Overall response rate is shown according to age, tumor type, drug type, nature of regimen, development status, and genomic rationale. Error bars provide 95% CIs.
Survival from time of single-patient use (SPU) initiation. Numbers above dotted lines provide point estimate of progression-free and overall survival rate at time point indicated. Blue shading indicates 95% CI; crosses, censored data.
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Feit NZ, Goldman DA, Smith E, et al. Use, Safety, and Efficacy of Single-Patient Use of the US Food and Drug Administration Expanded Access Program. JAMA Oncol. 2019;5(4):570–572. doi:10.1001/jamaoncol.2018.7002
The US Food and Drug Administration (FDA) Expanded Access (compassionate use) program permits patient access to investigational products outside clinical trials. Little is known about outcomes of this program.1-4 We sought to assess the use, safety, and efficacy associated with single-patient use (SPU) at our institution.
All cancer product SPUs approved by the Memorial Sloan Kettering Institutional Review Board and the FDA between January 1, 2012, and January 1, 2018, were included. This study was retrospectively approved by the Memorial Sloan Kettering Institutional Review Board. The need for informed consent (written or verbal) was waived by the Memorial Sloan Kettering Institutional Review Board. Data were collected and then deidentified after collection.
Medical records and regulatory documents were reviewed. Response was physician assessed at 6 weeks or more into treatment. Patients who clinically deteriorated before formal assessment were considered nonresponders. Serious adverse event data were collected. Overall response rates were estimated with binomial exact CIs. Progression-free survival and overall survival were estimated by Kaplan-Meier methods from the date of first dosing. For patients with multiple SPUs (n = 6), progression-free survival was assessed for the first instance of first progression, and overall survival was defined from the first dose of the last SPU before death.
In total, 208 SPUs were approved, and the product was administered in 185 instances to 179 patients (mean [SD] age, 39  years; 112 [55.4%] male; 137 [65.9%] adults). Treated patients had 43 cancer types (117 [57.9%] had solid tumors and 85 [42.1%] had hematologic cancer). Solid tumors included neuroblastoma (31 [15.3%]), lung (16 [7.9%]), primary brain (16 [7.9%]), breast (12 [5.9%]), and other (42 [20.8%]). Patients received 66 unique investigational products, including kinase inhibitors (60 [28.8%]), naked antibodies (26 [12.5%]), and allogeneic cell therapy (25 [12.0%]). Patients were heavily pretreated (median number of prior treatments, 4). At the time of SPU approval, most agents were in phase 2 (75 [36.1%]) or phase 3 (82 [39.4%]) studies, although 39 (18.8%) were still in phase 1 studies. Prior supporting clinical experience was cited in 128 applications (61.5%) and preclinical evidence in 64 (30.8%). Genomic data were additionally cited in 79 cases (38.0%). Median time from initial SPU request to treatment was 19 days (interquartile range, 11-35 days).
Twenty-six patients received therapy in a minimal residual disease state or remission and were thus not assessed for response. Of the remaining 159 patients with evaluable data, the overall response rate was 20.1% (95% CI, 14.2%-27.2%). Best response varied by patient and product characteristics (Figure 1). Responses occurred with a variety of agent types, most commonly kinase inhibitors (9 [16.7%]), allogeneic cell therapy (3 [17.6%]), and antibody drug conjugates (1 [5.3%]). Estimated progression-free survival rates were 38.9% (95% CI, 31.6%-46.1%) at 6 months and 24.5% (95% CI, 18.2%-31.4%) at 1 year (Figure 2A). Median overall survival was 11.4 months (95% CI, 8.7-18.9 months) (Figure 2B). Median follow-up for survivors was 16 months (range, 0-71 months).
A total of 55 of 185 patients (29.7%) experienced 1 or more treatment-related serious adverse event (12 [19.1%] in pediatric patients, 43 [35.3%] in adults). There were no treatment-related deaths.
The FDA Expanded Access program provided access to investigational products at all stages of development and to patients of all ages with a variety of cancer types. Despite being heavily pretreated, a small but meaningful proportion of patients appeared to benefit. Children represented 34.1% of the cohort despite being only approximately 2% of the patients seen at the center in 2017, suggesting SPUs may provide an important means of pediatric drug access.5
Our study has some important limitations. It was conducted at a single academic cancer center, and the retrospective design precluded the collection of certain data elements. Moreover, although the federal Right-to-Try law promises to further expand prescribing of unapproved products, differences in the precise requirements and implementation of this new access mechanism may make aspects of our current SPU analysis only partially applicable.3,4,6
In summary, our data provide an initial evidence basis to evaluate the FDA Expanded Access mechanism. We find its use is broad, involving a wide variety of patients and products, and clinical benefit was observed. Routine prospective collection of key safety and efficacy metrics should be considered moving forward.
Accepted for Publication: December 5, 2018.
Published Online: February 28, 2019. doi:10.1001/jamaoncol.2018.7002
Open Access: This article is published under the JN-OA license and is free to read on the day of publication.
Corresponding Author: David M. Hyman, MD, Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10128 (firstname.lastname@example.org).
Author Contributions: Mr Feit and Ms Goldman contributed equally to this work. Drs Iasonos, Zivanovic, and Hyman contributed equally to this work. Dr Hyman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Feit, Goldman, Smith, Iasonos, Zivanovic, Hyman.
Acquisition, analysis, or interpretation of data: Feit, Goldman, Deighan, Zivanovic, Hyman.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Feit, Goldman, Iasonos, Zivanovic.
Statistical analysis: Feit, Goldman, Iasonos.
Obtained funding: Feit.
Administrative, technical, or material support: Feit, Deighan, Zivanovic, Hyman.
Supervision: Smith, Zivanovic, Hyman.
Conflict of Interest Disclosures: Dr Iasonos reported being a consultant for Mylan. Dr Hyman reported being a paid adviser or a consultant for Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Debiopharm Group, and Genetech and has received research grants from AstraZeneca, Puma Biotechnology, and Loxo Oncology. No other disclosures were reported.
Funding/Support: This study was supported by grant P30 CA008748 from the National Institutes of Health (all authors), the St. Baldrick’s Foundation (Mr Feit), and the Nonna’s Garden Foundation Initiative in Precision Oncology (Dr Hyman).
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: The following people contributed to this work: Jenny Anopa, BA, Human Research Protection Program, Memorial Sloan Kettering Center, New York, New York; Erika Pamer, MS, Early Drug Development, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Alison M. Schram, MD, Early Drug Development, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, New York; Jeffrey Greenfield, MD, PhD, Department of Neurological Surgery, Weill Cornell Medicine, New York, New York; Neerva N. Shukla, MD, Weill Cornell Medical College and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Stephen S. Roberts, MD, Weill Cornell Medical College and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Theresa Gold, MS, Research and Technology Management, Memorial Sloan Kettering Cancer Center, New York, New York; Richard Ellis, BA, CCRP, Research and Technology Management, Memorial Sloan Kettering Cancer Center, New York, New York; Roy Cambria, BS, Human Research Protection Program, Memorial Sloan Kettering Center, New York, New York; and Roger S. Wilson, MD, Human Research Protection Program, Memorial Sloan Kettering Center, Weill Cornell Medical College, and Department of Anesthesia/Critical Care Medicine and Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.