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1259 Results

Comparison of Rates of Safety Issues and Reporting of Trial Outcomes for Medical Devices Approved in the European Union and United States: Cohort Study

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

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

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

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

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

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

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

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

Engelberg AB, Kesselheim AS - Nature Medicine

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

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

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

Treasure CL, Kesselheim AS - JAMA Internal Medicine

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

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

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

Caplan ES, Kesselheim AS - Drug Discovery Today

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

Rizvi Z, Kapczynski A, Kesselheim AS - Washington Post

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

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

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

Rathi VK, Kesselheim AS, Ross JS - JAMA Cardiology

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

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

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

Kapczynski A, Kesselheim AS - Health Affairs

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

Sarpatwari A, Kesselheim AS - JAMA

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

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

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

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

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

Kesselheim AS, Hwang TJ - Annals of Internal Medicine

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

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

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

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

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

Hey SP, Kesselheim AS - PLOS Medicine

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

Avorn J - Health Affairs Forefront

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

Wang B, Kesselheim AS - JAMA

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

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

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

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

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

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

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

Sarpatwari A, Kesselheim AS - PLOS Medicine

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

Hwang TJ, Kesselheim AS - Health Affairs

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

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

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

Luo J, Kesselheim AS - Lancet Diabetes & Endocrinology

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

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

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

Podolsky SH, Kesselheim AS - New England Journal of Medicine

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

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

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

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

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

Sarpatwari A, Kesselheim AS - Clinical Pharmacology & Therapeutics

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

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

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

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

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

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

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

Treasure CL, Avorn J, Kesselheim AS - Milbank Quarterly

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

Luo J, Kesselheim AS - JAMA

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

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

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

Luo J, Kesselheim AS - Lancet Diabetes & Endocrinology

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

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

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

Kesselheim AS, Maggs LR, Sarpatwari A - JAMA

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

Avorn J, Kesselheim AS - New England Journal of Medicine

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

Carrier MA, Kesselheim AS - Health Affairs Forefront

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

Luo J, Kesselheim AS - JAMA

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

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

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

Kesselheim AS, Gagne JJ - Drug Safety

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

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

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

Wang B, Kesselheim AS - BMJ

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

Ross JS, Kesselheim AS - Circulation

  • Research Publications
| September 2015
  • Regulation and Clinical Evidence
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This comprehensive review traces the FDA’s evolution from its 1862 origins through landmark legislation—the 1906 Pure Food and Drug Act, 1938 Food Drug and Cosmetic Act, 1962 Kefauver-Harris Amendments, and 1976 Medical Device Amendments—each enacted in response to public health crises and broadening the agency’s authority over drugs and devices. The authors discuss current FDA policies for approval and postmarket surveillance of new drugs, biologics, generics, and medical devices, with particular attention to their implications for cardiovascular clinical care.
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Comments on Proposed Rule, “Medicare Program; Revisions to Payment Policies Under the Physician Fee Schedule and Other Revisions to Part B for CY2016”

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

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

Sarpatwari A, Kesselheim AS - US Supreme Court

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

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

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

Bateman BT, Kesselheim AS - Drug Discovery Today

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

Sharfstein JM, Kesselheim AS - JAMA

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

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

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

Avorn J, Kesselheim AS - New England Journal of Medicine

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

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

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

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

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

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

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

Hwang TJ, Lehmann LS, Kesselheim AS - Nature Biotechnology

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

Kesselheim AS, Sarpatwari A - Health Affairs Forefront

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

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

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

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

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

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

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

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

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

Darrow JJ, Kesselheim AS - Food and Drug Law Journal

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

Sarpatwari A, Kesselheim AS - Health Affairs Forefront

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

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

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

Kramer DB, Kesselheim AS - New England Journal of Medicine

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

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

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

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

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

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

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

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

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

Kesselheim AS, Tan YT, Avorn J - Health Affairs

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

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

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

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

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

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

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

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

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

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

  • Research Publications
| January 2015
  • Price, Value, and Access
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The FDA’s expanded access system allows patients with serious conditions to receive investigational drugs before formal approval through 3 categories: individual use, intermediate-size populations, and widespread treatment protocols. The authors examine the practical, legal, and ethical challenges of reconciling protection of vulnerable, seriously ill patients from potentially useless or harmful products with the desire to provide timely access to treatments that may ultimately prove beneficial, drawing on cases like Josh Hardy’s widely publicized request for an experimental antiviral and the Ebola crisis.
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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
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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
An icon of a bill representing government policy.
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. Read his written testimony.
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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
Talk bubble graphics representing commentary and opinion.
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
Talk bubble graphics representing commentary and opinion.
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
Talk bubble graphics representing commentary and opinion.
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
An icon of a bill representing government policy.
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 notez that post-approval confirmatory studies and safety surveillance systems remain underdeveloped. Read his written 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
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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
An icon of a bill representing government policy.
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
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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
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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
Talk bubble graphics representing commentary and opinion.
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
Talk bubble graphics representing commentary and opinion.
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
Talk bubble graphics representing commentary and opinion.
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
Talk bubble graphics representing commentary and opinion.
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
Talk bubble graphics representing commentary and opinion.
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
Talk bubble graphics representing commentary and opinion.
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
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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
Talk bubble graphics representing commentary and opinion.
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
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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
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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
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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
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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
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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. Read his written 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
Talk bubble graphics representing commentary and opinion.
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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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
Talk bubble graphics representing commentary and opinion.
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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