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While the global burden of disease is complex and varied across geographies, ages and therapeutic areas, the unmet medical need among patients with rare diseases remains much higher than most other patient populations. Patients, physicians, regulators and researchers working to advance the development of treatments for rare diseases face numerous challenges; one of which is the small patient populations that make traditional approaches to drug development and clinical trial evaluations nearly impossible to follow.

One of the most heartbreaking outcomes of this reality is the dearth of treatments addressing rare diseases. There are approximately 7,000 different types of rare diseases, effecting more than 350 million people worldwide – half of them children. Even if a biopharma company begins development of a promising drug, it can be years before those treatments hit the market, which is often too late for many patients to benefit. But the European Medicines Agency (EMA) is attempting to make their future a little bit brighter.

Two years ago, EMA launched the adaptive pathways pilot program, a uniquely collaborative process designed to allow “early and progressive patient access to a medicine” for drugs that promise to meet unmet medical needs in the marketplace. EMA calls it “an opportunity for early brainstorming discussion among all relevant stakeholders, including regulators, companies Health Technology Assessment bodies (HTAs) and patient representatives, to explore ways to optimize development pathways and potentially accelerate patients’ access to medicines.”

The pathway allows for rapid approval and is based on three principles: 1) iterative development through either staggered approval going from a narrow restricted initial target population to wider patient populations or by reducing the uncertainty surrounding an initial authorisation with early or surrogate endpoints; 2) using real-world data to supplement clinical trial data and 3) involvement of patients and health technology assessment bodies. Once developers can prove a positive benefit/risk scenario they can secure approval at an earlier stage, then continue to collect real world evidence from patients using the drug to validate efficacy in a real world setting. The hope is that this innovative program will shorten the time it takes for patients to gain access to desperately needed drugs, while still requiring biopharma companies to complete the full regulatory process.

EMA has accepted 20 proposals to date for Stage 1 discussions.  Of these, 11 were selected for Stage II “in depth” meetings.  Companies which have announced their involvement in the program include: Bluebird Bio, a clinical- gene therapy company pursuing approval for LentiGlobin BB305, a candidate for the treatment of beta-thalassemia major; Immunocore Limited, a biotech company seeking conditional approval for IMCgp100, a biologic for the treatment of metastatic uveal melanoma, a rare and fatal disease with few available treatment options; Pluristem Therapeutics, a developer of placenta-based cell therapy developing a product that targets a subgroup of patients with critical limb ischemia (CLI); and GSK who have two products working together to treat systemic amyloidosis.

Just getting started

As of late last year, EMA was still seeking applicants with "well-developed" proposals to take part in the initial pilot, though getting accepted and making the most of this adaptive pathway opportunity will take some careful thought and planning. For drug developers interested in exploring this option, here are five steps to improve your odds of success.

  1. Determine whether your drug meets the criteria: Candidate selection is a major piece of the adaptive pathway process. EMA is looking for innovative drugs that fill an unmet need in society usually associated with a rare or orphan disease.  Companies need to be thinking about life-cycle development.
  2. Consider building a registry very early on. Once a drug receives early conditional approval, researchers will need to continue to collect real world evidence from users about how the treatment works, potential side effects, and how the drug compares to any existing treatments, or none at all.  However companies that build patients registries at the beginning of the development process can use them to provide data on the natural history of the disease possibly enabling single arm trials – an important option for rare diseases with no current effective treatment.  Patients can be rolled over from trials into the registry to gain valuable long term data.

  3. Engage early with EMA and HTAs: One of the key components of the adaptive pathway model is to provide developers with an opportunity for early brainstorming discussions with all relevant stakeholders, including regulators, HTAs, and patient representatives. These brainstorming sessions are meant to provide all participants with ideas for optimizing development pathways and potentially accelerating patients’ access to medicines, including the evidence you will need to gain both approval and reimbursement for your drug. Developers who are interested in following this pathway are encouraged to engage early on with stakeholders to share their results, gather feedback on next steps, and to use that feedback to adapt their development process and decision-making for the product.
  4. Choose brainstorming partners carefully: One of the biggest challenges in this process is choosing which regulators and HTAs to engage with. In contrast to the benefit-risk assessment carried out by regulators, HTA bodies compare the relative effectiveness of medicines so they can provide recommendations to their member state on whether the treatment should be paid for or reimbursed by the healthcare system. They carry out their own assessments of medicines, once they have received marketing authorization, and thus will have a different set of criteria. So if you want to get a drug into the marketplace, you have to worry about both regulator and HTA approval. It is unrealistic to think you can meet with all of the HTAs. Instead be strategic in who you chose to work with: You want to select HTA representatives who are in relevant markets for your drug and are open to talking with developers on this pathway. You also want diversity in the decision makers you talk to; to get the most robust feedback, choose HTAs who represent a diversity of regions, roles, and priorities.
  5. Ask specific questions: You may only have a brief opportunity to engage with HTA leaders and regulators, so don’t waste it asking for information you could find on their website. Do your research and be ready to ask detailed questions that pertain to your drug, and the approval and reimbursement process. 
  6. Think about your broader license continuum: The adaptive pathway is conditional for specific uses and user groups, and thus companies must have plans for augmenting the data following the initial approval. You have to keep working toward full licensing goals which means having plans for continued collection of data to reduce the uncertainty around estimations of the benefits and risks – particularly if the initial approval was based on small patient numbers and/or surrogate endpoints.

The adaptive pathway program could become a tremendous opportunity to speed key drugs to market – especially for rare diseases given the small patient size and large unmet medical need. But this innovative approach to regulatory approval does not in any way lessen the need for due diligence, careful planning and strong stakeholder engagement. The drug developers who put the time and expertise into the planning process will be best positioned to take advantage of this fast track opportunity to bring new drugs to the patients who need them most.

This post was co-authored by Janice Haigh, Principal, Quintiles Advisory Services