Seamless Clinical Trial Designs – Risks and Rewards

seamless clinical trialsAfter half a century of relying on the traditional three-phase clinical trial design, the US Food and Drug Administration (FDA) is providing guidelines to allow drug sponsors to change the way they test cancer therapeutics in the clinic. As we discussed in April, the FDA is embracing a variety of accelerated clinical trial designs, including the so-called seamless approach, which can use multiple expansion cohorts, in some cases shaving years off the classic three-phase approach. However, cohort expansion clinical trials have several risks, and according to the FDA’s recent draft guidance, these trials can lead to “exposing a large number of patients across multiple, simultaneously accruing, cohorts to potentially sub-optimal or toxic doses of an investigational drug” or the incorrect interpretation of preliminary trial results leading to fundamental flaws in the clinical development plan. Nevertheless, we agree with the FDA that expansion cohort trials are appropriate for select patient populations for whom the benefits outweigh the risks and there are no curative therapies available.

Upon the release of the FDA’s draft guidance in August, FDA Commissioner Scott Gottlieb said, “These clinical trial improvements can help ensure that innovative new therapies can be advanced efficiently to patients confronting a cancer diagnosis.”

In an expanded cohort trial, investigators and sponsors use surrogate endpoints to predict long-term outcomes. For instance, instead of measuring overall survival, oncology researchers might measure change in tumor size as a surrogate indicator of survival outcome. Another time-saving strategy of accelerated trials is to use a single-arm design without a comparator. This means investigators cannot fully determine a drug’s effectiveness compared to the standard of care and trades higher speed and lower cost with a greater uncertainty of effectiveness.

Although the FDA wants patients with the greatest clinical needs to have access to investigational drugs and biologics as quickly as possible, safeguards that protect patients from risk are still necessary. The FDA’s policy requires sponsors to submit cumulative safety summaries at least once a year and develop a plan for rapidly communicating serious safety issues to investigators and regulatory authorities.

Despite these challenges, expanded cohort trials may deliver life-saving drugs to the market more quickly than traditional oncology trials. Traditional cancer therapy clinical trials can take upwards of ten to fifteen years to complete with the timeline varying by cancer indication and therapeutic class. Merck’s Keytruda®, on the other hand, was tested using a multiple expansion cohort trial starting in 2011 and achieved FDA approval for treating melanoma in three years and metastatic non-small cell lung cancer three years later. The trial tested the biologic’s effectiveness against 15 cancer types across five simultaneous single-arm studies to determine the extent of its potential use as quickly as possible.

More recently the FDA granted Keytruda accelerated approval for the treatment of patients with metastatic squamous cell carcinoma of the head and neck (SCCHN) based on surrogate endpoints, including tumor response and the durability of this response. As with all accelerated approvals, this was conditional on Merck conducting a larger randomized confirmation trial compared with standard therapy. KEYNOTE-040, the confirmatory Phase III trial, revealed the biologic did not demonstrate a positive effect on overall survival compared to standard of care in second line SCCHN.. Nonetheless, according to Merck, the current approval in SCCHN remains unchanged and data presented recently during a presidential symposium at the European Society for Medical Oncology (ESMO) Conference described hitting its overall survival endpoint for the Phase 3 KEYNOTE-048 clinical trial, albeit a difficult to interpret cohort comparison to standard of care. Based on these results, Merck has disclosed plans to file a Supplemental Biologics License Application (sBLA) for Keytruda in first-line SCCHN and withdraw the sBLA for Keytruda as a second-line treatment. Given the rapid pace of drug development, the need for better biomarkers, and the underlying complexity of cancer we are bound to see similar instances of accelerated approvals with failed confirmatory trials that raise additional questions for researchers.

There are several dozen seamless oncology trials and with the FDA having just released a draft guidance reinforcing its endorsement of these trial designs, there is strong sponsor and regulatory support for seamless clinical trials. Commissioner Scott Gottlieb asserted the FDA will continue supporting the adoption of accelerated clinical trial designs because of their ability to deliver oncology drugs to market quickly.

If you’d like to learn more about the benefits and considerations relevant to multiple expanded cohort trial designs, please read our white paper, “Embracing Innovative Designs in Early Phase Oncology Studies: A Different Route to Faster Approvals, or contact us here.

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