Resources for Sponsors and Investigators Involved in Rare Disease Drug Development and Families Living with Someone with a Rare Disease



A rare disease (1) is any disease that affects a small percentage of the population. More often referred to as Orphan Disease, a rare disease means there is lack of a market large enough to gain support and resources for discovering treatments for it, except by the government granting economically advantageous conditions to creating and selling such treatments, often referred to as Orphan Drugs.

  • Although each rare disease affects fewer than 200,000 Americans, in total, these diseases affect an estimated 30 million people in the United States.
  • US organization Global Genes has estimated that more than 300 million people worldwide are living with one of ~7,000 diseases defined as rare in the US.
  • There is no single cut-off number that has been agreed upon for which a disease is considered rare.
  • A disease may be rare in one part of the world or in a particular group of people, but still be common in another.
  • Most rare diseases are genetic and, thus, are present throughout the person’s entire life, even if symptoms do not appear until later in life.
  • Many rare diseases appear early in life, and about 30% of children with rare diseases will die before reaching their fifth birthday.


As part of the preparation to write this whitepaper I engaged in a number of conversations with friends, family and colleagues. It came as a surprise to me when I learned that three of the persons I spoke with informed me that they have children with different confirmed rare diseases. Additionally, I learned of two other parents that were still trying to get a diagnosis for their respective children’s illnesses. I was shocked because they had never brought this up in conversation until I approached the subject.

The Pricing Question

There is an inherent economical challenge (2) with rare diseases. Anyone involved in orphan disease drug discovery will tell you that it is a daunting effort. The challenges are enormous and include research and disease awareness. As the market is, by definition, a small one, a company developing a treatment may find it hard to cover their costs, unless they charge a high price for the drug. This in itself puts a huge burden on patients and insurers and renders the treatment practically unavailable for many who need it.

Scientific American estimated the cost of developing a new drug at $2.5 BILLION. (3) Some estimates run as high as $5.5 billion. (4) The California Biomedical Research Association states that it takes 12 years for a drug to go from research development to becoming usable by a patient. Who is going to invest in that when a rare disease is defined as having fewer than 200,000 patients?

Clinical Trials

Beyond pricing questions, there are additional challenges in clinical trials because patients are few and often geographically scattered. Clinicians are unlikely to have seen a disease before and be able to diagnose it. It may be hard to recruit enough candidates for trials, and expensive to arrange the logistics of the trial. Sometimes, he notes, a separate trial site needs to be set up just for one patient. Regulators often have to accept that smaller patient cohorts, which would not be accepted for a more common condition, are necessary in orphan drugs.

Regulators still favor endpoints that can be compared to placebo groups. But not only is there a lack of established endpoints because of fewer trials in each rare disease, placebo groups are often also seen as unethical in orphan conditions, particularly those that affect children. It may, therefore, be more appropriate to use a patient’s natural history as a comparator; but even this is difficult when we still lack information about many rare diseases.

There are usually no natural history studies, little scientific literature, and few clinicians who have the expertise. Another major factor exacerbating this is that there is often extremely low awareness of the disease, not only in the general public, but also among healthcare professionals and the health system. This means that there is often no reimbursement pathway in some countries, and it’s very hard to make the case of the necessity of a treatment when no one has even heard of the condition.

What is Being Done

Regulatory pathways, such as the EMA’s Orphan Designation, are aimed at encouraging companies to take on development of drugs for rare conditions by allowing them a period of market exclusivity. Regulators realize that for rare diseases, the risk-benefit balance should be different, because people have no existing treatment options. For example, an efficacy bar that would not justify approval for a common condition, such as diabetes, could still merit approval for a drug that addresses a rare condition with no treatment alternatives.

To spur investment in innovation, Congress approved the Orphan Drug Act in 1983 with the goal of fast-tracking approval to bypass the 12 years and $5.5 billion cost. The effectiveness of this legislation has been measurable. In 1983, only 38 orphan drugs had been approved. Since 1983, the Food and Drug Administration (FDA) has approved more than 500.

But many challenges still remain in research and market access for orphan drugs, (3) and, in fact, recent analysis from Global Data shows that the number of drugs awarded orphan drug designations (ODDs) by both the FDA and the European Medicines Agency (EMA) has declined over the last six years, despite the benefits of these designations in speeding these drugs through development.


The FDA offers sponsors numerous opportunities for interaction when developing an investigational drug for a rare disease. The FDA provides formal advice through milestone meetings (e.g., pre-IND meeting, end of phase 1 meeting). But the FDA can also provide informal support through interactions with FDA staff and offices. The FDA has a forum called Critical Path Innovation Meetings (5, 6) (CPIM) in which CDER staff and investigators from industry, academia, patient advocacy groups, and government discuss improving efficiency and success in drug development. In CPIM, CDER staff members often provide general advice on how a technology or methodology might be used to enhance drug development. CBER participates in CPIM meetings when cross-cutting issues arise that involve both centers. In addition, CBER created the Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) (7) meeting program for potential sponsors to engage with CBER staff and obtain advice on a specific topic or issue that is critical to early drug product development. The advice provided by CBER staff to a potential sponsor during an INTERACT meeting may help streamline development by, for example, helping sponsors to avoid unnecessary preclinical studies.

Families can also check resources, such as the NIH National Center for Advancing Translational Science (8) or Patients Rising (9), which was formed in 2015. It has a significant following of patients and caregivers and helps guide them on their journeys to get the care and treatments they need to live a fulfilling life.

Ayd Group Icon


1) https://en.wikipedia.org/wiki/Rare_disease

2) The biggest challenges facing rare disease pharma – and how the industry can tackle them, https://pharmaphorum.com/r-d/views-analysis-r-d/biggest-challenges-rare-disease/

3) Cost to Develop New Pharmaceutical Drug Now Exceeds $2.5B – Scientific American https://www.scientificamerican.com/article/cost-to-develop-new-pharmaceutical-drug-now-exceeds-2-5b/

4) Free market policies needed to incentivize creation of new life-saving treatments – Orange County Register (ocregister.com)

5)  https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/critical-path-innovation-meetings-cpim#:~:text=Potential%20topics%20for%20a%20CPIM%20include%2C%20but%20are,ready%20for%20the%20Clinical%20Outcome%20Assessment%20Qualification%20Program

6) Rare Diseases: Common Issues in Drug Development Guidance for Industry February 2019 Rare Diseases Revision 1da.gov/media/120091/download

7) https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-meetings

8) https://rarediseases.info.nih.gov/news

9) https://www.patientsrising.org/patient-education/

Share This