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New FDA Guidance on Clinical Trails Recommendations for Accelerated Approvals

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Last week, the U.S. Food and Drug Administration (FDA) released a new draft guidance regarding clinical trials considerations to support accelerated approvals: Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.

The accelerated approval pathway is used for approval of oncology drugs due to the serious and life-threatening nature of cancer and because of available surrogate or intermediate clinical endpoints, considered likely to predict clinical benefit.

This guidance discusses the design of clinical trials, displaying ways to improve the availability of data at the time of accelerated approval application and reduce clinical uncertainty for patients by initiating post-marketing confirmatory studies in a timely manner.

Single-Arm Trials to Support Accelerated Approvals

A variety of trial designs and endpoints have historically been used to support accelerated approval, single-arm trial designs and response endpoints have most commonly been used in oncology. However, there are limits to the use of single-arm trials in support of accelerate approval, such as:

  • Safety databases are typically small and may not allow to identify rare potentially serious adverse events.
  • Common time-to-event efficacy endpoints in oncology (tumour progression, survival) are generally not interpretable due to failure to account for known and unknown confounding factors when compared to an external control.
  • Low magnitude response rates generally may not be reasonably likely to predict clinical benefit.
  • For combination regimens, the contribution of the individual components to the claimed effects generally may be challenging to establish.

Randomized Controlled Trials to Support Accelerated Approvals

When properly designed and executed, a randomized controlled trial can address the limitation of single-arm trials, including the following ways:

  • A randomized controlled trial provides a more robust efficacy and safety assessment and allows for direct comparison to a concurrent control arm.
  • In a context where the treatment landscape may have changed since the end of the trial for the available therapy, a randomized controlled trial makes it possible to study comparable student populations.
  • While trials for accelerated approval are typically conducted in patient with refractory disease, a randomized controlled trial may allow for the evaluation of a new drug in an earlier treatment setting.
  • When clinical trial sites span several geographic regions, a randomized control trial allows for an assessment of potential regional differences that may stem from multiple factors.

Recommendations on Randomized Controlled Trials

Sponsors can conduct separate randomized controlled trials – one trial with an earlier endpoint to support accelerated approval of the drug and a second trial powered for a long-term clinical endpoint to verify clinical benefit.

Alternatively, sponsors could design a single randomized controlled trial to support accelerated approval, that is also powered for the longer-term clinical endpoint with follow-up in the same trial to verify clinical benefit (i.e., “one-trial” approach).

The guideline presents recommendations for addressing the design, conduct, and analyses of data for either two separate randomized controlled clinical trials or for using the “one-trial” approach for accelerate approval and to verify clinical benefit.

Confirmatory Trial Following Accelerate Approvals

For drugs granted accelerated approval in oncology, post-marketing confirmatory trials have been required to verify and describe the anticipated clinical benefit. Such trials help address residual uncertainties regarding the relationship between the surrogate or intermediate endpoint to the ultimate clinical benefit. For this, FDA may require that studies indented to verify clinical benefit be underway prior to approval, or within a specified time period after the date of approval, of the applicable product.

Early discussions with FDA regarding the design and initiation of both the trial intended to support accelerated approval and the post-marketing trial are recommended to provide evidence of clinical benefit in an expeditious manner.

We hope you found this information interesting and useful, if you would like to read the complete guideline you can find it here.

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