Subgrouping Practice in Early Benefit Assessment in Germany Risks Misusing Evidence-based Medicine

Published Jul 3, 2014
Hannover, Germany - Since 2011, the German AMNOG (Act on the Reform of the Market for Medicinal Products) legislation regulates drug reimbursement in an attempt to reduce national health care costs. The Federal Joint Committee (G-BA) and the Institute for Quality and Efficiency in Health Care (IQWiG) are charged with evaluating a drug’s additional clinical benefit. Benefit decisions of the G-BA affect subsequent price negotiations with insurance funds and therefore have significant impact on health care provision. One controversial and potentially misleading assessment tool used by the G-BA and IQWiG is post hoc subgroup analysis, also termed as "slicing," to restrict the potential pool of people who may demonstrate an additional clinical benefit and thereby impact subsequent price negotiations and related reimbursement decisions. In their commentary, "Questioning Patient Subgroups for Benefit Assessment: Challenging the German Gemeinsamer Bundesausschuss Approach," published in Value in Health, the authors question the validity of such post hoc analyses as a basis for important decisions of drug reimbursement at a national level. The authors maintain that G-BA/IQWiG subgrouping may exclude patients who could benefit from therapy; and subgrouping as a means to cut costs abuses the principle of evidence-based medicine. In the authors´ view, this may also lead to biased treatment decisions. The authors put forward considerations for appropriate subgroup analyses contrasting those inappropriate to support important decision making. Specifically the authors suggest that subgroup analysis should be based on a firm and prospectively defined hypothesis that is grounded in a sound biologic rationale, such as e.g. respective biomarker testing:


Tests a hypothesis (confirmatory analysis)

Prospectively defined

Based on biologic rationale or at least solid previous experience

Small number (≤5) of prospectively defined subgroups

No hypothesis (exploratory analysis)

Post hoc analyses

Controversial biologic rationale; no previous experience

High number of post hoc subgroups (>5): increased risk of multiplicity

Table 1. Characteristics of appropriate and inappropriate subgroup analyses for decision making in drug reimbursement from: Ruof J, Dintsios CM, Schwartz FW. Questioning Patient Subgroups for Benefit Assessment: Challenging the German Gemeinsamer Bundesausschuss Approach. Value Health. 2014:17:307-309.
Ruof J, Dintsios CM, Schwartz FW. Questioning Patient Subgroups for Benefit Assessment: Challenging the German Gemeinsamer Bundesausschuss Approach. Value Health. 2014:17:307-309. Prof. Dr. med. Jörg Ruof, MPH, Head Market Access, Roche Pharma AG, and lead author, follows up in saying that, "Subgrouping standards specific to AMNOG are urgently needed and joint GBA/regulatory advice earlier in a drug development process would be highly desirable."

Value in Health (ISSN 1098-3015) publishes papers, concepts, and ideas that advance the field of pharmacoeconomics and outcomes research as well as policy papers to help health care leaders make evidence-based decisions. The journal is published bi-monthly and has over 8,000 subscribers (clinicians, decision-makers, and researchers worldwide).

International Society for Pharmacoeconomics and Outcomes Research (ISPOR) is a nonprofit, international, educational and scientific organization that strives to increase the efficiency, effectiveness, and fairness of health care resource use to improve health.

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