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1259 Results

The Promise of ESCAT: A New System for Evaluating Cancer Drug-Target Pairs

Gyawali B, Kesselheim AS - Nature Reviews Clinical Oncology

  • Commentary & Opinion
| March 2019
  • Regulation and Clinical Evidence
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The authors evaluate the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), praising it as a useful common language for classifying the evidence behind target-drug combinations in precision oncology, while identifying areas for improvement to increase its utility for clinical decision-making, trial planning, and reimbursement policy.
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Tepid Steps on Drug Pricing

Sarpatwari A, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| March 2019
  • Price, Value, and Access
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The authors critique the lack of meaningful progress on drug pricing under the Trump administration, noting that while some manufacturers made token gestures on price restraint, launch prices for new drugs continued to rise and most top-selling brand-name drugs saw substantial price increases.
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Analysis of Proposed Medicare Part B to Part D Shift with Associated Changes in Total Spending and Patient Cost-Sharing for Prescription Drugs

Hwang TJ, Jain N, Lauffenburger JC, Vokinger KN, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| March 2019
  • Price, Value, and Access
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The proposed shift of high-expenditure drugs from Medicare Part B to Part D would reduce total drug spending by 6.9% to 18.3%, but would increase out-of-pocket costs for some beneficiaries, particularly those with Medigap supplemental insurance, despite decreasing costs for low-income subsidy-eligible beneficiaries. The authors recommend that HHS ensure any reforms address cost-sharing impacts across different beneficiary groups to achieve benefits for both patients and payers.
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A Survey of Patients’ Perceptions of Pill Appearance and Responses to Changes in Appearance for Four Chronic Disease Medications

Sarpatwari A, Gagne JJ, Lu Z, Campbell EG, Carman WJ, Enger CL, Dutcher SK, Jiang W, Kesselheim AS - Journal of General Internal Medicine

  • Research Publications
| March 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Among 814 patients taking generic medications, 72% relied on pill appearance to verify correct medication use, and 21% mistakenly believed they received the wrong medication when appearance changed, with younger patients more likely to seek advice and lower-income patients more likely to adjust their medication use. The authors recommend implementing standardized pharmacy notification and education policies about pill appearance changes as a more feasible approach than requiring uniform pill appearance to improve medication adherence.
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Mitigating Health Risks of Prescription Drugs: Lessons From FDA Oversight of Opioid Products

Sarpatwari A, Curfman GD - JAMA

  • Commentary & Opinion
| February 2019
  • Regulation and Clinical Evidence
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The authors critique the FDA’s REMS system for opioids, noting that it has been both inadequately implemented for its safety goals and misused by brand-name manufacturers to block generic competition by refusing to share drug samples needed for bioequivalence testing.
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The Generic Drug Industry Embraces a Faster, Cheaper Pathway for Challenging Patents

Darrow JJ, Beall RF, Kesselheim AS - Applied Health Economics and Health Policy

  • Research Publications
| February 2019
  • Innovation Incentives and Competition
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Generic drug manufacturers have successfully used the inter partes review process to challenge pharmaceutical patents since 2011, overturning all claims in 43% of targeted patents and some claims in an additional 8%, with proceedings consistently completed within the statutorily required 12 months. The inter partes review process represents an effective administrative alternative to costly litigation that can help ensure invalid patents do not delay generic drug market entry.
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Role of Authorized Generics in Postapproval Surveillance of Generic Drug Products

Gagne JJ, Sarpatwari A, Desai RJ - Clinical Pharmacology & Therapeutics

  • Commentary & Opinion
| February 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Authorized generics can serve as a valuable tool for post-approval surveillance of generic drugs because they are chemically identical to brand-name products but are treated as generics on insurance formularies, thereby helping to control for biases related to negative perceptions of generics and socioeconomic confounding.
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New Drug Formulations and Their Respective Generic Entry Dates

Beall RF, Kesselheim AS, Sarpatwari A - Journal of Managed Care & Specialty Pharmacy

  • Research Publications
| February 2019
  • Innovation Incentives and Competition
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Among 17 new small-molecule drugs approved in 2002, manufacturers introduced new formulations in 53% of cases, and generic entry for new formulations occurred more than 2 years later than the original product in one-third of cases where generics were available. These findings suggest that new drug formulations can provide manufacturers with substantial additional periods of market exclusivity beyond the original product’s patent protection, potentially delaying generic competition and affecting access to affordable alternatives.
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Internal Medicine Physicians’ Financial Relationships with Industry: An Updated National Estimate

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

  • Research Publications
| February 2019
  • Regulation and Clinical Evidence
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A national survey of 686 internists and specialists found that 72% reported any financial relationship with industry in 2017, with the most common being free drug samples (55%) and meals at the workplace (48%), while fewer reported receiving small gifts (8%) or consulting payments (4%). Specialists reported more industry meals than generalists. While some categories of industry interaction appear to have declined in the era of public reporting under the Open Payments program, financial relationships between physicians and industry remain prevalent.
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Impact of the Priority Review Voucher Program on Drug Development for Rare Pediatric Diseases

Hwang TJ, Bourgeois FT, Franklin JM, Kesselheim AS - Health Affairs

  • Research Publications
| February 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Drugs for rare pediatric diseases progressed faster through all phases of clinical testing and were more likely to be first-in-class compared to drugs for rare adult diseases. The pediatric rare disease priority review voucher program was not associated with a change in the rate of new pediatric drugs starting or completing clinical testing, but there was a significant increase in the rate of progress from Phase I to Phase II clinical trials after the program was implemented, suggesting that new policies may be needed to further advance the pipeline of therapies for rare pediatric diseases.
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Assessment of Use of Combined Dextromethorphan and Quinidine in Patients with Dementia or Parkinson Disease After US Food and Drug Administration Approval for Pseudobulbar Affect

Fralick M, Sacks CA, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| February 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Though FDA approval of extromethorphan-quinidine for pseudobulbar affect was based on studies in ALS and MS patients, the combination therapy was predominantly prescribed to patients with dementia and/or Parkinson disease between 2011 and 2016, with prescriptions increasing 15.3-fold and Medicare spending rising from $3.9 million to $200.4 million. The off-label prescribing pattern raises concerns given that 13.3% of patients had heart failure, a contraindication for the drug, suggesting a need for closer monitoring.
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Testimony: Origins of and Solutions to High Drug Prices in the US

Kesselheim AS - 116th Congress, House Committee on Oversight and Reform

  • Policy Interactions
| January 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Kesselheim outlines how high US drug prices stem from government-granted patents and exclusivities that allow manufacturers to charge whatever the market will bear, combined with legal restrictions such as Medicare’s non-interference clause that prevent payors from negotiating effectively. He recommends allowing Medicare to create a program-wide formulary and negotiate prices, reforming patent policy to curb patent thickets, and passing the CREATES Act, arguing these changes would not harm innovation because much transformative drug discovery originates in publicly funded research. Read his written testimony.
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Implementation of a Health Plan Program for Switching From Analogue to Human Insulin and Glycemic Control Among Medicare Beneficiaries with Type 2 Diabetes

Luo J, Khan NF, Manetti T, Rose J, Kaloghlian A, Gadhe B, Jain SH, Gagne JJ, Kesselheim AS - JAMA

  • Research Publications
| January 2019
  • Price, Value, and Access
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A health plan intervention switching Medicare beneficiaries with type 2 diabetes from analogue to human insulin was associated with a small increase in mean HbA1c of 0.14% during the intervention period, with no significant changes in serious hypoglycemic or hyperglycemic events. The modest glycemic control decline suggests that while human insulin may be a lower-cost alternative for some patients, careful monitoring and individualized treatment approaches may be necessary when implementing such formulary switches at the population level.
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Does Helicobacter Pylori Eradication Therapy to Prevent Gastric Cancer Increase All‐Cause Mortality?

Gyawali B, Kesselheim AS, D'Andrea E - International Journal of Cancer

  • Research Publications
| January 2019
  • Regulation and Clinical Evidence
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An updated meta-analysis of 6 RCTs found that while H. pylori eradication therapy reduces gastric cancer risk, the pooled risk ratio for all-cause mortality remained above 1, consistent with a prior 2014 meta-analysis showing a similar nonsignificant 9% increase. While these findings should be generally reassuring, the authors note that recent evidence linking clarithromycin to increased long-term mortality warrants continued real-world surveillance and longer-term RCT follow-up to confirm that no meaningful mortality risk exists with widespread use of eradication therapy.
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Policy Options for Increasing Generic Drug Competition Through Importation

Cohen M, Gupta R, Bollyky TJ, Ross JS, Kesselheim AS - Health Affairs Forefront

  • Commentary & Opinion
| January 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The authors evaluate the FDA’s newly formed working group on drug importation as a response to dramatic price hikes on off-patent drugs with little or no generic competition, such as pyrimethamine (Daraprim). They argue that since the U.S. already imports 40% of finished pharmaceuticals and 80% of active ingredients from abroad, safety concerns about importation are manageable, and that the working group should expand its scope beyond single-source drugs to all off-patent drugs with three or fewer US manufacturers. They advocate for a system of reciprocal approval with trusted foreign regulators and harmonized bioequivalence standards to create permanent, competitive importation channels rather than temporary fixes.
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The US Biosimilar Market: Stunted Growth and Possible Reforms

Sarpatwari A, Barenie RE, Curfman GD, Darrow JJ, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| January 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The US biosimilar market has experienced limited growth since the 2010 creation of an abbreviated approval pathway, with only 13 FDA approvals and 6 products actually available to patients as of November 2018, due to manufacturing, regulatory, and marketing barriers. The authors recommend reforms to address these obstacles and accelerate biosimilar market entry and adoption.
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Patient-Centered Cancer Drug Development: Clinical Trials, Regulatory Approval, and Value Assessment

Gyawali B, Hwang TJ, Vokinger KN, Booth CM, Amir E, Tibau A - ASCO Educational Book

  • Research Publications
| January 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Historically, patient experience measures such as quality of life, symptomatic toxicities, and physical function have been secondary to efficacy endpoints in US cancer drug approval, in contrast to European regulatory practice that includes quality-of-life information in drug labeling. The authors examine the role of quality-of-life assessment in regulatory approval processes, patient perspectives on trial participation, and implications of expedited approval programs that are increasingly used in cancer drug development.
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Patent Term Restoration for Top-Selling Drugs in the United States

Beall RF, Darrow JJ, Kesselheim AS - Drug Discovery Today

  • Research Publications
| January 2019
  • Innovation Incentives and Competition
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The authors examined 170 top-selling drugs approved between 2000 and 2012 and found that 49% received patent term restoration extension, with a median extension of 2.75 years resulting in a median total exclusivity period of 13.75 years compared to 10.0 years for drugs without extensions. Because patent term restoration substantially prolongs market exclusivity, policies extending non-patent exclusivity periods must exceed extended patent terms to have meaningful impact.
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Pain Management and Opioid Regulation: Continuing Public Health Challenges

Bonnie RJ, Schumacher MA, Clark JD, Kesselheim AS - American Journal of Public Health

  • Commentary & Opinion
| January 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors review ongoing challenges at the intersection of chronic pain management and opioid harm reduction, emphasizing the need for better measurement of chronic pain prevalence and improved data infrastructure. They call for sustained investment in surveillance, research on alternative treatments, and a coordinated federal and state policy response.
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Effect of Lawyer-Submitted Reports on Signals of Disproportional Reporting in the Food and Drug Administration’s Adverse Event Reporting System

Rogers JR, Sarpatwari A, Desai RJ, Bohn JM, Khan NF, Kesselheim AS, Fischer MA, Gagne JJ, Connolly JG - Drug Safety

  • Research Publications
| January 2019
  • Regulation and Clinical Evidence
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Lawyer-submitted reports had variable effects on proportional reporting ratios (PRRs) for known drug-adverse event pairs in FAERS, with increases in isotretinoin-birth defects PRRs before 2008 and decreases in atorvastatin-rhabdomyolysis PRRs after 2013, though all cumulative PRRs continued to meet signaling criteria across analyses. The authors conclude that inclusion of lawyer-submitted reports in FAERS did not meaningfully distort known safety signals for drugs subject to high-profile litigation.
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Completion Rate and Reporting of Mandatory Pediatric Postmarketing Studies Under the US Pediatric Research Equity Act

Hwang TJ, Orenstein L, Kesselheim AS, Bourgeois FT - JAMA Pediatrics

  • Research Publications
| January 2019
  • Regulation and Clinical Evidence
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Between 2007 and 2014, only 33.8% of required pediatric postmarketing studies were completed by 2017, with significantly lower completion rates for efficacy studies (28.8%) compared to pharmacokinetic studies (55.9%). Improved timeliness in completing mandatory pediatric studies and better reporting of results in drug labels are needed to support evidence-based prescribing for children.
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Changes in Drug Pricing After Drug Shortages in the United States

Hernandez I, Sampathkumar S, Good CB, Kesselheim AS, Shrank WH - Annals of Internal Medicine

  • Research Publications
| January 2019
  • Price, Value, and Access
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An analysis of 90 drug products experiencing active shortages between 2015 and 2016 found that prices increased more than twice as fast as expected in the absence of shortages. Drugs supplied by 3 or fewer manufacturers seeing prices rise by 27.4% in the 11 months after shortage onset versus 12.1% in the preceding 11 months, compared to more modest increases for drugs with more than 3 manufacturers. These findings suggest that drug shortages, particularly in less competitive markets, may create conditions for opportunistic pricing behavior by manufacturers.
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Cell and Gene Therapy Trials: Are We Facing an ‘Evidence Crisis’?

Abou-El-Enein M, Hey SP - EClinicalMedicine

  • Commentary & Opinion
| January 2019
  • Regulation and Clinical Evidence
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Cell and gene therapies are being approved based on very small, often single-arm trials, creating a gap between what is known about their safety/efficacy and what clinicians and payers need. The authors propose improved trial reporting standards and novel evidence synthesis models to strengthen the evidence base for these therapies.
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An Export-Only Exception to Pharmaceutical Patents in Europe: Should the United States Follow Suit?

Minssen T, Kesselheim AS, Darrow JJ - Nature Biotechnology

  • Commentary & Opinion
| January 2019
  • Innovation Incentives and Competition
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The authors analyze a new EU policy allowing generic manufacturers to produce patented medicines during the supplementary protection certificate period exclusively for export to countries where patent protection has expired, discussing whether the US should adopt a similar exception to increase legitimate pharmaceutical supply in developing countries.
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A Systematic Review of Trial-Level Meta-Analyses Measuring the Strength of Association Between Surrogate End-Points and Overall Survival in Oncology

Haslam A, Hey SP, Gill J, Prasad V - European Journal of Cancer

  • Research Publications
| January 2019
  • Regulation and Clinical Evidence
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This systematic review of 78 meta-analyses found that only 12% of surrogate endpoints in oncology demonstrated high correlation with overall survival, while 38% showed only low correlations and 39% showed variable correlations depending on the surrogate marker used. The authors conclude that caution should be exercised when using surrogate markers as the basis for clinical trial conclusions and regulatory approvals, given the weak or modest associations most surrogates demonstrate with overall survival outcomes.
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Changes in Outpatient Use of Antibiotics By Adults in the United States, 2006-2015

Mundkur ML, Franklin JM, Huybrechts KF, Fischer MA, Kesselheim AS, Linder JA, Landon JE, Patorno E - Drug Safety

  • Research Publications
| December 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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From 2006 to 2015, outpatient antibiotic use among US adults declined significantly, with a 12% decrease for those under 65 years and a 5% decrease for those 65 and older. These findings suggest that antimicrobial stewardship initiatives have had a cumulative impact on reducing antibiotic use, though further investigation is needed to identify the specific drivers of the observed rapid shifts in prescribing patterns.
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A Method for Approximating Future Entry of Generic Drugs

Beall RF, Darrow JJ, Kesselheim AS - Value in Health

  • Research Publications
| December 2018
  • Innovation Incentives and Competition
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The authors developed and tested a method for predicting generic drug entry that achieved a median predicted market exclusivity of 12.5 years, matching the actual median of 12.5 years across 170 top-selling drugs that lost exclusivity between 2000 and 2012. The method performed accurately for drugs protected by active ingredient patents but overestimated exclusivity for drugs protected only by secondary patents. The procedure demonstrates reasonable utility for forecasting generic entry timing in most cases, though refinements are needed for drugs relying solely on secondary patent protections to improve accuracy in this subset.
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Prevalence of Publicly Available Expanded Access Policies

Jung EH, Zettler PJ, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| November 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The 21st Century Cures Act of 2016 required pharmaceutical manufacturers to publicly post 5 key pieces of information about their expanded access programs by February 2017 to improve transparency for patients with serious or life-threatening conditions seeking experimental treatments. The authors reviewed a sample of manufacturers’ online expanded access policies to assess compliance with these requirements and determine what information is readily available to patients.
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Predictors of Drug Shortages and Association with Generic Drug Prices: A Retrospective Cohort Study

Dave CV, Pawar AM, Fox ER, Brill G, Kesselheim AS - Value in Health

  • Research Publications
| November 2018
  • Innovation Incentives and Competition
  • Price, Value, and Access
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An analysis of 1,114 generic drugs using 1.3 billion prescription claims (2008–2014) found that low-priced generics were at higher risk of experiencing shortages, and that shortages were associated with price increases that grew with duration, ranging from 6.0% for shortages lasting less than 6 months to 14.0% for those lasting 18 months or longer. These findings suggest that the economics of low-priced generic drugs may make them particularly vulnerable to supply disruptions, and that shortages impose modest but meaningful cost increases on the health care system.
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Labeling Changes and Costs for Clinical Trials Performed Under the US Food and Drug Administration Pediatric Exclusivity Extension, 2007 to 2012

Sinha MS, Najafzadeh MN, Rajasingh EK, Love J, Kesselheim AS - JAMA Internal Medicine

  • Research Publications
| November 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Between 2007 and 2012, 141 pediatric clinical trials enrolling 20,240 children resulted in 29 extended indications, 3 new indications, and new safety information for 16 drugs, with a median trial investment cost of $36.4 million per drug but median net returns to manufacturers of $176.0 million. Policymakers should consider direct public funding of pediatric drug studies as an alternative to the current exclusivity extension program, given that consumer costs during the 6-month exclusivity period have exceeded the actual costs of conducting the trials.
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Information Transparency in the Drug Approval Process (Reply)

Gyawali B, Goldstein DA - JAMA Oncology

  • Commentary & Opinion
| November 2018
  • Regulation and Clinical Evidence
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Responding to ODAC members who accused them of misrepresenting the advisory committee’s review of adjuvant sunitinib, the authors maintain that the committee discussion placed excessive focus on disease-free survival over overall survival, even though two randomized trials already showed no OS improvement—making the question of whether DFS is a good surrogate for OS immaterial.
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Duration of Adjuvant Immunotherapy—Biologic, Clinical, and Economic Considerations

Stav I, Gyawali B, Goldstein DA - Medical Oncology

  • Research Publications
| October 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Most current adjuvant immunotherapy trials provide treatment for 1 year, with costs ranging from $165,000 per patient for 1-year nivolumab treatment to over $1,850,000 for 3-year ipilimumab treatment in melanoma, though the biological and clinical rationale for these durations remains unclear. The authors recommend conducting non-inferiority trials to test shorter treatment durations and call on healthcare payers to establish appropriate funding mechanisms for such research.
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Negative Phase 3 Randomized Controlled Trials: Why Cancer Drugs Fail The Last Barrier?

Gyawali B, Addeo A - International Journal of Cancer

  • Research Publications
| October 2018
  • Regulation and Clinical Evidence
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Among 16 negative Phase 3 RCTs of new cancer drugs published in major journals in 2016, only 3 were supported by a previous positive Phase 2 trial, while 3 proceeded despite a negative Phase 2, 5 were based on inconclusive Phase 2 data, and 1 had no prior Phase 2 at all. The authors argue that institutional review boards and regulatory authorities should discourage Phase 3 RCTs lacking positive Phase 2 data, and that prospective criteria for defining Phase 2 success should be established to prevent the waste of substantial human and financial resources on trials with a low probability of success.
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When Markets Fail: Patents and Infectious Disease Products

Darrow JJ, Sinha MS, Kesselheim AS - Food and Drug Law Journal

  • Research Publications
| October 2018
  • Innovation Incentives and Competition
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Patents alone have proven insufficient to incentivize development of new antibiotics and vaccines for infectious diseases, and recent legislative supplemental incentive schemes have achieved limited success because they fail to address the fundamental market dynamics that disconnect patent protections from antimicrobial product markets. The authors examine these market dynamics and evaluate existing and proposed policy solutions to identify the most promising interventions for stimulating innovation in infectious disease treatments and vaccines.
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The Tax Cuts and Jobs Act of 2017 and the Pharmaceutical Industry

Sinha MS, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Research Publications
| Fall 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The Tax Cuts and Jobs Act reduced the top 8 US pharmaceutical manufacturers’ estimated median effective tax rate from 17.7% to 10.6%, yielding a median tax savings of $2.5 billion per company, while a one-time repatriation holiday at 14.5% on median overseas holdings of $22–37 billion would generate far less revenue than the prior 2004 holiday at 5.25%. Despite these windfalls, early evidence showed manufacturers announcing share buybacks and dividend increases rather than drug price reductions or new R&D investment, echoing the 2004 repatriation experience, while reduced tax revenues may threaten public biomedical research funding.
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Reinforcing the Social Compromise of Accelerated Approval

Gyawali B, Kesselheim AS - Nature Reviews Clinical Oncology

  • Commentary & Opinion
| October 2018
  • Regulation and Clinical Evidence
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There exists a “social compromise” inherent in the accelerated approval pathway: granting early access based on surrogate endpoints in exchange for timely confirmatory trials. The authors argue that this compromise is being undermined by delayed or inadequate confirmatory studies and insufficient FDA enforcement of post-approval requirements.
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A Systematic Review of the Food and Drug Administration’s ‘Exception From Informed Consent’ Pathway

Feldman WB, Hey SP, Kesselheim AS - Health Affairs

  • Research Publications
| October 2018
  • Regulation and Clinical Evidence
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This systematic review of 41 FDA-approved “exception from informed consent” trials enrolling 46,964 patients found that 96% of participants were enrolled without consent, fewer than 1% withdrew before trial completion, only 8% of superiority trials demonstrated experimental benefit. Many interventions were also associated with serious adverse effects including increased mortality. The authors recommend that investigators in future EFIC trials improve management of participant withdrawals and ensure fair demographic representation.
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The FDA Amendments Act of 2007—Assessing Its Effects a Decade Later

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

  • Commentary & Opinion
| September 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The authors refelect on the FDAAA’s impact ten years after passage, noting that while the law represented a landmark expansion of FDA authority over postmarket drug safety surveillance, driven by the rofecoxib crisis, implementation has been uneven. They also discuss progress on clinical trial transparency, risk evaluation and mitigation strategies, and active safety surveillance systems over the previous decade.
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Promoting Patient Interests in Implementing the Federal Right to Try Act

Fernandez Lynch H, Zettler PJ, Sarpatwari A - JAMA

  • Commentary & Opinion
| September 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The authors outline key differences between the federal Right to Try Act and the FDA’s existing Expanded Access program, noting that Right to Try removes FDA and IRB oversight while providing fewer patient protections regarding informed consent, adverse event reporting, and safety monitoring. They propose clarifications to the law’s ambiguities that could minimize potential harms while advancing its stated goal of encouraging companies to provide pre-approval drug access.
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Medicare Spending on Brand-Name Combination Medications vs Their Generic Constituents

Sacks CA, Lee CC, Kesselheim AS, Avorn J - JAMA

  • Research Publications
| August 2018
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Medicare spent an estimated $925 million more in 2016 on 29 brand-name combination medications compared to what would have been spent on their generic constituents, with potential savings of $2.7 billion between 2011 and 2016 for the 10 most costly products. The authors recommend promoting generic substitution and therapeutic interchange through prescriber education and rational substitution policies to achieve savings in Medicare.
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Legal Liability of Generic vs Brand Drug Manufacturers for Inadequate Product Labels

Boumil MM, Curfman GD - JAMA

  • Commentary & Opinion
| August 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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This viewpoint examines the emerging legal doctrine of “innovator liability,” in which brand-name drug manufacturers can be held liable for injuries caused by generic versions of their drugs if they failed to update safety labeling. The authors discuss recent court decisions in Massachusetts and California, noting that because generic manufacturers are required by law to maintain identical labels, the brand manufacturer’s failure to update warnings can leave patients without legal recourse.
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Effectiveness and Value of 2 Novel Treatments for Tardive Dyskinesia

Atlas SJ, Agboola F, Curfman GD - JAMA Internal Medicine

  • Research Publications
| August 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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An ICER evidence review of valbenazine and deutetrabenazine—the first 2 FDA-approved treatments for tardive dyskinesia—found that both VMAT2 inhibitors produced clinically meaningful improvements in involuntary movement scores randomized trials, though the evidence was limited by short trial duration and lack of head-to-head comparisons. The review assessed the cost-effectiveness and potential budget impact of these novel treatments, given that TD affects an estimated 20–50% of patients taking antipsychotic drugs and previously had no FDA-approved therapies.
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The Shortage of Normal Saline in the Wake of Hurricane Maria

Sacks CA, Kesselheim AS, Fralick M - JAMA Internal Medicine

  • Commentary & Opinion
| July 2018
  • Price, Value, and Access
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Hurricane Maria’s devastation of Puerto Rico’s pharmaceutical manufacturing infrastructure created a national shortage of normal saline. The authors discuss the FDA’s multifaceted response including temporary importation and expedited review of new manufacturers.
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Implementing a Public Health Perspective in FDA Drug Regulation

Zettler PJ, Riley MF, Kesselheim AS - Food and Drug Law Journal

  • Research Publications
| July 2018
  • Regulation and Clinical Evidence
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The FDA’s traditional narrowly-focused drug approval process, which evaluates benefits and risks only within preapproval clinical trials, excludes critical real-world data about prescription opioid use and the public health harms associated with these drugs, thereby limiting the agency’s ability to address the opioid epidemic. The author argues that the Federal Food, Drug, and Cosmetic Act authorizes the FDA to adopt a broader public health perspective in its drug approval and withdrawal decisions and proposes principles for implementing this approach systematically to better regulate drugs with significant externalities like opioids.
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Government Patent Use to Address the Rising Cost of Naloxone: 28 U.S.C. § 1498 and Evzio

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

  • Commentary & Opinion
| Summer 2018
  • Innovation Incentives and Competition
  • Price, Value, and Access
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The federal government should use its patent use authority (28 U.S.C. § 1498) to address the rising cost of naloxone, as sovereign immunity could allow government procurement of lower-cost generic versions of patented naloxone delivery devices to expand opioid overdose prevention.
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A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer with PD-1 Inhibitors: A Meta-Analysis of Correlation and Differences in Effect Sizes

Gyawali B, Hey SP, Kesselheim AS - JAMA Network Open

  • Research Publications
| June 2018
  • Regulation and Clinical Evidence
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This meta-analysis of 12 randomized clinical trials of PD-1 inhibitors for cancer found that while progression-free survival (PFS) and overall survival (OS) hazard ratios were significantly correlated, their medians and median changes were not significantly correlated, and treatment protective effects were greater for OS than PFS. The authors conclude that PFS cannot adequately capture the benefit of PD-1 inhibitors in patients with solid tumors and recommend that OS remain the gold standard for evaluating the efficacy of these treatments.
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Efficacy, Safety, and Regulatory Approval of Food and Drug Administration-Designated Breakthrough and Nonbreakthrough Cancer Medicines

Hwang TJ, Franklin JM, Chen CT, Lauffenburger JC, Gyawali B, Kesselheim AS, Darrow JJ - Journal of Clinical Oncology

  • Research Publications
| June 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Between 2012 and 2017, 43% of newly FDA-approved cancer drugs received breakthrough therapy designation, which was associated with a 1.9-year faster approval timeline. However, breakthrough-designated drugs showed no statistically significant differences in progression-free survival gains, response rates, serious adverse events, or novelty of mechanism compared to non-breakthrough-designated drugs. The findings suggest that while the breakthrough therapy program successfully accelerated drug approval timelines, it did not result in demonstrable improvements in clinical efficacy, safety, or innovation relative to conventionally approved cancer medicines.
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An Incomplete Prescription: President Trump’s Plan to Address High Drug Prices

Sarpatwari A, Avorn J, Kesselheim AS - JAMA

  • Commentary & Opinion
| June 2018
  • Price, Value, and Access
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The authors critique the Trump administration’s HHS “blueprint” on drug pricing, arguing that while it correctly identified problems like opaque PBM rebates and high list prices, its proposed solutions were insufficient and failed to address fundamental issues like Medicare’s inability to negotiate drug prices.
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Comments for Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee

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

  • Policy Interactions
| June 2018
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The FDA should adopt a “comprehensive systems approach” when reviewing new opioid drug applications, as recommended by the National Academies of Sciences, by considering broader public health consequences—including risks of diversion, community impact, and the overall opioid market—alongside individual patient benefits and risks.
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Antitrust, Market Exclusivity, and Transparency in the Pharmaceutical Industry

Sinha MS, Curfman GD, Carrier MA - JAMA

  • Commentary & Opinion
| June 2018
  • Innovation Incentives and Competition
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The authors examine three recent antitrust cases involving exclusive dealing and bundling practices by pharmaceutical manufacturers, arguing that these anticompetitive strategies prevent competitor products from gaining market footholds and highlighting the role of antitrust law in addressing high drug prices.
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Towards a Global Definition of Responsible Antibiotic Use: Results of an International Multidisciplinary Consensus Procedure

Monnier AA, Eisenstein BI, Hulscher ME, Gyssens IC, the DRIVE-AB WP1 group, Adriaenssens N, Huttner B, Le Maréchal M, Milanič R, Pulcini C, Stanić Benić M, Tebano G, Versporten A, Vlahović-Palčevski V, Zanichelli V - Journal of Antimicrobial Chemotherapy

  • Research Publications
| June 2018
  • Regulation and Clinical Evidence
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Through a systematic review and RAND-modified Delphi consensus procedure involving 48 multidisciplinary stakeholders from 18 countries, the authors identified 22 key elements at the patient- and societal-level that should comprise a global definition of responsible antibiotic use. The consensus-derived framework provides an exhaustive list of elements for defining responsible use that integrates perspectives from the medical community, public health, patients, R&D, regulators, and governments, with the aspirational goal of addressing all elements to ensure comprehensive and relevant implementation across individual and societal levels.
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Quality Indicators for Responsible Antibiotic Use in the Inpatient Setting: A Systematic Review Followed By an International Multidisciplinary Consensus Procedure

Monnier AA, Schouten J, Le Maréchal M, Tebano G, Pulcini C, Stanić Benić M, Vlahović-Palčevski V, Milanič R, Adriaenssens N, Versporten A, Huttner B, Zanichelli V, Hulscher ME, Gyssens IC, the DRIVE-AB WP1 group, Antonisse A, Beović B, Borg M, Buyle F, Cavaleri M, Dhillon H, Dumartin C, Drew R, Findlay D, Ghafur A, Grayson L, Hermsen E, Hicks L, Howard P, Kenston M, Kesselheim AS, Knirsch C, Lacor P, Laxminarayan R, Paul M, Plachouras D, Poulakou G, Rabaud C, Rex JH, Rodriguez-Baño J, Srinivasan A, Lundborg CS, Tängdén T, Thamlikitkul V, Waluszewski A, Wellsteed S, Wertheim H, Wild C - Journal of Antimicrobial Chemotherapy

  • Research Publications
| June 2018
  • Regulation and Clinical Evidence
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Through a systematic review and RAND-modified Delphi consensus procedure involving 25 international stakeholders, researchers identified 51 quality indicators for responsible antibiotic use in inpatient settings, with the highest-priority indicators addressing antibiotic plan documentation, susceptibility testing documentation, alignment of local with national guidelines adapted to local resistance patterns, antibiotic stewardship programs, and consideration of allergy status in prescribing. These globally applicable quality indicators can be used to assess and improve the quality of inpatient antibiotic use across diverse health care settings.
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Metrics for Quantifying Antibiotic Use in the Hospital Setting: Results From a Systematic Review and International Multidisciplinary Consensus Procedure

Stanić Benić M, Milanič R, Monnier AA, Gyssens IC, Adriaenssens N, Versporten A, Zanichelli V, Le Maréchal M, Huttner B, Tebano G, Hulscher ME, Pulcini C, Schouten J, Vlahović-Palčevski V, the DRIVE-AB WP1 group, Antonisse A, Beović B, Borg M, Buyle F, Cavaleri M, Dhillon H, Dumartin C, Drew R, Findlay D, Ghafur A, Grayson L, Hermsen E, Hicks L, Howard P, Kenston M, Kesselheim AS, Knirsch C, Lacor P, Laxminarayan R, Paul M, Plachouras D, Poulakou G, Rabaud C, Rex JH, Rodriguez-Baño J, Srinivasan A, Lundborg CS, Tängdén T, Thamlikitkul V, Waluszewski A, Wellsteed S, Wertheim H, Wild C - Journal of Antimicrobial Chemotherapy

  • Research Publications
| June 2018
  • Regulation and Clinical Evidence
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Through a systematic literature review and international multidisciplinary consensus procedure, the authors identified 168 articles on measuring inpatient antibiotic use and developed a standardized set of 12 inpatient quantity metrics (IQMs). The authors recommend adoption of this evidence-based global standard for antibiotic use measurement to enable standardized comparison of antibiotic use across different hospital settings and time periods and to facilitate evaluation of stewardship interventions.
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Generic Versions of Narrow Therapeutic Index Drugs: A National Survey of Pharmacists’ Substitution Beliefs and Practices

Sarpatwari A, Lee MP, Gagne JJ, Lu Z, Dutcher SK, Jiang W, Campbell EG, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| June 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The survey of 710 pharmacists found that 87% perceived generic narrow therapeutic index drugs as effective and safe as brand-name versions, yet substitution practices varied significantly, with 82% substituting for initial prescriptions compared to only 60% for refills. Lower substitution rates were observed among non-chain pharmacists, more experienced practitioners, and those in states with affirmative consent laws or NTI-specific substitution requirements. The authors recommend educating non-chain and veteran pharmacists and eliminating NTI-specific substitution requirements to increase generic NTI substitution rates.
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Defining “True and Non-Misleading” for Pharmaceutical Promotion

Hey SP, Kesselheim AS - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Summer 2018
  • Regulation and Clinical Evidence
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The proposed “true and non-misleading” standard for pharmaceutical promotion, favored by industry as an alternative to restrictions on off-label marketing, is problematic because it lacks a clear, objective definition, and courts have permitted misleadingly narrow interpretations of “truth” that could undermine patient safety.
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Application and Impact of Run-In Studies for the Evaluation of Statin Efficacy and Safety

Fralick M, Avorn J, Franklin JM, Bartsch E, Abdurrob A, Kesselheim AS - Journal of General Internal Medicine

  • Research Publications
| June 2018
  • Regulation and Clinical Evidence
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Among 16 randomized controlled trials of statins, 10 included pre-randomization run-in phases that excluded non-adherent or intolerant patients before randomization, yet the reduction in overall mortality was similar between trials with and without run-in phases, as were rates of elevated aminotransferases. These findings suggest that run-in phases in statin trials did not meaningfully inflate efficacy estimates or obscure safety signals, consistent with similar observations for DPP4 inhibitors.
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U.S. Food and Drug Administration Precertification Pilot Program for Digital Health Software: Weighing the Benefits and Risks

Lee TT, Kesselheim AS - Annals of Internal Medicine

  • Commentary & Opinion
| May 2018
  • Regulation and Clinical Evidence
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The authors raise concerns about the FDA’s Pre-Cert program for digital health software, which would expedite regulatory review for companies demonstrating organizational excellence rather than requiring rigorous premarket testing of individual products. They argue that this approach could reduce incentives for developers to study safety and effectiveness before market release.
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Op-Ed: What Trump Should Actually Do About the High Cost of Drugs

Bollyky TJ, Kesselheim AS, Sharfstein JM - New York Times

  • Commentary & Opinion
| May 2018
  • Price, Value, and Access
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The authors contend that the Trump administration’s strategy of pressuring foreign countries to pay more for drugs misdiagnoses the problem and would do little to lower American prices. The real issue, they argue, is that the US uniquely combines strong patent protections with weak mechanisms for payers to appraise drug value and negotiate effectively, and they urge the adoption of a transparent, value-based pricing framework modeled on international best practices.
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The Next Forum for Unraveling FDA Off-Label Marketing Rules: State and Federal Legislatures

Sinha MS, Kesselheim AS - PLOS Medicine

  • Commentary & Opinion
| May 2018
  • Regulation and Clinical Evidence
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After courts weakened FDA enforcement of off-label promotion restrictions, the pharmaceutical industry is now pursuing state and federal legislation to further erode these rules, threatening the public health rationale for requiring evidence-based marketing.
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The US Food and Drug Administration’s Approval of Adjuvant Sunitinib for Renal Cell Cancer: A Case of Regulatory Capture?

Gyawali B, Goldstein DA - JAMA Oncology

  • Commentary & Opinion
| May 2018
  • Regulation and Clinical Evidence
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The FDA’s approval of adjuvant sunitinib (Sutent) was inappropriate because it was based on a modest improvement in disease-free survival despite available data showing no overall survival benefit, and because advisory committee members who voted in favor largely failed to address or acknowledge the overall survival data.
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Precision Medicines Have Faster Approvals Based on Fewer and Smaller Trials Than Other Medicines

Pregelj L, Hwang TJ, Hine DC, Siegel EB, Barnard RT, Darrow JJ, Kesselheim AS - Health Affairs

  • Research Publications
| May 2018
  • Regulation and Clinical Evidence
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Precision medicines received FDA approval approximately two years faster than non-precision medicines between 2013 and 2017, with 48% qualifying for breakthrough therapy designation, based on fewer pivotal trials with smaller patient populations and less rigorous trial designs. The findings suggest that the targeted nature of precision medicines enables faster regulatory pathways, though the reduced trial requirements raise questions about the evidentiary standards supporting their approval.
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Expansion of the Priority Review Voucher Program Under the 21st Century Cures Act: Implications for Innovation and Public Health

Sinha MS, Jain N, Hwang TJ, Kesselheim AS - American Journal of Law & Medicine

  • Research Publications
| May 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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The 21st Century Cures Act expanded the priority review voucher (PRV) program to include medical countermeasures against chemical, biological, radiological, and nuclear threats, despite limited evidence that the program has achieved its stated goal of incentivizing new drug development. The authors analyze the implications of this expansion, noting that vouchers have been sold for up to $350 million and raising concerns that the program’s broadening may further dilute its intended incentive effect while generating substantial financial rewards for manufacturers without requiring genuinely novel research.
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Evaluating the Impact of the Orphan Drug Act’s Seven-Year Market Exclusivity Period

Sarpatwari A, Beall RF, Abdurrob A, He M, Kesselheim AS - Health Affairs

  • Research Publications
| May 2018
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This study evaluates the effectiveness of the Orphan Drug Act’s seven-year market exclusivity incentive by analyzing 1985-2014 drug approvals, finding that orphan drug exclusivity outlasted patent protection in 33% of cases overall, declining from 50% for drugs approved in 1985-94 to only 18% for those approved in 2005-14. The results suggest that while rare disease drugs have substantially increased as a proportion of new drug approvals, the market exclusivity provision has played a diminishing role in protecting these drugs from competition as patent protections have become more durable.
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Delayed Generic Market Saturation After Patent Expiration—A Billion-Dollar Problem

Luo J, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| May 2018
  • Innovation Incentives and Competition
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In this invited commentary, the authors describe how brand-name manufacturers use strategies like authorized generics, formulary rebate contracts, and copay coupons to delay uptake of independent generics even after patent expiration. To address these practices, they propose various policy reforms, including FDA pre-approval of multiple generic manufacturers before patent expiry, temporary importation, and federal restrictions on coupon use when generics are available.
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Availability of Pediatric Information In European Medicines Agency Approvals

Hwang TJ, Tomasi PA, Saint-Raymond A, Bourgeois FT - Lancet Child & Adolescent Health

  • Research Publications
| May 2018
  • Regulation and Clinical Evidence
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Among 122 new medicines authorized by the EMA from 2010 to 2014 with pediatric study requirements, only 25% had pediatric safety or efficacy information at initial authorization, rising to 43% after a median follow-up of 4.8 years. While the EU’s 2007 Pediatric Regulation has contributed to meaningful additions of paediatric labeling information, 57% of medicines with requirements still lacked pediatric data after nearly 5 years, highlighting the need for additional measures to ensure timely completion of pediatric studies.
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Application and Impact of Run-In Studies

Fralick M, Avorn J, Franklin JM, Abdurrob A, Kesselheim AS - Journal of General Internal Medicine

  • Research Publications
| May 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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This meta-analysis of 106 randomized controlled trials for four DPP4 inhibitor medications found that trials with run-in phases and without run-in phases produced similar estimates of efficacy (hemoglobin A1C reduction) and safety (serious adverse events). Given the comparable outcomes and the substantial costs and time required for run-in phases, their use should be reconsidered in clinical trials of short duration.
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The FDA Breakthrough-Drug Designation—Four Years of Experience

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

  • Research Publications
| April 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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In its first 4 years, 26 (24%) of 108 newly approved drugs received the FDA’s breakthrough therapy designation, far exceeding the expected 2 per year. This development is the 6th expedited program added since the 1983 Orphan Drug Act, with manufacturers permitted to combine multiple programs to further shorten development timelines. While the designation has supported approval of some highly effective drugs, the authors examine whether the program’s widespread use, combined with encouragement to rely on historical controls and earlier-stage trials, risks undermining the evidentiary standards needed to ensure that approved drugs provide meaningful clinical benefit.
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Differences in Rates of Switchbacks After Switching From Branded to Authorized Generic and Branded to Generic Drug Products: Cohort Study

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 - BMJ

  • Research Publications
| April 2018
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
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Patients who switched from branded to authorized generic drug products had significantly lower rates of switching back to branded products compared to those who switched to conventional generic products, with a pooled hazard ratio of 0.72 across eight medications studied in commercial and Medicaid populations. These findings suggest that authorized generics, which maintain the same appearance and formulation as branded products, may improve medication persistence and reduce unnecessary switchbacks to more costly branded alternatives.
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Opioid Crisis in the US—Lessons from Western Europe

Vokinger KN - Journal of Law, Medicine & Ethics

  • Commentary & Opinion
| Spring 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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The author examines European approaches to opioid prescribing and addiction treatment, including educational campaigns, treatment guidelines, and substitution therapy programs, as potential models for US policy, noting that European opioid prescription rates are 2.5-4 times lower than in the US.
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Affordability and Price Increases of New Cancer Drugs in Clinical Guidelines, 2007-2016

Hwang TJ, Kesselheim AS, Gyawali B - JNCI Cancer Spectrum

  • Research Publications
| April 2018
  • Price, Value, and Access
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The National Comprehensive Cancer Network’s “Evidence Blocks” framework found that 95% of new cancer drugs approved between 2007-2016 were rated as “very expensive” or “expensive,” with no significant association between drug affordability and efficacy or safety data. The findings suggest that current pricing of new cancer drugs is not aligned with their clinical value, indicating a need for policy interventions to address the disconnect between drug costs and therapeutic benefits in cancer treatment guidelines.
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Affordability and Availability of Off-Patent Drugs in the United States—The Case for Importing From Abroad: Observational Study

Gupta R, Bollyky TJ, Cohen M, Ross JS, Kesselheim AS - BMJ

  • Research Publications
| March 2018
  • Innovation Incentives and Competition
  • Price, Value, and Access
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Among 170 off-patent drugs, 64% had at least one manufacturer approved by non-US regulatory agencies with similar standards to the FDA, and 48% of drugs without FDA-approved generics were available from non-US approved manufacturers. Facilitating US patient access to these internationally approved manufacturers could help address affordability and availability challenges for essential off-patent drugs, potentially saving Medicaid approximately $700 million annually on drugs lacking adequate domestic competition.
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Legal Challenges to State Drug Pricing Laws

Lee TT, Kesselheim AS, Kapczynski A - JAMA

  • Commentary & Opinion
| March 2018
  • Price, Value, and Access
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The authors provide an overview of pharmaceutical industry legal challenges to state drug pricing legislation, and argue that most state pricing laws—such as Maryland’s law targeting unconscionable generic drug price increases—should withstand legal scrutiny because they regulate in-state transactions rather than directly setting prices in other states.
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Delays in Completion and Results Reporting of Clinical Trials Under the Pediatric Regulation in the European Union: A Cohort Study

Hwang TJ, Tomasi PA, Bourgeois FT - PLOS Medicine

  • Research Publications
| March 2018
  • Regulation and Clinical Evidence
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Among 326 pediatric clinical trials required for 122 novel medicines authorized by the EMA between 2010 and 2014, only 38% were completed by November 2017, with studies planned after marketing authorization having significantly lower completion rates (23%) compared to those planned before authorization (86%). 50% of planned completion dates were postponed by a median of 2.2 years. These delays in pediatric trial completion highlight the need to examine current policies to ensure timely availability of pediatric drug information, particularly for studies scheduled after initial marketing authorization.
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Potential Roadblocks in Healthcare Big Data Collection: Gobeille v. Liberty Mutual, ERISA, and All-Payer Claims Databases

Shachar C, Kesselheim AS, Curfman GD, Sarpatwari A - Big Data, Health Law, and Bioethics

  • Commentary & Opinion
| February 2018
  • Price, Value, and Access
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This book chapter analyzes the Supreme Court’s decision in Gobeille v. Liberty Mutual, which held that ERISA preempts state laws requiring self-insured employer health plans to report claims data to all-payer claims databases (APCDs), significantly undermining the completeness and research utility of these databases. The authors evaluate potential solutions including Department of Labor rulemaking, voluntary data contributions by private insurers, and state-level incentives to encourage employer participation in APCDs.
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Data Sharing That Enables Postapproval Drug and Device Research and Protects Patient Privacy: Best Practice Recommendations

Sarpatwari A, Malin BA, Kesselheim AS, Gagne JJ, Schneeweiss SG - Big Data, Health Law, and Bioethics

  • Commentary & Opinion
| February 2018
  • Regulation and Clinical Evidence
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This book chapter evaluates the three HIPAA-compliant pathways for sharing health data in postapproval drug and device research — limited data sets, safe harbor deidentification, and expert determination — and identifies key limitations of each for pharmacoepidemiologic studies. The authors propose best practice recommendations for the underutilized expert determination pathway, including proportional risk thresholds, routine modeling of reidentification attack scenarios, and use of data-use agreements to balance research utility with patient privacy.
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Studying New Antibiotics for Multidrug Resistant Infections: Are Today’s Patients Paying for Unproved Future Benefits?

Powers JH, Evans SR, Kesselheim AS - BMJ

  • Research Publications
| February 2018
  • Price, Value, and Access
  • Regulation and Clinical Evidence
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Most new antibiotics are approved based on non-inferiority trial designs that permit lesser effectiveness than existing drugs, yet regulatory authorities increasingly extrapolate these results to presume superior outcomes in patients with multidrug-resistant infections who lack effective treatment options. argue that this approach raises both scientific and ethical concerns, as it exposes current patients with treatable life-threatening infections to the risk of receiving less effective therapies on the unproven premise that these drugs will benefit future patients facing resistant organisms.
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Drugs Don’t Work If People Can’t Afford Them: The High Price of Tisagenlecleucel

Kleutghen P, Mitchell D, Kesselheim AS, Najafzadeh MN, Sarpatwari A - Health Affairs Forefront

  • Commentary & Opinion
| February 2018
  • Price, Value, and Access
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Novartis priced the CAR-T therapy tisagenlecleucel (Kymriah) at $475,000 per infusion despite over $200 million in NIH-funded research underlying its development. Modeling suggests the company would achieve a 65% net profit margin over ten years—2.5 times its current portfolio performance—even after accounting for R&D reinvestment. The authors estimate a fair price of $160,000 and call for greater pricing transparency and NIH use of its statutory authority to ensure reasonable terms for taxpayer-funded innovations.
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The Regulatory Accountability Act of 2017—Implications for FDA Regulation and Public Health

Darrow JJ, Fuse Brown EC, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| February 2018
  • Regulation and Clinical Evidence
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The Regulatory Accountability Act would impose burdensome procedural requirements on FDA rulemaking, including expanded formal hearings, a “gag rule” on agency advocacy, and greater opportunities for regulated industries to delay action. The authors warn that these changes could severely hamper the FDA’s ability to issue health and safety regulations, from tobacco control to drug safety standards.
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Tertiary Patenting on Drug-Device Combination Products in the United States

Beall RF, Kesselheim AS - Nature Biotechnology

  • Research Publications
| February 2018
  • Innovation Incentives and Competition
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An analysis of drug-device combination products listed in the FDA’s Orange Book from 2000 to 2016 found that tertiary patents (those covering drug delivery devices rather than the drug itself) grew from 34% to 57% of all associated patents, with the median number of patents per product doubling from 2 to 4. Furtermore, 22% of products listing only device-related patents. These findings demonstrate how device patents on combination products increasingly block generic competition and enable price increases.
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Adaptive Design Clinical Trials: A Review of the Literature and ClinicalTrials.gov

Bothwell LE, Avorn J, Khan NF, Kesselheim AS - BMJ Open

  • Research Publications
| February 2018
  • Regulation and Clinical Evidence
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This systematic review of 142 adaptive design clinical trials found that seamless Phase II/III designs (57%), group sequential designs (21%), and biomarker adaptive designs (20%) were most common. These designs were used in only 9% of FDA submissions and 12% of EMA submissions, while approximately one-third of trials reported independent data monitoring committees and only 6% reported blinded interim analyses. The authors recommend that sponsors engage with regulatory scientists early in trial planning and that investigators improve their reporting of protections for confidentiality and operational bias mitigation during interim analyses.
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Research Ethics for Emerging Trial Designs: Does Equipoise Need to Adapt?

Hey SP, Weijer C, Taljaard M, Kesselheim AS - BMJ

  • Research Publications
| January 2018
  • Regulation and Clinical Evidence
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Emerging trial designs—including umbrella and basket trials, adaptive platform trials, and cluster randomized trials—present new challenges for applying Freedman’s 30-year-old concept of clinical equipoise, which was formulated in the context of traditional 2-arm RCTs and requires uncertainty about the relative merits of each trial arm. The authors propose developing specific guidelines to help ethics committees and trialists evaluate equipoise in the context of these new designs and biomarker-driven approaches, and to optimize risk communication with trial participants.
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Massachusetts’ Proposed Medicaid Reforms—Cheaper Drugs and Better Coverage?

Sommers BD, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| January 2018
  • Price, Value, and Access
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The authors discuss Massachusetts’ waiver proposal to shift low-income adults from Medicaid to private marketplace plans, examining whether this approach would improve care or simply shift costs, while also discussing the state’s innovative drug pricing provisions.
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Social Media Impact of the Food and Drug Administration’s Drug Safety Communication Messaging About Zolpidem: Mixed-Methods Analysis

Sinha MS, Freifeld CC, Brownstein JS, Donneyong MM, Rausch P, Lappin BM, Zhou EH, Dal Pan GJ, Pawar AM, Hwang TJ, Avorn J, Kesselheim AS - JMIR Public Health and Surveillance

  • Research Publications
| January 2018
  • Regulation and Clinical Evidence
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The FDA’s drug safety communications regarding zolpidem (Ambien) generated significant social media activity, with statistically significant increases in social media discussion and Google searches following the communications’ release. 16.63% of Twitter posts and 25.91% of Facebook posts released to the communication were classified as junk content, while adverse event mentions comprised 9.21% of Twitter posts and 5.11% of Facebook posts. The authors recommend that the FDA develop more active strategies for disseminating drug safety information through social media platforms and consider directly contributing to widely-accessed health information sources like Wikipedia to ensure accuracy and broader public understanding of safety concerns.
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Removing ERISA’s Impediment to State Health Reform

Fuse Brown EC, Sarpatwari A - New England Journal of Medicine

  • Commentary & Opinion
| January 2018
  • Price, Value, and Access
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ERISA has become a major barrier to state-level health care reforms addressing drug pricing and surprise medical billing, because it preempts state regulation of self-funded employer plans that cover over 60% of Americans with employer-based insurance.
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Use of Health Care Databases to Support Supplemental Indications of Approved Medications

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

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

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

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

Sinha MS, Kesselheim AS, Darrow JJ - Chest

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

Hey SP - Clinical Pharmacology & Therapeutics

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

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

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

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

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

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

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

Naci H, Kesselheim AS - JAMA

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

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

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

Hwang TJ, Darrow JJ, Kesselheim AS - JAMA

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

Darrow JJ, Beall RF, Kesselheim AS - Nature Biotechnology

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

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

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

Kapczynski A, Kesselheim AS - Washington Post

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

Luo J - Food and Drug Administration (FDA)

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

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

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

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

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

Bothwell LE, Kesselheim AS - Hastings Center Report

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

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

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

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

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

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

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

Sarpatwari A, Choudhry NK - New England Journal of Medicine

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

Darrow JJ, Kesselheim AS - Health Affairs Forefront

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

Kesselheim AS - Specimen Science: Ethics and Policy Implications

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

Seeley E, Kesselheim AS - The Commonwealth Fund

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

Fralick M, Kesselheim AS - JAMA

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

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

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

Mostaghim SR, Gagne JJ, Kesselheim AS - BMJ

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

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

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

Hwang TJ, Kesselheim AS, Sarpatwari A - JAMA

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

Naci H, Smalley KR, Kesselheim AS - JAMA

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

Kesselheim AS - Health Affairs

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

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

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

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

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

Hwang TJ, Kesselheim AS - Clinical Pharmacology & Therapeutics

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

Bonnie RJ, Kesselheim AS, Clark JD - JAMA

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

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

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

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

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

Bateman-House A, Sarpatwari A - Boston Globe

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

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

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

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

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

Mundkur ML, Gordon AJ, Kertesz SG - Substance Abuse

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

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

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

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

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

Kramer DB, Kesselheim AS - JAMA Cardiology

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

Sarpatwari A, Kesselheim AS - Bloomberg

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

Sinha MS, Kesselheim AS - American Journal of Bioethics

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

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

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

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

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

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

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

Chen CT, Kesselheim AS - Journal of Oncology Practice

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

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

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

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

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

Gellad WF, Kesselheim AS - New England Journal of Medicine

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

Fralick M, Kesselheim AS - JAMA

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

Hwang TJ, Kesselheim AS - Health Affairs Forefront

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

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

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

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

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

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

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

Fralick M, Kesselheim AS - Pharmacoepidemiology and Drug Safety

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

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

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

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

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

Fralick M, Kesselheim AS - BMJ

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

Kesselheim AS, Avorn J - JAMA

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

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

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

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

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

Avorn J - Health Affairs Forefront

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

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

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

Luo J - Connecticut General Assembly, Committee on Public Health

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

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

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

Hey SP, Kesselheim AS - Hastings Center Report

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

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

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

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

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

Kesselheim AS, Avorn J - JAMA

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Kesselheim AS, Treasure CL, Joffe S - PLOS Medicine

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

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

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

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

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

Kesselheim AS - US Supreme Court

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

Robertson CT, Kesselheim AS - New England Journal of Medicine

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

Sarpatwari A, Avorn J, Kesselheim AS - JAMA

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

Kesselheim AS, Avorn J - JAMA

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

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

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

Sinha MS, Kesselheim AS - Bioorganic & Medicinal Chemistry

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

Kesselheim AS - Nudging Health: Health Law and Behavioral Economics

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

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

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

Sarpatwari A, Sinha MS - Health Affairs Forefront

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

Hwang TJ, Kesselheim AS - BMJ

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

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

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

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

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

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

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

Kimmelman J, Kesselheim AS - Science Translational Medicine

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

Kesselheim AS, Gagne JJ - JAMA Internal Medicine

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

Payments to Physicians, Prescribing Rates, and More Appropriate Conclusions (Reply)

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

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

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

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

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

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

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

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

Kesselheim AS, Avorn J, Sarpatwari A - JAMA

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

Hey SP, Kesselheim AS - BMJ

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

Bothwell LE, Podolsky SH - New England Journal of Medicine

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

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

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

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

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

Yeh JS, Sarpatwari A, Kesselheim AS - Drug Safety

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

Sarpatwari A, Gagne JJ - Pharmacoepidemiology and Drug Safety

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

Hey SP, Kesselheim AS - Science

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

Kapczynski A, Kesselheim AS - Health Affairs Forefront

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

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

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

Luo J, Kesselheim AS - AMA Journal of Ethics

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

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

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

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

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

Sarpatwari A, Kesselheim AS - JAMA

  • Commentary & Opinion
| June 2016
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors highlight dramatic price increases for dermatologic drugs, with brand-name prices increasing a mean of 401% between 2009 and 2015, and discuss the implications for patient access and the need for policy interventions.
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