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Rapid network meta-analysis using data from Food and Drug Administration approval packages is feasible but with limitations.

ABSTRACT: OBJECTIVE:To test rapid approaches that use Drugs@FDA (a public database of approved drugs) and ClinicalTrials.gov to identify trials and to compare these two sources with bibliographic databases as an evidence base for a systematic review and network meta-analysis (NMA). STUDY DESIGN AND SETTING:We searched bibliographic databases, Drugs@FDA, and ClinicalTrials.gov for eligible trials on first-line glaucoma medications. We extracted data, assessed risk of bias, and examined the completeness and consistency of information provided by different sources. We fitted random-effects NMA models separately for trials identified from each source and for all unique trials from three sources. RESULTS:We identified 138 unique trials including 29,394 participants on 15 first-line glaucoma medications. For a given trial, information reported was sometimes inconsistent across data sources. Journal articles provided the most information needed for a systematic review; trial registrations provided the least. Compared to an NMA including all unique trials, we were able to generate reasonably precise effect estimates and similar relative rankings for available interventions using trials from Drugs@FDA alone (but not ClinicalTrials.gov). CONCLUSIONS:A rapid NMA approach using data from Drugs@FDA is feasible but has its own limitations. Reporting of trial design and results can be improved in both the drug approval packages and on ClinicalTrials.gov.

SUBMITTER: Wang L

PROVIDER: S-EPMC6773505 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Rapid network meta-analysis using data from Food and Drug Administration approval packages is feasible but with limitations.

Wang Lin L Rouse Benjamin B Marks-Anglin Arielle A Duan Rui R Shi Qiyuan Q Quach Kevin K Chen Yong Y Cameron Christopher C Schmid Christopher H CH Li Tianjing T

Journal of clinical epidemiology 20190618

<h4>Objective</h4>To test rapid approaches that use Drugs@FDA (a public database of approved drugs) and ClinicalTrials.gov to identify trials and to compare these two sources with bibliographic databases as an evidence base for a systematic review and network meta-analysis (NMA).<h4>Study design and setting</h4>We searched bibliographic databases, Drugs@FDA, and ClinicalTrials.gov for eligible trials on first-line glaucoma medications. We extracted data, assessed risk of bias, and examined the c ...[more]

PMID: 31226413

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Project description:ImportanceThe US Food and Drug Administration (FDA) grants accelerated approval according to surrogate measures of numerous drug indications for serious or life-threatening illnesses such as infectious diseases and cancer. Investigators, including the FDA, have evaluated the program's regulatory and clinical consequences in oncology, but evaluation of nononcology drugs is lacking.ObjectiveTo evaluate the accelerated approval program for nononcology drug indications over a period of 26 years.Design, setting, and participantsThis retrospective cohort study used publicly available data on FDA nononcology drug indications granted accelerated approval from June 1992 through May 2018, with preapproval and confirmatory trials for approved drugs. Data were analyzed from February to April 2022.Main outcomes and measuresThe study estimated the median time from accelerated approval to occurrence of regulatory outcomes such as regular approval conversion, postapproval boxed warning label changes, confirmatory trial completion, and confirmatory trial results publication.ResultsThe FDA granted accelerated approval of 48 drugs for 57 nononcology indications, including 23 (40%) HIV treatments, supported by 93 preapproval trials. Forty-three indications (75%) were converted to regular approval at a median time of 53.1 (95% CI, 38.7 to 70.2) months from accelerated approval. There were postapproval label modifications on boxed warnings in 27 indications (47%) with a median time of 248.6 (95% CI, 51.8 to not estimable) months from accelerated approval. Of the 86 required confirmatory trials, 17 (20%) had not fulfilled the postapproval requirements. The median time to confirmatory trial completion was 39.4 (95% CI, 30.7 to 47.9) months. Nine trials (10%) failed to verify clinical efficacy, but only 1 of 8 indications assessed (2%) was withdrawn owing to the failed confirmatory trial, which was 136 months after approval. Results were published in 56 completed confirmatory trials (65%), with the median time being 52.5 (95% CI, 35.6 to 82.2) months from accelerated approval to publication.Conclusions and relevanceAlthough the program expedited the approval of nononcology drug indications by a median (IQR) of 53.1 (26.8-133.2) months, safety-related label modifications were often added in boxed warnings after approval, and clinical efficacy was sometimes not confirmed. The study findings and long follow-up period suggest that comprehensive evaluation of such drugs may take more than a decade.

Project description:ImportanceWhile there have been multiple assessments of clinical trials leading to anticancer drug approvals by the US Food and Drug Administration (FDA), the cumulative percentage of approvals based on trials with a limitation remains uncertain.ObjectiveTo assess the percentage of clinical trials with limitations in 4 domains-lack of randomization, lack of significant overall survival advantage, inappropriate use of crossover, and use of suboptimal control arms-that led to FDA approvals from June 30, 2014, to July 31, 2019.Design, setting, and participantsThis observational analysis included all anticancer drug indications approved by the FDA from June 30, 2014, through July 31, 2019. All indications were investigated, and each clinical trial was evaluated for design, enrollment period, primary end points, and presence of a limitation in the domains of interest. The standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. The percentage of approvals based on clinical trials with any or all limitations of interest was then calculated.Main outcomes and measuresEstimated percentage of clinical trials with limitations of interest that led to an anticancer drug marketing authorization by the FDA.ResultsA total of 187 trials leading to 176 approvals for 75 distinct novel anticancer drugs by the FDA were evaluated. Sixty-four (34%) were single-arm clinical trials, and 123 (63%) were randomized clinical trials. A total of 125 (67%) had at least 1 limitation in the domains of interest; 60 of the 125 trials (48%) were randomized clinical trials. Of all 123 randomized clinical trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a suboptimal control, and 17 (14%) used crossover inappropriately.Conclusions and relevanceTwo-thirds of cancer drugs are approved based on clinical trials with limitations in at least 1 of 4 essential domains. Efforts to minimize these limitations at the time of clinical trial design are essential to ensure that new anticancer drugs truly improve patient outcomes over current standards.

Project description:ImportanceNumerous cancer drugs have received accelerated approval from the US Food and Drug Administration (FDA) based on clinical trial outcomes that are otherwise not acceptable for traditional FDA approval; the accelerated approval process allows outcomes based on surrogate measures that are only reasonably likely to estimate clinical benefits. In England, the National Institute for Health and Care Excellence (NICE) evaluates the clinical benefits and cost-effectiveness of drugs after they have received regulatory approval and issues recommendations regarding their coverage in the National Health Service (NHS). However, the level of concordance between European and FDA decision-making in the context of drugs qualifying for FDA accelerated approval is unknown.ObjectiveTo compare FDA accelerated approval decisions for cancer drugs with NICE coverage decisions.Design, setting, and participantsThis retrospective cohort study compared cancer drug indications that received FDA accelerated approval from December 11, 1992, to May 31, 2017, with the same set of drug indication pairs in England until August 31, 2019. Data from European Public Assessment Reports developed by the European Medicines Agency (EMA) and public appraisal documents from NICE were used to determine NHS coverage recommendations. National Institute for Health and Care Excellence (NICE) public appraisal documents were analyzed for drug indications, characteristics of clinical evidence, cost-effectiveness, and coverage decisions. Data were analyzed from September 1 to December 31, 2019.Main outcomes and measuresCancer drug indication coverage decision by NICE.ResultsFrom 1992 to 2017, 93 cancer drug indications received FDA accelerated approval, 6 of which were subsequently withdrawn, leaving 87 cancer drug indications on the market. As of August 2019, 5 of these indications had been withdrawn or denied market authorization for the European Union by the EMA. From the cohort of EMA-approved drugs, an additional 7 drug indications were not recommended by NICE and were not deemed to have sufficient clinical benefits or cost-effectiveness to warrant mandatory public coverage in England; 5 drugs were not recommended based on clinical benefit and cost-effectiveness criteria, and 2 drugs were not recommended based on cost-effectiveness criteria alone. In total, 12 drug indications were not recommended for public coverage in the NHS, and an additional 30 drug indications were not reviewed by either the EMA (14 drug indications) or NICE (16 drug indications) by the study end date. Most drug indications recommended by NICE were conditional on the negotiation of additional confidential discounts, the imposition of restricted indications that limited prescribing to specific patient subgroups, or the collection of additional data. Among the 9 drug indications with evidence of overall survival benefit at the time of NICE review, 2 were not recommended for public funding based on cost-effectiveness criteria.Conclusions and relevanceIn this cohort study, 30 cancer drug indications that were granted accelerated approval by the FDA were not subsequently reviewed by either European regulators or NICE, and 12 drugs were denied authorization or coverage owing to insufficient safety, clinical efficacy, or cost-effectiveness. National Health Service coverage of cancer drugs given FDA accelerated approval commonly required additional price concessions, restrictions to approved indications, or review of additional data.

Project description:ImportanceState Medicaid programs have reported concerns about rising drug prices and spending, particularly regarding drugs entering the market through the accelerated approval program under the US Food and Drug Administration (FDA). The accelerated approval program enables the FDA to approve drugs on the basis of unverified surrogate end points, meaning that clinical benefits for these products are uncertain at the time of approval. However, state Medicaid programs are legally required to cover these drugs. Little is known about the set of products with accelerated approval over time, their use among Medicaid beneficiaries, or the magnitude of their financial influence on state Medicaid programs.ObjectiveTo identify the number and class of drugs approved through the FDA's accelerated approval pathway and analyze state Medicaid programs' use and spending on these drugs from 2015 through 2019.Design setting and participantsIn this cross-sectional study, biannual FDA reports were used to identify products granted accelerated approval and their associated indications approved between December 1992 and December 2020. State Medicaid Drug Utilization Data files available for 1992 through 2019 were used to estimate national totals for spending and use of outpatient drugs.Main outcomes and measuresNational Medicaid use and gross and net spending on drugs with accelerated approval from 2015 through 2019.ResultsSince the inception of the FDA's accelerated approval pathway in 1992 through 2020, 216 product-indication pairs granted accelerated approval were identified, comprising 149 unique products. The composition of drugs approved through the pathway has changed over time, with 28 of 30 (93.3%) product-indication pairs receiving accelerated approval in 2020 being indicated for cancer. Relative to all outpatient prescription drugs paid for by Medicaid, products with accelerated approval ranged from 0.2% to 0.4% of use (1.3-2.4 million prescriptions annually). Despite their infrequent use, drugs with accelerated approval represented a minimum annual net spending on all drugs covered by Medicaid of 6.4% ($2.2 billion of $34.6 billion) in 2015 and a maximum of 9.1% ($2.5 billion of $27.6 billion) in 2018. Estimated annual gross spending on drugs with accelerated approval ranged from $4.2 billion to $4.9 billion over 2015 through 2019, and estimated net spending from $2.2 billion to $2.6 billion.Conclusions and relevanceIn this cross-sectional study of 216 drugs granted accelerated approval, state spending on drugs approved through the FDA's growing accelerated approval program represented an outsized amount of spending relative to use. Because drugs with accelerated approval have come to market on the basis of trials using surrogate end points, considerable amounts of this spending may have been attributable to products with unproven clinical benefits.

Project description:ImportanceTo date, an empirical evaluation of the quality of control arms in randomized clinical trials (RCTs) leading to anticancer drug approvals by the US Food and Drug Administration (FDA) has not been undertaken.ObjectiveWe sought to estimate the percentage of RCTs that used a control arm deemed suboptimal and led to FDA approval of anticancer drugs from January 1, 2013, to July 31, 2018.Design, setting, and participantsThis quality improvement study included 143 anticancer drug approvals granted by the FDA from January 1, 2013, to July 31, 2018. All approvals based on single-arm studies (48 approvals) were excluded. Approvals based on RCTs were further investigated and each trial was analyzed for design, time of patient accrual, control arm, and primary end point. Standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of trial enrollment. The percentage of approvals based on RCTs that used suboptimal control arms was then calculated. The quality of the control arm was deemed suboptimal if the choice of control agent was restricted to exclude a recommended agent, the control arm was specified but the recommended agent was unspecified, and if prior RCT data had demonstrated that the control agent was inferior to an available alternative.Main outcomes and measuresEstimated percentage of RCTs that used suboptimal control arms that led to FDA approval of anticancer agents between January 1, 2013, to July 31, 2018.ResultsA total of 145 studies that led to 143 drug approvals between January 1, 2013, and July 31, 2018, were included. Of these studies, 48 single-arm studies were excluded. The remaining 97 studies led to 95 drug approvals. Of these 95 approvals, 16 (17%) were based on RCTs with suboptimal control arms; 15 were international trials, and 1 was conducted in the United States. The type of approval was regular in 15 trials and accelerated in 1 trial. When categorized by the nature of suboptimal control, 4 (25%) trials omitted active treatment in control arm by limiting investigator's choice, 11 (63%) trials omitted active treatment in the control arm by using a control agent known to be inferior to other available agents or not allowing combinations, and 1 (13%) trial used a previously used treatment in the control arm with a known lack of benefit associated with reexposure.Conclusions and relevanceAlthough anticancer drug approvals are increasing, a proportion of these drugs are reaching the market without proven superiority to what is considered the standard of care at the time of patient enrollment in pivotal trials. The choice of control arm should be optimized to ensure that new anticancer agents being marketed are truly superior to what most clinicians would prescribe outside a clinical trial setting.

Dataset Information

Rapid network meta-analysis using data from Food and Drug Administration approval packages is feasible but with limitations.

Publications

Rapid network meta-analysis using data from Food and Drug Administration approval packages is feasible but with limitations.

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