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1377 Results

Use of Health Care Databases to Support Supplemental Indications of Approved Medications

Fralick M, Kesselheim AS, Avorn J, Schneeweiss SG - JAMA Internal Medicine

  • Research Publications
| January 2018
  • Regulation and Clinical Evidence
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This cohort study using insurance claims data from 2003 to 2009 found that telmisartan (Micardis) and ramipril (Altace) had similar composite risks of stroke, myocardial infarction, and heart failure hospitalization, replicating the results of the ONTARGET randomized clinical trial, while telmisartan showed substantially lower angioedema risk. These findings demonstrate how real-world database analyses can effectively support supplemental indication applications for already-approved medications in certain circumstances.
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The Supreme Court Ruling in Sandoz v. Amgen: A Victory for Follow-On Biologics

Sarpatwari A, Gluck AR, Curfman GD - JAMA Internal Medicine

  • Commentary & Opinion
| January 2018
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors analyze the Supreme Court’s unanimous ruling in Sandoz v. Amgen that biosimilar manufacturers are not required to share their licensing applications with originator companies and can provide the required 180-day market entry notice before FDA approval, removing key barriers to biosimilar competition.
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Pharmaceutical Advertising in Medical Journals

Sinha MS, Kesselheim AS, Darrow JJ - Chest

  • Commentary & Opinion
| January 2018
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Pharmaceutical advertising and medical journals have an enduring relationship. Journals remain heavily dependent on advertising revenue ,and studies show a $3-5 return on investment for every dollar spent on journal advertising, raising concerns about influence on prescribing.
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Ethical Challenges in Biomarker-Driven Drug Development

Hey SP - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| January 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The author reviews ethical challenges arising from the increasing use of biomarkers in drug development, including concerns about informed consent for biospecimen use, the justice implications of precision medicine increasing drug costs and limiting access, and a novel challenge relating to the “principle of efficiency” requiring studies to maximize their contribution to knowledge.
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Benefits, Limitations, and Value of Abuse-Deterrent Opioids

Curfman GD, Beletsky L, Sarpatwari A - JAMA Internal Medicine

  • Research Publications
| January 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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An ICER evidence review found that while abuse-deterrent (AD) opioid formulations reduced OxyContin abuse by 12–75% in postmarket analyses and showed lower drug-liking scores in premarket trials, several studies reported offsetting increases in abuse of other opioids. AD opioids were estimated to cost $231,000 per case of abuse prevented, $1.4 billion per overdose death prevented, and produced no difference in opioid-related deaths compared to non-AD opioids, with $533 million in additional spending. The authors conclude that while AD opioid use may be warranted in certain cases, mandatory substitution policies would be cost-prohibitive and potentially counterproductive, while current AD opioid prices are unjustified given the limited evidence of benefit.
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Prices of Generic Drugs Associated with Numbers of Manufacturers

Dave CV, Hartzema A, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| December 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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An analysis of 1.9 billion prescription claims (2008–2014) found a strong association between the number of generic manufacturers and relative drug prices. Generic prices were 87% of brand-name prices with 1 manufacturer, dropping to 77% with 2, 60% with 3, and continuing to decline with each additional entrant, with larger markets experiencing steeper price reductions. Compared to a prior FDA analysis, the entry of a 2nd generic manufacturer now produces a smaller price decrease, suggesting a shift in the competitive dynamics of the generic drug market that supports the FDA’s policy of expediting review for markets with fewer than 3 generic competitors.
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Is the Concept of Clinical Equipoise Still Relevant to Research?

Hey SP, London, AJ, Weijer C, Rid A, Miller F - BMJ

  • Commentary & Opinion
| December 2017
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
In this debate, Hey, London, and Weijer argue that clinical equipoise remains the best ethical framework for justifying randomized controlled trials because it protects patients from being systematically disadvantaged, prevents wasteful low-value trials, and promotes public trust in the research enterprise. In the opposing view, Rid and Miller counter that the equipoise requirement rests on a flawed attempt to align clinical research ethics with the norms of clinical practice, is internally inconsistent in how it treats different types of research risks, and can prevent valuable and acceptable trials from being conducted.
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Evidence Required for Drugs Granted Accelerated Approval (Reply)

Naci H, Kesselheim AS - JAMA

  • Commentary & Opinion
| December 2017
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
In this reply, the authors address the evidence standards for accelerated approval, reaffirming the importance of rigorous confirmatory trials following initial surrogate-based approvals.
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Speed, Safety, and Industry Funding—From PDUFA I to PDUFA VI

Darrow JJ, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| December 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The Prescription Drug User Fee Act, first enacted in 1992, authorized the FDA to collect fees from pharmaceutical companies to fund staff hiring and reduce drug review times. These fees have expanded from $100,000 per new drug application to a system generating hundreds of millions annually across drugs, devices, generics, and biosimilars, while FDA review times fell from over 35 months in 1979 to under 12 months. The authors trace the evolution of PDUFA through its sixth reauthorization in 2017, examining how the growing dependence of the FDA on industry-paid user fees has created tensions between expediting drug availability and ensuring adequate safety evaluation.
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The FDA’s Expedited Programs and Clinical Development Times for Novel Therapeutics, 2012-2016

Hwang TJ, Darrow JJ, Kesselheim AS - JAMA

  • Research Publications
| December 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 174 new drugs approved from 2012 to 2016, 60% qualified for at least 1 of the FDA’s 4 expedited programs, with breakthrough therapy-designated drugs having the shortest median development time, while drugs receiving only priority review or accelerated approval (without fast-track or breakthrough status) showed no significant difference in development times compared to non-expedited drugs. These findings suggest that the fast-track and breakthrough programs, which are specifically designed to shorten the clinical trial process, are achieving their intended effect, while the other expedited programs primarily accelerate regulatory review rather than overall development.
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Will Inter Partes Review Speed US Generic Drug Entry?

Darrow JJ, Beall RF, Kesselheim AS - Nature Biotechnology

  • Commentary & Opinion
| December 2017
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors describe how inter partes review—a newer, extra-judicial pathway for challenging pharmaceutical patents before the Patent Trial and Appeal Board—offers a faster, cheaper, and more successful alternative to traditional patent litigation for generic drug manufacturers. They argue this mechanism could help accelerate generic drug entry by invalidating improperly granted patents more efficiently than court proceedings.
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A New Approach to Treat Childhood Leukemia: Novartis’ CAR-T Therapy

Tessema FA, Darrow JJ - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Winter 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors describe the FDA’s approval of tisagenlecleucel (Kymriah), the first CAR-T cell therapy, highlighting its novel mechanism of genetically engineering patients’ own T-cells and the promising results from its pivotal trial in pediatric acute lymphoblastic leukemia.
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Op-Ed: Three Things Trump Can Do to Bring Drug Prices ‘Way Down’

Kapczynski A, Kesselheim AS - Washington Post

  • Commentary & Opinion
| November 2017
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors outline three executive actions available to address drug pricing without congressional action: allowing drug importation from Canada under existing statutory authority, invoking Bayh-Dole Act provisions to ensure fair pricing of drugs developed with federal research funding, and using the government’s existing legal authority to seek competitive bids for patented medicines covered by federal payers.
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Comments for Hearing, “Administering the Hatch-Waxman Amendments: Ensuring an Appropriate Balance Between Innovation and Access” (Luo)

Luo J - Food and Drug Administration (FDA)

  • Policy Interactions
| November 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
An icon of a bill representing government policy.
The FDA’s planned transition of insulin products from the small-molecule drug pathway to the biologics pathway could create regulatory uncertainty that discourages generic insulin competition. The commenter urges the agency to streamline pathways for follow-on insulin products given the urgent public health need for affordable insulin.
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Trends in Pricing and Generic Competition Within the Oral Antibiotic Drug Market in the United States

Alpern JD, Zhang L, Stauffer WM, Kesselheim AS - Clinical Infectious Diseases

  • Research Publications
| November 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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This quantitative analysis of 22 oral antibiotics found that while median prices and manufacturer numbers remained stable between 2013 and 2016, 14% of formulations experienced price increases of 90% or more, and reduced manufacturer competition was significantly associated with higher prices. The authors conclude that policy interventions are needed to maintain affordable access to essential generic antibiotics, particularly for formulations with limited manufacturer competition.
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Comments for Hearing, “Administering the Hatch-Waxman Amendments: Ensuring an Appropriate Balance Between Innovation and Access” (Sarpatwari, Sinha, Kesselheim)

Sarpatwari A, Sinha MS, Kesselheim AS - Food and Drug Administration (FDA)

  • Policy Interactions
| November 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The commenters outline how brand-name manufacturers misuse risk evaluation and mitigation strategies (REMS) and restricted distribution programs to block generic competitors from obtaining drug samples needed for bioequivalence testing. They recommend legislative and regulatory reforms to close these loopholes.
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The Real‐World Ethics of Adaptive‐design Clinical Trials

Bothwell LE, Kesselheim AS - Hastings Center Report

  • Research Publications
| November 2017
  • Regulation and Clinical Evidence
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The authors argue that while adaptive randomized controlled trials are promoted as more ethically advantageous than conventional RCTs because they reduce allocation to inferior treatments, the ethical justifications commonly offered for these designs often rely on theoretical equipoise rather than the more reliable standard of clinical equipoise. Clinical equipoise should be the primary ethical standard for evaluating adaptive trial designs, and the authorspropose ethical approaches to address concerns unique to adaptive designs as policymakers increasingly encourage their use.
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Strategies That Delay Market Entry of Generic Drugs

Vokinger KN, Kesselheim AS, Avorn J, Sarpatwari A - JAMA Internal Medicine

  • Research Publications
| November 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Brand-name drug manufacturers employ multiple strategies to delay generic competition, including peripheral patenting, reverse payment settlements, restricting access to drug samples, misusing risk mitigation strategies, and filing citizen petitions with the FDA. The authors recommend that the federal government strengthen patent standards, Congress enact legislation to discourage reverse payment settlements and require sample sharing, and the FDA provide earlier bioequivalence guidance and presume rejection of late-filed citizen petitions.
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Determinants of Market Exclusivity for Prescription Drugs in the United States

Kesselheim AS, Sinha MS, Avorn J - JAMA Internal Medicine

  • Research Publications
| November 2017
  • Innovation Incentives and Competition
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Brand-name prescription drugs in the US receive approximately 12 to 16 years of market exclusivity through a combination of patent protection (up to 20 years with extensions) and FDA-granted regulatory exclusivities (6-7 years for small-molecule drugs, 12 years for biologics), which enables manufacturers to maintain high prices by blocking generic competition. Policy reforms should aim to balance the need for fair industry returns on investment with timely access to lower-cost generic alternatives to improve drug affordability and address public health needs.
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The Price of Crossing the Border for Medications (Reply)

Fralick M, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| October 2017
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
In this exchange, the FDA officials safety concerns about drug importation from Canada, while the authors reply that a well-regulated importation program from licensed Canadian pharmacies could be implemented safely and would help address the significant price disparities between the two countries.
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Recalibrating Privacy Protections to Promote Patient Engagement

Sarpatwari A, Choudhry NK - New England Journal of Medicine

  • Commentary & Opinion
| October 2017
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Overly conservative interpretation of HIPAA privacy and security rules undermines the effectiveness of patient engagement tools at a time when missed appointments, medication nonadherence, and low vaccination rates cost the health care system billions. The authors propose that default privacy standards be reversed so patients would opt in to stringent protections rather than the current system requiring them to opt out, which would enable more personalized and accessible digital communication between clinicians and patients.
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Nearly One-Third of New Drugs Are No Better Than Older Drugs, and Some Are Worse

Darrow JJ, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| October 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Analysis of drugs approved between 1999 and 2012 reveals that 29% of new drug-indication pairs offered zero or negative health gains over existing treatments, including 41% of those approved through non-expedited pathways, with some therapeutic categories averaging net QALY losses. While FDA expedited programs do correctly prioritize higher-value drugs on average, the findings suggest that the policy focus on accelerating drug approvals should be balanced with a commensurate emphasis on measuring and reporting meaningful clinical efficacy.
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Introduction: Background and Foundations

Kesselheim AS - Specimen Science: Ethics and Policy Implications

  • Commentary & Opinion
| October 2017
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
This introductory book chapter frames the legal and ethical challenges surrounding the use of biospecimens in research, synthesizing contributions on privacy law, the Common Rule, property rights in biological materials, and the legacy of cases like Henrietta Lacks. The author argues that the field’s piecemeal oversight may benefit from more centralized governance to ensure consistent protections, patient engagement, and public trust.
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Outcomes-Based Pharmaceutical Contracts: An Answer to High U.S. Drug Spending?

Seeley E, Kesselheim AS - The Commonwealth Fund

  • Research Publications
| September 2017
  • Price, Value, and Access
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Pharmaceutical manufacturers and some private payers are increasingly adopting outcomes-based contracts for high-cost brand-name drugs, but their ability to curb spending is questionable due to limited applicability across drug types and a lack of meaningful metrics for evaluation, with no evidence demonstrating reduced spending or improved quality to date. The authors recommend voluntary testing and rigorous evaluation of outcomes-based contracts within Medicare and Medicaid programs to better understand the potential of this emerging model.
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Low-Dose Desmopressin Nasal Spray and FDA Approval (Reply)

Fralick M, Kesselheim AS - JAMA

  • Commentary & Opinion
| September 2017
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
In this exchange, the manufacturer of Noctiva disputes the authors’ characterization of the clinical data and basis for FDA approval, while the authors reiterate concerns about the drug’s modest benefits relative to its serious safety risks, particularly hyponatremia in elderly patients.
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Comments for Hearing, “Administering the Hatch-Waxman Amendments: Ensuring an Appropriate Balance Between Innovation and Access” (Sarpatwari et al.)

Sarpatwari A, Kesselheim AS, Karshtedt D, Carrier MA - Food and Drug Administration (FDA)

  • Policy Interactions
| September 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The commenters propose methods for the FDA to identify and address anticompetitive “product hopping,” in which brand-name manufacturers make minor modifications to their drugs and shift patients to new formulations in order to delay generic competition. They also recommend that the FDA solicit comparative effectiveness data for modified products filed near the end of patent exclusivity.
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Safety Related Label Changes for New Drugs After Approval in the US Through Expedited Regulatory Pathways: Retrospective Cohort Study

Mostaghim SR, Gagne JJ, Kesselheim AS - BMJ

  • Research Publications
| September 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Drugs approved through FDA expedited pathways were associated with significantly higher rates of safety-related label changes after approval compared to drugs approved through standard pathways, with a rate of 0.94 changes per drug per year versus 0.68 changes per year, and a 48% higher rate of changes to boxed warnings and contraindications. Although expedited pathways accelerate drug availability, additional research is needed to determine the causal factors behind these higher post-approval safety label changes.
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Influence, Integrity, and the FDA: An Ethical Framework

Hey SP, Cohen IG, Adashi EY, Kesselheim AS - Science

  • Research Publications
| September 2017
  • Regulation and Clinical Evidence
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The authors present an ethical decision framework for distinguishing between legitimate external influences that serve the FDA’s regulatory mission and illegitimate influences that corrupt or undermine the agency’s scientific deliberations. The framework is designed to assist regulators, policymakers, judges, physicians, and the public in evaluating whether external pressures on FDA decisions appropriately advance public health or compromise the agency’s core mission of ensuring drug and device safety and efficacy based on scientific evidence.
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Value-Based Pricing and State Reform of Prescription Drug Costs

Hwang TJ, Kesselheim AS, Sarpatwari A - JAMA

  • Commentary & Opinion
| August 2017
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
New York’s pioneering value-based pricing legislation, which authorized the state to set target prices for high-cost Medicaid drugs based on therapeutic benefit and negotiate supplemental rebates, represents the first such approach by a US public payer.
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Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval By the US Food and Drug Administration

Naci H, Smalley KR, Kesselheim AS - JAMA

  • Research Publications
| August 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Between 2009 and 2013, the FDA granted accelerated approval to 22 drugs for 24 indications based on preapproval trials with a median of 132 participants. At 3 years post-approval, only 50% of required confirmatory studies were completed, with clinical benefit confirmed in only 42% of indications while 58% had incomplete requirements including 8% with failed trials and 13% delayed more than 1 year. Postapproval confirmatory trials had similar design characteristics to preapproval studies and often relied on surrogate measures, raising concerns about the timeliness of confirming clinical benefit for accelerated approval indications, particularly for those approved 5 or more years prior without completed confirmatory evidence.
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The Pharmaceutical Market’s Adverse Effects

Kesselheim AS - Health Affairs

  • Commentary & Opinion
| August 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
In this review of Ben Goldacre’s Bad Pharma, Kesselheim discusses Goldacre’s account of systemic flaws in how drugs are developed, studied, approved, and prescribed—framing the problems not as individual fraud but as “institutional corruption” in which actors across the pharmaceutical ecosystem behave rationally within a poorly designed system. He notes that while Goldacre’s emphasis on transparency as a remedy is essential, transparency alone carries risks of complacency and more biased recommendations, and that fundamental cultural and regulatory changes are needed to address institutional corruption head-on.
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High Generic Drug Prices and Market Competition: A Retrospective Cohort Study

Dave CV, Kesselheim AS, Fox ER, Qiu P, Hartzema A - Annals of Internal Medicine

  • Research Publications
| August 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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This retrospective cohort study of 1.12 billion prescription claims from 2008-2013 found that generic drugs in highly competitive markets (quadropoly) experienced price decreases of 31.7%, while those in monopoly markets experienced price increases of 47.4%, demonstrating a strong inverse association between market competition and price changes. The authors conclude that measuring market competition levels using the Herfindahl-Hirschman Index may help identify older generic drugs at higher risk for future price increases.
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Effect of US Food and Drug Administration’s Cardiovascular Safety Guidance on Diabetes Drug Development

Hwang TJ, Franklin JM, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| August 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The FDA’s 2008 cardiovascular safety guidance for diabetes drugs was associated with a 31% differential decrease in the rate of diabetes drugs entering phase II trials, though the remaining drugs were significantly more likely to target novel biological pathways, with no measurable improvement in glycemic efficacy among phase III candidates. The findings demonstrate how regulatory actions can substantially impact pharmaceutical innovation trajectories and drug development priorities.
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Challenges in the Development of Novel Cardiovascular Therapies

Hwang TJ, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| August 2017
  • Innovation Incentives and Competition
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Cardiovascular drugs declined from 13% of all Phase 1 trials in 1990 to just 5% in 2015, and only 2% of breakthrough therapy designations went to cardiovascular products compared to 45% for oncology—despite cardiovascular disease accounting for nearly 1 in 3 deaths globally. The authors highlight recurring Phase 3 failures driven by reliance on surrogate endpoints that did not translate to clinical benefit and call for policies that support public translational research funding and encourage rigorous trials measuring hard clinical outcomes.
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Both Urgency and Balance Needed in Addressing Opioid Epidemic: A Report From the National Academies of Sciences, Engineering, and Medicine

Bonnie RJ, Kesselheim AS, Clark JD - JAMA

  • Commentary & Opinion
| August 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
This viewpoint summarizes a National Academies report calling for the FDA to balance access to opioids for legitimate pain management with stronger actions to combat the opioid crisis, including improved postmarket surveillance, evidence-based prescribing guidelines, and investment in alternative pain treatments. The authors emphasize that opioid prescribing in the US remains far higher than warranted by the evidence, with devastating consequences from both prescription opioids and illicit alternatives.
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The Price of Crossing the Border for Medications

Fralick M, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| July 2017
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
US per capita prescription drug spending far exceeds Canada’s and the OECD average, driven by lengthy market exclusivity periods and restricted government negotiating power, including for generic drugs whose US prices have recently increased by 1,000% or more. The authors argue that importing safe and effective medications from Canada represents a viable near-term strategy to address unaffordable drug prices, particularly for generic medications, and they outline proposed legislation that would create a “certified foreign seller” framework with robust safety safeguards.
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Testimony: Strategies that Delay Timely Generic Entry of Generic Drugs and Potential Policy Solutions: The CREATES Act and Beyond

Kesselheim AS - 115th Congress, House Committee on the Judiciary, Subcommittee on Regulatory Reform, Commercial, and Antitrust Law

  • Policy Interactions
| July 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
Kesselheim describes the life-cycle management tactics brand-name manufacturers use to delay generic competition, including secondary patenting and product hopping, reverse payment settlements, withholding samples needed for bioequivalence testing, REMS misuse, and citizen petition abuse. He endorses the CREATES Act as an important step to address these tactics, and he recommends additional reforms including routine PTAB review of secondary patents, stronger penalties for anticompetitive settlements, and procedural hurdles for late-filed citizen petitions. Watch his testimony.
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Op-Ed: Don’t Limit the Powers of the FDA

Bateman-House A, Sarpatwari A - Boston Globe

  • Commentary & Opinion
| July 2017
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Federal “right-to-try” legislation would dangerously undermine the agency’s consumer protection mission. The authors note that the FDA already approves the overwhelming majority of expanded access requests and that state right-to-try laws have produced no evidence of improved patient access, while the proposed federal version would prohibit the FDA from considering deaths or serious side effects arising from investigational drugs obtained under the law.
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Association of the Priority Review Voucher with Neglected Tropical Disease Drug and Vaccine Development

Jain N, Hwang TJ, Franklin JM, Kesselheim AS - JAMA

  • Research Publications
| July 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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An analysis of all novel products entering Phase I clinical trials from 2000 to 2014 found that the priority review voucher program was not associated with an increase in early-stage product development for neglected tropical diseases (NTDs), with the proportion of NTD drugs among all products declining at similar rates before and after the program’s creation. These findings suggest that the voucher program has not achieved its intended goal of stimulating innovative neglected tropical disease research, likely because the vouchers have primarily rewarded companies for products already in late-stage development or previously approved abroad.
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Public Participation in Drafting of the 21st Century Cures Act

Hwang TJ, Sachs RE, Kesselheim AS - Journal of Law, Medicine, & Ethics

  • Research Publications
| July 2017
  • Regulation and Clinical Evidence
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A review of public comments submitted during the drafting of the 21st Century Cures Act found that public input meaningfully shaped the legislation: the House committee added $8.75 billion in new NIH funding after comments criticized the initial draft’s lack of research funding, and dropped four of five proposed drug exclusivity extensions after commenters warned they would reward products that would have been developed anyway. However, payers, public health organizations, and individual physicians and researchers were underrepresented among commenters relative to patient groups, professional societies, and industry.
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Testimony: The Public Health Risks of Expanding Off-Label Promotion of Prescription Drugs and Devices

Kesselheim AS - 115th Congress, House Committee on Energy and Commerce, Subcommittee on Health

  • Policy Interactions
| July 2017
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
Kesselheim warns that proposed legislation would dangerously expand manufacturers’ permitted off-label communications, exposing patients to inadequately tested drugs and diverting use from FDA-validated therapies, citing Vioxx, Paxil, and antipsychotics in dementia patients as examples of past off-label marketing harms. He argues that disclaimers have been shown ineffective at modifying consumer behavior, and that loosening restrictions would reduce manufacturers’ incentives to conduct rigorous trials of new indications. Watch his testimony.
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Will Strict Limits on Opioid Prescription Duration Prevent Addiction? Advocating for Evidence-Based Policymaking

Mundkur ML, Gordon AJ, Kertesz SG - Substance Abuse

  • Commentary & Opinion
| July 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
State laws imposing strict duration limits on opioid prescriptions—prompted by the CDC’s 2016 guideline recommending no more than 7 days for acute pain—may not effectively prevent addiction and could harm patients who legitimately need short-term opioid therapy, highlighting the need for evidence-based rather than reflexive policy responses.
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Testimony in Support of Legislation on Pharmaceutical Transparency and Price Gouging

Sarpatwari A - Massachusetts General Court, Joint Committee on Health Care Financing

  • Policy Interactions
| July 2017
  • Price, Value, and Access
An icon of a bill representing government policy.
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The Opioid Epidemic: Fixing a Broken Pharmaceutical Market

Sarpatwari A, Sinha MS, Kesselheim AS - Harvard Law & Policy Review

  • Research Publications
| July 2017
  • Regulation and Clinical Evidence
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The authors analyze the US opioid epidemic through the lens of pharmaceutical market failures, examining how the intersection of aggressive manufacturer marketing, inadequate regulatory oversight of off-label promotion, and misaligned prescriber incentives contributed to widespread opioid misuse and abuse that prompted President Obama to request $1.1 billion for treatment access. They propose market-based reforms addressing the pharmaceutical supply chain to complement the $1 billion in state funding authorized by the 21st Century Cures Act.
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Coverage of Magnetic Resonance Imaging for Patients with Cardiac Devices: Improving the Coverage with Evidence Development Program

Kramer DB, Kesselheim AS - JAMA Cardiology

  • Commentary & Opinion
| July 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Medicare’s “coverage with evidence development” program has been problematic for MRI access in patients with cardiac implantable devices, as the program’s requirements create barriers that prevent patients from receiving clinically important imaging even though newer data support its safety under proper supervision.
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Op-Ed: Get Generic Drugs to Market Faster

Sarpatwari A, Kesselheim AS - Bloomberg

  • Commentary & Opinion
| June 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors advocate for passage of the bipartisan CREATES Act to combat brand-name manufacturers’ tactics for delaying generic competition. The CREATES Act would allow generic manufacturers to petition courts for access to withheld samples and empower the FDA to approve generics with independent REMS programs, with the Congressional Budget Office estimating the legislation would save the federal government over $3 billion.
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The Effects of the Sunshine Act: What Can and Should We Expect?

Sinha MS, Kesselheim AS - American Journal of Bioethics

  • Commentary & Opinion
| June 2017
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors evaluate the Physician Payments Sunshine Act’s mandatory disclosure requirements, discussing what effects on physician-industry relationships and prescribing behavior can realistically be expected from transparency alone.
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Comments for Public Workshop, “Generic Drug User Fee Amendments of 2012; Regulatory Science Initiatives Part 15”

Sinha MS, Kesselheim AS - Food and Drug Administration (FDA)

  • Policy Interactions
| June 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The FDA Office of Generic Drugs should prioritize research on strategies that delay generic drug availability (including secondary patenting and restricted drug distribution) and on post-approval studies of generic drug outcomes, to support a competitive market and build patient confidence in generic medicines.
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Success, Failure, and Transparency in Biomarker-Based Drug Development: A Case Study of Cholesteryl Ester Transfer Protein Inhibitors

Hey SP, Franklin JM, Avorn J, Kesselheim AS - Circulation: Cardiovascular Quality and Outcomes

  • Research Publications
| June 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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This systematic analysis of cholesteryl ester transfer protein inhibitors found that despite 100 clinical studies involving 96,944 human subjects, only 42% of the data were published, and discontinued drugs showed a consistent pattern of positive biomarker results followed by negative clinical outcomes. The authors conclude that regulators, funding bodies, and policymakers should play a greater role in evaluating and coordinating biomarker-driven research programs to prevent inefficiencies and harms from continued reliance on inadequately validated biomarkers.
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Patient and Physician Perceptions of Drug Safety Information for Sleep Aids: A Qualitative Study

Kesselheim AS, McGraw SA, Dejene SZ, Rausch P, Dal Pan GJ, Lappin BM, Zhou EH, Avorn J, Campbell EG - Drug Safety

  • Research Publications
| June 2017
  • Regulation and Clinical Evidence
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Patients and physicians reported awareness of general side effects of sleep aids (zolpidem and eszopiclone) but were largely unaware of specific FDA drug safety communications, particularly regarding next-morning impairment with zolpidem and lower recommended initial doses for women. The authors recommend that FDA and other disseminators of drug safety information develop more user-friendly resources to ensure timely communication of emerging medication risks to both patients and providers.
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Journey of Generic Imatinib: A Case Study in Oncology Drug Pricing

Chen CT, Kesselheim AS - Journal of Oncology Practice

  • Research Publications
| June 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Despite imatinib (Gleevec) being a groundbreaking targeted cancer therapy, its list price rose from $26,400/year at its 2001 launch to over $120,000/year by the time generic entry occurred in February 2016, delayed beyond the original 2013 patent expiration to 2019 by patent term restoration, pediatric exclusivity, and secondary patents. The authors detail how various market strategies slowed generic entry in the US compared to other countries and identify ongoing hurdles in the brand-to-generic transition, offering recommendations for improving generic access in oncology.
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Do Patients Trust the FDA?: A Survey Assessing How Patients View the Generic Drug Approval Process

Kesselheim AS, Gagne JJ, Franklin JM, Eddings W, Fulchino LA, Campbell EG - Pharmacoepidemiology and Drug Safety

  • Research Publications
| June 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 753 patients with chronic diseases, 74% reported little familiarity with the FDA’s generic drug approval process, yet 89% believed FDA approval ensures generic drug safety and effectiveness, with no significant differences in concerns between drugs approved through standard versus product-specific pathways. The findings suggest that patient trust in the FDA’s generic drug approval system remains high despite limited knowledge, and patients do not express greater skepticism toward generics approved through modified bioequivalence approaches.
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Changes in Prescribing and Healthcare Resource Utilization After FDA Drug Safety Communications Involving Zolpidem-Containing Medications: Prescribing After Drug Safety Communications

Kesselheim AS, Donneyong MM, Dal Pan GJ, Zhou EH, Avorn J, Schneeweiss SG, Seeger JD - Pharmacoepidemiology and Drug Safety

  • Research Publications
| June 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The FDA’s January and May 2013 Drug Safety Communications regarding zolpidem-containing medications did not halt the existing downward trend in new prescriptions, but they did result in a significant shift toward lower-dose formulations, with average prescribed doses decreasing from 9.7 mg to 9.4 mg and lower-dose forms increasing by 30%. These findings demonstrate that the safety communications successfully influenced prescribing practices to align with FDA recommendations for lower starting doses.
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Accelerated Approval and Expensive Drugs—A Challenging Combination

Gellad WF, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| May 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors examine the tension between the FDA’s accelerated approval pathway and the increasingly high prices manufacturers set for these products, creating a situation where insurers and patients pay premium prices for drugs whose real-world effectiveness has not yet been confirmed.
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FDA Approval of Desmopressin for Nocturia

Fralick M, Kesselheim AS - JAMA

  • Commentary & Opinion
| May 2017
  • Regulation and Clinical Evidence
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The authors critique the FDA’s approval of desmopressin nasal spray for nocturia, noting that the drug’s clinical benefit was modest while carrying serious risks including life-threatening hyponatremia and a black-box warning, with five deaths in the treatment group during clinical trials.
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Taxing Drug Price Spikes: Assessing the Potential Impact

Hwang TJ, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| May 2017
  • Price, Value, and Access
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A proposed excise tax on drug price increases exceeding inflation could generate billions annually from Medicare Part D alone, where 68% of drug spending in 2015 involved products with above-inflation price hikes. The tax would disproportionately burden companies relying on price increases rather than innovation to drive returns, potentially spurring industry-wide adoption of inflation-linked pricing commitments.
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The Failure of Solanezumab—How the FDA Saved Taxpayers Billions

Sacks CA, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| May 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The FDA’s decision not to approve solanezumab for Alzheimer’s disease, despite pressure to lower approval standards, saved taxpayers billions of dollars that would have been spent on an ineffective drug, illustrating the value of rigorous evidence requirements.
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Media Coverage of FDA Drug Safety Communications About Zolpidem: A Quantitative and Qualitative Analysis

Woloshin S, Schwartz LM, Dejene SZ, Rausch P, Dal Pan GJ, Zhou EH, Kesselheim AS - Journal of Health Communication

  • Research Publications
| May 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Following FDA Drug Safety Communications about zolpidem (Ambien), news media coverage increased substantially, with 64% of lay media stories focusing on DSC content, though coverage varied considerably. At least half of stories correctly reported three key safety messages but fewer than one-third reported other critical warnings such as impairment occurring even when users feel fully awake. The findings underscore the need for FDA to ensure more consistent translation of all key safety messages through media coverage to effectively communicate drug safety risks to the public.
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Letter to Louisiana Secretary of Health, “Hepatitis C in Louisiana: Recommendations on Drug Availability”

Sharfstein JM, Anderson GF, Ballreich JM, Brennan HW, Greene JA, Jackson MR, Kapczynski A, Kesselheim AS, Lee JJ, Sen AP, Trujillo AJ - Louisiana Department of Health

  • Policy Interactions
| May 2017
  • Price, Value, and Access
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The authors recommend that Louisiana ask HHS to address the state’s hepatitis C crisis by pursuing voluntary licensing of highly effective treatments for low-income populations, as proposed by the National Academy of Sciences. Simultaneously, they urges HHS to invoke 28 U.S.C. §1498 to authorize generic manufacturing of hepatitis C drugs at a fraction of market cost, with reasonable compensation paid to patent holders.
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Periodic Benefit‐Risk Evaluation Reports Have Substantial Promise to Guide Patient Care and Should Be Made Publicly Available

Fralick M, Kesselheim AS - Pharmacoepidemiology and Drug Safety

  • Commentary & Opinion
| May 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The FDA’s new Periodic Benefit-Risk Evaluation Reports (PBRERs), which provide cumulative assessments of a drug’s benefits and risks using both clinical trial and real-world data, represent a significant improvement over the older safety-focused reports and should be made publicly available to inform clinical decision-making.
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Medicaid Expenditures and Estimated Rebates for Epinephrine Autoinjectors, 2012 to 2016

Luo J, Kesselheim AS, Avorn J - JAMA Internal Medicine

  • Research Publications
| May 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The article examines Medicaid spending on EpiPen epinephrine autoinjectors in the context of Mylan’s price increase to $609 and the company’s $465 million DOJ settlement for alleged misclassification of the product to avoid higher Medicaid rebates. The analysis quantifies Medicaid expenditures and estimated rebates during the period of rapid price escalation, illustrating how drug-device combination product pricing and rebate classification can impose significant costs on public insurance programs.
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Ensuring Access to Injectable Generic Drugs—The Case of Intravesical BCG for Bladder Cancer

Davies BJ, Hwang TJ, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| April 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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A shortage of BCG for bladder cancer treatment—caused by one of only two manufacturers exiting the market—led patients to receive inferior alternative therapies and drove substantial price increases for substitute agents. The authors outline how this case illustrates broader vulnerabilities in the supply of injectable generic drugs that require policy intervention.
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Three Design Aspects for High Quality Post-Marketing Cohort Studies

Fralick M, Kesselheim AS - BMJ

  • Commentary & Opinion
| April 2017
  • Regulation and Clinical Evidence
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The authors identify three critical design features for rigorous post-marketing drug safety studies: a new-user active comparator design, propensity score matching for confounding control, and use of previously validated and clinically meaningful outcomes.
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FDA Approval of Eteplirsen for Muscular Dystrophy (Reply)

Kesselheim AS, Avorn J - JAMA

  • Commentary & Opinion
| April 2017
  • Regulation and Clinical Evidence
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In this exchange, DMD experts defend the eteplirsen approval by arguing for flexibility in evaluating small datasets for rare diseases, while the authors reiterate concerns about the quality of evidence and the precedent set by approving a drug without demonstrating meaningful clinical benefit.
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The Effect of Federal and State Off-Label Marketing Investigations on Drug Prescribing: The Case of Olanzapine

Wang B, Studdert DM, Sarpatwari A, Franklin JM, Landon JE, Kesselheim AS - PLOS ONE

  • Research Publications
| April 2017
  • Regulation and Clinical Evidence
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Federal and state investigations into off-label promotion of olanzapine resulted in $1.4 billion in federal and $290 million in state settlements between 2008 and 2010, but did not result in a significant reduction in prescribing rates regardless of whether states participated in federal investigations, pursued independent investigations, or conducted no investigations. Since settlement enforcement actions did not measurably decrease off-label prescribing, policymakers should consider alternative strategies to complement investigations in reducing non-evidence-based off-label drug use.
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Clinical Evidence Supporting US Food and Drug Administration Approval of Otolaryngologic Prescription Drug Indications, 2005‐2014

Rathi VK, Wang B, Ross JS, Downing NS, Kesselheim AS, Gray ST - Otolaryngology–Head and Neck Surgery

  • Research Publications
| April 2017
  • Regulation and Clinical Evidence
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Between 2005 and 2014, the FDA approved 48 otolaryngologic prescription drug indications supported by 64 pivotal studies with variable quality. Original indications had higher rates of randomization (95%) and double-blinding (67%) compared to supplemental indications (78% and 63% respectively), while 38-52% of all indications relied exclusively on surrogate marker endpoints rather than clinical outcomes. Otolaryngologists should be aware of the limitations in premarket clinical evidence when counseling patients about newly approved drugs.
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Prescription Drug Regulation, Promotion, and Advocacy Has Gotten More Vexing in 2017

Avorn J - Health Affairs Forefront

  • Commentary & Opinion
| March 2017
  • Regulation and Clinical Evidence
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Avorn critiques the 21st Century Cures Act for encouraging the FDA to further embrace surrogate endpoints as a basis for drug approval, arguing this addresses a nonexistent problem since FDA review times are already among the fastest in the world. He warns of converging threats to evidence-based prescribing: court-driven erosion of FDA authority over manufacturer marketing claims on First Amendment grounds, state-level “right-to-try” laws that undermine FDA gatekeeping, and the appointment of an FDA commissioner who has publicly characterized the agency as a barrier to drug access. He highlights academic detailing programs as a promising counterweight to industry-dominated prescribing information.
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Testimony in Support of Prescription Drug Price Transparency and Disclosure Legislation (SB 925)

Luo J - Connecticut General Assembly, Committee on Insurance and Real Estate

  • Policy Interactions
| March 2017
  • Price, Value, and Access
An icon of a bill representing government policy.
Luo outlines his support of proposed prescription drug price transparency legislation, emphasizing that unprecedented increases in net spending on specialty medicines are being passed through to employers and patients via higher premiums and out-of-pocket costs, or are forcing public payers to limit access. He urged Connecticut not to tolerate benefit cuts to preserve pharmaceutical industry profits and identified transparency as the necessary first step toward meaningful reform.
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Testimony in Support of Prescription Drug Price Transparency and Disclosure Legislation (SB 445)

Luo J - Connecticut General Assembly, Committee on Public Health

  • Policy Interactions
| March 2017
  • Price, Value, and Access
An icon of a bill representing government policy.
Luo expresses support for proposed prescription drug price transparency legislation, noting that while generic substitution laws keep generic prices low, Connecticut residents and insurers pay some of the world’s highest prices for brand-name drugs, including many “me-too” products offering little improvement over existing treatments. He argues that price transparency and accountability are essential first steps toward reforms targeting both drug manufacturers and pharmacy benefit managers.
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Strategies to Improve the Affordability of Insulin in the USA

Luo J, Kesselheim AS, Greene JA, Lipska KJ - Lancet Diabetes & Endocrinology

  • Commentary & Opinion
| March 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Insulin prices in the US have risen sharply despite the drug’s century-long history, with Medicare Part D spending over $4.3 billion on insulin glargine alone in 2015 To address this affordability challenge, the authors propose strategies including promoting older insulin formulations, creating biosimilar competition pathways, and implementing value-based pricing.
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Reprioritizing Research Activity for the Post‐Antibiotic Era: Ethical, Legal, and Social Considerations

Hey SP, Kesselheim AS - Hastings Center Report

  • Research Publications
| March 2017
  • Innovation Incentives and Competition
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The authors argue that current policies lowering the regulatory bar for antibiotic approval—including the GAIN Act’s extended exclusivity, the 21st Century Cures Act’s limited-population pathway, and widespread reliance on noninferiority trials—are ethically problematic because they fail to account for the social conditions driving resistance and can produce negative social value by approving drugs no better than existing therapies. They contend that antibiotic stewardship must take priority over drug development, and that regulatory and funding bodies should raise rather than lower the bar for approval to direct scarce research resources toward truly transformative interventions.
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Outcomes Associated with Generic Drugs Approved Using Product-Specific Determinations of Therapeutic Equivalence

Gagne JJ, Polinski JM, Jiang W, Dutcher SK, Xie J, Lii J, Fulchino LA, Kesselheim AS - Drugs

  • Research Publications
| March 2017
  • Innovation Incentives and Competition
  • Price, Value, and Access
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This study examined clinical outcomes before and after generic drug market entry for five medications approved using product-specific therapeutic equivalence determinations, finding three outcome rate increases and three decreases among study drugs upon generic introduction, with longer-term trends showing decreases in outcome rates across four study drugs. The authors conclude that generic drugs approved using product-specific equivalence determinations were not associated with worse clinical outcomes compared to brand-name versions.
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The Future of Precision Medicine: Great Promise, Significant Challenges

Darrow JJ, Kesselheim AS, Lasky-Su J - Health Affairs Forefront

  • Commentary & Opinion
| February 2017
  • Regulation and Clinical Evidence
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The Precision Medicine Initiative and Cancer Moonshot benefit from dramatic advances in genomic sequencing, computing power, and multi-omics technologies that were unavailable during earlier efforts like Nixon’s War on Cancer, creating a more favorable environment for translating genetic discoveries into clinical care. However, challenges including intra-tumor heterogeneity, population genetic diversity, and the outsized role of non-genetic determinants of health suggest that the greatest public health gains may still come from preventive interventions rather than laboratory breakthroughs alone.
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New “21st Century Cures” Legislation: Speed and Ease vs Science

Kesselheim AS, Avorn J - JAMA

  • Commentary & Opinion
| February 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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While the final 21st Century Cures Act signed in December 2016 included welcome NIH funding increases and provisions for opioid and mental health programs, its FDA-related provisions are problematic because they encourage the agency to rely on less rigorous evidence for drug approval, including insufficiently validated biomarkers, patient experience data, and “real world evidence” from observational data rather than randomized controlled trials. They contend that these changes, combined with an antiregulatory ideology in the new Trump administration, could undermine patient safety and the drug development enterprise by prioritizing speed over science.
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Six-Month Market Exclusivity Extensions to Promote Research Offer Substantial Returns for Many Drug Makers

Kesselheim AS, Rome BN, Sarpatwari A, Avorn J - Health Affairs

  • Research Publications
| February 2017
  • Innovation Incentives and Competition
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For 13 FDA-approved drugs that gained supplemental approval for rare disease indications between 2005 and 2010, the median projected clinical trial cost was $29.8 million, while the median discounted financial gain from a proposed six-month market exclusivity extension would have been $94.6 million, yielding median net returns of $82.4 million, with higher returns for top-selling products. The authors conclude that while market exclusivity extensions would substantially compensate manufacturers well beyond trial costs, alternative incentive strategies may achieve similar benefits at lower cost.
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Eliminating Coverage Discrimination Through the Essential Health Benefit’s Anti-Discrimination Provisions

Guo E, Jacobs DB, Kesselheim AS - American Journal of Public Health

  • Commentary & Opinion
| February 2017
  • Price, Value, and Access
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The authors analyze how the ACA’s anti-discrimination provisions can be used to combat coverage discrimination by health insurers who use benefit design features such as adverse tiering of drugs to discourage enrollment of patients with costly chronic conditions like HIV.
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Clinical Evidence Supporting US Food and Drug Administration Premarket Approval of High‐risk Otolaryngologic Devices, 2000‐2014

Rathi VK, Wang B, Ross JS, Downing NS, Kesselheim AS, Gray ST - Otolaryngology–Head and Neck Surgery

  • Research Publications
| February 2017
  • Regulation and Clinical Evidence
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Between 2000 and 2014, the FDA approved 23 high-risk otolaryngologic devices based on 28 pivotal studies with median enrollment of 118 patients and 26-week follow-up, of which fewer than half were randomized (46%), blinded (43%), or controlled (36%). 70% of approved devices required postapproval studies. Otolaryngologists should recognize the limitations in premarket evidence strength when evaluating newly approved devices for clinical use.
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Applying Academic Detailing and Process Change to Promote Choosing Wisely

Fralick M, Kesselheim AS, Avorn J - JAMA Internal Medicine

  • Commentary & Opinion
| February 2017
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors advocate for the use of academic detailing combined with process redesign to promote the Choosing Wisely campaign’s goal of reducing low-value medical care, arguing that physician education alone is insufficient without systemic changes to clinical workflows and shared decision-making tools.
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Active Surveillance of Follow-On Biologics: A Prescription for Uptake

Sarpatwari A, Gagne JJ, Levidow NL, Kesselheim AS - Drug Safety

  • Commentary & Opinion
| February 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Active post-market surveillance of biosimilars using insurance claims databases is both feasible and necessary to address physician skepticism about biosimilar safety and effectiveness, which remains a major barrier to prescribing and cost savings.
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Review Times and Adverse Events for Cardiovascular Devices

Stern AD, Kramer DB, Ouellet M, Kesselheim AS - Nature Biomedical Engineering

  • Research Publications
| January 2017
  • Regulation and Clinical Evidence
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Among 106 high-risk cardiovascular devices approved by the FDA over a decade starting in 2000, each additional month of regulatory review was associated with a 10.7% decrease in the probability of subsequent adverse event reports, an 8.8% decrease in reports of serious injury or death and a 20% decrease in the probability of being a high-report device. Only 45% of devices had any adverse events reported in the 4 years after approval, suggesting systematic underreporting. These findings highlight the trade-offs inherent in initiatives to expedite device review, and suggest that observable features of the review process could help regulators identify which devices are optimal candidates for enhanced post-approval surveillance.
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The Fight Against Multidrug-Resistant Bacteria (Reply)

Deak D, Powers JH, Outterson K, Kesselheim AS - Annals of Internal Medicine

  • Commentary & Opinion
| January 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors acknowledge that noninferiority trial designs for new antibiotics can benefit patients but emphasize their important limitations: such trials are conducted in patients with effective therapeutic options and do not directly address whether an investigational product is effective against resistant pathogens—and when antibiotics approved via noninferiority trials are used in patients with resistant disease, they may actually show worse clinical outcomes.
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Biomarker-Defined Subsets of Common Diseases: Policy and Economic Implications of Orphan Drug Act Coverage

Kesselheim AS, Treasure CL, Joffe S - PLOS Medicine

  • Research Publications
| January 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The number of orphan drug designations has roughly doubled over the past decade, with an increasing proportion targeting biomarker-defined subsets of common diseases rather than truly rare conditions, allowing manufacturers to obtain 7 years of market exclusivity, tax credits, and research grants for drugs that may rapidly expand into off-label use across large patient populations. The authors argue that orphan-designated drugs for biomarker-defined disease subsets have characteristics, including short development times and rapid indication expansion, that make them ill-suited for orphan drug incentives, risking the waste of resources better focused on genuinely rare conditions.
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Prioritization of Generic Drug Review (Reply)

Gupta R, Kesselheim AS, Ross JS - JAMA Internal Medicine

  • Commentary & Opinion
| January 2017
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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In this exchange, FDA officials describe their efforts to expedite review of first-generic and sole-source drug applications, while the authors argue that the FDA should go further by also prioritizing applications for drugs with three or fewer manufacturers and for generics of drugs that have experienced dramatic price increases, They also call for greater transparency around pending applications, failed applications, and reasons for non-approval.
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Comparative Effectiveness and Safety of Thalidomide and Lenalidomide in Patients with Multiple Myeloma in the United States of America: A Population-Based Cohort Study

Luo J, Gagne JJ, Landon JE, Avorn J, Kesselheim AS - European Journal of Cancer

  • Research Publications
| January 2017
  • Regulation and Clinical Evidence
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Lenalidomide initiators had a significantly lower risk of developing peripheral neuropathy compared with thalidomide initiators among 1,264 multiple myeloma patients, with no difference in mortality rates between the two treatments. These findings suggest that while thalidomide and lenalidomide are equivalent for survival outcomes, lenalidomide presents a safety advantage regarding neurotoxicity in routine clinical practice.
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Brief of Constitutional, Administrative, Contracts, and Health Law Scholars in Expressions Hair Design v. Schneiderman

Kesselheim AS - US Supreme Court

  • Policy Interactions
| December 2016
  • Regulation and Clinical Evidence
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New York’s ban on credit card surcharges regulates nonexpressive commercial conduct (price-setting) and is therefore subject only to rational basis review. The scholars warn that accepting petitioners’ theory (i.e., that regulations of economic conduct actuated through words constitute speech restrictions) would jeopardize vast swaths of established law, including FDA drug approval requirements, effectively reviving judicial second-guessing of economic regulation.
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Regulating Off-Label Promotion—A Critical Test

Robertson CT, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| December 2016
  • Regulation and Clinical Evidence
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The authors discuss the legal and regulatory landscape following the Caronia decision on off-label promotion, examining how courts and the FDA are navigating the tension between First Amendment commercial speech protections and the public health rationale for restricting manufacturers’ off-label marketing.
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Factors Influencing Prescription Drug Costs in the United States (Reply)

Sarpatwari A, Avorn J, Kesselheim AS - JAMA

  • Commentary & Opinion
| December 2016
  • Price, Value, and Access
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In this response, the authors explain that the PTO’s low “nonobviousness” threshold allows manufacturers to charge more for patent-protected minor modifications to existing drugs, that European research productivity per dollar has exceeded that of the US and that the pharmaceutical industry’s 24% profit margin suggests ample room to improve affordability while preserving innovation incentives. They also endorse a co-respondent’s data showing that pharmaceutical companies direct enormous sums toward share buybacks rather than R&D, further undermining the industry’s argument that high prices are necessary to fund innovation.
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Approving a Problematic Muscular Dystrophy Drug: Implications for FDA Policy

Kesselheim AS, Avorn J - JAMA

  • Commentary & Opinion
| December 2016
  • Regulation and Clinical Evidence
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The authors critique the FDA’s approval of eteplirsen for Duchenne muscular dystrophy, noting that the pivotal trial involved only 12 patients, failed to show clinically meaningful dystrophin production, and relied on post hoc analyses that excluded deteriorating patients to generate favorable results, while the FDA overruled both its scientific staff and advisory committee.
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Using Behavioral Economics to Promote Physicians’ Prescribing of Generic Drugs and Follow-On Biologics: What Are the Issues?

Sarpatwari A, Choudhry NK, Avorn J, Kesselheim AS - Nudging Health: Health Law and Behavioral Economics

  • Commentary & Opinion
| December 2016
  • Innovation Incentives and Competition
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This book chapter examines physician-centered strategies for increasing use of generic drugs and biosimilars, including formulary support, academic detailing, e-prescribing nudges, and direct financial incentives. The authors review the evidence base for each strategies as well as legal constraints under the federal Anti-Kickback Statute. They conclude that information-supplying interventions are broadly appropriate across substitution contexts, while direct financial incentives should be limited to bioequivalent substitution of non-narrow therapeutic index drugs, where the clinical risks of finacially-incentivized decision-making are lowest.
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Regulatory Incentives for Antibiotic Drug Development: A Review of Recent Proposals

Sinha MS, Kesselheim AS - Bioorganic & Medicinal Chemistry

  • Research Publications
| December 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors review two primary regulatory mechanisms proposed to incentivize antibiotic development: expedited FDA approval processes (including surrogate endpoints, noninferiority trial designs, and a Limited Population pathway) and enhanced market exclusivity incentives. While acknowledging positive attributes of these approaches, the authors conclude that expedited approval pathways present heightened patient risks from lower regulatory barriers, and market exclusivity incentives may fail to efficiently direct resources toward genuine sources of antibiotic innovation.
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Introduction: Behavioral Economics and the Doctor-Patient Relationship

Kesselheim AS - Nudging Health: Health Law and Behavioral Economics

  • Commentary & Opinion
| December 2016
  • Regulation and Clinical Evidence
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This introduction frames the tension between behavioral economics and the modern doctor-patient relationship, cautioning that “nudge”-style interventions risk reintroducing a subtle paternalism that could undermine informed consent and shared decision-making if not carefully evidence-based. The author discusses the approaches highlighted in the subsequent chapters and argues that centralized federal research investment to rigorously test these strategies is needed, potentially via a National Center for Behavioral Economics at NIH.
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Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results

Hwang TJ, Carpenter D, Lauffenburger JC, Wang B, Franklin JM, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| December 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 640 novel therapeutics entering pivotal trials between 1998 and 2008, 54% failed in clinical development primarily due to inadequate efficacy, while orphan-designated drugs were significantly more likely to gain FDA approval compared to non-orphan drugs. Cancer drugs and those sponsored by small companies were less likely to be approved. Only 40% of failed agents had their pivotal trial results published in peer-reviewed journals, with publication rates as low as 8.1% for drugs that failed for commercial reasons, highlighting a substantial gap in dissemination of negative trial results.
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The Current 21st Century Cures Legislation Is Still A Bad Deal for Patients

Sarpatwari A, Sinha MS - Health Affairs Forefront

  • Commentary & Opinion
| November 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The revised 21st Century Cures Act provides uncertain NIH and FDA funding contingent on annual appropriations while retaining provisions that could weaken drug and device approval standards through expanded use of “real-world evidence” and relaxed breakthrough device criteria. The bill’s potential benefits are outweighed by increased risk of patient harm from products reaching market without adequate evidence of safety and efficacy.
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Public Referendum on Drug Prices in the US: Will It Bring Relief?

Hwang TJ, Kesselheim AS - BMJ

  • Commentary & Opinion
| October 2016
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors analyze California’s Proposition 61, which proposed requiring state public payers to pay no more than the VA’s lowest drug price, discussing how this ballot measure could affect drug costs in California and nationally and examining the broader fragmented system of drug pricing in the U.S.
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Comments on Draft Intellectual Property Consultative Framework

Kapczynski A, Kesselheim AS, Ezer T - South Africa Department of Trade, Industry, and Competition

  • Policy Interactions
| October 2016
  • Innovation Incentives and Competition
An icon of a bill representing government policy.
The commenters argue that the right to health must supersede intellectual property protections and urge South Africa to replace its depository patent system with substantive search and examination, including patent opposition and priority examination mechanisms. They also recommends maximizing TRIPS flexibilities through stricter patentability criteria, streamlined government use and compulsory licensing procedures, and higher standards for granting interdicts in pharmaceutical cases.
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Switching Generic Antiepileptic Drug Manufacturer Not Linked to Seizures: A Case-Crossover Study

Kesselheim AS, Bykov K, Gagne JJ, Wang SV, Choudhry NK - Neurology

  • Research Publications
| October 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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While generic antiepileptic drug refilling was associated with an 8% increase in seizure-related events, switching to a different manufacturer during refill showed no additional risk beyond the refilling process itself after adjustment. The findings suggest that FDA-validated generic antiepileptic drugs from different manufacturers are clinically safe and bioequivalent, and switching manufacturers does not pose an additional seizure risk to patients.
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Physicians’ Trust in the FDA’s Use of Product-Specific Pathways for Generic Drug Approval

Kesselheim AS, Eddings W, Raj T, Campbell EG, Franklin JM, Ross KM, Fulchino LA, Avorn J, Gagne JJ - PLOS ONE

  • Research Publications
| October 2016
  • Regulation and Clinical Evidence
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A national survey of 718 physicians found that a strong majority (91-92%) expressed confidence in the FDA’s generic drug approval process and bioequivalence testing standards, though a minority (13-26%) remained uncomfortable prescribing certain generic drugs approved through product-specific pathways. The authors conclude that enhanced physician education about FDA generic drug approval processes and standards could help address remaining concerns and promote the use of cost-effective generic medications.
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Translational Research and the U.S. Federal Elections

Kimmelman J, Kesselheim AS - Science Translational Medicine

  • Commentary & Opinion
| October 2016
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors outline key translational research policy questions that presidential and congressional candidates should address, spanning basic research funding, preclinical reproducibility, clinical trial design, drug pricing, and the alignment of pharmaceutical innovation with public health priorities.
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Prescription Trends—Brand-Name Drugs vs Generic (Reply)

Kesselheim AS, Gagne JJ - JAMA Internal Medicine

  • Commentary & Opinion
| October 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors respond to commentary on their survey of physician generic drug skepticism by noting that brand-name manufacturers spend $30–60 billion annually on marketing that undermines faith in generics while generic manufacturers generally cannot afford counter-marketing. They call for policy reforms to prevent drug coupons and copay assistance programs from steering patients toward expensive brand-name drugs when lower-cost generic therapeutic alternatives are available, and support institutional restrictions on pharmaceutical detailing as a means of shifting prescribing toward generics.
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Payments to Physicians, Prescribing Rates, and More Appropriate Conclusions (Reply)

Yeh JS, Franklin JM, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| October 2016
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
In this exchange, critics question the authors’ study linking industry payments to brand-name statin prescribing, while the authors defend their methodology and reiterate that the association between payments and non-evidence-based prescribing patterns raises policy concerns.
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Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration-Approved Antibiotics, 2010-2015

Deak D, Outterson K, Powers JH, Kesselheim AS - Annals of Internal Medicine

  • Research Publications
| September 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Between January 2010 and December 2015, the FDA approved eight new antibiotics with a median clinical trial duration of 6.2 years and 666 enrolled patients per pivotal trial; seven were approved based on noninferiority rather than superiority, and seven are substantially more expensive than their comparators despite lacking demonstrated clinical superiority. The findings suggest that recent antibiotic approvals have not consistently addressed the need for demonstrably more effective treatments for multidrug-resistant infections, raising questions about whether current approval pathways adequately balance innovation incentives with evidence of meaningful clinical benefit.
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Generic Drug Approvals Since the 1984 Hatch-Waxman Act

Gupta R, Kesselheim AS, Downing NS, Greene JA, Ross JS - JAMA Internal Medicine

  • Research Publications
| September 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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An analysis of all novel tablet and capsule drugs approved by the FDA from 1984 to 2016 found that among those eligible for generic competition, a significant proportion lacked adequate generic alternatives, with the number of generic approvals associated with brand-name drug characteristics including therapeutic area, orphan status, and market size. The findings provide a comprehensive picture of the generic drug landscape since the Hatch-Waxman Act, supporting the observation that limited competition for some drugs—particularly those for smaller markets—contributes to the persistence of high prices.
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Effect of Generic Competition on Atorvastatin Prescribing and Patients’ Out-Of-Pocket Spending

Luo J, Seeger JD, Donneyong MM, Gagne JJ, Avorn J, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| September 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Limited initial generic competition for atorvastatin resulted in only an 18.1% reduction in brand-name prescriptions during the first 180 days after market exclusivity ended, while out-of-pocket spending remained similar between brand-name and generic formulations. Full generic competition subsequently reduced brand-name fills by 47.6% and decreased generic out-of-pocket costs to $5.10 monthly compared to $30.00 for brand-name. The findings suggest that patent exclusivity periods and delayed generic competition can substantially slow the adoption of lower-cost alternatives and delay patient savings on medication costs.
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The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform

Kesselheim AS, Avorn J, Sarpatwari A - JAMA

  • Research Publications
| August 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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US per capita prescription drug spending ($858 in 2013) far exceeds that of other industrialized nations (average $400), driven primarily by brand-name drug prices set based on what the market will bear rather than research and development costs, with government-granted monopoly rights and constrained payer negotiating power as the key enabling factors. The authors recommend short-term strategies including stricter exclusivity requirements, ensuring timely generic availability, expanding governmental price negotiation, generating comparative cost-effectiveness evidence, and better educating stakeholders to address rising drug costs.
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The FDA, Juno Therapeutics, and the Ethical Imperative of Transparency

Hey SP, Kesselheim AS - BMJ

  • Commentary & Opinion
| August 2016
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors argue that when serious safety events occur in clinical trials—as with three patient deaths in Juno Therapeutics’ CAR-T cell therapy trial—the details of FDA clinical holds should be publicly disclosed rather than treated as protected trade secrets, because companies have financial incentives to downplay problems with their investigational drugs.
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The Emergence of the Randomized, Controlled Trial

Bothwell LE, Podolsky SH - New England Journal of Medicine

  • Commentary & Opinion
| August 2016
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
This historical perspective traces the development of the randomized controlled trial from ancient comparative experiments through its formalization in the mid-20th century, arguing that the 1948 MRC streptomycin trial was part of a much longer evolution rather than a singular breakthrough. The authors show how intellectual, social, and regulatory forces shaped both the adoption of and resistance to controlled trials as a medical research standard.
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Temporal Trends and Factors Associated with Cardiovascular Drug Development, 1990 to 2012

Hwang TJ, Lauffenburger JC, Franklin JM, Kesselheim AS - JACC: Basic to Translational Science

  • Research Publications
| August 2016
  • Innovation Incentives and Competition
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Between 1990 and 2012, the number of new cardiovascular drugs entering clinical trials declined significantly across all development stages, though the probability of successful progression was comparable to noncardiovascular drugs, with small and medium-sized companies increasingly sponsoring trials and novel drugs entering Phase 3 development. The findings highlight challenges in cardiovascular drug development, particularly the high discontinuation rates due to inadequate efficacy (44%) and safety concerns (24%), along with poor publication of Phase 3 trial results for discontinued drugs, underscoring the need for improved translational research practices and publication standards.
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Switch-Backs Associated with Generic Drugs Approved Using Product-Specific Determinations of Therapeutic Equivalence: Generics Approved By Product-Specific Approaches

Gagne JJ, Polinski JM, Jiang W, Dutcher SK, Xie J, Lii J, Fulchino LA, Kesselheim AS - Pharmacoepidemiology and Drug Safety

  • Research Publications
| August 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Switch-back rates from generic to brand-name versions for four drugs approved via product-specific FDA pathways ranged from 5 to 37 per 100 person-years, with mixed results when compared to control drugs. The findings suggest that patients using these product-specific generic drugs do not systematically return to brand-name versions at elevated rates, supporting the adequacy of product-specific approval pathways for ensuring therapeutic equivalence.
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Ethical and Practical Considerations in Removing Black Box Warnings From Drug Labels

Yeh JS, Sarpatwari A, Kesselheim AS - Drug Safety

  • Commentary & Opinion
| August 2016
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The FDA should apply a higher standard for removing boxed warnings than for imposing them, because removal may lead physicians and patients to underestimate risks. The authors call for a uniform and transparent process governing these decisions.
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Balancing Benefits and Harms: Privacy Protection Policies

Sarpatwari A, Gagne JJ - Pharmacoepidemiology and Drug Safety

  • Commentary & Opinion
| August 2016
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors highlight the tension between patient privacy protections under HIPAA and the need for data sharing to conduct post-approval drug safety research, discussing how privacy frameworks can be balanced with the public health benefits of pharmacoepidemiological studies.
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Countering Imprecision in Precision Medicine

Hey SP, Kesselheim AS - Science

  • Research Publications
| July 2016
  • Regulation and Clinical Evidence
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Despite substantial promise, precision medicine has been plagued by three inherent scientific obstacles: pivotal trials cannot be agnostic about underlying biological theories, interventions are complex “biomarker ensembles” with multiple components and degrees of uncertainty, and no single stakeholder controls the biomarkers or coordinates the research program. The authors argue that meaningful progress requires new mechanisms of scientific oversight, given that many commercially available biomarker diagnostics have not been adequately validated and even seemingly successful precision medicines like trastuzumab have been characterized by uncertainty about diagnostic test interpretation.
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Why ‘Government Patent Use’ to Lower Drug Costs Won’t Stifle Innovation

Kapczynski A, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| July 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
Under 28 U.S.C. Section 1498, the federal government can produce or import generic versions of patented drugs for government programs while providing patent holders “reasonable and entire compensation” keyed to R&D investment, risk of failure, and reasonable profits. Contrary to industry objections, this approach would preserve innovation incentives because companies would still receive risk-adjusted returns on investment, while generating substantial societal benefits by improving access to drugs like the hepatitis C treatment sofosbuvir (Sovaldi).
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Four Ways to Address the Ethical Tensions Around Expedited Approval of New Prescription Drugs

Kesselheim AS, Hey SP, Deak D, Lo B - Health Affairs Forefront

  • Commentary & Opinion
| July 2016
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
FDA expedited approval pathways create ethical tensions between patient autonomy and adequate evidence, as drugs approved on surrogate endpoints with limited safety data may not ultimately prove effective, while patients and physicians often overestimate the rigor behind designations like “breakthrough therapy.” To address these tensions, the authors recommend strengthening post-market surveillance and confirmatory trial requirements, building consensus on definitions of unmet medical need, improving informed decision-making tools, and expanding pre-approval expanded access programs.
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Protecting Pharmaceutical Patents and Test Data: How the Trans-Pacific Partnership Agreement Could Affect Access to Medicines in the US and Abroad

Luo J, Kesselheim AS - AMA Journal of Ethics

  • Research Publications
| July 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The TPP Agreement would strengthen intellectual property protections for prescription drugs through extended patent and test data exclusivity provisions, which could affect reimbursement decisions by national health authorities across signatory countries. The authors conclude that these provisions may reduce access to medicines for low-income patients in TPP signatory nations.
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Federal Circuit Review of USPTO Inter Partes Review Decisions by the Numbers

Wallach EJ, Darrow JJ - Journal of the Patent and Trademark Office Society

  • Research Publications
| July 2016
  • Innovation Incentives and Competition
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The authors analyze how the America Invents Act’s inter partes review (IPR) process to provide a faster, less costly mechanism for challenging patent validity has impacted the Federal Circuit’s caseload and decision-making patterns since its implementation. By examining Federal Circuit review of USPTO IPR decisions, the study characterizes how this significant patent reform has functioned in practice and its implications for the broader patent system, including the pharmaceutical sector where patent challenges are central to generic drug competition.
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Using Antitrust Law to Challenge Turing’s Daraprim Price Increase

Carrier MA, Levidow NL, Kesselheim AS - Berkeley Technology Law Journal

  • Research Publications
| June 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Turing Pharmaceuticals’ restriction of pyrimethamine distribution to a single source, combined with its resulting monopoly power, enabled a 5000% price increase and constitutes unlawful monopolization under antitrust law. The author contends that Turing’s exclusionary distribution scheme, lacking legitimate business justification and designed to block generic competition, meets the legal standard for an antitrust violation.
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Navigating the Dermatological Drug Cost Curve

Sarpatwari A, Kesselheim AS - JAMA

  • Commentary & Opinion
| June 2016
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors highlight dramatic price increases for dermatologic drugs, with brand-name prices increasing a mean of 401% between 2009 and 2015, and discuss the implications for patient access and the need for policy interventions.
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Comparison of Rates of Safety Issues and Reporting of Trial Outcomes for Medical Devices Approved in the European Union and United States: Cohort Study

Hwang TJ, Sokolov E, Franklin JM, Kesselheim AS - BMJ

  • Research Publications
| June 2016
  • Regulation and Clinical Evidence
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Medical devices approved first in the European Union showed a 2.9-fold increased hazard ratio for post-marketing safety alerts and recalls compared to devices approved first in the United States, with 27% of EU-first devices experiencing safety issues versus 14% of US-first devices. Furthermore, only 49% of devices considered major innovations had their pivotal trial results published within five years of approval, demonstrating the need for greater transparency and mandatory trial publication to enable patients and clinicians to make fully informed treatment decisions.
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State Initiatives to Control Medication Costs—Can Transparency Legislation Help?

Sarpatwari A, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| June 2016
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
State-level drug pricing transparency legislation, requiring manufacturers to disclose R&D costs and justify price increases, may provide valuable insight into pricing decisions, but are unlikely to meaningfully address the drivers of prescription drug spending.
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Assessing the Gold Standard—Lessons from the History of RCTs

Bothwell LE, Green JA, Podolsky SH, Jones DS - New England Journal of Medicine

  • Research Publications
| June 2016
  • Regulation and Clinical Evidence
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A historical analysis of randomized controlled trials over the past 70 years reveals that while RCTs became the gold standard for evaluating medical interventions, their development and application have been shaped by economic and political forces as much as by scientific considerations. The authors draw lessons from this history about the limitations of RCTs, including the challenges they face in addressing the complexity of medicine and disease, and the ways in which pharmaceutical industry interests have influenced their design and interpretation.
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Variations in Patients’ Perceptions and Use of Generic Drugs: Results of a National Survey

Kesselheim AS, Gagne JJ, Franklin JM, Eddings W, Fulchino LA, Avorn J, Campbell EG - Journal of General Internal Medicine

  • Research Publications
| June 2016
  • Innovation Incentives and Competition
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Among 753 surveyed patients with chronic conditions, the vast majority (80-88%) perceived generic drugs as safe, effective, and equivalent to brand-name drugs, though non-White respondents were significantly more likely to request brand-name drugs and express skepticism about generic clinical equivalence. The authors conclude that while patient attitudes toward generics have improved substantially, persistent negative perception, particularly among non-White populations, must be addressed to maximize cost savings and health outcomes associated with generic drug use.
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Use the Bayh-Dole Act to Lower Drug Prices for Government Healthcare Programs

Engelberg AB, Kesselheim AS - Nature Medicine

  • Commentary & Opinion
| June 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The government should exercise its existing royalty-free license under Section 202 of the Bayh-Dole Act to authorize generic manufacturing of federally funded drugs for government healthcare programs, using enzalutamide (Xtandi) as a case study.
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Prevalence and Predictors of Generic Drug Skepticism Among Physicians: Results of a National Survey

Kesselheim AS, Gagne JJ, Eddings W, Franklin JM, Ross KM, Fulchino LA, Campbell EG - JAMA Internal Medicine

  • Research Publications
| June 2016
  • Innovation Incentives and Competition
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Among 718 surveyed physicians, generic drugs were widely supported; 89% perceived them as effective and 91% as safe as brand-name counterpart, but 32% qualified as “generic skeptics,” and 22% last learned about generic drug availability from pharmaceutical representatives, a source significantly associated with skepticism. These findings suggest that while physicians’ views of generics have improved since earlier surveys, pharmaceutical industry marketing remains an important predictor of generic drug skepticism that could undermine cost-effective prescribing.
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How Patent Troll Legislation Can Increase Timely Access to Generic Drugs

Treasure CL, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| June 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
Congressional patent reform legislation targeting “patent trolls” could benefit generic drug entry by strengthening mechanisms to challenge improperly granted pharmaceutical patents and discouraging anticompetitive patent litigation settlements.
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Association of Industry Payments to Physicians with the Prescribing of Brand-Name Statins in Massachusetts

Yeh JS, Franklin JM, Avorn J, Landon JE, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| June 2016
  • Regulation and Clinical Evidence
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Among Massachusetts physicians prescribing statins under Medicare in 2011, those receiving industry payments prescribed brand-name statins at significantly higher rates than those receiving no payments, with each $1,000 in total payments associated with a 0.1% increase in brand-name prescribing and educational training payments showing a particularly strong association with a 4.8% increase in brand-name prescribing. These findings raise concerns about the cost implications of industry payments to physicians and suggest that efforts to reduce prescription drug costs should consider addressing financial relationships between pharmaceutical companies and prescribing physicians.
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Anti-VEGF Therapy in Ophthalmology: A Qualitative Analysis of Transformative Drug Development

Caplan ES, Kesselheim AS - Drug Discovery Today

  • Research Publications
| June 2016
  • Innovation Incentives and Competition
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Anti-VEGF inhibitors have revolutionized treatment of vasoproliferative eye diseases through decades of extensive basic science research and multidisciplinary academic collaboration, particularly among Harvard-affiliated scientists and clinicians who developed a deep understanding of VEGF mechanisms. The development of these transformative drugs demonstrates that robust basic science and academic collaboration are critical drivers of breakthrough drug development, while competitive market forces subsequently drive private investment.
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Op-Ed: A Simple Way for the Government to Curb Inflated Drug Prices

Rizvi Z, Kapczynski A, Kesselheim AS - Washington Post

  • Commentary & Opinion
| May 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Drawing an analogy between overpriced patented drugs and strategic holdouts in eminent domain, the authors argue the federal government should use its existing “government patent use” authority to negotiate lower prices or purchase generic versions of essential medications for government programs. They cite the precedent of the 2001 anthrax crisis and argue that applying this approach to drugs like the hepatitis C treatment Sovaldi could dramatically expand patient access while still providing manufacturers reasonable compensation for their investment.
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Utilization of the First Biosimilar Infliximab Since Its Approval in South Korea

Kim SC, Choi N, Lee J, Kwon K, Eddings W, Sung Y, Ji Song H, Kesselheim AS, Solomon DH - Arthritis & Rheumatology

  • Research Publications
| May 2016
  • Innovation Incentives and Competition
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Following the introduction of biosimilar infliximab in South Korea in November 2012, biosimilar infliximab claims reached 19% of all infliximab claims by March 2014. The introduction also altered overall TNF inhibitor use patterns, with increases in combined infliximab usage and decline in etanercept and adalimumab prescriptions. The findings demosntrate how biosimilars can alter market dynamics within therapeutic classes, though results may differ in other countries.
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The US Food and Drug Administration 515 Program Initiative: Addressing the Evidence Gap for Widely Used, High-Risk Cardiovascular Devices?

Rathi VK, Kesselheim AS, Ross JS - JAMA Cardiology

  • Commentary & Opinion
| May 2016
  • Regulation and Clinical Evidence
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The authors analyze the FDA’s 515 Program Initiative—designed to reclassify high-risk medical devices that had been cleared through the less rigorous 510(k) pathway—using the Impella percutaneous ventricular assist device as a case study of how the FDA can promote rigorous assessment of widely used but inadequately evaluated devices.
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Leveraging Novel and Existing Pathways to Approve New Therapeutics to Treat Serious Drug-Resistant Infections

Hwang TJ, Kesselheim AS - American Journal of Law & Medicine

  • Research Publications
| May 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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This empirical analysis of FDA-approved clinical trials over the past decade finds that antibiotic trials are not larger or more difficult to conduct than trials for other drugs targeting high unmet medical needs, contradicting assumptions that trial size is a primary barrier to antibiotic development. The authors recommend that policymakers focus on alternative regulatory levers beyond trial size reduction and evaluate how new and existing approval pathways can be designed to prioritize and expedite therapeutics with the greatest potential to benefit patients with serious drug-resistant infections.
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‘Government Patent Use’: A Legal Approach to Reducing Drug Spending

Kapczynski A, Kesselheim AS - Health Affairs

  • Research Publications
| May 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors propose that the federal government invoke its existing “government patent use” authority to procure generic versions of patented drugs, such as direct-acting antivirals for hepatitis C, while paying patent holders reasonable royalties, thereby reducing drug costs that currently create treatment barriers and enable monopoly pricing. This approach would allow federal programs to treat more patients with clinically appropriate medicines at lower costs while still compensating companies for research and development investments.
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Efficacy of the Priority Review Voucher Program (Reply)

Sarpatwari A, Kesselheim AS - JAMA

  • Commentary & Opinion
| April 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors argue that the priority review voucher program is not a sensible way to incentivize tropical disease drug development because it disrupts the FDA’s calibrated review process, risks wasting public funds by accelerating reimbursement of potentially noninnovative drugs by government insurance programs, and is easily gamed. Instead, greater NIH funding should be directed toward translational tropical disease research.
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Physicians’ Knowledge About FDA Approval Standards and Perceptions of the “Breakthrough Therapy” Designation

Kesselheim AS, Woloshin S, Eddings W, Franklin JM, Ross KM, Schwartz LM - JAMA

  • Research Publications
| April 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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A survey of 675 board-certified internists and specialists found widespread misunderstanding of FDA approval standards. 73% incorrectly believed approval means a drug is as effective as others for the same condition, and only 6% correctly identified that FDA approval requires neither a statistically significant nor a clinically important result specifically. When presented with 2 identical hypothetical drugs differing only in whether one carried the “breakthrough” label, physicians significantly preferred prescribing the designated “breakthrough” drug, demonstrating that the term influences prescribing behavior independent of actual clinical evidence.
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Testimony on the Impact of S.1048: A Bill to Improve Transparency of Drug Research and Development Costs

Kesselheim AS - Massachusetts General Court, Joint Committee on Health Care Financing

  • Policy Interactions
| April 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
An icon of a bill representing government policy.
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Breakthrough Medical Devices and the 21st Century Cures Act

Kesselheim AS, Hwang TJ - Annals of Internal Medicine

  • Commentary & Opinion
| April 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The proposed “breakthrough device” designation in the 21st Century Cures Act should learn from the experience of the breakthrough therapy program for drugs, where the designation’s name can mislead consumers and some designated products subsequently failed in clinical trials.
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Drug Product Life-Cycle Management as Anticompetitive Behavior: The Case of Memantine

Capati VC, Kesselheim AS - Journal of Managed Care & Specialty Pharmacy

  • Research Publications
| April 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Forest Laboratories’ introduction of an extended-release memantine formulation while restricting access to the previous version exemplifies product hopping, a strategy that can disrupt stable patient treatment regimens and increase costs while potentially forestalling generic competition. Policy solutions to limit anticompetitive product hops include raising patentability standards for new drug formulations and reforming automatic generic substitution laws to preserve patient access to existing treatments.
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Did FDA Decisionmaking Affect Anti-Psychotic Drug Prescribing in Children?: A Time-Trend Analysis

Wang B, Franklin JM, Eddings W, Landon JE, Kesselheim AS - PLOS ONE

  • Research Publications
| March 2016
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This retrospective time-series analysis of antipsychotic prescriptions from 2003 to 2012 found that FDA action on pediatric supplemental new drug applications for olanzapine, quetiapine, and ziprasidone did not significantly alter prescribing patterns in children compared to adults, with no differential impact between approvals and rejections. The authors conclude that FDA determinations regarding pediatric antipsychotic use are not effectively translating into clinical practice and recommend improved communication strategies to convey the agency’s regulatory decisions to prescribers.
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An Uninformative Truth: The Logic of Amarin’s Off-Label Promotion

Hey SP, Kesselheim AS - PLOS Medicine

  • Research Publications
| March 2016
  • Regulation and Clinical Evidence
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The authors challenge the federal court ruling that sided with Amarin Pharmaceutical’s First Amendment claim to promote its fish oil product Vascepa for an unapproved indication, arguing that the company’s so-called “truthful and non-misleading” statement was actually a tautology—logically true by construction but not consistent with the state of scientific evidence and therefore misleading to prescribers. They propose that informativeness in asserting scientific facts, rather than mere truthfulness, should be the standard for evaluating commercial speech about pharmaceuticals.
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The First Amendment and Pharmaceutical Promotion

Avorn J - Health Affairs Forefront

  • Commentary & Opinion
| March 2016
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The growing movement to treat pharmaceutical promotional claims as constitutionally protected commercial free speech threatens FDA’s ability to regulate drug marketing, despite the fact that neither patients nor physicians can independently evaluate the voluminous proprietary data underlying drug approvals. History demonstrates the dangers of loosened regulation: from over $15 billion in industry settlements for illegal off-label promotion to the current flood of unsubstantiated claims for dietary supplements exempted from FDA oversight.
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Promoting Therapeutic Innovation: What Do We Do About Drug-Device Combinations?

Wang B, Kesselheim AS - JAMA

  • Commentary & Opinion
| March 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors examine the regulatory classification challenges for drug-device combination products, arguing that how these products are classified (as primarily a drug or device) has important implications for the evidence required before marketing and for patient safety.
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Inaccurate Reporting of Insulin Reimbursement (Reply)

Luo J, Avorn J, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| March 2016
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
In this exchange, critics argue that the authors’ analysis of Medicaid insulin reimbursement incorrectly assumed fixed rebate rates, while the authors address the methodological challenge of estimating net prices in a system where actual rebate amounts are confidential.
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Addressing Generic Drug Unaffordability and Shortages By Globalizing the Market for Old Drugs

Engelberg AB, Avorn J, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| February 2016
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
Consolidation among generic manufacturers, FDA approval backlogs, and predatory pricing strategies have created natural monopolies for many older generic drugs, leading to severe shortages and price spikes like Turing’s 5,000% increase for pyrimethamine (Daraprim). The FDA should accept quality assurance determinations from comparable foreign regulatory agencies and grant expedited review for drugs with three or fewer US manufacturers, creating a global market that restores competition without requiring new legislation.
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Expanding Coercive Treatment Is the Wrong Solution for the Opioid Crisis

Beletsky L, Parmet WE, Sarpatwari A - Health Affairs Forefront

  • Commentary & Opinion
| February 2016
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Massachusetts’s proposed STEP Act would allow clinicians and police to impose 72-hour involuntary holds on individuals with substance use disorders without judicial oversight, but evidence suggests forced treatment leads to higher relapse rates and could deter people from seeking help. Rather than expanding coercive measures that strain already overburdened treatment facilities and undermine civil liberties, policymakers should invest in evidence-based alternatives such as expanded treatment capacity, prescription monitoring, and emergency department case management.
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The Case for Reforming Drug Naming: Should Brand Name Trademark Protections Expire Upon Generic Entry?

Sarpatwari A, Kesselheim AS - PLOS Medicine

  • Commentary & Opinion
| February 2016
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
Allowing generic drugs to share the brand names of their originator counterparts after market exclusivity ends could help reduce wasteful spending on brand-name products, since persistent brand-name recognition contributes to slower generic uptake.
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Vaccine Pipeline Has Grown During the Past Two Decades with More Early-Stage Trials From Small and Medium-Size Companies

Hwang TJ, Kesselheim AS - Health Affairs

  • Research Publications
| February 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Over the past two decades, the proportion of new vaccine candidates entering clinical development increased by 3-5%, with small and medium-size companies initiating nearly twice as many Phase I trials as large companies, though late-stage trials remained dominated by large firms. The authors recommend policy interventions such as prizes and public-private partnerships targeted at smaller companies to support vaccine development for unmet medical needs and emerging public health threats.
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Key Features of Academic Detailing: Development of an Expert Consensus Using the Delphi Method

Yeh JS, Van Hoof TJ, Fischer MA - American Health & Drug Benefits

  • Research Publications
| February 2016
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Using a three-round Delphi method with 20 academic detailing experts, researchers achieved 92% consensus agreement on key features of academic detailing, including focused clinician education, tailored messaging with feasible strategies, and specific skill sets for detailers to overcome barriers to behavior change. The consensus-derived template of general principles can serve as a useful standard for implementing and evaluating academic detailing initiatives.
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Insulin Patents and Market Exclusivities: Unresolved Issues (Reply)

Luo J, Kesselheim AS - Lancet Diabetes & Endocrinology

  • Commentary & Opinion
| February 2016
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
Responding to commentary on the global implications of U.S. insulin patent landscapes, the authors outline two regulatory pathways for follow-on insulin approval—the 505(b)(2) pathway and the Biologics Price Competition and Innovation Act—and warn that after 2020, regulatory transitions could create a problematic gap in which no follow-on insulin application could be approved. They argue that the key factor for affordability will be whether follow-on insulins achieve interchangeability status, and caution that biosimilar insulins alone, without additional policy interventions, are unlikely to produce meaningful near-term cost reductions for patients.
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Testimony in Support of H.866: an Act Relating to Prescription Drug Manufacturer Cost Transparency

Sarpatwari A, Fischer MA - Vermont General Assembly, House Committee on Health Care

  • Policy Interactions
| January 2016
  • Price, Value, and Access
An icon of a bill representing government policy.
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Regulating Homeopathic Products—A Century of Dilute Interest

Podolsky SH, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| January 2016
  • Regulation and Clinical Evidence
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The authors trace the regulatory history of homeopathic products in the US, noting that these products have largely escaped the evidence-based scrutiny required of conventional drugs since the 1938 Food, Drug, and Cosmetic Act, and discuss recent FDA and FTC efforts to reconsider this regulatory gap.
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Benefit, Risk, and Outcomes in Drug Development: A Systematic Review of Sunitinib

Carlisle B, Demko N, Freeman G, Hakala A, MacKinnon N, Ramsay T, Hey SP, London AJ, Kimmelman J - Journal of the National Cancer Institute

  • Research Publications
| January 2016
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Across 103 clinical trials of sunitinib (Sutent) monotherapy, the drug achieved an objective response rate of 15.7% while 1.08% of patients died from drug-related toxicities and 13.7% experienced grade 3-4 adverse events, with the risk/benefit ratio worsening as the development program progressed. The authors recommend that research decision-making should evaluate evidence from entire drug development programs rather than isolated studies to better identify when continued testing in new indications is unlikely to be beneficial.
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Two Decades of New Drug Development for Central Nervous System Disorders

Kesselheim AS, Hwang TJ, Franklin JM - Nature Reviews Drug Discovery

  • Research Publications
| December 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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An analysis of 379 CNS drugs entering clinical trials between 1990 and 2012 revealed a substantial decline in the relative proportion of CNS drug Phase I trial starts compared to oncology drugs, and CNS drugs were 45% less likely than non-CNS drugs to progress from Phase III to regulatory filing with inadequate efficacy accounting for 46% of Phase III discontinuations. These findings support the need for greater investment in CNS basic research and biomarker validation rather than relaxed approval standards, given that high Phase III failure rates suggest many CNS drugs are advancing on the basis of marginal Phase II results.
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The 21st Century Cures Act: Opportunities and Challenges

Sarpatwari A, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| December 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors discuss the 21st Century Cures Act, analyzing how its provisions for expedited drug development and use of novel evidence could affect the balance between patient access and safety.
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Regulatory Solutions to the Problem of High Generic Drug Costs

Luo J, Sarpatwari A, Kesselheim AS - Open Forum Infectious Diseases

  • Commentary & Opinion
| December 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors examine dramatic price increases for select generic drugs (such as pyrimethamine’s 5,000% markup) that occur when companies acquire monopolies in markets with limited competition, and propose regulatory solutions including expedited FDA review for competitive generics, importation from regulated markets, and antitrust enforcement.
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Physicians and Insider Trading

Kesselheim AS, Sinha MS, Joffe S - JAMA Internal Medicine

  • Research Publications
| December 2015
  • Regulation and Clinical Evidence
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Recent high-profile cases demonstrate that physicians and scientists with access to confidential information about clinical trials or corporate governance have engaged in insider trading, which undermines the legitimate benefits of their involvement in business decision-making. Minimizing insider trading requires robust education, strictly enforced contracts, and selective prohibitions on high-risk activities such as expert consulting networks for individuals with access to valuable inside information.
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Medical Schools’ Industry Interaction Policies Not Associated with Trainees’ Self-Reported Behavior as Residents: Results of a National Survey

Yeh JS, Austad KE, Franklin JM, Chimonas S, Campbell EG, Avorn J, Kesselheim AS - Journal of Graduate Medical Education

  • Research Publications
| December 2015
  • Regulation and Clinical Evidence
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Residents who graduated from medical schools with restrictive industry interaction policies were no more or less likely than those from schools with permissive policies to accept industry gifts, attend sponsored lectures, or prefer brand-name medications, though residents with stronger evidence-based prescription knowledge were less likely to attend industry-sponsored lectures. The findings suggest that medical school policies’ protective effects against pharmaceutical marketing do not persist into residency, indicating that residency training environments play a critical role in shaping prescribing and industry interactions.
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Do March‐in Rights Ensure Access to Medical Products Arising From Federally Funded Research? A Qualitative Study

Treasure CL, Avorn J, Kesselheim AS - Milbank Quarterly

  • Research Publications
| December 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Since the Bayh-Dole Act’s enactment in 1980, the NIH has received only 5 march-in rights petitions for 4 federally-funded health products and rejected all of them, with qualitative analysis of expert interviews revealing little prospect that the agency will invoke march-in rights to address high drug prices or ensure public access. Although march-in rights may encourage government licensees to commercialize research results and extract minor concessions from licensees, the current statutory language makes these rights unlikely to serve as an effective policy tool for lowering prices of medical products derived from federal funding.
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Cost-Effectiveness of Statin Therapy for ASCVD

Luo J, Kesselheim AS - JAMA

  • Research Publications
| November 2015
  • Price, Value, and Access
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In response to a microsimulation study finding statin therapy cost-effective for over 60% of US adults aged 40-75, the authors highlight that real-world drug costs may substantially exceed the wholesale acquisition costs used in the modl and that widespread lack of transparency in drug pricing, including legislatively restricted disclosure of average manufacturer prices and Medicaid rebates, complicates interpretation of cost-effectiveness analyses that rely on prescription medication costs.
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Reductions in Use of Colchicine After FDA Enforcement of Market Exclusivity in a Commercially Insured Population

Kesselheim AS, Franklin JM, Kim SC, Seeger JD, Solomon DH - Journal of General Internal Medicine

  • Research Publications
| November 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Following FDA enforcement of market exclusivity for brand-name colchicine (Colcrys), colchicine initiation rates decreased significantly among both gout patients and FMF patients, while average monthly prescription drug costs increased from $418 to $651 and total health care costs rose from $3,406 to $3,534. The FDA’s enforcement action reduced colchicine use and increased patient spending without achieving improvements in avoiding potentially dangerous drug interactions with clarithromycin or cyclosporine.
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Evolution of Insulin Patents and Market Exclusivities in the USA

Luo J, Kesselheim AS - Lancet Diabetes & Endocrinology

  • Research Publications
| November 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
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A comparison of patents covering US insulin products in 2004 and 2014 reveals a dramatic shift in the intellectual property landscape: while active patents on insulin more than doubled (from 8 to 19), pen-device patents grew from 0% to 53% of all patents while the proportion of patents covering the active ingredient decreased from 50% to 21%. The authors note that intellectual property barriers alone do not fully explain the lack of generic competition, as many insulin active ingredients have no remaining patent or exclusivity protection, and they call on the FDA to issue clear guidance for follow-on insulin approval to reduce market entry hurdles for potential generic competitors.
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Comparative Effectiveness of Generic Versus Brand-Name Antiepileptic Medications

Gagne JJ, Kesselheim AS, Choudhry NK, Polinski JM, Hutchins D, Matlin OS, Brennan TA, Avorn J, Shrank WH - Epilepsy & Behavior

  • Research Publications
| November 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Patients initiating generic antiepileptic drugs (AEDs) experienced significantly fewer seizure-related hospitalizations or emergency room visits and demonstrated longer treatment persistence compared to those initiating brand-name versions of the same medications. These findings suggest that generic AEDs are at least as effective as brand-name formulations and may provide equivalent or superior clinical outcomes for Medicare beneficiaries with epilepsy.
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Experience with the Priority Review Voucher Program for Drug Development

Kesselheim AS, Maggs LR, Sarpatwari A - JAMA

  • Research Publications
| October 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Through August 2015, the FDA had issued 6 priority review vouchers—3 for neglected tropical diseases and 3 for rare pediatric diseases—but several vouchers were awarded for drugs that were already approved abroad, based on previously conducted trials, or associated with safety signals, while vouchers were sold for up to $350 million each. The authors detail how the program’s design has allowed companies to earn substantial financial rewards without necessarily conducting new research, suggesting that the voucher program may not be achieving its goal of incentivizing novel drug development for neglected diseases.
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The 21st Century Cures Act—Will It Take Us Back in Time? (Reply)

Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| October 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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In this exchange, supporters of the 21st Century Cures Act argue that it does not lower FDA standards but rather enables the use of new evidence tools like biomarkers and real-world data, while the authors reply that the bill’s provisions could authorize the FDA to rely on less rigorous data, particularly for antibiotic approvals and surrogate endpoints, potentially undermining patient safety.
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The Daraprim Price Hike and A Role for Antitrust

Carrier MA, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| October 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Turing Pharmaceuticals’ 5,000% price increase for pyrimethamine (Daraprim) was facilitated by a restricted distribution system that appears designed to prevent generic competitors from obtaining the drug samples needed for FDA bioequivalence testing. This conduct presents a viable antitrust claim under existing monopolization precedents that federal agencies and private plaintiffs should pursue.
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The Trans-Pacific Partnership Agreement and Implications for Access to Essential Medicines

Luo J, Kesselheim AS - JAMA

  • Commentary & Opinion
| October 2015
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The stronger patent protections and data exclusivity requirements demanded by the US in the Trans-Pacific Partnership (TPP) Agreement’s pharmaceutical intellectual property provisions could restrict access to essential medicines in developing partner countries by delaying generic drug availability.
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Trends in Medicaid Reimbursements for Insulin From 1991 Through 2014

Luo J, Avorn J, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| October 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Between 1991 and 2014, Medicaid reimbursement per unit of insulin increased substantially across all insulin types, rising from $2.36-$4.43 in the 1990s to $9.64-$19.81 by 2014, with patent-protected insulins increasing at a faster rate ($0.20 per quarter) than non-patented insulins ($0.05 per quarter). These findings indicate a lack of price competition in the US insulin market and suggest the need for policy interventions to address rising insulin costs for patients and insurers.
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Product-Specific Regulatory Pathways to Approve Generic Drugs: The Need for Follow-Up Studies to Ensure Safety and Effectiveness

Kesselheim AS, Gagne JJ - Drug Safety

  • Commentary & Opinion
| October 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors describe how the FDA uses product-specific testing pathways, rather than standard bioequivalence studies, to approve certain complex generic drugs. They argue that while these flexible approaches are necessary to avoid delays in generic availability, they should be followed by active post-approval surveillance to confirm safety and effectiveness.
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Trends in Utilization of FDA Expedited Drug Development and Approval Programs, 1987-2014: Cohort Study

Kesselheim AS, Wang B, Franklin JM, Darrow JJ - BMJ

  • Research Publications
| September 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 774 drugs approved by the FDA from 1987 to 2014, there was a significant 2.6% annual increase in the number of expedited programs (orphan drug, fast track, accelerated approval, and priority review) granted per newly approved drug, along with a 2.4% annual increase in the proportion of drugs associated with at least one such program. This trend was driven by an increase in the use of expedited programs for non-first-in-class drugs, which are potentially less innovative, suggesting that programs originally intended for drugs providing notable clinical advances are being applied increasingly broadly.
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Characteristics of Efficacy Evidence Supporting Approval of Supplemental Indications for Prescription Drugs in United States, 2005-14: Systematic Review

Wang B, Kesselheim AS - BMJ

  • Research Publications
| September 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 295 supplemental indications approved by the FDA from 2005 to 2014, only 30% of new indication approvals were supported by trials with active comparators compared to 51% of modified use approvals and 11% of population expansion approval. Clinical outcome endpoints were used in just 22-32% of trials across approval types. The findings highlight substantial variations in evidence standards for supplemental indications, particularly for pediatric population expansions.
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FDA Policy and Cardiovascular Medicine

Ross JS, Kesselheim AS - Circulation

  • Research Publications
| September 2015
  • Regulation and Clinical Evidence
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This comprehensive review traces the FDA’s evolution from its 1862 origins through landmark legislation—the 1906 Pure Food and Drug Act, 1938 Food Drug and Cosmetic Act, 1962 Kefauver-Harris Amendments, and 1976 Medical Device Amendments—each enacted in response to public health crises and broadening the agency’s authority over drugs and devices. The authors discuss current FDA policies for approval and postmarket surveillance of new drugs, biologics, generics, and medical devices, with particular attention to their implications for cardiovascular clinical care.
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Op-Ed: An Age-Old Battle: The FDA Versus the Shill

Greene JA, Kesselheim AS - The Atlantic

  • Commentary & Opinion
| September 2015
  • Regulation and Clinical Evidence
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In the wake of Kim Kardashian’s paid Instagram promotion of the morning sickness drug Diclegis in 2015, the authors trace the FDA’s longstanding challenge of regulating pharmaceutical marketing across successive new media, from national magazines and radio to social media. They argue that while the regulatory landscape has evolved significantly since the 1906 Pure Food and Drugs Act, celebrity testimonials and the tension between commercial speech and consumer protection remain as relevant as ever.
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Comments on Proposed Rule, “Medicare Program; Revisions to Payment Policies Under the Physician Fee Schedule and Other Revisions to Part B for CY2016”

Sarpatwari A, Kesselheim AS, Avorn J - Centers for Medicare and Medicaid Services (CMS)

  • Policy Interactions
| September 2015
  • Price, Value, and Access
An icon of a bill representing government policy.
CMS’s proposed blended reimbursement system for follow-on biologics would assign non-unique billing codes that prevent product-specific safety surveillance, undermining the pharmacovigilance research needed to build physician and patient confidence in this important new class of lower-cost treatments.
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Brief of Harvard Law School Center for Health Law and Policy Innovation, et al. in Gobeille v. Liberty Mutual

Sarpatwari A, Kesselheim AS - US Supreme Court

  • Policy Interactions
| September 2015
  • Price, Value, and Access
An icon of a bill representing government policy.
The amici argue that ERISA should not preempt Vermont’s statute requiring self-funded insurance plans to report health care claims data to the state’s all-payer claims database (APCD), because ERISA’s reporting requirements cover only financial information while APCDs collect entirely distinct clinical and utilization data. APCDs provide uniquely comprehensive datasets essential for health services research, policy analysis, and public health surveillance that cannot be adequately studied using fragmented data from individual insurers.
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Forbidden and Permitted Statements About Medications—Loosening the Rules

Avorn J, Sarpatwari A, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| September 2015
  • Regulation and Clinical Evidence
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A federal court ruling in 2015 sided with Amarin Pharmaceutical’s claim that the First Amendment protects its right to promote its fish oil product Vascepa for an unapproved indication, provided the statements are “truthful,” representing the latest in a series of legal and regulatory developments weakening FDA authority over off-label drug promotion. The authors examine how this expanding interpretation of commercial speech rights threatens the longstanding regulatory tradition of requiring manufacturers to demonstrate efficacy before making promotional claims, with potentially significant implications for patient safety and evidence-based prescribing.
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Propofol as a Transformative Drug in Anesthesia: Insights From Key Early Investigators

Bateman BT, Kesselheim AS - Drug Discovery Today

  • Research Publications
| August 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Through a modified Delphi survey and in-depth qualitative interviews, experts identified propofol (Diprivan) as the most transformative drug in anesthesiology over the past 25 years, with its development driven by a positive research environment at Imperial Chemical Industries and the central role of individual academic anesthesiologists outside the company. This case study provides lessons for promoting transformative drug innovation, highlighting the importance of clinician-scientists in translating early discoveries into clinically impactful products.
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The Safety of Prescription Drugs

Sharfstein JM, Kesselheim AS - JAMA

  • Commentary & Opinion
| July 2015
  • Regulation and Clinical Evidence
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The authors discuss the ongoing challenges of post-market drug safety surveillance, advocating for a consistent FDA decision-making framework that establishes evidence thresholds for different regulatory responses (further study, boxed warnings, market withdrawal) as recommended by the Institute of Medicine.
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Hatch-Waxman Turns 30: Do We Need a Re-Designed Approach for the Modern Era?

Kesselheim AS, Darrow JJ - Yale Journal of Health Policy, Law and Ethics

  • Research Publications
| July 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The Hatch-Waxman Act of 1984 successfully established the modern generic drug industry, which now accounts for 84 percent of all prescriptions but only 20 percent of drug costs; however, emerging challenges including deliberate system manipulation and unfavorable court decisions like PLIVA v. Mensing have created problems in the generic drug market. The authors propose updates to the Hatch-Waxman Act to address these challenges and ensure the continued timely emergence of safe generic drugs.
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The 21st Century Cures Act—Will It Take Us Back in Time?

Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| June 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
While the 21st Century Cures Act includes welcome NIH funding increases, key provisions could weaken FDA approval standards by encouraging reliance on less rigorous evidence such as observational data, surrogate endpoints, and adaptive trial designs. The authors argue that the current drug approval process is already efficient and that lowering evidence thresholds risks approving drugs that are ineffective or harmful.
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Progress and Hurdles for Follow-On Biologics

Sarpatwari A, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| June 2015
  • Innovation Incentives and Competition
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The authors assess the state of the biosimilar market following the FDA’s first biosimilar approval (filgrastim-sndz), identifying barriers to uptake including physician skepticism, insurer preauthorization requirements, and state substitution law restrictions.
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Methodological Approaches to Evaluate the Impact of FDA Drug Safety Communications

Kesselheim AS, Campbell EG, Schneeweiss SG, Rausch P, Lappin BM, Zhou EH, Seeger JD, Brownstein JS, Woloshin S, Schwartz LM, Toomey T, Dal Pan GJ, Avorn J - Drug Safety

  • Research Publications
| June 2015
  • Regulation and Clinical Evidence
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The authors describe a multidisciplinary research framework for evaluating the effectiveness of two FDA Drug Safety Communications issued in 2013 regarding zolpidem (Ambien), incorporating drug utilization analysis, health outcomes assessment, comparison with the non-affected comparator eszopiclone (Lunesta), patient surveys, and traditional and social media dissemination analysis. This integrated approach aims to generate insights that can optimize future FDA risk communications by better understanding how safety messaging influences physician and patient decision-making across multiple channels.
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Accelerating Innovation in Rapid Diagnostics and Targeted Antibacterials

Hwang TJ, Powers JH, Carpenter D, Kesselheim AS - Nature Biotechnology

  • Commentary & Opinion
| June 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Policy efforts to combat antibiotic resistance should prioritize narrow-spectrum antibiotics paired with rapid diagnostic tests. The atuhors argue that this approach could delay resistance and reduce adverse effects compared with broad-spectrum agents, and recommend a pilot regulatory pathway to facilitate their development.
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Precision Medicine and the FDA’s Draft Guidance on Laboratory-Developed Tests

Hwang TJ, Lehmann LS, Kesselheim AS - Nature Biotechnology

  • Commentary & Opinion
| May 2015
  • Regulation and Clinical Evidence
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In this letter to the editor, the authors discuss FDA regulatory policy around laboratory-developed tests in the context of precision medicine, addressing the regulatory framework for ensuring the safety and effectiveness of diagnostic technologies that underpin personalized treatment decisions.
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To Spur Medical Innovation, Make Corporate Cheaters Pay

Kesselheim AS, Sarpatwari A - Health Affairs Forefront

  • Commentary & Opinion
| April 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The Medical Innovation Act would require pharmaceutical companies that engage in illegal marketing practices to pay additional fees based on their profits and number of federally funded blockbuster drugs, channeling those funds to the NIH and FDA. The legislation would both increase accountability for industry fraud, whose profits far exceed existing penalties, and boost funding for the basic science research and regulatory infrastructure that drive truly transformative drug development.
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Practical, Legal, and Ethical Issues in Expanded Access to Investigational Drugs (Reply)

Sarpatwari A, Darrow JJ, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| April 2015
  • Price, Value, and Access
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In this exchange, FDA officials and the authors discuss the challenges and safeguards of expanded access to unapproved drugs, including the application process complexities and the balance between patient access and maintaining clinical trial integrity.
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Additional Comments on Proposed Rule, “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products”

Sarpatwari A, Kesselheim AS - Food and Drug Administration (FDA)

  • Policy Interactions
| April 2015
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The commenters opposed an industry-backed alternative to the FDA’s proposed generic drug labeling rule, arguing that the “Expedited Agency Review” proposal would remove incentives for manufacturers to monitor their products for emerging safety issues and result in fewer and slower label updates needed to protect patients.
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Variations in Time of Market Exclusivity Among Top-Selling Prescription Drugs in the United States

Wang B, Liu J, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| April 2015
  • Innovation Incentives and Competition
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Among 437 top-selling US prescription drugs from 2000 to 2011, only 40% experienced generic competition by end of 2012, with substantial variation by therapeutic area. Endocrinology drugs had the lowest rate of generic availability (14%) while infectious disease drugs had the highest (63%). The findings demonstrate how market exclusivity periods are influenced by a combination of regulatory exclusivities, original and secondary patents, settlement agreements, and other commercial factors, with implications for policies aimed at promoting more timely generic competition across therapeutic classes.
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Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes

Kesselheim AS, Polinski JM, Fulchino LA, Isaman DL, Gagne JJ - Drugs

  • Research Publications
| April 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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A systematic review of six drugs approved via modified bioequivalence approaches found limited post-approval evidence overall—only 26 studies met inclusion criteria, most were susceptible to bias, and notably, the brand-name manufacturers who raised scientific concerns about generic versions prior to approval did not conduct rigorous post-approval clinical testing to substantiate those concerns. Despite pre-approval controversy, the available evidence generally supported generic bioequivalence and clinical interchangeability, though the authors call for more systematic post-approval study of generic drugs subject to modified bioequivalence determinations.
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A New Wave of Vaccines for Non-Communicable Diseases: What Are the Regulatory Challenges?

Darrow JJ, Kesselheim AS - Food and Drug Law Journal

  • Research Publications
| April 2015
  • Regulation and Clinical Evidence
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A growing class of non-communicable disease (NCD) vaccines is being developed to target conditions such as cancer, hypertension, addiction, and obesity by modulating the immune system against disease-associated cells or molecules rather than pathogens, but these products differ fundamentally from traditional vaccines in their risk-benefit profile, target populations, and lack of herd immunity benefits. The authors argue that these differences raise important regulatory questions for the FDA about whether NCD vaccines should be evaluated under the same framework as infectious disease vaccines or as biologic drugs, and whether the term “vaccine” is even appropriate for this emerging therapeutic category.
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Ensuring Timely Approval of Generic Drugs

Sarpatwari A, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| March 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Brand-name manufacturers are exploiting FDA risk evaluation and mitigation strategies (REMS) to block generic competition by refusing to provide drug samples needed for required bioequivalence testing, and in some cases patenting their REMS programs to artificially extend market exclusivity. The authors advocate for the FAST Generics Act, which would create an FDA-authorized pathway for generic manufacturers to obtain brand-name drug samples regardless of REMS status, and call on Congress to create a safe harbor protecting generic manufacturers from patent infringement claims when replicating a brand-name drug’s REMS for a bioequivalent product.
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Paying Physicians to Prescribe Generic Drugs and Follow-On Biologics in the United States

Sarpatwari A, Choudhry NK, Avorn J, Kesselheim AS - PLOS Medicine

  • Research Publications
| March 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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With brand-name drug prices increasing 15% in 2014 alone while generic drugs (86% of prescriptions) have saved consumers nearly $1.5 trillion over the past decade, the authors examine strategies to promote greater generic and biosimilar prescribing, including traditional approaches like formulary decision support and academic detailing, as well as novel financial incentives for physicians. While private insurers may legally offer physicians payments for prescribing generics, the authors argue that the developing evidence base warrants caution for therapeutic substitution and narrow therapeutic index drugs, and that any physician-centered incentive programs must be accompanied by comparative cost-utility studies assessing patient outcomes.
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The Watchman Saga—Closure at Last?

Kramer DB, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| March 2015
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors trace the regulatory history of the Watchman left atrial appendage closure device, which was available in Europe for nearly a decade before US approval, highlighting differences between US and EU device regulation and the importance of requiring clinical evidence for high-risk implantable devices.
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Mandatory Disclaimers on Dietary Supplements Do Not Reliably Communicate the Intended Issues

Kesselheim AS, Connolly JG, Rogers JR, Avorn J - Health Affairs

  • Research Publications
| March 2015
  • Regulation and Clinical Evidence
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In this systemic review of dietary supplement disclaimer studies, larger and more rigorous studies revealed that many consumers were unaware of disclaimers or that they did not affect patient perceptions of supplements. These findings suggest that relying on disclaimers as an alternative to government restrictions on drug marketing would be inadequate for informing patients about drug efficacy and safety, and risk enabling a return to problematic levels of inappropriate prescription drug use.
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Availability and Utilization of Cardiovascular Fixed-Dose Combination Drugs in the United States

Wang B, Choudhry NK, Gagne JJ, Landon JE, Kesselheim AS - American Heart Journal

  • Research Publications
| March 2015
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among patients treated for diabetes, dyslipidemia, and hypertension in 2012, only 15% of the 20 most frequently filled single-agent drug pairs were available as fixed-dose combinations (FDCs), and FDCs that existed had substantially lower utilization rates than the most common single-agent pairs. The authors recommend implementing expedited approval pathways and increased investment in formulation studies to better align the development of FDCs with actual clinical use patterns.
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Paying for Innovation: Reimbursement Incentives for Antibiotics

Hwang TJ, Carpenter D, Kesselheim AS - Science Translational Medicine

  • Research Publications
| February 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Despite antibiotics’ tremendous social value, lower perceived commercial potential has driven several large pharmaceutical companies to abandon antibiotic research. The authors examine how reforming hospital reimbursement policies for inpatient antibiotic use could serve as a “pull” mechanism to better align financial incentives with the urgent clinical and public health need for new antibiotics targeting multidrug-resistant organisms.
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High-Cost Generic Drugs—Implications for Patients and Policymakers (Reply)

Alpern JD, Stauffer WM, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| February 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Responding to FDA officials, the authors acknowledge that faster generic drug application review is helpful but argue that additional interventions are needed to address the multiple causes of high generic drug prices, including fluctuating demand and anticompetitive business practices.
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The Roles of Academia, Rare Diseases, and Repurposing in the Development of the Most Transformative Drugs

Kesselheim AS, Tan YT, Avorn J - Health Affairs

  • Research Publications
| February 2015
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This study of twenty-six transformative drugs approved by the FDA between 1984 and 2009 found that most originated from academic research supported by federal funding or joint public-private development, with only a minority developed solely within pharmaceutical industry programs. Additionally, 35% were repurposed drugs and 38% were initially developed for rare diseases. These findings suggest that policies should recognize the critical roles of academic research, drug repurposing, rare disease research, and government funding in generating transformative pharmaceutical innovations.
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Prescription Drug Insurance Coverage and Patient Health Outcomes: A Systematic Review

Kesselheim AS, Huybrechts KF, Choudhry NK, Fulchino LA, Isaman DL, Kowal MK, Brennan TA - American Journal of Public Health

  • Research Publications
| February 2015
  • Price, Value, and Access
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Broader prescription drug insurance coverage reduces utilization of other healthcare services and improves patient health outcomes, while coverage gaps or caps lead to worse outcomes, based on a systematic review of 23 empirical studies. States should implement Affordable Care Act drug coverage expansions to enhance health outcomes for low-income patients enrolled in state-based health insurance programs.
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Development and Use of New Therapeutics for Rare Diseases: Views From Patients, Caregivers, and Advocates

Kesselheim AS, McGraw SA, Thompson L, O'Keefe K, Gagne JJ - The Patient

  • Research Publications
| February 2015
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Rare disease patients, caregivers, and advocates reported willingness to accept risks with novel or off-label treatments due to limited therapeutic options, while expressing frustration with high costs and insufficient scientific data about available treatments. Yet, respondents also valued the FDA’s regulatory oversight and the scientific rigor of drug development. These findings suggest that regulatory frameworks for rare disease therapeutics should balance accelerated access to treatments with maintained scientific standards, while addressing patient concerns about affordability and data transparency.
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Are Risk Evaluation and Mitigation Strategies Associated with Less Off-Label Use of Medications? The Case of Immune Thrombocytopenia

Sarpatwari A, Franklin JM, Avorn J, Seeger JD, Landon JE, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| February 2015
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The study found that when Risk Evaluation and Mitigation Strategies (REMS) requirements were in place for romiplostim and eltrombopag, prescribing was almost exclusively on-label; after these requirements were removed, off-label use of eltrombopag for hepatitis C virus patients increased significantly. The findings suggest that while REMS programs can promote patient safety by limiting off-label use, they may also restrict access to potentially beneficial off-label applications.
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A Cross‐National Comparison of 17 Countries’ Insulin Glargine Drug Labels

Polinski JM, Kesselheim AS, Seeger JD, Connolly JG, Choudhry NK, Shrank WH - Pharmacoepidemiology and Drug Safety

  • Research Publications
| February 2015
  • Regulation and Clinical Evidence
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This cross-national analysis of insulin glargine drug labels across 17 countries found substantial variability in label content, with critical gaps including only 12% describing care of fasting patients, 24% lacking guidance on missed doses, and 29% failing to recommend counseling about hypoglycemia risk; additionally, labels from regional or adopted regulatory bodies reported significantly fewer patients in efficacy studies compared to labels from independent drug regulatory agencies (365 vs. 3,560 patients). The authors conclude that these inconsistencies in drug label content may compromise the quality and consistency of insulin therapy and patient care internationally.
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Practical, Legal, and Ethical Issues in Expanded Access to Investigational Drugs

Darrow JJ, Sarpatwari A, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| January 2015
  • Price, Value, and Access
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The FDA’s expanded access system allows patients with serious conditions to receive investigational drugs before formal approval through 3 categories: individual use, intermediate-size populations, and widespread treatment protocols. The authors examine the practical, legal, and ethical challenges of reconciling protection of vulnerable, seriously ill patients from potentially useless or harmful products with the desire to provide timely access to treatments that may ultimately prove beneficial, drawing on cases like Josh Hardy’s widely publicized request for an experimental antiviral and the Ebola crisis.
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