Clinical evidence relating to therapeutic efficacy and safety is one of the most valuable criteria of the Health Technology Assessment (HTA) process. The HTA process typically involves an initial assessment of evidence followed by the appraisal of the assessed evidence from an expert committee that is producing reimbursement recommendations. As such, generating credible, appropriate, and robust data is key for a successful market access strategy.
Clinical Trial Design and Differences Between Countries
The design of a clinical trial can have a significant impact on the quality of evidence generated. Here, randomized controlled trials (RCTs) are considered as the most powerful research design for evaluating new health technologies and decision-making. However, whilst RCTs are regarded as the highest level of evidence, they are not always appropriate or even possible. For instance, in rare diseases it may not be possible to conduct RCTs, due to small patient population numbers or ethical issues. In this case, observational data, single arm trials or even expert opinion may be acceptable.
Additionally, there are differences across countries with regards to demographics, comparator treatments and in the value of clinical outcomes. Since it is not possible to conduct multiple clinical trials with each market’s specific requirements in mind, clinical trials are often designed and conducted with regulatory approval in mind. As such, the external validity of the trial (i.e. the extent to which results relate to the individual market) may decrease and will therefore be open to criticism from HTA bodies.
Common criticisms from HTA bodies regarding a trial’s external validity include:
- Lack of active comparators or selection of incorrect comparator: HTA agencies look for results that show clinical efficacy and cost-effectiveness compared to standard of care
- Trial duration: a short trial in a chronic disease area is not enough to demonstrate relevant health outcomes and will raise uncertainty as HTA agencies want to understand the long-term treatment effects
- Statistically significant findings are not necessarily clinically relevant: this can raise uncertainty as to the benefits of treatment
- Results not reflective of real-world practice (e.g. compliance, dosage, population, condition, etc): clinical trials may overestimate the clinical benefits of the new treatment due to it not being used under conditions reflecting actual clinical practice and settings.
- Patient subgroups (e.g. paediatrics, elderly, pregnancy) not relevant to current practice – patient population size in the study may be insufficient or may not show meaningful outcomes, in particular for rare disease.
What can manufactures do to reduce uncertainty?
It is important to remember that while regulators evaluate the benefit-risk balance of drugs, HTA bodies evaluate drug effects compared with available alternatives. Approved drugs can be rejected due to uncertainties related to clinical evidence. Nonetheless, there are strategies that can be employed to increase payer certainty in the evidence base:
- Positioning: it may be required to position the new drug in the treatment paradigm where clinical trial data are more compelling/ the unmet need is greatest.
- Price: Where clinical data can only justify a given maximum price, patient access schemes and price reductions may be necessary to gain access.
- Treatment duration: if long-term clinical benefit cannot be demonstrated in all patients, stopping rules may need to be implemented to ensure only those patients who are benefitting from the drug continue their treatment.
- Population: the drug may be restricted to certain populations if the HTA body is not convinced of the effectiveness or cost-effectiveness in a broader patient population.
Remap Consulting have significant expertise and up-to-date knowledge to support and help address with your questions around clinical trial design from a pricing, reimbursement, and market access perspective.