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Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.

ABSTRACT: Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated.To characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents.Cross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012.Pivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial end point. Surrogate outcomes were defined as any end point using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined.Between 2005 and 2012, the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. The median number of pivotal trials per indication was 2 (interquartile range, 1-2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%-92.2%]), double-blinded (79.5% [95% CI, 75.7%-83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%-90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%-40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%-52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%-39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%-23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval.The quality of clinical trial evidence used by the FDA as the basis for recent approvals of novel therapeutic agents varied widely across indications. This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents.

SUBMITTER: Downing NS

PROVIDER: S-EPMC4144867 | biostudies-literature | 2014 Jan 22-29

REPOSITORIES: biostudies-literature

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Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.

Downing Nicholas S NS Aminawung Jenerius A JA Shah Nilay D ND Krumholz Harlan M HM Ross Joseph S JS

JAMA 20140101 4

<h4>Importance</h4>Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated.<h4>Objectives</h4>To characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents.<h4>Design and setting</h4>Cross-sectional ...[more]

PMID: 24449315

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Project description:BackgroundCardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.ObjectivesThe authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.MethodsFrom the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.ResultsOverall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).ConclusionsAmong pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Project description:ImportanceThe US Food and Drug Administration (FDA) evaluates high-risk medical devices such as cardiac implantable electronic devices (CIEDs), including pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices, via the premarket approval (PMA) process, during which manufacturers submit clinical data demonstrating safety and effectiveness. Subsequent changes to approved high-risk devices are implemented via "supplements," which may not require additional clinical testing.ObjectiveTo characterize the prevalence and characteristics of changes to CIEDs made through the PMA supplement process.DesignUsing the FDA's PMA database, we reviewed all CIEDs approved as original PMAs or supplements from 1979 through 2012. For each supplement, we collected the date approved, type of supplement (panel-track, 180-day, real-time, special, and 30-day notice), and the nature of the changes. We calculated the number of supplements approved per PMA and analyzed trends relating to different supplement regulatory categories over time. For supplements approved via the 180-day regulatory pathway, which often involve significant design changes, from 2010-2012, we identified how often additional clinical data were collected.ResultsFrom 1979-2012, the FDA approved 77 original and 5829 supplement PMA applications for CIEDs, with a median of 50 supplements per original PMA (interquartile range [IQR], 23-87). Excluding manufacturing changes that do not alter device design, the number of supplements approved each year was stable around a mean (SD) of 2.6 (0.9) supplements per PMA per year. Premarket approvals remained active via successive supplements over a median period of 15 years (IQR, 8-20), and 79% of the 77 original PMAs approved during our study period were the subject of at least 1 supplement in 2012. Thirty-seven percent of approved supplements involved a change to the device's design. Among 180-day supplements approved from 2010-2012, 23% (15/64) included new clinical data to support safety and effectiveness.Conclusions and relevanceMany CIED models currently used by clinicians were approved via the PMA supplement process, not as original PMAs. Most new device models are deemed safe and effective without requiring new clinical data, reinforcing the importance of rigorous postapproval surveillance of these devices.

Project description:ImportanceClinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted.ObjectiveTo describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016.Design, setting, and participantsThis comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study.Main outcomes and measuresRegulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately.ResultsBetween 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months).Conclusions and relevanceIn this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

Project description:BackgroundMandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting. The Food and Drug Administration (FDA) Amendments Act (FDAAA) was enacted by Congress on September 27, 2007, requiring the registration of all non-phase I clinical trials involving FDA-regulated medical interventions and results reporting for approved drugs. The association between FDAAA enactment and the registration, results reporting, and publication bias of neuropsychiatric trials has not been studied.MethodsWe conducted a retrospective cohort study of all efficacy trials supporting FDA new drug approvals between 2005 to 2014 for neuropsychiatric indications. Trials were categorized as pre- or post-FDAAA based on initiation and/or completion dates. The main outcomes were the proportions of trials registered and reporting results in ClinicalTrials.gov, and the degree of publication bias, estimated using the relative risks pre- and post-FDAAA of both the publication of positive vs non-positive trials, as well as of publication of positive vs non-positive trials without misleading interpretations. Registration and results reporting proportions were compared pre- and post-FDAAA using the two-tailed Fisher exact test, and the degrees of publication bias were compared by calculating the ratio of relative risks (RRR) for each period.ResultsThe FDA approved 37 new drugs for neuropsychiatric indications between 2005 and 2014 on the basis of 142 efficacy trials, of which 101 were pre-FDAAA and 41 post-FDAAA. Post-FDAAA trials were significantly more likely to be registered (100% vs 64%; p < 0.001) and report results (100% vs 10%; p < 0.001) than pre-FDAAA trials. Pre-FDAAA, positive trials were more likely to be published (relative risk [RR] = 1.52; 95% confidence interval [CI] = 1.17-1.99; p = 0.002) and published without misleading interpretations (RR = 2.47; CI = 1.57-3.73; p < 0.001) than those with non-positive results. In contrast, post-FDAAA positive trials were equally likely to have been published (RR = 1; CI = 1-1, p = NA) and published without misleading interpretations (RR = 1.20; CI = 0.84-1.72; p = 0.30). The likelihood of publication bias pre-FDAAA vs post-FDAAA was greater for positive vs non-positive trials (RRR = 1.52; CI = 1.16-1.99; p = 0.002) and for publication without misleading interpretations (RRR = 2.06, CI = 1.17-3.61, p = 0.01).ConclusionsThe enactment of FDAAA was followed by significantly higher proportions of trials that were registered and reporting results on ClinicalTrials.gov and significantly lower degrees of publication bias among trials supporting recent FDA approval of drugs for neuropsychiatric indications.

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Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.

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Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.

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