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.

Trends in the Quality of Evidence Supporting FDA Drug Approvals: Results from a Literature Review.

CONTEXT: New drug approvals in the United States must be supported by substantial evidence from "adequate and well-controlled" trials. The Food and Drug Administration (FDA) has flexibility in how it applies this standard. METHODS: The authors conducted a systematic literature review of studies evaluating the design and outcomes of the key trials supporting new drug approvals in the United States. They extracted data on the trial characteristics, endpoint types, and expedited regulatory pathways. FINDINGS: Among 48 publications eligible for inclusion, 30 covered trial characteristics, 23 covered surrogate measures, and 30 covered regulatory pathways. Trends point toward less frequent randomization, double-blinding, and active controls, with variation by drug type and indication. Surrogate measures are becoming more common but are not consistently well correlated with clinical outcomes. Drugs approved through expedited regulatory pathways often have less rigorous trial design characteristics. CONCLUSIONS: The characteristics of trials used to approve new drugs have evolved over the past two decades along with greater use of expedited regulatory pathways and changes in the nature of drugs being evaluated. While flexibility in regulatory standards is important, policy changes can emphasize high-quality data collection before or after FDA approval.

Analysis of Supportive Evidence for US Food and Drug Administration Approvals of Novel Drugs in 2020.

Importance: In recent years, drug approvals have been based on fewer, smaller, and less rigorous pivotal trials. Less robust preapproval testing raises questions about the efficacy and clinical value of these drugs. Objective: To assess the regulatory context, pivotal design characteristics, and postmarket requirements (PMRs) and postmarket commitments (PMCs) of novel 2020 drug approvals to characterize the state of evidence at the time of approval. Design, Setting, and Participants: This cohort study identified novel drugs approved by the US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research in 2020. The Drugs@FDA database was used to extract key characteristics of each drug's pivotal trials. Drug approval packages provided regulatory information. The prevalence of key trial design features was compared between oncology and nononcology drugs. Exposures: Drug names, date of approval, indication on labeling, and clinical and regulatory details. Main Outcomes and Measures: Number of pivotal trials, pivotal trial design (randomization, masking, groups), trial comparator, trial hypothesis, trial end points, results, number and type of expedited pathway designations, and number and type of PMRs and PMCs. Results: The 49 novel therapeutics approved in 2020 were supported by 75 pivotal trials. More than half of drugs (28 [57.1%]) were supported by a single pivotal trial. Trial sizes ranged from 19 to 2230 participants. More than three-fourths of trials (57 [76.0%]) had a randomization component, and nearly two-thirds (46 [61.3%]) were double-masked. Most used a superiority approach. Roughly half (39 [52.0%]) compared the novel therapeutic with a placebo or vehicle control; 13 (17.3%), an active control; 2 (2.7%), both a placebo and active control; and 21 (28.0%), a historical, external, or other control. Nearly half of pivotal trials (34 [45.3%]) used a surrogate measure as a primary end point. Pivotal trials supporting oncology approvals were much more likely to have historical controls than nononcology approvals (13 of 18 [72.2%] vs 8 of 57 [14.0%]; P < .001) and to use at least 1 surrogate measure as a primary end point (17 [94.4%] vs 17 [29.8%]; P < .001). Forty drugs had at least 1 PMR or PMC, accounting for 178 PMRs and PMCs across the cohort. Conclusions and Relevance: These findings suggest that the increased flexibility in the characteristics of acceptable preapproval evidence can be partially explained by the increase in trials of drugs for rare and other serious conditions that require flexible testing strategies as well as the associated regulatory changes that have accumulated over time. The FDA and consumers may benefit from a revised approach that better balances time to market with ensuring that approved drugs show evidence of efficacy.

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.

Reporting bias in clinical trials: Progress toward transparency and next steps.

Mayookha Mitra-Majumdar and Aaron Kesselheim reflect on steps taken to combat reporting bias in clinical trials over the last two decades.

Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs.

Objective: To review the clinical evidence, regulatory background, and cost of antibiotics approved by the US Food and Drug Administration (FDA), 2016-19. Design: Cohort study of FDA approved drugs. Data sources: FDA databases, ClinicalTrials.gov, and drug labelling. Launch prices were extracted from IBM Micromedex Red Book. Eligibility criteria for selecting studies: Antibiotics approved by the FDA from October 2016 to December 2019 were identified, and key features of their clinical development were extracted from publicly available FDA databases, ClinicalTrials.gov, and drug labelling. Launch prices were extracted from IBM Micromedex Red Book to evaluate the cost of treatment against comparators. Results: 15 new antibiotics received at least one special regulatory designation and were supported by a median of two pivotal trials. More than half of the pivotal trials used an active control non-inferiority design. All drugs were approved based on surrogate outcome measures. 52 postmarketing requirements and commitments were included across the cohort (median 3 for each drug). From January 2021, 27 postmarketing requirements and commitments were listed as pending, seven as ongoing, three as delayed, one as submitted, eight as released, and four as fulfilled. The most expensive new antibiotic was pretomanid at $36 399 (£29 618; €34 582) for a course of treatment, and the least expensive was rifamycin ($176). Cost ratios between study drugs and comparators ranged from 0.48 to 134. Conclusions: New antibiotics have been approved by the FDA in recent years mostly based on fewer, smaller, and non-inferiority pivotal trials that often used surrogate outcome measures but were commonly more costly. Efforts to incentivise the development of antibiotics should balance growing the antibiotic development pipeline with ensuring that clinical trials provide clinically relevant evidence of effectiveness in showing added benefits for the patient.

A Multi-modal Approach to Evaluate the Impact of Risk Evaluation and Mitigation Strategy (REMS) Programs.

INTRODUCTION: Since 2007, the US Food and Drug Administration has had the authority to require risk evaluation and mitigation strategy (REMS) programs for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. Such programs can include requirements for patient monitoring, restrictions on dispensing or administration, and physician and pharmacy training and certification. However, there has been only scattered evidence on the impact of REMS programs on informed decision making, medication access, or patient outcomes. OBJECTIVE: The objective of this article was to describe a study that researchers at Brigham and Women's Hospital and Harvard Medical School will conduct in partnership with the Food and Drug Administration's Office of Surveillance and Epidemiology to investigate systematically how REMS programs have operated in practice. METHODS: Investigations include health insurance claims-based analyses to understand patterns of drug use, adherence to safety requirements, and patient outcomes under REMS programs; surveys and interviews to understand physician and patient experiences with REMS; and REMS program material-based and interview-based analyses to understand the effectiveness of risk communication in REMS programs. CONCLUSIONS: These research activities will evaluate the performance of REMS programs, provide information on the benefits and burdens to patients and healthcare providers, and generate recommendations for actionable steps to improve REMS programs overall.

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.