Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study

Abstract

BackgroundApproval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials.MethodsWe performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes.ResultsIn this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45–2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used.ConclusionsNearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

Intensive Pharmacy Care Improves Outcomes of Hepatitis C Treatment in a Vulnerable Patient Population at a Safety-Net Hospital

“…This cohort achieved SVR at a lower rate (71%) than that previously reported in clinical trials of DAA-based treatment for chronic HCV infection. The higher rate of SVR (95%) observed among subjects who completed treatment and returned for follow-up laboratory testing is more comparable to that reported in the setting of clinical trials, likely in less diverse, more affluent populations with more clinical resources available [3]. This may suggest that the reduced overall rate of SVR observed is attributable to difficulties in clinical implementation, rather than biological differences.…”

Patient engagement and study design of PROP UP: A multi-site patient-centered prospective observational study of patients undergoing hepatitis C treatment

“…Trials of sofosbuvir have included PROs to evaluate HRQOL, fatigue and work productivity 42,43 . These studies have shortcomings, including potentially limited generalizability to patients treated outside of registration trials 44 . Currently, no information exists to evaluate patient-reported similarities or differences among these regimens.…”

A real‐world observational cohort of patients with primary biliary cholangitis: TARGET‐primary biliary cholangitis study design and rationale

“…Importantly, phase III clinical trials are performed in highly selected adherent study participants who may lack significant comorbidities outside the disease area in question. This has been the case in several areas within hepatology . These trials are good measures of clinical efficacy; however, the more germane question for clinicians and their patients is one of real‐world effectiveness.…”

“…This has been the case in several areas within hepatology. (11) These trials are good measures of clinical efficacy; however, the more germane question for clinicians and their patients is one of real-world effectiveness. Confirming the safety and effectiveness of interventions under real-world conditions and establishing pragmatic methods of assessing disease diagnosis and progression are critical for developing appropriate clinical practice guidelines.…”