Whether a drug works better or has fewer side effects than current standard treatment is irrelevant for the approval. It is sufficient if the drug is effective and safe. An added benefit only becomes important in the second step, the benefit assessment of the drug. Then it is examined whether the new drug helps patients better than the standard treatment. For this assessment of added benefit, the drug manufacturers must submit studies in which the new drug is compared with the standard treatment.
In the German AMNOG procedure, the Institute for Quality and Efficiency in Health Care (IQWiG) examines the results of the comparative studies on behalf of the Federal Joint Committee (G-BA) and determines the added benefit of a new drug for clinical practice. On the basis of this assessment, the G-BA determines the extent of the added benefit, which is relevant for clinical practice, and which serves as the basis for price negotiations between statutory health insurance funds and the manufacturer.
"In practice, many manufacturers do not carry out comparative studies against a standard treatment. For the benefit assessment, they often only provide single-arm or placebo-controlled studies from the approval procedure," says Beate Wieseler, Head of IQWiG's Drug Assessment Department. This is why, in over 50 per cent of new drugs in the AMNOG procedure, IQWiG's assessment is "added benefit not proven". Wieseler demands: "We finally need effective incentives to encourage manufacturers to generate comparative data on a regular basis."
Against this background and in the run-up to the European benefit assessments starting in 2025, representatives of the European Medicines Agency (EMA), other regulatory agencies, and European agencies for Health Technology Assessment (HTA; including IQWiG) held several workshops in the course of 2024 to develop a common understanding of methodological challenges and solutions in the assessment of new drugs. "Discussions about potential solutions addressing respective evidence needs [...] across the life cycle must acknowledge the difference in scopes between marketing authorisation [...] and HTA decision making," a joint position paper from the workshops states. "In many cases, HTA and regulatory research questions are distinct but overlapping; wherever possible, studies should be designed to meet both decision makers' evidence needs simultaneously."
In summary, the participants identified the following key points to address joint evidence needs:
- Both regulators and HTA agencies prefer randomized studies when assessing benefit/risk and added benefit of drugs.
- There are substantial opportunities to complement pre-licensing clinical trial data with randomized trials in registries and routine care to inform regulatory and HTA decision making.
- Improving collection, analysis and reporting of a wider range of outcomes – beyond the so-called primary study outcomes – can substantially reduce uncertainty in decision-making.
- There are significant unresolved challenges with the use of observational real-world data to inform effect estimation by indirect comparisons.
"The very constructive discussions showed that all workshop participants prefer randomized controlled trials," emphasizes Beate Wieseler. "For challenging situations such as small patient populations, novel randomized study designs are seen as a promising alternative to single-arm studies." Examples include seamless phase I-II designs in early clinical development, multi-arm platform trials in therapeutic indications with evolving treatment options, and other flexible, adaptive designs that preserve randomization while potentially reducing sample size requirements and development timeframes.
Wieseler says: "There was also consensus in the international group on another aspect: There are substantial opportunities to complement pre-licensing clinical trial data with randomized trials in registries and routine care to inform regulatory and HTA decision making."
