A multi-stakeholder panel convened by the White House’s Office of Science and Technology Policy (OSTP) today met to consider how to prepare to run emergency clinical trials during future pandemics, natural disasters and other public health emergencies. The meeting prominently featured FDA Commissioner Robert Califf, as well as extensive discussion of regulatory topics of interest.
The question of trial governance during an emergency
- The White House Office of Science and Technology Policy (OSTP), said Grail Sipes, OSTP assistant director for biomedical regulatory policy and a former FDA official, is “looking at a number of issues related to clinical trials for some time including trying to prepare our infrastructure to respond better and in a more coordinated way in case of emergency.” At the start of the Covid-19 pandemic, “we saw a very fragmented research response in this country where we had a number of trials being carried out separately in different places that sometimes were too small to generate actionable data.” Time was lost because of that “early fragmentation,” she added.
- The question before today’s panel: “Should there be a U.S.-level coordinating or governance function?” asked Sipes. If so, she asked, what would the structure look like? An important and related question: “How do we build a more diverse and comprehensive network of sites in this country?” And to that end, “How do we develop a ‘warm’ base for clinical research,” that allows such a network to be developed? And finally, she asked, what would international cooperation in these efforts look like?
- FDA Commissioner Robert Califf kicked off comments on the question of a governance panel, offering a broad perspective: “I just can’t emphasize enough my belief that any notion that we can have an entirely separate response to emergencies versus having standing capability, I think is just flat out wrong – and I want to express that in the strongest possible terms.”
- Martin Landray, the Oxford physician and epidemiologist who was a principal investigator for the famously successful RECOVER trial, a multinational adaptive trial of multiple new and repurposed Covid-19 therapeutics, agreed that “you can’t invent a system just because there’s a pandemic and assume it will work. You have to be running something all the time.” Admitting that he had an outsider’s perspective (and with AgencyIQ’s observation that Landray operates within a national healthcare system), Landray further proposed that infrastructure, rather than governance, is the crux of successful emergency preparedness in the clinical trials arena.
- Califf also made the distinction between what he called “discovery trials,” which he dubbed as being “in the classic NIH mode,” compared to “so-called regulatory trials, which are companies trying to get products on the market.” Each has a place and serves a different role – but Califf noted a potential gap: “It might be that what we don’t have is the governance structure that identifies the most important questions for public health, and makes sure those questions get answered.”
- To Califf’s point, Lindsay Baden, vice president of clinical research at Brigham and Women’s Hospital, observed that it would be a mistake “to abrogate the hypothesis generation – the pathophysiologic determination – that may come from smaller studies […] versus the registration trials that are trying to develop a new product and bring it forward as rapidly as possible.” Baden advocated for “flexibility in what type of governance we have” so that both smaller, innovative trials and larger confirmatory studies can be conducted, with governance also mindful of “the tempo of the problem” at hand.
- Califf later looped back to Baden’s call to preserve the role of smaller studies in a future emergency governance plan for trials. Agreeing that “there are small, good trials,” Califf added, “but if you actually look at the analysis of Clinicaltrials.gov, whether it’s during the pandemic or during normal times, a huge number of small trials are small crappy trials. They couldn’t have possibly answered the question they were designed to complete. They didn’t finish, and they’re not published. It’s an enormous waste of money” that otherwise could have gone to address issues of community engagement and revamping infrastructure, he said.
- A standing cross-sector committee could help reduce conflicting efforts at sites “when it came to hospitals really implementing trials,” noted Stacey Adam, associate vice president for the Foundation for the National Institutes of Health. For example, simply coordinating starting times of trials could help with efficiency of trial conduct. Such a committee could also serve to direct traffic and prioritize the most important trials, or the ones likeliest to have high yield.
Decentralization and diversity of trial participants are related – but achieving the former doesn’t guarantee the latter
- Large academic research centers can stand up trials, but as in the early days of the pandemic, they may see a geographic “mismatch with patients who had disease,” noted Esther Krofah, executive vice president of the Milken Institute’s Faster Cures. Bringing trials to where people are located is possible, but requires a heavy lift in terms of training, technology, and staffing – all high-dollar items. Krofah also pointed out that, absent the exigencies of a global pandemic, the interagency and interinstitutional cooperative agreements required to run trials in this fashion would typically take months or years to craft. Contracting, data interoperability, and workforce development are just some of the additional “mountains of issues” to be addressed in achieving a nimble decentralized trial infrastructure that could respond to public health emergencies.
- “More community integration and involvement” is needed for these changes to happen, said Lisa Fitzpatrick, founder and CEO of Grapevine Health. “Where are the community voices, who could be represented at the table to bring out these issues around trust, around health education, around what sort of infrastructure is needed on the ground?”
- A culture shift is needed to really get participants and other stakeholders on board to enroll a representative and diverse trial population, said Baden. “We need to normalize the concept that advancing knowledge is part of care, so that being in a study is not exceptional, but more routine.” Baden also advocated for an approach to decentralized or remote trials that takes into account “proportionality of risk,” so that a trial that involves a new molecular entity might be conducted in a different setting and with different oversight than a repurposed drug, “that has been given to tens of millions of people for another condition.”
- Genentech’s Shalini Mohan pointed out that with lessons learned from Covid-19, trialists now know that “there’s a lot that can be done without the patient having to come into a healthcare center.” She advocated for constructing streamlined trial protocols that might reduce the number of measurements in some cases, with the goal of reducing the burden on patients and trial sites. The endpoints selected should have direct impact on patient care, she added.
- Other topics addressed included the potential role for so-called retail health care sites – such as those found in retail pharmacies – to serve as points of recruitment, enrollment, and data gathering for clinical trials. Several attendees pointed out various strengths of these sites. Ramita Tandon, Walgreens’ chief clinical trials officer noted, pharmacists and pharmacies are often seen as trusted pillars of the community. More than 270 million Covid-19 vaccinations have been administered at retail pharmacies, Tandon pointed out. “We certainly had to train and leverage our pharmacists and pharmacy care teams to be able to work with the consumers and patients and get them prepared so that they felt comfortable,” she added.
- But conducting trials using such non-traditional sites will require extensive training and education – of pharmacy and retail staff, of pharmacists themselves, and of patients and communities, Fitzpatrick and Krofah each pointed out. Local trusted partners such as primary care facilities and schools, and even libraries, churches, and other community organizations will have to be educated and enlisted in the effort to help patients and families understand what research participation does and does not entail.
- Brian Anderson of MITRE Health said that the right data approach could be part of the answer. “I do believe that pragmatic trials are at least part of the answer — and having the kind of common data models that are easily deployed and can be used — for two reasons: One, for standard of care, but also for trials to be able to get to the ascertainment level that’s needed.” But he echoed some of Krofah’s earlier remarks and noted that many partnerships and agreements forged during the pandemic will be winding down, with no clear plan for how these will be refunded or prioritized.
- In the end, Fitzpatrick held firm on the need for authentic community engagement: “I really want to double down on the need to prepare the community for this,” she said. “People are not ready […] If you use the word ‘study,” you use the word ‘research,’ it’s taboo.” Fitzpatrick called on federal agencies and other trial funders to determine “what it’s actually going to take to diversify clinical trials, and continue to make efforts to get underserved communities, and Black and brown people in these trials.” Even though these are known problems supported by ample data, “the system isn’t moving.”
- The panel found general agreement in many areas, including acknowledging early failures and wasted resources when Covid-19 therapeutics were being investigated; ongoing geographic and communication disconnects between academic medical centers, which traditionally conduct interventional trials, and communities, especially communities with diverse populations; and potential benefits of a more coordinated approach to clinical trials conducted in response to a public health emergency such as a pandemic. Perhaps the strongest point of agreement was that any effective emergency governance structure would have to be gathered and organized, and infrastructure secured, as part of “peacetime” efforts, before the emergency strikes.
- However, points of disagreement surfaced, with FDA Commissioner Califf pushing back hard against the relative value of many smaller trials, and Krofah and Fitzpatrick taking Federal and private stakeholders to task for much discussion and too little action in efforts to achieve authentic diversity in trials.
- Some mechanisms outlined in the updated August 2021 final guidance on conduct of clinical trials during the Covid-19 pandemic were featured in today’s discussion, including alternative safety and efficacy assessments. Last August, AgencyIQ explored the current state of decentralized trials, including noting pending FDA guidance on the topic. The FDA has identified dozens of guidance documents that have relevance for the ongoing Covid-19 pandemic; the discussion today touched on several areas included in these documents, including master protocols and the use of remote monitoring devices. Former acting Commissioner and now Principal Deputy Commissioner Janet Woodcock has been a longtime advocate of master protocols, along with other flexible and innovative trial designs, to lower the point of entry for smaller and community-based trial sites. [ Read AgencyIQ’s analysis of the Covid-19 master protocol guidance here.]
- Notably, the Zoom platform showed over 600 people in attendance in addition to panelists, indicating a significant level of interest in the topic. The chat function for the meeting was heavily used by participants from many sectors throughout the session, with some attendees asking (mostly unanswered) questions, and others adding commentary to piggyback or amplify points made by presenters. Comments were officially requested by December 27, 2022, but OSTP staff asked those commenters to submit questions, ideas, and suggestions via that mechanism, by emailing [email protected] and including “Emergency Clinical Trials RFI” in the subject line of the email.
To contact the author of this analysis, please email Kari Oakes.
To contact the editor of this analysis, please email Alexander Gaffney.