Room for Improvement in FDA’s Influence on Pivotal Drug Study Designs

Study reports on the interaction between pharmaceutical companies and the US FDA during the design phase of pivotal pharmaceutical trials

medwireNews: US researchers have found that pharmaceutical companies do not always consult with the US Food and Drug Administration (FDA) during the pivotal study design phase of new drug approvals and do not always comply with the FDA’s recommendations regarding study design or primary outcome measures.

A consultation between pharmaceutical companies and the FDA when designing the pivotal studies to evaluate drug efficacy and safety for the proposed indication is encouraged, but is not mandatory, and any recommendations by the FDA for improving the planned study are not enforced, explain Lisa Schwartz, from the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and colleagues.

Appraisal of FDA memos, meeting minutes, filing checklists, and medical, statistical and summary reviews relevant to new drug approvals between 1 February 2011 and 29 February 2012 showed that 20% of 35 drugs were approved without a consultation between the company in question and the FDA.

For 75% of the 28 drugs for which a meeting between the pharmaceutical companies and the FDA took place, the FDA made 53 recommendations pertaining to the study design or primary outcome. Almost all of the recommendations were judged by the authors to improve the study quality, for example, by adding controls, blinding or lengthening studies to assess outcome durability.

However, there were 13 (25%) cases of noncompliance with these recommendations in the completed studies involving 10 drugs, four of which were for oncology indications, they report in JAMA.

The FDA requested a randomised trial for crizotinib for the treatment of locally advanced or metastatic non-small-cell lung cancer positive for anaplastic lymphoma kinase. The FDA also recommended against using a time-to-event measure, such as progression-free survival, as a primary outcome in an uncontrolled study, but the company did not comply with either request.

The recommendation to conduct a randomised trial was also disregarded in case of the pivotal study for brentuximab for patients with systemic anaplastic large cell lymphoma who have failed at least one multi-agent chemotherapy regimen. And, despite the FDA’s recommendation to use overall survival, progression-free survival remained the primary outcome for a study assessing axitinib in individuals with advanced renal cell cancer after failure of a prior systemic therapy.

In the case of vismodegib for metastatic basal cell carcinoma or recurrent locally advanced basal cell carcinoma after surgery, the trial counted patients without a conclusive baseline biopsy as responders even though the FDA explicitly recommended against this measure.

Lisa Schwartz and co-authors say that an independent FDA-commissioned report suggests that “stronger early FDA involvement” could help streamline the drug approval procedure.

They conclude: “One approach for enhancing quality of drug approval studies would be to institute mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations, which may be even more important with increasingly flexible approval pathways.”


Woloshin S, Schwartz LM, Frankel B, Faerber A. US Food and Drug Administration and Design of Drug Approval Studies. JAMA 2014; 312: 2163–2165. doi:10.1001/jama.2014.13329

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