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Commercialization Imperatives for Success in Rare Diseases


To ensure patients have timely access to expensive new therapies, biopharma companies have to address commercialization challenges with innovative measures, even after getting regulatory approval.

Biopharma companies are actively developing new therapies to treat rare diseases which are expected to either cure or provide much needed relief to patients. However, in order to ensure that patients will have timely access to these expensive new therapies, biopharma companies, even after getting regulatory approval, have to address significant commercialization challenges with innovative measures, write Subbarao Jayanthi, Frank Koos, and Melissa Morales. 

A rare disease is typically chronic, genetic, and life-threatening. In the US, a rare disease is defined as a condition that affects fewer than 200,000 people. In the EU, a disease is defined as rare when it affects fewer than 1 in 2,000 people. It is estimated that there may be as many as 7,000 rare diseases and that the total number of Americans living with a rare disease is estimated at between 25-30 million. In the US, because most rare diseases are not tracked when diagnosed, except for certain infectious diseases, birth defects, and cancers, the exact number of patients affected is hard to determine.

Even when symptomatic, diagnosis is often a challenge to both patients and physicians. Due to the small population size, lack of biomarkers and screening protocols, most rare diseases are often undiagnosed or underdiagnosed and involve multiple visits to different physicians (7 on average) and years to reach a diagnosis. Once diagnosed, up to 90% of patients will discover that their rare disease has no FDA-approved therapy. 

Since the Orphan Drug Act was passed in 1983, additional legislation including Humanitarian Use Device (HUD) Designation Program, Pediatric Device Consortia (PDC) Grant Program, as well as Orphan Products Natural History Grants Program have helped further stimulate orphan product development. Many companies have been able to access these grants, as well as qualify for incentives such as 50% tax credit for qualified R&D costs, grants for clinical testing, exemption from marketing application fees, and 7-years market exclusivity. 

Because of significant unmet need, attractive economics, and recent success in developing cell and gene therapies, many companies have been actively developing novel therapies for rare diseases. In 2018, more than half of the new medical treatments approved by the FDA were for rare diseases. However, significant challenges persist in commercializing these new orphan drugs to ensure timely market access. 

This article highlights key challenges and imperatives in commercializing rare disease drugs and commonly used approaches to address these challenges in five key areas: 1) improving diagnosing, 2) developing and optimizing treatments, 3) gaining market access, 4) optimizing supply chain systems, and 5) engaging patients. 

Commercialization challenges and commonly used approaches

1.     Improving diagnosis

The diagnosis of rare diseases is often challenging for patients and physicians. Many rare diseases are initially misdiagnosed or underdiagnosed due to a variety of reasons such as lack of protocols or appropriate biomarkers, symptoms being confused with other common illnesses, lack of awareness by patients and physicians because of scarcity of experience with the disease or simply due to newly identified diseases. Some of the most common approaches used to alleviate these diagnostic challenges include:

  • Raising patient and caretaker awareness via access to reliable information to increase their knowledge of rare diseases so they can better recognize their symptoms. This awareness should enable them to take action and seek timely medical intervention. However, note that there is neither reliable information nor appropriate biomarkers available in most rare diseases today as our scientific understanding of these diseases is still evolving. 

  • Raising physician awareness of recent advancements and genetic testing to alleviate the education deficit among physicians on the latest developments in science and technology. These advancements are leading to significant breakthroughs in our understanding of the pathophysiology of diseases and our ability to develop predictive biomarkers. Establishing patient registries and patient-powered natural history studies can inform physicians about their ongoing medical research.  For example, IAMRARE (a NORD registry) helped to uncover a correlation of increased risk of oral health problems with patients of a rare tumor of a different body system, as well as linking indications in different body systems to progression of a disease.

  • Developing and institutionalizing diagnostic testing measures (e.g. family history / genetic make-up) for rare diseases. By establishing standard protocols around diagnosing and treating the disease earlier, physicians may be able to halt disease progression before irreversible damage occurs.

2.     Development of treatments

Though significant technological advancements are taking place, developing treatments for rare diseases is still a challenge due to the small, widely dispersed patient populations (clinical trial recruitment and enrollment difficulties), disease heterogeneity (lack of validated biomarkers and established clinical trial endpoints), and limited understanding of disease progression and pathophysiology (limitations in the development of animal models). Navigating the regulatory framework for orphan drugs and pediatric indications is also not as straightforward as some general diseases maybe, but some methods manufacturers have used to address these challenges include:

  • Designing collaborative clinical trials to increase recruitment-multi-center/multi-national collaboration to acquire patients are increasingly being utilized, as well as to “add feasibility and variability to the data” and to optimize clinical trials (trial design (e.g., surrogate short-term endpoints to demonstrate efficacy) and demonstrating clinical differentiation. 

  • Collaborating with FDA around adaptive trials and determining evidence requirements for approval, as well as potential opportunities for expedited review of orphan drugs (e.g. breakthrough therapy designation, priority review, fast-track designation, accelerated approval). FDA is showing more openness to leveraging patient-reported outcomesfor regulatory approvals in some rare diseases where clinical measures are not easily understood. 

  • Collaborating with thought leaders in establishing treatment guidelines and providing support to inter-disciplinary teams involved in the care continuum in terms of how best to optimize treatment.Manufacturers are working with researchers onleveraging natural history data and biomarkersto simulate disease progression and determine appropriate surrogate markers of disease progression.

3.     Ensuring market access

Market access continues to be challenging for rare disease drugs especially given that treatments tend to be expensive and the healthcare systems are in duress. This is further compounded by the fact that there is a disconnect between the actual and perceived value of these drugs. Current healthcare systems are not designed to support curative treatments in the current environment, however, payers are showing receptivity to adopt new reimbursement models such as distributed payments and capitation payment models linked to performance outcomes. Lack of appropriate access to new treatments (e.g. Spinraza® for spinal muscular atrophy was restricted by insurers to a narrow subset, though granted a broad label by the FDA) limits choices for patients and could disrupt the much-needed access to care.  Some of the common approaches taken to mitigate market access concerns today include:

  • Consideration of payer needs earlier during clinical development. In some cases, this has allowed manufacturers to account for appropriate health economic and outcomes data into the clinical development process. This data could ultimately become part of the label and support risk-sharing and outcomes-based contracts.

  • Continuous enhancement of payer value proposition. Due to the challenging economics of orphan drugs, demonstrating health-economic rationale and cost-effectiveness to payers is an imperative to maximize product potential. To do so, manufacturers are securing market access by supplementing clinical trials with real-world evidence and outcomes where data may otherwise be limited or scarce. 

  • New reimbursement models for curative treatments. Early collaboration with payers on how to best align value and outcomes to reimbursement models is vital, as curative or expensive one-time treatments require significant upfront payments. In 2017, Spark Therapeutics entered into pay-for-performance contracts for Luxturna and tied clinical outcomes to distributed payment options. Additionally, patients need to be informed on various healthcare plan coverage choicesand any drug coverage restrictions that may impact their access to newly approved or expensive treatments.  

4.     Optimizing supply chain systems

For rare diseases, manufacturers deal with complex supply chains (e.g. distribution to a small population over wide geographic areas, meeting needs for personalized medicine, treatment at limited centers of excellence-right dose, to the right person, at the right time), issues with treatment monitoring, and trouble with patient’s medication adherence (e.g. patient noncompliance due to inconvenient, difficult-to-use products). Typical areas of focus for manufacturers to address the above supply chain system challenges include:

·       Building treatment center driven networks accounting for patient geographic concentration, where they will be treated, special handling requirements, the expected inventory management needs, and the design of the ordering process.Special emphasis is placed oncenters of excellence where interdisciplinary teams diagnose and treat patients, ensure appropriate training and development, and increase chances for successful treatment outcomes when using novel therapeutic solutions (e.g. cell and gene therapies).

·      Developing patient support systems in collaboration with specialty pharmacies or in-house call centers to address product concerns, insurance coverage, financial support and reimbursement programs (e.g. patient/provider education programs), as well as potentially collect clinical patient data to meet manufacturer’s requirements for evidence of treatment efficacy

·      Leveraging supply-chain partners with appropriate risk management controls-Given the special properties of the drug product and how they may impact labeling and storage (e.g., packaging materials, temperature control, time-sensitivity), proper distribution and storage management are some keys to avoid supply chain risks.Manufacturers will need to institute risk management programs to proactively address quality and supply chain risks.

5.     Engaging and empowering patients 

Patients with rare diseases often are part of communities supported by family members, caregivers, friends, and advocacy groups. It’s critical to engage patients / caregivers to ensure that they are aware of the condition and seek timely intervention. Studies have shown that patients who are engaged in active discussions tend to manage their condition better. Patient awareness and engagement levels tend to vary significantly across rare diseases, and manufacturers have the responsibility to support patients and connect them. Manufacturers are using a variety of patient engagement approaches such as: 

  • Empowering patients to take control of their disease via access to reliable information on treatments (via online and offline channels) and access to support systems (community organizations, social media, and advocacy groups). Some of the socio-economic challenges are being addressed via patient ecosystems developed by the advocacy groups. 

  • Improving treatment monitoring using digital tools are increasingly being used to allow patients to monitor their disease and its progression as well as enabling patient / physician connectivity.  New technologies are facilitating self / remote monitoring, which allows patients to remain compliant to treatment to realize the best outcome.  

  • Care coordination and referral systems (pre-treatment, during treatment, post-treatment) are being implemented to effectively route patients to CoEs for treatment.  For example, in the case of Amyloidosis, leading academic centers like Cleveland Clinic and Mayo Clinic have interdisciplinary teams to properly diagnose and treat this condition.  However, care coordination is inefficient in most community settings where patients could be misdiagnosed or underdiagnosed. Providing additional support in the form of personalized treatments is essential in rare diseases and supports the transition of care from pediatric to adult physicians.

Commercialization imperatives for success

The key to commercial success for any rare disease drug is contingent on how well manufacturers can address the above challenges, and position products in this continuously evolving complex healthcare environment. Some of the below foundational questions are critical to address in any commercial planning efforts to devise the best approaches to maximize product potential in rare diseases.

Subbarao Jayanthi is Managing Partner; Frank Koos is Executive Partner & Head of Business Development; and Melissa Morales is Senior Research Analyst, all at RxC International.

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