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.

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.

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.

How Do Risk Evaluation and Mitigation Strategies Impact Clinical Practice? A National Survey of Physicians.

The US Food and Drug Administration can require risk evaluation and mitigation strategy (REMS) programs for prescription drugs to ensure the benefits of use outweigh the risks. We conducted a national survey of physicians' experiences prescribing eight REMS-covered drugs: (1) ambrisentan; (2) bosentan; (3) clozapine; (4) isotretinoin; (5-7) the multiple myeloma (MM) drugs lenalidomide, pomalidomide, thalidomide; and (8) sodium oxybate. Between May 2022 and January 2023, we surveyed 5,331 physician prescribers of these drugs, and 1,295 (24%) returned surveys (range: 149 for bosentan to 226 for MM drugs). Although 765 (68%) respondents thought the certification process provided useful drug information, 757 (67%) wanted materials to include benefit data and 944 (84%) non-REMS-related risk data. A majority (704, 63%) thought the safe use requirements facilitated discussion with patients, but a similar number (637, 57%) attributed delayed medication access to these requirements. In multivariable modeling, MM drug and isotretinoin respondents were less likely than sodium oxybate respondents to agree that the certification process provided useful drug information (MM drug: odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.25-0.55; isotretinoin: OR = 0.39, 95% CI = 0.25-0.61), and isotretinoin, clozapine, and bosetan respondents were more likely than sodium oxybate respondents to agree that the safe use requirements often delayed medication access (isotretinoin: OR = 5.83, 95% CI = 3.70-9.19; clozapine: OR = 1.65, 95% CI = 1.08-2.54; bosentan: OR = 1.78, 95% CI = 1.12-2.85). Most physicians believe REMS programs convey useful drug safety information and facilitate discussion with patients but also seek information on benefits and non-REMS-related risks and better integration of REMS processes into clinical workflows.

Physicians' Perspectives On FDA Regulation Of Drugs And Medical Devices: A National Survey.

Physicians' knowledge of Food and Drug Administration (FDA) approval processes is important in informing clinical decisions and patient discussions. Among a randomly selected national sample of 509 internists, cardiologists, and oncologists, 41 percent reported moderate or better understanding of the FDA's drug approval process, and 17 percent reported moderate or better understanding of the FDA's medical device approval process. Nearly all physicians thought that randomized, blinded trials that met primary endpoints should be very important factors required to secure regulatory approval. Also, nearly all physicians thought that the FDA should revoke approval for accelerated-approval drugs or breakthrough devices that did not show benefit in postapproval studies. Our findings suggest that physicians commonly lack familiarity with drug and medical device regulatory practices and are under the impression that the data supporting FDA drug and high-risk device approvals are more rigorous than they often are. Physicians would value more rigorous premarket evidence, as well as regulatory action for drugs and devices that do not demonstrate safety and effectiveness in the postmarket setting.

Federal Enforcement of Pharmaceutical Fraud under the False Claims Act, 2006-2022.

CONTEXT: The False Claims Act is the US federal government's primary tool for identifying and penalizing pharmaceutical fraud. The Department of Justice uses the False Claims Act to bring civil cases against drug manufacturers that allegedly obtain improper payment from federal programs. METHODS: The authors searched the Department of Justice website for press releases published between 2006 and 2022 that announced fraud actions brought against drug companies. They then used the World Health Organization's Anatomical Therapeutic Classification index to identify the classes of prescription drugs implicated in fraud actions. FINDINGS: During fiscal years 2006-2022, payments by six manufacturers amounted to more than 28% of total payments made as a result of federal False Claims Act actions. Nervous system and cardiovascular drugs were the classes of medications most commonly implicated in alleged fraud. Federal officials most frequently alleged that companies improperly promoted nervous system drugs and paid kickbacks to increase revenues from cardiovascular, antineoplastic and immunomodulating, and alimentary tract and metabolism drugs. CONCLUSIONS: Despite frequent pharmaceutical fraud settlements and penalties, incidence of alleged fraud among drug companies remains high. Alternative methods for preventing and deterring fraud could help safeguard our health systems and promote public health, and policy makers should ensure that effective fraud enforcement complements preventive public health regulation.

National Comprehensive Cancer Network Guideline Recommendations of Cancer Drugs With Accelerated Approval.

Importance: Many cancer drugs are approved under the US Food and Drug Administration (FDA) accelerated approval pathway based on preliminary evidence. It is unclear how this limited evidence is integrated into the National Comprehensive Cancer Network (NCCN) guidelines, which are common references for clinicians and are used by public and private payers to determine reimbursement for oncology treatments. Objective: To analyze the NCCN guidelines' assessments for cancer drug indications that received FDA accelerated approval compared with cancer drug indications that received FDA regular approval. Design, Setting, and Participants: This cross-sectional study analyzes FDA-approved indications for cancer drugs that were granted accelerated approval from program inception in 1992 to June 30, 2022. For each drug, the FDA-approved labeling was reviewed to identify all indications. All analyses were performed at the drug-indication level. Exposure: The exposure was FDA regulatory status as of October 2022, including regular approval, accelerated approval, accelerated approval converted to regular approval, and withdrawn accelerated approval. Main Outcomes and Measures: The level of evidence and consensus (category 1, 2A, 2B, and 3) and treatment preference (preferred, alternative preferred, other recommended, and useful in certain circumstances) ratings assigned by NCCN committees as of February 2023. Results: A total of 315 oncology indications for 100 drugs were analyzed. These indications included 156 (50%) with regular approval, 60 (38%) with accelerated approval, 78 (49%) with accelerated approval that was converted to regular approval, and 21 (13%) with withdrawn accelerated approvals. Among all indications, 105 (33%) were rated by the NCCN as having category 1 evidence, 185 (59%) with category 2A, 6 (2%) with category 2B, and 2 (1%) with category 3 evidence. Compared with indications with regular approval, those with accelerated approval were less frequently assigned category 1 evidence (47% vs 3%; P < .001) and were less often listed as preferred treatment options (58% vs 40%; P = .008). Among the 21 withdrawn accelerated approval indications, 8 (38%) remained in the NCCN guidelines, with most having level 2A evidence ratings. Conclusions and Relevance: This study found that cancer drug indications with accelerated approval were less likely to be assigned high-level evidence ratings and preferred status in the NCCN guidelines compared with indications with regular approval; most accelerated and regular approval drugs had low-quality evidence ratings but high levels of consensus among oncologists on NCCN committees. Greater clarity on the thresholds and definitions of evidence levels would make the NCCN guidelines more useful to clinicians, patients, and payers.

Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis.

Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.

Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011-20): retrospective cohort study.

OBJECTIVE: To analyze the therapeutic value of supplemental indications compared with first indications for drugs approved in the US and Europe. DESIGN: Retrospective cohort study. SETTING: New and supplemental indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2011 and 2020. MAIN OUTCOME MEASURES: Proportion of first and supplemental indications rated as having high therapeutic value using ratings from the French and German national, independent health authorities. RESULTS: The cohort study included 124 first and 335 supplemental indications approved by the FDA and 88 first and 215 supplemental indications approved by the EMA between 2011 and 2020; the largest subset was for cancer disorders. Therapeutic ratings were available for 107 (86%) first and 179 (53%) supplemental indications in the US and for 87 (99%) first and 184 (86%) supplemental indications in Europe. Among FDA approved indications with available ratings, 41% (44/107) had high therapeutic value ratings for first indications compared with 34% (61/179) for supplemental indications. In Europe, 47% (41/87) of first and 36% (67/184) of supplemental indications had high therapeutic value ratings. Among FDA approvals, when the sample was restricted to the first three approved indications, second indication approvals were 36% less likely to have a high value rating (relative ratio 0.64, 95% confidence interval 0.43 to 0.96) and third indication approvals were 45% less likely (0.55, 0.29 to 1.01) compared with the first indication approval. Similar findings were observed for Europe and when weighting by the inverse number of indications for each drug. CONCLUSIONS: The proportion of supplemental indications rated as having high therapeutic value was substantially lower than for first indications. When first or supplemental indications do not offer added therapeutic value over other available treatments, that information should be clearly communicated to patients and physicians and reflected in the price of the drugs.

High Cost of Chimeric Antigen Receptor T-Cells: Challenges and Solutions.

Chimeric antigen receptor (CAR) T-cells are a cellular immunotherapy with remarkable efficacy in treating multiple hematologic malignancies but they are associated with extremely high prices that are, for many countries, prohibitively expensive. As their use increases both for hematologic malignancies and other indications, and large numbers of new cellular therapies are developed, novel approaches will be needed both to reduce the cost of therapy, and to pay for them. We review the many factors that lead to the high cost of CAR T-cells and offer proposals for reform.

Physician Perspectives on the Food and Drug Administration's Decision to Grant Accelerated Approval to Aducanumab for Alzheimer's Disease.

In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval to aducanumab, a monoclonal antibody indicated for the treatment of Alzheimer's disease. The accelerated approval decision was controversial due to concerns about the use of an unvalidated surrogate measure, beta-amyloid, as the basis for approval and a lack of clinical outcome benefit. Between October 2021 and September 2022, we conducted a survey of a nationally representative group of internists, medical oncologists, and cardiologists to understand perspectives around aducanumab's approval and how this FDA decision may influence trust in other drugs approved through the accelerated approval program. Among 214 physician respondents familiar with the accelerated approval of aducanumab, 184 (86%) would not prescribe or recommend aducanumab. Further, 143 (67%) physicians reported losing trust in other drugs approved through the accelerated approval program due to the FDA's decision with aducanumab. As a growing number of similar novel Alzheimer's disease treatments are on the horizon, the first of which, lecanemab, already has received accelerated approval in January 2023, our survey findings provide insight into the impact of the FDA's regulatory decisions on the perspectives and prescribing behavior of physicians concerning these novel drug treatments.

Trends in Medicare Spending on Oral Drugs for Chronic Lymphocytic Leukemia From 2014 to 2020.

This cross-sectional study analyzes trends in Medicare Part D use and spending on oral-targeted drugs for chronic lymphocytic leukemia from 2014 to 2020.

Added Therapeutic Benefit of Top-Selling Brand-name Drugs in Medicare.

Importance: The Inflation Reduction Act of 2022 authorizes Medicare to negotiate prices of top-selling drugs based on several factors, including therapeutic benefit compared with existing treatment options. Objective: To determine the added therapeutic benefit of the 50 top-selling brand-name drugs in Medicare in 2020, as assessed by health technology assessment (HTA) organizations in Canada, France, and Germany. Design, Setting, and Participants: In this cross-sectional study, publicly available therapeutic benefit ratings, US Food and Drug Administration documents, and the Medicare Part B and Part D prescription drug spending dashboards were used to determine the 50 top-selling single-source drugs used in Medicare in 2020 and to assess their added therapeutic benefit ratings through 2021. Main Outcomes and Measures: Ratings from HTA bodies in Canada, France, and Germany were categorized as high (moderate or greater) or low (minor or no) added benefit. Each drug was rated based on its most favorable rating across countries, indications, subpopulations, and dosage forms. We compared the use and prerebate and postrebate (ie, net) Medicare spending between drugs with high vs low added benefit. Results: Forty-nine drugs (98%) received an HTA rating by at least 1 country; 22 of 36 drugs (61%) received a low added benefit rating in Canada, 34 of 47 in France (72%), and 17 of 29 in Germany (59%). Across countries, 27 drugs (55%) had a low added therapeutic rating, accounting for $19.3 billion in annual estimated net spending, or 35% of Medicare net spending on the 50 top-selling single-source drugs and 11% of total Medicare net prescription drug spending in 2020. Compared with those with high added benefit, drugs with a low added therapeutic rating were used by more Medicare beneficiaries (median 387 149 vs 44 869) and had lower net spending per beneficiary (median $992 vs $32 287). Conclusions and Relevance: Many top-selling Medicare drugs received low added benefit ratings by the national HTA organizations of Canada, France, and Germany. When negotiating prices for these drugs, Medicare should ensure they are not priced higher than reasonable therapeutic alternatives.