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What we know about Makary’s emerging proposal for ‘continuous trial’ reforms

Life Sciences | By Alexander Gaffney, MS, RAC

Oct. 23, 2025

FDA Commissioner MARTIN MAKARY has repeatedly said in recent months that the agency is preparing to unveil a major new proposal related to “continuous trials,” which he says could help make the drug development and regulatory review processes more efficient. Here’s what we know so far about Makary’s plan.

Background and context

  • Most clinical trials operate according to a stepwise approach intended to minimize the overall costs –and risks – of drug development: A company will pursue clinical development in phases, with each phase intended to provide data about the drug to determine if the company should pursue additional development. For example, a Phase 1 study will typically assess a candidate drug’s safety and test a range of doses, Phase 2 will assess additional safety endpoints and initial efficacy endpoints, and Phase 3 is most often the stage at which companies will collect “pivotal” data to support their eventual application to regulators. While these phases of progression are not absolute (for example, some Phase IIb studies are sufficient to support a regulatory application), they are generally representative.
  • The traditional phases and designs of clinical trials have long spurred companies to find innovative approaches meant to solve problems. For example, most clinical trials have control groups, participants given either a placebo or a comparator active treatment, to generate evidence about safety and efficacy. This requirement, though, has led companies developing similar drugs to consider the use of a shared or common control group as part of a “master protocol” design, as championed by Janet Woodcock, the longtime head of FDA’s drug review division. Another approach is to use a synthetic control group (such as a natural history study or data from a patient registry).
  • One of the biggest features of the phased approach to clinical development can also be perceived as one of its flaws. Because each defined phase of clinical development is run according to a protocol and typically as a separate study, there is generally a hiatus in the development program after the trial ends, during which the company examines the data before starting the next phase of development. While this assessment ensures that companies are learning from the study to make future plans, including deciding whether to proceed with further development, it also slows the pace of product development.
  • However, some trial designs get around these pauses to make clinical trials more “continuous,” without the stoppages between phases. The concept of a “continuous trial” isn’t a new idea, either for industry or the FDA. The agency convened a workshop on the topic in February 2024 focused on oncology trials (which AgencyIQ covered in depth), which explored some of the practical challenges associated with seamless trials based on experience with actual studies, such as a Phase 2B/3 study looking at Merck’s Gardasil HPV vaccine. Other examples include SUNRAY-01, an assessment of Eli Lilly’s olomorasib; the Phase 1/2 AURA Study of osimertinib in patients with advanced non-small cell lung cancer; the B-FAST trial of multiple targeted therapies and immunotherapies to treat certain patients with NSCL; the AGILE trial of Covid-19 treatments; a different GBM AGILE trial evaluating glioblastoma treatments; and the HORIZON III study of cediranib. These trials tend to fall into two categories: “operationally seamless” designs allowing one protocol to span several development phases, or “inferentially seamless” designs allowing multiple phases to be considered as part of a single analysis using statistical methods.
  • The FDA has also already released limited guidance on this topic. The agency released a guidance document during the first Trump administration supporting the idea of “seamless” clinical trials that would allow companies to avoid the start-and-stop of clinical trial phases, and instead shift more toward continuous studies. A second guidance mentions the concept in the context of adaptive trial designs. And the FDA in recent years has also supported the idea of ongoing studies to support the collection of confirmatory evidence.
  • The first of these guidance documents offers the FDA’s advice on the use of “expansion cohorts” to ensure rapid scale-up of trials. The guidance, which was finalized in 2022, specifically applies to first-in-human clinical trials for oncology drugs and biologics. As the FDA explains in the guidance, the “FIH multiple expansion cohort trials are intended to expedite development by seamlessly proceeding from initial determination of a tolerated dose to assessments that are more typical of phase 2 trials (i.e., to estimate antitumor activity) within individual expansion cohorts.” The guidance also explains that sponsors should be prepared to provide scientific rationale for each proposed cohort, “including specific endpoints, eligibility, monitoring plan, and statistical considerations.” However, a significant portion of the guidance is dedicated to the potential risks associated with this approach.
  • The second guidance relates to the use of “adaptive designs,” including features allowing a trial to change its scale to include more patients, different patient populations, additional treatment arms or modified endpoints. An important part of this approach is the use of prospectively planned interim analyses, which determine further actions that should take place while the trial is ongoing, such as scaling up a study. While this approach can be challenging for a variety of different reasons including logistical concerns related to trial conduct and integrity, as well as statistical challenges, it allows flexibility and continuity in a product’s development program.

In recent months, FDA Commissioner MARTIN MAKARY has frequently touted his vision for seamless, continuous trials

  • Makary has been talking about his vision for continuous trials since at least May 2025, when AgencyIQ first started to hear him regularly mention the concept in public appearances. Below, we have tracked down what we think are all the examples of his mentioning this concept in public remarks to date.
  • In a keynote address at the Food and Drug Law Institute (FDLI) conference in May, Makary said he wants to “get decisions to sponsors quicker, and I think it’s been a longstanding goal at the agency. But if we can think big, we can ask ourselves: What can be done in the design of that process? Can we think really big and ask, can we run more continuous trials with the endpoints in the cloud available to the reviewers to look onto, rather than resubmitting large applications after each step? You wouldn’t submit a 64-page application after your freshman year to start your sophomore year in college, and again from your junior year, and again before graduation day. And so, can we think creatively about ways to run more continuous trials and use cloud-based endpoints? These are, by the way, ideas that folks in the industry have proposed in the past.”
  • In an interview with the Epoch Times in July, Makary lauded the merits of “continuous trials” when asked about things the FDA could help make more efficient. “[T]here’s a lot we can do more efficiently,” Makary said, according to a transcript of the interview. “We can run more continuous trials. The idea now is you do a step and submit an application, do another step, resubmit another application; you do Phase 1, Phase 2, Phase 3. You wouldn’t apply for college after every year of college.”
  • In another appearance on C-SPAN (skip to 18:35) in July, Makary said, “We think there is a lot of wasted time where we can increase efficiencies without cutting corners on safety to deliver more cures and meaningful treatments.”
  • In an interview with CNN’s Sanjay Gupta on Oct. 3, Makary mentioned his interest in continuous trials using now-familiar language. “Look, well, first of all, you have to keep the same high standards of safety because that’s our number one job. But when an application sits on a desk for three months, you’re not increasing the safety evaluation by just adding time. There’s so much idle time. For example, after a preclinical study, the company reapplies then for a phase one trial, then they reapply for a phase two, then the reapply for a, you know, Phase 3, and then they do a final [New Drug Application]. You wouldn’t apply for college after each year. So, we can run more continuous trials using modern technology to have eyes on the endpoints of a trial in real time. Our regulators look on and we have a lot of offices. It’s a bureaucracy and the applications get farmed out when we could use our convening power to bring people together in a tumor board style meeting. That’s something that we’re starting. And so, we can get decisions out in our new program in weeks, which is unprecedented at the FDA,” Makary said, according to a CNN transcript of the interview.
  • In an interview hosted by PragerU in October, Makary seemed to indicate that the concept of continuous trials could be a cornerstone of how the agency plans to accelerate drug approvals. “We’re going to run more continuous trials,” he said. “We’re going to use cloud technology to watch the endpoints so the regulators look at studies as they’re occurring,” he added.
  • And in an “FDA Direct” episode on Oct. 17, Makary made yet another mention of continuous trials. “People can see early on signs of a real game-changing therapy. And so we want to know early. We want to facilitate. We want to increase communication with the company. We want to eventually have some of our streamlined reforms that are taking the final [Biologics License Application]-NDA application down to a month or two for a review time. Eventually, we want to take those reforms downstream and go to the [Investigational New Drug application], phase one, phase two. And so between the steps, there’s a lot of idle time, and there’s probably an opportunity for continuous trials and endpoints in the cloud at some point. But this is the initial step. It’s going to take a large bureaucratic process that may involve people,” he said, according to an FDA transcript.

Makary’s vision, as outlined over the past six months, has mapped a consistent plan for a future continuous trial policy

  • The commissioner’s basic idea seems to be that the FDA should be able to monitor sponsors’ studies “as they’re occurring” so both regulators and sponsors have a better sense of what to expect. These data would be available in a cloud environment, allowing the FDA – and potentially other regulators – to follow along with the trial as it is happening. The continuous trial design would also allow the company to accelerate its development process, making both drug development and the FDA’s review faster and more efficient.
  • The new Commissioner’s National Priority Voucher Program also seems to complement Makary’s vision for continuous trials. The CNPV is built on the idea that if regulators have advanced notice of what is happening in a trial, then they will be able to make decisions about a drug in weeks instead of months. [Read AgencyIQ’s analysis of the first nine CNPV recipients here.]
  • As Makary previously noted, industry has already expressed support for his vision. For example, as part of the Prescription Drug User Fee program commitment letter, the FDA had committed to prioritizing the launch of several demonstration programs meant to “explore [the] application of cloud-based technologies in applicant-regulator interactions.” A 2023 assessment of this approach was published by Eagle Hill Consulting, and the FDA also published its own response, which provided some specifics about plans to accelerate cloud adoption and build out infrastructure to address challenges identified in the consultant’s report. The commitment letter also called for demonstration projects to “develop increasingly rich and flexible technical capabilities that can be leveraged for multiple purposes by regulators and industry, either internally within a regulator’s or industry’s environment, or through a trusted third-party.” The results of these three initial demonstration projects haven’t yet been made available.
  • Another key part of the commitment letter called on the FDA to develop guidance concerning “complex innovative” trial designs and to boost staff capacity. For example, by the end of fiscal year 2025, the agency was supposed to have published a draft guidance on the “use of Bayesian methodology in clinical trials of drugs and biologics” – an important statistical concept that is helpful for flexible trial designs. However, the FDA has not yet published this guidance document (though it is on its 2025 guidance agenda, and a 2010 guidance addresses Bayesian statistics in medical device clinical trials).

Analysis

  • As of now, the specifics of Makary’s continuous trials plan remain sparse. We don’t know when to expect this policy, whether the FDA is waiting to see how its CNPV pilot program fares before announcing next steps, whether Makary will provide additional details in a medical journal in advance of the official publication of a policy, or other key details. Makary and his top scientific deputies, including Center for Biologics Evaluation and Researh head and Chief Medical and Scientific Officer VINAY PRASAD, have generally been relatively open about the development status of their marquee policies. That we haven’t heard Makary talk about when to expect this policy leads us to believe that it is not yet close to publication.
  • There are plenty of practical challenges associated with Makary’s idea for continuous trials, including some previously identified by the FDA itself. For example, its expansion cohort guidance makes note of dozens of potential concerns, including the risk that rapid enrollment and the “evolving nature of the information obtained in these trials” may subject participants to harms from minimally characterized toxicity profiles in ways that slower, more deliberate enrollment might not. Companies also need to be prepared to “disseminate new safety information to investigators, [institutional review boards], and regulators as soon as possible.”
  • The continuous trial approach may not be a good fit for all trial sponsors or all products. A stepwise approach to development can be helpful for companies that are most focused on the risks and costs of drug development, rather than on the speed of drug development. For companies focused on speed, however, continuous trials might be a good fit. However, even then, a continuous trial might not be the only answer. During the Covid-19 pandemic, some companies opted to make use of parallel clinical trials, with phases of testing proceeding concurrently based on interim results (see Figure 8 in this Government Accountability Office report). This approach allows companies to keep trial protocols relatively simple and straightforward as compared to an adaptive, seamless trial.
  • One could also argue that one of the key benefits Makary is interested in – the FDA having quicker insights into the results of a clinical trial – doesn’t depend on a continuous trial as much as the agency having access to the trial data in the cloud. And this may be the important policy development for companies to watch because we very much doubt that most companies will be comfortable undertaking seamless trials (which they can do right now anyway), but many might be willing to provide the FDA greater access to ongoing clinical data if it meant they could accelerate a review process. It could be the case in the future that participation in the CNPV program could be predicated on the agency’s cloud access to a study environment, for example.
  • Another significant challenge for the FDA could be the technology component of doing this. While the FDA is no stranger to the use of cloud technologies (and neither is industry), any adaptation takes time, money and effort. In the current fiscal environment, and following the termination of some of the agency’s most experienced technology leaders (including VID DESAI, its former chief technology officer), the agency may lack the capacity for a major technological undertaking such as this unless it heavily leverages platforms already in use in industry that also already meet federal security standards (such as FedRAMP). These platforms do exist (and we wrote about one effort leveraging existing FDA technologies last year), but we suspect the operational side of this plan will be far more complex than the policy side of it.

To contact the author of this analysis, please email Alec Gaffney ( agaffney@agencyiq.com)
To contact the editors of this analysis, please email Kari Oakes ( koakes@agencyiq.com) or Jason Wermers ( jwermers@agencyiq.com).

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