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.
Abbreviations and Acronyms:
AA (accelerated approval), ALL (acute lymphoblastic leukemia), CCyR (complete cytogenetic response), CLL (chronic lymphocytic lymphoma), CML (chronic myeloid leukemia), CRC (colorectal carcinoma), CR (complete response), CRi (complete response with incomplete blood count recovery), CRPC (castrate-resistant prostate cancer), CTCL (cutaneous T-cell lymphoma), DFS (disease-free survival), DOR (duration of response), FDA (Food and Drug Administration), GEJ (gastroesophageal junction), GIST (gastrointestinal stromal tumor), HER2 (human epidermal growth factor receptor 2), HR (hazard ratio), MaHR (major hematologic response), MCyR (major cytogenetic response), MMR (major molecular response), MRD (minimal residual disease), NET (neuroendrocine tumor), NSCLC (non-small cell lung cancer), OR (odds ratio), ORR (objective response rate), OS (overall survival), pCR (pathologic complete remission), PFS (progression-free survival), Ph (Philadelphia chromosome), PR (partial remission), PTCL (peripheral T-cell lymphoma), RCC (renal cell cancer), RR (response rate), SLL (small lymphocytic lymphoma), TA (traditional approval), TTP (time to progression)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: May 25, 2016
Footnotes
For editorial comment, see page 689
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