Leah Z. Rand, Daniel P. Carpenter, Aaron S. Kesselheim, Anushka Bhaskar, Jonathan J. Darrow, and William B. Feldman Reply.

The authors respond to a letter by Mitchell Berger in the March-April 2024 issue of the Hastings Center Report concerning their essay "Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines."

Physicians' Perspectives On FDA Regulation Of Drugs And Medical Devices: A National Survey.

Physicians' knowledge of Food and Drug Administration (FDA) approval processes is important in informing clinical decisions and patient discussions. Among a randomly selected national sample of 509 internists, cardiologists, and oncologists, 41 percent reported moderate or better understanding of the FDA's drug approval process, and 17 percent reported moderate or better understanding of the FDA's medical device approval process. Nearly all physicians thought that randomized, blinded trials that met primary endpoints should be very important factors required to secure regulatory approval. Also, nearly all physicians thought that the FDA should revoke approval for accelerated-approval drugs or breakthrough devices that did not show benefit in postapproval studies. Our findings suggest that physicians commonly lack familiarity with drug and medical device regulatory practices and are under the impression that the data supporting FDA drug and high-risk device approvals are more rigorous than they often are. Physicians would value more rigorous premarket evidence, as well as regulatory action for drugs and devices that do not demonstrate safety and effectiveness in the postmarket setting.

Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines.

The Covid-19 pandemic highlighted the need to examine public trust in the U.S. Food and Drug Administration (FDA) vaccine approval process and the role of political influence in the FDA's decisions. Ensuring that the FDA is itself trustworthy is important for justifying public trust in its actions, like vaccine approvals, thereby promoting public health. We propose five conditions of trustworthiness that the FDA should meet when it reviews vaccines, even during emergencies: consistency with rules, proper expert or political decision-makers, proper decision-making and noninterference, connection to public preference, and transparency of both reasons and procedures. The five conditions provide a road map of procedural and substantive requirements, which the FDA has variably implemented, focused on ensuring appropriate influence of political interests. While being a trustworthy agency cannot guarantee the public's trust, implementing these conditions builds a groundwork for public trust.

Prioritizing Early Disease Intervention.

Scholars and practitioners have described how investing in health care earlier rather than later can be beneficial, from how "biomarkers" offer promise for early disease detection to healthcare system "incentives" that can promote early preventive medicine. Work by health economists has also made clear that the "health capital" of an individual depreciates over time in the absence of investments in health. Yet, our current policy makers and healthcare system continue prioritizing care of late-stage complex symptomatic illness, often when cure is impossible and disease reversal is improbable, thus exacerbating public health burdens. Critically missing are predicates to address this challenge include the following: first, identifying and validating the specific set of presymptomatic biomarkers that will inform the most appropriate intervention timing for those medical conditions amenable to early intervention; second, shifting fundamental health economic incentives to influence the appropriate disease prevention market; and third, formulating and executing a viable economic framework of reimbursement. We examine these predicates and propose actionable policy recommendations that may help align stakeholder interests to improve public health.

An Empirical Review of Key Glucose Monitoring Devices: Product Iterations and Patent Protection.

INTRODUCTION: Each year, people with diabetes and their insurers or governments spend billions of dollars on blood glucose monitors and their associated components. These monitors have evolved substantially since their introduction in the 1970s, and manufacturers frequently protect original medical devices and their modifications by applying for and obtaining patent protection. RESEARCH DESIGN AND METHODS: We tracked the product iterations of five widely used blood glucose monitors-manufactured by LifeScan, Dexcom, Abbott, Roche, and Trividia-from information published by the U.S. Food and Drug Administration (FDA), and extracted relevant U.S. patents. RESULTS: We found 384 products made by the five manufacturers of interest, including 130 devices cleared through the 510(k) pathway, 251 approved via the premarket approval (PMA) pathway or via PMA supplements, and three for which de novo requests were granted. We identified 8095 patents potentially relevant to these devices, 2469 (31%) of which were likely to have expired by July 2021. CONCLUSIONS: Manufacturers of blood glucose monitoring systems frequently modified their devices and obtained patent protection related to these device modifications. The therapeutic value of these new modifications should be critically evaluated and balanced against their additional cost. Older glucose monitoring devices that were marketed in decades past are now in the public domain and no longer protected by patents. Newer devices will join them as their patents expire. Increased demand from people with diabetes and the health care system for older, off-patent devices would provide an incentive for the medical device industry to make these devices more widely available, enabling good care at lower cost when such devices are substantially equivalent in effectiveness and safety. In turn, availability and awareness of older, off-patent devices could help stimulate such demand.

Physician Perspectives on the Food and Drug Administration's Decision to Grant Accelerated Approval to Aducanumab for Alzheimer's Disease.

In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval to aducanumab, a monoclonal antibody indicated for the treatment of Alzheimer's disease. The accelerated approval decision was controversial due to concerns about the use of an unvalidated surrogate measure, beta-amyloid, as the basis for approval and a lack of clinical outcome benefit. Between October 2021 and September 2022, we conducted a survey of a nationally representative group of internists, medical oncologists, and cardiologists to understand perspectives around aducanumab's approval and how this FDA decision may influence trust in other drugs approved through the accelerated approval program. Among 214 physician respondents familiar with the accelerated approval of aducanumab, 184 (86%) would not prescribe or recommend aducanumab. Further, 143 (67%) physicians reported losing trust in other drugs approved through the accelerated approval program due to the FDA's decision with aducanumab. As a growing number of similar novel Alzheimer's disease treatments are on the horizon, the first of which, lecanemab, already has received accelerated approval in January 2023, our survey findings provide insight into the impact of the FDA's regulatory decisions on the perspectives and prescribing behavior of physicians concerning these novel drug treatments.

Trust and Regulation: Assuring Scientific Independence in the FDA's Emergency Use Authorization Process.

Since 2004, the US Food and Drug Administration (FDA) has had the authority to allow access to unapproved medical products via the Emergency Use Authorization (EUA) pathway during times of emergency. It was rarely used until the COVID-19 pandemic, when concerns arose regarding the role of political pressure in the FDA's issuance of some EUAs, such as for hydroxychloroquine. Although US government officials should be responsive to the public, democratic accountability must be balanced against the need for thoughtful science-based decision-making. Inadequate agency independence can diminish public confidence in government leaders and the FDA. To consider whether reform of the EUA process might be appropriate, we considered three possible sources of inspiration for balancing independence and accountability in government scientific decision-making: models in other countries, models in other US agencies, and models within the FDA itself. Strategies used in these settings include: (1) expanding the role of advisory committees, (2) increasing transparency of the agency's decision-making process and supporting rationale, and (3) improving management of internal agency disagreement. Such reforms could improve public trust in public health regulation both related to and separate from future emergencies.

Frequency of Approval and Marketing of Biosimilars With a Skinny Label and Associated Medicare Savings.

This cohort study assesses the frequency of approval and marketing of skinny-label biosimilars and their savings to Medicare.

Two views of cancer medicines: Imagery versus evidence.

Despite advertising imagery portraying cancer medicines as offering substantial improvement or cure, most patients can expect modest or no incremental benefit from most new treatments, according to pre-specified criteria. When improvements in overall survival are demonstrated, they average just 2.1 months. Despite limited benefits, drug prices have risen while median household incomes have remained largely unchanged, and these higher prices are poorly correlated with improved outcomes. Better alignment of perception with demonstrated drug benefit could be achieved by limitations on advertising and improved labeling or other disclosures. Reforms are also needed to remove financial incentives to prescribe costlier drugs.

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.

Communication of Drug Efficacy Information via a Popular Online Platform.

BACKGROUND: Open-source online information channels have become increasingly important to the dissemination of medical information, including information about pharmaceuticals. We sought to determine the extent to which one prominent source of online information, Wikipedia, presented quantitative efficacy data about drugs. METHODS: Using the Drugs@FDA website, we identified all new drugs approved by the Food and Drug Administration (FDA) from 1982 to 2020 and their associated Wikipedia pages, and used dummy variables to code for the presence of efficacy data, safety data, and usage data. RESULTS: Approximately 98% of 1201 drugs approved from 1982 to 2020 had Wikipedia pages. While most pages provided indirect indicia of efficacy, such as indication (98%) or mechanism of action (86%), fewer (21%) quantified evidence of benefit. Wikipedia drug pages were associated with indicia of high impact, including a median of more than 23,000 annual page views. CONCLUSION: Wikipedia is an important source of information that has the potential to shape public views about drug efficacy, but the absence of quantitative efficacy information in most pages limits public understanding of the benefits that drugs actually offer.

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.

Generating Evidence from Expanded Access Use of Rare Disease Medicines: Challenges and Recommendations.

Patients with rare diseases often have limited or no options for approved treatments or participation in clinical trials. In such cases, expanded access (or "compassionate use") provides a potential means of accessing unapproved investigational medicines. It is also possible to capture and analyze clinical data from such use, but doing so is controversial. In this perspective, we offer examples of evidence derived from expanded access programs for rare diseases to illustrate its potential value to the decision-making of regulators and payers in the European Union and the United States. We discuss ethical and regulatory aspects to the use of expanded access data, with a focus on rare disease medicines. The heterogeneous approach to expanded access among countries within the European Union leaves uncertainties to what extent data can be collected and analyzed. We recommend the issuance of new guidance on data collection during expanded access, harmonization of European pathways, and an update of existing European compassionate use guidance. We hereby aim to clarify the supportive role of expanded access in evidence generation. Harmonization across Europe of expanded access regulations could reduce manufacturer burdens, improve patient access, and yield better data. These changes would better balance the need to generate quality evidence with the desire for pre-approval access to investigational medicine.

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.

Incremental benefits of novel pharmaceuticals in the UK: a cross-sectional analysis of NICE technology appraisals from 2010 to 2020.

OBJECTIVES: To evaluate the incremental value of new drugs across disease areas receiving favourable coverage decisions by the UK's National Institute for Health and Care Excellence (NICE) over the past decade. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study assessed favourable appraisal decisions of drugs between 1 January 2010 and 31 December 2020. Estimates of incremental benefit were extracted from NICE's evidence review groups reports. PRIMARY OUTCOME MEASURE: Incremental benefit of novel drugs relative to the best alternative therapeutic option, expressed in quality-adjusted life-years (QALYs). RESULTS: 184 appraisals of 129 drugs provided QALYs. The median incremental value was 0.27 QALY (IQR: 0.07-0.73). Benefits varied across drug-indication pairs (range: -0.49 to 5.22 QALY). The highest median benefits were found in haematology (0.70, IQR: 0.55-1.22) and oncology (0.46, IQR: 0.20-0.88), the lowest in ophthalmology (0.09, IQR: 0.04-0.22) and endocrinology (0.02, IQR: 0.01-0.06). Eight appraisals (4.3%) found contributions of more than two QALYs, but one in four (50/184) drug-indication pairs provided less than the equivalent of 1 month in perfect health compared to existing treatments. CONCLUSIONS: In our review period, the median incremental value of novel drugs approved for use within the English National Health System, relative to the best alternative therapeutic option, was equivalent to 3-4 months of life in perfect health, but data were heterogeneous. Objective evaluations of therapeutic value helps patients and physicians to develop reasonable expectations of drugs and delivers insights into disease areas where medicinal therapeutic progress has had the most and least impact.

Strategies to Manage Drugs and Devices Approved Based on Limited Evidence: Results of a Modified Delphi Panel.

Prescription drugs and medical devices are increasingly coming to market through expedited US Food and Drug Administration (FDA) pathways that require only limited evidence of safety and efficacy, such as nonrandomized, unblinded trial data in small numbers of patients, or the use of surrogate end points. Reliance on more limited evidence means that there is often greater uncertainty about risks and benefits. Using a modified Delphi process, we sought to identify promising policy approaches that address physician-patient decision-making needs about the use of such drugs and medical devices. We convened 13 national leaders from academia, government, nonprofits, payors, and industry who had expertise in medical product regulation, payor policymaking, bioethics, physician practice, patient advocacy, public health expertise/advocacy, clinical trials, the pharmaceutical and device industry, institutional review board oversight, and real-world evidence. Through multiple rounds of voting and meetings focused on evaluating the feasibility and impact of various interventions, the 13 participants reached the broadest consensus on 4 interventions: strengthening FDA post-approval study requirements to ensure postmarket evidence is generated in a timely manner, better informing patients about the risks and benefits and level of evidence supporting therapies via simplified and patient-centered product information "boxes" modeled on nutrition labels, limiting prices for drugs and medical devices approved based on surrogate end point data until confirmatory clinical evidence is generated, and improving health professional education about FDA regulation to better support clinician use of drugs and devices as well as communication with patients.

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.