(177) Justification for The Acceptance of Uncontrolled Pivotal Trials to Support Marketing Authorisation of Medicines in Europe (1995-2020)

Sunday, August 28, 2022

8:00 AM – 1:45 PM CEST

Location: Hall C

Publication Number: 1222

Presenting Author(s)

Jasmin Schelhaas
– University of Utrecht, Utrecht, Utrecht, Netherlands

Co-Author(s)

Lourens Bloem, PharmD, PhD
– Assistant Professor Clinical Therapeutics, Utrecht University, Utrecht, Utrecht, Netherlands
Jarno Hoekman
– Innovation Studies, Copernicus Institute of Sustainable Development, Utrecht University, Utrecht, the Netherlands, Netherlands
Aukje Mantel-Teeuwisse
– Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands, Netherlands
Paula B. Hennik, van
– Alternate CHMP, Dutch Medicines Evaluation Board, Utrecht, the Netherlands, Utrecht, Netherlands
Carla Herberts
– Dutch Medicines Evaluation Board, Utrecht, the Netherlands, Utrecht, Utrecht, Netherlands

Background: Randomised controlled trials are the gold standard to evaluate clinical efficacy and safety for marketing authorisation (MA) of medicines. Use of uncontrolled trials must generally be justified. In Europe, when the benefit risk balance is positive and data are considered comprehensive by the European Medicines Agency (EMA), a standard marketing authorisation (SMA) can be granted. When data are not comprehensive, an authorisation under exceptional circumstances (AEC) or a conditional marketing authorisation (CMA) can be granted.

Objectives: We aimed to assess the number of new medicines that were granted SMA, AEC or CMA supported by uncontrolled pivotal trials and the EMA’s justification for the acceptance of these trials over time.

Methods: We included all initial MAs approved by the EMA in 1995-2020 that were based on new complete dossiers (i.e., excluding, among others, generics and biosimilars) and were supported by uncontrolled pivotal trials. We extracted EMA’s arguments for the acceptance of uncontrolled pivotal trials from European Public Assessment Reports. Data were analysed descriptively overall and for SMAs, AECs and CMAs separately and were visualised.

Results: Among 1.454 MAs, 751 (52%) were approved on the basis of a complete dossier. Of these, 49/624 SMAs (8%), 22/73 AECs (30%) and 28/54 CMAs (52%) were supported by uncontrolled trials. The five most frequently used arguments to accept uncontrolled pivotal trials were lack of satisfactory treatment (n=28, 29%), rarity of disease (n=16, 16%), effect size on the efficacy endpoint (n=16, 16%), severity of disease (n=15, 15%) and adherence to a product-specific regulatory guideline (n=14, 14%). For AECs, the most frequently used arguments included rarity of disease (n=11, 50%). For CMAs, the most frequently used arguments included lack of satisfactory treatment and effect size (both n=10, 36%), and severity of disease (n=6, 21%). For 15 SMAs (31%), no arguments were provided. Over time, more arguments were provided per MA.

Conclusions: Uncontrolled pivotal trials were more often found for AECs and CMAs than for SMAs and main arguments for acceptance differed between MA types. For many SMAs no arguments were provided. While the level of detail of EMA’s justification has improved over time, it should be further improved to ensure that doctors and patients understand why uncontrolled pivotal trials were considered sufficient to support MA and can make informed treatment decisions.