Generating clinical evidence for HTA: challenges and solutions

By Prof. Dr Lieven Annemans, expert-trainer of the courses 
Health Economics for Non-Health-Economists and Critical New HTA Developments in Europe: Challenges & Solutions.
 

Clinical evidence serves as a cornerstone for Health Technology Assessment (HTA) and subsequent payer decisions. Demonstrating how an intervention translates into patient benefit and healthcare value hinges on the quality and relevance of the data presented. While regulatory approval primarily requires demonstrating efficacy in controlled environments, HTA bodies and payers prioritise relative effectiveness—the (estimated) real-world impact of the intervention compared to existing alternatives. These different angles create challenges for pharma and MedTech companies when planning for optimal market access.
 

Challenge 1: Relative Effectiveness Over Efficacy 📊 

HTA bodies require evidence that mirrors routine clinical practice, whereas traditional trials are optimised for regulatory scrutiny, prioritising internal validity. Highly controlled trial designs, while necessary for demonstrating efficacy, often struggle to capture the complexities of real-world patient populations and care pathways. Typical exclusions, such as elderly patients and individuals with comorbidities, limit external validity, making the generalisation to broader populations difficult.

A growing trend is the push towards pragmatic, or "effectiveness," trial designs. These designs bridge the gap between clinical rigor and real-life applicability. Recommendations include aligning inclusion criteria with actual clinical practice, collaborating with clinicians to adapt protocols towards standard care routines, and ensuring that data collection reflects variables relevant to HTA evaluations, including resource utilisation and patient-reported outcomes.
 

Challenge 2: Relative vs. Absolute Risk Metrics ⚖️ 

Risk communication also becomes a critical focal point. While pharmaceutical companies may emphasise Relative Risk Reduction (RRR) to highlight favourable intervention outcomes, HTA bodies focus on Absolute Risk Reduction (ARR) as it directly informs value-for-money calculations. The ARR, which is inherently influenced by baseline risk levels in the population, offers a more tangible measure of how much patient outcomes will improve per healthcare euro spent. Presenting ARR alongside RRR can strengthen payer engagement and better reflect real-world value.
 

Challenge 3: Accounting for Adherence 💊 

Effectiveness in practice is shaped by patient adherence. A frequent oversight is assuming that adherence in the real-world will be the same as in RCTs. HTA evaluations increasingly expect real-world data that adjust predicted outcomes to reflect actual adherence patterns. Factoring adherence into modelling ensures realistic projections of clinical and economic benefits.
 

Challenge 4: Bridging Surrogate to Clinical Endpoints 🔗 

Payers are cautious when trials rely on surrogate markers rather than hard clinical outcomes. The acceptance of such surrogates hinges on robust epidemiological evidence linking them to ultimate health outcomes. Access strategies should therefore anticipate payer scrutiny and, where possible, integrate long-term cohort data or real-world evidence to strengthen these linkages.
 

Challenge 5: Durability of Effect ⏳ 

Finally, sustainability of treatment effect poses a critical concern, particularly for chronic conditions where long-term benefit is paramount. Payers may question the duration for which therapy should be continued and its associated costs over time. Including data on effect durability and well-defined stopping rules within submission dossiers can enhance the perceived credibility of a product’s value proposition.
 

Conclusion

Market access teams must prioritise evidence generation strategies that embrace real-world relevance, consider health economic priorities, and address payer scepticism around trial generalisability. A proactive approach to these challenges not only supports a smoother HTA review but also strengthens the overall case for reimbursement and broader patient access.