Characterization of accelerated approval status, trial endpoints and results, and recommendations in guidelines for oncology drug treatments from the National Comprehensive Cancer Network: cross sectional study.

Objectives: To evaluate National Comprehensive Cancer Network (NCCN) guideline recommendations for oncology drug treatments that have been granted accelerated approval, and to determine whether recommendations are updated based on the results of confirmatory trials after approval and based on status updates from the US Food and Drug Administration (FDA). Design: Cross sectional study. Setting: US FDA and NCCN guidelines. Population: Oncology therapeutic indications (ie, specific oncological conditions for which the drug is recommended) that have been granted accelerated approval in 2009-18. Main outcome measures: NCCN guideline reporting of accelerated approval status and postapproval confirmatory trials, and guideline recommendation alignment with postapproval confirmatory trial results and FDA status updates. Results: 39 oncology drug treatments were granted accelerated approval for 62 oncological indications. Although all indications were recommended in NCCN guidelines, accelerated approval status was reported for 10 (16%) indications. At least one postapproval confirmatory trial was identified for all 62 indications, 33 (53%) of which confirmed benefit; among these indications, NCCN guidelines maintained the previous recommendation or strengthened the category of evidence for 27 (82%). Postapproval confirmatory trials failed to confirm benefit for 12 (19%) indications; among these indications, NCCN guidelines removed the previous recommendation or weakened the category of evidence for five (42%). NCCN guidelines reflected the FDA's decision to convert 30 (83%) of 36 indications from accelerated to traditional approval, of which 20 (67%) had guideline updates before the FDA's conversion decision. NCCN guidelines reflected the FDA's decision to withdraw seven (58%) of 12 indications from the market, of which four (57%) had guidelines updates before the FDA's withdrawal decision. Conclusions: NCCN guidelines always recommend drug treatments that have been granted accelerated approval for oncological indications, but do not provide information about their accelerated approval status, including surrogate endpoint use and status of postapproval confirmatory trials. NCCN guidelines consistently provide information on postapproval trial results confirming clinical benefit, but not on postapproval trials failing to confirm clinical benefit. NCCN guidelines more frequently update recommendation for indications converted to traditional approval than for those approvals that were withdrawn.

Spending by the Centers for Medicare & Medicaid Services Before and After Confirmation of Benefit for Drugs Granted US Food and Drug Administration Accelerated Approval, 2012 to 2017.

Importance: Accelerated approval by the US Food and Drug Administration (FDA) grants market authorization for drugs based on clinical trials using surrogate end points likely to anticipate a clinical benefit. The FDA requires postapproval trials to confirm benefit, after which the accelerated approval is converted to a standard approval or is withdrawn. However, trials frequently fail to assess clinical benefit, and expenditure for these drugs may be substantial. Objective: To evaluate spending by the Centers for Medicare & Medicaid Services (CMS) on drugs granted FDA accelerated approval before and after confirmation of benefit. Design and Setting: This was a cross-sectional study of CMS spending on drugs granted FDA accelerated approval for original indications from 2012 to 2017, with follow-up through 2020. Using data from the Drugs@FDA database and a validated methodology, the characteristics of new drugs granted FDA accelerated approval were identified and analyzed, including indication area, type of drug, type of confirmatory trial end point, orphan designation, number of supplemental indications, and conversion status. Main Outcomes and Measures: Overall and annualized spending by Medicare Parts B and D and Medicaid from 2012 to 2020, before and after conversion to standard approval. Analyses were conducted from June 30, 2021, to March 21, 2022. Results: From 2012 to 2017, the FDA granted accelerated approval to 38 drugs for 42 original indications. Through 2020, CMS spending for these drugs was $67.9 billion (median [IQR], $329.3 million [$54.4 million-$1.6 billion]). For 22 drugs (58%) that were converted to standard approval on the basis of clinical trial results, annualized spending increased substantially after conversion ($35.0 million vs $199.0 million), and spending after conversion accounted for $51.0 billion (75%) of overall spending. However, only 6 conversions (27%) of the 22 were supported by confirmatory trials evaluating clinical outcomes as primary end points. Drugs evaluated using surrogate end points accounted for $40.3 billion (59%) of CMS spending. Conclusions and Relevance: The findings of this cross-sectional study indicate that most of the drugs granted FDA accelerated approval for original indications from 2012 to 2017 lacked confirmatory trials evaluating clinical outcomes to support conversion to standard approval. Automatic coverage mandates produced substantial CMS spending for drugs with unproven clinical benefits.

Agreement of treatment effects from observational studies and randomized controlled trials evaluating hydroxychloroquine, lopinavir-ritonavir, or dexamethasone for covid-19: meta-epidemiological study.

OBJECTIVE: To systematically identify, match, and compare treatment effects and study demographics from individual or meta-analysed observational studies and randomized controlled trials (RCTs) evaluating the same covid-19 treatments, comparators, and outcomes. DESIGN: Meta-epidemiological study. DATA SOURCES: National Institutes of Health Covid-19 Treatment Guidelines, a living review and network meta-analysis published in The BMJ, a living systematic review with meta-analysis and trial sequential analysis in PLOS Medicine (The LIVING Project), and the Epistemonikos "Living OVerview of Evidence" (L·OVE) evidence database. ELIGIBILITY CRITERIA FOR SELECTION OF STUDIES: RCTs in The BMJ's living review that directly compared any of the three most frequently studied therapeutic interventions for covid-19 across all data sources (that is, hydroxychloroquine, lopinavir-ritonavir, or dexamethasone) for any safety and efficacy outcomes. Observational studies that evaluated the same interventions, comparisons, and outcomes that were reported in The BMJ's living review. DATA EXTRACTION AND SYNTHESIS: Safety and efficacy outcomes from observational studies were identified and treatment effects for dichotomous (odds ratios) or continuous (mean differences or ratios of means) outcomes were calculated and, when possible, meta-analyzed to match the treatment effects from individual RCTs or meta-analyses of RCTs reported in The BMJ's living review with the same interventions, comparisons, and outcomes (that is, matched pairs). The analysis compared the distribution of study demographics and the agreement between treatment effects from matched pairs. Matched pairs were in agreement if both observational and RCT treatment effects were significantly increasing or decreasing (P<0.05) or if both treatment effects were not significant (P≥0.05). RESULTS: 17 new, independent meta-analyses of observational studies were conducted that compared hydroxychloroquine, lopinavir-ritonavir, or dexamethasone with an active or placebo comparator for any safety or efficacy outcomes in covid-19 treatment. These studies were matched and compared with 17 meta-analyses of RCTs reported in The BMJ's living review. 10 additional matched pairs with only one observational study and/or one RCT were identified. Across all 27 matched pairs, 22 had adequate reporting of demographical and clinical data for all individual studies. All 22 matched pairs had studies with overlapping distributions of sex, age, and disease severity. Overall, 21 (78%) of the 27 matched pairs had treatment effects that were in agreement. Among the 17 matched pairs consisting of meta-analyses of observational studies and meta-analyses of RCTs, 14 (82%) were in agreement; seven (70%) of the 10 matched pairs consisting of at least one observational study or one RCT were in agreement. The 18 matched pairs with treatment effects for dichotomous outcomes had a higher proportion of agreement (n=16, 89%) than did the nine matched pairs with treatment effects for continuous outcomes (n=5, 56%). CONCLUSIONS: Meta-analyses of observational studies and RCTs evaluating treatments for covid-19 have summary treatment effects that are generally in agreement. Although our evaluation is limited to three covid-19 treatments, these findings suggest that meta-analyzed evidence from observational studies might complement, but should not replace, evidence collected from RCTs.

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018.

BACKGROUND/AIMS: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. METHODS: We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. RESULTS: From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. CONCLUSIONS: The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.

Reporting of Study Participant Demographic Characteristics and Demographic Representation in Premarketing and Postmarketing Studies of Novel Cancer Therapeutics.

Importance: Adequate representation of demographic subgroups in premarketing and postmarketing clinical studies is necessary for understanding the safety and efficacy associated with novel cancer therapeutics. Objective: To characterize and compare the reporting of demographic data and the representation of individuals by sex, age, and race in premarketing and postmarketing studies used by the Food and Drug Administration (FDA) to evaluate novel cancer therapeutics. Design, Setting, and Participants: In this cross-sectional study, premarketing and postmarketing studies for novel cancer therapeutics approved by the FDA from 2012 through 2016 were identified. Study demographic information was abstracted from publicly available sources, and US cancer population demographic data was abstracted from US Cancer Statistics. Analyses were conducted from February 25 through September 21, 2020. Main Outcomes and Measures: The percentages of trials reporting sex, age, and race/ethnicity were calculated, and participation to prevalence ratios (PPRs) were calculated by dividing the percentage of study participants in each demographic group by the percentage of the US cancer population in each group. PPRs were constructed for premarketing and postmarketing studies and by cancer type. Underrepresentation was defined as PPR less than 0.8. Results: From 2012 through 2016, the FDA approved 45 cancer therapeutics. The study sample included 77 premarketing studies and 56 postmarketing studies. Postmarketing studies, compared with premarketing studies, were less likely to report patient sex (42 studies reporting [75.0%] vs 77 studies reporting [100%]; P < .001) and race (27 studies reporting [48.2%] vs 62 studies reporting [80.5%]; P < .001). Women were adequately represented in premarketing studies (mean [SD] PPR, 0.91; 95% CI, 0.90-0.91) and postmarketing studies (mean PPR, 1.00; 95% CI, 1.00-1.01). Although older adults and Black patients were underrepresented in premarketing studies (older adults: mean PPR, 0.73; 95% CI, 0.72-0.74; Black patients: mean PPR, 0.32; 95% CI, 0.31-0.32), these groups continued to be underrepresented in postmarketing studies (older adults: mean PPR, 0.75; 95% CI, 0.75-0.76; Black patients: mean PPR, 0.21; 95% CI, 0.21-0.21). Conclusions and Relevance: This study found that older adults and Black patients were underrepresented in postmarketing studies of novel cancer therapeutics to a similar degree that they were underrepresented in premarketing studies. These findings suggest that postmarketing studies are not associated with improvements to gaps in demographic representation present at the time of FDA approval.

Publishing at any cost: a cross-sectional study of the amount that medical researchers spend on open access publishing each year.

OBJECTIVE: To estimate the financial costs paid by individual medical researchers from meeting the article processing charges (APCs) levied by open access journals in 2019. DESIGN: Cross-sectional analysis. DATA SOURCES: Scopus was used to generate two random samples of researchers, the first with a senior author article indexed in the 'Medicine' subject area (general researchers) and the second with an article published in the ten highest-impact factor general clinical medicine journals (high-impact researchers) in 2019. For each researcher, Scopus was used to identify all first and senior author original research or review articles published in 2019. Data were obtained from Scopus, institutional profiles, Journal Citation Reports, publisher databases, the Directory of Open Access Journals, and individual journal websites. MAIN OUTCOME MEASURES: Median APCs paid by general and high-impact researchers for all first and senior author research and review articles published in 2019. RESULTS: There were 241 general and 246 high-impact researchers identified as eligible for our study. In 2019, the general and high-impact researchers published a total of 914 (median 2, IQR 1-5) and 1471 (4, 2-8) first or senior author research or review articles, respectively. 42% (384/914) of the articles from the general researchers and 29% (428/1471) of the articles from the high-impact medical researchers were published in fully open access journals. The median total APCs paid by general researchers in 2019 was US$191 (US$0-US$2500) and the median total paid by high-impact researchers was US$2900 (US$0-US$5465); the maximum paid by a single researcher in total APCs was US$30115 and US$34676, respectively. CONCLUSIONS: Medical researchers in 2019 were found to have paid between US$0 and US$34676 in total APCs. As journals with APCs become more common, it is important to continue to evaluate the potential cost to researchers, especially on individuals who may not have the funding or institutional resources to cover these costs.

Analysis of Postapproval Clinical Trials of Therapeutics Approved by the US Food and Drug Administration Without Clinical Postmarketing Requirements or Commitments.

Importance: The US Food and Drug Administration (FDA) can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics. Pharmaceutical companies can also agree to conduct nonmandated clinical trials as postmarketing commitments. However, when therapeutics are approved by the FDA without postmarketing requirements or postmarketing commitments, it is not well known how often pharmaceutical companies voluntarily conduct trials and report results monitoring safety or efficacy after approval. Objective: To characterize postapproval clinical trials sponsored by pharmaceutical companies of therapeutics initially approved by the FDA without clinical postmarketing requirements or commitments. Design, Setting, and Participants: This cross-sectional analysis included postapproval clinical trials conducted with at least 1 site in the United States sponsored by pharmaceutical companies of therapeutics first approved by the FDA from 2009 through 2012. Analyses were conducted June 11, 2018, to November 30, 2018. Main Outcomes and Measures: Postapproval clinical trials registered on ClinicalTrials.gov generating safety or efficacy data, characteristics including whether trials focused on approved or unapproved indications, study design elements, and rates of study completion and results reporting. Results: From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications, of which 37 novel therapeutics for 39 indications did not have postmarketing requirements or commitments for new clinical studies at the time of first approval. For 31 therapeutics (83.8%), there were 600 postapproval clinical trials sponsored by pharmaceutical companies. Most trials investigated therapeutics for new indications (363 [60.5%]) or expanded populations of the originally indicated disease (122 [20.3%]). Trials were often small (median [interquartile range] enrollment, 44 [21-131] participants), nonrandomized (359 [59.8%]), unblinded (455 [75.8%]), and lacked comparators (381 [63.5%]). Approximately half of the trials (311 [51.8%]) assessed at least 1 clinical outcome. Of 300 terminated or completed trials, 204 trials (68.0%) had reported results on ClinicalTrials.gov a median (interquartile range) 16 (13-25) months after their primary completion date. For the 96 trials (32.0%) without reported results, a median (interquartile range) 35 (13-62) months had passed since their primary completion date. Conclusions and Relevance: Pharmaceutical companies frequently conducted clinical trials after approval, even when there were no clinical postmarketing requirements or commitments at approval. However, most of these trials evaluated new indications or expanded patient populations rather than monitored approved uses, and nearly half of the trials remained incomplete more than 5 years after original therapeutic approval.