An orphan drug is a product intended for the treatment, diagnosis, or prevention of a rare disease. A rare disease also affects fewer than 200,000 people in the United States.
Although orphan drugs treat only a small number of patients, orphan drug development shows a large return on investment for potential Sponsors. For instance, companies researching solutions for rare diseases have little competition from branded and generic alternatives. Companies also have the opportunity to carve out a specialized orphan market that no other company is actively pursuing. In addition, the FDA offers a fast-tracked regulatory review process and lower-cost late-stage development to aid in the development of orphan drugs because they treat serious or life-threatening conditions.
To reduce challenges associated with orphan drug development and improve the patient experience, Sponsors should take a patient centric approach to clinical trials. Shifting a trial design to a patient centric approach for rare disease trials does not require an overhaul of current trial standards. However, it does mean that researchers must change their focus to see the trial through the eyes of patients and caregivers. Sponsors can reduce risk and increase effectiveness of orphan drug clinical trials as a result of making these changes in the study design.
History – The U.S. Orphan Drug Act
From 1967 to 1983, only 34 drugs were approved by the FDA to qualify as orphan drugs. The FDA recognized the lack of incentive for
pharmaceutical companies to develop cures for rare diseases. As a result, the FDA established the Office of Orphan Product Development (OOPD) in 1982. In addition, Congress passed the Orphan Drug Act with financial incentives for companies developing products for rare diseases in 1983. The three primary incentives that the Orphan Drug Act gives manufacturers are:
- Federal funding of grants and contracts to perform clinical trials of orphan products
- A tax credit of 50% of clinical testing costs
- An exclusive right to market the orphan drug for seven years from the date of marketing approval. This allows for greater discretion in pricing.
Other benefits for Sponsors for orphan-designated products include:
- Close coordination with the FDA throughout the drug’s development
- Priority FDA review
- A waiver of drug application fees
As a result, the OOPD assigned a total of 2,112 orphan drug designations and the FDA approved 347 between 1983 and 2009. The Orphan Drug Act has played a major role in the development of certain rare disease products that may have never made it to market without the OOPD. For example, an effective treatment for infant botulism (a rare neurological disease affecting approximately 100 children in the United States annually), was developed because of the California Department of Health Services and OOPD grants, and was also in close coordination with the FDA.
Today, as a result of the implementation of the OOPD, more than 575 orphan drugs have been successfully developed and marketed. Worldwide sales of these drugs are predicted to reach $176 billion by the end of 2020.
Logistical Challenges of Orphan Drug Development
As orphan drug development expands, clinical trials are becoming more complex and expensive. For instance, the average cost of moving one orphan drug to market can cost $350 million. Clinical trials account for a large percentage of the overall price. In addition, a drug typically takes 10 to 15 years to make it to market.
When designing an orphan drug trial, Sponsors may have difficulty finding historical disease information such as disease prevalence and examples of treatment patterns. Developing a study protocol without this information can be challenging. In addition, for many rare diseases no standard clinical trial designs or study outcomes exist. This makes it difficult to select endpoints, outcome measures, tools, and biomarkers. The lifelong nature of a rare disease also makes it difficult to determine appropriate study durations.
The potential patient population of a study is limited since rare diseases affect a small number of individuals. This is because small patient populations decrease study variation. In addition, the genetic basis or associated comorbidities of many rare diseases can be confounding factors in study predictability. Also, potential clinical trial patients, investigators, and clinical centers are rare and located around the world. So, finding individuals to participate in a study can be time consuming and require high travel costs.
In addition, rare diseases are frequently discovered at birth or during childhood. For ethical reasons it is considered appropriate for drugs to be tested in adults before in children. Therefore, pediatric studies require Sponsors to carefully balance the ethical considerations of conducting studies in a vulnerable population with concerns about site selection, recruitment, compliance, and statistical powering.
Patient Centricity as a Solution for Orphan Drug Trials
To best meet the needs of the scientific, and regulatory communities, Sponsors must employ new approaches to accelerate the research process and also encourage more interest from Sponsors to explore cures for rare diseases.
Since historical research on rare diseases is typically sparse, investigators can look to patients, patient advocacy groups, and families as the thought leaders on their disease. These individuals and groups can identify the clinical outcomes that are most meaningful to a small subset of individuals with highly specialized needs. 
Research and Development – Patients can provide input on identifying health research priorities and participate in the design and undertaking of research projects. For instance, one study on patient involvement in orphan drug trials found that patients prefer equal collaboration with researchers. This is because researchers are guided towards designing more relevant trials with useful outcome measures. Patient experience and input can be especially beneficial when:
- Setting the research agenda
- Promoting collaborative research networks
- Initiating studies
- Providing financial support for research infrastructures
Research and development organizations or departments should engage with patient associations and families that have a special interest in, and experience with, rare diseases. As a result, researchers gain a greater understanding of the natural history of the disease and the potential therapeutic impacts that would be most meaningful for patients to find relevant trial patients and produce accurate outcomes. Researchers can also conduct qualitative research studies on the internet habits of these groups provide insights into what a patient population will need from a clinical trial. Additionally, advocacy groups can provide feedback on the appropriateness of a trial’s protocol and help drug developers reach patient populations. Sponsors must use these varieties of communication methods to embrace patient centricity and focus on the quality of life for potential patients.
Clinical Development – Patient involvement in clinical development may contribute to the successful delivery of trials because of the increased likelihood of recruitment and retention. Some companies investigating orphan drugs involve patients at all stages of clinical development, from providing input into study protocol, the selection of endpoints, to the dissemination and implementation of findings. Since they often have advanced networks, patients can help to enhance communication about research participation opportunities. In addition, patients can disseminate trial-related findings in a manner that is most meaningful to other patients.
Also, consideration of acceptable physical burden, treatment durations, and travel requirements is necessary when looking towards optimal recruitment and retention. Rare diseases affect individuals on a global level and many patients are children so caregivers and parents must be accounted for when evaluating travel time and costs. In addition, implementing trial centers across several countries may enable higher levels of participation. An alternative to traditional trial design is the idea of in-home clinical services, where the majority of simple clinical procedures (treatment administration, blood draws, and health monitoring) are administered by trial professionals at home. Therefore, travel to designated trial sites is reduced as is the disruption to the life of the patient and their family.
Approval and Market Access – The FDA has introduced a Patient Engagement Advisory Committee to facilitate patient involvement in the regulatory process. Companies also collaborate with patient advocates to demonstrate the burden of the disease, add it to the policy agenda, and help to incorporate the benefit-risk preferences into a structured evaluation process.
Educating a small but dispersed market is essential for market success. As a result, disseminating knowledge and awareness amongst physicians, patients, and payers is necessary for orphan drug advocacy. One way to approach drug education is by leveraging clinical programs to establish an active and engaged treatment community. Consequently, this aids in rapid product uptake because the clinical program may have already identified a high proportion of available patients. Sponsoring patient registries can also enhance disease understanding during development and enable tracking of patient progress post product launch. Since education is critical for successful market access for orphan drugs, targeted communications are also more effective than traditional, large-scale sales forces. Target audience assessments are less complex for orphan drugs than non-orphan drugs because the patient population is less diverse. With fewer disease experts, micro-targeting and micro-messaging personalized to individual needs is feasible and therefore yields favorable results.
While orphan drug clinical trials may require customized patient centric design, these trials have the potential to produce effective outcomes for patients and Sponsors alike. Furthermore, with regulatory support, financial incentives, and effective study design and management, orphan drug trials can be a valuable to any Sponsor’s clinical trial landscape.