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

Floor A C Berden, Robert J de Knegt, Hans Blokzijl, Sjoerd D Kuiken, Karel J L van Erpecum, Sophie B Willemse, Jan den Hollander, Marit G A van Vonderen, Pieter Friederich, Bart van Hoek, Carin M J van Nieuwkerk, Joost P H Drenth, Wietske Kievit

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)e0161821
JournalPLoS ONE
Volume11
Issue number9
DOIs
Publication statusPublished - 2016

Cite this

Berden, F. A. C., de Knegt, R. J., Blokzijl, H., Kuiken, S. D., van Erpecum, K. J. L., Willemse, S. B., ... Kievit, W. (2016). Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study. PLoS ONE, 11(9), e0161821. https://doi.org/10.1371/journal.pone.0161821
Berden, Floor A C ; de Knegt, Robert J ; Blokzijl, Hans ; Kuiken, Sjoerd D ; van Erpecum, Karel J L ; Willemse, Sophie B ; den Hollander, Jan ; van Vonderen, Marit G A ; Friederich, Pieter ; van Hoek, Bart ; van Nieuwkerk, Carin M J ; Drenth, Joost P H ; Kievit, Wietske. / Limited Generalizability of Registration Trials in Hepatitis C : A Nationwide Cohort Study. In: PLoS ONE. 2016 ; Vol. 11, No. 9. pp. e0161821.
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abstract = "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.",
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Berden, FAC, de Knegt, RJ, Blokzijl, H, Kuiken, SD, van Erpecum, KJL, Willemse, SB, den Hollander, J, van Vonderen, MGA, Friederich, P, van Hoek, B, van Nieuwkerk, CMJ, Drenth, JPH & Kievit, W 2016, 'Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study' PLoS ONE, vol. 11, no. 9, pp. e0161821. https://doi.org/10.1371/journal.pone.0161821

Limited Generalizability of Registration Trials in Hepatitis C : A Nationwide Cohort Study. / Berden, Floor A C; de Knegt, Robert J; Blokzijl, Hans; Kuiken, Sjoerd D; van Erpecum, Karel J L; Willemse, Sophie B; den Hollander, Jan; van Vonderen, Marit G A; Friederich, Pieter; van Hoek, Bart; van Nieuwkerk, Carin M J; Drenth, Joost P H; Kievit, Wietske.

In: PLoS ONE, Vol. 11, No. 9, 2016, p. e0161821.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Limited Generalizability of Registration Trials in Hepatitis C

T2 - A Nationwide Cohort Study

AU - Berden, Floor A C

AU - de Knegt, Robert J

AU - Blokzijl, Hans

AU - Kuiken, Sjoerd D

AU - van Erpecum, Karel J L

AU - Willemse, Sophie B

AU - den Hollander, Jan

AU - van Vonderen, Marit G A

AU - Friederich, Pieter

AU - van Hoek, Bart

AU - van Nieuwkerk, Carin M J

AU - Drenth, Joost P H

AU - Kievit, Wietske

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1371/journal.pone.0161821

DO - 10.1371/journal.pone.0161821

M3 - Article

VL - 11

SP - e0161821

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 9

ER -

Berden FAC, de Knegt RJ, Blokzijl H, Kuiken SD, van Erpecum KJL, Willemse SB et al. Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study. PLoS ONE. 2016;11(9):e0161821. https://doi.org/10.1371/journal.pone.0161821