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1259 Results

Frequency of First Generic Drug Approvals with “Skinny Labels” in the United States

Walsh BS, Sarpatwari A, Rome BN, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| July 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 56 brand-name drugs first facing generic competition from 2015 to 2019, 43% had generics approved with “skinny labels” that carved out patent- or exclusivity-protected indications, with a median of 3.2 years between skinny-label approval and expiration of the carved-out protections. Skinny labeling was particularly common among high-revenue brand-name drugs (median net sales of $852 million vs. $522 million for those with full-label generics), demonstrating its important role in facilitating timely generic entry while navigating secondary patents and exclusivities.
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FDA Approval Standards for Anticancer Agents—Lessons From Two Recent Approvals in Breast Cancer

Gyawali B, Kesselheim AS - Nature Reviews Clinical Oncology

  • Commentary & Opinion
| July 2021
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Two breast cancer drug approvals (neratinib and margetuximab) serve as evidence that FDA approval standards are declining, with one drug delaying radiological progression by only 3 days without improving overall survival or quality of life, while the other showed similarly marginal benefits.
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A Multi-Modal Approach to Evaluate the Impact of Risk Evaluation and Mitigation Strategy (REMS) Programs

Sarpatwari A, Mitra-Majumdar M, Bykov K, Avorn J, Woloshin S, Toyserkani GA, LaCivita C, Manzo C, Zhou EH, Pinnow E, Dal Pan GJ, Gagne JJ, Huybrechts KF, Feldman WB, Chin K, Kesselheim AS - Drug Safety

  • Research Publications
| July 2021
  • Regulation and Clinical Evidence
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A systematic, multi-method study describes a framework for evaluating how FDA Risk Evaluation and Mitigation Strategy (REMS) programs have operated in practice, incorporating insurance claims analyses of drug use and patient outcomes, physician and patient surveys and interviews, and assessments of risk communication effectiveness. The research aims to address the current lack of evidence on REMS program impacts on informed decision-making, medication access, and patient outcomes, with the goal of generating actionable recommendations for program improvement.
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Over-The-Counter Monograph Safety, Innovation, and Reform Act

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

  • Research Publications
| Summer 2021
  • Regulation and Clinical Evidence
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The prior FDA system for establishing over-the-counter (OTC) drug safety and effectiveness relied on a cumbersome rulemaking process that took decades, creating barriers to new OTC market entry and slow responses to emerging safety concerns. The CARES Act of 2020 reformed this system by replacing rulemaking with a more efficient administrative order process and establishing user fees to support FDA review, though the authors note it will be important to monitor how the OTC market evolves under these new regulatory features.
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Op-Ed: The FDA Has Reached a New Low

Kesselheim AS, Avorn J - New York Times

  • Commentary & Opinion
| June 2021
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The FDA’s approval of aducanumab (Adulhelm) for Alzheimer’s represents a dangerous erosion of the agency’s evidence standards. Despite an advisory committee’s near-unanimous finding that the drug failed to demonstrate clinical benefitand caused brain swelling in roughly a third of higher-dose patients, the FDA approved it based on an unvalidated surrogate measure. The authors call for independent oversight of drug approvals to prevent further regulatory decline.
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Association of California’s Prescription Drug Coupon Ban with Generic Drug Use

Rome BN, Gagne JJ, Kesselheim AS - JAMA

  • Research Publications
| June 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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California’s 2018 ban on manufacturer co-payment coupons for drugs with available generics was associated with a nonsignificant 0.42% increase in generic use relative to surrounding states, with generic use already trending upward in both California and comparison states during the study period. The limited observed effect suggests that while coupon bans may theoretically promote generic substitution, their practical impact may be modest when generic adoption is already high and other factors driving brand-name prescribing remain in play.
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Prospects for Enforcing Prohibitions on Off-Label Drug Promotion After United States v. Caronia: An Analysis of Litigated Cases

Liu S, Mello MM, Kesselheim AS - Journal of Health Politics, Policy and Law

  • Research Publications
| June 2021
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 42 litigated cases citing United States v. Caronia from 2012 to 2019, 52% followed the ruling that truthful off-label drug promotion is protected speech, while 48% declined to follow or distinguished it, demonstrating inconsistent judicial application of First Amendment protections to pharmaceutical marketing. The authors conclude that Caronia has significantly weakened FDA enforcement of off-label promotion restrictions, allowing manufacturers greater latitude to market drugs for unapproved uses despite associated public health risks.
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Postmarket Safety Communication for Protection of Public Health: A Comparison of Regulatory Policy in Australia, Canada, the European Union, and the United States

Bhasale AL, Sarpatwari A, De Bruin ML, Lexchin J, Lopert R, Bahri P, Mintzes BJ - Clinical Pharmacology & Therapeutics

  • Research Publications
| June 2021
  • Regulation and Clinical Evidence
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The authors compare postmarket safety communication systems across four major regulatory jurisdictions (US, European Union, Canada, and Australia), examining their governance structures, legislative authorities, risk communication capabilities, and transparency mechanisms for issuing safety advisories about emerging drug risks. Regulators’ shift to communicating postmarket safety issues through letters to healthcare professionals, drug safety bulletins, media alerts, and website announcements highlights a part of the “life cycle” approach to medicine regulation adopted in response to the withdrawal of rofecoxib.
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Factors Associated with Generic Drug Uptake in the United States, 2012 to 2017

Rome BN, Lee CC, Gagne JJ, Kesselheim AS - Value in Health

  • Research Publications
| June 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 227 drugs facing new generic competition, mean generic uptake was 66.1% in the first year and 82.7% in the second year, but declined 4.3% annually in year one and 3.2% annually in year two. Uptake was substantially lower for injected drugs compared to oral drugs. The authors recommend implementing policies to encourage generic competition, particularly for injectable drugs administered in hospital or clinic settings, to counteract declining early generic uptake and reduce prescription drug spending.
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Continual Learning in Medical Devices: FDA’s Action Plan and Beyond

Vokinger KN, Feuerriegel S, Kesselheim AS - Lancet Digital Health

  • Commentary & Opinion
| June 2021
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors discuss the regulatory challenges of AI/ML medical devices capable of continual learning, noting that no such adaptive device has yet been FDA-approved. Known risks, including dataset shift, bias, and catastrophic forgetting, require novel regulatory frameworks.
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The Wrong Cure: Financial Incentives for Unimpressive New Antibiotics

Sinha MS, Powers JH, Kesselheim AS - Journal of Infectious Diseases

  • Research Publications
| May 2021
  • Innovation Incentives and Competition
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US policymakers have relied primarily on market-based financial incentives—including extended exclusivity periods and expedited approval pathways—to encourage antibiotic development, but these incentives do not require demonstration of added clinical benefit over existing therapies, contributing to a pattern of commercially unsuccessful approvals like plazomicin. The authors argue that innovation policies should be redesigned to prioritize antibiotics with demonstrated superiority over available treatments, rather than simply rewarding new market entrants regardless of their clinical value.
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Testimony: Addressing Pharmaceutical Patent Abuses Could Lower Drug Spending and Improve Patient Outcomes

Kesselheim AS - 117th Congress, House Committee on Oversight and Reform

  • Policy Interactions
| May 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Kesselheim argues that brand-name drug manufacturers exploit the US market exclusivity system particularly through patent thickets to delay generic and biosimilar competition well beyond reasonable exclusivity periods, citing adalimumab (Humira) as a case study. He documents how these strategies inflate US drug spending and recommends various reforms, including strengthening USPTO resources and patent quality standards, requiring Patent Trial and Appeals Board review of all FDA-listed drug patents, limiting enforcement to a single primary patent per drug, invoking the government’s existing patent use rights, and reforming orphan drug and biologic exclusivity periods to ensure timely competition. Read his written testimony.
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Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility

Alexander GC, Emerson SS, Kesselheim AS - JAMA

  • Commentary & Opinion
| May 2021
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors critiques the regulatory review of aducanumab, noting that its two pivotal trials were halted for futility and produced conflicting results, with post hoc analyses raising concerns about data-driven endpoint changes. They also question the unusually close FDA-manufacturer collaboration throughout the approval process and argue that the clinical significance of the observed treatment effect was uncertain.
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Correlation Between Changes in Brand-Name Drug Prices and Patient Out-Of-Pocket Costs

Rome BN, Feldman WB, Desai RJ, Kesselheim AS - JAMA Network Open

  • Research Publications
| May 2021
  • Price, Value, and Access
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From 2015 to 2017, list prices for brand-name drugs increased by a median of 16.7%, net prices increased by 5.4%, and out-of-pocket (OOP) spending increased by 3.5%, with changes in list prices showing weak correlation with overall out-of-pocket spending but moderate correlation among patients with deductibles or coinsurance who experienced a 15.0% median increase in OOP spending. Policies regulating uncontrolled list price increases may be necessary to reduce out-of-pocket spending for patients with high-deductible or coinsurance-based plans, as manufacturer rebates do not appear to translate into reduced patient costs.
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Antibiotic Development Incentives That Reflect Societal Value of Antibiotics (Reply)

Rome BN, Kesselheim AS - Clinical Infectious Diseases

  • Commentary & Opinion
| May 2021
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
In this reply, the authors respond to advocates of transferable market exclusivity vouchers as an incentive for antibiotic development, arguing that the government report used to estimate the societal value of new antibiotics had significant methodological flaws and that most recently approved antibiotics entered saturated markets with limited added clinical benefit. They contend that exclusivity vouchers are inefficient and ethically problematic and propose alternative approaches.
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Frequency of Generic Drug Price Spikes and Impact on Medicaid Spending

Patel AN, Kesselheim AS, Rome BN - Health Affairs

  • Research Publications
| May 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Using Medicaid data from 2014 to 2017, the authors found that one in five generic drugs experienced a price spike (doubling within one year), with the frequency of spikes declining from 7.8% in 2014 to 5.8% in 2017. These spikes cost Medicaid $1.5 billion, or 4.2% of all generic drug spending, from 2014-2016 and particularly affected injected products and drugs with few manufacturers. The authors conclude that while regulatory action may have reduced the frequency of price spikes for generic drugs, additional policies are needed to enhace generic competition and constrain prices.
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Few New Drugs Deserve Expedited Regulatory Treatment

Darrow JJ - Journal of Managed Care & Specialty Pharmacy

  • Commentary & Opinion
| May 2021
  • Regulation and Clinical Evidence
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While expedited FDA approval pathways were originally intended for truly transformative therapies, most new drugs offer only modest incremental benefits over existing treatments, yet the majority now receive some form of expedited designation. The expansion of these programs has distracted from the more fundamental question of whether approved drugs provide meaningful clinical benefit.
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Diabetes Drugs: List Price Increases Were Not Always Reflected in Net Price; Impact of Brand Competition Unclear

Sarpatwari A, Tessema FA, Zakarian M, Najafzadeh MN, Kesselheim AS - Health Affairs

  • Research Publications
| May 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Between 2005 and 2017, list prices for three classes of diabetes drugs (GLP-1 agonists, DPP4 inhibitors, and SGLT2 inhibitors) increased 8-15% despite the introduction of competing brand-name drugs. Net prices showed a more variable pattern, with GLP-1 net prices rising 10% while net prices for other classes declined. These findings suggest that brand-name competition may have a variable impact on net prices, and that list price changes may not always correspond to changes in net price.
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Safeguarding Evidence-Based Decision Making in the FDA for COVID-19 Vaccines

Angelis A, Darrow JJ - Vaccine

  • Commentary & Opinion
| April 2021
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Political pressure, premature government statements about unproven treatments (e.g., hydroxychloroquine, convalescent plasma), and unclear communication about Emergency Use Authorizations eroded public trust in the FDA during the pandemic. The authors propose measures to restore confidence in vaccine decision-making, including greater transparency and research coordination.
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Public Sector and Non-Profit Contributions to Drug Development—Historical Scope, Opportunities, and Challenges

Sarpatwari A, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Spring 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Per capita US prescription drug spending reached $1,024 million in 2017 (45% more than the next highest country), driven in part by high-priced new therapies like gene treatments priced at up to $2.1 million, many of which benefited from critical public-sector research support, including NIH funding that contributed at some level to all new drugs approved between 2008 and 2017. This introduction to a special journal issue frames the tension between substantial taxpayer-funded contributions to drug discovery and the high prices subsequently charged to US patients, arguing for policies that ensure public investment is reflected in drug accessibility and affordability.
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Characteristics of Clinical Trials Launched Early in the COVID-19 Pandemic in the US and in France

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

  • Research Publications
| Spring 2021
  • Regulation and Clinical Evidence
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An analysis of 200 COVID-19 clinical trials registered early in the pandemic found that most evaluated repurposed drugs (73%) and were funded without industry participation (75%), with French trials less often classified as high-rigor (30%) compared to US trials (47%) and industry funding considerably more common in US trials. Despite the registration of a large number of trials, only a minority had design characteristics usually associated with producing robust and relevant evidence, raising concerns about the efficiency and coordination of the pandemic clinical research response.
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A Non-Profit Approach to Address Foreign Dependence of Generic Drugs

Liljenquist D, Bai G, Sarpatwari A, Anderson GF - Journal of Law, Medicine & Ethics

  • Research Publications
| Spring 2021
  • Innovation Incentives and Competition
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The COVID-19 pandemic exposed critical vulnerabilities in the US generic drug supply chain, with approximately 90% of pharmaceutical ingredients for essential generics manufactured in China and production disruptions threatening availability of key medications. The authors argue that nonprofit drug manufacturers like Civica Rx may be better positioned than for-profit companies to support domestic generic drug production, as they can prioritize supply reliability and public health over profit maximization while complementing legislative efforts to reduce foreign dependence.
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Comments on Proposed Rule, “Rights to Federally Funded Inventions and Licensing of Government Owned Inventions”

Sinha MS - National Institute of Standards and Technology (NIST)

  • Policy Interactions
| April 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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NIST should clarify processes for exercising Bayh-Dole Act march-in rights on federally funded research and ensure that unreasonable pricing of publicly funded medical products remains a legitimate basis for government action. The commenters point to the substantial federal investment in pharmaceutical development including COVID-19 vaccines and therapeutics as an example of the need for such authority.
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Substitution of Generic Drugs and Biosimilars (Reply)

Sarpatwari A, Kesselheim AS, Sacks CA - JAMA Internal Medicine

  • Commentary & Opinion
| April 2021
  • Innovation Incentives and Competition
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The authors acknowledge that many biologics bypass pharmacy dispensing, but note that several top-selling biologics accounting for billions in spending are primarily pharmacy-dispensed, meaning meaningful savings can result from optimizing state drug product selection laws. They also note that the profit-margin dynamics favoring generic substitution for small-molecule drugs may not apply to interchangeable biologics given their manufacturing complexity and fewer competitors, and emphasize that state law optimization should be coupled with educational outreach and closer oversight of pharmacy benefits management practices.
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Public Funding and the Importance of Reasonable Pricing for Buprenorphine

Barenie RE, Kesselheim AS - Drug and Alcohol Dependence

  • Commentary & Opinion
| April 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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In this letter, the authors respond to commentary on their research quantifying NIH contributions to buprenorphine’s development as an opioid use disorder treatment, arguing that when public funding meaningfully supports drug development, policymakers should consider mechanisms to ensure the resulting products are available at fair prices.
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International Reference Pricing for Prescription Drugs in the United States: Administrative Limitations and Collateral Effects

Rand LZG, Kesselheim AS - Value in Health

  • Research Publications
| April 2021
  • Price, Value, and Access
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The authors identify four key administrative challenges to implementing international reference pricing in the US: lack of price transparency, delays in market approvals, the frequency of price revisions, and the prevalence of cross-referencing. Failure to address these issues will result in overspending from price overestimation while likely increasing drug prices in other countries. Policymakers should adopt international reference pricing as a supplementary tool alongside other cost-containment strategies such as value-based pricing or volume agreements, rather than as a standalone policy, given these challenges.
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Identifying Potential Prescription Drug Product Hopping

Gowda V, Beall RF, Kesselheim AS, Sarpatwari A - Nature Biotechnology

  • Research Publications
| April 2021
  • Innovation Incentives and Competition
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The authors define and apply a systematic process for prospectively detecting product hopping. They distinguish between “soft” switches (relying on marketing to shift patients) and “hard” switches (discontinuing the original product), and argue that prospective identification of potential product hops could help policymakers and regulators intervene before patients and the health care system incur unnecessary costs.
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Characteristics of Postmarketing Studies for Vaccines Approved By the US Food and Drug Administration, 2006-2020

Moneer O, Lee CC, Avorn J, Kesselheim AS - JAMA Network Open

  • Research Publications
| April 2021
  • Regulation and Clinical Evidence
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Among 35 vaccines approved by the FDA from 2006 to 2020, all but one were issued postmarketing requirements (PMRs) or commitments (PMCs)—128 total studies with a median of 4 per vaccine—but only 48.4% were fulfilled, with a median time to completion of 50 months. Postmarketing commitments, which lack the same enforcement mechanisms as requirements, had a higher fulfillment rate (54.2%) than PMRs (41.1%), raising concerns about the completeness and timeliness of postapproval safety evidence for vaccines as COVID-19 vaccines enter the postmarketing phase.
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Assessment of Coverage in England of Cancer Drugs Qualifying for US Food and Drug Administration Accelerated Approval

Cherla A, Naci H, Kesselheim AS, Gyawali B, Mossialos E - JAMA Internal Medicine

  • Research Publications
| April 2021
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 87 cancer drug indications that received FDA accelerated approval between 1992 and 2017, 30 were not subsequently reviewed by either the EMA or the UK National Institute for Health and Care Excellence (NICE), and 12 drugs were denied authorization or coverage owing to insufficient safety, clinical efficacy, or cost-effectivenes. National Health Service (NHS) coverage of cancer drugs given FDA accelerated approval commonly required additional price concessions, restrictions to approved indications, or review of additional data.
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Testimony: High Drug Prices in the US: What We Can Learn From Other Countries and Some US States

Kesselheim AS - 117th Congress, Senate Committee on Health, Education, Labor, and Pensions

  • Policy Interactions
| March 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Kesselheim argues that US brand-name drug prices are far higher than in peer countries because manufacturers can freely set launch prices, raise prices annually above inflation, and extend market exclusivity through patent thickets, while Medicare and Medicaid are legally constrained from meaningful negotiation. Drawing on approaches used in Germany, France, Canada, Australia, Japan, and several US states, he proposes a three-pronged reform: establishing a publicly-funded body to negotiate drug prices based on health technology assessment; limiting annual price increases to the rate of inflation; and ensuring efficient transition to generic and biosimilar competition by strengthening USPTO patent quality review and expanding PTAB scrutiny of drug patents. Read his written testimony.
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ASHP Foundation Pharmacy Forecast 2021: Strategic Planning Advice for Pharmacy Departments in Hospitals and Health Systems

DiPiro JT, Fox ER, Kesselheim AS, Chisholm-Burns M, Finch CK, Spivey C, Carmichael JM, Meier J, Woller T, Pinto B, Bates DW, Hoffman JM, Armitstead JA, Segovia D, Dodd MA, Scott MA - American Journal of Health-System Pharmacy

  • Research Publications
| March 2021
  • Price, Value, and Access
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The ASHP Foundation’s 9th annual Pharmacy Forecast surveyed 272 pharmacy leaders and experts to identify emerging trends likely to affect health-system pharmacy practice, including the impact of COVID-19 on pharmacy operations, evolving technology and informatics needs, workforce challenges, and changing regulatory and reimbursement landscapes.
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Paying for Prescription Drugs in the New Administration

Kesselheim AS, Hwang TJ, Avorn J - JAMA

  • Commentary & Opinion
| March 2021
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors outline drug pricing policy options for the Biden administration, including establishing inflation-based rebates for Medicare, creating a Drug Affordability Commission, implementing international reference pricing, and promoting generic and biosimilar competition to address the fact that US per capita drug spending is more than twice the average of comparable countries.
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Why France Spends Less Than the United States on Drugs: A Comparative Study of Drug Pricing and Pricing Regulation

Raimond VC, Feldman WB, Rome BN, Kesselheim AS - Milbank Quarterly

  • Research Publications
| March 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The US spends significantly more per capita on prescription drugs than France, with Medicare potentially saving $5.1 billion annually on six high-expenditure drugs if it paid French prices. This difference is driven by France’s use of health technology assessment, value-based pricing, price regulation at drug launch, and restrictions on price increases. The authors recommend that the US adopt French regulatory approaches to drug pricing to control prescription drug spending.
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Trends in Medicare Part D Inhaler Spending: 2012-2018

Feldman WB, Gagne JJ, Kesselheim AS - Annals of the American Thoracic Society

  • Research Publications
| March 2021
  • Price, Value, and Access
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Medicare Part D spent $39.7 billion on inhalers between 2012 and 2018, with spending growing 45.2% over the period. 88.4% of this spending was driven by increased utilization of combination long-acting maintenance inhalers rather than rising per-inhaler costs. These findings highlight that limited generic competition for inhalers, combined with growing use of expensive combination products, has been a major driver of Medicare respiratory drug expenditures.
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Preventing Medical-Device-Borne Outbreaks: High-Level Disinfection Policy for Duodenoscopes

Mehrotra P, Weber DJ, Sarpatwari A - Infection Control and Hospital Epidemiology

  • Commentary & Opinion
| March 2021
  • Regulation and Clinical Evidence
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The authors examine outbreaks of antibiotic-resistant bacteria traced to contaminated duodenoscopes, describing the regulatory responses including enhanced post-market surveillance and revised reprocessing requirements, and argue that infection prevention must be more centrally integrated into the medical device regulatory framework.
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Non-Warfarin Oral Anticoagulant Copayments and Adherence in Atrial Fibrillation: A Population-Based Cohort Study

Rome BN, Gagne JJ, Avorn J, Kesselheim AS - American Heart Journal

  • Research Publications
| March 2021
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Higher copayments for non-warfarin oral anticoagulants were associated with significantly lower medication adherence and higher discontinuation rates among commercially-insured atrial fibrillation patients over one year of follow-up. Policies to reduce or cap cost-sharing for NOACs may improve medication adherence and clinical outcomes in this population.
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Federal Spending on Off-Patent Drugs That Lack Generic Competition

Rome BN, Kesselheim AS - Journal of General Internal Medicine

  • Research Publications
| March 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Among 137 off-patent drugs lacking generic competition with available Medicare or Medicaid spending data, total post-rebate federal spending was approximately $1.6 billion in 2018, with the top 20 drugs accounting for 89% of that spending. Policies to increase competition or reduce prices could have saved $328 million to $1.3 billion. While such policies would meaningfully benefit patients who depend on these essential medicines, this cohort represents a relatively small share of the over $100 billion in annual federal drug spending, suggesting these interventions alone are unlikely to curb overall prescription drug expenditures.
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Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program

Sarpatwari A, He M, Tessema FA, Gagne JJ, Kesselheim AS - Drug Safety

  • Research Publications
| March 2021
  • Regulation and Clinical Evidence
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This interrupted time-series analysis of commercial insurance claims data found that implementation and enforcement of a REMS program for erythropoiesis stimulating agents did not produce statistically significant changes in initiation rates for darbepoetin alfa or epoetin alfa among cancer patients, nor did it significantly reduce inappropriate use in patients with hemoglobin above 10 g/dL. The findings raise concerns about the effectiveness of this REMS program in improving safe prescribing practices for these drugs.
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Associations Between Copays, Coverage Limits for Opioid Use Disorder Medications, and Prescribing in Medicaid, 2018

Barenie RE, Kesselheim AS, Tsacogianis T, Fischer MA - Medical Care

  • Research Publications
| March 2021
  • Price, Value, and Access
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This cross-sectional study of 2018 Medicaid data found substantial state-level variation in use of medication for opioid use disorder (mOUD), but no significant associations between mOUD prescribing rates and copay requirements, copay amounts, or coverage limits. Further research is needed to examine other elements of benefit design that may impact access to mOUD treatment in Medicaid.
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Assessing the Legality of Mandates for Vaccines Authorized via an Emergency Use Authorization

Parasidis E, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| February 2021
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The EUA statute requires that individuals be informed of “the option to accept or refuse” an authorized product and “the consequences, if any, of refusing,” but the most plausible legal interpretation limits “consequences” to health-related disclosures rather than authorizing mandates. Both legal and policy considerations, including the lower evidentiary standard for EUAs compared to full approval and heightened vaccine hesitancy among vulnerable populations, counsel against mandating COVID-19 vaccines until they receive full BLA approval.
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The Future of Drug-Pricing Transparency

Feldman WB, Rome BN, Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| February 2021
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
Amid the release of the Trump administration’s “Transparency in Coverage” Final Rule requiring disclosure of drug prices, the authors arguing that while drug-pricing transparency enjoys bipartisan support, key debates remain about whether disclosure of confidential rebates will empower payers to negotiate better prices or allow manufacturers to push net prices higher.
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Market Exclusivity Length for Drugs with New Generic or Biosimilar Competition, 2012-2018

Rome BN, Lee CC, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| February 2021
  • Innovation Incentives and Competition
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From 2012-2018, market exclusivity periods were longer for biologic drugs than small molecule drugs (median 21.5 vs. 14.4 years), longer for drugs with annual revenue
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Factors Affecting Buprenorphine Utilization and Spending in Medicaid, 2002-2018

Barenie RE, Sinha MS, Kesselheim AS - Value in Health

  • Research Publications
| February 2021
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Brand-name buprenorphine-naloxone (Suboxone) formulations accounted for 2.7 times more prescriptions and 4.4 times higher spending than all other buprenorphine formulations combined in Medicaid from 2002-2018, with various market and regulatory factors delaying market entry of generic versions by 6-9 years. Earlier availability of affordable generic alternatives could have expanded access to buprenorphine treatment during the opioid crisis and reduced Medicaid expenditures.
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Buprenorphine for Opioid Use Disorder: The Role of Public Funding in Its Development

Barenie RE, Kesselheim AS - Drug and Alcohol Dependence

  • Research Publications
| February 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Buprenorphine was developed for opioid use disorder over four decades with primarily through government and academic research, with an estimated $62.3 million in NIH awards supporting its development through pivotal studies and a formal government-industry partnership. Despite substantial public sector investment in buprenorphine’s development, the medication remains expensive and inaccessible to many patients, indicating a need to ensure affordable access to this effective, government-funded treatment.
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Beyond the High Prices of Prescription Drugs: A Framework to Assess Costs, Resource Allocation, and Public Funding

Darrow JJ, Light DW - Health Affairs

  • Research Publications
| February 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors argue that the total societal cost of prescription drugs extends well beyond list prices, encompassing an accumulation of publicly funded mechanisms—including tax benefits, fee waivers, publicly funded basic and translational research, new exclusivities that delay competition, and government insurance programs that guarantee payment regardless of price. They propose a more comprehensive framework for assessing drug costs and recommend that Congress direct the Government Accountability Office to study public contributions underlying the highest-cost drugs and require manufacturers to periodically report the direct and indirect public funding they receive.
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A Correlation Analysis to Assess Event-Free Survival as a Trial-Level Surrogate for Overall Survival in Early Breast Cancer

Gyawali B, D'Andrea E, Franklin JM, Kesselheim AS - eClinicalMedicine

  • Research Publications
| February 2021
  • Regulation and Clinical Evidence
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This correlation analysis of seven randomized controlled trials found a moderate but non-significant association between treatment effects on event-free survival (EFS) and overall survival (OS) in early breast cancer. The authors conclude that while current evidence is insufficient to support EFS as a surrogate endpoint for traditional approval in early breast cancer, it may still be considered for accelerated approval pathways.
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Op-Ed: Biden Can Lower Drug Prices Without Congress Doing Anything

Bloomfield D, Kesselheim AS - Washington Post

  • Commentary & Opinion
| January 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The Biden administration can meaningfully address high drug prices through executive action at the Patent and Trademark Office, without needing legislation. The authors contend that the PTO’s fee structure and time pressures incentivize examiners to grant weak secondary patents that enable brand-name manufacturers to build patent thickets blocking generic competition. They propose giving examiners more time and resources, revising guidance to make it easier to reject ineligible applications, and restructuring fees to eliminate the agency’s bias toward granting patents.
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Repurposing Existing Drugs for New Uses: A Cohort Study of the Frequency of FDA-Granted New Indication Exclusivities Since 1997

Sahragardjoonegani B, Beall RF, Kesselheim AS, Hollis A - Journal of Pharmaceutical Policy and Practice

  • Research Publications
| January 2021
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 197 new drugs that subsequently experienced generic entry between 1997 and 2020, only 32% received at least one new indication added, with the probability of a new indication peaking above 4% at 7-8 years before generic entry and declining to near zero 15 years post-approval. The findings suggest that current indication-specific exclusivity periods are insufficient to incentivize drug repurposing, and policymakers should consider strengthening incentives to encourage clinical investigations for novel uses of existing drugs.
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Public Funding for Transformative Drugs: The Case of Sofosbuvir

Barenie RE, Avorn J, Tessema FA, Kesselheim AS - Drug Discovery Today

  • Research Publications
| January 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors identified approximately $60.9 million in NIH funding that directly or indirectly supported the development of sofosbuvir (Sovaldi), with $7.7 million in direct awards and $53.2 million in indirect awards to academic institutions and companies involved in the drug’s creation. These findings demonstrate the key role of public funding in enabling this transformative hepatitis C treatment and the need for affordable access to government-supported therapeutics.
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Generic Competition for Drugs Treating Rare Diseases

Beall RF, Quinn AE, Kesselheim AS, Tessema FA, Sarpatwari A - Journal of Law, Medicine & Ethics

  • Research Publications
| Winter 2021
  • Innovation Incentives and Competition
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Among 167 drugs approved with a rare disease indication between 1983 and 2017, only 42% of the 57 that were eligible for generic competition had a generic available, and just 50% of those with Orange Book–listed patents had been challenged, with both generic availability and patent challenges significantly associated with higher prescription volume. These findings suggest that drugs treating rare diseases face elevated risk of insufficient generic competition due to small market sizes, leaving patients vulnerable to high and rising prices for older, off-patent medications.
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Ensuring Safe Access to Mifepristone During the Pandemic and Beyond

Brown BL, Wood SF, Sarpatwari A - Annals of Internal Medicine

  • Commentary & Opinion
| January 2021
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The FDA’s REMS program for mifepristone is not justified by the drug’s safety profile and creates access barriers, particularly for low-income and rural patients, that were exacerbated by the COVID-19 pandemic. The authors contend that the REMS requirements may paradoxically push patients toward later surgical abortions that carry greater risk.
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Assessment of Variation in State Regulation of Generic Drug and Interchangeable Biologic Substitutions

Sacks CA, Van de Wiele VL, Fulchino LA, Patel L, Kesselheim AS, Sarpatwari A - JAMA Internal Medicine

  • Research Publications
| January 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
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This cross-sectional analysis of state drug product selection laws found substantial variation across US states in generic drug substitution requirements, with only 19 states mandating generic substitution for small-molecule drugs, 7 states requiring patient consent, and 45 states imposing more stringent requirements for interchangeable biologic substitution compared to generic small-molecule drugs. The authors conclude that state drug product selection laws should be optimized to better promote generic and biosimilar substitution in order to improve medication adherence and reduce drug spending.
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An Overview of Vaccine Development, Approval, and Regulation, with Implications for COVID-19

Kesselheim AS, Darrow JJ, Kulldorff M, Brown BL, Mitra-Majumdar M, Lee CC, Moneer O, Avorn J - Health Affairs

  • Research Publications
| January 2021
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The FDA approves vaccines through a standard evaluation process that weighs benefits against risks, and has established expedited pathways such as Emergency Use Authorization to accelerate vaccine availability. Among 35 new vaccines approved in the US from 2006 to October 2020, approximately two-thirds relied on surrogate immune response markers rather than actual disease incidence in their pivotal trials. Robust postapproval safety surveillance mechanisms are essential to detect adverse events that may warrant changes in vaccine recommendations or market withdrawal, and regulatory oversight must balance the need for speed with scientific rigor in addressing pandemic threats.
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Social, Cultural and Economic Aspects of Antimicrobial Resistance

Minssen T, Outterson K, Rogers Van Katwyk S, Batista PHD, Chandler CIR, Ciabuschi F, Harbarth S, Kesselheim AS, Laxminarayan R, Liddell K, Osterholm MT, Price L, Hoffman SJ - Bulletin of the World Health Organization

  • Research Publications
| December 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Antimicrobial resistance is an evolutionary challenge accelerated by social, cultural, and economic factors, including misuse of antimicrobials, inadequate sanitation infrastructure, and insufficient innovation incentives, that existing global efforts may be too slow to counter given the lack of political commitment and difficulty in balancing resistance with other priorities. The authors announce the creation of the International Network for Antimicrobial Resistance Social Science (INAMRSS) to champion interdisciplinary social science research as part of a One Health perspective, arguing that sustainable solutions require understanding the human behavioral drivers of resistance rather than relying solely on new antimicrobial discovery.
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Reducing Prescription Drug Costs: Policy Options for a Public Plan

Hwang TJ, Kesselheim AS - Urban Institute

  • Research Publications
| December 2020
  • Price, Value, and Access
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An analysis of three policy options for reducing prescription drug spending under a proposed Public Plan found that applying the basic Medicaid rebate (23.1%) would reduce net drug spending by 9–15% relative to private insurance, the total Medicaid rebate would achieve 46–49% savings, and the Big 4 agency rebate would yield 28–34% savings. These projections suggest that adopting existing public payer rebate structures could meaningfully lower drug costs for a Public Plan, though each option carries different trade-offs in administrative complexity and potential effects on other payers’ prices.
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Heterogeneity of Antidiabetic Treatment Effect on the Risk of Major Adverse Cardiovascular Events in Type 2 Diabetes: A Systematic Review and Meta-Analysis

D'Andrea E, Kesselheim AS, Franklin JM, Jung EH, Hey SP, Patorno E - Cardiovascular Diabetology

  • Research Publications
| December 2020
  • Regulation and Clinical Evidence
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Both GLP-1 receptor agonists and SGLT-2 inhibitors demonstrated a 14% risk reduction in major adverse cardiovascular events among patients with established cardiovascular disease, but showed no significant benefit in at-risk patients without prior cardiovascular events, with trends toward greater benefits in patients with chronic kidney disease or uncontrolled diabetes. These findings suggest that antidiabetic treatment selection should consider baseline cardiovascular disease status, while chronic kidney disease and uncontrolled diabetes warrant further investigation as potential treatment effect modifiers.
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Comparing Onset of Biosimilar Versus Generic Competition in the United States

Beall RF, Ronksley PE, Wick J, Darrow JJ, Sarpatwari A, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| December 2020
  • Innovation Incentives and Competition
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Expected market exclusivity periods are similar for biologic and small molecule drugs in the US, with median expected entry dates of 12.3 years after FDA approval for biologics and 12.2 years for small molecule drugs, with biosimilar entry occuring in only 12% of cases compared to 65% for generic entry by 2019. Statutory exclusivity was found to play a more substantial role in market exclusivity protection for biologics than for small molecule drugs.
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Efficacy and Costs of Spinal Muscular Atrophy Drugs

Darrow JJ, Sharma M, Shroff M, Wagner AK - Science Translational Medicine

  • Research Publications
| November 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Despite being lauded as “dramatically effective” and “curative,” FDA review documents reveal that the two approved treatments for spinal muscular atrophy—nusinersen (Spinraza, $125,000 per injection for life) and onasemnogene abeparvovec (Zolgensma, $2,125,000 per infusion)—demonstrated benefits more modest than their public reception suggests, with treated patients showing only limited improvements from very low baseline motor function scores. These findings raise broader questions about the pricing and value assessment of rare disease medicines, particularly when clinical benefits are uncertain and costs are extreme.
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A Qualitative Study of Biosimilar Manufacturer and Regulator Perceptions on Intellectual Property and Abbreviated Approval Pathways

Druedahl LC, Almarsdóttir AB, Kälvemark Sporrong S, De Bruin ML, Hoogland H, Minssen T, Van de Weert M, Kesselheim AS, Sarpatwari A - Nature Biotechnology

  • Research Publications
| November 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Qualitative interviews with 25 participants, including EU national medicines regulators and pharmaceutical manufacturer employees, revealed that while trade secrets were generally viewed as surmountable barriers to biosimilar development, patents on manufacturing processes and formulations posed more significant obstacles, and abbreviated regulatory approval pathways have had mixed success in fostering price-lowering competition. Despite the creation of biosimilar pathways in both the US and EU, expected widespread price reductions have not materialized, with scientific, legal, and regulatory challenges continuing to limit biosimilar market entry and uptake.
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Up Is Down—Pharmaceutical Industry Caution vs. Federal Acceleration of COVID-19 Vaccine Approval

Avorn J, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| October 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors highlight the unusual role reversal in which pharmaceutical companies publicly pledged to wait for adequate trial data before seeking COVID-19 vaccine approval, while the federal government pushed for rapid authorization before the 2020 election. They analyze how conflicting pressures from clinical trial design, regulatory standards, and politics could shape approval decisions.
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Comments on Implementation of Executive Order 13937, “Executive Order on Access to Affordable Life-Saving Medications.”

Bollyky TJ, Kesselheim AS - Health Resources and Services Administration (HRSA)

  • Policy Interactions
| October 2020
  • Price, Value, and Access
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The commenters outline the history of failed efforts to legalize large-scale prescription drug importation from Canada, arguing that importation could be most effectively used to address generic drug shortages rather than to broadly lower brand-name drug prices.
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Transferrable Market Exclusivity Extensions to Promote Antibiotic Development: An Economic Analysis

Rome BN, Kesselheim AS - Clinical Infectious Diseases

  • Research Publications
| October 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Transferrable market exclusivity vouchers proposed in the 2018 REVAMP Act to encourage antibiotic drug development would result in median excess spending of $187 million per drug extended, totaling approximately $4.5 billion over 10 years, based on analysis of 10 qualifying antimicrobials matched to high-revenue drugs facing generic entry. The authors conclude that while market exclusivity extensions are a politically attractive policy mechanism to incentivize antibiotic development, this approach would impose substantial costs on public and private payers.
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Producing and Using Timely Comparative Evidence on Drugs: Lessons From Clinical Trials for COVID-19

Naci H, Kesselheim AS, Røttingen J, Salanti G, Vandvik PO, Cipriani A - BMJ

  • Research Publications
| October 2020
  • Regulation and Clinical Evidence
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The COVID-19 pandemic exposed critical flaws in the evidence ecosystem for evaluating new treatments, with over 1,000 trials registered on ClinicalTrials.gov by mid-2020. Yet most featured fragmented designs, heterogeneous endpoints, disproportionate focus on hyped treatments like hydroxychloroquine, and fewer than one-third using randomized controlled designs. The authors call for greater collaboration among trialists, meta-analysts, and guideline developers to improve coordination, reduce redundancy, and ensure that the rush to produce evidence translates into robust comparative effectiveness data that can reliably guide clinical and regulatory decisions.
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Accounting for US Public Funding in Drug Development: How Can We Better Balance Access, Affordability, and Innovation?

Sarpatwari A, Avorn J, Kesselheim AS - BMJ

  • Research Publications
| October 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Despite industry claims that high drug prices are necessary to sustain innovation, the US government is the world’s largest single funder of biomedical research ($39 billion through NIH in 2019), contributing at some level to all 210 new drugs approved between 2010 and 2016, with approximately a quarter of small-molecule drugs having direct late-stage links to publicly supported institutions. The authors identify policy reforms, including strengthened march-in rights, reasonable pricing clauses, and greater transparency about public contributions, to help ensure that drugs arising from public funding are affordably accessible to patients.
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Association Between FDA and EMA Expedited Approval Programs and Therapeutic Value of New Medicines: Retrospective Cohort Study

Hwang TJ, Ross JS, Vokinger KN, Kesselheim AS - BMJ

  • Research Publications
| October 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 320 FDA-approved and 268 EMA-approved new drugs from 2007-2017, only 31% received high therapeutic value ratings from one of five health technology assessment organizations. Drugs approved under expedited review pathways were more likely to be highly rated than non-expedited drugs, while most expedited drugs approved by the FDA but not the EMA were rated as having low therapeutic value.
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Regulatory Decision-Making on COVID-19 Vaccines During a Public Health Emergency

Avorn J, Kesselheim AS - JAMA

  • Commentary & Opinion
| October 2020
  • Regulation and Clinical Evidence
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Political pressure to rush COVID-19 vaccine approval, including through Emergency Use Authorizations, risks undermining both the scientific rigor of the evaluation process and public trust in vaccination. The authors draw parallels to earlier missteps with hydroxychloroquine and convalescent plasma to illustrate the dangers of politicizing regulatory decisions.
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Using Real‐World Safety Data in Regulatory Approval Decisions: Sotagliflozin and the Risk of Diabetic Ketoacidosis

Fralick M, Kesselheim AS - Pharmacoepidemiology and Drug Safety

  • Commentary & Opinion
| October 2020
  • Regulation and Clinical Evidence
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The authors use sotagliflozin (a dual SGLT1/SGLT2 inhibitor) to illustrate how real-world safety data from related drugs already on the market can inform regulatory decisions for new medications under review, noting that diabetic ketoacidosis was an unanticipated adverse event with SGLT2 inhibitors that only became apparent through post-marketing surveillance.
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Understanding When Real World Data Can Be Used to Replicate A Clinical Trial: A Cross‐Sectional Study of Medications Approved in 2011

Fralick M, Bartsch E, Darrow JJ, Kesselheim AS - Pharmacoepidemiology and Drug Safety

  • Research Publications
| October 2020
  • Regulation and Clinical Evidence
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Among 28 medications approved by the FDA in 2011, only 2 drugs (ticagrelor and linagliptin) had pre-approval clinical trials that could potentially be replicated using insurance claims databases, primarily because 79% of trials measured outcomes not captured in claims data such as patient-reported symptoms, imaging findings, and laboratory values. The authors conclude that when pre-approval trials meet the criteria for replication in claims databases, such real-world data studies could be valuable for assessing whether they produce concordant results.
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Reputation and Authority: The FDA and the Fight Over U.S. Prescription Drug Importation

Bollyky TJ, Kesselheim AS - Vanderbilt Law Review

  • Research Publications
| October 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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US prescription drug importation requires the FDA to recognize foreign regulatory equivalence, but the FDA has historically resisted making such determinations because it maintains its gatekeeping authority and “gold standard” reputation by oversee drug safety independently rather than relying on foreign regulators. The authors propose that the FDA could successfully use prescription drug importation to address generic drug shortages and identify other contexts where foreign regulatory cooperation would help fulfill the agency’s institutional mandates without compromising its reputation.
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Origins and Ownership of Remdesivir: Implications for Pricing

Lee CC, Darrow JJ, Avorn J, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Remdesivir—the first drug shown in a well-controlled trial to have activity against COVID-19—was developed through extensive public-private collaboration, with key contributions from the US Army Medical Research Institute of Infectious Diseases (USAMRIID), the CDC, NIH-funded institutions, and multiple academic universities, before Gilead Sciences set its price at $3,120 per treatment course for privately insured patients. The authors detail how federal funding and military research infrastructure were instrumental throughout remdesivir’s discovery and development, raising questions about whether the drug’s pricing adequately reflects these substantial public-sector contributions.
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Implementing U.S. COVID-19 Testing: Regulatory and Infrastructural Challenges

Tan YT, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Fall 2020
  • Regulation and Clinical Evidence
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The authors examine how delays in COVID-19 testing authorization and rollout in the U.S., including the FDA’s initial restriction of testing to CDC-developed assays and slow Emergency Use Authorization process, significantly hampered the pandemic response.
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Drug Shortages and the Defense Production Act

Raunig BL, Kesselheim AS, Darrow JJ - American Journal of Public Health

  • Research Publications
| October 2020
  • Price, Value, and Access
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During the COVID-19 pandemic, US hospitals faced critical shortages of sedatives, neuromuscular blocking agents, opioids, antibiotics, and bronchodilators needed to treat patients, and while the Trump administration invoked the Defense Production Act (DPA) for ventilators and personal protective equipment, its application to drug shortages presents greater challenges. The authors outline how the DPA’s authorities could be deployed to address pharmaceutical supply chain vulnerabilities, while noting that statutory limitations to domestic industry and the complexity of drug manufacturing require additional government interventions beyond DPA authority alone.
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Clinical Development Times for Biosimilars in the United States

Lee CC, Kesselheim AS, Sarpatwari A - Mayo Clinic Proceedings

  • Research Publications
| October 2020
  • Innovation Incentives and Competition
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Biosimilars approved in the US required a median of 69.9 months from phase I initiation to approval, with most undergoing phase III testing averaging 22 months in length. The extensive clinical development requirements impose a high testing bar that likely restricts market entry and limits the competitive benefits biosimilars could provide in reducing drug spending.
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Clinical Benefit and Cost of Breakthrough Cancer Drugs Approved By the US Food and Drug Administration

Molto C, Hwang TJ, Borrell M, Andres M, Gich I, Barnadas A, Amir E, Kesselheim AS, Tibau Martorell A - Cancer

  • Research Publications
| October 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Among 106 trials supporting 52 cancer drug approvals, breakthrough-designated drugs showed higher odds of clinically meaningful benefit scores on the ASCO Value Framework and NCCN Evidence Blocks but not on the ASCO-CRC or ESMO-MCBS scales, while median costs of breakthrough drugs were significantly higher than nonbreakthrough drugs. The findings suggest that breakthrough designation is inconsistently associated with greater clinical benefit by validated frameworks, with these drugs commanding substantially higher prices despite mixed evidence of superiority.
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An International Review of Health Technology Assessment Approaches to Prescription Drugs and Their Ethical Principles

Rand LZG, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2020
  • Price, Value, and Access
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A review of health technology assessment (HTA) methods across six countries (Australia, Canada, France, Germany, Japan, and the UK) found significant differences in evaluation methodologies, interpretation of findings, and condition-specific exceptions, all of which influence drug pricing and coverage recommendations. The authors argue that US proposals to link domestic drug prices to these countries’ assessments should carefully consider the ethical implications of relying on HTA frameworks shaped by distinct political, social, and cultural values.
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Op-Ed: Increase Transparency at the FDA: We Need Sunlight to Fight the Pandemic

Bendicksen L, Sharfstein JM, Kesselheim AS - STAT

  • Commentary & Opinion
| September 2020
  • Regulation and Clinical Evidence
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The FDA’s lack of transparency in its COVID-19 regulatory decisions has eroded public trust at a critical moment. The authors propose four specific reforms: timely public explanations of clinical holds, disclosure of reviews for products that fail to win approval, release of the full scientific basis for emergency authorizations, and sharing of pooled de-identified clinical datasets with qualified researchers to accelerate therapeutic development.
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Getting the Right Evidence After Drug Approval

Vreman RA, Leufkens HGM, Kesselheim AS - Frontiers in Pharmacology

  • Commentary & Opinion
| September 2020
  • Regulation and Clinical Evidence
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Post-approval evidence generation (particularly comparative effectiveness data) should be prospectively planned and linked to value-based pricing and reimbursement decisions, to ensure that drugs approved with limited pre-market evidence are adequately evaluated in real-world settings.
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US Spending Associated with Transition From Daily to 3-Times-Weekly Glatiramer Acetate

Rome BN, Tessema FA, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| September 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The 2014 launch of a 3-times-weekly formulation of glatiramer acetate (Copaxone) delayed generic competition for the daily version by 2.5 years, resulting in excess US spending of $4.3 billion to $6.5 billion from 2015 to 2017, as quarterly spending remained around $962 million following this “product hop” despite the entry of generic daily formulations. Extended market exclusivity from introducing a new version of an existing brand-name drug can yield manufacturer returns out of proportion to the level of investment or risk involved; more limited incentives could encourage incremental innovations to existing drugs at a lower societal cost.
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Projected Spending for Brand-Name Drugs in English Primary Care Given US Prices: A Cross-Sectional Study

Liu M, MacKenna B, Feldman WB, Walker AJ, Avorn J, Kesselheim AS, Goldacre B - Journal of the Royal Society of Medicine

  • Research Publications
| September 2020
  • Price, Value, and Access
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If the National Health Service (NHS) in England had paid US Medicare Part D prices for the 50 most expensive brand-name drugs in primary care, spending would have increased from £1.39 billion to £6.42 billion (a 4.6-fold increase), with US-England price ratios ranging from 1.3 to 9.9. The authors conclude that adopting US drug prices could substantially reduce NHS England’s ability to fund medicines and other health services.
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Need for Transparency and Reliable Evidence in Emergency Use Authorizations for Coronavirus Disease 2019 (COVID-19) Therapies

Zhai MZ, Lye CT, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| September 2020
  • Regulation and Clinical Evidence
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The authors critique the FDA’s Emergency Use Authorization for hydroxychloroquine and chloroquine for COVID-19, noting that unlike the earlier EUA for peramivir during the H1N1 pandemic, the hydroxychloroquine EUA lacked reliable clinical evidence and adequate transparency in the agency’s decision-making.
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Challenging Patents to Promote Timely Generic Drug Entry: The Second Look Act and Other Options

Bendicksen L, Darrow JJ, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| August 2020
  • Innovation Incentives and Competition
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The Second Look Act would increase awareness of inter partes review as a faster, cheaper alternative to court litigation for challenging improperly issued drug patents, leveraging a more favorable evidentiary standard and expert patent judges at the PTAB. However, the bill’s impact is likely limited since it does not change existing processes, and more impactful reforms would include reducing the 30-month litigation stay, shifting the burden of proof to patent holders, or restricting which patents trigger automatic stays of generic approval.
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False Negative Tests for SARS-CoV-2 Infection—Challenges and Implications

Woloshin S, Patel NG, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| August 2020
  • Regulation and Clinical Evidence
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While much debate about COVID-19 testing focused on test availability and antibody test accuracy, the authors highlight that false negative results from diagnostic RT-PCR tests may prove a larger long-term problem for containment efforts. The analysis examines how FDA Emergency Use Authorization validation methods, including the use of contrived specimens and known positive samples rather than natural clinical specimens with independent adjudication, may overestimate test sensitivity, with significant implications for public health strategies relying on testing to reopen society.
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Preferences for and Experiences with Pill Appearance Changes: National Surveys of Patients and Pharmacists

Barenie RE, Kesselheim AS, Gagne JJ, Lu Z, Campbell EG, Dutcher SK, Jiang W, Sarpatwari A - American Journal of Managed Care

  • Research Publications
| August 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Surveys of 1,000 patients and 710 pharmacists found that while most patients experienced changes in generic pill appearance and strongly preferred to be notified, fewer than half recalled receiving notification, and 12% of those experiencing a change reported stopping or reducing their medication as a result. A significant perception gap also emerged, with most pharmacists reporting they frequently notify patients about appearance changes, suggesting a disconnect between pharmacist communication efforts and patient recall that represents an important target for improvement.
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Internet Searches for Unproven COVID-19 Therapies in the United States

Liu M, Caputi TL, Dredze M, Kesselheim AS, Ayers JW - JAMA Internal Medicine

  • Research Publications
| August 2020
  • Regulation and Clinical Evidence
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Following high-profile endorsements of chloroquine and hydroxychloroquine as COVID-19 treatments in March 2020, Google searches indicative of shopping for these drugs surged (442% higher for chloroquine and 1,389% higher for hydroxychloroquine) despite no reliable clinical evidence of efficacy and known cardiovascular toxicity risks. The findings demonstrate how prominent public endorsements of unproven therapies during a pandemic can rapidly drive dangerous consumer behavior, underscoring the need for responsible public health communication.
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Decision Making Under Uncertainty: Comparing Regulatory and Health Technology Assessment Reviews of Medicines in the United States and Europe

Vreman RA, Naci H, Goettsch WG, Mantel‐Teeuwisse AK, Schneeweiss SG, Leufkens HGM, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| August 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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US and European regulators identified safety uncertainties for 85-94% of approved drugs while health technology assessment (HTA) bodies less frequently reported safety concerns (53-59%). By contrast, HTA bodies raised uncertainties related to effects against relevant comparators for almost all drugs (88–100%) compared to only 12-32% for regulators. The findings suggest that increased coordination between regulators and HTA bodies is necessary to streamline evidence collection and address the clinical uncertainties each organization identifies.
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Testimony: Congress Should Support Development of New Treatments for Pediatric Rare Diseases, But Not with Priority Review Vouchers

Kesselheim AS - 116th Congress, House Committee on Energy and Commerce, Subcommittee on Health

  • Policy Interactions
| July 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
Kesselheim argues that the FDA priority review voucher program has failed to stimulate meaningful drug development, citing PORTAL research showing no significant change in the rate of new drugs entering clinical trials after voucher introduction. He documents multiple flaws in the program, including vouchers being awarded for drugs already developed through public funding or previously approved abroad, the lack of affordability requirements for voucher-awarded drugs, and FDA concerns that the program strains agency resources. He recommends letting the rare pediatric disease voucher sunset and instead supporting pediatric rare disease drug development through direct mechanisms with proven track records: expanded NIH funding, research tax credits, and public-private partnerships that include affordability guarantees for resulting products. Read his written testimony.
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Missed Opportunities on Emergency Remdesivir Use

Sarpatwari A, Kaltenboeck A, Kesselheim AS - JAMA

  • Commentary & Opinion
| July 2020
  • Regulation and Clinical Evidence
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The authors critique the FDA’s Emergency Use Authorization for remdesivir, arguing that the agency missed opportunities to impose adequate conditions for monitoring outcomes and safety, set appropriate pricing terms, and collect the systematic data needed to determine the drug’s true effectiveness.
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Drug Prices, Rebates, and Discounts

Rome BN, Feldman WB, Kesselheim AS - JAMA

  • Commentary & Opinion
| July 2020
  • Price, Value, and Access
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This letter to the editor highlights the complexities of drug pricing, rebates, and discounts, addressing how the opaque system of manufacturer rebates to insurers and PBMs complicates efforts to understand actual drug costs and develop effective pricing policies.
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Regulatory Approval Characteristics of Antimicrobial Versus Non-Antimicrobial Products, 1984-2018: An Evaluation of Food and Drug Administration Flexibilities

Darrow JJ, Najafzadeh MN, Stefanini K, Kesselheim AS - Lancet Infectious Diseases

  • Research Publications
| July 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Antimicrobial products approved by the FDA between 1984 and 2018 were more frequently granted priority review, fast-track designation, and accelerated approval compared to non-antimicrobial products, and had a shorter median development time from investigational new drug application to approval (5.9 years versus 7.6 years). The findings indicate that the FDA has already exercised substantial regulatory flexibility for antimicrobial drugs, contradicting arguments that antimicrobial development faces more burdensome approval timelines than non-antimicrobial products.
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Rates and Costs of Dispensing Naloxone to Patients at High Risk for Opioid Overdose in the United States, 2014-2018

Barenie RE, Gagne JJ, Kesselheim AS, Pawar AM, Tong A, Luo J, Bateman BT - Drug Safety

  • Research Publications
| July 2020
  • Price, Value, and Access
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Among over 5.2 million new opioid initiators in a large US commercial insurance database from 2014 to 2018, 12% met criteria for high overdose risk, yet only 0.5% of those high-risk patients were dispensed naloxone, with average out-of-pocket costs for naloxone ($31.01) roughly 2.3 times higher than for the opioid itself ($13.48). These findings highlight extremely low naloxone co-prescribing rates despite guideline recommendations and suggest that cost barriers may be contributing to limited access for patients most in need.
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Novelty of Active Ingredients in High-Cost Brand-Name Drugs

Jung EH, Sarpatwari A, Kesselheim AS - Journal of General Internal Medicine

  • Research Publications
| July 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Among the 27 active ingredients in the 25 highest-spending Medicare Part D brand-name drugs in 2017, 41% had previously been approved in other formulations or products, with a median of 19.2 years since their first FDA approval, and only 22% had FDA-approved generic or biosimilar alternatives. These findings challenge the common justification that high brand-name drug prices are needed to sustain new drug development, given that many of the costliest products contain active ingredients that have been known and used for decades.
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Lessons From the Impact of Price Regulation on the Pricing of Anticancer Drugs in Germany

Lauenroth VD, Kesselheim AS, Sarpatwari A, Stern AD - Health Affairs

  • Research Publications
| July 2020
  • Price, Value, and Access
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Using data on 57 anticancer drugs launched in Germany from 2002 to 2017, the authors found that the 2011 AMNOG price regulation framework was associated with drug prices becoming more closely aligned with clinical benefit, with price negotiations resulting in a 24.5 percent decrease in negotiated prices relative to launch prices, and no evidence that manufacturers compensated by setting higher initial prices. The findings suggest that government price negotiation can be structured to align drug prices with clinical benefit while maintaining timely patient access to new medications.
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Reconsidering the Scope of US State Laws Allowing Pharmacist Substitution of Generic Drugs

Darrow JJ, Chong JE, Kesselheim AS - BMJ

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Pharmacists currently lack sufficient authority to substitute generic alternatives for branded drugs, despite high generic prescribing rates, which contributes to branded medicines remaining the primary driver of drug costs. Expanding pharmacist substitution authority to include clinically similar alternatives could substantially reduce pharmaceutical spending.
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Testimony: Drug Approval During the COVID-19 Pandemic: Following the Evidence

Rome BN - 116th Congress, House Committee on Science, Space, and Technology, Subcommittee on Investigations and Oversight

  • Policy Interactions
| June 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Rome argues that the COVID-19 pandemic has shown it is possible to conduct rigorous, high-quality clinical trials of repurposed drugs on a rapid timeline, but that the FDA should not abandon evidence-based standards under pressure to act quickly. He emphasizes the critical role of federal funding in generating high-quality evidence, particularly for repurposed drugs where industry incentives are weak, and notes that observational real-world data studies can complement but not replace randomized trials. Congress should hold government officials accountable for evidence-based statements, invest in clinical trials and a coordinated national clinical trial network to support repurposing research, and reform the emergency use authorization (EUA) process to clarify evidentiary standards, improve transparency, and facilitate evidence generation. Read his written testimony.
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Drug Evaluation During the COVID-19 Pandemic

Rome BN, Avorn J - New England Journal of Medicine

  • Commentary & Opinion
| June 2020
  • Regulation and Clinical Evidence
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The authors discuss the importance of maintaining rigorous Medicaid coverage during the COVID-19 pandemic and argue against proposals to cap federal Medicaid contributions, emphasizing that Medicaid expansion is a rapid, proven way to bring needed resources into the health care system during a crisis.
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Specialty Drugs—A Distinctly American Phenomenon

Naci H, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| June 2020
  • Price, Value, and Access
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The category of “specialty drugs”—high-cost medications requiring special handling—is a unique feature of the US drug pricing system. The authors contrast the US approach with Germany’s value-based negotiation framework that controls drug spending without restricting physician prescribing.
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Utilization and Treatment Costs of Tumor Necrosis Factor Inhibitors After the Introduction of Biosimilar Infliximab in the United States

Kim SC, Sarpatwari A, Landon JE, Desai RJ - Arthritis & Rheumatology

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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After the 2016-2017 market entry of two biosimilar infliximab (Remicade) products in the US, biosimilar uptake was minimal—accounting for just 0.9% of total TNF inhibitor use by early 2019—while mean quarterly insurer costs per patient gradually increased for all 5 originator products. Biosimilar infliximab costs were alsosimilar to those of originator infliximab. These findings contrast sharply with European experience, where mandatory biosimilar switching yielded 64% discounts, and suggest that without more aggressive policy interventions, biosimilar entry alone may be insufficient to reduce biologic drug spending in the US.
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Grounding Value‐Based Drug Pricing in Population Health

Kaltenboeck A, Calsyn M, Frederix GWJ, Lowenthal J, Mitchell D, Rector B, Sarpatwari A - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| June 2020
  • Price, Value, and Access
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The authors argue that the term “value-based pricing” should be restricted to arrangements where drugs are priced according to their population-level health impact through a transparent, replicable process, distinguishing this from other arrangements loosely labeled as value-based that may not align drug prices with clinical benefit.
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FDA and EMA Biosimilar Approvals

Jung EH, Sarpatwari A, Kesselheim AS, Sinha MS - Journal of General Internal Medicine

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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A comparison of clinical testing requirements for 16 biosimilars approved by both the FDA and EMA found that among 10 biosimilars approved first by the EMA, 5 were approved by the FDA based on the same clinical trials, while 6 newer biosimilars received earlier FDA approval with increasingly streamlined requirements. These findings suggest the US biosimilar approval process has evolved to become more efficient and aligned with the European approach, potentially supporting faster growth of the US biosimilar market.
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Estimating the Cost of Delayed Generic Drug Entry to Medicaid

Dave CV, Sinha MS, Beall RF, Kesselheim AS - Health Affairs

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Among 69 brand-name drugs expected to lose market exclusivity between 2010 and 2016, 45% experienced delayed or absent generic entry, resulting in excess Medicaid spending of $761 million over seven years ($109 million annually). Patent litigation identified as the primary cause of delays, with the authors recommending policies that expedite the resolution of such litigation to facilitate timely generic entry.
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Comparative Outcomes of Treatment Initiation with Brand vs. Generic Warfarin in Older Patients

Desai RJ, Gopalakrishnan C, Dejene SZ, Sarpatwari A, Levin R, Dutcher SK, Wang Z, Wittayanukorn S, Franklin JM, Gagne JJ - Clinical Pharmacology & Therapeutics

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Using Medicare claims and electronic medical records from older patients, this cohort study found no significant differences in ischemic stroke/venous thromboembolism, major hemorrhage, or one-year mortality outcomes between brand and generic warfarin initiators. These findings suggest that generic warfarin is therapeutically equivalent to brand warfarin in older patients, including high-risk subgroups with atrial fibrillation or high bleeding/stroke risk scores.
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Expedited Regulatory Review of Low-Value Drugs

Darrow JJ, Beall RF - Healthcare Policy | Politiques de Santé

  • Research Publications
| May 2020
  • Regulation and Clinical Evidence
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The authors argue that the most important reform to expedited review programs is to reserve accelerated pathways for drugs whose preliminary measures of benefit are so large that traditional approval thresholds can be met earlier in the clinical trial process. They propose eliminating user fees and fully funding the review process with public funds, improving labeling to quantitatively communicate drug benefits and risks, and avoiding designations like “priority” review that may imply a degree of clinical superiority not actually established.
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Increasing Access to FDA Inspection Reports on Irregularities and Misconduct in Clinical Trials

Dal-Ré R, Kesselheim AS, Bourgeois FT - JAMA

  • Commentary & Opinion
| May 2020
  • Regulation and Clinical Evidence
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FDA inspection reports revealing data integrity problems and research misconduct at clinical trial sites should be made publicly available. The authors point to examples where serious violations in pivotal trials (including ARISTOTLE and RECORD4) were not disclosed in published papers, leading to potentially misleading meta-analyses and clinical guidance.
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March-In Rights and Compulsory Licensing-Safety Nets for Access to A COVID-19 Vaccine

Liu M, Feldman WB, Avorn J, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| May 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Despite massive public investment in COVID-19 vaccine development, there are no safeguards ensuring affordability, and companies have already attempted to profit-maximize through mechanisms like orphan drug designations. The federal government has two legal tools—Bayh-Dole march-in rights for publicly funded patents and Section 1498 compulsory licensing for any patent—that could serve as safety nets to ensure broad vaccine access.
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Real-World Evidence And Regulatory Drug Approval

Raphael MJ, Gyawali B, Booth CM - Nature Reviews Clinical Oncology

  • Commentary & Opinion
| May 2020
  • Regulation and Clinical Evidence
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The authors examine three recent examples where the FDA used real-world evidence to support cancer drug approval, cautioning that while RWE can complement clinical trials, comparisons with low-quality historical controls risk approving ineffective drugs, particularly when post-approval confirmatory studies are delayed or poorly designed.
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Prices and Clinical Benefit of Cancer Drugs in the USA and Europe: A Cost-Benefit Analysis

Vokinger KN, Hwang TJ, Grischott T, Reichert S, Tibau Martorell A, Rosemann TJ, Kesselheim AS - Lancet Oncology

  • Research Publications
| May 2020
  • Price, Value, and Access
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This cost-benefit analysis of 65 cancer drugs approved between 2009 and 2019 found that US monthly treatment costs were 2.31 times higher than in four European countries, yet there was no significant association between drug prices and clinical benefit levels as measured by ASCO and ESMO frameworks. The authors conclude that these value frameworks should guide price negotiations to prioritize affordable access to drugs with high clinical benefit while enabling stricter pricing for therapies with low or uncertain clinical value.
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Insulin Access and Affordability in the USA: Anticipating the First Interchangeable Insulin Product

Luo J, Kesselheim AS, Sarpatwari A - Lancet Diabetes & Endocrinology

  • Commentary & Opinion
| May 2020
  • Price, Value, and Access
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The authors discuss the FDA’s regulatory reclassification of insulin that will for the first time create a clear pathway for interchangeable insulin products, which could enable automatic pharmacy substitution and substantially reduce prices for the estimated quarter of insulin users who ration their medication due to cost.
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Generic but Expensive: Why Prices Can Remain High for Off-Patent Drugs

Tessema FA, Kesselheim AS, Sinha MS - Hastings Law Journal

  • Research Publications
| May 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The US drug pricing system relies on generic competition following the expiration of brand-name market exclusivities as the primary mechanism for substantially lowering prescription drug prices, but this process frequently fails to operate as intended. Prices may not fall after exclusivity expires, or generic drug prices may actually increase due to a variety of market factors. The authors examine the barriers that undermine expected generic cost savings, particularly for older off-patent drugs, and propose policy solutions to stabilize the generic marketplace and reduce the frequency and impact of generic price increases.
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What Do High Drug Prices Buy Us?

Frank RG, Avorn J, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| April 2020
  • Price, Value, and Access
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An analysis of all 46 new drugs approved in the US in 2017 found that nearly 37 percent were consistently rated by health technology assessment agencies in Canada, Germany, and France as offering little or no clinical benefit over existing treatments, many at high cost. These findings challenge the pharmaceutical industry’s argument that high US prices are necessary to fund innovation and suggest that government price negotiation tied to therapeutic value could incentivize more meaningful drug development while improving affordability.
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Communicating Emerging Risks of SGLT2 Inhibitors—Timeliness and Transparency of Medicine Regulators

Bhasale AL, Mintzes BJ, Sarpatwari A - BMJ

  • Research Publications
| April 2020
  • Regulation and Clinical Evidence
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A comparison of how the FDA, EMA, Health Canada, and Australia’s TGA communicated emerging safety risks for SGLT2 inhibitors revealed significant differences in the number, timeliness, and strength of safety communications, including one instance where a regulator identified the risk of lower limb amputation during pre-market assessment, yet 3 years passed before any public warning was issued. The authors found that in some cases the wording of warnings was weakened after industry interactions, calling for greater transparency to ensure that regulatory safety decisions prioritize public over commercial interests.
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The Evidence Landscape in Precision Medicine

Hey SP, Gerlach CV, Dunlap G, Prasad V, Kesselheim AS - Science Translational Medicine

  • Commentary & Opinion
| April 2020
  • Regulation and Clinical Evidence
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The authors propose the concept of “evidence landscapes” as a tool for mapping and coordinating the complex evidence needed in precision medicine, where therapeutic strategies involve ensembles of diagnostic tests, biomarker validations, and targeted treatments that each require independent evaluation.
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Op-Ed: Searching for an Effective COVID-19 Treatment: Promise and Peril

Alexander GC, Kesselheim AS, Moore TJ - STAT

  • Commentary & Opinion
| April 2020
  • Regulation and Clinical Evidence
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The authors warn that the urgency of the COVID-19 pandemic risks undermining the scientific rigor needed to identify safe and effective treatments. Citing the FDA’s emergency authorization of hydroxychloroquine without identified clinical evidence, the premature promotion of unproven therapies, and the power of the placebo effect, they argue it is a false choice between speed and rigor—and call for international coordination of trials, transparent sharing of results, and evaluation of meaningful clinical outcomes rather than surrogate measures.
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Using Data From Routine Care to Estimate the Effectiveness and Potential Limitations of Outcomes-Based Contracts for Diabetes Medications

Fralick M, Gagne JJ, Patorno E, Levin R, Kesselheim AS - Value in Health

  • Research Publications
| April 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Using real-world data from newly prescribed diabetes patients, three medications with outcomes-based contracts (exenatide, dulaglutide, and sitagliptin) were found to achieve hemoglobin A1C targets below 8% in majority of patients, though hypoglycemia rates varied by therapy. Simulatenously, these branded medications cost $550-$859 monthly compared to $14 for generic glipizide, which achieved similar A1C control, suggesting that while outcomes-based contracts have potential to reduce medication costs, using hemoglobin A1C as the performance metric may be problematic because comparable glycemic control can be achieved with generic alternatives.
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Evaluating the Evidence Behind the Surrogate Measures Included in the FDA’s Table of Surrogate Endpoints as Supporting Approval of Cancer Drugs

Gyawali B, Hey SP, Kesselheim AS - eClinicalMedicine

  • Research Publications
| April 2020
  • Regulation and Clinical Evidence
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An evaluation of the 5 surrogate endpoints listed by the FDA for breast cancer (pCR, EFS, DFS, ORR, and PFS) found that treatment effects on none of these measures were strongly correlated with treatment effects on overall survival, except for DFS in HER2-positive early breast cancer. These findings raise concerns about the FDA’s reliance on these surrogate measures for regular drug approval in breast cancer, given that weak surrogate-to-survival correlations mean approved drugs may not provide the clinical benefit patients and prescribers expect.
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Estimation of Medicare Part D Spending on Insulin for Patients with Diabetes Using Negotiated Prices and a Defined Formulary

Feldman WB, Rome BN, Lehmann LS, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| April 2020
  • Price, Value, and Access
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Medicare Part D spent an estimated $7.8 billion after rebates on 31 insulin products in 2017. Applying VA-negotiated prices could yield substantial savings, with further reductions possible by adopting the VA’s national formulary, which covers fewer branded insulin products. The findings support legislative proposals to allow Medicare to negotiate drug prices directly with manufacturers, using insulin as a prominent case study given the intense public and Congressional attention to insulin affordability.
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Development of a National Public Pharmaceutical Research and Development Institute

Sarpatwari A, Brown D, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Spring 2020
  • Innovation Incentives and Competition
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The authors propose creating a publicly supported institute to advance taxpayer-funded basic science discoveries through regulatory approval, arguing this would complement existing private-sector drug development and help ensure that publicly funded research translates into affordable medicines.
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A Systematic Review and Meta-Analysis of Bevacizumab in First-Line Metastatic Breast Cancer: Lessons for Research and Regulatory Enterprises

Hey SP, Gyawali B, D'Andrea E, Kanagaraj M, Franklin JM, Kesselheim AS - Journal of the National Cancer Institute

  • Research Publications
| April 2020
  • Regulation and Clinical Evidence
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This systematic review and meta-analysis of 52 studies found that bevacizumab demonstrated a progression-free survival (PFS) benefit in first-line metastatic breast cancer, but this did not translate to overall survival benefit. The evidence demonstrates that the FDA’s withdrawal of bevacizumab’s accelerated approval was justified by the evolving evidence, and future cancer drug trials should prioritize clinically meaningful endpoints rather than relying on PFS as a surrogate measure for overall survival.
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Prescribing Systemic Steroids for Acute Respiratory Tract Infections in United States Outpatient Settings: A Nationwide Population-Based Cohort Study

Lin KJ, Dvorin E, Kesselheim AS - PLOS Medicine

  • Research Publications
| March 2020
  • Regulation and Clinical Evidence
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Among 9.76 million US outpatients with acute respiratory tract infections from 2007-2016, 11.8% were prescribed systemic steroids despite lack of evidence-based support, with substantial geographical variation and increasing prescribing trends over time. These findings demonstrate a need for targeted education programs to reduce systemic steroid use in acute respiratory tract infections, which lacks clear clinical benefit.
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Sponsorship and Funding for Gene Therapy Trials in the United States

Kassir Z, Sarpatwari A, Kocak B, Kuza CC, Gellad WF - JAMA

  • Research Publications
| March 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 341 active US gene therapy trials identified on ClinicalTrials.gov, academia sponsored 50% and the NIH provided funding for 29%, while industry sponsored 40%. Academic and NIH involvement was particularly prominent in ex vivo therapies and cancer trials. These findings demonstrate the substantial public-sector contribution to gene therapy clinical development, relevant to ongoing pricing debates given that the 4 FDA-approved gene therapies carry list prices ranging from $373,000 to $2.1 million for one-time infusions.
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Revisiting the National Institutes of Health Fair Pricing Condition: Promoting the Affordability of Drugs Developed with Government Support

Sarpatwari A, LaPidus AK, Kesselheim AS - Annals of Internal Medicine

  • Research Publications
| March 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The NIH’s 1989 fair pricing condition for cooperative research agreements was removed in 1995 based on claims it chilled industry collaboration, but the authors’ review found that standard CRADA volume remained stable during the condition’s tenure, and the post-removal surge was largely attributable to a new expedited materials CRADA pathway introduced in 1996. The authors recommend reinstating a well-designed pricing condition applied consistently to all drugs with key NIH-supported contributions, arguing that industry dependence on government research makes a chilling effect unlikely.
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Why High Drug Pricing Is A Problem for Research Ethics

Hey SP - Journal of Bioethical Inquiry

  • Commentary & Opinion
| March 2020
  • Price, Value, and Access
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The future price of a drug should not be ignored during the ethical evaluation of clinical trials, because high drug pricing undermines all three major principles of research ethics: respect for participants who may not benefit from the resulting product, beneficence in risk-benefit assessments, and justice in ensuring future patients can access the treatment.
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Potential Medicare Savings on Inhaler Prescriptions Through the Use of Negotiated Prices and a Defined Formulary

Feldman WB, Avorn J, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| March 2020
  • Price, Value, and Access
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Medicare Part D spent an estimated $7.3 billion on 31 inhalers in 2017, and applying VA-negotiated prices would have reduced spending by $1.4 billion (19.4%), while implementing the VA formulary could have saved $4.2 billion (57.8%). These findings demonstrate the substantial potential savings from allowing Medicare to negotiate directly with pharmaceutical companies and employ formulary tools for inhaler prescriptions without compromising patient care quality.
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New Drug Approvals in Oncology

Kurzrock R, Kantarjian HM, Kesselheim AS, Sigal EV - Nature Reviews Clinical Oncology

  • Commentary & Opinion
| March 2020
  • Regulation and Clinical Evidence
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This viewpoint presents a debate about the evolving regulatory paradigm for cancer drugs, with the authors arguing that newer expedited approval pathways have accelerated access to beneficial therapies and that delays in drug approval have historically cost tens of thousands of patient life-years, while acknowledging the need for rigorous evidence standards.
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Generating Comparative Evidence on New Drugs and Devices Before Approval

Naci H, Salcher-Konrad M, Kesselheim AS, Wieseler B, Rochaix L, Redberg RF, Salanti G, Jackson E, Garner S, Stroup TS, Cipriani A - Lancet

  • Research Publications
| March 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Fewer than half of new drugs approved in Europe and the US have comparative evidence against existing treatments at the time of approval, and this gap is even more pronounced for medical devices, creating uncertainty that is exacerbated by expedited regulatory programmes. The authors propose five stratgies to ensure the appropriate generation of comparative effectiveness data: including a statement of comparative data availability on drug, more selective use of expedited approval pathways, regulator encouragment of active-comparator randomized trials, use of prospective network meta-analyses, and leveraging payer negotiating power to incentivize comparative evidence generation.
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European Medicines Agency’s Priority Medicines Scheme at 2 Years: An Evaluation of Clinical Studies Supporting Eligible Drugs

Neez E, Hwang TJ, Sahoo SA, Naci H - Clinical Pharmacology & Therapeutics

  • Research Publications
| March 2020
  • Regulation and Clinical Evidence
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An evaluation of the EMA’s Priority Medicines (PRIME) scheme found that among 39 designated agents and their 138 associated studies, there was no significant difference in the use of randomization or blinding between trials initiated before versus after PRIME designation, nor between PRIME and non-PRIME products overall. However, post-designation trials were significantly more likely to include clinical endpoints and less likely to rely solely on surrogate measures, suggesting PRIME’s regulatory guidance may improve the clinical relevance of trial designs.
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Improving Competition to Lower US Prescription Drug Costs

Kesselheim, Aaron S - Washington Center for Equitable Growth

  • Commentary & Opinion
| February 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The author argues that no single policy can address high US drug prices and proposes targeted reforms across four phases of a drug’s lifecycle, including reasonable pricing provisions for publicly funded research, Medicare price negotiation, restrictions on secondary and tertiary patents that delay generic entry, and importation or government-sponsored manufacturing to address price spikes for off-patent and generic drugs.
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Testimony: More Cures for More Patients: Overcoming Barriers

Kesselheim AS - 116th Congress, House Committee on Ways and Means, Subcommittee on Health

  • Policy Interactions
| February 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Kesselheim argues that despite substantial US government support for pharmaceutical innovation, many new drugs offer little clinical improvement over existing treatments despite high prices. NIH funding has been shown to be the most effective driver of transformative drug development while the research and experimentation tax credit has been misapplied to activities like regulatory compliance and minor product improvements. To improve the value of these incentives, he recommends expanding NIH funding paired with reasonable royalty and pricing clauses for taxpayer-funded discoveries, narrowing qualifying activities under the research tax credit, making Orphan Drug Act credits repayable for blockbuster rare disease drugs, and using the tax code to penalize above-inflation price increases and failure to complete confirmatory trials. Read his written testimony.
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Letter on S.3133/H.R.5497, The Conditional Approval Act

Fernandez Lynch H, Joffe S, Zettler PJ, Caplan AL, Darrow JJ, Bateman-House A, Sarpatwari A, Snyder J, Naci H, Robertson CT, Andrews JA, Kesselheim AS - 116th Congress, Office of Representative Bruce Westerman & Office of Senator Mike Braun

  • Policy Interactions
| February 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The signatories oppose the proposed Conditional Approval Act, arguing it duplicates the FDA’s existing accelerated approval pathway and risks replicating its shortcomings, including reliance on weak surrogate endpoints and delayed postapproval evidence. Instead, they recommend strengthening accelerated approval with stricter confirmatory trial requirements and improving the expanded access pathway to preserve rigorous preapproval evidence generation while maintaining patient access.
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Confidentiality Orders and Public Interest in Drug and Medical Device Litigation

Egilman AC, Kesselheim AS, Krumholz HM, Ross JS, Kim J, Kapczynski A - JAMA Internal Medicine

  • Research Publications
| February 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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While legal standards recognize public interest in accessing safety and efficacy information from drug and medical device litigation, courts and litigants frequently impose overly broad confidentiality orders that prevent disclosure of important public health information to patients, clinicians, and the FDA. The authors recommend strengthening mechanisms to challenge these orders and highlight the role of medical experts in advancing access to litigation-derived information critical to public health.
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FDA Approval and Regulation of Pharmaceuticals, 1983-2018

Darrow JJ, Avorn J, Kesselheim AS - JAMA

  • Research Publications
| January 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Over the past four decades, FDA drug approval has undergone substantial transformation. Annual new drug approvals rose from a mean of 25 in 2000-2009 to 41 in 2010-2018, orphan drug designations grew from 18% to 41% of approvals, 81% of new drugs in 2018 benefited from at least one expedited program, and industry user fees expanded from a mean of $66 million annually in 1993-1997 to $820 million in 2013-2017, funding approximately 80% of review staff salaries by 2018. Alongside these changes, the FDA has increasingly accepted less evidence—the proportion of approvals supported by at least 2 pivotal trials dropped from 80.6% in 1995–1997 to 52.8% in 2015–2017—and while FDA review times fell from over 3 years to under 1 year, total development time from clinical testing authorization to approval has remained at approximately 8 years.
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Right to Try Requests and Oncologists’ Gatekeeping Obligations

Fernandez Lynch H, Sarpatwari A, Vonderheide RH, Zettler PJ - Journal of Clinical Oncology

  • Commentary & Opinion
| January 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Oncologists will be at the forefront of Right to Try requests given the strong demand for pre-approval access to cancer therapies, and physicians face difficult gatekeeping obligations in managing patient expectations while navigating a law that removes FDA and IRB oversight from the access process.
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Changes in Utilization of Generic Angiotensin Receptor Blockers Following Product Recalls in the United States

Desai RJ, Sarpatwari A, Gautam N, Lii J, Fischer MA, Gagne JJ - JAMA

  • Research Publications
| January 2020
  • Regulation and Clinical Evidence
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Following FDA recalls of multiple lots of generic valsartan, losartan, and irbesartan due to potentially carcinogenic nitrosamine impurities, valsartan use dropped substantially while total generic ARB prescriptions remained stable, indicating patients shifted within the ARB class rather than discontinuing treatment. The findings suggest that the recall primarily caused substitution to non-recalled ARBs, particularly losartan and olmesartan, potentially averting major treatment disruptions despite the widespread confusion the recalls caused among patients, physicians, and pharmacists.
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US Food and Drug Administration Recommendations on the Use of Surrogate Measures as End Points in New Anti-Infective Drug Approvals

Hey SP, Kesselheim AS, Patel P, Mehrotra P, Powers JH - JAMA Internal Medicine

  • Research Publications
| January 2020
  • Regulation and Clinical Evidence
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FDA guidance documents for anti-infective drug development recommend surrogate measures (such as microbial culture status) as primary end points in 21 of 27 infectious disease indications, despite regulatory standards stipulating that such indirect measures should only be used for serious or life-threatening chronic conditions when substantial benefit over existing therapy is expected. The authors conclude that FDA guidance documents should be updated to align with established scientific and regulatory principles by recommending direct clinical outcome measures rather than surrogate measures as primary trial endpoints.
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The Supreme Court’s Latest Ruling on Drug Liability and Its Implications for Future Failure-To-Warn Litigation

Morten CJ, Kesselheim AS, Ross JS - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Winter 2020
  • Regulation and Clinical Evidence
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The authors discuss the Supreme Court’s decision in Merck v. Albrecht, which preserved patients’ ability to bring failure-to-warn lawsuits against drug manufacturers despite FDA approval of drug labeling, highlighting the important role such litigation plays in uncovering safety information and incentivizing timely label updates.
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Response Rates and Durations of Response for Biomarker-Based Cancer Drugs in Nonrandomized Versus Randomized Trials

Gyawali B, D'Andrea E, Franklin JM, Kesselheim AS - Journal of the National Comprehensive Cancer Network

  • Research Publications
| January 2020
  • Regulation and Clinical Evidence
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Response rates for biomarker-based cancer drugs were similar between nonrandomized and randomized trials, but durations of response were longer in nonrandomized trials than randomized trials, with nonrandomized trial outcomes being poor surrogates for overall survival. Caution should be exercised when approving or prescribing targeted cancer drugs based on nonrandomized trial data on durable responses, as these responses may be overestimated and fail to predict actual survival benefits.
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Incentivizing Antibiotic Development: Why Isn’t the Generating Antibiotic Incentives Now (GAIN) Act Working?

Darrow JJ, Kesselheim AS - Open Forum Infectious Diseases

  • Research Publications
| January 2020
  • Innovation Incentives and Competition
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The GAIN Act of 2012, designed to incentivize antibiotic development through 5 years of additional nonpatent exclusivity, has produced disappointing results because its eligibility criteria lack sufficient targeting to unmet clinical needs and disproportionately reward modifications to existing drugs over new treatments. The authors recommend narrowing QIDP eligibility criteria to a more targeted list of pathogens, greater use of animal data in eligibility determination, and conditioning benefits on companion diagnostic availability to improve the program’s effectiveness.
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Lifecycle Regulation of Artificial Intelligence- and Machine Learning-Based Software Devices in Medicine

Hwang TJ, Kesselheim AS, Vokinger KN - JAMA

  • Commentary & Opinion
| December 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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AI/ML-based medical devices require a lifecycle regulatory approach rather than the current one-time clearance model. The authors note that many AI/ML products have been cleared through the 510(k) pathway without new clinical testing by claiming substantial equivalence to devices that may be decades old.
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Op-Ed: Do Large Pharma Companies Provide Drug Development Innovation? Our Analysis Says No

Jung EH, Engelberg AB, Kesselheim AS - STAT

  • Commentary & Opinion
| December 2019
  • Innovation Incentives and Competition
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Examining the origins of top-selling drugs at Pfizer and Johnson & Johnson, the authors found that only 23% and 11% of each company’s leading products, respectively, were discovered in-house—with the vast majority acquired from other companies, universities, or publicly funded research. They argue this undermines the pharmaceutical industry’s claim that drug pricing reforms would devastate innovation, since large manufacturers are primarily acquirers rather than discoverers of new medicines, and that lower prices could instead free government resources for greater NIH investment in the research ecosystem that actually drives drug discovery.
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Prescription Opioid Epidemic and Trends in the Clinical Development of New Pain Medications

Hwang TJ, Sinha MS, Dave CV, Kesselheim AS - Mayo Clinic Proceedings

  • Research Publications
| December 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The proportion of new pain drugs entering early-stage clinical trials declined from 2.5% (2000-2002) to 1.7% (2013-2015), while most new pain drugs failed to advance through development stages, with only 52% progressing from phase 1 to phase 2 and 11% reaching phase 3 trials. The authors conclude that pain drug development has shifted toward reformulated products rather than novel therapeutics and recommend increased funding for basic pain research to address the critical need for new pain management options.
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Potential Medicare Savings From Generic Substitution and Therapeutic Interchange of ACE Inhibitors and Angiotensin-II-Receptor Blockers

Growdon ME, Sacks CA, Kesselheim AS, Avorn J - JAMA Internal Medicine

  • Research Publications
| December 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Medicare could have saved approximately $676 million (89.6%) of the $754 million spent on brand-name ACEIs and ARBs in 2016–2017 by maximizing generic substitution and therapeutic interchange, with the largest savings from interchanging brand-name olmesartan with generic losartan given that clinical guidelines do not recommend specific agents within these classes. These findings highlight the substantial savings available from simple formulary management strategies for drug classes where clinical evidence does not support meaningful differences in outcomes between agents.
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Expanding Coverage of Oncology Drugs in an Aging, Upper-Middle-Income Country: Analyses of Public and Private Expenditures in Chile

Vargas V, Leopold C, Castillo-Riquelme M, Darrow JJ - Journal of Global Oncology

  • Research Publications
| December 2019
  • Price, Value, and Access
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Oncology drug expenditures in Chile rose 120% between 2012-2013 and 2016-2017, with the public sector accounting for 84.2% of spending and increased drug use driving over 90% of growth in the public sector. Policymakers should urgently implement measures to promote generic drug use, optimize the balance between on-protocol and off-protocol drugs, and reduce off-label prescribing to address the fiscal unsustainability of current spending growth rates.
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Comments for Hearing, “Standards for Future Opioid Analgesic Approvals and Incentives for New Therapeutics to Treat Pain and Addiction”

Bonnie RJ, Kesselheim AS, Riley MF, Zettler PJ - Food and Drug Administration (FDA)

  • Policy Interactions
| November 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The commenters reiterate their support for the FDA’s proposal to consider broader public health effects in opioid regulatory decisions and calls on the agency to take additional steps to fully implement the comprehensive systems approach to opioid regulation recommended by the National Academies.
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The U.S. Insulin Crisis—Rationing a Lifesaving Medication Discovered in the 1920s

Fralick M, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| November 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors trace the history of insulin pricing from its discovery in 1922 to the present crisis in which the price of insulin has risen dramatically, leading Americans to ration a lifesaving medication. They attribute the crisis to an oligopolistic market dominated by three manufacturers and a US system that allows unchecked drug pricing, and propose policy solutions including importation and price transparency.
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Variation in Prescription Drug Prices By Retail Pharmacy Type: A National Cross-Sectional Study

Luo J, Kulldorff M, Sarpatwari A, Pawar AM, Kesselheim AS - Annals of Internal Medicine

  • Research Publications
| November 2019
  • Price, Value, and Access
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Using data from over 68,000 pharmacies across 16,325 ZIP codes, this study found substantial variation in cash prices for generic drugs by pharmacy type, with big box pharmacies offering prices 48% lower than large chains while independent pharmacies charged 61% higher prices. Brand-name drug prices varied minimally across pharmacy types. The findings suggest that consumers seeking lower cash prices for generic medications should consider a broader range of pharmacies, while policy efforts should address the significant pricing disparities for generic drugs across independent and small chain pharmacies.
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Randomized Study of Providing Evidence Context to Mitigate Physician Misinterpretation Arising From Off-Label Drug Promotion

Schwartz LM, Woloshin S, Lu Z, Ross KM, Tessema FA, Peter D, Kesselheim AS - Circulation: Cardiovascular Quality and Outcomes

  • Research Publications
| November 2019
  • Regulation and Clinical Evidence
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Among physicians surveyed, those who received manufacturer off-label promotion of Vascepa were five times more likely to prescribe it off-label (38% versus 7%). Providing physicians with additional context on the limited data supporting off-label use was found to reduce physician support of the treatment, suggesting this approach may be necessary to reduce inappropriate off-label prescribing and mitigate misinterpretation arising from manufacturer promotional materials.
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Physician Perceptions of Step Therapy Prescribing Requirements

Fischer MA, Kesselheim AS, Lu Z, Ross KM, Tessema FA, Avorn J - Journal of Managed Care & Specialty Pharmacy

  • Research Publications
| November 2019
  • Price, Value, and Access
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Most physicians surveyed (55%) acknowledged that step therapy policies could improve medication affordability and clinical appropriateness (59%), though 70% reported interactions with the pharmaceutical industry and subspecialists held more negative views of these utilization management strategies. While physicians recognized the potential benefits of step therapy for cost-effectiveness, they expressed significant concerns about inefficient and inflexible implementation that often failed to account for patient-specific information, suggesting that improved policy design and execution could enhance physician acceptance and compliance.
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Multimodal Analysis of FDA Drug Safety Communications: Lessons From Zolpidem

Kesselheim AS, Sinha MS, Campbell EG, Schneeweiss SG, Rausch P, Lappin BM, Zhou EH, Avorn J, Dal Pan GJ - Drug Safety

  • Research Publications
| November 2019
  • Regulation and Clinical Evidence
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A multi-modal study of two FDA Drug Safety Communications issued in 2013 regarding zolpidem (Ambien) found that key safety messages were incompletely disseminated through traditional and social media, and surveys and interviews revealed significant limitations in patient-provider communication that hindered the sharing of new safety information. Analysis of zolpidem dispensing patterns after the communications suggested that uptake of safety knowledge into clinical practice was suboptimal, pointing to opportunities for improving how FDA safety messages reach and influence both prescribers and patients.
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Impact of State Laws Restricting Opioid Duration on Characteristics of New Opioid Prescriptions

Dave CV, Patorno E, Franklin JM, Huybrechts KF, Sarpatwari A, Kesselheim AS, Bateman BT - Journal of General Internal Medicine

  • Research Publications
| November 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Following implementation of 7-day opioid duration limits for opioid-naïve patients in Massachusetts, Connecticut, and New York in 2016, pooled analysis showed a decreased probability of initiating a >7-day prescription and shorter opioid duration, though without an immediate reduction in total morphine equivalent dose. Between-state heterogeneity was notable, with Massachusetts and Connecticut showing immediate declines in opioid duration while New York’s effect was delayed, suggesting variable implementation and enforcement of these laws across states.
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Public Sector Financial Support for Late Stage Discovery of New Drugs in the United States: Cohort Study

Nayak RK, Avorn J, Kesselheim AS - BMJ

  • Research Publications
| October 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Between 2008 and 2017, publicly supported research contributed to the late stage development of at least 25% of FDA-approved new drugs, and drugs with public sector origins were significantly more likely to receive expedited approval (68% vs. 47%) or first-in-class designation (45% vs. 26%). These findings highlight the importance of considering public sector investment in a drug development when determining fair pricing and manufacturer revenue for new drugs.
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Desmopressin and the Risk of Hyponatremia: A Population-Based Cohort Study

Fralick M, Schneeweiss SG, Wallis CJD, Jung EH, Kesselheim AS - PLOS Medicine

  • Research Publications
| October 2019
  • Regulation and Clinical Evidence
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Adults prescribed the original formulation of desmopressin had a 13-fold higher rate of hyponatremia compared to those prescribed oxybutynin for urinary tract symptoms, with similar elevated risks observed within 30 days of initiation and when using tamsulosin as a comparator. The risks of hyponatremia associated with desmopressin should be clearly communicated to patients prescribed this formulation, particularly given the approval of a new intranasal formulation in 2017.
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Fool Me Twice? The Reemergence of Rofecoxib and the Orphan Drug Act

Lee TT, Solomon DH, Kesselheim AS - Annals of Internal Medicine

  • Commentary & Opinion
| October 2019
  • Innovation Incentives and Competition
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The authors examine how a small manufacturer obtained orphan drug designation for rofecoxib (formerly Vioxx, withdrawn for cardiovascular risks) to treat hemophilic arthropathy, warning that orphan drug approval could serve as a gateway for widespread off-label use in the much larger osteoarthritis market.
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Characteristics of Recent Generic Drug Approvals By the US Food and Drug Administration

Jiao K, Gupta R, Fox ER, Kesselheim AS, Ross JS - JAMA Network Open

  • Research Publications
| October 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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A cross-sectional study of all abbreviated new drug applications (ANDAs) approved from July 2016 to December 2018 founds increases in the proportion of generic approvals for drugs with limited competition (≤2 existing manufacturers) and for drugs with prior shortage history, consistent with the FDA’s Drug Competition Action Plan and Generic Drug User Fee Amendments. The findings suggest that FDA regulatory initiatives have begun to target the specific market segments where generic entry is most needed to address high prices and supply disruptions.
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Transformative Models to Promote Prescription Drug Innovation and Access: A Landscape Analysis

Hong P, Kesselheim AS, Sarpatwari A - Yale Journal of Health Policy, Law and Ethics

  • Research Publications
| October 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The current patent-based pharmaceutical innovation system in the US fails to prioritize drugs with the greatest public health impact and has resulted in unaffordable prices, prompting consideration of three alternative approaches: delinkage models that base payments on public health value, public manufacturing models led by governments and nonprofits, and public-private partnership models that combine public funding with private sector expertise. Each of these transformative models shows promise for promoting both pharmaceutical innovation and drug access, though each carries distinct advantages and limitations that warrant detailed examination.
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The 505(B)(2) Drug Approval Pathway

Darrow JJ, He M, Stefanini K - Food and Drug Law Journal

  • Research Publications
| October 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The Section 505(b)(2) drug approval pathway has grown dramatically and now annually exceeds the number of new drug approvals, driven by factors including accumulating exclusivities unavailable to generics, expedited programs, user fee funding, pediatric study requirements, and heightened generic market competition. An examination of all 505(b)(2) approvals from 1993 through 2016 suggests the pathway primarily functions to increase competition rather than extend brand-name exclusivity, as evidenced by the predominance of small or generic manufacturers as sponsors and the infrequency with which applicants request or receive non-patent exclusivity.
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Surrogate Endpoints and Drug Regulation: What Is Needed to Clarify the Evidence

Hey SP, Feldman WB, Jung EH, D'Andrea E, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2019
  • Regulation and Clinical Evidence
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Surrogate endpoints are widely used in pivotal drug trials because they can be measured sooner than direct clinical outcomes, but unlike drugs, biomarkers typically have no single owner or stakeholder responsible for generating validation evidence—creating a collective action problem where drug developers may underinvest in validating surrogates that would benefit their competitors. The authors argue that this structural gap, combined with the absence of a central regulator tracking evidence for or against particular biomarkers, has led to the systematic use of poorly validated surrogate measures in drug approval, and they propose policy reforms to strengthen the evidence base for surrogates.
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Patients’ Knowledge of Key Messaging in Drug Safety Communications for Zolpidem and Eszopiclone: A National Survey

Kesselheim AS, Sinha MS, Rausch P, Lu Z, Tessema FA, Lappin BM, Zhou EH, Dal Pan GJ, Zwanziger L, Ramanadham A, Loughlin A, Enger CL, Avorn J, Campbell EG - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2019
  • Regulation and Clinical Evidence
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Among 594 patients taking zolpidem or eszopiclone, two-thirds reported hearing about drug safety information generally, but only two-thirds of zolpidem users and half of eszopiclone users had heard about the specific Drug Safety Communications for these drugs. Patients also showed limited ability to accurately identify key messages in these communications. The authors recommend that the FDA work collaboratively with providers and pharmacies to improve the reach and comprehension of Drug Safety Communications among patients taking these medications.
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Lung Cancer Survival Gains: Contributions of Academia and Industry

Gyawali B, Bouche G, Pantziarka P, Kesselheim AS, Sarpatwari A - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2019
  • Regulation and Clinical Evidence
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Among 57 NCCN-recommended interventions for non-small cell lung cancer, 39 (68%) were based on at least one RCT, of which only 19 (49%) demonstrated overall survival gains across 26 published trials. Sponsorship and funding analysis also revealed the relative contributions of academic and industry stakeholders to these life-extending outcomes. The findings inform resource allocation discussions by identifying which types of interventions and institutional contributors have driven the most meaningful survival improvements in the leading cause of cancer death worldwide.
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Challenges and Opportunities for Biomarker Validation

Hey SP, D'Andrea E, Jung EH, Tessema FA, Luo J, Gyawali B, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Fall 2019
  • Regulation and Clinical Evidence
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Rigorous biomarker validation is critical to clinical practice and drug development. The authors argue that relying on unvalidated biomarkers can harm patients and propose a framework for improving the validation process.
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Application of Orphan Drug Designation to Cancer Treatments (2008-2017): A Comprehensive and Comparative Analysis of the USA and EU

Vokinger KN, Kesselheim AS - BMJ Open

  • Research Publications
| October 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Between 2008 and 2017, the FDA approved 135 cancer drugs with orphan indications, of which 75% were also approved by the EMA, but only 41% of these received orphan designation from the EMA. Notably, 79% were first approved in the US, and the FDA approved significantly more drugs for biomarker-based indications (33%) and solid tumors (78%) compared to the EMA. The findings suggest that the FDA’s more liberal orphan designation criteria, particularly for cancer subgroups derived from biomarkers and solid tumors, differ substantially from the EMA’s requirements, resulting in divergent regulatory approaches to orphan drug approvals.
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Design Characteristics, Risk of Bias, and Reporting of Randomised Controlled Trials Supporting Approvals of Cancer Drugs by European Medicines Agency, 2014-16: Cross Sectional Analysis

Naci H, Davis C, Savović J, Higgins JPT, Sterne JAC, Gyawali B, Romo-Sandoval X, Handley N, Booth CM - BMJ

  • Research Publications
| September 2019
  • Regulation and Clinical Evidence
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Among 41 randomized controlled trials supporting EMA approval of 32 new cancer drugs between 2014 and 2016, 49% were judged to be at high risk of bias, with only 26% measuring overall survival as a primary endpoint and the remainder relying on surrogate measures. Risk of bias was lower for trials evaluating overall survival (20%) compared to surrogate endpoints (55%). Regulatory documents and journal publications inconsistently reported trial limiations acknowledged by regulators, suggesting a need for more transparent and complete reporting of cancer drug trial evidence.
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Changes in Price for Generic Drugs in the USA, 2008-2016

Dave CV, Brill G, Kesselheim AS - Journal of General Internal Medicine

  • Research Publications
| September 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Among 1,099 generic drugs available throughout 2008–2016, mean prices increased by 39.9% while median prices fell 30.0%, reflecting a bifurcated market where 17.2% of drugs more than doubled in price while 60.8% experienced price decreases. The most commonly prescribed drugs saw the largest declines and infrequently prescribed drugs experienced the greatest increases These findings suggest that while the generic drug market is functioning well for high-volume products, low-volume generic drugs remain vulnerable to substantial price increases due to insufficient competition.
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Assessing the Justification, Funding, Success, and Survival Outcomes of Randomized Noninferiority Trials of Cancer Drugs: A Systematic Review and Pooled Analysis

Gyawali B, Tessema FA, Jung EH, Kesselheim AS - JAMA Network Open

  • Research Publications
| August 2019
  • Regulation and Clinical Evidence
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Among 23 randomized noninferiority trials of cancer drugs with overall survival as the primary endpoint, 39% lacked justification for the noninferiority design. Industry-funded trials were significantly more likely to lack proper justification, though funding was not associated with success in achieving noninferiority. The pooled analysis showed no beneficial or detrimental effect on overall survival, suggesting that regulators should increase scrutiny of noninferiority trial designs in cancer drug development.
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Promoting Pediatric Drug Research and Labeling—Outcomes of Legislation

Bourgeois FT, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| August 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Despite over 20 years of legislative efforts including the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, significant gaps persist in pediatric labeling for FDA-approved drugs remain. The authors review the outcomes of these landmark pediatric drug laws, examining whether the financial incentives and regulatory mandates have succeeded in generating adequate prescribing information for children.
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Comments on Notice, “New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication” (Doshi et al.)

Doshi P, Herder M, Alexander GC, Bero L, Bijl D, Bourgeois FT, Cassels A, Chirac P, Darrow JJ, Dickersin K, Erviti J, Gøtzsche PC, Healy D, Helfand M, Hemkens LG, Heneghan C, Jefferson T, Jones M, Jørgensen L, Jureidini J, Kapczynski A, Kesselheim AS, Kirsch I, Krumholz HM, Leache L, Lexchin J, Li T, Lurie P, Marciniak T, Mayo-Wilson E, McDonagh M, McHenry LB, Mello MM, Miller JE, Mintzes BJ, Moore TJ, Morten CJ, Naci H, O'Sullivan C, Perry TL, Powers JH, Prasad V, Puhan M, Puil L, Redberg RF, Ross JS, Saiz LC, Sarpatwari A, Seife C, Turner EH, Vitry A, Wallach JD, Woloshin S, Zarin DA - Food and Drug Administration (FDA)

  • Policy Interactions
| August 2019
  • Regulation and Clinical Evidence
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The commenters oppose the FDA’s plan to replace individual discipline-specific drug reviews with a single “integrated review,” arguing this would reduce transparency by eliminating detailed reviewer analyses, dissenting opinions, and granular safety data that researchers and the public rely on to understand FDA decision-making.
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Comments on Draft Guidance, “Opioid Analgesic Drugs: Considerations for Benefit-Risk Assessment Framework”

Bonnie RJ, Kesselheim AS, Riley MF, Zettler PJ - Food and Drug Administration (FDA)

  • Policy Interactions
| August 2019
  • Regulation and Clinical Evidence
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The commenters applaud the FDA’s draft guidance incorporating “broader public health effects” into opioid benefit-risk assessments as an important first step in implementing the National Academies’ recommendations, while urging further action to fully adopt a comprehensive systems approach to opioid regulation.
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Why Are Biosimilars Not Living Up to Their Promise in the US?

Zhai MZ, Sarpatwari A, Kesselheim AS - AMA Journal of Ethics

  • Research Publications
| August 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Despite Congress creating an abbreviated approval pathway for biosimilars in 2010 to stimulate competition and reduce the high costs of biologic drugs, only 17 biosimilars had been approved by February 2019, with just 7 on the market and limited overall utilization. The authors characterize the tactics employed by originator biologic manufacturers to delay biosimilar market entry and deter prescribing—including patent thickets, rebate structures, and misinformation campaigns—and assess the ethical dimensions of increasing biosimilar adoption to improve patient access to valuable therapies.
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Characteristics of Trials and Regulatory Pathways Leading to US Approval of Innovative vs. Non-Innovative Oncology Drugs

Vokinger KN, Kesselheim AS - Health Policy

  • Research Publications
| August 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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First-generation oncology drugs and most second-generation variants across four drug classes (BCR-ABL TKIs, ALK+ TKIs, CD20 monoclonal antibodies, and HER2 monoclonal antibodies) were approved through expedited pathways and predominantly based on single-arm trials, with second-generation drugs showing similar approval patterns to their first-generation counterparts. While expedited approval facilitates earlier patient access, this regulatory approach is associated with increased risk of post-approval safety-related labeling changes and unanticipated adverse events.
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Designing Development Programs for Non-Traditional Antibacterial Agents

Rex JH, Fernandez Lynch H, Cohen IG, Darrow JJ, Outterson K - Nature Communications

  • Commentary & Opinion
| July 2019
  • Innovation Incentives and Competition
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The distinction between “traditional” and “non-traditional” antibacterial agents has limited regulatory relevance, and most agents in both categories should be developed using standard clinical efficacy measures, while acknowledging that some products with population-level benefits may require novel regulatory paradigms.
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Competition and Price Among Brand-Name Drugs in the Same Class: A Systematic Review of the Evidence

Sarpatwari A, DiBello J, Zakarian M, Najafzadeh MN, Kesselheim AS - PLOS Medicine

  • Research Publications
| July 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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A systematic review of 10 empirical studies found no evidence that brand-name competition within the same drug class lowers list prices of existing drugs, though two studies suggested it may modestly restrain pricing of newly introduced drugs. The authors conclude that policies promoting brand-brand competition alone are unlikely to reduce drug prices without additional structural reforms to the pharmaceutical market.
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Public Approval of Exception From Informed Consent in Emergency Clinical Trials: A Systematic Review of Community Consultation Surveys

Feldman WB, Hey SP, Franklin JM, Kesselheim AS - JAMA Network Open

  • Research Publications
| July 2019
  • Regulation and Clinical Evidence
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This systematic review of survey respondents across 27 FDA-approved exception from informed consent (EFIC) trials found that public approval of EFIC varied significantly, with more people willing to approve initiation of EFIC trials in their community (86.5%) than personal enrollment (73.0%), enrollment of a family member (68.6%), or the principle of enrollment without consent (58.4%). Surveyed populations were demographically skewed, with African American individuals and men underrepresented. The authors recommend that the FDA strengthen community consultation by standardizing survey instruments and reporting, requiring broader inclusion of African American and male respondents, and clarifying how survey results inform trial protocol development.
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Comments on Notice, “New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication” (Herder et al.)

Herder M, Doshi P, Wallach JD, Graham JE, Lexchin J, Lemmens T, Ross JS, Gonsalves G, Persaud N, Lurie P, Naci H, Jones M, Jefferson T, Alexander GC, Turner EH, Mayo-Wilson E, Miller JE, Hemkens LG, Healy D, Jureidini J, Li T, Dickersin K, Kesselheim AS, Bruckner T, Reed T, Davis C - Food and Drug Administration (FDA)

  • Policy Interactions
| July 2019
  • Regulation and Clinical Evidence
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The FDA should complete and expand its Clinical Study Report pilot project by making public disclosure of clinical study reports mandatory for all approved drugs, as transparency of these company-generated trial documents is essential for identifying underreported safety and efficacy information
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Biosimilar Approvals and the BPCIA: Too Soon to Give Up

Darrow JJ - Health Affairs Forefront

  • Commentary & Opinion
| July 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Critics who compare biosimilar approval numbers unfavorably to the Hatch-Waxman Act’s success with generics overlook key structural differences that explain the slower pace of biosimilar market entry. US biosimilar approvals have actually outpaced the EU’s during comparable post-enactment periods, and an upward trend in approvals, promising price discounts abroad, and a robust development pipeline suggest the BPCIA framework should be refined rather than abandoned.
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Spending on World Health Organization Essential Medicines in Medicare Part D, 2011-15: Retrospective Cost Analysis

Li DG, Najafzadeh MN, Kesselheim AS, Mostaghimi A - BMJ

  • Research Publications
| July 2019
  • Price, Value, and Access
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Medicare Part D spending on 265 World Health Organization (WHO) essential medicines increased 116% from $11.9 billion in 2011 to $25.8 billion in 2015, driven primarily by the introduction of expensive novel hepatitis C treatments and per-unit cost increases in existing drugs. Patient out-of-pocket spending rose 47% over the same period. These escalating costs for essential medicines may restrict patient access and increase overall healthcare system burden, warranting attention to policy mechanisms to improve medication affordability.
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Price Increases of Protected-Class Drugs in Medicare Part D, Relative to Inflation, 2012-2017

Hwang TJ, Dusetzina SB, Feng J, Maini L, Kesselheim AS - JAMA

  • Research Publications
| July 2019
  • Price, Value, and Access
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Among 143 brand-name drugs in Medicare Part D’s 6 protected classes, 88.1% had 1-year list price increases exceeding inflation, and over a 3-year period the median list price increase was 25.8% versus 3.5% inflation. The analysis also found that commercial and ACA marketplace insurers already exclude many protected-class drugs from their formularies, suggesting that Medicare’s protected-class requirements, while important for ensuring patient access, may limit plans’ ability to negotiate effectively on price.
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Reforming the Orphan Drug Act for the 21st Century

Sarpatwari A, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| July 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors argue that the Orphan Drug Act needs reform to address exploitation of its incentives, including strategies by manufacturers to obtain serial exclusivity and the potential for orphan-designated drugs to be widely used off-label for common conditions.
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The Impact of Price Regulation on the Availability of New Drugs in Germany

Stern AD, Pietrulla F, Herr A, Kesselheim AS, Sarpatwari A - Health Affairs

  • Research Publications
| July 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The 2011 German Pharmaceutical Market Restructuring Act implemented price regulation based on clinical benefit assessment, resulting in 98% of drugs with positive benefit assessments remaining on the market compared to only 75% of those without positive assessments. Drugs lacking positive assessments were more than ten times more likely to exit the German market. US policymakers considering drug cost containment strategies can learn from Germany’s experience with benefit-based price regulation and its impact on drug market availability.
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Pre-Market Development Times for Biologic Versus Small-Molecule Drugs

Beall RF, Hwang TJ, Kesselheim AS - Nature Biotechnology

  • Research Publications
| July 2019
  • Innovation Incentives and Competition
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Using key patent filing dates to measure total development time, the authors found that biologic drugs did not spend significantly longer in development than small-molecule drugs before FDA approval—challenging the legislative rationale behind the 12-year exclusivity period granted to biologics under the BPCIA, which was justified in part by presumed longer development timelines. These findings have important policy implications for ongoing debates about biologic exclusivity periods in both domestic legislation and international trade agreements.
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Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval

Gyawali B, Hey SP, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| July 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Of 93 cancer drug indications granted accelerated approval by the FDA between 1992 and 2017, only about one-fifth (20%) had confirmatory trials demonstrating an improvement in overall survival, while 37% of completed confirmatory trials relied on the same surrogate endpoints used in the preapproval studies rather than more clinically meaningful measures. These findings suggest the need to reassess confirmatory trial requirements to ensure the accelerated approval pathway generates more robust evidence of genuine clinical benefit for patients.
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Transparency on Prescription Drug Research Expenditures: A Lever for Restraining Pricing?

Sarpatwari A, Avorn J, Kesselheim AS - Transparency in Health and Health Care in the United States: Law and Ethics

  • Commentary & Opinion
| June 2019
  • Price, Value, and Access
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This book chapter reviews state legislative efforts to require pharmaceutical companies to disclose research and development costs for high-priced drugs, evaluating the ethical, legal, and practical merits and limitations of these transparency bills. The authors conclude that while research cost disclosure faces significant methodological and political challenges, transparency focused on supply chain markups by intermediaries such as pharmacy benefit managers and on prescription drug coupon programs would be more actionable for state policymakers seeking to address rising drug prices.
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Trust and Transparency in Medical Device Regulation

Kramer DB, Kesselheim AS - BMJ

  • Commentary & Opinion
| June 2019
  • Regulation and Clinical Evidence
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The authors discuss the FDA’s decision to end its controversial “alternative summary reporting” program for medical device adverse events, which had allowed manufacturers to report safety problems outside public view, arguing that all adverse event reports should be publicly accessible to maintain trust in device regulation.
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Landscape of Cardiovascular Device Registries in the United States

Rajan PV, Holtzman JN, Kesselheim AS, Yeh RW, Kramer DB - Journal of the American Heart Association

  • Research Publications
| June 2019
  • Regulation and Clinical Evidence
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Among 138 US cardiovascular device registries identified, the majority (55.8%) were industry-funded with academic stewardship (74.0%), but substantial inconsistencies existed in enrollment procedures (voluntary vs. required), informed consent requirements, and data access policies. The authors recommend that regulators strengthen guidelines to improve quality, consistency, and ethical standards across cardiovascular device registries.
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Orphan Drug Designation and Exclusivity for “Same Drugs”

Hong P, Sarpatwari A, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Summer 2019
  • Innovation Incentives and Competition
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The authors describe how Eagle Pharmaceuticals exploited a legal loophole in the Orphan Drug Act to achieve “serial exclusivity” for bendamustine (Bendeka), effectively extending the monopoly of an existing cancer drug by obtaining new orphan drug exclusivity for a reformulated version with the same active ingredient.
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Evaluation of Socioeconomic Status Indicators for Confounding Adjustment in Observational Studies of Medication Use

Gopalakrishnan C, Gagne JJ, Sarpatwari A, Dejene SZ, Dutcher SK, Levin R, Franklin JM, Schneeweiss SG, Desai RJ - Clinical Pharmacology & Therapeutics

  • Research Publications
| June 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This methodologic study evaluated how different socioeconomic status (SES) indicators affect confounding adjustment in observational medication studies, finding that claims-based variables alone substantially improved balance on SES measures. While adding SES data further improved balance, it did not materially change outcome estimates for cardiovascular events or emergency department visits in a cohort of 7,109 Medicare patients initiating atorvastatin. The results suggest that claims-based proxies may be sufficient for mitigating SES confounding when aggregate-level SES information is unavailable in observational studies.
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Comments for Hearing, “The Future of Insulin Biosimilars: Increasing Access and Facilitating the Efficient Development of Biosimilar and Interchangeable Insulin Products”

Luo J, Tessema FA, Kesselheim AS, Sarpatwari A - Food and Drug Administration (FDA)

  • Policy Interactions
| May 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The FDA should exempt insulin from the requirement for additional pre-approval switching studies to demonstrate interchangeability, applying the same evidentiary standards used for bioequivalent small-molecule generics, given insulin’s well-characterized molecular profile and the urgent affordability crisis facing patients.
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Pharmaceutical Protections in U.S. Trade Deals—What Do Americans Get in Return?

Bollyky TJ, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| May 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors outline the history of pharmaceutical intellectual property provisions in US trade agreements, arguing that while these protections have benefited the pharmaceutical industry, they have not demonstrably lowered drug prices for American consumers or improved US. trade balances. They question whether the claimed rationale—that stronger IP protections abroad will reduce drug costs at home—holds up to scrutiny.
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US Food and Drug Administration Approval of New Drugs Based on Noninferiority Trials in Oncology: A Dangerous Precedent?

Gyawali B, Kesselheim AS - JAMA Oncology

  • Commentary & Opinion
| May 2019
  • Regulation and Clinical Evidence
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The FDA’s approval of lenvatinib (Lenvima) for hepatocellular carcinoma based on a noninferiority trial—when the new drug was neither safer, easier to administer, nor cheaper than the comparator sorafenib—sets a concerning precedent by lowering the bar for cancer drug approval without providing clear patient benefit.
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Physicians’ Perspectives on FDA Approval Standards and Off-Label Drug Marketing

Kesselheim AS, Woloshin S, Lu Z, Tessema FA, Ross KM, Schwartz LM - JAMA Internal Medicine

  • Research Publications
| May 2019
  • Regulation and Clinical Evidence
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A national survey of 686 internists, endocrinologists, and cardiologists found that 80% viewed the FDA’s approval process as helping protect the public, 78% preferred that drugs be tested in 2 prospective randomized trials, and 65% were satisfied with current approval standards. 60% opposed allowing off-label promotion to physicians and 71% considered office-based off-label promotion by sales representatives a “bad” or “terrible” idea. A majority predicted that off-label promotion would increase prescriptions for drugs without meaningful benefits (61%) and were more likely to believe it would worsen rather than improve clinical decisions (42% vs. 30%).
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Cost Implications of Escalating Intravenous Acetaminophen Use in Children

Bourgeois FT, Graham DA, Kesselheim AS, Randolph AG - JAMA Pediatrics

  • Research Publications
| May 2019
  • Price, Value, and Access
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Among 4.7 million pediatric hospitalizations from 2010 to 2017, intravenous acetaminophen use increased from near zero to 13% of hospitalizations, reaching $16.0 million in annual costs in 2017, even as oral formulation use remained stable at 41% and the intravenous product’s price more than doubled. On 20% of hospital days when IV acetaminophen was administered, patients were also receiving other oral medications, raising questions about whether the substantially more expensive intravenous formulation was clinically necessary in many cases.
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Assessment of the Role of Niacin in Managing Cardiovascular Disease Outcomes: A Systematic Review and Meta-Analysis

D'Andrea E, Hey SP, Ramirez CL, Kesselheim AS - JAMA Network Open

  • Research Publications
| April 2019
  • Regulation and Clinical Evidence
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This systematic review and meta-analysis of 17 randomized clinical trials found no preventive association of niacin with cardiovascular outcomes in secondary prevention overall, though niacin monotherapy showed reduced risk of acute coronary syndrome, stroke, and revascularization in patients not receiving statins, findings primarily from studies conducted in the 1970s-1980s. The authors conclude that niacin may have limited utility in lipid control for secondary prevention as monotherapy, potentially for statin-intolerant patients, but current evidence derives from older studies on populations that may not represent modern cardiovascular disease patients.
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Testimony on the Impact of S.706/H. 1333: An Act to Ensure Prescription Drug Cost Transparency and Affordability

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

  • Policy Interactions
| April 2019
  • Price, Value, and Access
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Pharmaceutical Policy in the United States in 2019: An Overview of the Landscape and Avenues for Improvement

Kesselheim AS, Sinha MS, Avorn J, Sarpatwari A - Stanford Law & Policy Review

  • Research Publications
| April 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This comprehensive review examines the US pharmaceutical policy landscape across multiple domains—including innovation, drug pricing, generic and biosimilar competition, and regulatory oversight—noting that while the US spends approximately $450 billion annually on prescription drugs and benefits from a vibrant generic marketplace, high brand-name drug prices threaten access to both new transformative therapies and decades-old essential products like insulin and antibiotics. The authors identify avenues for improvement through reforms to the FDA’s regulatory framework, strategies to curb brand-name manufacturers’ tactics for delaying generic competition, and measures to address rising prices for both new and existing drugs.
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Luxturna: FDA Documents Reveal the Value of a Costly Gene Therapy

Darrow JJ - Drug Discovery Today

  • Research Publications
| April 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Despite widespread media characterization of voretigene neparvovec-rzyl (Luxturna) as a curative gene therapy that “restores vision,” FDA review documents reveal a more nuanced picture. The drug is not expected to restore normal vision, only about half of treated patients met the threshold for minimally meaningful improvement, long-term durability is uncertain, and 2 patients experienced permanent vision loss. The $850,000 price tag also understates the true cost, as over $100 million in additional publicly funded expenses are not reflected in that figure.
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Experiences with and Challenges Afforded By Expedited Regulatory Pathways

Liu S, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| April 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 154 novel therapeutics approved from 2014 to 2017, 60% received priority review and two-thirds received multiple expedited designations, but studies have found a 38% increased risk of safety-related labeling changes for expedited drugs and that only half of accelerated approval cancer drugs completed required confirmatory studies within 3 years. The authors emphasize that while expedited pathways have enabled transformative therapies, persistent challenges around delayed confirmatory evidence, emerging safety risks, and inadequate communication of therapeutic uncertainty require stronger enforcement of postapproval study requirements.
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Battling Over Patents: The Impact of Oil States on the Generic Drug Industry

Darrow JJ, Sarpatwari A, Curfman GD - Yale Journal of Health Policy, Law and Ethics

  • Research Publications
| April 2019
  • Innovation Incentives and Competition
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The Supreme Court’s 2018 upholding of inter partes review (IPR), a faster, less costly alternative to litigation for challenging erroneously granted patents, in Oil States has proven particularly significant for the pharmaceutical industry, where generic drug companies have filed hundreds of challenges with moderate success since its creation in 2011. As biologics increasingly dominate the pharmaceutical landscape and are often protected by large patent portfolios, IPR is expected to become an even more important tool for addressing patent validity in this sector.
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Association Between Progression-Free Survival and Patients’ Quality of Life in Cancer Clinical Trials

Hwang TJ, Gyawali B - International Journal of Cancer

  • Research Publications
| April 2019
  • Regulation and Clinical Evidence
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This umbrella review of 78 meta-analyses examining the correlation between surrogate endpoints and overall survival in cancer trials found that only 12% of validation studies showed high correlations, while 38% reported only low correlations and 39% showed variable correlations depending on the surrogate marker used. Caution should be exercised when using surrogate markers as the basis for clinical conclusions and regulatory decisions in oncology, as most surrogates demonstrate low or modest correlation with overall survival outcomes.
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Approximating Future Generic Entry for New Drugs

Beall RF, Darrow JJ, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Spring 2019
  • Innovation Incentives and Competition
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The authors developed a methodology for estimating first generic entry dates based on manufacturers’ patent expiration dates, patent term restoration, and pediatric exclusivity extensions, finding that for innovative drugs, this approach predicted generic entry within a median of 6 months of the actual date. The tool is intended to help physicians, patients, and policymakers anticipate when generic competition will become available.
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Pharmacy Benefit Managers: Practices, Controversies, and What Lies Ahead

Seeley E, Kesselheim AS - The Commonwealth Fund

  • Research Publications
| March 2019
  • Price, Value, and Access
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PBMs’ percentage-based compensation structure may incentivize prioritizing expensive brand-name drugs over cost-effective alternatives, and small payers report not receiving rebate pass-through that PBMs claim is standard practice. The authors conclude that while rebate reform, including pass-throughs to payers or patients, may improve transparency and reduce some out-of-pocket costs, it will not lower overall pharmaceutical spending without accompanying changes such as reimbursement based on comparative clinical effectiveness. Policymakers must also consider these reforms in the context of accelerating vertical integration between PBMs and insurers.
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Major Events in the Life Course of New Drugs, 2000-2016

Beall RF, Hwang TJ, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| March 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This interactive graphic allows viewers to explore data on the time required for investigational drugs to reach important US milestones, such as new drug applications, FDA approval, expiration of market exclusivity, and market entry of a generic version.
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Comparative Effectiveness of Generic and Brand-Name Medication Use: A Database Study of US Health Insurance Claims

Desai RJ, Sarpatwari A, Dejene SZ, Khan NF, Lii J, Rogers JR, Dutcher SK, Raofi S, Bohn JM, Connolly JG, Fischer MA, Kesselheim AS, Gagne JJ - PLOS Medicine

  • Research Publications
| March 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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This study of 2.3 million matched patient pairs found that generic medications demonstrated comparable clinical outcomes to brand-name products across 8 drug products, with the majority of endpoints showing similar results between generics and authorized generics. The findings suggest that educational interventions promoting patient and provider confidence in generic medications are warranted, as differences in psychiatric hospitalization outcomes between brand and generic users appear attributable to perception bias rather than actual drug efficacy differences.
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Testimony: High US Prescription Drug Prices: Anatomy of the Problem and Prospects for Reform

Sarpatwari A - 116th Congress, House Committee on Ways and Means, Subcommittee on Health

  • Policy Interactions
| March 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
An icon of a bill representing government policy.
Sarpatwari documents surging US drug spending driven by high launch prices and routine price increases on existing brand-name drugs, rejecting industry claims R&D costs justify current prices and pointing instead to manufacturers’ ability to charge whatever the market will bear alongside tactics that undercut generic and biosimilar competition. He evaluates several reform proposals, expressing skepticism about the Trump administration’s rebate safe harbor changes and illusory “outcomes-based” contracts while endorsing enhanced public payer negotiating authority, value-based pricing, and the CREATES Act. Read his written testimony.
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