Holly Fernandez Lynch

The US Food and Drug Administration (FDA) has historically exercised substantial regulatory flexibility to adjust the type, amount, and quality of evidence necessary to support drug approval for areas of unmet need. Our objective was to characterize how FDA officials described and justified regulatory flexibility in recent public statements. We conducted a thematic analysis of quotations related to regulatory flexibility from 31 FDA officials published in Pink Sheet and STAT, two leading news sources covering FDA, from January 2021 to June 2024. In these statements, FDA officials typically justified prioritizing patient access to promising treatments over certainty regarding efficacy at the time of approval, even outside the accelerated approval pathway. Regulators also highlighted confirmatory studies conducted after accelerated approval as important for establishing drug efficacy. However, they recognized challenges to their completion, including insufficient industry incentives and FDA enforcement, and were reticent to interpret failed studies as evidence of failed drugs. Overall, in public statements from 2021–2024, FDA officials acknowledged challenges posed by regulatory flexibility but publicly justified its broad use to improve patient access for serious diseases despite even extended uncertainty. Under the Trump Administration, many officials have changed but efforts to advance regulatory flexibility continue.

Despite substantial progress, many serious diseases continue to lack safe and effective therapies. Building on a recent National Academies consensus study report that offers several recommendations to better align investments in therapeutic development with unmet needs, in this commentary, we focus on the Food and Drug Administration's role in advancing this goal. Historically, FDA has encouraged investment where market incentives fall short, undertaken efforts to address broad scientific challenges, and administered programs to expedite development and review of drugs targeting unmet needs. Under the second Trump administration, FDA has launched several initiatives that continue these key themes, although some have been controversial, primarily due to concerns about resource sufficiency and the potential for political interference. Regarding other domains addressed by the National Academies report, FDA has recently given mixed signals on its commitment to upholding rigorous approval standards; paid limited attention to noted gaps, including improving rigorous postmarket evidence generation and validating the surrogate markers often used to support product approval; and failed to ensure adequate financial and human resources to support the agency's critical work. Engagement with the National Academies report's recommendations can help ensure that FDA continues to advance progress toward addressing unmet medical needs.

Despite initiatives to enhance diversity in clinical trials (CTs), disparities persist in hematologic malignancy (HM) studies. We reviewed 1,230 US-based phase II-III HM CTs (2000-2023) including 149,434 participants and compared enrollment to SEER benchmarks. Race was reported in 59% of trials and ethnicity in 40%, with significant improvement over time. Trials initiated in 2016 or later were more likely to report race (OR 36.3) and ethnicity (OR 8.0) than those before 2008. Compared with NIH-sponsored studies, institutional (OR 0.34) and industry trials (OR 0.52) had lower odds of reporting demographics. Black and Hispanic individuals were consistently underrepresented, most notably in multiple myeloma (7.0% vs. 20.0% expected) and acute lymphoblastic leukemia (21.5% vs. 36.9% expected). NIH-funded trials enrolled more Black participants than other sponsor types. These findings emphasize the need for enforceable mandates on race and ethnicity reporting, as well as representation targets, to ensure equitable access and generalizability.

Psychedelic medicines hold the promise of therapeutic benefit for many suffering from serious unmet mental health needs, leading to substantial demand even before these drugs receive FDA approval based on demonstrated safety and effectiveness for particular conditions. Recognizing FDA approval as the ideal path for psychedelics intended for medical use and drawing on lessons from medical marijuana, we encourage policymakers to balance the need for evidence, the importance of patient safeguards, and the desire for speed. They should increase support for psychedelic research, reject approaches that could inhibit that research, explore improvements to FDA’s existing pre-approval access pathway, and avoid politically motivated FDA approval of psychedelic medicines.

A number of patient organizations have recently embraced venture philanthropy, a model of patient advocacy that purports to use practices from venture capitalism in pursuit of philanthropic goals. However, a clear understanding of what venture philanthropy entails and what these organizations do remains elusive, hindering efforts to assess ethical implications of the model's growth. We conducted a qualitative content analysis of self-reported profiles of 130 organizations in an affinity network promoting principles of venture philanthropy. We analyzed organizations' research goals, funding strategies, activities, and patient engagement efforts. Despite finding substantial variation in age, revenue, and disease focus, we identified shared assumptions and approaches that represent defining characteristics of venture philanthropy. First, organizations consistently present facilitating the development of new therapies as the most urgent need for patients. Second, organizations participate in financing and managing research across the development pipeline, rather than focusing on basic research as many patient organizations historically have done. Third, organizations seek to position themselves within established research and drug development networks, fostering collaborative relationships with key stakeholders, including pharmaceutical companies. We also find that some of the most transformative practices associated with venture philanthropy, such as direct investment in for-profit companies, remain relatively uncommon. Venture philanthropy represents an evolution in the ambitions and activities of patient organizations, with organizations becoming more fully enmeshed in the drug development process. Our findings raise ethical questions about how patient organizations conceptualize and advance patient interests and about tradeoffs inherent to the venture philanthropy model.

Introduction: Concerns about completing postmarketing requirements (PMRs) following accelerated approval (AA) of new drugs have been well documented. However, there has been little examination of specific barriers and facilitators to timely, rigorous PMRs (eg, blinded, randomized trials in the approved population) from the perspective of key stakeholders. Methods: To understand these factors, especially for cancer and rare diseases, we interviewed 56 regulators, industry executives, patient advocates, and payers. Results: Stakeholders focused on predictable PMR barriers and, except for payers, offered weak solutions, including those that would trade rigor for feasibility (eg, avoiding randomization, conducting PMRs outside approved indications), could raise other concerns (eg, conducting PMRs abroad), or are likely to fall short (eg, patient education). Stakeholders supported requiring that confirmatory studies begin before AA but were unsure how to retain rigor thereafter, emphasized tradeoffs, and sought rare disease exceptions. Although regulators and payers supported payment reforms for AA drugs, all stakeholder groups questioned practicability. Conclusion: Stakeholders recognize PMR shortcomings but prioritize flexibility, raising questions about AA's foundations and suggesting that further documenting poor rigor is unlikely to change policy. Beyond recent reforms, future efforts should emphasize confirming benefit for rare disease AAs, encouraging PMR rigor, and exploring AA payment reform.

This qualitative study investigates the frequency of reports of difficulty in voting for drug approval by members of the Food and Drug Administration Oncologic Drugs Advisory Committee.

Preventing and addressing research misconduct demands more than imploring scientists to do better. It is also essential to address the structural issues that allow misconduct to flourish. With these structural factors in mind, this Special Issue explores the institutional obligations of journals and publishers, research institutions, funders, and the government to promote scientific integrity and advance trust in science. Articles from researchers affected by fraud, science “sleuths,” systematic reviewers, journal editors, academic officials, regulators, and leading experts on research integrity offer a range of ideas for responding to the research misconduct crisis, including increased transparency, stronger journal processes for review and retraction, improved scientific lab culture, and efforts to hold investigators prospectively accountable for scientific integrity, among several others.