Challenges and Criteria for Accepting Lower-Level of Evidence in Early Benefit Assessments (EBA) in Germany

Speaker(s)

Tomeczkowski J1, Herrmann K2, Eichinger B3, Leverkus F4, Osowski U5, Dintsios CM6, Heidbrede T7, Zimmermann T8, Bussilliat P9, Bluhmki T10
1EGDE - Evidence-generating Data Evaluation, Neuss, NW, Germany, 2Pharming Group, Leiden, Netherlands, 3Novartis Pharma GmbH, Nuremberg, BY, Germany, 4EGDE - Evidence-generating Data Evaluation, Berlin, BE, Germany, 5Merck Healthcare Germany GmbH, Weiterstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, 6Heinrich Heine University, Düsseldorf, NW, Germany, 7UCB, Monheim, NW, Germany, 8Boehringer Ingelheim International GmbH, Ingelheim / Rhein, Germany, 9German Association of Research-Based Pharmaceutical Companies (vfa), Berlin, BE, Germany, 10Bristol Myers Squibb, Munich, BY, Germany

Presentation Documents

OBJECTIVES: Randomized trials (RCTs) are standard for conducting EBA but sometimes not feasible or ethical. We investigated the conditions under which single-arm studies (with/without external control) or evidence transfer (from RCT with/without SAT) was accepted.

METHODS: Using a specific EBA database (as of May 1, 2024), we evaluated 1,407 subpopulations fully assessed by both G-BA and IQWiG, and 222 subpopulations assessed only by G-BA (orphan assessments).

RESULTS: Single-arm trials (SATs) were accepted for subpopulations in 21.8% of full assessments (81.2% for Hepatitis C) and in 3.8% of orphan assessments (only minor, considerable or major additional benefit (i.e., not on legal grounds)). When evidence transfer was considered by regulatory, acceptance was at 85.2%.

G-BA cited over time the following main reasons for acceptance of SAT:

- Citing Chapter 2 § 13 Abs. 2 VerfO (for less side effects in chronic Hepatitis C) (53.1%), 2015-2017

- Rare disease or limitations to conduct clinical study (6.3%), 2020-2024

- Lack of treatment alternatives considering disease progression (12.8%), 2015-2022

- Dramatic effect (15.6%) 2015-2021

-Complete response (patient-relevant) (9.4%), 2012-2016

-Less side effects in chronic Hepatitis C (3.1%), 2018

IQWiG accepted only 23.1% of those cases (mostly Hepatitis C).

For rare diseases, defined as those affecting <250 patients in Germany, the likelihood of additional benefit in full assessments, considering all evidence (RCT and non-RCT), was 19.9%. This contrasts with an acceptance rate of 30.0% when not restricted to rare diseases. When the comparator was not active (like best supportive care) the acceptance was 54.8%.

CONCLUSIONS: SAT with/without external control face challenges in achieving additional benefit in full assessments. The reasons for accepting SAT are not consistently applied and not always plannable. This analysis emphasizes the need for binding criteria and flexible assessment methods for SAT when RCTs not feasible/ethical.

Code

HTA366

Topic

Health Technology Assessment, Study Approaches

Topic Subcategory

Decision & Deliberative Processes, Meta-Analysis & Indirect Comparisons, Systems & Structure, Value Frameworks & Dossier Format

Disease

No Additional Disease & Conditions/Specialized Treatment Areas, Personalized & Precision Medicine, Rare & Orphan Diseases