Patients suffering from conditions with no available treatments, rarely have the time to wait decades for a new drug to come to market. The European Medicines Agency (EMA) is trying to address this issue through its adaptive pathways program, which aims to shorten the time it takes to bring innovative new medicines to market that meet unmet medical needs, while still adhering to the existing EU regulatory framework. The adaptive pathways approach is based on the principles of iterative development, where clinical trial data is supplemented by real-world evidence. Products accepted into this program are granted conditional marketing authorization based on early clinical data, with observational studies used to support the subsequent full marketing authorization.
The decision on when to grant marketing approval for a drug is based on the goal of giving patients rapid access to promising new medicines while still ensuring that these medicines are as safe as possible. Yet the adaptive pathways initiative has faced criticism for its perceived potential to lower safety standards by allowing new products onto the market more quickly. This criticism tends to assume that the role of the regulator is to guarantee safety rather than ensuring that there is a positive risk/benefit balance. For patient populations with life-threatening diseases and no existing treatments, tolerance for risk may be higher, which makes allowing access to a new drug while collecting additional data an appealing option for these groups. In fact, even with products which proceed to full marketing authorization via the more traditional route, safety issues rarely arise until after marketing authorization, when large numbers of patients have been exposed to the therapy.
But will they pay
The real challenge developers will face if they pursue an adaptive pathway is demonstrating efficacy or effectiveness through an observational study design. They may struggle with limiting factors related to randomization, dosing, choice of comparator, recruitment, a complicated disease pathway or patient population, or the fact that multiple centers for rare diseases may use different approaches and standards of care.
Convincing Health Technology Assessment (HTA) bodies to support the product may also be a challenge. HTAs have not yet evaluated any product accepted for adaptive pathway approval, but there are analogous situations. The most obvious involves products given conditional marketing authorization (CMA) by the EMA, as this is the regulatory route for adaptive pathway drugs. In order to achieve this level of approval, the products in review must demonstrate:
- A positive benefit-risk balance
- No changes were made to the standard for evaluation
- The benefit of immediate availability of the product to the patient outweighs the risks related to incomplete data
- Clear plans for continued evidence gathering with comprehensive data required after marketing authorization application (MAA)
- To date, 25 products have received a CMA, of which 14 were orphan and 18 were for oncology indications. Evidence suggests that drugs with a CMA have a higher probability of receiving a negative recommendation than the average of all HTAs, based on data from QuintilesIMS HTA Accelerator. However, unmet need does seem to be taken into account.
In reviewing drugs approved on an adaptive pathway, HTAs may be concerned about extensions of indications. Going from initial indication to full indication in the adaptive pathway is analogous to an extension of indication from a payer’s perspective (e.g., extending to a different disease stage or different treatment line/stage). They may also balk if the drug involves clinical evidence based on single arm trials. Payers have already highlighted the uncertainty of results in clinical and cost-effectiveness of products with a CMA due to immature data, and in some cases, this uncertainty has resulted in negative recommendations by payers.
The many rejections by HTAs for drugs with EMA conditional approval and extension of indication suggest that their assessments of drugs approved on an adaptive pathway will be challenging. Even with all the essential elements in place some products will fail to gain HTA approval. That doesn’t mean developers should eschew this path, rather they must consider HTA requirements early in the development process to best position their drug for these reviews.
Help them help you
Companies can improve their chances of positive HTA decision by undertaking effective consultation with HTA bodies early in their research program. This is one environment where closed questions are more powerful than open questions, and the quality of advice depends entirely on the quality of questions asked. HTA bodies cannot tell sponsors what to do, but they are able to respond to specific questions. It is therefore essential to support questions and concepts with data and analysis.
Companies also need to understand how different HTA bodies approach evaluation of products differently so they can provide the best package of information to achieve their goals for each reviewing body. For example, if an HTA body uses cost-effectiveness analysis as part of its review process, you should develop an early health economic model that allows for highly specific feedback. In addition, the EMA and the HTAs will need to see solid plans for future development and analysis.
Before meeting with any HTA body, companies should review previous HTA decisions on related products to assess gaps in their own data, and look for opportunities to validate their questions and approach before the formal meeting. In preparation for these meetings they should develop clear and consistent arguments to defend their plans.
The adaptive pathway is still a new and uncertain approach. While it offers real benefits for patients with unmet medical needs, sponsors need to be prepared for the challenges they face in demonstrating the safety and efficacy of treatments brought to market through this approach. It will not be an easy journey, but sponsors who can present a compelling case for approval by building a credible development plan, demonstrating controlled access, and effectively managing risks through strict surveillance may be able to cut years from their drug development lifecycle.