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Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs.

ABSTRACT: Background:In July 2018, the FDA first published a table listing all surrogate measures that it has used, and may accept for future use, in regulatory approval. However, the strength of surrogacy for those measures was not formally assessed. Using the case example of breast cancer, we aimed to evaluate the strength of correlation of surrogate measures listed in the FDA's Table with overall survival. Methods:This cross-sectional study of the FDA's Table of Surrogate Endpoints was conducted in May 2019. All surrogate measures listed in the FDA table as appropriate for accelerated or regular approval for breast cancer were extracted. We identified studies evaluating the correlation of treatment benefit in the surrogate with treatment benefit in overall survival and extracted results from the correlation analysis. Findings:Five surrogate endpoints were listed for breast cancer in the FDA website: pathological complete response rates (pCR), event-free survival (EFS), disease-free survival (DFS), objective response rates (ORR), and progression-free survival (PFS), of which pCR was listed as appropriate only for accelerated approval, while the rest were considered appropriate for accelerated or regular approval. No correlation study evaluated the correlation of treatment effects on EFS with that on OS. The results from correlation studies evaluating pCR, DFS, ORR, and PFS suggest that the treatment effects on none of these surrogate measures were strongly correlated with treatment effects on OS (r<0.85 or R2 < 0.7, except for DFS in HER2 positive early breast cancer (R2 = 0.75). Interpretation:Using breast cancer as an example, we evaluated the underlying evidence for the surrogate endpoints for solid tumors listed in the FDA's Table of Surrogate Endpoints and found weak or missing correlations of treatment effects on these surrogates with treatment effects on OS . Surrogate measures should be predictive of clinical benefit to be useful in supporting regular FDA approval. Funding:Work on this project was funded by the Arnold Ventures. Dr. Kesselheim is also supported by the Harvard-MIT Center for Regulatory Science. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

SUBMITTER: Gyawali B

PROVIDER: S-EPMC7201012 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs.

Gyawali Bishal B Hey Spencer P SP Kesselheim Aaron S AS

EClinicalMedicine 20200413

<h4>Background</h4>In July 2018, the FDA first published a table listing all surrogate measures that it has used, and may accept for future use, in regulatory approval. However, the strength of surrogacy for those measures was not formally assessed. Using the case example of breast cancer, we aimed to evaluate the strength of correlation of surrogate measures listed in the FDA's Table with overall survival.<h4>Methods</h4>This cross-sectional study of the FDA's Table of Surrogate Endpoints was c ...[more]

PMID: 32382717

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Project description:BackgroundGeneric drugs are cost-effective versions of brand-name drugs approved by the Food and Drug Administration (FDA) following proof of pharmaceutical equivalence and bioequivalence. Generic drugs are widely prescribed by physicians, although there is disagreement over the clinical comparability of generic drugs to brand-name drugs within the physician community. The objective of this survey was to assess physicians' perceptions of generic drugs and the generic drug approval process.Methods and findingsA survey was administered to a national sample of primary care internists and specialists between August 2014 and January 2015. In total, 1,152 physicians comprising of internists with no reported specialty certification and those with specialty certification in hematology, infectious diseases, and endocrinology were surveyed. The survey assessed physicians' perceptions of the FDA's generic drug approval process, as well as their experiences prescribing six generic drugs approved between 2008 and 2012 using product-specific approval pathways and selected comparator drugs. Among 718 respondents (62% response rate), a majority were comfortable with the FDA's process in ensuring the safety and effectiveness of generic drugs overall (91%) and with letting the FDA determine which tests were necessary to determine bioequivalence in a particular drug (92%). A minority (13-26%) still reported being uncomfortable prescribing generic drugs approved using product-specific pathways. Overall, few physicians heard reports of concerns about generic versions of the study drugs or their comparators, with no differences between the two groups. Physicians tended to hear about concerns about the safety or effectiveness of generic drugs from patients, pharmacists, and physician colleagues.ConclusionsPhysicians hold largely positive views of the FDA's generic drug approval process even when some questioned the performance of certain generic drugs in comparison to brand-name drugs. Better education about the generic drug approval process and standards may alleviate concerns among the physician community and support the delivery of cost-effective health care.

Project description:BackgroundIn situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and findingsWe used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.ConclusionsThe pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.

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Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs.

Publications

Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs.

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