Sponsor- vs. FDA-Initiated Changes to Pediatric Clinical Trial Protocols: A Comparison of Associated Participant Burden.

Abstract

Introduction: Risks associated with clinical trial participation are a foremost consideration during protocol development whereas trial-associated burdens receive less focus despite their measurable impact on enrollment and retention. Of late, the U.S. Food and Drug Administration (FDA) has elevated discussions on barriers to research participation resulting from overly burdensome trials. Given the agency's role in shaping clinical protocol design, this study examined the perceived burden associated with FDA-proposed study changes in the context of pediatric, off-patent, labeling studies.

Materials and methods: Pediatric Trials Network (PTN) studies conducted between 2013 and 2023 for which there existed a record of formal communication between the PTN and FDA were evaluated. All protocol versions and regulatory communications were reviewed, and every protocol change with the potential to alter participant burden was extracted and attributed to the PTN Sponsor or FDA. Changes were grouped into 11 themes (e.g. change in the number of visits, change in invasive procedures) and each change assigned a perceived burden score on an 11-point Likert scale by pediatric clinical trialists who were blinded to attribution. An abbreviated list of protocol changes were reviewed and scored by children to examine their concordance with adult scores. Quantitative and qualitative differences between changes introduced by Sponsors and the FDA were compared.

Results: Twenty-one studies (94 protocol versions) met the criteria for inclusion (18 drug, 3 device). Half of the protocol versions incorporated changes (n = 123) that could perceivably affect participant burden (77 initiated by the sponsor, 46 proposed by the FDA). Changes classified as introducing, increasing, or extending protocol features occurred almost twice as often (64%) as changes that reduced, removed, or restricted features of the protocol (36%), the latter also occurring later in the life of the protocol (1.2 vs. 2.0 year, p < 0.01). Changes recommended by the FDA were primarily related to ensuring safety (77%), optimizing trial design (16%) and adequately capturing effectiveness (7%) and, on average, were associated with statistically higher burden scores. Modifications driven by sponsors reflected trial design refinements (34%), safety assessment (32%), expansion of primary/secondary scientific questions (22%), and effectiveness evaluation (12%). Burden scores demonstrated strong concordance between trialists and children (r = 0.7).

Conclusions: Half of all protocol amendments are associated with changes that conceivably alter the burden of clinical trial participation, and these changes are twice as likely to add to (vs. reduce) participant burden. Given the time and effort involved with protocol amendments, we suggest that modifications to trial protocols be accompanied by a reassessment of the role and utility of all existing protocol elements at the time of resubmission.