Overall Survival, Progression-Free Survival, and Tumor Response Benefit Supporting Initial US Food and Drug Administration Approval and Indication Extension of New Cancer Drugs, 2003-2021.

Clinical trial evidence is routinely evaluated for initial drug approvals, yet the benefit of indication extensions remains uncertain. This study evaluates the clinical benefit supporting new cancer drugs' initial and supplemental US Food and Drug Administration (FDA) indication approval. Clinical trial evidence supporting each indication's FDA approval was collected from the Drugs@FDA database between 2003 and 2021. Drug, indication, and clinical trial characteristics are described. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk for tumor response were meta-analyzed. Out of 124 FDA-approved drugs, 78 were approved across multiple indications. Out of 374 indications, 141 were approved as combination therapies, 255 for solid cancers, 121 with biomarkers, and 182 as first-line therapy. Approval was mostly supported by open-label (267 [71%]) phase III (238 [64%]) concurrent randomized controlled trials (248 [66%]) with a median of 331 enrolled patients (interquartile range [IQR], 123-665 patients). Across 234 randomized controlled trials with available data, drugs' HRs were 0.73 (95% CI, 0.72 to 0.75; = 29.6%) for OS and 0.57 (95% CI, 0.54 to 0.60; = 90.6%) for PFS, whereas tumor response was 1.38 (95% CI, 1.33 to 1.42; = 80.7%). Novel pharmaceuticals increased patient survival by a median of 2.80 months (IQR, 1.97-4.60 months) for OS and 3.30 months (IQR, 1.50-5.58 months) for PFS. Initial indications more frequently received accelerated approval, supported by single-arm trials for advanced-line monotherapies, than indication extensions. Initial approvals provided a higher PFS (HR, 0.48 0.58; = .002) and tumor response (relative risk, 1.76 1.36; < .001). New cancer drugs substantially reduce the risk of death and tumor progression, yet only marginally extend patient survival. The FDA, physicians, patients, and insurers must evaluate and decide on a drug's safety and efficacy approval, pricing, coverage, and reimbursement on an level.

Michaeli DT ，Michaeli T 《-》

Breast cancer drugs: FDA approval, development time, efficacy, clinical benefits, innovation, trials, endpoints, quality of life, value, and price.

Michaeli JC ，Michaeli T ，Trapani D ，Albers S ，Dannehl D ，Würstlein R ，Michaeli DT ... -  《-》

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA.

Previous research focused on the clinical evidence supporting new cancer drugs' initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. To examine the clinical trial evidence supporting new targeted cancer drugs' initial and supplementary indication approval in the US, EU, Canada, and Australia. 25 cancer drugs across 100 indications were identified with FDA approval between 2009-2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07-6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38-8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17-5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14-30.65], p < 0.05) than supplementary indications. Initial indications' pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93-0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09-0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01-1.39], p < 0.05). Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication's differential clinical and economic value.

Michaeli DT ，Mills M ，Michaeli T ，Miracolo A ，Kanavos P ... -  《-》

Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016.

Ladanie A ，Schmitt AM ，Speich B ，Naudet F ，Agarwal A ，Pereira TV ，Sclafani F ，Herbrand AK ，Briel M ，Martin-Liberal J ，Schmid T ，Ewald H ，Ioannidis JPA ，Bucher HC ，Kasenda B ，Hemkens LG ... -  《JAMA Network Open》

Cancer Drug Prices in the United States: Efficacy, Innovation, Clinical Trial Evidence, and Epidemiology.

Rising cancer drug prices challenge patients and healthcare systems. Although prices are routinely assigned to original drug indications receiving US Food and Drug Administration (FDA) approval, the pricing of supplemental indication approvals remains uncertain. This study identifies and quantifies factors associated with cancer drug prices, distinctly analyzing original and supplemental indications. Clinical trial evidence and epidemiologic data supporting new indications' FDA approval (2003-2022) were collected from the Drugs@FDA database, ClinicalTrials.gov, and Global Burden of Disease study. Indication-specific monthly treatment costs were calculated for Medicare patients. The association between log-prices and collected variables were assessed in regression analyses. We identified 145 drugs approved across 373 cancer indications. Drugs were priced at $24 444 per month on average (median = $16 013). For original indications, prices weakly correlated to improvements in overall survival (β = 0.28, P = .037) and progression-free survival (β = 0.16, P = .001). Original indications' prices were as follows: (1) negatively associated with disease incidence (β = -0.21, P < .001) and prevalence; (2) positively correlated with first-in-class drugs (26%, P = .057), gene and cell therapies (176%, P < .001), hematologic cancers (62%, P < .001), and severe diseases with substantial unmet needs (6% per disability-adjusted life-year, P < .001); and (3) negatively correlated to indications with randomized-controlled phase 3 trials. Prices were poorly associated with supplemental indications' efficacy, clinical evidence, and epidemiology. Cancer drug prices are set based on the original indication's characteristics, thereby omitting the value of supplemental indications. Indication-specific pricing, coverage, and reimbursement policies considering each indication's safety, efficacy, innovativeness, and unmet needs are necessary to align a drug's value and price.

Michaeli DT ，Michaeli T 《-》