The New HHS Trial Reforms are More Ambitious Than They Look
A Deeper Dive into Operation TrialBlazer
Yesterday was a big day for clinical trial abundance.
HHS announced “Operation TrialBlazer”: a package of reforms aimed at making the US clinical trial system faster, cheaper, and more globally competitive. The announced reforms are broad and cross-cutting but focused heavily on early-phase trials, an area where the US is rapidly losing ground to other countries that have made it easier to advance promising therapies.
Others have already started to weigh in. Ruxandra shared some thoughts yesterday, calling the new HHS initiative a “welcome move.” Alex Tabarrok was more skeptical. While he was supportive of some the reforms, he also argued that the government missed an opportunity to follow Australia’s approach to phase I trials. As Ruxandra has discussed on this blog, Australia allows most phase I trials to proceed without any prospective government review under the supervision of an ethics committee. That approach has made early-phase trials in Australia faster and cheaper—and it has helped attract trials away from the US.
I share Alex’s desire for further reform. But I think HHS deserves more credit here. The officials who developed this plan appeared to be doing two things at once: improving the current clinical trials system, while also laying the groundwork for more transformative reforms that may eventually require Congress. Given the constraints they faced, that is no small achievement.
Reforming the current system
HHS is taking numerous steps to reform the current approach to trial oversight, including new FDA policies and new resources for manufacturers. Among the most important new initiatives is its effort to provide greater clarity around its phase I drug manufacturing requirements.
As Ruxandra noted in her overview, onerous manufacturing “requirements” are one of the biggest barriers to starting Phase I trials; and are probably a major reason we are losing trials to other countries like China and Australia. The reason these requirements pose such a great challenge for researchers—and the reason I put “requirements” in scare quotes above— is because there is little agreement on what FDA’s phase I manufacturing requirements actually are.
Researchers and drug companies believe that the FDA requirements are onerous. And they act on that belief: For example, they often go out of their way to document a full commercial manufacturing process, even for products that are still in early phase trials. Yet the FDA itself has suggested that its regulations are more flexible than that, and that early phase trials don’t actually require this level of documentation.
A stark example of this disconnect appeared just last week, when the Reagan-Udall Foundation issued a report proposing reforms to FDA’s oversight of early phase trials. The report, which was informed by industry experts, suggested that FDA’s “stability requirements for study material often far exceed study duration”. For example, a company might have to prove that its investigational drug is shelf-stable for six months, even if the trial only lasts for a few weeks. If that were truly required, that would be a clear example of an excessively onerous FDA requirement. But FDA’s own regulations appear to state otherwise: they only require companies to submit “information sufficient to assure the product’s stability during the planned clinical studies.”
This kind of confusion is common in drug development. Drug makers have a tendency to be excessively risk averse and “overcomply” with perceived FDA regulations. FDA, for its part, has a tendency to ask for more data than necessary. The incentives push companies towards excessive documentation. The new clarifications help by laying out—for both industry and for FDA reviewers—what the phase I manufacturing regulations actually require. Even if the clarifications seem minor, they could make a big difference in reducing unnecessary documentation in early phase trials.
Setting the stage for transformative change
Clarifications are helpful, but if we truly want to see the US compete with other countries like China and Australia, we will need to explore different regulatory models altogether. To that end, I was excited to see HHS announce a new pilot program that may help lay the groundwork for a more ambitious approach.
The pilot is designed to improve the speed and quality of IND submissions by partnering clinical trial sponsors with “qualified research institutions”. These institutions, which could be academic medical centers or contract research organizations, would provide expert consultation to sponsors developing their IND packages.
The pilot is designed to achieve two goals: First, by giving sponsors access to expert institutions, it should help them produce higher-quality IND submissions that are less likely to result in clinical holds. Second, the pilot could speed up IND review by allowing sponsors who work with these institutions to submit components of their IND application to FDA on a rolling basis. Along those lines, the pilot will also explore ways for trial initiation steps—including IND preparation, site contracting, and IRB review—to proceed in parallel. The hope is that by the time of the formal IND submission, FDA’s review will be substantially complete, ethics review and contracting will already be underway, and the study can begin much faster. This could shave months off of IND development times.
On its face, the pilot represents and exciting new approach to clinical trial reform. But it also may be laying the groundwork for something larger: the eventual creation of an Australian-style clinical trial notification system in the US. Australia’s system depends on the existence of a set of independent committees called HRECs who possess the expertise to determine whether a trial may proceed. By creating a class of qualified research institutions, FDA is also building the institutional capacity that an Australian-style notification-based system would require.
To be clear, it’s not obvious that this is HHS’ intent. And even if many in the administration wanted to move towards an Australian-style model, they would have good political and legal reasons not to say so explicitly in this roadmap—it’s a move that would likely require Congress. But if I wanted to move the US towards an Australian-style clinical trial notification scheme, this is exactly how I’d go about doing it.
Modernizing Trial Infrastructure
Too often, trial reform efforts focus exclusively on FDA. But in addition to regulatory reforms, the US also needs to build national-level infrastructure that makes trials easier to run—things like standard approaches to contracting, centralized IRB review, and the ability to leverage electronic health records to run trials. Countries like China are making major investments in their national clinical trials infrastructure, and the US will need to do the same if it wishes to keep pace.
That’s why I was pleased to see that the roadmap calls on other HHS agencies to help build that infrastructure: NIH anticipates leveraging its position as a major funder of early-phase research to push for greater efficiency in research. ONC, which oversees health IT, will support technology standards for trial matching and digital trial protocols, streamlining trial operations and patient recruitment. HHS is also exploring regulatory reforms that could remove barriers to patient compensation. In my own writing, I’ve advocated for much greater involvement from NIH and ONC in building trial infrastructure, and the work outlined in this roadmap is a promising start.
The bigger reform agenda
Operation TrialBlazer is a strong start. But if we wish to truly reform clinical trials in the United States, there is much more to be done. I hope that we continue to explore an Australian-style notification model for early phase trials. I’d also like to see even greater investment in trials infrastructure, and a broader effort to improve the efficiency of our large late-phase trials, which are the largest driver of overall clinical trial costs. And while these administrative actions are helpful, many of the most ambitious reforms will require legislation from Congress.
Still, for those of us who have been advocating for clinical trial abundance, yesterday’s announcements from HHS were an important step. They are a sign that the administration is coordinated, is taking the challenge seriously, and is setting the stage for further reforms to come. That’s great news for clinical trial abundance.