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Market Approval Based on a Single Clinical Trial is Possible, But…: FDA
(Thursday, September 21, 2023) Although traditional FDA approval for a new drug or biologic requires evidence from two or more clinical trials, it is possible for the FDA to approve new products based on evidence from a single clinical trial under certain conditions. A new FDA Guidance Document released this week describes these conditions. The law provides the FDA with significant authority to consider data from one adequate and well-controlled clinical trial if the FDA determines that such data are sufficient to establish effectiveness. However, such data must be supported by additional confirmatory evidence to constitute substantial evidence of effectiveness. The new guidance builds on previous guidance on this topic to further clarify when a single well-controlled trial may be sufficient for approval of a new drug. Drug developers must provide substantial evidence of both effectiveness and safety to ensure that their product is fit for public consumption. Typically, it involves multiple clinical trials along with extensive non-clinical studies. However, in some cases, a single adequate and well-controlled pivotal clinical trial may suffice to demonstrate substantial evidence of effectiveness, if there is “sufficient” confirmatory evidence from alternate sources. This regulatory paradigm was originally introduced in 1997 with FDA’s first guidance on the topic released in 1998. Another guidance document released in 2019 further strengthened the principle of using one adequately designed well-controlled clinical trial for market approval by the FDA. The new guidance further builds on the previous Guidance documents. The principle has been used by the FDA over the last two decades with 100s of new products approved based on evidence from one pivotal clinical trial. It is crucial to understand that substantial evidence of effectiveness is a non-negotiable requirement for FDA approval. In most cases, it takes more than one clinical trial to show that a new drug is not only effective but also safe for its intended use. However, in some cases, other data (called “confirmatory evidence” by the FDA) may be added to the one from a single adequate and well-controlled clinical investigation to help meet the threshold for scientifically acceptable evidence for FDA approval. Confirmatory evidence must be of high quality and derived from appropriate sources. The new guidance document lists seven types of confirmatory evidence that may be acceptable to the FDA. Acceptable evidence could come from clinical trial data from a related indication. Sometimes, evidence of a drug's effectiveness in treating a closely related indication can be used to support approval for a different but related indication. This is particularly true for market approval under the 505(b)(2) regulatory pathway. This approach relies on the similarity between the indications, the drug's mechanism of action, and the endpoints measured. The 505(b)(2) pathway is the most common case of approval based on one pivotal clinical trial. Strong mechanistic evidence of a drug's treatment effect in a disease can be appropriate for confirmatory evidence in cases where there is a clear understanding of the disease's pathophysiology and the drug's mechanism of action. Animal data, when translational and predictive of human responses, can serve as confirmatory evidence. Evidence from other drugs in the same pharmacological class with similar mechanisms of action and clinical outcomes could be another confirmatory evidence used to support the approval of the new drug. Natural history data can provide the context of the trial results when the outcomes observed in the control group are not self-evident of the expected outcome in the absence of the intervention. Natural history data being used as confirmatory evidence should be distinct from any data used as a control for the single adequate and well-controlled clinical trial. Real-world evidence (RWE) derived from real-world data (RWD) may serve as confirmatory evidence if it is generated from reliable and relevant sources, comes from high-quality study design for data collection and cleaning, and uses appropriate prespecified statistical methods and analyses. Lastly, patient outcome information collected under expanded use or emergency use programs may be considered as confirmatory evidence if there is sufficient quantity and quality of such data. Certain conditions around new drugs or the target disease render them suitable for approaches for using a single clinical trial for approval. Although diseases with unmet needs, and/or small size of the patient population are generally most likely to seek alternative evidence to support data from a single clinical trial, this regulatory paradigm has been applied to all kinds of new drugs and diseases. Sponsors who believe that a single clinical trial will be sufficient to support their market approval application should discuss their clinical development plan early with the FDA, even as early as a pre-IND meeting but no later than the end-of-phase 2 meeting. This engagement allows for a thorough evaluation of the proposed approach and ensures that it aligns with FDA requirements. Key considerations during these discussions include providing a strong scientific rationale, describing the trial's design, and outlining the confirmatory evidence sources. Ultimately, the FDA needs to agree that a single adequate and well-controlled clinical investigation and confirmatory evidence are sufficient to demonstrate substantial evidence of effectiveness for a given program. While the FDA's regulatory process for drug approval is rigorous, it does allow for flexibility in certain situations. Using a single clinical trial, supported by appropriate confirmatory evidence, can be a viable path to demonstrate substantial evidence of effectiveness. However, this approach requires careful planning, robust scientific justification, and close collaboration with the FDA throughout the drug development journey. It also must be noted that the single pivotal trial may be based on smaller proof-of-concept exploratory trials that came before it. Ultimately, the approval of a drug depends on the results generated by the development program and their alignment with FDA standards. 
AUTHOR
Dr. Mukesh Kumar Founder & CEO, FDAMap Email: [email protected] Linkedin: Mukesh Kumar, PhD, RAC Instagram: mukeshkumarrac Twitter: @FDA_MAP Youtube: MukeshKumarFDAMap |
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