Drug manufacturers bringing therapies to market for rare diseases face challenges typically unseen with therapies for more prevalent conditions. These challenges span multiple stages—from clinical development through commercialization—and require coordinated efforts from medical affairs, health economics and outcomes research, policy, advocacy, and market access functions to execute successful evidence planning, stakeholder engagement, and patient access strategy.

• Thousands of rare diseases fragmented into small patient populations make it more onerous to understand the clinical manifestations and patient impacts of each rare disease.
• Small patient populations also pose challenges in clinical trial recruitment, where issues around equity, access to care, and representation may be exacerbated due to lacking availability of trial sites.

• The diagnostic journey for patients with rare diseases is long compared to more common diseases, with a high likelihood of initial misdiagnosis.
• Patients and their caregivers may face additional cost burdens associated with testing and treatment options.
• Delayed diagnosis can result in diagnosis at a later stage, with greater impacts on the patient; this is especially relevant for conditions that have cumulative non-recoverable degenerative impact.

• The lack of approved treatments in most rare diseases poses ethical challenges with placebo arms in randomized control trials, requiring innovative approaches to control groups and use of real-world data.
• Patients may face delays in navigating insurance coverage and support programs for high-cost drugs with small target patient populations.

• Specialists who have the experience and knowledge to diagnose and treat a rare condition are usually located only at major academic medical centers.
• A lack of expertise at local providers and healthcare systems may result in a delayed diagnosis, disruptions in treatment, or inappropriate care.
• Rare diseases have disproportionate and severe impacts on children and require significant time and resources from caregivers.

Evidence Strategy: Defining Value and Identifying Appropriate Research Design

Defining value through a patient-centered lens is critical for all conditions but is especially important for rare disease treatment, as patients encounter disease impacts that don’t routinely occur in non-rare populations. For example, adults with rare diseases are more likely to travel or relocate to be near specialists, incurring direct costs such as transportation and temporary lodging and indirect costs such as lost workdays or lost career opportunities. Spouses, other family members, or parents of children with a rare condition may have to change or prematurely end their careers to become full-time caregivers, resulting in major financial implications for the entire family. Limited research exists on these impacts and how to quantify them, which is needed to support more holistic value assessments.

Conducting research in the rare-disease space necessitates creative approaches to study design and recruitment to accommodate the small participant pools. Comparative effectiveness studies can be challenging with small patient populations, so innovative approaches, such as studies looking at total disease burden and the effect of therapies on patient- and caregiver-centered disease impacts can provide important context and perspective for payers. Further, manufacturers can capture longitudinal data to assess real-world safety and efficacy for new modalities of drug delivery and mechanisms of action that take place at the cellular and genetic level using patient registries and patient-reported outcomes. Endpoints in clinical trials can be designed in anticipation of potentially innovative contracting strategies and the outcomes that will need to be tracked from real-world data. For providers and health plans, few quality measures specific to rare disease and suited to this purpose are available. Because of the small populations, the impact of any one rare disease on the general population’s quality outcomes is minimal. Patients with rare conditions share similar challenges that, when considered in aggregate, affect quality outcomes such as readmissions, adverse events, and the total cost of care, and can have a major impact on a providers’ or plans’ performance in quality-driven payment programs.

Market Access Considerations

Developers of rare disease treatments must navigate a complex regulatory and commercialization landscape. Manufacturers often take on higher research and development (R&D) costs due to small clinical trial population size and difficulties in identifying and validating endpoints, especially in heterogeneous rare diseases, which poses additional barriers to manufacturers who already must navigate the changing policy environment (e.g., Inflation Reduction Act implementation). The Food and Drug Administration (FDA) recognizes these challenges and continues to invest in various programs focused on rare diseases that could help advance endpoint development and validation, promote innovative study designs, and enhance patient identification.

Patient access to available treatments may be a more significant challenge in the rare disease space given the diagnostic odyssey through which patients go before receiving a correct diagnosis. For 0pediatric patient populations, newborn screening is available, but not all conditions are included and due to budgetary constraints not all states screen for diseases on the Recommended Uniform Screening Panel (RUSP) or additional diseases outside the RUSP. Conditions not detected by newborn screening or those manifesting in adolescence and adulthood may be detected by novel testing approaches, such as whole genome or exome sequencing, but utilization management requirements may restrict patient access to these diagnostic tools, further delaying access to treatment.

Patient support resources needed in the rare disease space require a more tailored approach to address the unique challenges faced by patients and caregivers. Manufacturers may need to develop more patient-support education and resources about specific rare diseases. Demand for care coordination and case management support services may be even higher for rare diseases compared to non-rare diseases. Additionally, caregiver support resources and programs that mitigate breaks in care and disruption in therapy—such as bridge programs and site-of-care locators—are also important to consider for access. Once patients begin treatment, resources that enable tracking adherence and persistence also become critical as part of a robust suite of patient support offerings.

In addition, price sensitivities, driven by the need to balance R&D efforts with the associated return on investment, differ in the rare-disease space as compared to more common diseases. Downstream impacts include more restrictive utilization management by payers, who often replicate clinical trial inclusion/exclusion criteria in their formulary designs. Payers may also want to see the total cost of care when evaluating a product, but total cost of care may not be widely studied or is poorly understood for many rare diseases. To address some of these issues, manufacturers may need to develop stakeholder engagement strategies early in the clinical development process inclusive of payers, providers, and other key stakeholders.

Federal and State Policy Opportunities

Federal and state policies shape the rare disease landscape, influencing patient access and the broader R&D environment. Given the unique care journey and high-cost burden that patients with rare diseases and their families often face, policies may provide flexibilities and enable novel approaches to support access to treatments and drug development, or create specific policy exemptions for rare disease treatments in instances where patients could be adversely affected.

Federal and state policymakers are increasingly pursuing efforts to reduce cost exposure and improve patient access across the unique rare disease care journey (e.g., patient support and reimbursement for ancillary costs associated with traveling to treatment centers, limiting use of copay accumulator and maximizer programs). Meanwhile, Medicare drug price negotiation aims to reduce costs for high-spending drugs but could potentially have adverse implications for rare-disease drug development due to the orphan drug exclusion’s limitation that only enables a drug to qualify with a single rare-disease designation.

Approximately half of states have created rare-disease advisory councils. As novel treatments continue to emerge, opportunity exist to bolster and expedite efforts that shorten the diagnostic and treatment journey for patients, such as through newborn screening. Meanwhile, several states have been active in implementing prescription-drug affordability review boards aimed at reducing state costs for a subset of high-cost drugs, many of which could implicate rare disease treatments if not otherwise carved out of the policy. Looking ahead, federal flexibilities for novel financing arrangements through the value-based purchasing rule, combined with efforts from the Centers for Medicare & Medicaid Services Innovation Center and state-driven initiatives, signal growing opportunity for stakeholders to engage in innovative models aimed at improving access and outcomes for patients.

Dive Deeper

Avalere applies our expertise in FDA regulatory strategy and evidence generation planning, access strategies for rare disease treatments, and strategizing impacts of Inflation Reduction Act implementation to help healthcare stakeholders meet their strategic business objectives for approval and lifecycle management. To learn more about how Avalere can help you with clinical development planning, value, and access strategies for rare and ultra-rare disease assets, connect with us.