Strength of Validation for Surrogate End Points Used in the US Food and Drug Administration's Approval of Oncology Drugs

Abstract

Objective: To determine the strength of the surrogate-survival correlation for cancer drug approvals based on a surrogate.

Participants and methods: We performed a retrospective study of the US Food and Drug Administration (FDA) database, with focused searches of MEDLINE and Google Scholar. Among cancer drugs approved based on a surrogate end point, we examined previous publications assessing the strength of the surrogate-survival correlation. Specifically, we identified the percentage of surrogate approvals lacking any formal analysis of the strength of the surrogate-survival correlation, and when conducted, the strength of such correlations.

Results: Between January 1, 2009, and December 31, 2014, the FDA approved marketing applications for 55 indications based on a surrogate, of which 25 were accelerated approvals and 30 were traditional approvals. We could not find any formal analyses of the strength of the surrogate-survival correlation in 14 out of 25 accelerated approvals (56%) and 11 out of 30 traditional approvals (37%). For accelerated approvals, just 4 approvals (16%) were made where a level 1 analysis (the most robust way to validate a surrogate) had been performed, with all 4 studies reporting low correlation (r≤0.7). For traditional approvals, a level 1 analysis had been performed for 15 approvals (50%): 8 (53%) reported low correlation (r≤0.7), 4 (27%) medium correlation (r>0.7 to r<0.85), and 3 (20%) high correlation (r≥0.85) with survival.

Conclusions: The use of surrogate end points for drug approval often lacks formal empirical verification of the strength of the surrogate-survival association.

FIGURE 1

All indications receiving Food and Drug Administration marketing authorization for oncology drugs between 2009 and 2014. Approvals are grouped based on traditional or accelerated authorization and the efficacy end point met to garner approval. *Drugs approved based on bioequivalence (mercaptopurine (2014): ALL, asparaginase Erwinia chrysanthemi (2011): ALL) were removed from the analysis. ALL = acute lymphoblastic leukemia; CLL = chronic lymphocytic lymphoma; CML = chronic myeloid leukemia; CRC = colorectal carcinoma; CRPC = castration-resistant prostate cancer; CTCL = cutaneous T-cell lymphoma; DFS = disease-free survival; GEJ = gastroesophageal junction; GIST = gastrointestinal stromal tumor; HER2 = human epidermal growth factor receptor 2; NET = neuro-endrocine tumor; NSCLC = non-small cell lung cancer; OS = overall survival; PFS = progression-free survival; Ph = Philadelphia chromosome; PTCL = peripheral T-cell lymphoma; RCC = renal cell cancer; RR = response rate; SLL = small lymphocytic lymphoma.

FIGURE 2

The strength of evidence between a surrogate-survival correlation for accelerated (A) and traditional (B) drug approvals based on surrogate end points. Level 1 studies were scored based on a modification to criteria proposed by the Institute for Quality and Efficiency in Health Care: low correlation (r≤0.7), medium correlation (r>0.7 to r<0.85), and high correlation (r≥0.85). No level 1 or 2 means that we could not identify a single association study in the literature. Where multiple level 1 studies exist, the median r was used for scoring.