TY - JOUR

T1 - Statistical Methods for Adjusting Estimates of Treatment Effectiveness for Patient Non-adherence in the Context of Time-to-Event Outcomes and Health Technology Assessment: A Systematic Review of Methodological Papers

AU - Alshreef, Abualbishr

AU - Latimer, Nicholas

AU - Tappenden, Paul

AU - Wong, Ruth

AU - Hughes, Dyfrig

AU - Fotheringham, James

AU - Dixon, Simon

N1 - This report is independent research funded by a National Institute for Health Research (NIHR) Doctoral Research Fellowship awarded to Mr Abualbishr Alshreef (DRF-2017-10-025)

PY - 2019/11

Y1 - 2019/11

N2 - Introduction. Medication nonadherence can have a significant negative impact on treatment effectiveness. Standard intention-to-treat analyses conducted alongside clinical trials do not make adjustments for nonadherence. Several methods have been developed that attempt to estimate what treatment effectiveness would have been in the absence of nonadherence. However, health technology assessment (HTA) needs to consider effectiveness under real-world conditions, where nonadherence levels typically differ from those observed in trials. With this analytical requirement in mind, we conducted a review to identify methods for adjusting estimates of treatment effectiveness in the presence of patient nonadherence to assess their suitability for use in HTA. Methods. A "Comprehensive Pearl Growing" technique, with citation searching and reference checking, was applied across 7 electronic databases to identify methodological papers for adjusting time-to-event outcomes for nonadherence using individual patient data. A narrative synthesis of identified methods was conducted. Methods were assessed in terms of their ability to reestimate effectiveness based on alternative, suboptimal adherence levels. Results. Twenty relevant methodological papers covering 12 methods and 8 extensions to those methods were identified. Methods are broadly classified into 4 groups: 1) simple methods, 2) principal stratification methods, 3) generalized methods (g-methods), and 4) pharmacometrics-based methods using pharmacokinetics and pharmacodynamics (PKPD) analysis. Each method makes specific assumptions and has associated limitations. Five of the 12 methods are capable of adjusting for real-world nonadherence, with only g-methods and PKPD considered appropriate for HTA. Conclusion. A range of statistical methods is available for adjusting estimates of treatment effectiveness for nonadherence, but most are not suitable for use in HTA. G-methods and PKPD appear to be more appropriate to estimate effectiveness in the presence of real-world adherence.

AB - Introduction. Medication nonadherence can have a significant negative impact on treatment effectiveness. Standard intention-to-treat analyses conducted alongside clinical trials do not make adjustments for nonadherence. Several methods have been developed that attempt to estimate what treatment effectiveness would have been in the absence of nonadherence. However, health technology assessment (HTA) needs to consider effectiveness under real-world conditions, where nonadherence levels typically differ from those observed in trials. With this analytical requirement in mind, we conducted a review to identify methods for adjusting estimates of treatment effectiveness in the presence of patient nonadherence to assess their suitability for use in HTA. Methods. A "Comprehensive Pearl Growing" technique, with citation searching and reference checking, was applied across 7 electronic databases to identify methodological papers for adjusting time-to-event outcomes for nonadherence using individual patient data. A narrative synthesis of identified methods was conducted. Methods were assessed in terms of their ability to reestimate effectiveness based on alternative, suboptimal adherence levels. Results. Twenty relevant methodological papers covering 12 methods and 8 extensions to those methods were identified. Methods are broadly classified into 4 groups: 1) simple methods, 2) principal stratification methods, 3) generalized methods (g-methods), and 4) pharmacometrics-based methods using pharmacokinetics and pharmacodynamics (PKPD) analysis. Each method makes specific assumptions and has associated limitations. Five of the 12 methods are capable of adjusting for real-world nonadherence, with only g-methods and PKPD considered appropriate for HTA. Conclusion. A range of statistical methods is available for adjusting estimates of treatment effectiveness for nonadherence, but most are not suitable for use in HTA. G-methods and PKPD appear to be more appropriate to estimate effectiveness in the presence of real-world adherence.

KW - causal inference

KW - cost-effectiveness analysis

KW - medication nonadherence

KW - noncompliance

KW - survival analysis

U2 - 10.1177/0272989X19881654

DO - 10.1177/0272989X19881654

M3 - Article

C2 - 31646932

VL - 39

SP - 910

EP - 925

JO - Medical Decision Making

JF - Medical Decision Making

SN - 0272-989X

IS - 8

ER -