Product/Indication

FDA Reviewer Comments On RWE In Submission

EMD Serono Inc./Pfizer Inc.’s Bavencio (avelumab)

Accelerated approval in March 2017 for metastatic Merkel cell carcinoma

Application included a multicenter, retrospective chart review analysis intended to serve as an external, historically controlled comparison.

Reviewers said the natural history analyses were considered exploratory and examined only to further characterize the drug’s risk/benefit profile in the context of the natural history of Merkel cell carcinoma and treatment outcomes with cytotoxic chemotherapy.

Although the data are limited and subject to selection bias and other problems inherent in the use of an external historical control, the response rate and duration of response results of the pivotal study compared favorably with the historical control data, the FDA said. (Also see "Real-World Evidence At US FDA: Bavencio, Blincyto Approvals Point Way Toward Broader Use " - Pink Sheet, 8 August, 2018.)

Shire PLC’s Motegrity (prucalopride)

Approval in December 2018 for chronic idiopathic constipation

At an October 2018 advisory committee meeting, FDA reviewers said a pharmacoepidemiology study using European health records and claims databases was a useful source of reassuring evidence about the drug’s cardiovascular safety, but they highlighted confounding factors that limited the interpretability of the results. (Also see "Real-World Evidence: US FDA’s Prucalopride Review Shows Datasets' Utility And Limitations" - Pink Sheet, 23 October, 2018.)

In review documents, agency staff cited a “serious risk of bias due to confounding” with the observational study. The agency accepted the findings as evidence that reasonably excludes a greater than three-fold increased risk of major adverse cardiovascular events with prucalopride, but could not use the study “to reliably bound MACE risk at levels lower than three-fold.”

Pfizer’s Ibrance (palbociclib)

Supplemental approval in April 2018 for males with breast cancer

FDA reviewers concluded substantial evidence of efficacy for the supplemental indication came from the two pivotal breast cancer trials in women that served as the basis for the drug’s initial approval.

RWE based on electronic health records and claims data was viewed as supportive evidence of efficacy but had some limitations. (Also see "Pfizer’s Ibrance And The Realities Of 'Real-World' Evidence " - Pink Sheet, 18 August, 2019.)

Karyopharm Therapeutics Inc.’s Xpovio (selinexor)

Accelerated approval in July 2019 for relapsed/refractory multiple myeloma

Results of a retrospective, observational study using electronic health records data were inadequate to support regulatory decision-making, FDA reviewers said.

The observational study had “major methodological issues,” including immortal time bias, selection bias, misclassification, confounding and missing data. In addition, “post-hoc strategies to create greater comparability across cohorts were inadequate and resulted in very limited sample size and unstable estimates,” the agency’s review states.

Sources: FDA review documents; Pink Sheet

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