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 ... -  《-》

Breakthrough Therapy Cancer Drugs and Indications With FDA Approval: Development Time, Innovation, Trials, Clinical Benefit, Epidemiology, and Price.

The breakthrough therapy designation (BTD) facilitates the development of drugs with a large preliminary benefit in treating serious or life-threatening diseases. This study analyzes the FDA approval, trials, benefits, unmet needs, and pricing of breakthrough and nonbreakthrough therapy cancer drugs and indications. We analyzed 355 cancer indications with FDA approval (2012-2022). Breakthrough and nonbreakthrough indications were compared regarding their FDA approval, innovativeness, clinical trials, epidemiology, and price. Data were extracted from FDA labels, the Global Burden of Disease study, and the Centers for Medicare & Medicaid Services. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) of tumor response were meta-analyzed across randomized controlled trials. Objective response rates (ORRs) were meta-analyzed for single-arm trials. We identified 137 breakthrough and 218 nonbreakthrough cancer indications. The median clinical development time was 3.2 years shorter for breakthrough drugs than for nonbreakthrough drugs (5.6 vs 8.8 years; P=.002). The BTD was more frequently granted to biomarker-directed indications (46% vs 34%; P=.025) supported by smaller trials (median, 149 vs 326 patients; P<.001) of single-arm (53% vs 27%; P<.001) and phase I or II design (61% vs 31%; P<.001). Breakthrough indications offered a greater OS (HR, 0.69 vs 0.74; P=.031) and tumor response (RR, 1.48 vs 1.32; P=.006; ORR, 52% vs 40%; P=.004), but not a PFS benefit (HR, 0.53 vs 0.58; P=.212). Median improvements in OS (4.8 vs 3.2 months; P=.002) and PFS (5.4 vs 3.3 months; P=.005) but not duration of response (8.7 vs 4.7 months; P=.245) were higher for breakthrough than for nonbreakthrough indications. The BTD was more frequently granted to first-in-class drugs (42% vs 28%; P=.001) and first-in-indication treatments (43% vs 29%; P<.001). There were no differences in treatment and epidemiologic characteristics between breakthrough and nonbreakthrough drugs. Breakthrough drugs were more expensive than nonbreakthrough drugs (mean monthly price, $38,971 vs $22,591; P=.0592). The BTD expedites patient access to effective and innovative, but also expensive, new cancer drugs and indications.

Michaeli DT ，Michaeli T 《-》

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 《-》

Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

Over the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. This study reviews the FDA's five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price. We conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview. Expedited approval reduces new drugs' time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as "breakthroughs", are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US. Special FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

Michaeli DT ，Michaeli T ，Albers S ，Boch T ，Michaeli JC ... -  《-》

A Survey of Survival Outcomes for Targeted Cancer Drugs Approved by the US Food and Drug Administration.

The last two decades have witnessed the vigorous development of targeted cancer drugs and the potent therapeutic effects of these drugs have been validated by various true and surrogate end points. Overall survival (OS) and progression-free survival (PFS) outcomes were two important end points used in targeted cancer drugs clinical trials but investigation on which was rare as a consequence of inherent heterogeneity and complexity. Here, we present the review and analysis of OS and PFS outcomes of all targeted cancer drugs approved by the U.S. Food and Drug Administration (FDA) through December 31, 2019, in the setting of clinical studies. The targeted cancer drug directory was accessed via NCI website. The survival outcomes of those drugs in the setting of clinical trials were collected from publicly available Package Inserts and ClinicalTrials.gov. Median overall (OS) and progression-free survival (PFS) outcomes were summarized for targeted cancer drugs that were evaluated as monotherapies in clinical trials, contributions of targeted drugs to combination therapies in terms of survival benefit were analyzed, survival outcomes of FDA-approved first-line targeted therapies in different cancers were investigated, and the correlation between the absolute OS gain (ΔOS) and PFS gain (ΔPFS) as well as the hazard ratios for PFS (HR) and OS (HR) between comparative arms of available randomized clinical trials was evaluated. A total of 223 indications for 126 targeted cancer drugs have been approved by the FDA through December 31, 2019, among which 28 indications of 23 drugs have been approved for first-line therapies. Eighty indications for leukemia, lymphoma, and rare cancer types without survival data were excluded in the investigation of survival outcomes. For the remaining 143 indications, 99 were approved as monotherapies and 72 were approved as combination therapies. Among monotherapy subset, 18 of 72 (25%) indications with available OS outcomes have maximum median OS less than 12 months, 55 of 72 (76%) drug indications have maximum median OS less than 24 months, and 67 of 72 (93%) have maximum median OS less than 36 months. Regarding PFS, 38 of 88 (43%) drug indications have maximum median PFS less than 6 months, 69 of 88 (78%) drug indications have maximum median PFS less than 12 months, and 84 of 88 (95%) drug indications have maximum median PFS less than 24 months. The addition of targeted drugs to combination regimens under FDA's approval provided notable survival benefit, but the median value of OS gain rate of the available combination regimens was lower than that of PFS. The univariate Spearman Rank correlation coefficient suggested a significant positive correlation between ΔOS and ΔPFS (R = 0.62) but a weak correlation between HR and HR (R = 0.11) in 46 randomized clinical trials that investigated contributions of targeted cancer drugs to combination therapies with available data. A moderate correlation between ΔOS and ΔPFS (R = 0.43) and a rather weak correlation between HR and HR (R = 0.07) were also found in other randomized clinical trials that included in our study with available data. The survival benefit provided by targeted cancer drugs varied a lot among cancer types. Though targeted cancer drugs showed improvements in both OS and PFS in approved combination regimens, the median value of OS gain rate was lower than that of PFS. As only weak correlation was found between HR and HR, the evidence supporting the use of PFS as a surrogate to OS in the setting of targeted cancer drugs might also be limited.

He Q ，Li Q ，Lv F ，Kaitin KI ，Shao L ... -  《-》