Accelerated approval and accelerated withdrawal – will the new clinical trial guidance bring US closer to Europe?

Written by: Srishti Gupta, PhD; Senior Consultant

Contact: [email protected]

In March 2023, the Food and Drug Administration (FDA) published, a first of its kind, draft guidance titled “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics”[1]. This document provides recommendations to the manufacturers of anti-cancer drugs or biological products on requirements for designing trials intended to support accelerated approval (AA) ensuring that drugs approved under this process are effective. AA is a pathway for the approval of drugs for serious or life-threatening diseases that demonstrate a meaningful improvement in a clinically relevant surrogate endpoint(s) over available therapies.

In this draft guidance, the FDA highlights the limitations of single-arm trials and use of surrogate endpoints that add uncertainty to the assessment of the safety and/or effectiveness of a drug and prefers a randomized controlled trial (RCT) approach instead. The FDA recommends that manufacturers targeting the AA pathway to support the approval of their drug(s) can elect to conduct:

  1. Separate trials – one to support the AA and another, a confirmatory trial, to verify clinical benefit, or
  2. A single RCT i.e., follow a “one-trial” approach to verify clinical benefit, or
  3. Only in certain circumstances, a single-arm trial when RCTs are not feasible

Considerations on each of the recommendations are described below:

  1. Separate trials (trial to support AA + confirmatory trial)

Manufacturers can conduct separate randomized trials, one with an early endpoint (e.g., overall response rate [ORR]) to support the AA and a second trial powered for a longer-term clinical endpoint (e.g., progression-free survival [PFS] or overall survival [OS]) to verify the clinical benefit of a therapy. The FDA strongly recommends that a confirmatory trial should be well underway, if not fully enrolled, when the marketing application for AA is submitted. However, a confirmatory trial, evaluating the drug in the same cancer but in another line of therapy will also be accepted, e.g., the drug was approved via AA in the relapse/refractory setting and the confirmatory trial evaluates its clinical benefit in the first line (1L) setting.

  1. A single RCT i.e., a “one-trial” approach

Alternatively, the manufacturers could design a single RCT to support AA, which is also powered for the longer-term clinical endpoint and follow-up in the same trial to verify the clinical benefit (i.e., “one trial” approach) of a therapy. If following a “one-trial” approach, it will be important for the drug manufacturers to carefully assess the available preliminary data from Ph I or II studies prior to initiating the trial. The manufacturers should also discuss with the FDA whether based on the available preliminary clinical data, the expected effect on ORR or other early endpoint is of sufficient magnitude to be likely to predict clinical benefit. Additional factors such as the anticipated impact of crossover (if permitted), the preliminary data on the drug’s effects, including toxicity profile, the treatment landscape, and the treatment used in the control arm, etc. should also be considered. The trial sample size should be chosen so that it is adequately powered to detect a clinically meaningful and statistically significant improvement in both the endpoints for AA (e.g., ORR) and verification of clinical benefit (e.g., PFS or OS). Protocols should also specify a plan to strongly control the overall false positive rate (type-I error) for the endpoint supporting AA and the endpoint supporting verification of clinical benefit. If there are concerns over the safety profile of the drug, then the FDA may request summary results of the analysis on survival data to support this assessment.

  1. Single-arm trial for special cases

RCT is the preferred approach but there can be circumstances where there are concerns on feasibility of conducting such a trial. In these cases, a single-arm trial will be appropriate for an AA. In oncology, ORR is the most frequently used endpoint to support accelerated approval based on a single-arm trial however appropriate criteria for assessing the response rate should be used (e.g., ORR by Response evaluation criteria in solid tumors [RECIST]). Use of new response assessment criteria or modifications of established criteria should be supported by strong underlying rationale and should be discussed with FDA at the trial design stage. A single arm trial should be sized to allow adequate precision around the point estimate, provide robust estimation of duration of response, and sufficiently describe the adverse event (AE) profile of the drug. It will also be important to consider the follow-up time necessary to adequately characterize the ORR and the durability of response in a particular disease setting. In most cases, a minimum follow-up of 6 months after the response is needed for most of the responders to characterize durability of response. However, there may be instances where a longer minimum follow-up after response is necessary to adequately characterize clinical benefit. In some cases, FDA may request additional data on the durability of response during the review of an application.

Regardless of the approach, the FDA recommends early discussions with the agency before and during the conduct of a trial. With two different approaches to support AA, the new guidance will help reduce time between AA and confirmation of clinical benefit. This will result in faster withdrawal of drugs from the market for which clinical benefit is not confirmed in an additional Ph III study, especially when the initiation of a confirmatory study is planned after the AA. Advantage of the “one-trial” approach is that a separate confirmatory trial may not be necessary. However, two separate trials would be beneficial if the manufacturer wants to consider line extensions for their therapy.

The guidance will likely make it more difficult for companies to obtain AA for their drugs, and it could add to the cost and time required to bring a drug to market meaning that patient access to innovative, rare diseases therapies will be delayed. The new guidance could be less beneficial for smaller pharmaceutical companies hoping to receive AA for their drugs based on smaller Ph I/II studies, as it may be less financially feasible as companies will now be required to invest earlier into larger Phase III studies prior to receiving AA. However, pharmaceutical companies often design trials focusing primarily on the US market and they often face criticism in other regions like Europe. This new draft guidance brings considerations for oncology agents closer to the European recommendations for conducting clinical trials, meaning that the stricter US guidance can open routes for therapies to other markets such as the EU, which could be a blessing in disguise. This draft guidance will likely be finalized in H2 2023 and its impact on market access for oncology agents remains to be seen.

With the Inflation Reduction Act and FDA reforms in the US, is there a trend that the US is now moving away from healthcare innovation? P4A has been monitoring the recent changes in the US and other markets and will continue to do so to best advise our clients how to react, plan, and adapt to the changing environment. Contact P4A to learn more about our services to support with determining ideal access pathways and to remain up to date on how to seize opportunities in an ever-changing space.



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