Scholarly Commentary
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Holly Fernandez Lynch, Reshma Ramachandran, Rachel Sachs, Patricia J. Zettler, Steven Joffe
Health Affairs Forefront. 2026;06:20260604.485666.
FDA issued draft guidance for its “plausible mechanism” framework for regulatory approval of treatments for patients with n-of-1 or n-of-few genetic disorders. These pieces provide background on the development of individualized genetic therapies, describe key elements of the draft guidance, and examine the appropriate scope of a plausible mechanism approach. FDA should further clarify within the guidance the scope of the plausible mechanism framework, address manufacturing challenges, the product and reach of the approval granted under this framework, and consider post-approval requirements for safety and efficacy.
Holly Fernandez Lynch, Reshma Ramachandran, Rachel Sachs, Patricia J. Zettler, Steven Joffe
Health Affairs Forefront. 2026;06:20260604.803734.
Personalized medicine has advanced to the point that, in some cases, a patient’s unique disease-causing variant can be treated through an individualized genetic intervention. FDA is working to adapt its regulatory approval process to account for these individualized approaches. Given the limited evidence that will be available for products developed under the plausible mechanism framework, it is critical that FDA maintain a strong standard for demonstrated improvement in clinical outcomes or course, one of the five elements listed as central to the framework.
The FDA Amendments Act and Drug Safety: Where Are We Twenty Years Later?
Joshua D. Wallach, Erfan Taherifard, Shaimaa Elshafie, Reshma Ramachandran, Joseph S. Ross
Health Affairs Forefront. 2026;06:20260601.485632.
In 2007, FDA passed the US Food and Drug Administration Amendments Act of 2007 (FDAAA). FDA was granted enforcement authorities to ensure timely reporting of clinical trial results, require additional postmarket safety studies, and reduce the risk of potential serious adverse events while maintaining patient access through REMS. Evidence from the nearly two decades since FDAAA was implemented highlights both progress and persistent challenges in postmarket drug safety oversight.
Never Waste a Crisis: The Past, Present, and Future of FDA Reform
Patricia J. Zettler JD, Reshma Ramachandran, MD, MPP, MHS, Holly Fernandez Lynch
J Health Polit Policy Law. 2026;04:285–307.
A core mission of FDA is to advance public health through regulatory decision-making, demanding both scientific expertise and political judgment. In overseeing the approval of many products that Americans use every day, the FDA must make timely, scientifically informed, and politically informed decisions that serve the public interest while withstanding scrutiny from industry, advocacy groups, elected officials, judges, patients, clinicians, and the public. Scientific rigor and public trust in FDA’s decisions are at stake. Yet this crisis may offer an opportunity to rebuild and re-envision FDA for the future.
Naveen Kumar Reddy, Michael A. Steinman, Joseph S. Ross, Eric Widera, Nina Zeldes, Robert Steinbrook, Reshma Ramachandran
BMJ Evid Based Med. 2026;03.114142.
FDA’s decision to approve benzgalantamine illustrates how the 505(b)(2) pathway, originally intended to speed access to modified, similar versions of existing medicines, has the potential to become a shortcut to market access for products with uncertain clinical value. To safeguard public trust, regulators should ensure that evidentiary standards evolve alongside industry innovation and subject commercial claims to rigorous scrutiny.
Reshma Ramachandran, Christopher J. Morten
JAMA. 2026;02:585-587.
On September 19, 2025, HHS Secretary Robert F. Kennedy Jr and FDA’s Commissioner Martin Makary announced that HHS would be conducting “a study on the safety of the current [Risk Evaluation and Mitigation Strategy (REMS)]” for mifepristone to “determine whether modifications are necessary.” Transparency must be required from the start, as patients and clinicians should not need to wait for documents to be made available in response to FOIA requests, which frequently take years to be completed, to understand the current FDA’s decision-making on this essential drug.
The Promise And Perils of FDA’s New ‘Plausible Mechanism’ Pathway (Part 2)
Holly Fernandez Lynch, Reshma Ramachandran, Rachel Sachs, Steven Joffe, and Patricia J. Zettler
Health Affairs. 2026;01:20260121.824818.
While promising, the plausible mechanism approach as described to date raises a number of important questions and potential concerns. To ensure that the plausible mechanism pathway can achieve its important goals, FDA’s immediate next steps (before granting any approvals under the pathway) should include issuing draft guidance that incorporates the substantive limits and clarifications suggested. FDA should open a broad public comment process, hold an advisory committee meeting, and should work with Congress to codify a narrow plausible mechanism approach in legislation.
The Promise And Perils of FDA’s New ‘Plausible Mechanism’ Pathway (Part 1)
Holly Fernandez Lynch, Reshma Ramachandran, Rachel Sachs, Steven Joffe, and Patricia J. Zettler
Health Affairs. 2026;01:20260121.824818.
FDA leadership via journal publication proposed a new approach to facilitating ultrarare disease drug development and approval through the “plausible mechanism pathway” While such a pathway holds great promise for facilitating the future development of truly individualized treatments, there are important questions about how the approach will work in practice, as well as concern about how it might be extended beyond narrowly defined cases. Before FDA implements this new approach, the agency immediately issue draft guidance and pursue several additional steps to provide clarity and establish narrow boundaries for when the pathway will apply.
Automatic Medicare Coverage for New Medical Techologies-Here We Go Again
Kushal T. Kadakia, Sanket S. Dhruva, Joseph S. Ross, Vinay K. Rathi
NEJM. 2026;01:213-215.
The U.S. Congress is considering bills that would substantially expand Medicare coverage of putatively transformative technologies: medical devices that receive breakthrough designation from the FDA and multicancer early detection (MCED) tests. This bipartisan legislation reflects a years-long, industry-backed effort to expand Medicare coverage for new technologies, but there is a fundamental tension between regulatory speed and clinical certainty for new medical technologies.
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Enhancing FDA Drug-Safety Surveillance - Beyond Releasing Daily Adverse-Event Data
Joshua D. Wallach, Joseph S. Ross, Reshma Ramachandran
NEJM. 2025;12: 2284-2286.
FAERS is FDA’s primary database for passive postmarketing surveillance of small-molecule drugs and biologic agents, but releasing this information daily will not improve drug safety signal detection. Significant investment and comprehensive action by FDA will be necessary to achieve the goal of identifying adverse events and responding to adverse-event reports in real time to protect patients and public health.
Expanding Prior Authorization in Traditional Medicare-The WISeR Model
Vinay K Rathi, Sanket S. Dhruva, Joseph S. Ross
JAMA. 2025;08:1423-1424.
Insurers impose prior authorization requirements for high-cost tests and treatments with the stated aims of preventing medically unnecessary care, reducing low-value spending, and deterring fraud and abuse. Based on CMS’ budding experience with prior authorization in traditional Medicare, the WISeR model holds promise to generate meaningful savings and deter medically unnecessary, potentially harmful care. WISeR may reduce traditional Medicare spending, but at what cost remains unclear.
Diffusing Authority to Make Drug Approval Decisions at the US Food and Drug Administration
Caleb Rhodes, Reshma Ramachandran, Holly Fernandez Lynch
Nat Med. 2025;09:3244-3247.
Decisions about new drug approvals are often straightforward, with scientific evidence either clearly supporting approval or not. Yet some decisions demand substantial scientific and policy judgment from FDA. There is an urgent need to strengthen the integrity of drug approvals and rejections by diffusing the decision-making authority of individual officials and improving transparency when disagreements arise.
Reforming the Prescription Drug User Fee Program
Therese J. Ziaks, Jason L. Schwartz, Joseph S. Ross, Reshma Ramachandran
NEJM. 2025;08:734-736.
The scope of PDUFA legislation and its effects on drug regulation have expanded considerably. For more than 30 years, the FDA, the pharmaceutical industry, and Congress have agreed that user fees are needed to supplement the FDA’s operations budget and ensure sufficient staffing to support timely review of medical products. Amid bipartisan calls for program reform, PDUFA’s future remains unclear.
Regulatory Change Could Improve Biosimilar Access in the US
Tiffany E Jiang, Reshma Ramachandran, Joshua J. Skydel
BMJ. 2025;07:e084860.
Biological medicines (biologics) such as monoclonal antibodies have improved the treatment of numerous cancers, autoimmune diseases, and other conditions. They provide targeted treatment that enables patients to control their disease and lead healthier lives. To ensure patients have access to affordable biologic therapies, biosimilar development should be supported by FDA policy changes loosening—and ultimately eliminating—the interchangeable designation.
Cell and Gene Therapies- Improving Access and Outcomes for Medicare and Medicaid Beneficiaries
Joseph S. Ross
NEJM. 2025;02:521-523.
An executive order issued in October 2022 tasked HHS with directing CMMI to develop and test payment and delivery models that would lower drug costs and promote access to innovative therapies for Medicare and Medicaid enrollees. Future agreements pertaining to cell- and gene-therapy access models may not be as straightforward, however, which could lead to concerns about the limited opportunity for public input and other precedents set by CMS in negotiations with the manufacturers of exa-cel and lovo-cel.
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Enhancing Medical Device Postmarketing Safety Surveillance-The Case of Inferior Vena Cava Filters
Behnood Bikdeli, Joseph S. Ross
JAMA. 2024;12:2065-2067.
Nearly 90% of medical devices that undergo regulatory review are classified as moderate risk and receive authorization through the 510(k) process, which additionally requires manufacturers to demonstrate “substantial equivalence” to a previously authorized (predicate) device, usually without being required to show evidence of device safety and effectiveness from clinical studies. The FDA is making progress in postmarket medical device safety surveillance, and the SAFE-IVC study is an important step toward better understanding IVCF use and safety.
Integrating Equity Into Licensing Agreements For Taxpayer-Funded Technologies
Jishian Ravinthiran, Bryce Robinson, Peter Maybarduk, Rachel M. Cohen, Pascale Boulet, Michelle Childs, Mihir Mankad, Isabel Parkey, James Love, Melissa Barber, and Brook Baker
Health Affairs Forefront. 2024;12:2340.
Privatizing publicly funded technology without sufficient public interest protections has deadly consequences. Extending the access policy beyond licensing intramural inventions to extramural funding agreements with medical centers, universities, and other institutions. could have transformative consequences for global health needs as most of the NIH’s support is funneled through these agreements.
Technology transfer, intellectual property, and the fight for the soul of WHO
Melissa Barber
PLOS Global Public Health.2024;12:e0003940.
Debates over the scope, terms, and governance of technology transfer–the sharing of essential technical information, know-how, and materials needed to manufacture a health product–are prominent and controversial in international health diplomacy. When past, equity-driven models for drug access become unrememberable as legitimate policy precedents, the field of vision for viable future options to address pandemics and other health challenges narrows.
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Aligning US Agency Policies for Cardiovascular Devices Through the Breakthrough Devices Program
Osman Moneer, Vinay K. Rathi, James L. Johnston, Joseph S. Ross, Sanket S. Dhruva
JAMA Cardiology. 2023;10:1174-1181.
FDA's Breakthrough Devices Program 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. FDA could apply more selectivity to eligibility, specify objective criteria for revoking Breakthrough designation when appropriate, and ensure timely postmarket evidence generation. 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.
Medical device risk (re)classification: lessons from the FDA’s 515 Program Initiative
Maryam Mooghali, Vinay K. Rathi, Kushal T. Kadakia, Joseph S. Ross, Sanket S. Dhruva
BMJ Surgery, Interventions, & Health Technologies. 2023;09:e000186
FDA classifies medical devices into low-, moderate-, and high-risk categories, which has implications for the amount of information manufacturers need to submit to provide ‘reasonable assurance of safety and effectiveness’ for market authorization. The 515 Program Initiative offers insights into how FDA synthesises postmarket data to recalibrate the risk classification for medical devices and lessons for modernising medical device classification more broadly to advance access to medical devices while maintaining patient safety.
The Accelerated Approval Program for Cancer Drugs — Finding the Right Balance
Bishal Gyawali, Aaron S. Kesselheim, Joseph S. Ross
NEJM. 2023;09:968-971
FDA’s accelerated approval program allows drugs designed to treat serious conditions for which there is an unmet medical need to be approved on the basis of changes in surrogate measures that are only reasonably expected to predict clinical outcomes. While FDA’s proposal to improve the accelerated approval pathway for cancer drugs is a step in the right direction, additional measures could promote an appropriate balance among supporting early access to potentially effective cancer drugs, confirming that drugs improve patient outcomes for the accelerated approval indications, and ensuring that patients aren’t unnecessarily exposed to drugs that have unconfirmed benefits but often carry substantial risks.
Extending the US Food and Drug Administration’s Postmarket Authorities
Holly Fernandez Lynch, Rachel E. Sachs, Sejin Lee, Matthew Herder, Joseph S. Ross, Reshma Ramachandran
JAMA Health Forum. 2023;06:e231313.
FDA’s regulatory flexibility with respect to standards for approval has not been matched by sufficient stringency in its exercise of postmarket safeguards, including FDA’s authority and willingness to require confirmation of benefit through postmarket efficacy studies or to withdraw approval when benefit is not confirmed. Drawing on the broad language of the federal Food, Drug, and Cosmetic Act, FDA could independently extend its core accelerated approval authorities—required postmarket efficacy studies and expedited withdrawal procedures—to any drug approved with substantial residual uncertainty regarding benefit, such as those supported by a single pivotal trial.
Joseph S. Ross
BMJ. 2023;05:37160304.
In 1983 Congress enacted the Orphan Drug Act, establishing financial incentives for companies to develop new drugs and biologics for rare diseases, including a partial tax credit for clinical trial expenditures, waived user fees, and eligibility for seven years of marketing exclusivity. After 40 years, the Orphan Drug Act has had an immeasurable impact on the scope and scale of development of new drugs and biologics for rare diseases. However, steps are needed to ensure that patients are getting the best possible value from the program given the high cost of orphan drugs to both health systems and the public.
Challenges and solutions to advancing health equity with medical devices
Kushal T. Kadakia, Vinay K. Rathi, Reshma Ramachandran, James L. Johnston, Joseph S. Ross, Sanket S. Dhruva
Nature Biotechnology. 2023;04:607-609.
Created by Congress in 2016, the Breakthrough Devices Program (BDP) is intended to expedite developing and authorizing devices that diagnose or treat life-threatening conditions and represent technologies that either lack approved alternatives or offer substantial advantages when compared to existing modalities. FDA is now proposing to broaden eligibility for the BDP — and the program’s associated regulatory and financial benefits to manufacturers — to include devices that could promote and advance health equity. While such disparities warrant action, FDA’s BDP proposal does not address the systemic factors underlying them.
Ensuring Public Trust in an Empowered FDA | NEJM
Joseph S. Ross, Karina M. Berg, Reshma Ramachandran
NEJM. 2023;04:1249-1251.
On January 6, 2023, FDA. granted accelerated approval to lecanemab (Leqembi). Accelerated approval is based on results from pivotal trials using surrogate end points that are deemed “reasonably likely” to predict clinical benefit and requires postmarketing studies verifying such benefit. An empowered FDA may prioritize using its regulatory authority to enable timely access to innovative products, but to ensure continued trust in the agency, this priority should be balanced against the challenges clinicians, patients, and caregivers face when there is substantial residual uncertainty about product safety and efficacy.