Research from a retrospective analysis of 10 randomized clinical trials reporting on 390 subjects in investigator-initiated trials found 178 participants (45.6%) were noncompliant, while 212 participants (54.4%) were compliant. Analysis of the study indicated that regression models identified 17 variables that were significant in determining subject noncompliance. A number of these variables included distance (from travel), comorbidities, diabetic status, concomitant medications, previous clinic visits, length of study, disease under study, and severe adverse events. The investigator-initiated trials included nAMD, proliferative diabetic retinopathy (PDR), and retinal venous occlusive diseases (RVO).
From FDA statistics across all types of pivotal studies, the cost of a mean study was estimated at $19M per trial, after which just under a tenth of all such trials lead to a therapeutic regulatory approval. While there are of course multiple reasons for trials not to complete such studies, one includes a loss-to-follow-ups (LTFU), which can then lead to under-powered studies. The research has stated that “noncompliance during prospective studies can bias results and limit conclusions.” One independent study had estimated that “a study initially powered at 90% could have an actual power of 50% to 87% depending on the percentage of subjects (40% to 5%, respectively) contributing noninformative data owing to noncompliance to study procedures.”
In the study, subjects recorded noncompliance issues such as worsening health (18.9%), death (15.1%), no longer wishing to participate in the study (13.2%), adverse event (AE) occurrence (9.43%), work (5.66%), relocation (5.66%), or transportation problems (1.89%), with over 30% subjects being lost to follow-up without documented explanation owing to termination of contact, despite multiple attempts to maintain contact. In the study, noncompliance rates decreased significantly with increasing age, with a rate of 58.7% for subjects aged <60 years, 45.7% for subjects aged 60 to 74.5 years, and 32.3% for subjects aged >75 years. In their discussion, the report had commented that “retina research has suffered many setbacks, with 3 failed phase 3 trial programs in 2018 for either nAMD or geographic atrophy secondary to AMD.” The study highlighted that in sponsored studies of HAWK and HARRIER, there was mean completion rates of 89.5% and 93.4%, respectively. Similarly, in RISE and RIDE, there was mean completion rates of 83.3% and 84.6%, respectively, and VISTA and VIVID had mean completion rates of 76.6% and 74.4%, respectively. Further review may need to be required to show more specific details between investigator-initiated studies compared to commercial sponsored clinical research studies.