Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: Facilitating development approaches for an emerging epidemic

Abstract

Due to the increasing prevalence of nonalcoholic steatohepatitis (NASH) and its associated health burden, there is a high need to develop therapeutic strategies for patients with this disease. Unfortunately, its long and asymptomatic natural history, the uncertainties about disease progression, the fact that most patients are undiagnosed, and the requirement for sequential liver biopsies create substantial challenges for clinical development. Adaptive design methods are increasingly used in clinical research as they provide the flexibility and efficiency for identifying potential signals of clinical benefit of the test treatment under investigation and make prompt preplanned adaptations without undermining the validity or integrity of the trial. Given the high unmet medical need and the lack of validated surrogate endpoints in NASH, the use of adaptive design methods appears reasonable. Furthermore, due to the limited number of patients willing to have multiple liver biopsies and the need for long‐term exposure to assess an impact in outcomes, a continuous seamless adaptive design may reduce the overall sample size while allowing patients to continue after each one of the phases. Here, we review strategic frameworks that include potential surrogate endpoints as well as statistical and logistical approaches that could be considered for applying adaptive designs to clinical trials in NASH with the goal of facilitating drug development for this growing medical need. (Hepatology Communications 2017;1:577–585)

qFIBS: An Automated Technique for Quantitative Evaluation of Fibrosis, Inflammation, Ballooning, and Steatosis in Patients With Nonalcoholic Steatohepatitis

“…Notable issues with the traditional histological scores relate to the nature of semiquantitative grading systems used by both NAS and SAF, which conflate anatomical distribution of specific lesions with features of severity in order to facilitate data capture by the human eye. These scores necessitate that continuous measures be assigned into discrete categorical grading bins, a constraint that inevitably leads to discrepancies related to inter‐ and intraobserver judgment, especially with cases at the margins between two categories. It also produces a blunting of sensitivity to detect change given that semiquantitative grades may fail to report clinically relevant, but modest, alterations in severity that do not transition across a predefined, but arbitrary, categorical boundary.…”

Progress and challenges in the prevention and control of nonalcoholic fatty liver disease

“…Adaptive designs allow for planned modifications in one or more aspects of the study design based on responses in earlier phases. This design also reduces the need to find additional subjects for treatment trials who are willing to accept multiple biopsies …”

Designing Clinical Trials in Pediatric Nonalcoholic Steatohepatitis: Tips for Patient Selection and Appropriate Endpoints

“…It is reasonable to use an adaptive trial design to transition from phase 2 to phase 3 trials to eliminate the need for repeat histologic assessment in some patients given the limited number of adolescents/families who are willing to consent to several liver biopsies. Furthermore, due to the fact that long‐term treatment with a specific drug is needed to assess the effects on clinical outcomes, an adaptive design may help decrease the overall sample size while allowing patients to continue treatment from one phase to the next . According to the FDA, pediatric phase 3 efficacy trials are not necessarily required for drug approval as long as pediatric safety and dosing information are available.…”

“…Furthermore, due to the fact that long-term treatment with a specific drug is needed to assess the effects on clinical outcomes, an adaptive design may help decrease the overall sample size while allowing patients to continue treatment from one phase to the next. (38) According to the FDA, pediatric phase 3 efficacy trials are not necessarily required for drug approval as long as pediatric safety and dosing information are available. Therefore, it is possible that some NASH drugs that show efficacy on surrogate endpoints in children may not need to show efficacy on reducing the occurrence of hard clinical outcomes, such as progression to cirrhosis or hepatic decompensation, as long as these data can be extrapolated from adequate and well-controlled adult trials.…”