Let’s start by going into the way back time machine. It was in 1962 that Congress amended the Food, Drug and Cosmetic Act (FD&C Act) to require that drugs be effective as well as safe prior to approval for marketing. The law required that effectiveness of a drug was to be established by substantial evidence, defined as “adequate and well controlled investigations.” The standard FDA interpretation has been that “investigations” means more than one study. Thus, the requirement for two adequate and well-controlled studies. In 1997, Congress amended the FD&C Act to make it clear that FDA may consider data from one adequate and well-controlled study and confirmatory evidence sufficient to establish efficacy.
As biologic products are regulated under Section 351 of the Public Health Services Act (PHS Act), the legal requirements for biologics are slightly different. The PHS Act requires that biologic products are “safe, pure and potent,” where potency has been determined to include effectiveness. Coming back from our time machine, in recent years FDA has largely considered the efficacy requirements for drugs and biologics to be similar.
For drugs and biologics being developed for rare diseases or for many cancers, FDA has selectively implemented the 1997 revisions and generally requires one adequate and well controlled study together with supporting evidence. In oncology, one adequate and well controlled study with multiple endpoints (e.g., response rate, progression free survival, overall survival), in which the expectation is that the study will meet its primary endpoint, and the secondary endpoints will also favor the investigational agent, has been routinely accepted. This approach has also been true for additional indications of marketed products for long-term chronic use. In these cases, one pivotal study is generally sufficient for the follow-on indications. The FDA guidance, Demonstrating Substantial Evidence of Effectiveness with One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence dated September 2023 provides additional guidance concerning the one-study approach.
If we compare where we are now with where we were in 1962, I think it is fair to say that clinical research has evolved. For example, multinational clinical studies with large numbers of patients and multiple endpoints are now the norm rather than the exception. Each “adequate and well controlled” study is required to be designed and powered such that a positive study will be based on both statistically and clinically significant differences between treatment groups. These clinical development programs generally include two or more similarly designed studies that are conducted at the same time. Replication of the data further supports the robustness of the findings.
FDA has announced and published in the New England Journal of Medicine (NEJM) (Prasad V & Makary MA. One pivotal trial, the new default option for FDA approval – ending the two-trial dogma. N Engl J Med. 2026;394(8):815-817) a policy change whereby the FDA standard will now be one rather than two “adequate and well controlled” studies. This policy change has been met with criticism and mixed reviews. This may be related to how the message was relayed and the unanswered questions, to the actual message itself or perhaps to both. Normally, when FDA proposes a policy change, a new draft guidance is issued. The first step is the drafting of the guidance and internal FDA review. The draft guidance is then released to the public for comment prior to finalization. In the current case, neither of these two steps occurred. As outlined in the title of the article, one pivotal trial is the new default option for FDA approval and we in the industry learned about it through a press release and a journal article.
Before unilaterally accepting this as the new norm, we need to keep in mind that no additional FDA requirements have changed. Studies still need to be powered such that a positive result will be both statistically and clinically significant. Conducting one overpowered study rather than two adequately powered studies will not help Sponsors develop their products quicker.
In addition, there are no changes in FDA requirements for safety. For example the FDA guideline, The Extent of Population Exposure to Assess Clinical Safety still applies to regulatory expectations regarding the number of subjects treated in a clinical programs for drugs for the treatment of non-life-threatening diseases intended for chronic or repeated use (6 or more months).
This guidance states that the safety evaluation during clinical drug development should characterize the safety profile of the drug. As most adverse events generally occur within the first few months of treatment, a minimum number of patients treated for 6 months at the clinical dose is needed to characterize the pattern of adverse events over time. The cohort of exposed subjects (those treated with the investigational product) should be large enough to observe whether more frequently occurring events increase or decrease over time, as well as to observe delayed events of reasonable frequency (e.g., generally 0.5%-5%). Usually, 300 to 600 patients are adequate. The overall incidence of adverse events or of certain adverse events may increase over time, resulting in the need to have data on patients treated with the drug for 12 months. In the guidance, 100 patients exposed for a minimum of 1 year is considered to be acceptable. When no serious adverse drug reaction is observed in a 1-year exposure period, this number of patients can provide reasonable assurance that the true cumulative 1-year incidence is no greater than 3%. The guidance goes on to say that the total number of subjects treated with the investigational product, including short-term exposure, should be about 1500. For drugs that may cause late developing adverse events or where events may increase in frequency over time, a larger database may be required. When controlled clinical trials are used to generate adverse event data to characterize the safety profile of a drug, clearly one study with a long-term follow-up is not going to be sufficient. If the clinical development program includes a robust Phase 2 dose‑ranging program with long term exposure, these data together with the data from the Phase 3 study may be sufficient to meet this requirement.
While the NEJM article states that one pivotal study will now be the default, it does not address the minimum requirements for the confirmatory evidence. Will this be similar to what we see for rare diseases, where this could be supported primarily by nonclinical data, or will the requirement be a robust Phase 2 program? If it is the latter, Sponsors who start Phase 3 based on limited data from early studies would still be required to submit two pivotal trials.
Again, the devil is in the details. The NEJM article outlines some of the requirements for a single study to stand on its own. The authors admit that there may be situations in which two studies are required and they provide examples. FDA will carefully review study designs with particular focus on controls, endpoints, effect size, and statistical analyses. Sponsors should discuss with FDA the study designs, sample sizes, and minimum criteria for clinical and statistical significance. We in industry also need to ask the FDA hard questions and listen carefully to the responses, requesting clarification where necessary. I say this as it has become clear from reading some of the “complete response” letters that FDA has made public after NDA/BLA reviews, that the FDA and Sponsors may not have been on the same page during clinical development. For example, a response from FDA that the study approach appears reasonable should not be interpreted as complete agreement. It is up to the Sponsor to present their case, together with supporting information. I am reminded of a regulatory interaction I had many years ago. In discussing the clinical studies we planned to include in an NDA, we were told that the information was sufficient for “filing and review,” but that FDA could not comment on the “approvability.” This is important to remember, as the decision on “approvability” can only be made after review of the data. All of the additional considerations that we in industry might get for developing a product that has the potential to produce a significant clinical benefit (e.g., fast track, breakthrough, priority review) only get our applications to “filing” stage. The data must meet the required efficacy and safety standards to assess “approvability.” When the studies are reported, the results must be robustly clinically and statistically significant with a positive benefit-risk balance.
In conclusion, I find that this new “default option” is not as simple as it appears due to unanswered questions as to how to fulfill the other two major requirements: sufficient safety data and confirmatory evidence. I also fear that this will result in a greater number of “complete response” letters wherein the request is that the Sponsor conduct another study to support efficacy, safety or both.
Clearly if one chooses to focus a clinical program on one pivotal study, careful study design and flawless execution, together with written agreement from FDA on the strategy, including how the required safety data will be collected as well as the acceptability of the confirmatory evidence, are a must.
We at PROMETRIKA are well versed in these requirements and are helping our clients with regulatory, statistical and clinical support to navigate these regulatory hurdles of clinical program design and execution that meet regulatory requirements and result in expeditious approvals.
