There are about 7,000 rare diseases affecting 350 million people globally and 30 million in the U.S. In the past, there was a time when the patient numbers in these diseases were considered too small to justify any meaningful investment in new treatments. That scenario changed dramatically in the U.S. in 1983 with the passage of the Orphan Drug Act (ODA).

The ODA defined an “Orphan Drug” as a treatment for a disease with a prevalence of 200,000 people. It provided for special incentives for rare disease drug developers who could obtain “Orphan Drug Designation” from the FDA for their drug:

  • Seven year market exclusivity for the first sponsor
  • Tax credits of 25 percent (reduced from 50 percent in 2017) of qualified clinical research costs
  • Waiver of Prescription Drug User Fees during NDA submission to the FDA
  • Possible research grants to fund phase I-III clinical trials
  • Fast-track procedure for FDA approval – according to FDA data between 2009-2013, 60 percent (31/52) of rare disease drugs approvals, were based on a single “adequate and well-controlled (A&WC)” clinical trial plus supporting evidence, compared to 28 percent (30/107) for common disease drug approvals. Over 70 percent (75/107) of common disease drugs required two or more A&WC trials for approval

In addition, orphan drugs enjoy a five to six-fold advantage in median pricing compared to non-orphan drugs. According to EvaluatePharma®, the average annual cost per patient in 2016 for an orphan drug was $140,443 compared to $27,756 for a non-orphan drug.

The post-ODA drug approval statistics are staggering. Between 1973 and 1983 (pre-ODA), there were only 10 rare disease drug approvals. Since 1983, however, the FDA has granted over 4,500 orphan drug designations and approved over 660 orphan drugs. (Ironically, a third of these are for cancers that meet the U.S. prevalence criterion of less than 200,000 patients.) More than 560 drugs are in development for rare diseases.

The spectacular success of the ODA in the U.S. has prompted other countries to pass laws with similar, but not identical criteria for orphan designation and incentive structures. They include Singapore (1991), Japan (1993), Australia (1997) and the European Union (1999).

It has also led to perhaps unintended consequences that have resulted in putting additional pressure on patient recruitment.

Enter venture capital (VC). The marketing, financial and regulatory incentives combined with attractive pricing have created a perfect storm for investing in orphan drug companies. In 2014, VCs invested over $350 million in rare disease/orphan drug startups worldwide. Biotech startups focused on potential orphan drugs continue to find VC investments.

Several companies marketing orphan drugs have multi-billion dollar market valuations including Genzyme/Sanofi, BioMarin, Alexion, Vertex, Xoma, and Celgene.

Challenges in Patient Recruitment for Rare Diseases

The Orphanet database of rare diseases lists large numbers of diseases with single digit cases of incidence or prevalence in the U.S. According to a study reported in 2010, median disease prevalence for orphan drug designations in the U.S. is 39,000 patients. This, in a nutshell, represents the fundamental challenge for patient recruitment. We have a large number of entities, including VC-funded startups and big pharma companies, chasing a small pool of patients.

Patients with rare diseases tend to be geographically dispersed widely across the country. This, coupled with limited availability of clinical trial centers, and late or incorrect diagnosis due to a lack of well-validated diagnostic tests, is a major stumbling block for patients wanting to be study participants, and constitutes a major barrier to effective recruitment.

Adding stringent inclusion and exclusion criteria in the trial protocol could further reduce the subject patient pool due to natural biological diversity in an already small and heterogeneous patient population. (As discussed below, this may be overcome to some extent by thoughtful design of the trial protocol and endpoints.)

However, limited understanding or data on the natural history of the disease, and a lack of well-developed outcome measurements for clinical or surrogate biomarker endpoints further constrain the development of robust study protocols.

Patient Recruitment Solutions

There are two broad approaches to the issue of patient availability: (i) Increasing outreach to gain access to the limited pool of patients, and (ii) Decreasing the number of study subjects required to gain regulatory approval.

Increasing patient access has two components – scientific and organizational. On the scientific side, the key driver is improved diagnostic assays and better understanding of the pathophysiology and natural history of the disease, including potential outcome measurements, clinical endpoints and surrogate biomarkers.

On the organizational side, the remarkable commercial success of orphan drugs has led to tremendous growth of rare disease-specific foundations, patient registries and databases, advocacy groups, and other support organizations. These are logical places to start patient outreach and access programs through conventional marketing, communications, and social media.

Below is a partial list of general resources for rare diseases:

The second approach – reducing the number of study subjects required – is best achieved by devoting significant time early on to develop a better understanding of the level of evidence required. The goal is to try and limit the number of pivotal trials required and convince the FDA to live with no more than one A&WC, plus supporting evidence rather than the more conventional two A&WC. Better yet, one should develop data to support single-arm, open-label trials using historical control groups, and altogether avoid double-blinded trials. The sponsor company could then negotiate with the FDA and agree to extensive post-approval monitoring. These are best illustrated by two case studies.

Myozyme (alglucosidase alfa) – US approval in April 2006

Myozyme (alglucosidase alfa) is an enzyme replacement therapy (ERT) for Pompe disease (acid-α-glucosidase deficiency) in infants and pediatric patients, with a U.S. prevalence of 12,000 patients (1 in 28,000). U.S. approval of Myozyme was based on two international, multicenter, open-label clinical trials, which enrolled a combined 39 patients with Pompe disease.

One study enrolled 18 patients, ages seven months or less, and showed significantly improved survival (12-month mortality of 0 percent and 10 percent mortality in 20 months), compared to the historical baseline (the 12-month mortality for 61 infants born with the disease between 1982 and 2002 was 98 percent (n=6-/61). The second study, which enrolled 21 Pompe patients, ages three months to 3.5 years at first treatment, was inconclusive. Genzyme, the sponsor company, agreed to conduct several post-marketing studies.

Vimizim (elosulfase alfa) – US approval in February 2014

Vimizim (elosulfase alfa) is an ERT for the treatment of Morquio Syndrome Type A (Mucopolysaccharidosis (MPS) IVA), with a U.S. prevalence of 500-800 patients (one in 1-2 million live births). U.S. approval was based on one A&WC trial – a randomized, double-blind, placebo-controlled trial over 24 weeks, n=176 patients with MPS IVA, ages 5-57 years, randomized 1:1:1 elosulfase every week, every other week or placebo, followed by an open-label extension where all patients received elosulfase, n=173.

In spite of the ultra-rare prevalence, the disease was reasonably well understood and characterized, with the FDA determining the natural history data and biochemical pathophysiology were well-described. The sponsor company, BioMarin, also agreed to continued evaluation post-approval.

Both these cases are remarkable, for the flexibility shown by the agency in agreeing to accept historical baseline in lieu of a placebo arm in the case of Myozyme, and a single pivotal trial, A&WC, in the case of Vimizim. The key drivers here are: (i) the availability of supporting data, including natural history and pathophysiology to enable robust endpoints, and (ii) the continued post-approval monitoring.

Conducting Clinical Trials for Rare Diseases – What Does the Future Look Like?

One of the big drivers of the commercial success of orphan drugs has been the attractive price of the drugs that mitigates low patient numbers. That model will be subject to tremendous pressure in the U.S. with health care costs continuing to rise in an unsustainable trajectory. Orphan drug developers have to find ways to lower development costs.

This means running clinical trials more efficiently, with improved clinical trial designs and innovative statistical methods to achieve significance with smaller patient numbers. Trial designs could incorporate external data derived from patient or disease registries, provided the detail and quality of data available satisfy FDA requirements.

The rapid pace of technology, particularly the incorporation of big data analytics for pre-clinical and clinical data, as well as Augmented Intelligence (AI) approaches, will play a key role in accelerating knowledge of disease mechanisms, developing better diagnostics assays, and validating biomarkers and clinical endpoints.


Ramani A. Aiyer, PhD. MBA 


Shasta BioVentures



1) Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years – Nat Rev Drug Discov. 2010 Jul;9(7):519-22. doi: 10.1038/nrd3160. Epub 2010 Jun 7.

2) Utilizing Innovative Statistical Methods and Trial Designs in Rare Disease Settings