The Power of One: Using One-Patient Trials for FDA Approval
[Thursday, October 17, 2019]

A one-patient clinical trial could lead to a heartwarming story but requires incredible motivation and endless resources, and presents formidable regulatory, scientific and practical challenges for use beyond that one patient as is highlighted by such a trial reported this week. Doctors at Harvard Medical School, Boston Children’s Hospital with numerous partners announced a one-patient clinical trial in a 7 year-old girl with a rare life-threatening genetic disorder. Although one-patient trials have been used for more than a decade, this trial got more publicity because of the higher profile of the patient and the doctors, so much so that the report got an associated editorial by the chiefs of the centers for drugs and biologics at the FDA discussing regulatory challenges with using data from one-patient trials to additional patients. In this case, the researchers devised an antisense oligo-based therapy for the girl based on her specific genetic mutation and successfully administered without any major adverse events and some benefits. Several unique scientific and regulatory strategies were employed for this trial. The anti-sense oligo was manufactured under small scale Phase 1 GMP conditions. The same material was used for nonclinical studies and the clinical trial. The in vitro efficacy was confirmed with the patient’s own cells using a surrogate marker. The sponsors of the trial used FDA’s previous approval of another antisense oligo-based therapy to claim safety of their product for the IND. A repeat dose toxicity study was conducted to show safety, and the clinical trial could be initiated while the animal tox was ongoing. The study was conducted as a compassionate use treatment IND. The sponsor worked closely with FDA to develop the clinical protocol and get the IND cleared. The FDA editorial accompanying the report highlighted the challenges of repeating such an experiment in additional patients. While theoretically FDA could accept data from one-patient studies in support of regulatory decisions, there are several factors that need to be considered such as highly persuasive mechanistic and functional data for the investigational treatment, the essential CMC information needed to assure quality, the design of the endpoints, assurance of unbiased measure of patient reported outcomes, and the stopping rules that would terminate the study even if the patient disagrees. Besides, one-patient trials are not feasible for most patients for financial, logistical and practical reasons. In this case, the parents of the girl performed the herculean task of creating a successful foundation that could raise finances and find motivated academic researchers to conduct a study. Repeating this feat is not easy. There is precedence to FDA approving new products based on very small clinical trials and while one-patient study is the lowest possible patient number, technically FDA can approve treatments based on one-patient trials; after all, if FDA can approve products based on a 10 patient study why can’t it do so based on convincing data from one patient. That said, while the one-patient model presents a viable option for patients with access to significant resources, it has a long way to go to be an option for most patients.