Sales revenues for new therapeutic agents approved by the US Food and Drug Administration from 1995 to 2014: a retrospective study.

OBJECTIVES: To analyze worldwide sales of new therapeutic agents and to estimate the time it takes for product sales to exceed industry-wide average drug development costs. METHODS: Data obtained from company reports were analyzed to track worldwide sales of new medicines approved by the US Food and Drug Administration from 1995 to 2014. All sales figures were reported in 2019 US dollars. Kaplan-Meier curves were used to evaluate the time it took for discounted product sales to exceed the average costs associated with developing one new drug (accounting for the costs of failed trials), using published estimates of these costs. RESULTS: Based on data for 361 of 558 new therapeutic agents approved over the study period (median follow-up: 13.2 years), mean sales revenue per product was $15.2 billion through the end of 2019; the median was $6.7 billion. These products jointly generated global sales of $5.5 trillion since approval. Revenues were highly skewed, with the 25 best selling products (7%, 25/361) accounting for 38% of this amount ($2.1 trillion/$5.5 trillion). About 47% of products had discounted sales that exceeded the estimated industry-wide average costs of development within 5 years of approval, and 75% within 10 years. After attributing potential production, marketing, and other costs, these numbers dropped to 21% of products within 5 years of approval, and 46% within 10 years. CONCLUSIONS: Sales of new medicines approved from 1995 to 2014 were highly skewed, but a majority of products had net discounted sales that exceeded the industry-wide average costs of development within 10 years of approval. An understanding of how sales revenues accrue in the years after initial approval, alongside data on business costs, can inform discussions about how to incentivize private investment in innovation while ensuring affordable prices for patients and the health-care system.

Commercial markups on pediatric oncology drugs at 340B pediatric hospitals.

Eligible pediatric hospitals can purchase clinician-administered drugs at discounted rates through the 340B Drug Pricing Program and charge payers prices exceeding drug acquisition costs, but the magnitude of these markups is not known. In a study of newly approved oncology drugs at pediatric 340B hospitals, median negotiated prices ranged from 102% (interquartile range [IQR]: 91%-156%) of average sales price (ASP) at Phoenix Children's Hospital to 630% (IQR: 526%-630%) at Driscoll Children's Hospital. Pediatric hospitals participating in the federal 340B Drug Pricing Program can extract steep payments on new drugs from commercial insurers, though with wide variation between and within hospitals.

Measuring and Understanding Market Exclusivity Length for New Prescription Drugs in France, Australia, and the USA.

BACKGROUND: Originator drug manufacturers use several strategies to delay generic competition in the USA, but it remains unclear whether this results in longer market exclusivity compared to other countries. OBJECTIVES: We sought to understand how drug market exclusivity lengths vary between the USA and two comparable countries. METHODS: We focused on drugs approved within 2 years of each other in the USA, France, and Australia from 1995 to 2005, and we compared the lengths of exclusivity from marketing approval through first generic competition or June 2023 using Kaplan-Meier analyses. RESULTS: Among 165 drugs in common between the USA and France, the median length of exclusivity was slightly longer in France (15.0 years, interquartile range [IQR]: 13.0-19.6) than the USA (14.5 years, IQR: 11.7-17.6). Among 100 drugs in common between the USA and Australia, the median length of exclusivity was longer in Australia (16.3 years, IQR: 13.9-22.4) than in the USA (14.4 years, IQR: 12.0-17.1). CONCLUSIONS: Market exclusivity lengths in the USA are not longer than in France and Australia. Potential reasons include the larger US market and incentives that offer transient high generic drug prices in the USA for manufacturers that successfully challenge originator market exclusivity.

Regulating Laboratory Tests: What Framework Would Best Support Safety and Validity?

Policy Points With increasing public attention to cases of inaccurate and misleading laboratory-developed tests, there have been calls for regulatory reform. To protect patients from faulty laboratory tests, we need a framework that balances comprehensive test review with laboratory flexibility. The Verifying Accurate Leading-edge IVCT [In Vitro Clinical Test] Development (VALID) Act would have helped ensure laboratory test safety and validity through a much-needed expansion of Food and Drug Administration (FDA) oversight. However, Congress did not pass the VALID Act in 2022, forcing the FDA to start the regulatory reform process on its own.

Trends in Use and Evidence of Adherence to Risk Evaluation and Mitigation Strategy Pregnancy Testing Requirements for Thalidomide, Lenalidomide, and Pomalidomide in the USA, 2000-2020.

INTRODUCTION: Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter. OBJECTIVE: We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs. METHODS: Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential. RESULTS: Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing. CONCLUSION: Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.

How health technology assessment can help to address challenges in drug repurposing: a conceptual framework.

Drug repurposing faces various challenges that can impede its success. We developed a framework outlining key challenges in drug repurposing to explore when and how health technology assessment (HTA) methods can address them. We identified 20 drug-repurposing challenges across the categories of data access, research and development, collaboration, business case, regulatory and legal challenges. Early incorporation of HTA methods, including literature review, empirical research, stakeholder consultation, health economic evaluation and uncertainty assessment, can help to address these challenges. HTA methods canassess the value proposition of repurposed drugs, inform further research and ultimately help to bring cost-effective repurposed drugs to patients.

Medicare Should Cover Weight Loss Drugs as Long as the Prices are Affordable.

Glucagon-like peptide-1 receptor agonists are effective for treating obesity, but the high cost of these medications endangers the financial viability of our health care system. To ensure that these drugs are available to Medicare beneficiaries, pharmaceutical manufacturers must lower their prices.

Patent Portfolios Protecting 10 Top-Selling Prescription Drugs.

Importance: Brand-name drugs are sold at high prices in the US during market exclusivity periods protected by patents. Multiple overlapping patents protecting a drug are known as patent thickets and can effectively delay the emergence of price-lowering generic competition for many years. Objective: To evaluate the composition of patent thickets of 10 top-selling prescription drugs in the US and compare the characteristics of drug patents filed during development with those filed on these products after US Food and Drug Administration (FDA) approval. Design and Setting: This cross-sectional study examined US patent thickets of the 10 prescription drugs with the highest US net sales revenue in 2021 using information on issued patents and patent applications as of June 30, 2022, obtained from a public database by the Initiative for Medicines, Access, and Knowledge. Data were analyzed from September 2022 to June 2023. Main Outcomes and Measures: Prevalence of patents filed before and after FDA approval; types of claims present in issued patents (ie, chemical composition, method of use, process or synthesis, formulation, and delivery device); and patent thicket density (number of active patents at a given time). Results: The 10 top-selling prescription drugs in the US for 2021 included 4 small-molecule drugs and 6 biologics. These 10 drugs were linked to 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. Almost three-quarters of patent applications (1028 [72%]) were filed after FDA approval. The postapproval proportion was higher for biologics (80%) than for small-molecule drugs (58%). Postapproval filing of patent applications peaked in the first 5 years after FDA approval for small-molecule drugs and 12 years after FDA approval for biologics. Of 465 patents issued for applications filed after FDA approval, 189 (41%) had method of use claims, 127 (27%) had formulation claims, and 103 (22%) had process or synthesis claims, while 86 (19%) had chemical composition claims and 46 (10%) had device claims. Patent thicket density peaked 13 years after FDA approval, at which time these 10 drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% of which were filed after FDA approval. Conclusions and Relevance: This study found that among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims covering aspects other than the active ingredient of the drug contributed to patent thickets. Scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic or biosimilar competition.

Federal Trade Commission Actions on Prescription Drugs, 2000-2022.

Importance: The Federal Trade Commission's (FTC) oversight role in the pharmaceutical market is critical to the health of patients and the health care system. This study characterized the FTC's policy on the pharmaceutical market in recent decades, identifying the types of actions it has favored, barriers it has faced, and authorities that remain untested. Objective: To review FTC legal actions in the pharmaceutical market from 2000-2022. Evidence Review: Legal actions were determined through manual review of search results from the FTC's online Legal Library as well as a 2023 FTC report on pharmaceutical actions. The alleged misconduct, type of legal action taken, timing, and outcome were collected from press releases, complaints, orders, and other legal documents. Findings: From 2000-2022, the FTC challenged 62 mergers, brought 22 enforcement actions against allegedly unlawful business practices, and made 1 rule related to pharmaceuticals. Alleged misconduct in enforcement actions involved anticompetitive settlements in patent litigation (n = 11), unilateral actions by brand manufacturers to delay generic competition (n = 6), noncompete agreements (n = 4), and monopolization (n = 3), with 10 outcomes involving monetary payment, totaling $1.6 billion. Of the 62 mergers the FTC challenged, 61 were allowed to continue, 58 after divesting certain drugs to third-party competitors. The FTC's reliance on drug divestitures decreased from 18 drugs per year from 2000-2017 to 4.3 per year from 2017-2023. Conclusions and Relevance: The FTC brought about 1 enforcement action and 3 merger actions per year against pharmaceutical manufacturers from 2000-2022, pursuing a small fraction of the estimated misconduct and consolidation in the pharmaceutical marketplace. Although the FTC faces substantial legal and practical limitations, important tools remain untested, including a rule defining "unfair methods of competition," that may allow it to more effectively prevent repetitive patterns of anticompetitive behavior.

Trust in the Food and Drug Administration: A National Survey Study.

Building trust in public health agencies like the US Food and Drug Administration (FDA) has become a key government priority. Understanding the roots of FDA mistrust is important if the agency is to develop targeted messaging and reforms aimed at building confidence in the agency. We conducted a survey of 2,021 respondents in the US probing attitudes toward the FDA. The primary outcome was FDA trust, defined as the mean score that each respondent assigned to the FDA across four prespecified axes: (1) competence and effectiveness; (2) commitment to acting in the best interests of the American public; (3) abiding by the rules and regulations set forth by policy or law; and (4) expertise in health, science, and medicine. On multivariable ordinal logistic regression, FDA mistrust was associated with female gender (odds ratio [OR] = 0.74, 95% confidence interval [CI] 0.62-0.88), rural community (OR 0.85, 95% CI 0.75-0.96), conservative political views (OR 0.77, 95% CI 0.74-0.81), worse self-reported health (OR 0.89, 95% CI 0.80-0.98), lower satisfaction with health care received (OR 0.63, 95% CI 0.56-0.71), less attention to health and science news (OR 0.72, 95% CI 0.64-0.80), and not having children under the age of 18 (OR 0.72, 95% CI 0.60-0.86). These findings underscore the challenges faced by US political leaders in convincing a heterogeneous American public to trust the FDA. The FDA should develop and deploy targeted outreach strategies to populations with lower levels of trust and strengthen internal processes that minimize biases and ensure sound decision-making.

Leah Z. Rand, Daniel P. Carpenter, Aaron S. Kesselheim, Anushka Bhaskar, Jonathan J. Darrow, and William B. Feldman Reply.

The authors respond to a letter by Mitchell Berger in the March-April 2024 issue of the Hastings Center Report concerning their essay "Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines."

Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies.

Importance: The number of new genome-targeted cancer drugs has increased, offering the possibility of personalized therapy, often at a very high cost. Objective: To assess the validity of molecular targets and therapeutic benefits of US Food and Drug Administration-approved genome-targeted cancer drugs based on the outcomes of their corresponding pivotal clinical trials. Design and Settings: In this cohort study, all genome-targeted cancer drugs that were FDA-approved between January 1, 2015, and December 31, 2022, were analyzed. From FDA drug labels and trial reports, key characteristics of pivotal trials were extracted, including the outcomes assessed. Main Outcomes and Measures: The strength of evidence supporting molecular targetability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit for their approved indications was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Substantial clinical benefit was defined as a grade of A or B for curative intent and 4 or 5 for noncurative intent. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-based cancer treatments. Results: A total of 50 molecular-targeted drugs covering 84 indications were analyzed. Forty-five indications (54%) were approved based on phase 1 or phase 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials, and 48 (57%) were approved on the basis of subgroup analyses. By each indication, 46 of 84 primary end points (55%) were overall response rate (median [IQR] overall response rate, 57% [40%-69%]; median [IQR] duration of response, 11.1 [9.2-19.8] months). Among the 84 pivotal trials supporting these 84 indications, 38 trials (45%) had I-A ESCAT targetability, and 32 (38%) had I-B targetability. Overall, 24 of 84 trials (29%) demonstrated substantial clinical benefit via ESMO-MCBS. Combining these ratings, 24 of 84 indications (29%) were associated with high-benefit genomic-based cancer treatments. Conclusions and Relevance: The results of this cohort study demonstrate that among recently approved molecular-targeted cancer therapies, fewer than one-third demonstrated substantial patient benefits at approval. Benefit frameworks such as ESMO-MCBS and ESCAT can help physicians, patients, and payers identify therapies with the greatest clinical potential.

Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval.

Importance: The US Food and Drug Administration's (FDA) accelerated approval pathway allows approval of investigational drugs treating unmet medical needs based on changes to surrogate measures considered "reasonably likely" to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit. Objective: To determine whether cancer drugs granted accelerated approval ultimately demonstrate clinical benefit and to evaluate the basis of conversion to regular approval. Design, Setting, and Participants: In this cohort study, publicly available FDA data were used to identify cancer drugs granted accelerated approval from 2013 to 2023. Main Outcomes and Measures: Demonstrated improvement in quality of life or overall survival in accelerated approvals with more than 5 years of follow-up, as well as confirmatory trial end points and time to conversion for drug-indication pairs converted to regular approval. Results: A total of 129 cancer drug-indication pairs were granted accelerated approval from 2013 to 2023. Among 46 indications with more than 5 years of follow-up (approved 2013-2017), approximately two-thirds (29, 63%) were converted to regular approval, 10 (22%) were withdrawn, and 7 (15%) remained ongoing after a median of 6.3 years. Fewer than half (20/46, 43%) demonstrated a clinical benefit in confirmatory trials. Time to withdrawal decreased from 9.9 years to 3.6 years, and time to regular approval increased from 1.6 years to 3.6 years. Among 48 drug-indication pairs converted to regular approval, 19 (40%) were converted based on overall survival, 21 (44%) on progression-free survival, 5 (10%) on response rate plus duration of response, 2 (4%) on response rate, and 1 (2%) despite a negative confirmatory trial. Comparing accelerated and regular approval indications, 18 of 48 (38%) were unchanged, while 30 of 48 (63%) had different indications (eg, earlier line of therapy). Conclusions and Relevance: Most cancer drugs granted accelerated approval did not demonstrate benefit in overall survival or quality of life within 5 years of accelerated approval. Patients should be clearly informed about the cancer drugs that use the accelerated approval pathway and do not end up showing benefits in patient-centered clinical outcomes.

Changes in Use of Hepatitis C Direct-Acting Antivirals After Access Restrictions Were Eased by State Medicaid Programs.

Importance: Direct-acting antivirals (DAAs) are safe and highly effective for curing hepatitis C virus (HCV) infection, but their high cost led certain state Medicaid programs to impose coverage restrictions. Since 2015, many of these restrictions have been lifted voluntarily in response to advocacy or because of litigation. Objective: To estimate how the prescribing of DAAs to Medicaid patients changed after states eased access restrictions. Design, Setting, and Participants: This modified difference-in-differences analysis of 39 state Medicaid programs included Medicaid beneficiaries who were prescribed a DAA from January 1, 2015, to December 31, 2019. DAA coverage restrictions were measured based on a series of cross-sectional assessments performed from 2014 through 2022 by the US National Viral Hepatitis Roundtable and the Center for Health Law and Policy Innovation. Exposure: Calendar quarter when states eased or eliminated 3 types of DAA coverage restrictions: limiting treatment to patients with severe liver disease, restricting use among patients with active substance use, and requiring prescriptions to be written by or in consultation with specialists. States with none of these restrictions at baseline were excluded. Main Outcomes and Measures: Quarterly number of HCV DAA treatment courses per 100 000 Medicaid beneficiaries. Results: Of 39 states, 7 (18%) eliminated coverage restrictions, 25 (64%) eased restrictions, and 7 (18%) maintained the same restrictions from 2015 to 2019. During this period, the average quarterly use of DAAs increased from 669 to 3601 treatment courses per 100 000 Medicaid beneficiaries. After states eased or eliminated restrictions, the use of DAAs increased by 966 (95% CI, 409-1523) treatment courses per 100 000 Medicaid beneficiaries each quarter compared with states that did not ease or eliminate restrictions. Conclusions and Relevance: The results of this study suggest that there was greater use of DAAs after states relaxed coverage restrictions related to liver disease severity, sobriety, or prescriber specialty. Further reductions or elimination of these rules may improve access to a highly effective public health intervention for patients with HCV.