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.

Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020.

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, -6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, -10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (-2.1 weeks [95% CI, -11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

Advancing Patient-Centered Outcomes and Equity in Clinical Trials for BCG-Unresponsive Nonmuscle Invasive Bladder Cancer.

This Viewpoint encourages investigators to move beyond FDA guidance toward patient-centered therapies and health equity for BCG-unresponsive bladder cancer.

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.

Estimates of Medicaid and Non-Medicaid Net Prices of Top-Selling Brand-name Drugs Incorporating Best Price Rebates, 2015 to 2019.

Importance: The US spends far more on brand-name prescription drugs than other comparable countries. However, studies of prescription drug spending in the US are often limited because there can be substantial differences in the confidential rebates that drug manufacturers pay to Medicaid vs other payers. Objectives: To demonstrate an approach for improved estimation of Medicaid rebates through case studies of 18 top-selling drugs to better understand trends in net Medicaid and non-Medicaid spending and prices for brand-name drugs. Design, Settings, and Participants: This was a cross-sectional study of US pricing data from 2015 to 2019 derived from Medicaid State Drug Utilization data SSR Health, Medi-Span, the Federal Supply Schedule, and IQVIA. Pricing data for 18 top-selling brand-name drugs measured consistently in both SSR Health, which captures US sales reported by publicly traded companies, and IQVIA's top US prescription drugs by nondiscounted spending in 2015 to 2019. Data were accessed and analyzed from January 2019 to June 2021. Main Outcomes and Measures: Gross and net Medicaid and non-Medicaid drug spending for the sample of 18 drugs and prices corresponding to a 30-day supply of medication. Results: Medicaid aggregate gross spending for the 18 drugs in the sample increased 173%, from $3.6 billion in 2015 to $9.9 billion in 2019, and estimated net spending after discounts increased by 119%, from $1.4 billion to $3.0 billion. Medicaid inflation-linked rebates reduced average gross price per 30-day supply by an estimated 43% in 2019, and up to 67% for individual drugs. In addition to the basic rebate, the best price provision reduced the average gross price per 30-day supply by an estimated 3% in 2019 and up to 54% for individual drugs. Between 2015 and 2019 across all study drugs, estimated average non-Medicaid net 30-day prices were between 1.9 and 2.6 times higher than Medicaid net prices. Excluding adalimumab-a spending anomaly because of the entry of a new high-cost formulation-net prices weighted by average gross spending decreased annually by 1% from 2015 through 2019 for Medicaid, while increasing by 2% for non-Medicaid payers. Conclusions and Relevance: In this cross-sectional study of 18 top-selling brand-name drugs, excluding 1 anomaly, Medicaid average net prices declined from 2015 to 2019. Simultaneously, for non-Medicaid payers, net price increased more than previously published marketwide growth rates, raising the importance of restraining drug price growth in non-Medicaid markets. Rigorous and transparent methods to estimate Medicaid discounts are imperative to understand patterns in Medicaid and non-Medicaid prices and develop policies that better align drug prices with clinical benefits.

Therapeutic Value of Drugs Frequently Marketed Using Direct-to-Consumer Television Advertising, 2015 to 2021.

This cohort study assesses whether drugs with the most direct-to-consumer television advertising represent advances over existing treatments.

High-risk Therapeutic Devices Approved by the US Food and Drug Administration for Use in Children and Adolescents From 2016 to 2021.

This cohort study examines the characteristics of high-risk therapeutic devices approved by the US Food and Drug Administration for use in children and adolescents between 2016 and 2021.

Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US and Europe From 2007 to 2021.

Importance: The number of drugs approved through the accelerated approval or conditional marketing authorization pathways has increased with unclear evidence of their therapeutic value. Objectives: To assess the therapeutic value of drug indications granted accelerated approval in the US or conditional marketing authorization in the European Union (EU) overall and for cancer indications. Design, Setting, and Participants: This cohort study used the public databases of the US Food and Drug Administration and the European Medicines Agency to identify all drugs (initial and supplemental indications) granted accelerated approval in the US or conditional marketing authorization (initial indications only) in the EU between January 1, 2007, and December 31, 2021. Therapeutic value ratings were obtained from national health authorities in Germany, France, and Canada. Main Outcomes and Measures: Descriptive statistics were used to assess the proportion of accelerated approvals and conditional marketing authorizations overall and for cancer vs noncancer indications rated as having high added therapeutic value. Results: The cohort included 146 drug indications (94 first indications, 52 supplemental indications) in the US and 58 (all first indications) in the EU. Most drugs were approved for cancer (122 [83.6%] in the US; 40 [69.0%] in the EU). Therapeutic value ratings were available for 90 drug indications (61.6%) in the US and 56 (96.6%) in the EU. Overall, 35 drug indications granted accelerated approval (38.9%) and 21 granted conditional marketing authorization (37.5%) had high added therapeutic value in the US and EU, respectively, at the time of approval. The proportions of indications rated as having high added therapeutic value were 36.0% (27 of 75) for cancer vs 53.3% (8 of 15) for noncancer indications in the US and 30.8% (12 of 39) for cancer vs 52.9% (9 of 17) for noncancer indications in the EU. Conclusions and Relevance: In this cohort study, among new drug indications approved through the accelerated approval or conditional marketing authorization pathways in the US and Europe from 2007 to 2021, 38.9% and 37.5%, respectively, demonstrated high therapeutic value. A substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value. Policy makers and regulators should increase enforcement of timely postapproval study completion for drugs qualifying for these pathways.

Reforming the World Health Organization's Essential Medicines List: Essential but Unaffordable.

This Viewpoint proposes restructuring the WHO Essential Medicines List to remove consideration of cost and cost-effectiveness from the expert committee reviews of clinical effectiveness, safety, and public health value, and chartering a new framework for pooled global negotiation and procurement of costly medicines included in the list.

Clinical Benefit and Expedited Approval of Cancer Drugs in the United States, European Union, Switzerland, Japan, Canada, and Australia.

PURPOSE: Regulatory agencies have sought to speed up the review of new cancer medicines and reduce delays in approval between countries. We examined trends in regulatory review times and association with clinical benefit for new cancer medicines in six jurisdictions: United States (Food and Drug Administration [FDA]), European Union (European Medicines Agency [EMA]), Switzerland (Swissmedic), Japan (Pharmaceuticals and Medical Devices Agency [PMDA]), Canada (Health Canada), and Australia (Therapeutic Goods Administration). METHODS: We studied all new cancer drugs approved in the six aforementioned jurisdictions from 2007 to 2020. We extracted all applicable expedited programs, total regulatory review times, and, for drugs first approved by the FDA, times to subsequent regulatory approval. Clinical benefit was assessed using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale value framework and ASCO-Cancer Research Committee's targets. Nonparametric Kruskal-Wallis test was used to compare total review times for high versus low clinical benefit drugs. RESULTS: One hundred and twenty eight drugs received initial approval in at least one of the six included jurisdictions. Most drugs approved by the FDA (91%) and Health Canada (59%) qualified for at least one expedited program within those jurisdictions, compared with 46% of EMA approvals and 18% of PMDA approvals. The FDA was the first regulator to approve 102 (80%) drugs. Delays in submission accounted for a median of 20.2% (EMA) to 83.8% (PMDA) of the time to subsequent approval. There was no association between high clinical benefit and shorter total review times. CONCLUSION: Most new cancer therapies were approved first by the FDA, and delays in submission of regulatory applications accounted for substantial delays in approving cancer drugs in other countries. Regulators should prioritize faster review for drugs with high clinical benefit.

Coverage of New Drugs in Medicare Part D.

Policy Points Only a small minority of new drugs in "nonprotected" classes are widely covered by Part D plans nationwide in the year after US Food and Drug Administration (FDA) approval. Part D plans frequently apply utilization management restrictions such as prior authorizations to newly approved drugs in both protected and nonprotected classes. Drug price influences both formulary inclusion (in nonprotected classes) and coverage restrictions (in both protected and nonprotected classes), while other drug characteristics such as therapeutic benefits are not consistently associated with formulary design. Plans do not seem to favor the minority of drugs that are determined to offer added therapeutic benefit over existing alternatives. CONTEXT: Medicare Part D is an outpatient prescription drug benefit for older Americans covering more than 46 million beneficiaries. Except for mandatory coverage for essentially all drugs in six protected classes, plans have substantial flexibility in how they design their formularies: which drugs are covered, which drugs are subject to restrictions, and what factors determine formulary placement. Our objective in this paper was to document the extent to which Part D plans limit coverage of newly approved drugs. METHODS: We examined the formulary design of 4,582 Part D plans from 2014 through 2018 and measured (1) the decision to cover newly approved drugs in nonprotected classes, (2) use of utilization management tools in protected and nonprotected classes, and (3) the association between plan design and drug-level characteristics such as 30-day cost, therapeutic benefit, and the US Food and Drug Administration (FDA) expedited regulatory pathway. FINDINGS: The FDA approved 109 new drugs predominantly used in outpatient settings between 2013 and 2017. Of these, 75 fell outside of the six protected drug classes. One-fifth of drugs in nonprotected classes (15 out of 75) were covered by more than half of plans during the first year after approval. Coverage was often conditional on utilization management strategies in both protected and nonprotected classes: only seven drugs (6%) were covered without prior authorization requirements in more than half of plans. Higher 30-day drug costs were associated with more widespread coverage in nonprotected classes: drugs that cost less than $150 for a 30-day course were covered by fewer than 20% of plans while those that cost more than $30,000 per 30 days were covered by more than 50% of plans. Plans were also more likely to implement utilization management tools on high-cost drugs in both protected and nonprotected classes. A higher proportion of plans implemented utilization management strategies on covered drugs with first-in-class status than drugs that were not first in class. Other drug characteristics, including availability of added therapeutic benefit and inclusion in FDA expedited regulatory approval, were not consistently associated with plan coverage or formulary restrictions. CONCLUSIONS: Newly approved drugs are frequently subject to formulary exclusions and restrictions in Medicare Part D. Ensuring that formulary design in Part D is linked closely to the therapeutic value of newly approved drugs would improve patients' welfare.