TABLE 4.
Conducting future clinical trials in ALF: challenges and possible solutions
| Design aspects | Challenges | Possible solutions |
|---|---|---|
| Recruitment | Difficult to enroll target sample size due to rarity and acuity of the syndrome Acuity and severity of illness introduces emotional stressors into obtaining consent Study sites lack training on best practices for the process of consent |
Outreach to neighboring centers for referrals Provide study site personnel training in obtaining consent to improve the patient/family’s understanding of the study, and thus improve enrollment Identify mechanisms of informed consent such as exception from informed consent in time-sensitive settings |
| Blinding | Depends on the intervention—more difficult with device or surgical interventions | Consider sham or, at a minimum, blinded outcome assessments |
| Outcomes | Need objective measures that are relevant to patient improvement Common to measure TFS but the targeted effect size can be difficult to define Transplant times vary by etiology and center |
Consider what is most important to patient and clinical communities (mortality, quality of life) Consider the mechanism of action of the experimental intervention to define the outcome of interest (mortality, TFS, change in clinical labs) If transplant is not part of the outcome, then account for transplant as an intercurrent event. Etiology is a known prognostic factor and should be adjusted for in the analysis |
| Follow-up | ALFSG commonly looked at 21-day TFS but also captured long-term outcomes at 3, 12, and 24 mo Missing data occurs with longer follow-up; participants lost to follow-up |
During the study planning stages, consider approaches for participant contact beyond in person visits (eg, phone, text, email) Frequent contact at some level can help with retention |
| Intercurrent events | Events, most importantly, transplant, that alter the measurement of defined outcomes (most importantly, transplant) | Consider a composite outcome that includes death and transplant (ie, TFS) Consider competing risk and survival analyses for certain outcomes to account for transplant if not part of your outcome |
Abbreviations: ALFSG, Acute Liver Failure Study Group; TFS, transplant-free survival.