific health problems. In the meantime, we urge sponsors and investigators to use ClinicalTrials.gov to inform landscape analyses prior to starting new studies, and to post their study results as rapidly as possible so that they are available to inform research, clinical and policy decisions.