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


METHODS
We 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.


RESULTS
In 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.


CONCLUSIONS
Nearly 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.
Department of Gastroenterology and Hepatology, Radboud university medical center, Nijmegen, the Netherlands.
Floor A C
http://orcid.org/0000-0003-1899-4421
FA
Berden
Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
Robert J
RJ
de Knegt
Department of Gastroenterology and Hepatology, University medical center Groningen, Groningen, the Netherlands.
Hans
H
Blokzijl
Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, location West, Amsterdam, the Netherlands.
Sjoerd D
SD
Kuiken
Department of Gastroenterology and Hepatology, University medical center Utrecht, Utrecht, the Netherlands.
Karel J L
KJ
van Erpecum
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.
Sophie B
SB
Willemse
Department of Internal Medicine, Maasstad hospital, Rotterdam, the Netherlands.
Jan
J
den Hollander
Department of Internal Medicine, Medical center Leeuwarden, Leeuwarden, the Netherlands.
Marit G A
MG
van Vonderen
Department of Gastroenterology and Hepatology, Catharina hospital, Eindhoven, the Netherlands.
Pieter
P
Friederich
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
Bart
B
van Hoek
Department of Gastroenterology and Hepatology, VU university medical center, Amsterdam, the Netherlands.
Carin M J
CM
van Nieuwkerk
Department of Gastroenterology and Hepatology, Radboud university medical center, Nijmegen, the Netherlands.
Joost P H
JP
Drenth
Department for Health Evidence, Radboud university medical center, Nijmegen, the Netherlands.
Wietske
W
Kievit
D000328:Adult; D000368:Aged; D000740:Anemia / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D004608:Eligibility Determination / Q000379:methods; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D009426:Netherlands; D009503:Neutropenia / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D018579:Patient Selection; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012044:Regression Analysis; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects; D012307:Risk Factors
D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a