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1377 Results

Pharmaceutical Gatekeepers

Darrow JJ - Indiana Law Review

  • Research Publications
| January 2015
  • Price, Value, and Access
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Drawing on Kraakman’s influential framework on third-party gatekeepers in corporate finance, the article applies a gatekeeping analysis to the pharmaceutical marketplace, examining how diverse entities, including the FDA, USPTO, FTC, physicians, insurance companies, and patients, serve as potential gatekeepers against pharmaceutical misconduct. The analysis explores how these federal agencies and private actors, each wielding different powers to withhold support from potentially harmful pharmaceutical practices, can more effectively deter wrongdoing in a complex regulatory landscape.
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Medical Device Postapproval Safety Monitoring: Where Does the United States Stand?

Rajan PV, Kramer DB, Kesselheim AS - Circulation: Cardiovascular Quality and Outcomes

  • Research Publications
| January 2015
  • Regulation and Clinical Evidence
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As the FDA considers expedited approval pathways for high-risk medical devices to address unmet medical needs, the reduced premarket evidence places greater pressure on postapproval surveillance to identify emerging safety problems. The authors analyze the FDA’s current postmarket programs, including passive reporting through Medical Device Reporting, prospective clinical studies, and active device registries, assessing their effectiveness for monitoring cardiovascular devices and identifying prospects for strengthening the postmarket surveillance network.
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FDA Designations for Therapeutics and Their Impact on Drug Development and Regulatory Review Outcomes

Kesselheim AS, Darrow JJ - Clinical Pharmacology & Therapeutics

  • Research Publications
| January 2015
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The FDA’s expedited development and review pathways, including the 2012 breakthrough therapy designation, allow approval of drugs with less rigorous data than standard requirements and now account for a majority of new drug approvals, offering benefits in bringing transformative drugs to market more efficiently. However, these pathways carry risks of post-approval determinations of ineffectiveness or safety problems and create confusion among patients and physicians about what FDA approval signifies.
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Comments on Proposed Criteria for “First Generic” Submissions for Purposes of ANDA Review Prioritization Under GDUFA

Alpern JD, Stauffer WM, Kesselheim AS - Food and Drug Administration (FDA)

  • Policy Interactions
| December 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The FDA should expand its generic drug application review prioritization criteria to include markets experiencing significant price increases due to lack of competition, in order to help counteract the growing trend of exorbitant price hikes for older, off-patent generic drugs.
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Burden of Changes in Generic Pill Appearance (Reply)

Kesselheim AS, Choudhry NK, Avorn J - Annals of Internal Medicine

  • Commentary & Opinion
| December 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors counter the FDA’s concern that requiring generic drugs to resemble their brand-name counterparts would violate “trade dress” protections, arguing that Supreme Court precedent prohibits trade-dress rights for functional product features. They urge the FDA to formally acknowledge in a guidance document that bioequivalent generic drugs resembling their brand-name counterparts enhance patient safety, which would provide factual input guiding courts to find such appearance features functional and therefore unprotectable by trademark.
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Innovative Research Methods for Studying Treatments for Rare Diseases: Methodological Review

Gagne JJ, Thompson L, O'Keefe K, Kesselheim AS - BMJ

  • Research Publications
| November 2014
  • Regulation and Clinical Evidence
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This methodological review identified 16 research strategies for studying health outcomes in rare diseases, with innovative clinical trial methods primarily focusing on minimizing sample size requirements and maximizing patient access to active treatment. While unique clinical trial designs have been developed for rare disease research, there is a significant gap in innovative observational study methods for this population, suggesting a need for greater methodological development in observational research approaches.
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Testimony: Why Are Some Generic Drugs Skyrocketing in Price?

Kesselheim AS - 113th Congress, Senate Committee on Health, Education, Labor, and Pensions

  • Policy Interactions
| November 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Kesselheim explains that while generic drugs reliably deliver low-cost, high-quality medications, competition among manufacturers can collapse due to business decisions, supply disruptions, anticompetitive behavior, or re-assertion of exclusivity righs. To mitigate generic drug price spikes, he recommends mandatory reporting of price increases above 100%, expedited FDA review for new generic entrants into monopolized markets, increased FTC enforcement resources, and waiving Medicare Part D’s non-interference clause for multisource drugs.
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High-Cost Generic Drugs—Implications for Patients and Policymakers

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

  • Commentary & Opinion
| November 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors document dramatic price increases for off-patent drugs with limited competition driven by manufacturer consolidation, supply disruptions, and the discontinuation of therapeutic alternatives. To mitigate these price spikes, they propose various policy solutions, including FDA-triggered public solicitations for new generic manufacturers when substantial price increases occur, expedited reviews and user fee waivers for companies entering these markets, and temporary importation.
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The Short-Term and Long-Term Outlook of Drug Coupons

Maggs LR, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| November 2014
  • Price, Value, and Access
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While manufacturer drug coupons reduce patients’ out-of-pocket costs and may improve short-term adherence, they undermine cost-sharing mechanisms designed to steer prescribing toward equally effective, less expensive alternatives, ultimately increasing insurer spending and premiums for all patients. Policymakers face a tension between individual patient savings and systemwide costs, and coupons further dampen public pressure for broader drug pricing reform by masking the true price burden.
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Chemotherapy Parity Laws: A Remedy for High Drug Costs?

Wang B, Joffe S, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| November 2014
  • Price, Value, and Access
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While oral chemotherapy parity laws (requiring insurers to cover oral cancer drugs on terms comparable to intravenous chemotherapy) improve patient access, they are an inadequate response to the fundamental problem of rising cancer drug costs and may actually reduce pressure on manufacturers to moderate prices.
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Ensuring Patient Privacy in Data Sharing for Postapproval Research

Sarpatwari A, Kesselheim AS, Malin BA, Gagne JJ, Schneeweiss SG - New England Journal of Medicine

  • Commentary & Opinion
| October 2014
  • Regulation and Clinical Evidence
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The authors detail the HIPAA and HITECH Act pathways for sharing health data for post-approval drug safety research, assessing the usefulness and liability risks of each pathway and arguing for frameworks that enable robust pharmacoepidemiological research while protecting patient privacy.
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Association of Medical Students’ Reports of Interactions with the Pharmaceutical and Medical Device Industries and Medical School Policies and Characteristics: A Cross-Sectional Study

Yeh JS, Austad KE, Franklin JM, Chimonas S, Campbell EG, Avorn J, Kesselheim AS - PLOS Medicine

  • Research Publications
| October 2014
  • Regulation and Clinical Evidence
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Students attending medical schools with the most stringent policies on pharmaceutical and medical device industry interactions were significantly less likely to report receiving gifts and interacting with industry representatives compared to those at schools with less restrictive policies, though this association was attenuated when accounting for NIH funding levels. Medical schools should emphasize policies that limit gifts, meals, and faculty participation in speaking bureaus, and policymakers should prioritize implementing stronger industry interaction regulations at less research-intensive institutions.
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Health Policy Basics: The Physician Payment Sunshine Act and the Open Payments Program

Kirschner NM, Sulmasy LS, Kesselheim AS - Annals of Internal Medicine

  • Commentary & Opinion
| October 2014
  • Regulation and Clinical Evidence
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The Open Payments program is a US government transparency initiative that requires public reporting of financial relationships between pharmaceutical and device industries and physicians or teaching hospitals, without assessing the appropriateness of those relationships. The authors outline the program’s requirements and implementation timeline, examine implications for physicians and patients, and offer recommendations to help physicians and teaching hospitals prepare for compliance.
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Existing FDA Pathways Have Potential to Ensure Early Access To, and Appropriate Use Of, Specialty Drugs

Kesselheim AS, Tan YT, Darrow JJ, Avorn J - Health Affairs

  • Research Publications
| October 2014
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The FDA has multiple regulatory tools to balance timely patient access to specialty drugs, which offer substantial clinical benefits but carry significant risks and high costs, including expanded access programs and expedited approval pathways to accelerate availability, as well as post-approval mechanisms like narrow indications, companion diagnostics, and Risk Evaluation and Mitigation Strategies (REMS). The authors argue that effective implementation of these existing approaches can promote access for patients most likely to benefit while preventing expensive and potentially harmful overuse.
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A Matter of Trust: Patient Barriers to Primary Medication Adherence

Polinski JM, Kesselheim AS, Frolkis JP, Wescott P, Allen-Coleman C, Fischer MA - Health Education Research

  • Research Publications
| October 2014
  • Price, Value, and Access
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Focus groups with 26 patients who failed to fill initial antihypertensive prescriptions revealed key barriers to primary medication adherence, including anger and suspicion about the hypertension diagnosis, doubts about the need for medication, and concerns about provider credibility. Participants indicated that a trusting patient-provider relationship, shared decision-making, full disclosure of side effects, and cost sensitivity could improve adherence, suggesting that decision support interventions focused on building trust and credibility before prescribing may be more effective than current approaches.
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Electronic Medication Packaging Devices and Medication Adherence: A Systematic Review

Checchi KD, Huybrechts KF, Avorn J, Kesselheim AS - JAMA

  • Research Publications
| September 2014
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Electronic medication packaging (EMP) devices show variable effectiveness in improving medication adherence, with effect estimates ranging from a 2.9% decrease to a 34.0% increase in mean adherence across 37 studies. Devices integrated into the care delivery system and designed to record dosing events demonstrated the most consistent associations with improved adherence. Higher-quality evidence is needed to definitively establish the effectiveness of EMP devices in addressing medication nonadherence and to identify which specific device components are most beneficial.
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Comparative Effectiveness of Generic and Brand-Name Statins on Patient Outcomes: A Cohort Study

Gagne JJ, Choudhry NK, Kesselheim AS, Polinski JM, Hutchins D, Matlin OS, Brennan TA, Avorn J, Shrank WH - Annals of Internal Medicine

  • Research Publications
| September 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Medicare patients who initiated generic statins demonstrated higher medication adherence and had an 8% lower rate of acute coronary syndrome, stroke, or all-cause mortality compared to those initiating brand-name statins. These findings suggest that generic statins may offer clinical advantages over brand-name statins, though results may not generalize to populations with different incomes or drug benefit structures.
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Regulating Incremental Innovation in Medical Devices

Kesselheim AS, Rajan PV - BMJ

  • Commentary & Opinion
| September 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The rapid evolution of medical devices through incremental design changes—with cardiac devices averaging 50 FDA applications over their regulatory lifespans—creates patient safety risks when these modifications are cleared without clinical testing. The authors call for active post-marketing surveillance linked to compulsory research.
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The Role of Black Box Warnings in Safe Prescribing Practices

Maggs LR, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| August 2014
  • Regulation and Clinical Evidence
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The authors discuss how the FDA’s accelerated approval timelines under PDUFA have contributed to a rise in post-approval black box warnings and market withdrawals, using cases like rofecoxib (Vioxx) and the SSRI-suicidality controversy to illustrate the challenges of calibrating drug safety communications. Black box warnings must be data-driven, appropriately nuanced, and timely despite manufacturer resistance, and over-broad application risks diluting their signal value.
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The Food and Drug Administration’s Role in Promoting Consistent Labels for Generic Drugs

Duke JD, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| August 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors examine an FDA proposal that would allow generic drug manufacturers to independently update their product labels with new safety information, arguing that while the rule could improve the timeliness of safety warnings, the potential for temporarily inconsistent labels across manufacturers of the same drug is a valid but manageable concern given that generic labels already frequently differ in practice.
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Introduction to a Supplement on Innovative Approaches to Studying Health Outcomes in Rare Diseases

Kesselheim AS, Gagne JJ - Journal of General Internal Medicine

  • Commentary & Opinion
| August 2014
  • Regulation and Clinical Evidence
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The authors introduce a journal supplement highlighting the growing importance of rare diseases in health policy and the need for innovative research methods, noting that rare disease drugs are increasingly approved on weaker evidence and that novel approaches to trial design, patient registries, and outcome measurement are needed.
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Improving Evidence-Based Practices Through Health Literacy

Yeh JS - JAMA Internal Medicine

  • Commentary & Opinion
| August 2014
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This letter to the editor discusses the importance of health literacy in enabling patients to meaningfully participate in clinical decision-making, arguing that mismatches between patient skills and the complexity of health information lead to poor communication and suboptimal care.
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Association of Marketing Interactions with Medical Trainees’ Knowledge About Evidence-Based Prescribing: Results From a National Survey

Austad KE, Avorn J, Franklin JM, Campbell EG, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| August 2014
  • Regulation and Clinical Evidence
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Medical trainees with higher acceptance of pharmaceutical industry interactions demonstrated significantly lower odds of selecting evidence-based prescribing choices and were more likely to recommend brand-name drugs over generics. The findings suggest that institutional policies limiting direct pharmaceutical sales representative interactions with medical students and residents may improve trainees’ evidence-based prescribing knowledge and reduce bias toward branded medications.
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FDA Regulation of Mobile Health Technologies

Cortez NG, Cohen IG, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| July 2014
  • Regulation and Clinical Evidence
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With over 97,000 mobile health apps available as of 2013 and the market nearly doubling annually, the FDA faces a major regulatory challenge in overseeing an increasingly diverse range of mHealth products—from smartphone-connected glucometers to cardiac monitoring apps—that blur the line between consumer wellness tools and medical devices. The authors examine how to balance the FDA’s public health mandate to ensure device safety and effectiveness with concerns from Congress and industry that excessive regulation could inhibit innovation in this rapidly growing market.
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Burden of Changes in Pill Appearance for Patients Receiving Generic Cardiovascular Medications After Myocardial Infarction: Cohort and Nested Case-Control Studies

Kesselheim AS, Bykov K, Avorn J, Tong A, Doherty M, Choudhry NK - Annals of Internal Medicine

  • Research Publications
| July 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Among 11,513 post-MI patients initiating generic cardiovascular medications, 29% experienced a change in pill color or shape. These changes were significantly associated with medication nonpersistence, as odds of discontinuation increased 34% after a color change and 66% after a shape change. These findings suggest that inconsistencies in generic drug appearance may meaningfully disrupt adherence to essential cardiovascular therapies and highlight the importance of pill appearance standardization or better patient communication around such changes.
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Testimony: 21st Century Cures: Modernizing Clinical Trials

Kesselheim AS - 113th Congress, House Committee on Energy and Commerce, Subcommittee on Health

  • Policy Interactions
| July 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Kesselheim argues that the FDA’s requirement for rigorous premarket testing of drugs and high-risk devices emerged as a rational response to public health tragedies, and that the agency already has substantial flexibility to expedite important new products. He cautions that approving drugs based on unvalidated trial designs or surrogate endpoints puts patients at risk, citing bedaquiline as a cautionary example, and notes that post-approval confirmatory studies and safety surveillance systems remain underdeveloped. Watch his testimony.
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New FDA Breakthrough-Drug Category—Implications for Patients (Reply)

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

  • Commentary & Opinion
| July 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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In this reply, the authors maintain that the FDA itself acknowledges its expedited-approval programs lower evidentiary thresholds, and that the breakthrough-therapy designation can indirectly weaken standards by generating premature enthusiasm that pressures the agency into approving drugs based on truncated trials and unvalidated biomarkers.
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New Drug and Device Approval: What Is Sufficient Evidence?

Darrow JJ, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| July 2014
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Growing pressure to expedite drug and device approvals through pathways like accelerated approval creates risks of premature market entry for products later found ineffective or harmful, as illustrated by cases like the Wingspan stent where a larger trial revealed increased stroke and death rates. While expedited access is appropriate for seriously ill patients with no alternatives, the FDA must maintain robust evidentiary standards as its default position, since Type I approval errors are unusually resistant to correction once products reach the market.
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Drug Development and FDA Approval, 1938-2013

Darrow JJ, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| June 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This interactive graphic shows major legislative and regulatory events related to approval of new drugs by the Food and Drug Administration (FDA), drug approvals by year and by therapeutic category, and trends in the use of the FDA’s various programs for expedited approval.
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Restrictions on Pharmaceutical Detailing Reduced Off-Label Prescribing of Antidepressants and Antipsychotics in Children

Larkin I, Ang D, Avorn J, Kesselheim AS - Health Affairs

  • Research Publications
| June 2014
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Restrictions on pharmaceutical detailing at academic medical centers reduced off-label prescribing of antidepressants and antipsychotics in children by 11%, while on-label prescribing of promoted drugs fell 34% and prescriptions shifted toward nonpromoted drugs. These findings suggest that anti-detailing policies can effectively limit pharmaceutical marketing’s influence on prescribing in pediatric populations and promote evidence-based treatment practices.
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Prospects for Regulation of Off-Label Promotion in an Era of Expanding Commercial Speech Protection

Kesselheim AS, Mello MM - North Carolina Law Review

  • Research Publications
| June 2014
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The Second Circuit Court of Appeals ruled in United States v. Caronia that the criminal prosecution of a pharmaceutical sales representative for orally promoting an FDA-approved drug (Xyrem) for off-label uses violated First Amendment protections of commercial speech, overturning his misbranded drug conspiracy conviction. The decision represents a legal setback for government efforts to regulate aggressive pharmaceutical marketing and raises questions about the government’s ability to enforce FDA restrictions on off-label drug promotion under expanding commercial speech protections.
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Evidence, Errors, and Ethics

Miller FG, Joffe S, Kesselheim AS - Perspectives in Biology and Medicine

  • Research Publications
| June 2014
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Evidence-based decisions relating to the development and use of novel medical interventions are liable to false positive and false negative errors: adverse consequences that ensue from making or omitting to make a given decision. The authors examine the propensity to false positive and false negative errors in light of competing value judgments in the areas of designing randomized controlled trials, pharmaceutical licensing, coverage of medical treatments, and clinical practice.
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Crowdsourcing Public Health Experiments: A Response to Jonathan Darrow’s Crowdsourcing Clinical Trials

Sarpatwari A, Robertson CT, Yokum DV, Joiner K - Minnesota Law Review

  • Research Publications
| June 2014
  • Regulation and Clinical Evidence
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Responding to Darrow’s proposal for crowdsourcing post-approval drug surveillance through observational data collection, the authors qualify the ethical framing of early clinical drug use as equivalent to research and highlight the limitations of observational approaches compared to randomized designs for drawing causal inferences. They expand on Darrow’s core insights by proposing that crowdsourcing platforms could be used not only for pharmaceutical surveillance but also for truly randomized interventional trials in lifestyle-driven domains which are primary drivers of health outcomes and spending.
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Approval of High-Risk Medical Devices in the US: Implications for Clinical Cardiology

Rome BN, Kramer DB, Kesselheim AS - Current Cardiology Reports

  • Research Publications
| June 2014
  • Regulation and Clinical Evidence
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Recent high-risk medical device recalls, particularly involving ICD leads, have highlighted concerns that FDA premarket approval does not guarantee superior safety or effectiveness, as many widely used devices are approved as supplements to existing PMA-approved devices with limited clinical testing. Cardiologists should recognize the variable levels of evidence underlying FDA device approvals and prioritize clinician and patient engagement in postmarket surveillance and comparative effectiveness research to ensure optimal device safety and performance.
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Target Small Firms for Antibiotic Innovation

Hwang TJ, Carpenter D, Kesselheim AS - Science

  • Research Publications
| May 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Analysis of 4,715 drugs entering Phase 1 trials between 1990 and 2012 found that antibiotics were 43% more likely than other drugs to survive Phase 2 and 17% more likely to survive Phase 3, while small and medium-sized companies grew from under 30% to 60% of antibiotic clinical trial sponsors during this period. The authors argue that policies should focus on supporting these smaller firms through targeted R&D tax credits, public-private partnerships, and increased basic research funding rather than extending market exclusivity or lowering regulatory standards.
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Postmarketing Trials and Pediatric Device Approvals

Hwang TJ, Kesselheim AS, Bourgeois FT - Pediatrics

  • Research Publications
| May 2014
  • Regulation and Clinical Evidence
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Most high-risk pediatric devices approved between 2008 and 2011 (88% of 25 devices) were based on nonrandomized, open-label studies using surrogate endpoints, with 84% never studied in patients under 18 years of age before approval. While the FDA mandated postmarketing studies for 76% of approved devices, only 18% of these studies required enrollment of pediatric patients, indicating limited postmarket surveillance in the intended pediatric population.
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Using a Drug-Safety Tool to Prevent Competition

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

  • Commentary & Opinion
| April 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors document how some brand-name manufacturers have exploited FDA REMS requirements to block generic competition by refusing to provide drug samples for bioequivalence testing and hindering development of shared REMS programs.
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Accelerating Medicines Partnership: A New Public-Private Collaboration for Drug Discovery

Kesselheim AS, Tan YT - Health Affairs Forefront

  • Commentary & Opinion
| April 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The Accelerating Medicines Partnership brings together the NIH, ten major pharmaceutical companies, and nonprofit groups with $230 million in initial funding to collaboratively identify and validate biological targets for Alzheimer’s disease, type 2 diabetes, rheumatoid arthritis, and lupus, with all early-stage data made publicly accessible. Key challenges include managing the transition from open collaboration to proprietary development, aligning divergent public and private incentives, and ensuring that drugs emerging from taxpayer-supported research are priced fairly rather than imposing a double burden on the public.
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New FDA Breakthrough-Drug Category—Implications for Patients

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

  • Research Publications
| March 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Created by Congress in 2012, the FDA’s breakthrough therapy designation was intended to expedite approval of drugs showing “exceptional results for patients,” yet in its first year the FDA received 92 applications, far exceeding expectations of approximately 2 per year, and approved 27 designations, raising concerns about a potential surge in drugs approved on the basis of limited clinical data. The authors trace the history of prior expedited-access programs and examine the clinical, ethical, and regulatory implications of this latest pathway, noting the dangers illustrated by cases like ponatinib, which was briefly suspended after accelerated approval when serious thromboembolic events emerged in up to 48% of patients.
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Comments on Proposed Rule, “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products”

Kesselheim AS, Avorn J, Duke JD - Food and Drug Administration (FDA)

  • Policy Interactions
| March 2014
  • Regulation and Clinical Evidence
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The commenters support an FDA proposed rule that would allow generic drug manufacturers to update their drug labels through expedited procedures, addressing a gap in safety oversight that leaves generic drug labels outdated when new safety information emerges after brand-name exclusivity ends.
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Comments on Draft Guidance, “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules”

Kesselheim AS, Avorn J, Engelberg AB - Food and Drug Administration (FDA)

  • Policy Interactions
| March 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The FDA should expand its guidance on generic drug appearance to address pill color, given research showing that changes in the color and shape of generic medications contribute to patient confusion, medication non-adherence, and negative health outcomes.
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What Is the Public’s Right to Access Medical Discoveries Based on Federally Funded Research?

Treasure CL, Avorn J, Kesselheim AS - JAMA

  • Commentary & Opinion
| March 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors examine the Bayh-Dole Act’s march-in rights as a mechanism to ensure public access to drugs developed with federal funding, reviewing the history of march-in petitions to the NIH and arguing that these rights should be exercised when publicly funded drugs are priced beyond patients’ reach.
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Underrepresentation of Older Adults in Cancer Trials

Luo J, Kesselheim AS - JAMA

  • Commentary & Opinion
| March 2014
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
This letter to the editor discusses methodological issues in observational studies examining testosterone therapy and cardiovascular outcomes, including the use of inverse probability weighting and the importance of accounting for time-varying treatment initiation.
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Strategies for Postmarketing Surveillance of Drugs for Rare Diseases

Kesselheim AS, Gagne JJ - Clinical Pharmacology & Therapeutics

  • Research Publications
| March 2014
  • Regulation and Clinical Evidence
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Rare diseases affect 6-8% of the population and represent the fastest-growing category of new drug approvals, yet traditional postmarketing surveillance methods like meta-analyses and spontaneous adverse event reporting are inadequate for these populations due to their low prevalence and poorly characterized natural history. Bayesian trials, distributed networks of electronic databases, natural history studies, adaptive clinical trial designs, and patient-organized registries offer promising alternative methodological approaches for active and prospective monitoring of rare disease therapeutics.
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Assessing the Chiral Switch: Approval and Use of Single-Enantiomer Drugs, 2001 to 2011

Gellad WF, Choi P, Mizah M, Good CB, Kesselheim AS - American Journal of Managed Care

  • Research Publications
| March 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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From 2001 to 2011, the FDA approved 9 single-enantiomer drugs as chiral switches, yet only 3 had preapproval trials directly comparing them to their racemic precursors, and none demonstrated superior efficacy at comparable doses. Meanwhile, Medicaid spent approximately $6.3 billion on these products during this period. The findings suggest that chiral switches are often approved and widely adopted without robust evidence of clinical superiority over existing racemic formulations, raising questions about the drug approval process.
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Clinicians’ Contributions to the Development of Coronary Artery Stents: A Qualitative Study of Transformative Device Innovation

Kesselheim AS, Xu S, Avorn J - PLOS ONE

  • Research Publications
| February 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Three teams of physician-inventors, Palmaz and Schatz, Gianturco and Roubin, and Sigwart, independently identified the clinical need for coronary artery stents and developed prototypes with support from academic medical centers before larger companies subsequently entered the field with engineering expertise. Innovation policy should prioritize supporting early-stage physician-inventors working at academic institutions, as this case study demonstrates that transformative medical device innovation originates from clinicians addressing unmet clinical needs rather than from corporate-led development.
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The Evolving Role of Biomarker Patents in Personalized Medicine

Kesselheim AS, Shiu N - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| February 2014
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors analyze how recent Supreme Court decisions have narrowed the scope of biomarker patents by ruling that purely mental processes correlating biomarkers with clinical outcomes are unpatentable, while processes integrating biomarkers into practical clinical steps can still receive patent protection.
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Quantifying the Food and Drug Administration’s Rulemaking Delays Highlights the Need for Transparency

Hwang TJ, Avorn J, Carpenter D, Kesselheim AS - Health Affairs

  • Research Publications
| February 2014
  • Regulation and Clinical Evidence
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FDA rules published between 2000 and 2012 had a median finalization time of 7.3 years, with mandatory cost-benefit analyses adding approximately two years of delay, and longer review times associated with less stringent final rules compared to proposed versions. The authors recommend increasing FDA resources to improve rulemaking efficiency and implementing transparency initiatives across the FDA and executive branch.
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FDA Approval of Cardiac Implantable Electronic Devices Via Original and Supplement Premarket Approval Pathways, 1979-2012

Rome BN, Kramer DB, Kesselheim AS - JAMA

  • Research Publications
| January 2014
  • Regulation and Clinical Evidence
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From 1979 to 2012, the FDA approved 77 original premarket approval applications for cardiac implantable electronic devices with a median of 50 supplements per original application. 37% of supplements involved design changes, yet only 23% of the supplements approved from 2010 to 2012 included new clinical data. The findings highlight that most modifications to high-risk cardiac devices are approved without additional clinical testing, underscoring the critical need for rigorous postapproval surveillance to ensure ongoing safety and effectiveness.
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Assessment of US Pathway for Approving Medical Devices for Rare Conditions

Hwang TJ, Carpenter D, Kesselheim AS - BMJ

  • Research Publications
| January 2014
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The humanitarian device exemption (HDE), established by the Safe Medical Devices Act of 1990 for devices treating diseases affecting fewer than 4,000 US patients annually, does not require manufacturers to demonstrate effectiveness, only safety and a favorable benefit-risk balance. Restrictions on for-profit sales were also removed for pediatric devices in 2007 and all HDE devices in 2012. The authors examine the scientific and regulatory characteristics of HDE-approved devices since the pathway’s inception, considering benefits and risks of this reduced evidentiary standard and drawing lessons for ongoing regulatory reform efforts in both the US and EU.
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Medical Innovation Then and Now: Perspectives of Innovators Responsible for Transformative Drugs

Xu S, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Winter 2014
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors surveyed innovators responsible for transformative drugs from the 1980s and 1990s about how the drug development process has changed and what factors drove breakthrough discoveries. The insights from these key historical figures provide an empirical basis for evaluating current proposals to stimulate medical innovation, including whether reducing regulatory approval hurdles or creating new translational research incentives are likely to address the underlying causes of the slowdown in transformative drug development.
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Life Cycle of Medical Product Rules Issued By the US Food and Drug Administration

Hwang TJ, Avorn J, Kesselheim AS - Journal of Health Politics, Policy and Law

  • Research Publications
| January 2014
  • Regulation and Clinical Evidence
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The FDA’s rulemaking process for medical products involves extensive stakeholder participation and input from multiple branches of government and the public, but the process’s duration, complexity, and adversarial nature can impede the agency’s ability to achieve its public health objectives, with considerable variation in transparency across different stages. The authors recommend reforms focused on improving both transparency and efficiency in the rulemaking process to address delays in finalization timelines.
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Ensuring Medical Device Effectiveness and Safety: A Cross-National Comparison of Approaches to Regulation

Kramer DB, Tan YT, Sato C, Kesselheim AS - Food and Drug Law Journal

  • Research Publications
| January 2014
  • Regulation and Clinical Evidence
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This cross-national legal and policy review identifies that major medical device regulatory markets in the US, EU, Japan, and China rely heavily on passive adverse event reporting but are increasingly adopting active surveillance mechanisms such as unique device identification. The authors recommend that US and EU regulators implement scheduled, compulsory re-examination of selected devices similar to practices in Japan and China to enhance post-market patient protection and public health outcomes.
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New and Unproved Medical Devices

Kesselheim AS, Avorn J - BMJ

  • Commentary & Opinion
| December 2013
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The rapid adoption of new medical devices by “innovator” and “early adopter” surgeons—as demonstrated by half of hip prosthesis brands in use having been on the market less than three years—poses public health risks because most devices are cleared through the 510(k) pathway without clinical effectiveness testing.
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Clinical and Regulatory Features of Drugs Not Initially Approved by the FDA

Wang B, Avorn J, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| December 2013
  • Regulation and Clinical Evidence
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The FDA denied approval in the first review cycle for 52% of new drugs and biologics evaluated by FDA advisory committees between 2007 and 2009, though 63% eventually received approval by 2013, with products initially flagged for safety concerns being far more likely to achieve eventual approval (62%) compared to those with efficacy concerns (8%).
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Same Song, Different Audience: Pharmaceutical Promotion Targeting Non-Physician Health Care Providers

Yeh JS, Kesselheim AS - PLOS Medicine

  • Commentary & Opinion
| November 2013
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Pharmaceutical marketing has expanded to target non-physician providers such as nurse practitioners and physician assistants, who now have significant prescribing authority. The authors argue that the same evidence showing promotional influence on physician prescribing likely applies to these providers.
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The Role of Direct-To-Consumer Pharmaceutical Advertising in Patient Consumerism

Wang B, Kesselheim AS - AMA Journal of Ethics

  • Research Publications
| November 2013
  • Regulation and Clinical Evidence
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Direct-to-consumer (DTC) pharmaceutical advertising in the US totaled more than $4 billion in 2012 and is increasingly delivered through digital channels like smartphones and the Internet. While these advertisements can inform patients about treatment options, the absence of firm regulatory guidelines governing DTC advertising may result in suboptimal treatment decisions and negative health and economic outcomes.
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Physician Trainees’ Interactions with the Pharmaceutical Industry (Reply)

Austad KE, Avorn J, Franklin JM, Kesselheim AS - Journal of General Internal Medicine

  • Commentary & Opinion
| October 2013
  • Regulation and Clinical Evidence
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In this reply, the authors clarify that their finding should not diminish the importance of institutional policies on industry interactions. They emphasize that meaningful enforcement of such policies remains essential and that further research is needed to identify the most effective interventions.
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Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs

Light DW, Lexchin J, Darrow JJ - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2013
  • Regulation and Clinical Evidence
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Institutional corruption in the pharmaceutical industry has enabled companies to hide, misrepresent, or ignore drug safety evidence, resulting in millions of adverse patient reactions despite limited therapeutic benefits. The authors argue that institutional corruption, rather than isolated misconduct, is the underlying cause of the epidemic of pharmaceutical harms and the gap between marketed safety claims and actual patient outcomes.
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Approval and Withdrawal of New Antibiotics and Other Antiinfectives in the US, 1980-2009

Outterson K, Powers JH, Seoane-Vazquez E, Rodriguez-Monguio R, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2013
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors examine patterns of FDA approval and subsequent withdrawal of new antibiotics and other antiinfective drugs over three decades, documenting the decline in new antibiotic approvals alongside the growing threat of antimicrobial resistance. The analysis underscores that sustainable long-term antibiotic effectiveness requires complementary strategies of conservation (infection control and stewardship to reduce demand) and production of novel agents, with policy reforms needed to address the commercial dynamics that have led manufacturers to underinvest in antibiotic development.
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Prescription-Drug Coupons—No Such Thing as a Free Lunch

Ross JS, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| September 2013
  • Price, Value, and Access
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The authors examine the growing use of manufacturer drug coupons and copayment assistance programs, arguing that while they reduce patients’ immediate out-of-pocket costs, they undermine formulary-based cost management by steering patients toward expensive brand-name drugs when cheaper therapeutic alternatives are available.
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Postmarket Surveillance of Medical Devices: A Comparison of Strategies in the US, EU, Japan, and China

Kramer DB, Tan YT, Sato C, Kesselheim AS - PLOS Medicine

  • Research Publications
| September 2013
  • Regulation and Clinical Evidence
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A comparison of medical device postmarket surveillance strategies across 4 major markets—the US, EU, Japan, and China—reveals significant differences in adverse event reporting systems, registry-based monitoring, and postmarket study requirements. The analysis highlights how each system’s approach to ongoing safety and effectiveness monitoring reflects different regulatory philosophies and institutional capacities, offering lessons for ongoing policy reforms in all 4 jurisdictions.
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Who Is Now Responsible for Discovering and Warning About Adverse Effects of Generic Drugs?

Kesselheim AS, Green MD, Avorn J - JAMA

  • Commentary & Opinion
| September 2013
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors examine three Supreme Court decisions that created a legal gap in which generic drug manufacturers cannot be held liable for inadequate warnings (because they must use the brand-name label) while brand-name manufacturers may not be liable for generic products they didn’t produce, leaving patients injured by generic drugs with limited legal recourse.
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The Medical Device Excise Tax—Over Before It Begins? (Reply)

Kramer DB, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| September 2013
  • Regulation and Clinical Evidence
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In this exchange, industry representatives challeng the authors’ analysis of the ACA’s 2.3% medical device excise tax, claiming it has already caused job losses, reduced R&D spending, and will not generate the predicted revenue benefits. The authors reply that they remain skeptical of industry’s anecdotal claims, note that imaging utilization data from Massachusetts do not support the critics’ conclusions due to confounding factors.
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Speaking the Same Language? International Variations in the Safety Information Accompanying Top-Selling Prescription Drugs

Kesselheim AS, Franklin JM, Avorn J, Duke JD - BMJ Quality & Safety

  • Research Publications
| September 2013
  • Regulation and Clinical Evidence
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Across 20 top-selling prescription drugs, prescribing information approved by different regulatory agencies showed substantial variations in safety content, with Canada reporting 50% more adverse drug reactions than the US, while the UK and Australia reported 15% and 21% fewer, respectively. Black box warnings also differing significantly in presence and content across countries. The authors recommend improved international coordination in presenting safety data to enhance the effectiveness of prescribing information for patient safety and decision-making.
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Pharmaceutical Efficacy: The Illusory Legal Standard

Darrow JJ - Washington and Lee Law Review

  • Research Publications
| September 2013
  • Regulation and Clinical Evidence
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The author argues that despite lengthy and expensive drug development processes, the FDA’s efficacy standard under the Federal Food, Drug, and Cosmetic Act permits approval of drugs with minimal effectiveness, as it requires only “substantial evidence” of an effect without establishing any meaningful threshold for the magnitude of that efficacy. The author concludes that FDA approval should not be interpreted as assurance that approved medicines, particularly new and expensive drugs, possess efficacy meaningfully greater than no effiacy at all, with the responsibility for determining acceptable efficacy levels delegated to market forces.
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Patterns and Predictors of Generic Narrow Therapeutic Index Drug Use Among Older Adults

Gagne JJ, Polinski JM, Kesselheim AS, Choudhry NK, Hutchins D, Matlin OS, Tong A, Shrank WH - Journal of the American Geriatrics Society

  • Research Publications
| September 2013
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 36,832 Medicare beneficiaries initiating narrow therapeutic index (NTI) drugs in 2006–2007, 81.5% started on generics, with older age, higher comorbidity burden, prior generic drug use, and residing in areas with high generic utilization all independently associated with greater likelihood of generic initiation. These findings suggest that demographic, clinical, and geographic factors are important determinants of brand versus generic NTI drug selection and may represent targets for educational interventions to reduce disparities in prescribing patterns.
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Defining “Innovativeness” in Drug Development: A Systematic Review

Kesselheim AS, Wang B, Avorn J - Clinical Pharmacology & Therapeutics

  • Research Publications
| September 2013
  • Innovation Incentives and Competition
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This systematic review of 42 studies found that conclusions about whether pharmaceutical innovation is declining depend critically on the measurement method used: studies using simple drug approval counts were more likely to find favorable innovation trends, while studies using other measures of innovation were more likely to find unfavorable trends or reach no conclusion. The ongoing debate about pharmaceutical innovation trends reflects fundamental disagreements about how to define and measure innovativeness in drug development, necessitating clearer methodological consensus.
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Gene Patenting—The Supreme Court Finally Speaks

Kesselheim AS, Cook-Deegan RM, Winickoff DE, Mello MM - New England Journal of Medicine

  • Commentary & Opinion
| August 2013
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors discuss the Supreme Court’s unanimous ruling in Association for Molecular Pathology v. Myriad Genetics that naturally occurring human DNA segments are not patentable, while synthetically created complementary DNA (cDNA) remains patentable. They outline the decision’s implications for genetic testing, personalized medicine, and biomedical research.
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Changing Interactions Between Physician Trainees and the Pharmaceutical Industry: A National Survey

Austad KE, Avorn J, Franklin JM, Kowal MK, Campbell EG, Kesselheim AS - Journal of General Internal Medicine

  • Research Publications
| August 2013
  • Regulation and Clinical Evidence
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Among medical students and residents surveyed, industry-sponsored gifts increased significantly across training levels, rising from 33.0% among first-year students to 56.8% among fourth-year students and 54% among residents. The perception that physicians receive valuable education through industry interactions also increased from 64.1% to 79.8%. Schools with higher NIH funding reported fewer industry gifts, but institutional conflict of interest policies showed no association with reduced gift-giving. Despite recent policy efforts to limit pharmaceutical industry access to trainees, stronger or more effectively enforced policies may be needed to meaningfully reduce these interactions.
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Regulation of Drugs for Early Alzheimer’s Disease

Light DW, Darrow JJ - New England Journal of Medicine

  • Commentary & Opinion
| July 2013
  • Regulation and Clinical Evidence
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In this exchange, the authors argue that further loosening FDA approval standards for early-stage Alzheimer’s drugs risks encouraging development of ineffective medications. The FDA officials reply their proposed accelerated approval framework for disease-modifying therapies in very early Alzheimer’s is distinct from symptom-based approvals and includes appropriate safeguards.
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Balancing Access and Innovation: India’s Supreme Court Rules on Imatinib

Rajkumar R, Kesselheim AS - JAMA

  • Commentary & Opinion
| July 2013
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors discuss the Indian Supreme Court’s decision upholding India’s patent law provision (Section 3(d)) that denied a patent on a new form of imatinib, discussing how India’s approach to limiting secondary patents on incremental drug modifications balances innovation incentives with access to essential medicines.
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Views from Academia, Industry, Regulatory Agencies, and the Legal System (2nd Ed)

Avorn J, Mo J, Reynolds RF, Dal Pan GJ, Arlett P, Kesselheim AS - Textbook of Pharmacoepidemiology, 2nd Edition

  • Commentary & Opinion
| July 2013
  • Regulation and Clinical Evidence
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This textbook chapter presents four complementary perspectives on the role of pharmacoepidemiology across the drug lifecycle, covering its use in academia, industry, and regulatory agencies. The final section examines the legal system’s intersection with pharmacoepidemiology.
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FTC v. Actavis: The Supreme Court Issues A Reversal on Reverse Payments

Kesselheim AS, Shiu N - Health Affairs Forefront

  • Commentary & Opinion
| June 2013
  • Innovation Incentives and Competition
  • Price, Value, and Access
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In a 5-3 decision, the Supreme Court ruled that “reverse payment” settlements are not automatically shielded from antitrust scrutiny by the existence of a patent, rejecting the lower court’s permissive “scope of the patent” test. The Court applied a “rule of reason” standard allowing the FTC to challenge such agreements based on factors like payment size and justification, a ruling expected to reduce anticompetitive settlements that the FTC estimated cost consumers up to $35 billion per decade in delayed generic competition.
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Op-Ed: Healing the Overwhelmed Physician

Avorn J - New York Times

  • Commentary & Opinion
| June 2013
  • Regulation and Clinical Evidence
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Physicians are overwhelmed by a flood of clinical evidence that is sometimes distorted by pharmaceutical industry funding of clinical-practice guidelines. The author advocates for independent “curator-docent” approaches—rigorous, conflict-free evidence synthesis paired with outreach programs like academic detailing—to help doctors navigate the literature and make prescribing decisions based on the best available science rather than industry marketing.
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Rising Health Care Costs and Life-Cycle Management in the Pharmaceutical Market

Kesselheim AS - PLOS Medicine

  • Commentary & Opinion
| June 2013
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The author examines how brand-name pharmaceutical manufacturers use “life-cycle management” strategies—including patents on peripheral product aspects, authorized generics, and product reformulations—to extend market exclusivity and delay generic competition, contributing to rising drug costs without corresponding clinical benefit.
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The Most Transformative Drugs of the Past 25 Years: A Survey of Physicians

Kesselheim AS, Avorn J - Nature Reviews Drug Discovery

  • Research Publications
| June 2013
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Approximately 180 expert physicians across 15 medical specialties used an iterative Delphi process to identify the most transformative drugs approved over the past 25 years, with effectiveness and superiority over existing alternatives emerging as the primary factors influencing their assessments. The authors argue that establishing consensus on what constitutes transformative drug innovation can better inform strategic and legislative efforts to catalyze pharmaceutical development.
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Crowdsourcing Clinical Trials

Darrow JJ - Minnesota Law Review

  • Research Publications
| June 2013
  • Regulation and Clinical Evidence
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The article identifies a fundamental ethical flaw in pharmaceutical regulation: newly FDA-approved drugs are effectively “tested” on an unknowing general public in the months and years after approval, due to the inherent inability of even the largest preapproval clinical trials to detect rare adverse events. The author proposes a “crowdsourcing” framework to improve post-approval drug surveillance, addressing the gap between the limited safety data available at the time of FDA approval and the full risk profile that only emerges through widespread clinical use.
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Distributions of Industry Payments to Massachusetts Physicians

Kesselheim AS, Robertson CT, Siri K, Batra P, Franklin JM - New England Journal of Medicine

  • Research Publications
| May 2013
  • Regulation and Clinical Evidence
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Analysis of Massachusetts mandatory disclosure data between 2009 and 2011 revealed 32,227 payments totaling $76.7 million to 11,734 physicians, with 25% of all licensed Massachusetts physicians receiving at least 1 payment—led by specialists such as urologists (61%), gastroenterologists (57%), and cardiologists (46%), compared to just 19% of general internists. Compensation for bona fide services accounted for 88% of total expenditures ($67.3 million). Between 2010 and 2011, the number of physicians receiving payments decreased while the average payment increased, likely reflecting the impact of institutional gift bans at major academic medical centers and a state law prohibiting most meals, though the meal ban was subsequently repealed.
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The Medical Device Excise Tax—Over Before It Begins?

Kramer DB, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| May 2013
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors discuss the Affordable Care Act’s 2.3% medical device excise tax and the intense industry lobbying that led to an overwhelming Senate vote for repeal, questioning whether the industry’s claims about job losses and innovation impacts were supported by evidence.
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Drug Company Gifts to Medical Students: The Hidden Curriculum

Kesselheim AS - BMJ

  • Commentary & Opinion
| February 2013
  • Regulation and Clinical Evidence
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The author discusses a study showing that medical school policies restricting pharmaceutical industry gifts to students were associated with decreased prescribing of heavily promoted brand-name drugs years later, suggesting that the “hidden curriculum” of institutional norms around industry relationships has lasting effects on prescribing behavior.
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Variations in Pill Appearance of Antiepileptic Drugs and the Risk of Nonadherence

Kesselheim AS, Misono AS, Shrank WH, Greene JA, Doherty M, Avorn J, Choudhry NK - JAMA Internal Medicine

  • Research Publications
| February 2013
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Changes in the color appearance of antiepileptic drugs significantly increase the risk of medication nonpersistence, with color discordance associated with a 27% increased odds of nonpersistence overall and a 53% increased odds among patients with seizure disorder diagnoses. The findings suggest that current regulatory policy permitting wide variation in the appearance of bioequivalent drugs should be reconsidered to reduce medication interruptions and their associated clinical and financial consequences.
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FDA Regulation of Off-Label Drug Promotion Under Attack

Kesselheim AS, Mello MM, Avorn J - JAMA

  • Commentary & Opinion
| February 2013
  • Regulation and Clinical Evidence
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The Second Circuit’s Caronia decision, which held that the government cannot prosecute pharmaceutical sales representatives for truthful off-label promotion, threatens the FDA’s ability to ensure that drugs are marketed based on adequate evidence and could lead to more unsafe off-label prescribing.
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The Ethics of Intellectual Property Rights in an Era of Globalization

Shah AK, Warsh J, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Winter 2013
  • Innovation Incentives and Competition
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The TRIPS Agreement, which became a condition for WTO membership, required developing countries to adopt pharmaceutical patent protections comparable to developed nations—fundamentally merging the debate over intellectual property with globalization and threatening access to affordable medicines in low- and middle-income countries where patients bear over 70% of health care costs directly. The authors examine the ethical tensions inherent in applying a uniform global intellectual property framework to pharmaceutical products.
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An Exploration of Compulsory Licensing as an Effective Policy Tool for Antiretroviral Drugs in India

Jain D, Darrow JJ - Health Matrix: The Journal of Law-Medicine

  • Research Publications
| January 2013
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Compulsory licensing, a TRIPS-permitted mechanism allowing generic production of patented pharmaceuticals, represents an underutilized policy tool that governments can deploy to balance patent protection with affordable drug access, particularly in developing countries like India facing high HIV disease burden. Drawing on successful precedents in Brazil, Thailand, Canada, and the US, the authors conclude that compulsory licensing is a feasible policy instrument for India to facilitate access to essential medicines within the current patent regime.
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Drug Labels: A Flawed Source of Data for Studying Orphan Drug Approvals

Kesselheim AS, Avorn J - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| December 2012
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors critique a study comparing orphan and non-orphan drug development programs, arguing that using drug labels rather than FDA-designated pivotal trials as data sources introduces methodological flaws because labels contain many non-pivotal studies that obscure meaningful differences in the evidence standards applied to orphan versus non-orphan drugs.
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Risk, Responsibility, and Generic Drugs

Kesselheim AS, Avorn J, Greene JA - New England Journal of Medicine

  • Commentary & Opinion
| November 2012
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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he authors addresses issues of risk and responsibility in the generic drug market, examining how legal and regulatory frameworks assign liability for adverse effects between brand-name and generic drug manufacturers and the implications for patient safety.
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Origins of Medical Innovation: The Case of Coronary Artery Stents

Xu S, Avorn J, Kesselheim AS - Circulation: Cardiovascular Quality and Outcomes

  • Research Publications
| November 2012
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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An analysis of 245 patents related to bare metal coronary stents filed between 1984 and 1994 revealed that the foundational innovations originated from individual physician-inventors within academic medical centers and their associated private companies, with the most-cited patents dominated by entities created by or dependent on these independent academics. Over time, large public companies came to dominate the field, suggesting that policies aimed at fostering transformative medical device innovation would be most effective if targeted at supporting individual inventors during the early stages of technology development.
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User Fees and Beyond—The FDA Safety and Innovation Act of 2012

Kramer DB, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| October 2012
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors discuss the FDA Safety and Innovation Act, which reauthorized FDA user fees and introduced new expedited pathways including the breakthrough therapy designation, noting that while user fees have become essential to FDA operations, the legislation’s emphasis on streamlining approvals raises questions about the balance between speed and evidence requirements.
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The Food and Drug Administration Has the Legal Basis to Restrict Promotion of Flawed Comparative Effectiveness Research

Kesselheim AS, Avorn J - Health Affairs

  • Research Publications
| October 2012
  • Regulation and Clinical Evidence
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The FDA possesses legal authority to restrict pharmaceutical manufacturers’ promotional claims based on flawed observational research that fails to meet the agency’s “substantial evidence” standard. As comparative effectiveness research methods improves, the FDA should develop formal guidance clarifying which high-quality observational studies can satisfy the legal standard of “adequate and well-controlled investigations” for promotional purposes.
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Secondary Patenting of Branded Pharmaceuticals: A Case Study of How Patents on Two HIV Drugs Could Be Extended for Decades

Amin T, Kesselheim AS - Health Affairs

  • Research Publications
| October 2012
  • Innovation Incentives and Competition
  • Price, Value, and Access
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An examination of the patent landscape for the HIV antiretrovirals ritonavir (Norvir) and lopinavir/ritonavir (Kaletra) identified 108 patents—many on secondary features like alternate formulations and methods of administration with questionable inventiveness—that could collectively delay generic competition until at least 2028, 12 years beyond expiration of the base compound patents and 39 years after the first ritonavir patents were filed. The authors argue that increased patent transparency, stricter patentability standards, and expanded opportunities to challenge patents are needed to curb inappropriate market exclusivity extensions and facilitate earlier access to lower-cost generics.
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Insights From a National Conference: “Conflicts of Interest in the Practice of Medicine”

Kesselheim AS, Orentlicher D - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Fall 2012
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors introduce proceedings from a national conference examining conflicts of interest in medicine, framing how financial relationships between physicians, industry, and health systems create tensions between personal interests and patient care responsibilities.
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Effect of Financial Relationships on the Behaviors of Health Care Professionals: A Review of the Evidence

Robertson CT, Rose SL, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2012
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This review synthesizes the evidence on how financial relationships between health care professionals and pharmaceutical or medical device companies affect professional behaviors, including prescribing patterns, clinical decision-making, and research conduct. The authors examine the mechanisms through which industry payments, gifts, meals, and other transfers of value influence physician behavior, providing an evidence base for policies aimed at managing conflicts of interest in health care.
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A Randomized Study of How Physicians Interpret Research Funding Disclosures

Kesselheim AS, Robertson CT, Myers JA, Rose SL, Gillet V, Ross KM, Glynn RJ, Joffe S, Avorn J - New England Journal of Medicine

  • Research Publications
| September 2012
  • Regulation and Clinical Evidence
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In a randomized experiment with 269 board-certified internists, physicians appropriately distinguished among trials of varying methodologic rigor, but disclosure of industry funding independently led them to rate trials as less rigorous, feel less confident in the results, and be roughly half as willing to prescribe the study drug compared to NIH-funded trials. These effects persisted across all levels of actual methodologic quality. These findings suggest that industry sponsorship carries a reputational penalty that may influence how clinical research is translated into practice, regardless of a study’s true scientific merit.
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Changes in Direct-To-Consumer Pharmaceutical Advertising Following Shifts From Prescription-Only to Over-The-Counter Status

Greene JA, Choudhry NK, Kesselheim AS, Brennan TA, Shrank WH - JAMA

  • Research Publications
| September 2012
  • Regulation and Clinical Evidence
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An analysis of 133 advertisements for 4 drugs (loratadine, omeprazole, orlistat, cetirizine) that switched from prescription to OTC status found that after the OTC shift, advertisements more frequently described benefits while the proportion mentioning specific adverse effects or precautions declined, as regulatory oversight shifted from the FDA’s “fair balance” requirement to the FTC’s more permissive “reasonable consumer” standard. These findings suggest that the transition from prescription to OTC status may reduce the quality of risk information provided to consumers in drug advertising.
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Conflict of Interest Reporting By Authors Involved in Promotion of Off-Label Drug Use: An Analysis of Journal Disclosures

Kesselheim AS, Wang B, Studdert DM, Avorn J - PLOS Medicine

  • Research Publications
| August 2012
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 39 physicians and scientists identified as having undisclosed financial relationships with pharmaceutical companies for promoting off-label drug uses, only 15% of their published articles contained adequate disclosure of these relationships, with commentaries showing significantly lower disclosure rates than original research articles. Thse findings indicate that current journal disclosure practices are inadequate, highlighting the need for greater author compliance and journal enforcement of reporting requirements.
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Ethical Considerations in Orphan Drug Approval and Use

Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| August 2012
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The Orphan Drug Act aims to advance therapeutic options for rare disease patients, but orphan drugs typically undergo more limited premarket testing than non-orphan drugs, resulting in greater clinical uncertainty. The authors argue that the ethical principles of justice and beneficence necessitate enhanced informed consent procedures for patients receiving orphan drugs and increased investment in postmarket surveillance and confirmatory testing.
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How Does Medical Device Regulation Perform in the United States and the European Union? A Systematic Review

Kramer DB, Xu S, Kesselheim AS - PLOS Medicine

  • Research Publications
| July 2012
  • Regulation and Clinical Evidence
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This systematic review identified 20 empirical studies evaluating medical device regulation in the US or EU, providing evidence of quality problems in pre-market submissions in the US, providing conflicting views of device safety based largely on recall data, and relaying perceptions of some industry leaders from self-surveys. These findings highlight the need for further research into medical device regulation in both jurisdictions, with existing studies demonstrating the need for policy reforms, including improved US device classication and enhanced post-market oversight in the EU.
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Paying Patients for Their Tissue: The Legacy of Henrietta Lacks

Truog RD, Kesselheim AS, Joffe S - Science

  • Commentary & Opinion
| July 2012
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Prompted by the story of Henrietta Lacks and the HeLa cell line, advocates have urged policymakers to require financial compensation of tissue donors. The authors argue that while the sense of injustice is understandable, establishing a precedent for paying tissue donors requires careful ethical analysis.
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Biomarkers Unbound—The Supreme Court’s Ruling on Diagnostic-Test Patents

Kesselheim AS, Karlawish J - New England Journal of Medicine

  • Commentary & Opinion
| June 2012
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors analyze the Supreme Court’s unanimous ruling in Mayo v. Prometheus that patents cannot cover basic correlations between biomarker levels and clinical outcomes, discussing its implications for the growing field of personalized medicine and the balance between incentivizing biomarker discovery and preserving access to diagnostic methods.
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Regulation of Medical Devices in the United States and European Union

Kramer DB, Xu S, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| March 2012
  • Regulation and Clinical Evidence
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The article compares the US and EU medical device regulatory systems, noting that while the FDA requires demonstration of safety and effectiveness before marketing high-risk devices, with most moderate-risk devices cleared through the 510(k) “substantial equivalence” pathway, the EU system has been characterized as faster but has drawn criticism for conflicts of interest in its evaluation process and high-profile product recalls. As policymakers in both jurisdictions weigh reforms, the authors examine the evidence on each system’s performance, including the trade-offs between earlier patient access to new devices in Europe and more rigorous premarket evaluation in the US.
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Ethical Issues in New Drug Prescribing

Cole LW, Kesselheim JC, Kesselheim AS - Journal of Bioethical Inquiry

  • Research Publications
| March 2012
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This case study examines ethical and legal considerations physicians face when prescribing newly FDA-approved drugs, highlighting the limitations of both the drug approval system and post-approval surveillance mechanisms. The authors argue that physicians have ethical obligations to seek independent information sources, report adverse effects, and inform patients about the incomplete knowledge base surrounding new therapies.
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The Prevalence and Cost of Unapproved Uses of Top-Selling Orphan Drugs

Kesselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J - PLOS ONE

  • Research Publications
| February 2012
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Three of four top-selling orphan drugs studied (lidocaine patch, modafinil, and cinacalcet) were used predominantly for unapproved, non-orphan indications, with prescriptions for these uses increasing at substantially higher rates than approved uses. Spending on off-label uses exceeded 75% for lidocaine patch and modafinil. The authors recommend continued post-approval monitoring of orphan drugs for off-label use, particularly those lacking adequate efficacy evidence.
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Brief of Health Law & Policy Scholars and Prescription Policy Choices in Florida v. HHS

Kesselheim AS - US Supreme Court

  • Policy Interactions
| February 2012
  • Price, Value, and Access
An icon of a bill representing government policy.
The amici argue that the ACA’s Medicaid expansion is a constitutional exercise of Congress’s spending power and builds on a long history of mandatory Medicaid amendments tied to broader health policy goals. They contends that the expansion is not coercive because the federal government funds roughly 95% of its cost, the HHS Secretary retains discretion over enforcement, and several “early adopter” states have voluntarily embraced the expansion ahead of schedule.
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Testimony: Reauthorization of MDUFA: What It Means for Jobs, Innovation, and Patients

Kesselheim AS - 112th Congress, House Committee on Energy and Commerce, Subcommittee on Health

  • Policy Interactions
| February 2012
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
Kesselheim argues against proposals to loosen FDA device approval standards to match the European Union’s faster pathway, noting that EU Notified Bodies generally require only evidence of safety and basic performance rather than clinical benefit, a framework resembling the pre-1962 US drug market. He cited cases like the PIP breast implants, PleuraSeal lung sealant, and Acorn CorCap device, where FDA’s more rigorous standards protected US patients from ineffective or unsafe products, and urged Congress to use MDUFA to strengthen FDA funding and post-market surveillance. Watch his testimony.
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Pharmacoepidemiology and the Law

Kesselheim AS - Pharmacoepidemiology, 5th Edition

  • Research Publications
| January 2012
  • Regulation and Clinical Evidence
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This textbook chapter outlines 3 critical intersections of pharmacoepidemiology and the law—tort law (where product liability lawsuits seek damages from drug manufacturers, with pharmacoepidemiologists often serving as expert witnesses), contract law (governing sponsored research agreements with implications for data access and publication rights), and intellectual property law (where patents may secure ownership of discoveries but can also raise research costs and hinder collaboration).
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Conflict of Interest in Oncology Publications: A Survey of Disclosure Policies and Statements

Kesselheim AS, Lee JL, Avorn J, Servi A, Shrank WH, Choudhry NK - Cancer

  • Research Publications
| January 2012
  • Regulation and Clinical Evidence
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Most oncology journals had conflict-of-interest policies, with 94% requiring financial disclosure and 42% also seeking nonfinancial disclosures. However, only 61% of higher-impact journals consistently published disclosure statements in over 90% of articles, and no nonfinancial conflicts were published in any reviewed article. Only 52% of journals published disclosures for editorials and commentaries. Given these inconsistencies in disclosure practices across oncology journals, standardized, comprehensive conflict-of-interest reporting policies are necessary.
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Meta-Analyses Involving Cross-Over Trials: Methodological Issues

Stedman MR, Curtin F, Elbourne DR, Kesselheim AS, Brookhart MA - International Journal of Epidemiology

  • Research Publications
| December 2011
  • Regulation and Clinical Evidence
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This methodological paper provides a corrected description of the Becker-Balagtas approach for combining results from cross-over trials with binary outcomes alongside parallel-design trials in meta-analyses. The authors present a revised formulation of the marginal odds ratio estimation method and demonstrate its implementation with a worked example comparing brand-name and generic anti-epileptic drugs, providing practical guidance for researchers conducting meta-analyses that include both cross-over and parallel trial designs.
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Full Coverage for Preventive Medications After Myocardial Infarction

Choudhry NK, Avorn J, Glynn RJ, Antman EM, Schneeweiss SG, Toscano M, Reisman L, Fernandes J, Spettell C, Lee JL, Levin R, Brennan TA, Shrank WH - New England Journal of Medicine

  • Research Publications
| December 2011
  • Price, Value, and Access
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In the MI FREEE trial, post-MI patients randomized to full prescription drug coverage (no copayments) for statins, beta-blockers, ACE inhibitors, or ARBs had 4-6% higher adherence rates, significantly fewer total major vascular events, and reduced patient spending without increasing overall health costs compared to usual coverage, though the primary composite outcome did not reach significanc. These findings demonstrate that eliminating copayments for evidence-based post-MI medications can improve adherence and clinical outcomes while maintaining cost neutrality for the health care system.
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False Claims Act Prosecution Did Not Deter Off-Label Drug Use in the Case of Neurontin

Kesselheim AS, Darby D, Studdert DM, Glynn RJ, Levin R, Avorn J - Health Affairs

  • Research Publications
| December 2011
  • Regulation and Clinical Evidence
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Using segmented time-series analysis, the authors found that off-label prescriptions of gabapentin (Neurontin) continued to grow steadily during the federal investigation into the drug’s manufacturer for illegal off-label promotion, only declining after the case was settled. This trend suggests that False Claims Act enforcement actions may not substanially deter off-label prescribing until after settlement, and the authors recommend that such actions be supported with additional enforcement resources and steeper financial penalties for off-label promotion.
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Clinical Decision Support Systems Could Be Modified to Reduce ‘Alert Fatigue’ While Still Minimizing the Risk of Litigation

Kesselheim AS, Cresswell K, Phansalkar S, Bates DW, Sheikh A - Health Affairs

  • Research Publications
| December 2011
  • Regulation and Clinical Evidence
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Clinical decision support systems can reduce prescribing errors through real-time alerts, but excessive warnings contribute to “alert fatigue” that leads physicians to ignore even critical alerts, while system vendors resist allowing customization due to liability concerns. However, analysis of product liability principles suggests that more tailored, parsimonious alert systems could reduce fatigue without significant litigation risk, and the authors recommend stronger government regulation and international practice guidelines to further limit liability and improve system effectiveness.
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“Pay for Delay” Settlements of Disputes Over Pharmaceutical Patents

Kesselheim AS, Murtagh L, Mello MM - New England Journal of Medicine

  • Research Publications
| October 2011
  • Innovation Incentives and Competition
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“Pay for delay” settlements have become increasingly common, with one example involving $40 million in annual payments to delay generic diltiazem. The authors review the history and public health implications of these settlements, which the FTC has sought to make presumptively illegal, arguing that they delay generic competition and cost consumers billions while both brand-name and generic manufacturers profit at the expense of patients and payers.
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The NIH Translational Research Center Might Trade Public Risk for Private Reward

Avorn J, Kesselheim AS - Nature Medicine

  • Commentary & Opinion
| October 2011
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The new National Center for Advancing Translational Sciences aims to convert biological research findings into therapeutic products, but this model risks translatning public investment of risky research into private pharmaceutical profits. If taxpayer-funded research culminates in new breakthrough therpaies, public entities should share in the resulting economic benefits.
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Who Owns Federally Funded Research? The Supreme Court and the Bayh-Dole Act

Kesselheim AS, Rajkumar R - New England Journal of Medicine

  • Commentary & Opinion
| September 2011
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The article examines a recent Supreme Court decision concerning contracts between academic researchers and private companies in federally funded research, highlighting the tension between collaboration for medical innovation and the public interest in such agreements. The decision addresses fundamental questions about ownership and control of federally funded research results under the Bayh-Dole Act framework.
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Conflict of Interest Disclosure in Early Education of Medical Students

Austad KE, Kesselheim AS - JAMA

  • Commentary & Opinion
| September 2011
  • Regulation and Clinical Evidence
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Conflict-of-interest disclosure policies should extend to preclinical medical education, not just CME lectures, because early exposure to disclosure norms helps shape students’ critical evaluation skills and professional development. The authors contend that the “hidden curriculum” of institutional practices around industry relationships influences students long before they begin prescribing.
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The Backlash Against Bioequivalence and the Interchangeability of Brand-Name and Generic Drugs

Kesselheim AS - Canadian Medical Association Journal

  • Commentary & Opinion
| September 2011
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The author addresses skepticism about generic drug interchangeability, arguing that while case reports of adverse outcomes from generic substitution have fueled concerns, particularly for narrow therapeutic index drugs, the overall evidence strongly supports the bioequivalence framework, and that opposition is often driven by anecdote rather than systematic data.
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An Empirical Review of Major Legislation Affecting Drug Development: Past Experiences, Effects, and Unintended Consequences

Kesselheim AS - Milbank Quarterly

  • Research Publications
| September 2011
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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This empirical review of four major US legislative developments affecting prescription drugs (Bayh-Dole Act, Orphan Drug Act, Hatch-Waxman Act, and pediatric exclusivity provisions) finds that while market exclusivity incentives successfully attract interest in drug development, the evidence supporting their success relies primarily on descriptive rather than rigorous comparative analyses. The authors recommend implementing reevaluation mechanisms and tying incentives to public health outcomes to mitigate unintended consequences of these programs.
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Reputation and Precedent in the Bevacizumab Decision

Carpenter D, Kesselheim AS, Joffe S - New England Journal of Medicine

  • Commentary & Opinion
| July 2011
  • Regulation and Clinical Evidence
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The authors discuss the FDA’s decision to withdraw bevacizumab’s (Avastin) accelerated approval for metastatic breast cancer after confirmatory trials failed to show the expected benefit, arguing that the decision was appropriate and consistent with the regulatory framework for accelerated approval.
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Why Do the Same Drugs Look Different? Pills, Trade Dress, and Public Health

Greene JA, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| July 2011
  • Regulation and Clinical Evidence
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Trade-dress protections in trademark law grant drug manufacturers legal exclusivity over pill characteristics such as size, shape, and color, which the authors identify as creating potential adverse public health effects. The authors propose strategies to mitigate these negative consequences of trade-dress protection in the pharmaceutical industry.
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Characteristics of Clinical Trials to Support Approval of Orphan vs Nonorphan Drugs for Cancer

Kesselheim AS - JAMA

  • Research Publications
| June 2011
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Orphan cancer drugs approved between 2004 and 2010 had pivotal trials with significantly smaller sample sizes compared to trials for non-orphan drugs, were less likely to be randomized or double-blinded, and more frequently reported serious adverse events. These findings suggest that the regulatory pathway for orphan drugs relies on less rigorous trial designs and surrogate endpoints, raising questions about the adequacy of evidence supporting their approval relative to nonorphan cancer drugs.
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Off-Label Drug Use and Promotion: Balancing Public Health Goals and Commercial Speech

Kesselheim AS - American Journal of Law & Medicine

  • Research Publications
| June 2011
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Off-label drug use accounts for approximately 21% of prescriptions overall, yet 73% of off-label uses lack evidence of clinical efficacy. The FDA’s blanket prohibition on manufacturer promotion of these unapproved uses faces growing legal challenge under the commercial speech doctrine, as courts have increasingly applied the Central Hudson test to side with manufacturers’ First Amendment claims. The author proposes a “scaled oversight” framework that would replace the current all-or-nothing approach by categorizing off-label uses into subtypes (genotypic, phenotypic, and dosing variants) and providing expedited FDA review for biologically plausible extensions while maintaining stricter requirements for more substantial departures from approved uses.
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Medical Students’ Exposure to and Attitudes About the Pharmaceutical Industry: A Systematic Review

Austad KE, Avorn J, Kesselheim AS - PLOS Medicine

  • Research Publications
| May 2011
  • Regulation and Clinical Evidence
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This systematic review of 32 studies found that 40%-100% of medical students are exposed to pharmaceutical industry marketing, with 13%-69% believing such gifts influence prescribing, and Substantial pharmaceutical marketing exposure during medical education is associated with positive attitudes toward these interactions, and the authors recommend further research into the factors that shape students’ attitudes of the pharmaceutical industry during their training.
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Safety, Supply, and Suits—Litigation and the Vaccine Industry

Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| April 2011
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The US Supreme Court’s 2011 ruling in Bruesewitz v. Wyeth granted vaccine manufacturers immunity from design defect lawsuits, a decision supported by physicians and public health organizations who argue it ensures vaccine availability and appropriate use, while critics raise concerns about patient rights and accountability. The case highlights the tension between protecting vaccine supply and addressing the market position of vaccines as essential public health products subject to different liability standards than other consumer goods.
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A Hemorrhage of Off-Label Use

Avorn J, Kesselheim AS - Annals of Internal Medicine

  • Commentary & Opinion
| April 2011
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors highlight the pervasive problem of off-label drug prescribing unsupported by evidence, using recombinant factor VIIa as a case study. They argue that the gap between FDA approval requirements and the freedom physicians have to prescribe off-label creates significant safety and cost concerns.
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Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints

Kesselheim AS, Mello MM, Studdert DM - PLOS Medicine

  • Research Publications
| April 2011
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Analysis of 41 whistleblower complaints from US federal fraud cases revealed that pharmaceutical off-label marketing schemes most commonly sought to expand drug use to unapproved diseases (85%), unapproved disease subtypes (54%), and unapproved doses (34%), relying heavily on prescriber-targeted practices such as financial incentives to physicians (85%) and self-serving literature presentations (76%). The findings suggest that off-label marketing pervades multiple areas of the health care system, with the most prevalent practices also being the hardest to regulate through external oversight.
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Innovation and the Orphan Drug Act, 1983-2009: Regulatory and Clinical Characteristics of Approved Orphan Drugs

Kesselheim AS - Rare Diseases and Orphan Products: Accelerating Research and Development

  • Research Publications
| April 2011
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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This appendix to a National Academies report reviews the regulatory and clinical characteristics of 279 drugs approved under the Orphan Drug Act from 1983 to 2009, finding that most were approved for oncology-related conditions, roughly a third were truly novel molecular entities, and many were approved on the basis of small, sometimes unblinded trials using surrogate endpoints. The analysis also found that orphan drug designation often occurred late in clinical development and that a substantial share of approved orphan drugs targeted conditions for which alternative therapies already existed.
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The Consequences of Requesting “Dispense as Written”

Shrank WH, Liberman JN, Fischer MA, Avorn J, Kilabuk E, Chang A, Kesselheim AS, Brennan TA, Choudhry NK - American Journal of Medicine

  • Research Publications
| April 2011
  • Innovation Incentives and Competition
  • Price, Value, and Access
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An analysis of 5.6 million prescriptions found that 2.7% were designated dispense as written (DAW) by physicians and 2.0% by patients, with significant variation by medication class, patient and physician age, geographic region, and specialty. Specialists had 78.5% greater odds of requesting DAW than generalists. Both physician and patient DAW requests were associated with significantly higher odds of patients not filling their prescriptions, suggesting that reducing DAW rates could both lower costs and improve medication adherence.
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Improving Antibiotic Markets for Long-Term Sustainability

Kesselheim AS, Outterson K - Yale Journal of Health Policy, Law and Ethics

  • Research Publications
| April 2011
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors examine the challenges facing antibiotic markets, where the unique dynamics of antimicrobial resistance combined with the need for stewardship that limits the volume of new antibiotic prescriptions create commercial disincentives for development that standard market-based approaches fail to address. They propose reforms to improve antibiotic market sustainability through mechanisms that delink revenues from sales volume, ensuring adequate returns for innovative products while preserving their long-term effectiveness through appropriate use.
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Ethical and Legal Views Regarding Deactivation of Cardiac Implantable Electrical Devices in Patients with Hypertrophic Cardiomyopathy

Kramer DB, Kesselheim AS, Salberg L, Brock DW, Maisel WH - American Journal of Cardiology

  • Research Publications
| April 2011
  • Regulation and Clinical Evidence
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Among 546 hypertrophic cardiomyopathy patients surveyed, only 46% had completed advance directives and 51% had healthcare proxies, with Cardiac Implantable Electrical Devices (CIEDs) rarely addressed in either document. Additionally, 29% of respondents characterized pacemaker deactivation as euthanasia and over 50% expressed uncertainty about the legality of device deactivation. The authors conclude that patients with CIEDs require improved advance care planning and education regarding the ethical and legal options for managing these devices at end of life.
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Covert Pharmaceutical Promotion in Free Medical Journals

Kesselheim AS - Canadian Medical Association Journal

  • Commentary & Opinion
| March 2011
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The author discusses the role of free “controlled-circulation” medical journals, funded entirely by advertising revenue and distributed without subscription, as potential vehicles for covert pharmaceutical promotion, arguing that their business model creates vulnerability to biased content that may inappropriately influence prescribing behavior.
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Where Cost, Medical Necessity, and Morality Meet: Should US Government Insurance Programs Pay for Erectile Dysfunction Drugs?

Polinski JM, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| January 2011
  • Price, Value, and Access
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The authors discuss whether Medicare and Medicaid should reimburse phosphodiesterase inhibitor drugs for erectile dysfunction, which cost over $1 billion annually worldwide, by analyzing the justifications and arguments for and against coverage as case studies. They conclude that coverage decisions should be based primarily on clinical effectiveness and cost considerations rather than moral attitudes toward sexual performance.
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Pharmaceutical Marketing and the New Social Media

Greene JA, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| November 2010
  • Regulation and Clinical Evidence
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Pharmaceutical companies are using social media platforms like Facebook and Twitter for drug marketing, raising concerns that existing FDA regulations governing drug promotion are inadequate to address the unique challenges of digital and social media marketing, including user-generated content and the blurring of promotional and educational messaging.
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Op-Ed: Superbugs Call for Super Changes in Drug-Sale Rules

Kesselheim AS, Outterson K - Boston Globe

  • Commentary & Opinion
| November 2010
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The traditional pharmaceutical business model—which incentivizes companies to maximize antibiotic sales before patents expire—accelerates the development of drug-resistant infections. The authors propose restructuring antibiotic economics by pricing new antibiotics higher to reflect their true societal value, but conditioning continued marketing exclusivity on meeting government-set conservation and resistance targets, thereby aligning manufacturers’ financial incentives with public health goals of antibiotic stewardship. They also advocate for a Strategic Antibiotic Reserve to preserve the most valuable new antibiotics for future use.
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Using Market-Exclusivity Incentives to Promote Pharmaceutical Innovation

Kesselheim AS - New England Journal of Medicine

  • Research Publications
| November 2010
  • Innovation Incentives and Competition
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The author examines how federal laws offering extended market exclusivity have been used to incentivize pharmaceutical innovation, while identifying the unintended consequences of these policy mechanisms. More carefully designed regulations are necessary to effectively balance the goal of promoting drug development with the need for affordable, accessible medications.
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Ethical and Legal Views of Physicians Regarding Deactivation of Cardiac Implantable Electrical Devices: A Quantitative Assessment

Kramer DB, Kesselheim AS, Brock DW, Maisel WH - Heart Rhythm

  • Research Publications
| November 2010
  • Regulation and Clinical Evidence
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A survey of 185 internal medicine physicians found they were significantly less experienced with and less comfortable discussing withdrawal of pacemakers and defibrillators compared to other life-sustaining therapies. Only 34% had participated in device withdrawal versus 86% for mechanical ventilation and 74% for feeding tubes, and many mischaracterized the practice, with 19% labeling pacemaker deactivation as physician-assisted suicide and 9% as euthanasia. Compounding these gaps, only 65% correctly identified the legal status of euthanasia and just 20% accurately reported the legal status of physician-assisted suicide in the US, underscoring a significant need for education on end-of-life device management.
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Designing Comparative Effectiveness Research on Prescription Drugs: Lessons From the Clinical Trial Literature

Chokshi DA, Avorn J, Kesselheim AS - Health Affairs

  • Research Publications
| October 2010
  • Regulation and Clinical Evidence
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An analysis of prior comparative effectiveness research identified key methodological challenges in 3 areas that have limited the clinical applicability of such studies: choice of comparison treatments, study time frames, and generalizability of results. The authors recommend strategies to improve future research, including the use of surrogate endpoints that meet specific validity thresholds, to maximize the potential of comparative effectiveness studies to improve patient outcomes.
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Questions About the 10 X ’20 Initiative

Outterson K, Powers JH, Gould I, Kesselheim AS - Clinical Infectious Diseases

  • Commentary & Opinion
| September 2010
  • Regulation and Clinical Evidence
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The authors question the feasibility and cost-effectiveness of the proposal to develop 10 new antibiotics by 2020, arguing that without reforms to clinical trial design and post-approval stewardship, simply incentivizing new antibiotic development could cost billions while failing to address resistance.
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Fighting Antibiotic Resistance: Marrying New Financial Incentives to Meeting Public Health Goals

Kesselheim AS, Outterson K - Health Affairs

  • Research Publications
| September 2010
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Traditional financial incentives for antibiotic development, such as patent extensions, conflict with the critical need to reduce unnecessary antibiotic prescriptions and may actually increase inappropriate use. The authors recommend a two-pronged strategy that ties increased reimbursement to both appropriate, evidence-based antibiotic use and achievement of specific public health goals, including reducing disease burden while limiting risk of antimicrobial resistance.
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State Generic Substitution Laws Can Lower Drug Outlays Under Medicaid

Shrank WH, Choudhry NK, Agnew-Blais J, Federman AD, Liberman JN, Liu J, Kesselheim AS, Brookhart MA, Fischer MA - Health Affairs

  • Research Publications
| July 2010
  • Innovation Incentives and Competition
  • Price, Value, and Access
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States with generic substitution policies requiring patient consent prior to switching from brand-name to generic medications experienced 25 percent lower substitution rates, while eliminating such consent requirements could save state Medicaid programs more than $100 million in coverage for three major medications approaching patent expiration. Policymakers should weigh concerns of patient choice against the substantial cost savings that could be achieved by removing consent requirements for generic substitution.
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Managing Financial and Nonfinancial Conflicts of Interest in Healthcare Delivery

Kesselheim AS, Maisel WH - American Journal of Therapeutics

  • Commentary & Opinion
| July 2010
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors identify various types of financial and nonfinancial conflicts of interest that arise in healthcare delivery and examine policy options designed to address these conflicts while balancing transparency, patient safety, and the benefits of industry-provider relationships. Effective conflicts of interest policies must account for both the need to protect patients through disclosure mechanisms and the recognition that some industry relationships are important to medical product development.
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Incentives for Drug Development—The Curious Case of Colchicine

Kesselheim AS, Solomon DH - New England Journal of Medicine

  • Commentary & Opinion
| June 2010
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors describe how colchicine—a 3,000-year-old gout treatment that had never been formally FDA-approved—received market exclusivity after a manufacturer conducted modest confirmatory studies, leading to dramatic price increases that paradoxically punished patients who had been using the drug safely for decades.
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Permitting Product Liability Litigation for FDA-Approved Drugs and Devices Promotes Patient Safety

Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| June 2010
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The author analyzes the Supreme Court’s contrasting rulings on federal preemption for drugs (Wyeth v. Levine) versus devices (Riegel v. Medtronic), arguing that allowing product liability litigation for FDA-approved products serves important public health functions by uncovering safety data, correcting manufacturer behavior, and complementing the FDA’s limited post-market surveillance authority.
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Gene Patenting—Is the Pendulum Swinging Back?

Kesselheim AS, Mello MM - New England Journal of Medicine

  • Commentary & Opinion
| May 2010
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors discuss the evolving legal landscape around gene patenting, examining a district court ruling that challenged the patentability of human genes and analyzing whether this represented a shift in the courts’ approach to intellectual property protections for genetic discoveries.
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Whistle-Blowers’ Experiences in Fraud Litigation Against Pharmaceutical Companies

Kesselheim AS, Studdert DM, Mello MM - New England Journal of Medicine

  • Research Publications
| May 2010
  • Regulation and Clinical Evidence
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Whistle-blowers who initiated successful qui tam cases against pharmaceutical companies for health care fraud experienced substantial personal hardships throughout litigation that averaged 5 years in duration, despite receiving a median settlement of $3 million. The findings suggest that while financial compensation is substantial, the personal costs of whistleblowing in pharmaceutical fraud cases warrant consideration in future policy discussions on whistleblower protections.
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Seizure Outcomes Following the Use of Generic Versus Brand-Name Antiepileptic Drugs: A Systematic Review and Meta-Analysis

Kesselheim AS, Stedman MR, Bubrick EJ, Gagne JJ, Misono AS, Lee JL, Brookhart MA, Avorn J, Shrank WH - Drugs

  • Research Publications
| March 2010
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
A meta-analysis of seven randomized controlled trials found no significant difference in seizure control between patients taking brand-name antiepileptic drugs and those taking generic alternatives, though observational studies suggested possible utilization changes were attributable to patient or physician concerns about generic effectiveness. Physicians should consider intensive monitoring of high-risk patients when switching antiepileptic drugs, but the available evidence does not support the superiority of brand-name formulations over bioequivalent generics.
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The Supreme Court, Process Patents, and Medical Innovation

Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| December 2009
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The author discusses the implications of the Supreme Court’s decision in Bilski v. Kappos for process patents in the pharmaceutical context, examining how patent law intersects with medical innovation and drug development policy.
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Balancing Innovation, Access, and Profits—Market Exclusivity for Biologics

Engelberg AB, Kesselheim AS, Avorn J - New England Journal of Medicine

  • Commentary & Opinion
| November 2009
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors argue that proposed legislation granting 12 years of market exclusivity for biologic drugs—far longer than the 5 years provided for small-molecule drugs under the Hatch-Waxman Act—is excessive and would delay competition from biosimilar products while generating substantial costs for patients and the healthcare system.
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Using Patent Data to Assess the Value of Pharmaceutical Innovation

Kesselheim AS, Avorn J - Journal of Law, Medicine & Ethics

  • Research Publications
| Summer 2009
  • Innovation Incentives and Competition
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Despite the pharmaceutical industry’s claims that its research is primarily responsible for new medicines, an analysis of drug innovation found that while industry generates a greater volume of drug-related patents, those originating from non-profit research institutions appear to hold greater importance, underscoring the significant role of publicly funded research in driving drug development. This finding emerged amid concerns about declining FDA approvals, which fell to just 22 new molecular entities and biologics in 2007 (the lowest in 24 years), even as industry revenues continued to rise and regulatory review times remained stable.
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Comments to the FDA Transparency Task Force

Coukell A, Avorn J, Kesselheim AS, Nissen S, Psaty BM, Ross JS, Turner EH, Dickersin K, Caplan AL, Mann H, Maschke M, Pew Prescription Project - Food and Drug Administration (FDA)

  • Policy Interactions
| June 2009
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The FDA should adopt a presumption that safety and efficacy data submitted in drug applications should be made publicly available at the earliest possible time, including clinical study reports and FDA reviewer analyses, to enable independent scientific evaluation and strengthen the quality of agency decisions.
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Priority Review Vouchers: An Inefficient and Dangerous Way to Promote Neglected-Disease Drug Development

Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| June 2009
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The priority review voucher program—designed to incentivize development of neglected-disease drugs by rewarding manufacturers with expedited FDA review for a subsequent product—is cost-ineffective, unlikely to yield meaningful results, and potentially dangerous because it accelerates review of drugs that may not warrant expedited treatment.
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Testimony: Making Health Care Work for American Families: Saving Money, Saving Lives

Avorn J - 111th Congress, House Committee on Energy and Commerce, Subcommittee on Health

  • Policy Interactions
| April 2009
  • Regulation and Clinical Evidence
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Avorn argues that physicians and patients lack the comparative information needed to choose among treatments because FDA approval only requires a drug to beat placebo, not to demonstrate superiority over existing alternatives, and manufacturers have the incentive to suppress unfavorable findings. He calls for government-funded comparative effectiveness research as a public good and proposes pairing it with academic detailing, citing programs he established in Pennsylvania, Massachusetts, and DC.
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The Supreme Court, Preemption, and Malpractice Liability

Kesselheim AS, Studdert DM - New England Journal of Medicine

  • Commentary & Opinion
| February 2009
  • Regulation and Clinical Evidence
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The authors outline the Supreme Court’s ruling in Wyeth v. Levine, examining whether FDA approval of a drug’s labeling should preempt state product liability lawsuits, and discussing the implications for patient safety and manufacturer accountability.
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How Medicare Could Get Better Prices on Prescription Drugs

Outterson K, Kesselheim AS - Health Affairs

  • Research Publications
| January 2009
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors examine alternative policy mechanisms to reduce Medicare prescription drug costs beyond direct government price negotiation, including value-based pricing, generic substitution expansion, formulary diversity, drug importation, and limited antitrust waivers. These alternative approaches could potentially reduce federal spending on Part D drugs without requiring changes to the current noninterference provision that restricts Medicare’s negotiating authority.
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Expert Review of Drug Patent Applications: Improving Health in the Developing World

Amin T, Rajkumar R, Radhakrishnan P, Kesselheim AS - Health Affairs

  • Research Publications
| January 2009
  • Innovation Incentives and Competition
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As developing countries implement pharmaceutical patent laws required by the WTO’s TRIPS agreement, engaging outside experts in the patent review process is critical to prevent the granting of unmerited patents that can sustain high prices for essential medicines, as demonstrated by case studies including the antiretroviral tenofovir disoproxil fumarate. The authors argue that patent review systems in resource-poor countries require information-sharing among developing nations and active consultation with local public health authorities to balance legitimate intellectual property protection with access to affordable drugs.
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Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease: A Systematic Review and Meta-Analysis

Kesselheim AS - JAMA

  • Research Publications
| December 2008
  • Regulation and Clinical Evidence
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A systematic review and meta-analysis of 47 articles found clinical equivalence between generic and brand-name cardiovascular drugs across multiple drug classes, indicating no superiority of brand-name drugs. The findings support the clinical interchangeability of generic and brand-name cardiovascular medications, suggesting that generic drugs can be safely used to reduce prescription drug spending without compromising clinical outcomes.
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Drug Development for Neglected Diseases—The Trouble with FDA Review Vouchers

Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| November 2008
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The FDA’s priority review voucher program provides expedited review to companies that develop drugs for neglected tropical diseases (NTDs), but this mechanism is an inefficient and potentially dangerous approach to incentivizing research in this area. The program’s current design fails to adequately address the underlying challenges in NTD drug development and may pose risks to the integrity of the FDA’s review process.
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Whistleblower-Initiated Enforcement Actions Against Health Care Fraud and Abuse in the United States, 1996 to 2005

Kesselheim AS, Studdert DM - Annals of Internal Medicine

  • Research Publications
| September 2008
  • Regulation and Clinical Evidence
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Between 1996 and 2005, 379 unsealed federal qui tam cases recovered $9.3 billion in health care fraud settlements, with whistleblowers receiving over $1.0 billion and pharmaceutical companies accounting for disproportionately large recoveries ($3.6 billion across 13 cases). The findings demonstrate that whistleblower-initiated enforcement actions are a critical mechanism for detecting and prosecuting health care fraud.
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Brief of Daniel Carpenter, Aaron Kesselheim, Jerry Avorn, Marc Law, and Daniel Polsky in Wyeth v. Levine

Carpenter DP, Kesselheim AS, Avorn J, Law MT, Polsky D - US Supreme Court

  • Policy Interactions
| August 2008
  • Regulation and Clinical Evidence
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The amici argue that state failure-to-warn litigation plays a critical role in promoting drug safety by supplementing the FDA’s limited post-market surveillance capabilities, deterring manufacturers from downplaying safety risks, and facilitating the diffusion of new information about drug effects. They rebuts petitioner’s claims that the FDA is overly cautious in drug labeling, contending instead that empirical evidence shows the FDA faces significant pressures for faster approvals and that state tort liability complements, rather than distorts, the federal regulatory regime.
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Think Globally, Prescribe Locally: How Rational Pharmaceutical Policy in the U.S. Can Improve Global Access to Essential Medicines

Kesselheim AS - American Journal of Law & Medicine

  • Commentary & Opinion
| June 2008
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Global disparities in access to essential medicines stem from multiple factors including high product costs, inadequate government and aid agency cooperation, rigid intellectual property protections, and weak local health leadership, while pharmaceutical innovation has disproportionately focused on developed country health problems. The US can help address these disparities by working with international organizations like the WHO and Médecins Sans Frontières to strengthen pharmaceutical delivery systems in low- and middle-income countries.
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Testimony: Should FDA Drug and Medical Device Regulation Bar State Liability Claims

Kesselheim AS - 110th Congress, House Committee on Oversight and Government Reform

  • Policy Interactions
| May 2008
  • Regulation and Clinical Evidence
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Kesselheim argues against federal preemption of failure-to-warn lawsuits against drug manufacturers, explaining that FDA approval cannot fully certify ongoing drug safety and that manufacturers face inherent conflicts of interest in collecting and reporting post-market safety data. Citing Vioxx and Baycol as examples where manufacturers misrepresented safety findings and delayed reporting adverse signals, he contends that litigation plays an essential oversight role by bringing data to light, deterring improper conduct, and revealing gaps in FDA regulation. Watch his testimony.
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Pharmaceutical Promotion to Physicians and First Amendment Rights

Kesselheim AS, Avorn J - New England Journal of Medicine

  • Research Publications
| April 2008
  • Regulation and Clinical Evidence
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Legal restrictions on off-label drug promotion, which are being challenged as First Amendment violations, are justified because pharmaceutical promotion presents unique public health concerns that distinguish it from other commercial speech. Courts should permit more stringent regulation of pharmaceutical promotion despite First Amendment protections for commercial speech.
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The International Pharmaceutical Market as a Source of Low-Cost Prescription Drugs for U.S. Patients

Kesselheim AS, Choudhry NK - Annals of Internal Medicine

  • Research Publications
| April 2008
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors discuss the feasability of US importation of prescription drugs from foreign markets. While individual importation of essential medicines from certain regulated international markets may be reasonable, they recommend that the most effective domestic strategy for reducing prescription drug costs is increased use of available generic drugs rather than large-scale importation of branded products.
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Rethinking Global Access to Vaccines

Chokshi DA, Kesselheim AS - BMJ

  • Commentary & Opinion
| April 2008
  • Price, Value, and Access
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The authors challenge three common arguments used to explain inadequate vaccine access in low-income countries—the primacy of infrastructure, insufficient funding, and the need for prior approval in wealthy nations—arguing that each can be overcome with targeted policy interventions. They contend that vaccination programs can themselves strengthen health infrastructure and that mechanisms like advance market commitments and tiered pricing can address funding and access gaps.
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Testimony: Under the Influence: Can We Provide Doctors an Alternative to Biased Drug Reviews?

Avorn J - 110th Congress, Senate Special Committee on Aging

  • Policy Interactions
| March 2008
  • Regulation and Clinical Evidence
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Avorn describes how pharmaceutical sales representatives dominate physicians’ drug information environment, driving prescribing toward heavily promoted and expensive products rather than the safest or most cost-effective options, as seen with Vioxx, Avandia, and Vytorin. He advocates for academic detailing as an alternative, citing randomized trial evidence and analysis of Pennsylvania’s PACE program showing that such programs improve prescribing and save roughly $2 for every $1 invested. Watch his testimony.
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Scientific and Legal Viability of Follow-On Protein Drugs

Dudzinski DM, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| February 2008
  • Regulation and Clinical Evidence
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With recombinant protein drugs (biologics) costing $15,000-$150,000 per year and patents expiring on products representing over $15 billion in annual costs, no general mechanism existed under US federal law for approving “follow-on” protein products, unlike the established pathway for small-molecule generics, allowing manufacturers to sustain high prices even after patent expiration. The authors evaluate the scientific feasibility and policy considerations for creating a follow-on biologics approval pathway, noting that alternative versions could offer savings of at least 10-30% while maintaining high standards of safety.
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Market-Based Licensing for HPV Vaccines in Developing Countries

Outterson K, Kesselheim AS - Health Affairs

  • Research Publications
| January 2008
  • Innovation Incentives and Competition
  • Price, Value, and Access
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While HPV vaccines hold great promise for preventing cervical cancer, 93% of related mortality occurs in low- and middle-income countries where high costs limit access, and existing mechanisms like differential pricing and advance market commitments have had only partial success. The authors propose a new licensing model that would leverage generic competition to lower prices in these countries while still ensuring pharmaceutical manufacturers receive appropriate returns on their research and development investments.
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Patent Law and Policy

Kesselheim AS, Avorn J - Macrosocial Determinants of Population Health

  • Commentary & Opinion
| September 2007
  • Innovation Incentives and Competition
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This book chapter examines the intersection of patent law and public health, analyzing how patents affect health care costs, access to therapeutics, medical practice, and the direction of medical research. The authors propose a range of regulatory, legislative, and market-based reforms to better balance the promotion of innovation with the protection of public health.
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The Variability and Quality of Medication Container Labels

Shrank WH, Agnew-Blais J, Choudhry NK, Wolf MS, Kesselheim AS, Avorn J, Shekelle P - Archives of Internal Medicine

  • Research Publications
| September 2007
  • Regulation and Clinical Evidence
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This quantitative study of 85 medication container labels from pharmacies across four cities found that label formatting prioritizes pharmacy identification over medication instructions and warnings, with substantial variability in warning and instruction stickers across pharmacy types. The authors conclude that current labeling practices inadequately emphasize patient safety information and recommend reformatting labels to prioritize use instructions and warnings while standardizing sticker content across pharmacies.
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Intellectual Property Policy in the Pharmaceutical Sciences: The Effect of Inappropriate Patents and Market Exclusivity Extensions on the Health Care System

Kesselheim AS - AAPS Journal

  • Research Publications
| September 2007
  • Innovation Incentives and Competition
  • Price, Value, and Access
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While patents promote pharmaceutical innovation, inappropriate patents that stretch statutory requirements and legal extensions of market exclusivity create monopolistic control that limits patient options, increases healthcare costs, and hinders collaborative research. Government and market-based interventions are necessary to develop more equitable patent policies that balance innovation incentives with broader dissemination of ideas and more affordable healthcare delivery.
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Confidentiality Laws and Secrecy in Medical Research: Improving Public Access to Data on Drug Safety

Kesselheim AS, Mello MM - Health Affairs

  • Research Publications
| March 2007
  • Regulation and Clinical Evidence
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Pharmaceutical manufacturers classify clinical trial results as confidential trade secrets even after FDA submission, and courts have limited Freedom of Information Act access to this data, yet cases of approved drugs later found to have serious side effects demonstrate the critical need for complete safety information disclosure. The authors recommend regulatory and legislative policy changes to how the FDA manages confidential information in order to enhance public understanding of prescription drug risks.
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The Role of Litigation in Defining Drug Risks

Kesselheim AS, Avorn J - JAMA

  • Commentary & Opinion
| January 2007
  • Regulation and Clinical Evidence
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Product liability litigation plays a valuable role in the drug safety system by uncovering previously unavailable data about adverse effects through the discovery process, filling gaps left by the FDA’s limited post-market surveillance authority and correcting misleading manufacturer communications about risks and benefits.
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Medical-Process Patents—Monopolizing the Delivery of Health Care

Kesselheim AS, Mello MM - New England Journal of Medicine

  • Research Publications
| November 2006
  • Innovation Incentives and Competition
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Medical-process patents—which claim proprietary rights over methods of diagnosis or treatment, such as a patent on diagnosing vitamin deficiency based on homocysteine levels at issue in the Supreme Court case LabCorp v. Metabolite Laboratories—threaten to complicate medical practice, increase costs, and restrict access to procedures, with the AMA declaring that they compromise patient access. The authors examine the growing controversy over medical-process patents, noting that while US law allows them unlike nearly 80 other countries, Congress curtailed enforcement consequences for physicians in 1996, and the LabCorp case highlighted ongoing tensions between intellectual property rights and the delivery of health care.
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Extensions of Intellectual Property Rights and Delayed Adoption of Generic Drugs: Effects on Medicaid Spending

Kesselheim AS, Fischer MA, Avorn J - Health Affairs

  • Research Publications
| November 2006
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Extensions of intellectual property rights, elevated generic drug prices, and low substitution rates delayed generic adoption by an average of twenty-six months for amoxicillin/clavulanate, metformin, and omeprazole, costing Medicaid $1.5 billion between 2000 and 2004. Policymakers should consider reforms to intellectual property protections and strategies to accelerate generic substitution to reduce unnecessary Medicaid expenditures on prescription drugs.
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The Rise and Fall of Natrecor for Congestive Heart Failure: Implications for Drug Policy

Kesselheim AS, Fischer MA, Avorn J - Health Affairs

  • Research Publications
| July 2006
  • Regulation and Clinical Evidence
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Using nesiritide (Natrecor) for congestive heart failure as a case study, this article examines how FDA approval standards, pharmaceutical marketing practices, and physicians’ prescribing decisions can shape the risk-benefit profile of widely used drugs. The authors draw policy lessons from the Natrecor experience and propose reforms to drug approval, postmarketing surveillance, and drug utilization to better protect patient safety.
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Biomedical Patents and the Public’s Health: Is There a Role for Eminent Domain?

Kesselheim AS, Avorn J - JAMA

  • Commentary & Opinion
| January 2006
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors explore whether the legal concept of eminent domain could be applied to biomedical patents when restrictive patent management threatens public health, citing historical examples including wartime vitamin D patents, ciprofloxacin during the anthrax scare, and HIV drug pricing.
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University-Based Science and Biotechnology Products: Defining the Boundaries of Intellectual Property

Kesselheim AS, Avorn J - JAMA

  • Research Publications
| February 2005
  • Innovation Incentives and Competition
  • Price, Value, and Access
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University-based biomedical innovation relies on patents to allocate ownership and control, but excessive upstream patenting of genes and molecular targets can hinder follow-on research through costly cross-licensing, while limiting such patents risks allowing private firms to commercialize publicly funded discoveries without compensating academic innovators. Drawing on recent court cases, the article examines this tension and proposes mechanisms such as basic science patent pools and mandatory arbitration to balance rewards for foundational discoveries in the public sector with incentives for continued biomedical innovation.
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The Swinging Pendulum: The Supreme Court Reverses Course on ERISA and Managed Care

Kesselheim AS, Brennan TA - Yale Journal of Health Policy, Law and Ethics

  • Research Publications
| January 2005
  • Price, Value, and Access
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The authors analyze how the Supreme Court reversed its prior expansive interpretation of ERISA preemption of state-law claims against managed care organizations, marking a significant shift in the legal landscape governing patients’ ability to sue health plans for denials of care. This jurisprudential reversal has important implications for the balance between federal uniformity in employee benefit plan regulation and state-level protections for patients in managed care settings.
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