52Background: Postmarketing commitments are clinical studies that drug sponsors agree to conduct at the 53 time of FDA approval, but which are not required by statute or regulation. The objective of this study was 54 to determine the characteristics, completion, and dissemination of postmarketing commitments agreed 55 upon by sponsors at first FDA approval. 56 Methods: We performed a cross-sectional analysis of postmarketing commitments for new drugs and 57 biologics approved 2009-2012. Using public FDA documents, ClinicalTrials.gov, and Scopus, we 58 determined postmarketing commitments and their characteristics known at the time of FDA approval; 59 number of postmarketing commitments subject to reporting requirements, for which FDA is required to 60 make study status information available to the public ("506B studies"), and their statuses; and rates of 61 registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all 62 clinical trials, with follow-up through July 2018.63 Results: Among 110 novel drugs and biologics approved by the FDA between 2009-2012, 61 (55.5%) 64 had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing 65 commitments, 271 (81.9%) were non-human subjects research, predominantly chemistry, manufacturing, 66 and controls studies; 49 (14.8%) were clinical trials (33 new and 16 ongoing trials for which follow-up 67 results would be reported). Study descriptions for the new clinical trials often lacked information to 68 establish study design features. Of the 89 (26.9%) 506B studies subject to public reporting requirements, 69 of which 42 were clinical trials, 59 (66.3%) did not have an up-to-date status provided by FDA. Nearly all 70 new clinical trials (28 of 31, 90.3%) were registered on ClinicalTrials.gov; of the 23 registered trials that 71 were completed or terminated, 22 (95.7%) had reported results. Only half (14 of 29, 48.3%) of completed 72 or terminated clinical trials, registered or unregistered, were published in peer-reviewed journals.73 Conclusions: The majority of postmarketing commitments agreed to by sponsors at the time of FDA 74 approval for novel drugs and biologics approved between 2009-2012 were chemistry, manufacturing, and 75 controls studies. While only 15% were clinical trials, these trials were nearly always registered with 76 3 reported results on ClinicalTrials.gov. However, despite FDA public reporting requirements, up-to-date 77 study status information was often unavailable for 506B studies.78

This cross-sectional study characterizes postapproval clinical trials sponsored by pharmaceutical companies of therapeutics approved by the US Food and Drug Administration (FDA) without postmarketing requirements or commitments.

Background Postmarketing commitments are clinical studies that pharmaceutical companies agree to conduct at the time of FDA approval, but which are not required by statute or regulation. As FDA increasingly adopts a lifecycle evaluation process, greater emphasis will be placed on postmarket evidence as a component of therapeutic evaluation. Therefore, the objectives of this study were to determine how often postmarketing commitments agreed upon by pharmaceutical companies at first FDA approval lead to new clinical trials and to establish the characteristics and rates of completion and dissemination of postmarketing commitments. Methods For new drugs and biologics approved in 2009–2012, we used public FDA documents, ClinicalTrials.gov, and Scopus, to determine postmarketing commitments and their characteristics known at the time of FDA approval; number subject to reporting requirements, for which FDA is required to make study status information available to the public (“506B studies”), and their statuses; and rates of registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all clinical trials. Results Among 110 novel drugs and biologics approved by the FDA between 2009 and 2012, 61 (55.5%) had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing commitments, 33 (10.0%) were for new clinical trials; 27 of these were 506B studies subject to public reporting requirements, of which 12 (44.4%) did not have a recent (i.e., up-to-date) or closed (i.e., fulfilled or released) status provided publicly by the FDA. Although two postmarketing commitments were insufficiently described in FDA records to perform searches on ClinicalTrials.gov, nearly all (28, 90.3%) of the 31 remaining postmarketing commitments for new clinical trials were registered on ClinicalTrials.gov. Among the registered trials, 23 (23 of 28, 82.1%) were classified as completed or terminated, of which 22 (95.7%) had reported results. When considering all 29 completed or terminated clinical trials, registered or unregistered on ClinicalTrials.gov, only half (14, 48.3%) were published in peer-reviewed journals. Conclusions While only 15% of postmarketing commitments agreed to by pharmaceutical companies at the time of FDA approval were for new clinical trials, these trials were nearly always registered with reported results on ClinicalTrials.gov. However, only half were published, and despite FDA public reporting requirements, recent status information was often unavailable for 506B studies. Electronic supplementary material The online version of this article (10.1186/s12916-019-1344-3) contains supplementary material, which is available to authorized users.

Based on an analysis of relevant laws and policies, regulator data portals, and information requests, we find that clinical data, including clinical study reports, submitted to the European Medicines Agency and Health Canada to support approval of medicines are routinely made publicly available.

BackgroundThere is growing interest in evaluating differences in healthcare interventions across routinely collected demographic characteristics. However, individual subgroup analyses in randomized controlled trials are often not prespecified, adjusted for multiple testing, or conducted using the appropriate statistical test for interaction, and therefore frequently lack credibility. Meta-analyses can be used to examine the validity of potential subgroup differences by collating evidence across trials. Here, we characterize the conduct and clinical translation of age-treatment subgroup analyses in Cochrane reviews.MethodsFor a random sample of 928 Cochrane intervention reviews of randomized trials, we determined how often subgroup analyses of age are reported, how often these analyses have a P < 0.05 from formal interaction testing, how frequently subgroup differences first observed in an individual trial are later corroborated by other trials in the same meta-analysis, and how often statistically significant results are included in commonly used clinical management resources (BMJ Best Practice, UpToDate, Cochrane Clinical Answers, Google Scholar, and Google search).ResultsAmong 928 Cochrane intervention reviews, 189 (20.4%) included plans to conduct age-treatment subgroup analyses. The vast majority (162 of 189, 85.7%) of the planned analyses were not conducted, commonly because of insufficient trial data. There were 22 reviews that conducted their planned age-treatment subgroup analyses, and another 3 reviews appeared to perform unplanned age-treatment subgroup analyses. These 25 (25 of 928, 2.7%) reviews conducted a total of 97 age-treatment subgroup analyses, of which 65 analyses (in 20 reviews) had non-overlapping subgroup levels. Among the 65 age-treatment subgroup analyses, 14 (21.5%) did not report any formal interaction testing. Seven (10.8%) reported P < 0.05 from formal age-treatment interaction testing; however, none of these seven analyses were in reviews that discussed the potential biological rationale or clinical significance of the subgroup findings or had results that were included in common clinical practice resources.ConclusionAge-treatment subgroup analyses in Cochrane intervention reviews were frequently planned but rarely conducted, and implications of detected interactions were not discussed in the reviews or mentioned in common clinical resources. When subgroup analyses are performed, authors should report the findings, compare the results to previous studies, and outline any potential impact on clinical care.