Diminishing clinical impact for post-approval cancer clinical trials: A retrospective cohort study

by Charlotte Ouimet, Gauthier Bouche, Jonathan Kimmelman

Once a drug gets FDA approved, researchers often attempt to discover new applications in different indications. The clinical impact of such post-approval activities is uncertain. We aimed to compare the clinical impact of research efforts started after approval with those started before for cancer drugs.

We used Drugs@FDA to perform a retrospective cohort study of secondary approvals for cancer drugs that were initially FDA approved between 2005 and 2017. Clinicaltrials.gov was used to identify the beginning of each research trajectory that resulted in a secondary FDA approval. Each trajectory was classified as pre- or post-approval depending on if it was initiated before or after initial drug licensure. Clinical impact was assessed by comparing secondary approvals and NCCN off-label recommendations deriving from pre- vs. post-approval trajectories, pooled effect sizes, incidence, and level of evidence.

We identified 77 broad secondary approvals, 60 of which had at least 6 years follow-up. Of these, 9 (15%) resulted from post-approval trajectories, a proportion that is significantly lower than would be expected if the timing of research didn’t impact approval (McNemar’s test p = 0.001). Compared to pre-approval trajectories, approvals resulting from post-approval trajectories were for cancers with lower mean incidence (6.11 vs 14.83, p = 0.006) and were based on pivotal trials with smaller pooled effect sizes (0.69 vs 0.57, p = 0.02) that were less likely to be randomized (38.5% vs 64.1%, p = 0.145). We identified 69 NCCN off-label recommendations. The proportion stemming from post-approval trajectories was similar to that for pre-approval (56.5% vs. 43.5%). However, recommendations from post-approval trajectories were significantly more likely to involve rare diseases (76.7% vs 51.4%, p = 0.019) and nonsignificantly less likely to be based on level 1 evidence (11.6% vs 22.9%, p = 0.309).

Secondary FDA approvals are less likely to result from post-approval trajectories and tend to be less impactful compared to approvals originating from research started before first FDA licensure. However, post-approval trajectories may be as likely to lead to NCCN recommendations for off-label use. Limitations of this work include our use of indirect measures of impact and limited follow-up time for trajectories. Our study protocol was pre-registered (https://osf.io/5g3jw/).