Contact

Our Work

  • Reset Filters

  • Topic Areas

  • Content Types

  • Authors / Speakers

  • Date Range

  • Reset Filters

1377 Results

Decision Making Under Uncertainty: Comparing Regulatory and Health Technology Assessment Reviews of Medicines in the United States and Europe

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

  • Research Publications
| August 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
US and European regulators identified safety uncertainties for 85-94% of approved drugs while health technology assessment (HTA) bodies less frequently reported safety concerns (53-59%). By contrast, HTA bodies raised uncertainties related to effects against relevant comparators for almost all drugs (88–100%) compared to only 12-32% for regulators. The findings suggest that increased coordination between regulators and HTA bodies is necessary to streamline evidence collection and address the clinical uncertainties each organization identifies.
View Source

Testimony: Congress Should Support Development of New Treatments for Pediatric Rare Diseases, But Not with Priority Review Vouchers

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

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

Missed Opportunities on Emergency Remdesivir Use

Sarpatwari A, Kaltenboeck A, Kesselheim AS - JAMA

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

Drug Prices, Rebates, and Discounts

Rome BN, Feldman WB, Kesselheim AS - JAMA

  • Commentary & Opinion
| July 2020
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
This letter to the editor highlights the complexities of drug pricing, rebates, and discounts, addressing how the opaque system of manufacturer rebates to insurers and PBMs complicates efforts to understand actual drug costs and develop effective pricing policies.
View Source

Regulatory Approval Characteristics of Antimicrobial Versus Non-Antimicrobial Products, 1984-2018: An Evaluation of Food and Drug Administration Flexibilities

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

  • Research Publications
| July 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Antimicrobial products approved by the FDA between 1984 and 2018 were more frequently granted priority review, fast-track designation, and accelerated approval compared to non-antimicrobial products, and had a shorter median development time from investigational new drug application to approval (5.9 years versus 7.6 years). The findings indicate that the FDA has already exercised substantial regulatory flexibility for antimicrobial drugs, contradicting arguments that antimicrobial development faces more burdensome approval timelines than non-antimicrobial products.
View Source

Rates and Costs of Dispensing Naloxone to Patients at High Risk for Opioid Overdose in the United States, 2014-2018

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

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

Novelty of Active Ingredients in High-Cost Brand-Name Drugs

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

  • Research Publications
| July 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among the 27 active ingredients in the 25 highest-spending Medicare Part D brand-name drugs in 2017, 41% had previously been approved in other formulations or products, with a median of 19.2 years since their first FDA approval, and only 22% had FDA-approved generic or biosimilar alternatives. These findings challenge the common justification that high brand-name drug prices are needed to sustain new drug development, given that many of the costliest products contain active ingredients that have been known and used for decades.
View Source

Lessons From the Impact of Price Regulation on the Pricing of Anticancer Drugs in Germany

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

  • Research Publications
| July 2020
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Using data on 57 anticancer drugs launched in Germany from 2002 to 2017, the authors found that the 2011 AMNOG price regulation framework was associated with drug prices becoming more closely aligned with clinical benefit, with price negotiations resulting in a 24.5 percent decrease in negotiated prices relative to launch prices, and no evidence that manufacturers compensated by setting higher initial prices. The findings suggest that government price negotiation can be structured to align drug prices with clinical benefit while maintaining timely patient access to new medications.
View Source

Reconsidering the Scope of US State Laws Allowing Pharmacist Substitution of Generic Drugs

Darrow JJ, Chong JE, Kesselheim AS - BMJ

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Pharmacists currently lack sufficient authority to substitute generic alternatives for branded drugs, despite high generic prescribing rates, which contributes to branded medicines remaining the primary driver of drug costs. Expanding pharmacist substitution authority to include clinically similar alternatives could substantially reduce pharmaceutical spending.
View Source

Testimony: Drug Approval During the COVID-19 Pandemic: Following the Evidence

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

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

Drug Evaluation During the COVID-19 Pandemic

Rome BN, Avorn J - New England Journal of Medicine

  • Commentary & Opinion
| June 2020
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors discuss the importance of maintaining rigorous Medicaid coverage during the COVID-19 pandemic and argue against proposals to cap federal Medicaid contributions, emphasizing that Medicaid expansion is a rapid, proven way to bring needed resources into the health care system during a crisis.
View Source

Specialty Drugs—A Distinctly American Phenomenon

Naci H, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| June 2020
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The category of “specialty drugs”—high-cost medications requiring special handling—is a unique feature of the US drug pricing system. The authors contrast the US approach with Germany’s value-based negotiation framework that controls drug spending without restricting physician prescribing.
View Source

Utilization and Treatment Costs of Tumor Necrosis Factor Inhibitors After the Introduction of Biosimilar Infliximab in the United States

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

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

Grounding Value‐Based Drug Pricing in Population Health

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

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

FDA and EMA Biosimilar Approvals

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

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
A comparison of clinical testing requirements for 16 biosimilars approved by both the FDA and EMA found that among 10 biosimilars approved first by the EMA, 5 were approved by the FDA based on the same clinical trials, while 6 newer biosimilars received earlier FDA approval with increasingly streamlined requirements. These findings suggest the US biosimilar approval process has evolved to become more efficient and aligned with the European approach, potentially supporting faster growth of the US biosimilar market.
View Source

Estimating the Cost of Delayed Generic Drug Entry to Medicaid

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

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 69 brand-name drugs expected to lose market exclusivity between 2010 and 2016, 45% experienced delayed or absent generic entry, resulting in excess Medicaid spending of $761 million over seven years ($109 million annually). Patent litigation identified as the primary cause of delays, with the authors recommending policies that expedite the resolution of such litigation to facilitate timely generic entry.
View Source

Comparative Outcomes of Treatment Initiation with Brand vs. Generic Warfarin in Older Patients

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

  • Research Publications
| June 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Using Medicare claims and electronic medical records from older patients, this cohort study found no significant differences in ischemic stroke/venous thromboembolism, major hemorrhage, or one-year mortality outcomes between brand and generic warfarin initiators. These findings suggest that generic warfarin is therapeutically equivalent to brand warfarin in older patients, including high-risk subgroups with atrial fibrillation or high bleeding/stroke risk scores.
View Source

Expedited Regulatory Review of Low-Value Drugs

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

  • Research Publications
| May 2020
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
The authors argue that the most important reform to expedited review programs is to reserve accelerated pathways for drugs whose preliminary measures of benefit are so large that traditional approval thresholds can be met earlier in the clinical trial process. They propose eliminating user fees and fully funding the review process with public funds, improving labeling to quantitatively communicate drug benefits and risks, and avoiding designations like “priority” review that may imply a degree of clinical superiority not actually established.
View Source

Increasing Access to FDA Inspection Reports on Irregularities and Misconduct in Clinical Trials

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

  • Commentary & Opinion
| May 2020
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
FDA inspection reports revealing data integrity problems and research misconduct at clinical trial sites should be made publicly available. The authors point to examples where serious violations in pivotal trials (including ARISTOTLE and RECORD4) were not disclosed in published papers, leading to potentially misleading meta-analyses and clinical guidance.
View Source

March-In Rights and Compulsory Licensing-Safety Nets for Access to A COVID-19 Vaccine

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

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

Real-World Evidence And Regulatory Drug Approval

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

  • Commentary & Opinion
| May 2020
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors examine three recent examples where the FDA used real-world evidence to support cancer drug approval, cautioning that while RWE can complement clinical trials, comparisons with low-quality historical controls risk approving ineffective drugs, particularly when post-approval confirmatory studies are delayed or poorly designed.
View Source

Prices and Clinical Benefit of Cancer Drugs in the USA and Europe: A Cost-Benefit Analysis

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

  • Research Publications
| May 2020
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
This cost-benefit analysis of 65 cancer drugs approved between 2009 and 2019 found that US monthly treatment costs were 2.31 times higher than in four European countries, yet there was no significant association between drug prices and clinical benefit levels as measured by ASCO and ESMO frameworks. The authors conclude that these value frameworks should guide price negotiations to prioritize affordable access to drugs with high clinical benefit while enabling stricter pricing for therapies with low or uncertain clinical value.
View Source

Insulin Access and Affordability in the USA: Anticipating the First Interchangeable Insulin Product

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

  • Commentary & Opinion
| May 2020
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors discuss the FDA’s regulatory reclassification of insulin that will for the first time create a clear pathway for interchangeable insulin products, which could enable automatic pharmacy substitution and substantially reduce prices for the estimated quarter of insulin users who ration their medication due to cost.
View Source

Generic but Expensive: Why Prices Can Remain High for Off-Patent Drugs

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

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

What Do High Drug Prices Buy Us?

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

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

Communicating Emerging Risks of SGLT2 Inhibitors—Timeliness and Transparency of Medicine Regulators

Bhasale AL, Mintzes BJ, Sarpatwari A - BMJ

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

The Evidence Landscape in Precision Medicine

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

  • Commentary & Opinion
| April 2020
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors propose the concept of “evidence landscapes” as a tool for mapping and coordinating the complex evidence needed in precision medicine, where therapeutic strategies involve ensembles of diagnostic tests, biomarker validations, and targeted treatments that each require independent evaluation.
View Source

Op-Ed: Searching for an Effective COVID-19 Treatment: Promise and Peril

Alexander GC, Kesselheim AS, Moore TJ - STAT

  • Commentary & Opinion
| April 2020
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors warn that the urgency of the COVID-19 pandemic risks undermining the scientific rigor needed to identify safe and effective treatments. Citing the FDA’s emergency authorization of hydroxychloroquine without identified clinical evidence, the premature promotion of unproven therapies, and the power of the placebo effect, they argue it is a false choice between speed and rigor—and call for international coordination of trials, transparent sharing of results, and evaluation of meaningful clinical outcomes rather than surrogate measures.
View Source

Using Data From Routine Care to Estimate the Effectiveness and Potential Limitations of Outcomes-Based Contracts for Diabetes Medications

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

  • Research Publications
| April 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Using real-world data from newly prescribed diabetes patients, three medications with outcomes-based contracts (exenatide, dulaglutide, and sitagliptin) were found to achieve hemoglobin A1C targets below 8% in majority of patients, though hypoglycemia rates varied by therapy. Simulatenously, these branded medications cost $550-$859 monthly compared to $14 for generic glipizide, which achieved similar A1C control, suggesting that while outcomes-based contracts have potential to reduce medication costs, using hemoglobin A1C as the performance metric may be problematic because comparable glycemic control can be achieved with generic alternatives.
View Source

Evaluating the Evidence Behind the Surrogate Measures Included in the FDA’s Table of Surrogate Endpoints as Supporting Approval of Cancer Drugs

Gyawali B, Hey SP, Kesselheim AS - eClinicalMedicine

  • Research Publications
| April 2020
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
An evaluation of the 5 surrogate endpoints listed by the FDA for breast cancer (pCR, EFS, DFS, ORR, and PFS) found that treatment effects on none of these measures were strongly correlated with treatment effects on overall survival, except for DFS in HER2-positive early breast cancer. These findings raise concerns about the FDA’s reliance on these surrogate measures for regular drug approval in breast cancer, given that weak surrogate-to-survival correlations mean approved drugs may not provide the clinical benefit patients and prescribers expect.
View Source

Estimation of Medicare Part D Spending on Insulin for Patients with Diabetes Using Negotiated Prices and a Defined Formulary

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

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

Development of a National Public Pharmaceutical Research and Development Institute

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

  • Commentary & Opinion
| Spring 2020
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors propose creating a publicly supported institute to advance taxpayer-funded basic science discoveries through regulatory approval, arguing this would complement existing private-sector drug development and help ensure that publicly funded research translates into affordable medicines.
View Source

A Systematic Review and Meta-Analysis of Bevacizumab in First-Line Metastatic Breast Cancer: Lessons for Research and Regulatory Enterprises

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

  • Research Publications
| April 2020
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
This systematic review and meta-analysis of 52 studies found that bevacizumab demonstrated a progression-free survival (PFS) benefit in first-line metastatic breast cancer, but this did not translate to overall survival benefit. The evidence demonstrates that the FDA’s withdrawal of bevacizumab’s accelerated approval was justified by the evolving evidence, and future cancer drug trials should prioritize clinically meaningful endpoints rather than relying on PFS as a surrogate measure for overall survival.
View Source

Prescribing Systemic Steroids for Acute Respiratory Tract Infections in United States Outpatient Settings: A Nationwide Population-Based Cohort Study

Lin KJ, Dvorin E, Kesselheim AS - PLOS Medicine

  • Research Publications
| March 2020
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 9.76 million US outpatients with acute respiratory tract infections from 2007-2016, 11.8% were prescribed systemic steroids despite lack of evidence-based support, with substantial geographical variation and increasing prescribing trends over time. These findings demonstrate a need for targeted education programs to reduce systemic steroid use in acute respiratory tract infections, which lacks clear clinical benefit.
View Source

Sponsorship and Funding for Gene Therapy Trials in the United States

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

  • Research Publications
| March 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 341 active US gene therapy trials identified on ClinicalTrials.gov, academia sponsored 50% and the NIH provided funding for 29%, while industry sponsored 40%. Academic and NIH involvement was particularly prominent in ex vivo therapies and cancer trials. These findings demonstrate the substantial public-sector contribution to gene therapy clinical development, relevant to ongoing pricing debates given that the 4 FDA-approved gene therapies carry list prices ranging from $373,000 to $2.1 million for one-time infusions.
View Source

Revisiting the National Institutes of Health Fair Pricing Condition: Promoting the Affordability of Drugs Developed with Government Support

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

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

Why High Drug Pricing Is A Problem for Research Ethics

Hey SP - Journal of Bioethical Inquiry

  • Commentary & Opinion
| March 2020
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The future price of a drug should not be ignored during the ethical evaluation of clinical trials, because high drug pricing undermines all three major principles of research ethics: respect for participants who may not benefit from the resulting product, beneficence in risk-benefit assessments, and justice in ensuring future patients can access the treatment.
View Source

Potential Medicare Savings on Inhaler Prescriptions Through the Use of Negotiated Prices and a Defined Formulary

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

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

New Drug Approvals in Oncology

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

  • Commentary & Opinion
| March 2020
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
This viewpoint presents a debate about the evolving regulatory paradigm for cancer drugs, with the authors arguing that newer expedited approval pathways have accelerated access to beneficial therapies and that delays in drug approval have historically cost tens of thousands of patient life-years, while acknowledging the need for rigorous evidence standards.
View Source

Generating Comparative Evidence on New Drugs and Devices Before Approval

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

  • Research Publications
| March 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Fewer than half of new drugs approved in Europe and the US have comparative evidence against existing treatments at the time of approval, and this gap is even more pronounced for medical devices, creating uncertainty that is exacerbated by expedited regulatory programmes. The authors propose five stratgies to ensure the appropriate generation of comparative effectiveness data: including a statement of comparative data availability on drug, more selective use of expedited approval pathways, regulator encouragment of active-comparator randomized trials, use of prospective network meta-analyses, and leveraging payer negotiating power to incentivize comparative evidence generation.
View Source

European Medicines Agency’s Priority Medicines Scheme at 2 Years: An Evaluation of Clinical Studies Supporting Eligible Drugs

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

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

Improving Competition to Lower US Prescription Drug Costs

Kesselheim, Aaron S - Washington Center for Equitable Growth

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

Testimony: More Cures for More Patients: Overcoming Barriers

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

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

Letter on S.3133/H.R.5497, The Conditional Approval Act

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

  • Policy Interactions
| February 2020
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The signatories oppose the proposed Conditional Approval Act, arguing it duplicates the FDA’s existing accelerated approval pathway and risks replicating its shortcomings, including reliance on weak surrogate endpoints and delayed postapproval evidence. Instead, they recommend strengthening accelerated approval with stricter confirmatory trial requirements and improving the expanded access pathway to preserve rigorous preapproval evidence generation while maintaining patient access.
View Source

Confidentiality Orders and Public Interest in Drug and Medical Device Litigation

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

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

FDA Approval and Regulation of Pharmaceuticals, 1983-2018

Darrow JJ, Avorn J, Kesselheim AS - JAMA

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

Right to Try Requests and Oncologists’ Gatekeeping Obligations

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

  • Commentary & Opinion
| January 2020
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Oncologists will be at the forefront of Right to Try requests given the strong demand for pre-approval access to cancer therapies, and physicians face difficult gatekeeping obligations in managing patient expectations while navigating a law that removes FDA and IRB oversight from the access process.
View Source

Changes in Utilization of Generic Angiotensin Receptor Blockers Following Product Recalls in the United States

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

  • Research Publications
| January 2020
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Following FDA recalls of multiple lots of generic valsartan, losartan, and irbesartan due to potentially carcinogenic nitrosamine impurities, valsartan use dropped substantially while total generic ARB prescriptions remained stable, indicating patients shifted within the ARB class rather than discontinuing treatment. The findings suggest that the recall primarily caused substitution to non-recalled ARBs, particularly losartan and olmesartan, potentially averting major treatment disruptions despite the widespread confusion the recalls caused among patients, physicians, and pharmacists.
View Source

US Food and Drug Administration Recommendations on the Use of Surrogate Measures as End Points in New Anti-Infective Drug Approvals

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

  • Research Publications
| January 2020
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
FDA guidance documents for anti-infective drug development recommend surrogate measures (such as microbial culture status) as primary end points in 21 of 27 infectious disease indications, despite regulatory standards stipulating that such indirect measures should only be used for serious or life-threatening chronic conditions when substantial benefit over existing therapy is expected. The authors conclude that FDA guidance documents should be updated to align with established scientific and regulatory principles by recommending direct clinical outcome measures rather than surrogate measures as primary trial endpoints.
View Source

The Supreme Court’s Latest Ruling on Drug Liability and Its Implications for Future Failure-To-Warn Litigation

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

  • Commentary & Opinion
| Winter 2020
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors discuss the Supreme Court’s decision in Merck v. Albrecht, which preserved patients’ ability to bring failure-to-warn lawsuits against drug manufacturers despite FDA approval of drug labeling, highlighting the important role such litigation plays in uncovering safety information and incentivizing timely label updates.
View Source

Response Rates and Durations of Response for Biomarker-Based Cancer Drugs in Nonrandomized Versus Randomized Trials

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

  • Research Publications
| January 2020
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Response rates for biomarker-based cancer drugs were similar between nonrandomized and randomized trials, but durations of response were longer in nonrandomized trials than randomized trials, with nonrandomized trial outcomes being poor surrogates for overall survival. Caution should be exercised when approving or prescribing targeted cancer drugs based on nonrandomized trial data on durable responses, as these responses may be overestimated and fail to predict actual survival benefits.
View Source

Incentivizing Antibiotic Development: Why Isn’t the Generating Antibiotic Incentives Now (GAIN) Act Working?

Darrow JJ, Kesselheim AS - Open Forum Infectious Diseases

  • Research Publications
| January 2020
  • Innovation Incentives and Competition
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
The GAIN Act of 2012, designed to incentivize antibiotic development through 5 years of additional nonpatent exclusivity, has produced disappointing results because its eligibility criteria lack sufficient targeting to unmet clinical needs and disproportionately reward modifications to existing drugs over new treatments. The authors recommend narrowing QIDP eligibility criteria to a more targeted list of pathogens, greater use of animal data in eligibility determination, and conditioning benefits on companion diagnostic availability to improve the program’s effectiveness.
View Source

Lifecycle Regulation of Artificial Intelligence- and Machine Learning-Based Software Devices in Medicine

Hwang TJ, Kesselheim AS, Vokinger KN - JAMA

  • Commentary & Opinion
| December 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
AI/ML-based medical devices require a lifecycle regulatory approach rather than the current one-time clearance model. The authors note that many AI/ML products have been cleared through the 510(k) pathway without new clinical testing by claiming substantial equivalence to devices that may be decades old.
View Source

Op-Ed: Do Large Pharma Companies Provide Drug Development Innovation? Our Analysis Says No

Jung EH, Engelberg AB, Kesselheim AS - STAT

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

Prescription Opioid Epidemic and Trends in the Clinical Development of New Pain Medications

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

  • Research Publications
| December 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
The proportion of new pain drugs entering early-stage clinical trials declined from 2.5% (2000-2002) to 1.7% (2013-2015), while most new pain drugs failed to advance through development stages, with only 52% progressing from phase 1 to phase 2 and 11% reaching phase 3 trials. The authors conclude that pain drug development has shifted toward reformulated products rather than novel therapeutics and recommend increased funding for basic pain research to address the critical need for new pain management options.
View Source

Potential Medicare Savings From Generic Substitution and Therapeutic Interchange of ACE Inhibitors and Angiotensin-II-Receptor Blockers

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

  • Research Publications
| December 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Medicare could have saved approximately $676 million (89.6%) of the $754 million spent on brand-name ACEIs and ARBs in 2016–2017 by maximizing generic substitution and therapeutic interchange, with the largest savings from interchanging brand-name olmesartan with generic losartan given that clinical guidelines do not recommend specific agents within these classes. These findings highlight the substantial savings available from simple formulary management strategies for drug classes where clinical evidence does not support meaningful differences in outcomes between agents.
View Source

Expanding Coverage of Oncology Drugs in an Aging, Upper-Middle-Income Country: Analyses of Public and Private Expenditures in Chile

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

  • Research Publications
| December 2019
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Oncology drug expenditures in Chile rose 120% between 2012-2013 and 2016-2017, with the public sector accounting for 84.2% of spending and increased drug use driving over 90% of growth in the public sector. Policymakers should urgently implement measures to promote generic drug use, optimize the balance between on-protocol and off-protocol drugs, and reduce off-label prescribing to address the fiscal unsustainability of current spending growth rates.
View Source

Comments for Hearing, “Standards for Future Opioid Analgesic Approvals and Incentives for New Therapeutics to Treat Pain and Addiction”

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

  • Policy Interactions
| November 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The commenters reiterate their support for the FDA’s proposal to consider broader public health effects in opioid regulatory decisions and calls on the agency to take additional steps to fully implement the comprehensive systems approach to opioid regulation recommended by the National Academies.
View Source

The U.S. Insulin Crisis—Rationing a Lifesaving Medication Discovered in the 1920s

Fralick M, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| November 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors trace the history of insulin pricing from its discovery in 1922 to the present crisis in which the price of insulin has risen dramatically, leading Americans to ration a lifesaving medication. They attribute the crisis to an oligopolistic market dominated by three manufacturers and a US system that allows unchecked drug pricing, and propose policy solutions including importation and price transparency.
View Source

Variation in Prescription Drug Prices By Retail Pharmacy Type: A National Cross-Sectional Study

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

  • Research Publications
| November 2019
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Using data from over 68,000 pharmacies across 16,325 ZIP codes, this study found substantial variation in cash prices for generic drugs by pharmacy type, with big box pharmacies offering prices 48% lower than large chains while independent pharmacies charged 61% higher prices. Brand-name drug prices varied minimally across pharmacy types. The findings suggest that consumers seeking lower cash prices for generic medications should consider a broader range of pharmacies, while policy efforts should address the significant pricing disparities for generic drugs across independent and small chain pharmacies.
View Source

Randomized Study of Providing Evidence Context to Mitigate Physician Misinterpretation Arising From Off-Label Drug Promotion

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

  • Research Publications
| November 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among physicians surveyed, those who received manufacturer off-label promotion of Vascepa were five times more likely to prescribe it off-label (38% versus 7%). Providing physicians with additional context on the limited data supporting off-label use was found to reduce physician support of the treatment, suggesting this approach may be necessary to reduce inappropriate off-label prescribing and mitigate misinterpretation arising from manufacturer promotional materials.
View Source

Physician Perceptions of Step Therapy Prescribing Requirements

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

  • Research Publications
| November 2019
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Most physicians surveyed (55%) acknowledged that step therapy policies could improve medication affordability and clinical appropriateness (59%), though 70% reported interactions with the pharmaceutical industry and subspecialists held more negative views of these utilization management strategies. While physicians recognized the potential benefits of step therapy for cost-effectiveness, they expressed significant concerns about inefficient and inflexible implementation that often failed to account for patient-specific information, suggesting that improved policy design and execution could enhance physician acceptance and compliance.
View Source

Multimodal Analysis of FDA Drug Safety Communications: Lessons From Zolpidem

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

  • Research Publications
| November 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
A multi-modal study of two FDA Drug Safety Communications issued in 2013 regarding zolpidem (Ambien) found that key safety messages were incompletely disseminated through traditional and social media, and surveys and interviews revealed significant limitations in patient-provider communication that hindered the sharing of new safety information. Analysis of zolpidem dispensing patterns after the communications suggested that uptake of safety knowledge into clinical practice was suboptimal, pointing to opportunities for improving how FDA safety messages reach and influence both prescribers and patients.
View Source

Impact of State Laws Restricting Opioid Duration on Characteristics of New Opioid Prescriptions

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

  • Research Publications
| November 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Following implementation of 7-day opioid duration limits for opioid-naïve patients in Massachusetts, Connecticut, and New York in 2016, pooled analysis showed a decreased probability of initiating a >7-day prescription and shorter opioid duration, though without an immediate reduction in total morphine equivalent dose. Between-state heterogeneity was notable, with Massachusetts and Connecticut showing immediate declines in opioid duration while New York’s effect was delayed, suggesting variable implementation and enforcement of these laws across states.
View Source

Public Sector Financial Support for Late Stage Discovery of New Drugs in the United States: Cohort Study

Nayak RK, Avorn J, Kesselheim AS - BMJ

  • Research Publications
| October 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Between 2008 and 2017, publicly supported research contributed to the late stage development of at least 25% of FDA-approved new drugs, and drugs with public sector origins were significantly more likely to receive expedited approval (68% vs. 47%) or first-in-class designation (45% vs. 26%). These findings highlight the importance of considering public sector investment in a drug development when determining fair pricing and manufacturer revenue for new drugs.
View Source

Desmopressin and the Risk of Hyponatremia: A Population-Based Cohort Study

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

  • Research Publications
| October 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Adults prescribed the original formulation of desmopressin had a 13-fold higher rate of hyponatremia compared to those prescribed oxybutynin for urinary tract symptoms, with similar elevated risks observed within 30 days of initiation and when using tamsulosin as a comparator. The risks of hyponatremia associated with desmopressin should be clearly communicated to patients prescribed this formulation, particularly given the approval of a new intranasal formulation in 2017.
View Source

Fool Me Twice? The Reemergence of Rofecoxib and the Orphan Drug Act

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

  • Commentary & Opinion
| October 2019
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors examine how a small manufacturer obtained orphan drug designation for rofecoxib (formerly Vioxx, withdrawn for cardiovascular risks) to treat hemophilic arthropathy, warning that orphan drug approval could serve as a gateway for widespread off-label use in the much larger osteoarthritis market.
View Source

Characteristics of Recent Generic Drug Approvals By the US Food and Drug Administration

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

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

Transformative Models to Promote Prescription Drug Innovation and Access: A Landscape Analysis

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

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

The 505(B)(2) Drug Approval Pathway

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

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

Surrogate Endpoints and Drug Regulation: What Is Needed to Clarify the Evidence

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

  • Research Publications
| Fall 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Surrogate endpoints are widely used in pivotal drug trials because they can be measured sooner than direct clinical outcomes, but unlike drugs, biomarkers typically have no single owner or stakeholder responsible for generating validation evidence—creating a collective action problem where drug developers may underinvest in validating surrogates that would benefit their competitors. The authors argue that this structural gap, combined with the absence of a central regulator tracking evidence for or against particular biomarkers, has led to the systematic use of poorly validated surrogate measures in drug approval, and they propose policy reforms to strengthen the evidence base for surrogates.
View Source

Patients’ Knowledge of Key Messaging in Drug Safety Communications for Zolpidem and Eszopiclone: A National Survey

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

  • Research Publications
| Fall 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 594 patients taking zolpidem or eszopiclone, two-thirds reported hearing about drug safety information generally, but only two-thirds of zolpidem users and half of eszopiclone users had heard about the specific Drug Safety Communications for these drugs. Patients also showed limited ability to accurately identify key messages in these communications. The authors recommend that the FDA work collaboratively with providers and pharmacies to improve the reach and comprehension of Drug Safety Communications among patients taking these medications.
View Source

Lung Cancer Survival Gains: Contributions of Academia and Industry

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

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

Challenges and Opportunities for Biomarker Validation

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

  • Commentary & Opinion
| Fall 2019
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
Rigorous biomarker validation is critical to clinical practice and drug development. The authors argue that relying on unvalidated biomarkers can harm patients and propose a framework for improving the validation process.
View Source

Application of Orphan Drug Designation to Cancer Treatments (2008-2017): A Comprehensive and Comparative Analysis of the USA and EU

Vokinger KN, Kesselheim AS - BMJ Open

  • Research Publications
| October 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Between 2008 and 2017, the FDA approved 135 cancer drugs with orphan indications, of which 75% were also approved by the EMA, but only 41% of these received orphan designation from the EMA. Notably, 79% were first approved in the US, and the FDA approved significantly more drugs for biomarker-based indications (33%) and solid tumors (78%) compared to the EMA. The findings suggest that the FDA’s more liberal orphan designation criteria, particularly for cancer subgroups derived from biomarkers and solid tumors, differ substantially from the EMA’s requirements, resulting in divergent regulatory approaches to orphan drug approvals.
View Source

Design Characteristics, Risk of Bias, and Reporting of Randomised Controlled Trials Supporting Approvals of Cancer Drugs by European Medicines Agency, 2014-16: Cross Sectional Analysis

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

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

Changes in Price for Generic Drugs in the USA, 2008-2016

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

  • Research Publications
| September 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 1,099 generic drugs available throughout 2008–2016, mean prices increased by 39.9% while median prices fell 30.0%, reflecting a bifurcated market where 17.2% of drugs more than doubled in price while 60.8% experienced price decreases. The most commonly prescribed drugs saw the largest declines and infrequently prescribed drugs experienced the greatest increases These findings suggest that while the generic drug market is functioning well for high-volume products, low-volume generic drugs remain vulnerable to substantial price increases due to insufficient competition.
View Source

Assessing the Justification, Funding, Success, and Survival Outcomes of Randomized Noninferiority Trials of Cancer Drugs: A Systematic Review and Pooled Analysis

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

  • Research Publications
| August 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 23 randomized noninferiority trials of cancer drugs with overall survival as the primary endpoint, 39% lacked justification for the noninferiority design. Industry-funded trials were significantly more likely to lack proper justification, though funding was not associated with success in achieving noninferiority. The pooled analysis showed no beneficial or detrimental effect on overall survival, suggesting that regulators should increase scrutiny of noninferiority trial designs in cancer drug development.
View Source

Promoting Pediatric Drug Research and Labeling—Outcomes of Legislation

Bourgeois FT, Kesselheim AS - New England Journal of Medicine

  • Research Publications
| August 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Despite over 20 years of legislative efforts including the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, significant gaps persist in pediatric labeling for FDA-approved drugs remain. The authors review the outcomes of these landmark pediatric drug laws, examining whether the financial incentives and regulatory mandates have succeeded in generating adequate prescribing information for children.
View Source

Comments on Notice, “New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication” (Doshi et al.)

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

  • Policy Interactions
| August 2019
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The commenters oppose the FDA’s plan to replace individual discipline-specific drug reviews with a single “integrated review,” arguing this would reduce transparency by eliminating detailed reviewer analyses, dissenting opinions, and granular safety data that researchers and the public rely on to understand FDA decision-making.
View Source

Comments on Draft Guidance, “Opioid Analgesic Drugs: Considerations for Benefit-Risk Assessment Framework”

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

  • Policy Interactions
| August 2019
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The commenters applaud the FDA’s draft guidance incorporating “broader public health effects” into opioid benefit-risk assessments as an important first step in implementing the National Academies’ recommendations, while urging further action to fully adopt a comprehensive systems approach to opioid regulation.
View Source

Why Are Biosimilars Not Living Up to Their Promise in the US?

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

  • Research Publications
| August 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Despite Congress creating an abbreviated approval pathway for biosimilars in 2010 to stimulate competition and reduce the high costs of biologic drugs, only 17 biosimilars had been approved by February 2019, with just 7 on the market and limited overall utilization. The authors characterize the tactics employed by originator biologic manufacturers to delay biosimilar market entry and deter prescribing—including patent thickets, rebate structures, and misinformation campaigns—and assess the ethical dimensions of increasing biosimilar adoption to improve patient access to valuable therapies.
View Source

Characteristics of Trials and Regulatory Pathways Leading to US Approval of Innovative vs. Non-Innovative Oncology Drugs

Vokinger KN, Kesselheim AS - Health Policy

  • Research Publications
| August 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
First-generation oncology drugs and most second-generation variants across four drug classes (BCR-ABL TKIs, ALK+ TKIs, CD20 monoclonal antibodies, and HER2 monoclonal antibodies) were approved through expedited pathways and predominantly based on single-arm trials, with second-generation drugs showing similar approval patterns to their first-generation counterparts. While expedited approval facilitates earlier patient access, this regulatory approach is associated with increased risk of post-approval safety-related labeling changes and unanticipated adverse events.
View Source

Designing Development Programs for Non-Traditional Antibacterial Agents

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

  • Commentary & Opinion
| July 2019
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The distinction between “traditional” and “non-traditional” antibacterial agents has limited regulatory relevance, and most agents in both categories should be developed using standard clinical efficacy measures, while acknowledging that some products with population-level benefits may require novel regulatory paradigms.
View Source

Competition and Price Among Brand-Name Drugs in the Same Class: A Systematic Review of the Evidence

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

  • Research Publications
| July 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
A systematic review of 10 empirical studies found no evidence that brand-name competition within the same drug class lowers list prices of existing drugs, though two studies suggested it may modestly restrain pricing of newly introduced drugs. The authors conclude that policies promoting brand-brand competition alone are unlikely to reduce drug prices without additional structural reforms to the pharmaceutical market.
View Source

Public Approval of Exception From Informed Consent in Emergency Clinical Trials: A Systematic Review of Community Consultation Surveys

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

  • Research Publications
| July 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
This systematic review of survey respondents across 27 FDA-approved exception from informed consent (EFIC) trials found that public approval of EFIC varied significantly, with more people willing to approve initiation of EFIC trials in their community (86.5%) than personal enrollment (73.0%), enrollment of a family member (68.6%), or the principle of enrollment without consent (58.4%). Surveyed populations were demographically skewed, with African American individuals and men underrepresented. The authors recommend that the FDA strengthen community consultation by standardizing survey instruments and reporting, requiring broader inclusion of African American and male respondents, and clarifying how survey results inform trial protocol development.
View Source

Comments on Notice, “New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication” (Herder et al.)

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

  • Policy Interactions
| July 2019
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The FDA should complete and expand its Clinical Study Report pilot project by making public disclosure of clinical study reports mandatory for all approved drugs, as transparency of these company-generated trial documents is essential for identifying underreported safety and efficacy information
View Source

Biosimilar Approvals and the BPCIA: Too Soon to Give Up

Darrow JJ - Health Affairs Forefront

  • Commentary & Opinion
| July 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
Critics who compare biosimilar approval numbers unfavorably to the Hatch-Waxman Act’s success with generics overlook key structural differences that explain the slower pace of biosimilar market entry. US biosimilar approvals have actually outpaced the EU’s during comparable post-enactment periods, and an upward trend in approvals, promising price discounts abroad, and a robust development pipeline suggest the BPCIA framework should be refined rather than abandoned.
View Source

Spending on World Health Organization Essential Medicines in Medicare Part D, 2011-15: Retrospective Cost Analysis

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

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

Price Increases of Protected-Class Drugs in Medicare Part D, Relative to Inflation, 2012-2017

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

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

Reforming the Orphan Drug Act for the 21st Century

Sarpatwari A, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| July 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors argue that the Orphan Drug Act needs reform to address exploitation of its incentives, including strategies by manufacturers to obtain serial exclusivity and the potential for orphan-designated drugs to be widely used off-label for common conditions.
View Source

The Impact of Price Regulation on the Availability of New Drugs in Germany

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

  • Research Publications
| July 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
The 2011 German Pharmaceutical Market Restructuring Act implemented price regulation based on clinical benefit assessment, resulting in 98% of drugs with positive benefit assessments remaining on the market compared to only 75% of those without positive assessments. Drugs lacking positive assessments were more than ten times more likely to exit the German market. US policymakers considering drug cost containment strategies can learn from Germany’s experience with benefit-based price regulation and its impact on drug market availability.
View Source

Pre-Market Development Times for Biologic Versus Small-Molecule Drugs

Beall RF, Hwang TJ, Kesselheim AS - Nature Biotechnology

  • Research Publications
| July 2019
  • Innovation Incentives and Competition
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Using key patent filing dates to measure total development time, the authors found that biologic drugs did not spend significantly longer in development than small-molecule drugs before FDA approval—challenging the legislative rationale behind the 12-year exclusivity period granted to biologics under the BPCIA, which was justified in part by presumed longer development timelines. These findings have important policy implications for ongoing debates about biologic exclusivity periods in both domestic legislation and international trade agreements.
View Source

Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval

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

  • Research Publications
| July 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Of 93 cancer drug indications granted accelerated approval by the FDA between 1992 and 2017, only about one-fifth (20%) had confirmatory trials demonstrating an improvement in overall survival, while 37% of completed confirmatory trials relied on the same surrogate endpoints used in the preapproval studies rather than more clinically meaningful measures. These findings suggest the need to reassess confirmatory trial requirements to ensure the accelerated approval pathway generates more robust evidence of genuine clinical benefit for patients.
View Source

Transparency on Prescription Drug Research Expenditures: A Lever for Restraining Pricing?

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

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

Trust and Transparency in Medical Device Regulation

Kramer DB, Kesselheim AS - BMJ

  • Commentary & Opinion
| June 2019
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The authors discuss the FDA’s decision to end its controversial “alternative summary reporting” program for medical device adverse events, which had allowed manufacturers to report safety problems outside public view, arguing that all adverse event reports should be publicly accessible to maintain trust in device regulation.
View Source

Landscape of Cardiovascular Device Registries in the United States

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

  • Research Publications
| June 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 138 US cardiovascular device registries identified, the majority (55.8%) were industry-funded with academic stewardship (74.0%), but substantial inconsistencies existed in enrollment procedures (voluntary vs. required), informed consent requirements, and data access policies. The authors recommend that regulators strengthen guidelines to improve quality, consistency, and ethical standards across cardiovascular device registries.
View Source

Orphan Drug Designation and Exclusivity for “Same Drugs”

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

  • Commentary & Opinion
| Summer 2019
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
The authors describe how Eagle Pharmaceuticals exploited a legal loophole in the Orphan Drug Act to achieve “serial exclusivity” for bendamustine (Bendeka), effectively extending the monopoly of an existing cancer drug by obtaining new orphan drug exclusivity for a reformulated version with the same active ingredient.
View Source

Evaluation of Socioeconomic Status Indicators for Confounding Adjustment in Observational Studies of Medication Use

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

  • Research Publications
| June 2019
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
This methodologic study evaluated how different socioeconomic status (SES) indicators affect confounding adjustment in observational medication studies, finding that claims-based variables alone substantially improved balance on SES measures. While adding SES data further improved balance, it did not materially change outcome estimates for cardiovascular events or emergency department visits in a cohort of 7,109 Medicare patients initiating atorvastatin. The results suggest that claims-based proxies may be sufficient for mitigating SES confounding when aggregate-level SES information is unavailable in observational studies.
View Source

Comments for Hearing, “The Future of Insulin Biosimilars: Increasing Access and Facilitating the Efficient Development of Biosimilar and Interchangeable Insulin Products”

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

  • Policy Interactions
| May 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
An icon of a bill representing government policy.
The FDA should exempt insulin from the requirement for additional pre-approval switching studies to demonstrate interchangeability, applying the same evidentiary standards used for bioequivalent small-molecule generics, given insulin’s well-characterized molecular profile and the urgent affordability crisis facing patients.
View Source

Pharmaceutical Protections in U.S. Trade Deals—What Do Americans Get in Return?

Bollyky TJ, Kesselheim AS - New England Journal of Medicine

  • Commentary & Opinion
| May 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
The authors outline the history of pharmaceutical intellectual property provisions in US trade agreements, arguing that while these protections have benefited the pharmaceutical industry, they have not demonstrably lowered drug prices for American consumers or improved US. trade balances. They question whether the claimed rationale—that stronger IP protections abroad will reduce drug costs at home—holds up to scrutiny.
View Source

US Food and Drug Administration Approval of New Drugs Based on Noninferiority Trials in Oncology: A Dangerous Precedent?

Gyawali B, Kesselheim AS - JAMA Oncology

  • Commentary & Opinion
| May 2019
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
The FDA’s approval of lenvatinib (Lenvima) for hepatocellular carcinoma based on a noninferiority trial—when the new drug was neither safer, easier to administer, nor cheaper than the comparator sorafenib—sets a concerning precedent by lowering the bar for cancer drug approval without providing clear patient benefit.
View Source

Physicians’ Perspectives on FDA Approval Standards and Off-Label Drug Marketing

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

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

Cost Implications of Escalating Intravenous Acetaminophen Use in Children

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

  • Research Publications
| May 2019
  • Price, Value, and Access
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 4.7 million pediatric hospitalizations from 2010 to 2017, intravenous acetaminophen use increased from near zero to 13% of hospitalizations, reaching $16.0 million in annual costs in 2017, even as oral formulation use remained stable at 41% and the intravenous product’s price more than doubled. On 20% of hospital days when IV acetaminophen was administered, patients were also receiving other oral medications, raising questions about whether the substantially more expensive intravenous formulation was clinically necessary in many cases.
View Source

Assessment of the Role of Niacin in Managing Cardiovascular Disease Outcomes: A Systematic Review and Meta-Analysis

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

  • Research Publications
| April 2019
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
This systematic review and meta-analysis of 17 randomized clinical trials found no preventive association of niacin with cardiovascular outcomes in secondary prevention overall, though niacin monotherapy showed reduced risk of acute coronary syndrome, stroke, and revascularization in patients not receiving statins, findings primarily from studies conducted in the 1970s-1980s. The authors conclude that niacin may have limited utility in lipid control for secondary prevention as monotherapy, potentially for statin-intolerant patients, but current evidence derives from older studies on populations that may not represent modern cardiovascular disease patients.
View Source

Testimony on the Impact of S.706/H. 1333: An Act to Ensure Prescription Drug Cost Transparency and Affordability

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

  • Policy Interactions
| April 2019
  • Price, Value, and Access
An icon of a bill representing government policy.
View Source

Pharmaceutical Policy in the United States in 2019: An Overview of the Landscape and Avenues for Improvement

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

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

Luxturna: FDA Documents Reveal the Value of a Costly Gene Therapy

Darrow JJ - Drug Discovery Today

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

Experiences with and Challenges Afforded By Expedited Regulatory Pathways

Liu S, Kesselheim AS - Clinical Pharmacology & Therapeutics

  • Research Publications
| April 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
Among 154 novel therapeutics approved from 2014 to 2017, 60% received priority review and two-thirds received multiple expedited designations, but studies have found a 38% increased risk of safety-related labeling changes for expedited drugs and that only half of accelerated approval cancer drugs completed required confirmatory studies within 3 years. The authors emphasize that while expedited pathways have enabled transformative therapies, persistent challenges around delayed confirmatory evidence, emerging safety risks, and inadequate communication of therapeutic uncertainty require stronger enforcement of postapproval study requirements.
View Source

Battling Over Patents: The Impact of Oil States on the Generic Drug Industry

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

  • Research Publications
| April 2019
  • Innovation Incentives and Competition
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
The Supreme Court’s 2018 upholding of inter partes review (IPR), a faster, less costly alternative to litigation for challenging erroneously granted patents, in Oil States has proven particularly significant for the pharmaceutical industry, where generic drug companies have filed hundreds of challenges with moderate success since its creation in 2011. As biologics increasingly dominate the pharmaceutical landscape and are often protected by large patent portfolios, IPR is expected to become an even more important tool for addressing patent validity in this sector.
View Source

Association Between Progression-Free Survival and Patients’ Quality of Life in Cancer Clinical Trials

Hwang TJ, Gyawali B - International Journal of Cancer

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

Approximating Future Generic Entry for New Drugs

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

  • Research Publications
| Spring 2019
  • Innovation Incentives and Competition
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
The authors developed a methodology for estimating first generic entry dates based on manufacturers’ patent expiration dates, patent term restoration, and pediatric exclusivity extensions, finding that for innovative drugs, this approach predicted generic entry within a median of 6 months of the actual date. The tool is intended to help physicians, patients, and policymakers anticipate when generic competition will become available.
View Source

Pharmacy Benefit Managers: Practices, Controversies, and What Lies Ahead

Seeley E, Kesselheim AS - The Commonwealth Fund

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

Major Events in the Life Course of New Drugs, 2000-2016

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

  • Research Publications
| March 2019
  • Innovation Incentives and Competition
  • Price, Value, and Access
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
This interactive graphic allows viewers to explore data on the time required for investigational drugs to reach important US milestones, such as new drug applications, FDA approval, expiration of market exclusivity, and market entry of a generic version.
View Source

Comparative Effectiveness of Generic and Brand-Name Medication Use: A Database Study of US Health Insurance Claims

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

  • Research Publications
| March 2019
  • Innovation Incentives and Competition
  • Regulation and Clinical Evidence
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
This study of 2.3 million matched patient pairs found that generic medications demonstrated comparable clinical outcomes to brand-name products across 8 drug products, with the majority of endpoints showing similar results between generics and authorized generics. The findings suggest that educational interventions promoting patient and provider confidence in generic medications are warranted, as differences in psychiatric hospitalization outcomes between brand and generic users appear attributable to perception bias rather than actual drug efficacy differences.
View Source

Testimony: High US Prescription Drug Prices: Anatomy of the Problem and Prospects for Reform

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

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

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

Tepid Steps on Drug Pricing

Sarpatwari A, Kesselheim AS - JAMA Internal Medicine

  • Commentary & Opinion
| March 2019
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
An icon of a bill representing government policy.
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. Watch his testimony.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

Information Transparency in the Drug Approval Process (Reply)

Gyawali B, Goldstein DA - JAMA Oncology

  • Commentary & Opinion
| November 2018
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

Reinforcing the Social Compromise of Accelerated Approval

Gyawali B, Kesselheim AS - Nature Reviews Clinical Oncology

  • Commentary & Opinion
| October 2018
  • Regulation and Clinical Evidence
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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.
View Source

Antitrust, Market Exclusivity, and Transparency in the Pharmaceutical Industry

Sinha MS, Curfman GD, Carrier MA - JAMA

  • Commentary & Opinion
| June 2018
  • Innovation Incentives and Competition
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

Legal Challenges to State Drug Pricing Laws

Lee TT, Kesselheim AS, Kapczynski A - JAMA

  • Commentary & Opinion
| March 2018
  • Price, Value, and Access
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

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
Simple graphic of magnifying glass examining papers to signify reviewing research publications.
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.
View Source

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
Talk bubble graphics representing commentary and opinion.
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.
View Source

Program On Regulation, Therapeutics, And Law (PORTAL)
Division of Pharmacoepidemiology and Pharmacoeconomics
Brigham and Women's Hospital • Harvard Medical School
41 Avenue Louis Pasteur, Suite 0B17, Boston, MA 02115

©2026 Program On Regulation, Therapeutics, And Law (PORTAL). All rights reserved.