Failure due to formal reasons within German benefit assessment of medicinal products: the dilemma between marketing authorization and HTA

ABSTRACT

Objective: Due to the impact of the Federal Joint Committee’s (FJC) appraisal on following price negotiations, it is crucial to understand the underlying reasons of failure in early benefit assessment (EBA) of medicinal products in Germany.

Methods: Medicinal products for which no added benefit was granted, the underlying reasons given by the FJC were extracted and grouped into respective categories according to predefined working definitions. Several reasons may hold for one subgroup. Furthermore, binomial proportion analysis was performed to gather proportions and their precision for each therapeutic area regarding possible failure.

Results: 293/427 subgroups did not receive an added benefit. For 265/293 the following main formal reasons were stated: deviation of label to the pivotal studies (59%), wrong comparator (20.5%), and methodological deficiencies of indirect comparisons (12.3%). The proportion of failure in EBA is heterogeneous and therapeutic area depending (p = 0.0005). For most of the therapeutic areas, the confidence intervals of binomial proportions include 50%.

Conclusion: Various different reasons led to the failure of EBAs in the past. Despite different objectives, a better alignment between the requirements and methods in the marketing authorization procedure and the EBA might facilitate the design of pivotal studies, which may be useful in both procedures.

KEYWORDS:

• AMNOG
• content-related failure reasons
• early benefit assessment
• formal failure reasons
• marketing authorization
• pivotal studies

Article highlights

• The framework of early benefit assessment laid out by the AMNOG has different objectives and therefore follows different principles than the process of obtaining a marketing authorization.

• The vast majority of early benefit assessments being not granted an added benefit by the Federal Joint Committee in Germany were due to formal reasons. Formal reasons concerned a variety of issues, which were classified in respective categories. The most frequent formal failure reason was the deviation of the label with regard to the pivotal studies.

• If the pharmaceutical entrepreneur aims at successful price negotiations in the context of the AMNOG, the differences between market authorization and early benefit assessment need to be taken into account already during the development process of medicinal products. However, many of the formal failure reasons could have been avoided either by joining a common scientific advice with EMA and FJC or by adapting pivotal study design to the German HTA requirements as far as possible.

• A very high number of subgroups failed due to missing evidence. Allowing within German HTA the transferability of best-available evidence to these subgroups may significantly increase the number of subgroups with a granted added benefit.

Author Contributions

The study conception and study design were developed by both authors. Data extraction as well as descriptive analysis was performed by M Molitor. Inferential statistics and binomial proportion analysis was performed by CM Dintsios. All authors approved the final version to be published; and agree to be accountable for all aspects of the work. The contribution represents original work that has not been previously published or simultaneously submitted for publication elsewhere.

Acknowledgments

The authors thank Pauline Klassen for checking, editing, and proof-reading the frequency tables used.

Data availability statement

The data that support the findings of this study are publicly available in the stated information sources of the methods parts (https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/).

Declaration of interest

CM Dintsios is employed by Bayer Vital GmbH, Leverkusen, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Additional information

Funding

This paper was not funded.