Characteristics of Clinical Studies Used for US Food and Drug Administration Approval of High-Risk Medical Device Supplements.
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ABSTRACT: Importance
High-risk medical devices often undergo modifications, which are approved by the US Food and Drug Administration (FDA) through various kinds of premarket approval (PMA) supplements. There have been multiple high-profile recalls of devices approved as PMA supplements.Objective
To characterize the quality of the clinical studies and data (strength of evidence) used to support FDA approval of panel-track supplements (a type of PMA supplement pathway that is used for significant changes in a device or indication for use and always requires clinical data).Design and setting
Descriptive study of clinical studies supporting panel-track supplements approved by the FDA between April 19, 2006, and October 9, 2015.Exposure
Panel-track supplement approval.Main outcomes and measures
Methodological quality of studies including randomization, blinding, type of controls, clinical vs surrogate primary end points, use of post hoc analyses, and reporting of age and sex.Results
Eighty-three clinical studies supported the approval of 78 panel-track supplements, with 71 panel-track supplements (91%) supported by a single study. Of the 83 studies, 37 (45%) were randomized clinical trials and 25 (30%) were blinded. The median number of patients per study was 185 (interquartile range, 75-305), and the median follow-up duration was 180 days (interquartile range, 84-270 days). There were a total of 150 primary end points (mean [SD], 1.8 [1.2] per study), and 57 primary end points (38%) were compared with controls. Of primary end points with controls, 6 (11%) were retrospective controls and 51 (89%) were active controls. One hundred twenty-one primary end points (81%) were surrogate end points. Thirty-three studies (40%) did not report age and 25 (30%) did not report sex for all enrolled patients. The FDA required postapproval studies for 29 of 78 (37%) panel-track supplements.Conclusions and relevance
Among clinical studies used to support FDA approval of high-risk medical device modifications, fewer than half were randomized, blinded, or controlled, and most primary outcomes were based on surrogate end points. These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved.
SUBMITTER: Zheng SY
PROVIDER: S-EPMC5817595 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeTo analyze all recalls involving radiation oncology devices (RODs) from the US Food and Drug Administration (FDA)'s recall database, comparing these with non-radiation oncology device recalls to identify discipline-specific trends that may inform improvements in device safety.Methods and materialsRecall data on RODs from 2002 to 2015 were sorted into 4 product categories (external beam, brachytherapy, planning systems, and simulation systems). Outcomes included determined cause of recall, recall class (severity), quantity in commerce, time until recall termination (date FDA determines recall is complete), and time since 510(k) approval. Descriptive statistics were performed with linear regression of time-series data. Results for RODs were compared with those for other devices by Pearson χ2 test for categorical data and 2-sample Kolmogorov-Smirnov test for distributions.ResultsThere were 502 ROD recalls and 9534 other class II device recalls during 2002 to 2015. Most recalls were for external beam devices (66.7%) and planning systems (22.9%), and recall events peaked in 2011. Radiation oncology devices differed significantly from other devices in all recall outcomes (P≤.04). Recall cause was commonly software related (49% vs 10% for other devices). Recall severity was more often moderate among RODs (97.6% vs 87.2%) instead of severe (0.2% vs 4.4%; P<.001). Time from 510(k) market approval to recall was shorter among RODs (P<.001) and progressively shortened over time. Radiation oncology devices had fewer recalled devices in commerce than other devices (P<.001).ConclusionsCompared with other class II devices, RODs experience recalls sooner after market approval and are trending sooner still. Most of these recalls were moderate in severity, and software issues are prevalent. Comprehensive analysis of recall data can identify areas for device improvement, such as better system design among RODs.
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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.
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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.
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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.
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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.
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