Aligning US Agency Policies for Cardiovascular Devices Through the Breakthrough Devices Program.

Importance: The US Food and Drug Administration (FDA) and Centers for Medicare & Medicaid Services (CMS) have different statutory authorities; FDA evaluates safety and effectiveness for market authorization of medical devices while CMS determines whether coverage is "reasonable and necessary" for its beneficiaries. CMS has recently enacted policies automatically providing supplemental reimbursement for new, costly devices authorized after designation in FDA's Breakthrough Devices Program (BDP) and in June 2023 issued notice for a new Transitional Coverage for Emerging Technologies pathway, accelerating coverage for Breakthrough devices. Observations: Aiming to incentivize innovation, FDA awards Breakthrough designations early in device development to expedite market authorization and can accept greater uncertainty in benefit and risk, contingent on postmarket evidence generation. Since 2020, Breakthrough designation has effectively automatically qualified devices to receive supplemental Medicare reimbursement after CMS waived a long-standing requirement that devices demonstrate "substantial clinical improvement" for beneficiaries. Using publicly available information, 3 examples of cardiovascular devices illustrate that the BDP may allow for FDA authorization based on less rigorous evidence, such as single-arm trials focused on surrogate end points with short-term follow-up whose participants are often not representative of Medicare beneficiaries. In 1 case, Breakthrough designation allowed a 30% decrease in enrollment of a trial used to support approval. Initial positive findings for some devices have remained unverified, and in 1 case even partially nullified, by postmarket studies. Manufacturers have also used Breakthrough designations to set the price of devices to facilitate additional pass-through payments, leading to higher short-term and long-term costs to CMS and health care systems. Conclusions and Relevance: The BDP may qualify new, costly devices for higher and automatic Medicare reimbursement despite evidence not being representative of CMS beneficiaries and persistent uncertainty of benefit and risk. To ensure the best evidence is generated to inform clinical care, FDA could apply more selectivity to BDP eligibility, specify objective criteria for revoking Breakthrough designation when appropriate, and ensure timely postmarket evidence generation, whereas CMS could independently review clinical evidence, advise manufacturers about standards for coverage review, and make supplemental payments and long-term device reimbursement contingent on clinical outcome benefit and postmarket evidence generation.

Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016.

This cohort study used the Drugs@FDA database to identify new drugs approved by the US Food and Drug Administration (FDA) and assess fulfillment of postmarket commitments and requirements.

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.

New Drug Postmarketing Requirements and Commitments in the US: A Systematic Review of the Evidence.

INTRODUCTION: After the approval of a new drug, the Food and Drug Administration (FDA) may issue postmarketing requirements (PMRs), studies that the law requires manufacturers to conduct for drugs approved under certain conditions, and postmarketing commitments (PMCs), studies that the FDA and manufacturers agree should be conducted as a condition of approval. OBJECTIVE: With regulators' increasing reliance on gathering important evidence after initial product approval, we sought to assess the track record of PMRs and PMCs by synthesizing information about postmarketing study completion rates, timeliness, study types, and results reporting. METHODS: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. Studies published in academic journals or government reports that reported original data about the characteristics of PMRs or PMCs were included. Studies of post-approval trial mandates issued by regulators outside the USA were excluded, as were those that addressed post-approval research without mentioning either PMCs or PMRs or a specific approval pathway associated with statutorily required PMRs. Two investigators independently screened and extracted data from studies and reports. Data sources included the Federal Register from 2003 to 2020, FDA backlog reviews from 2008 to 2020, PubMed from January 2006 to April 2021, and the US Government Accountability Office (GAO) database for reports from January 2006 to April 2021. PMR/PMC characteristics (e.g., completion rates, timeliness, results reporting, outcomes) were not meta-analyzed due to the heterogeneity in study designs. RESULTS: Twenty-seven peer-reviewed articles from PubMed, five GAO reports, 17 annual Federal Register notices, and 12 annual backlog reviews were included. Among the 27 studies, 13 reviewed PMRs and PMCs, one reviewed only PMCs, and 13 reviewed only PMRs. A majority of new drugs were approved with at least one PMR or PMC. PMCs were completed at higher rates than PMRs, although delays were common and neither was found to be completed more than two-thirds of the time. Over two-thirds of PMRs and PMCs reported their findings in publications and trial registries. Over half of PMCs and PMRs produced novel information for clinical practice or leading to regulatory action, such as confirmation of benefit or a labeling change. CONCLUSION: PMRs and PMCs are common for new drugs and can lead to worthwhile outcomes, but are often delayed or incomplete. Greater attention is needed to timely completion, improving transparency of findings, and ensuring that PMRs and PMCs produce optimally useful information for prescribers and patients.

An Overview Of Vaccine Development, Approval, And Regulation, With Implications For COVID-19.

The Food and Drug Administration (FDA) approves vaccines when their benefits outweigh the risks for their intended use. In this article we review the standard FDA approach to vaccine evaluation, which underpins its current approaches to assessment of vaccines to prevent coronavirus disease 2019 (COVID-19). The FDA has established pathways to accelerate vaccine availability before approval, such as Emergency Use Authorization, and to channel resources to high-priority products and allow more flexibility in the evidence required for approval, including accelerated approval based on surrogate markers of effectiveness. Among the thirty-five new vaccines approved in the US from 2006 through October 2020, about two-thirds of their pivotal trials used the surrogate outcome of immune system response, and only one-third evaluated actual disease incidence. Postapproval safety surveillance of new vaccines, and particularly vaccines receiving expedited approval, is crucial. This has generally been accomplished through such mechanisms as the Centers for Disease Control and Prevention (CDC) and FDA Vaccine Adverse Event Reporting System, the CDC Vaccine Safety Datalink, and the CDC Clinical Immunization Safety Assessment Project. Adverse events detected in this way may lead to changes in a vaccine's recommended use or withdrawal from the market. Regulatory oversight of new vaccines must balance speed with rigor to effectively address the pandemic.