Increasing FDA-accelerated approval of single-arm trials in oncology (1992 to 2020).

OBJECTIVES: We aimed to map the characteristics of single-arm trials (SAT), report the Food and Drug Administration (FDA) transparency in presenting historical control, and to assess the confirmatory randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: This metaresearch included a review of all oncology indication approved using SAT by FDA-AA (FDA-Accelerated Approval) from 1992 to 2020. Two independent reviewers identified SAT, extracted data from FDA full medical reviews for historical controls reported and MEDLINE for searching for confirmatory RCT published. RESULTS: Of 254 FDA-AA approvals, 119 (47%) were approved for oncologic indications using SAT. Fifty-four drugs for 72 oncology indications were for leukemia, lymphoma, lung cancer, urothelial cancer, multiple myeloma, and thyroid cancer. Overall, 37 (52%) treatments were converted into regular approval. Of these, 17 (46%) were based on confirmatory RCTs using overall survival (OS) as an outcome. Five indications were withdrawn from the market. Most trials outcomes were blindly assessed by independent research committees. Median trial sample size was 105 patients (min:8 to max:532). The FDA did not fully specify historical control selection in 75% of cases. CONCLUSION: The granting of FDA-AAs based on SAT in oncology is increasing with more target drugs approved over time. Transparency in historical control reporting is necessary.

Single-arm clinical trials that supported FDA accelerated approvals have modest effect sizes and were at high risk of bias.

OBJECTIVE: To describe effect sizes of single-arm clinical trials that supported AA approvals. STUDY DESIGN AND SETTING: We reviewed all the single-arm approvals granted by the FDA-AA pathway between June1992 to December2020. Two independent reviewers identified single-arm studies and extracted data from FDA Full-Medical Reviews. We performed a meta-analysis to estimate the effect sizes and compared it between studies that met post-approval FDA requirements for RCTs with those that did not. RESULTS: From the total of 254 approvals, single arm clinical trials describing effects of 54 drugs for 72 clinical indications were evaluated. The effect size estimated was OR:2.22(CI95%:1.76-2.81) [relative risk (RR) = 1.63(95CI% 1.38-1.92)]; 53% of treatments had a lower 95% CI bound crossing the null effect. Effect size did not differ between the treatments that met the FDA requirement for conducting post-approval RCTs. CONCLUSIONS AND RELEVANCE: Treatment effects observed in the FDA AA single-arm studies was modest and can be to ascribed to bias.

Scleromyxedema: clinical diagnosis and autopsy findings

Abstract Scleromyxedema is a rare chronic cutaneous mucinosis of unknown etiology. It is characterized by papular eruption and scleroderma with microscopic evidence of mucin deposition, fibroblast proliferation, and fibrosis. Most patients with scleromyxedema have monoclonal gammopathy and systemic manifestations resulting in significant morbidity and mortality. Several types of treatment have been reported with partial or inconsistent responses. Despite showing unpredictable evolution, systemic consequences of scleromyxedema and treatment side effects may result in death. We describe a rare case of a patient with scleromyxedema without paraproteinemia with systemic involvement that evolved to death despite treatment with cyclophosphamide.

Scleromyxedema: clinical diagnosis and autopsy findings.

Scleromyxedema is a rare chronic cutaneous mucinosis of unknown etiology. It is characterized by papular eruption and scleroderma with microscopic evidence of mucin deposition, fibroblast proliferation, and fibrosis. Most patients with scleromyxedema have monoclonal gammopathy and systemic manifestations resulting in significant morbidity and mortality. Several types of treatment have been reported with partial or inconsistent responses. Despite showing unpredictable evolution, systemic consequences of scleromyxedema and treatment side effects may result in death. We describe a rare case of a patient with scleromyxedema without paraproteinemia with systemic involvement that evolved to death despite treatment with cyclophosphamide.