Why restrict medical effective altruism?

In a challenge trial, research subjects are purposefully exposed to some pathogen in a controlled setting, in order to test the efficacy of a vaccine or other experimental treatment. This is an example of medical effective altruism (MEA), where individuals volunteer to risk harms for the public good. Many bioethicists rejected challenge trials in the context of Covid-19 vaccine research on ethical grounds. After considering various grounds of this objection, I conclude that the crucial question is how much harm research subjects can permissibly risk. But we lack a satisfying way of making this judgment that does not appeal simply to the intuitions of doctors or bioethicists. I consider one recent and structurally plausible approach to critically evaluating the harm question. Alex London defends a social consistency test for research risks: we should compare the risks undertaken by research subjects to relevantly similar risks which are accepted in other spheres of society. I argue there is no good reason not to consider volunteer military service as a relevant social comparison. This implies there is essentially no cap on acceptable risks on the social consistency rationale. In short, if soldiers can be heroes, why can't research volunteers?

Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas.

PURPOSE: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas. EXPERIMENTAL DESIGN: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m(2) twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment. RESULTS: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months. CONCLUSIONS: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.

A phase II and pharmacokinetic study of ecteinascidin 743 in patients with gastrointestinal stromal tumors.

PURPOSE: To assess the efficacy, tolerability, and pharmacokinetics of ecteinascidin 743 (ET-743) in patients with advanced gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: The study was confined to adult patients with radiographically measurable GISTs. ET-743 was administered as a 24-hour continuous i.v. infusion at a dose of 1.5 mg/m(2) repeated every 3 weeks. Pharmacokinetic blood sampling was performed during the first cycle of therapy. Tumors were restaged after every second cycle of therapy. RESULTS: A total of 20 patients was enrolled in the study, 19 of whom were treated with 47 cycles of ET-743 (median 2, range 1-10). Severe toxicities were limited to reversible grade 3 transaminitis in 10 patients and grade 3 fatigue in one patient. There were no objective responses, and disease stabilization occurred in two patients lasting for periods of 4 and 10 months. The 1-year survival rate was 71.1%. Mean +/- standard deviation values of the maximum plasma concentration and total plasma clearance were 1.1 +/- 0.4 ng/ml and 44 +/- 16 l/h/m(2), respectively, for 19 of the 20 patients. CONCLUSION: This study is the first report of a prospective phase II trial to evaluate a cytotoxic agent in patients with GISTs. This study underscores the primary resistance of GISTS to chemotherapy and stands in stark contrast to the encouraging results recently achieved with STI571. The lack of response may be associated with a therapeutically ineffective exposure to the drug based upon the lower incidence of severe toxicities and greater clearance than described in phase I and II trials of ET-743.