Project description:ImportanceDrugs treating serious or life-threatening conditions can receive US Food and Drug Administration (FDA) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit. Confirmatory trials are then required to determine whether these effects translate to clinical improvements.ObjectiveTo characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval.Design and settingPublicly available FDA documents were reviewed to identify the preapproval trials leading to accelerated approval between 2009 and 2013. Information on the status and findings of required confirmatory studies was extracted from the FDA's database of postmarketing requirements and commitments, ClinicalTrials.gov, and matched peer-reviewed publications. Follow-up ended on April 7, 2017.ExposuresGranting of accelerated approval.Main outcomes and measuresCharacteristics of preapproval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary end point). Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized.ResultsThe FDA granted accelerated approval to 22 drugs for 24 indications (19 for indications involving cancer treatment) between 2009 and 2013. A total of 30 preapproval studies supported the 24 indications. The median number of participants enrolled in the preapproval studies was 132 (interquartile range, 89-224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, -15% to 46%; P = .31). Postapproval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior.Conclusions and relevanceAmong 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in postapproval trials a minimum of 3 years after approval, although confirmatory trials and preapproval trials had similar design elements, including reliance on surrogate measures as outcomes.

Project description:BACKGROUND:Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear. PURPOSE:To validate results posted on ClinicalTrials.gov against publicly available U.S. Food and Drug Administration (FDA) reviews on Drugs@FDA. DATA SOURCES:ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical and statistical reviews). STUDY SELECTION:100 parallel-group, randomized trials for new drug approvals (January 2013 to July 2014) with results posted on ClinicalTrials.gov (15 March 2015). DATA EXTRACTION:2 assessors extracted, and another verified, the trial design, primary and secondary outcomes, adverse events, and deaths. RESULTS:Most trials were phase 3 (90%), double-blind (92%), and placebo-controlled (73%) and involved 32 drugs from 24 companies. Of 137 primary outcomes identified from ClinicalTrials.gov, 134 (98%) had corresponding data at Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results. Most differences were nominal (that is, relative difference <10%). Primary outcome results in 14 trials could not be validated. Of 1927 secondary outcomes from ClinicalTrials.gov, Drugs@FDA mentioned 1061 (55%) and included results data for 367 (19%). Of 96 trials with 1 or more serious adverse events in either source, 14 could be compared and 7 had discordant numbers of persons experiencing the adverse events. Of 62 trials with 1 or more deaths in either source, 25 could be compared and 17 were discordant. LIMITATION:Unknown generalizability to uncontrolled or crossover trial results. CONCLUSION:Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half the secondary outcomes, as well as serious events and deaths, could not be validated because Drugs@FDA includes only "key outcomes" for regulatory decision making and frequently includes only adverse event results aggregated across multiple trials. PRIMARY FUNDING SOURCE:National Library of Medicine.

Project description:BackgroundWe examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here.MethodsWe identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety-related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns.ResultsFifty-five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety-related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions-new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety-related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety-related changes in the first 2 years after approval.ConclusionBased on our analysis we conclude that although there was a greater incidence of substantial safety-related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit-risk profile of the drug.Implications for practiceThe majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.

Dataset Information

Participation of Black US Residents in Clinical Trials of 24 Cardiovascular Drugs Granted FDA Approval, 2006-2020.

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