There are about 7,000 rare diseases affecting 350 million people globally and 30 million in the U.S. There was a time was when 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. with the passage of the Orphan Drug Act (ODA) in 1983.

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).

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In an earlier article, we discussed the challenges of patient recruitment for rare diseases, and two case studies on an approach based on reducing the number of study subjects required for USFDA drug approval.

In this concluding article, we elaborate further on decreasing patient size requirements and discuss patient recruitment issues related to improving outreach.

Scientific Drivers Improved Implementation of Diagnostic Tests

Recently, Global Genes published the results of a survey that found for patients with a rare disease, the mean length of time from symptom onset to accurate diagnosis was 4.8 years (range: 0-20 years). Forty-four percent of patients felt that a slow diagnosis caused delayed treatment and had a negative impact on their condition.

A survey published by Invitae at the March 2016 Annual Clinical Genetics Meeting, highlighted the tremendous obstacles faced by patients and clinicians in obtaining a diagnosis for a rare disease. On average, the diagnostic “journey” (or “ordeal,” more likely) took 3.9 years. This was further compounded by incorrect diagnoses leading to unnecessary payments for ineffective treatments (39 percent of patients). Patients reported going through seven diagnostic tests, while clinicians reported an average of 14 tests. A lack of a proper diagnosis for rare disease patients hinders a clinician’s ability to provide effective care, as indicated by approximately 67 percent of clinicians.

The importance (or the lack thereof) of accurate and timely diagnostic tests for rare diseases cannot be overstated. The single biggest obstacle for patients getting these tests was a lack of information (79 percent) followed by inadequate insurance coverage (23 percent). A lack of sufficient information was also echoed by clinicians with respect to genetic testing (54 percent), particularly with respect to cost of testing (49 percent) and indications (31 percent). This was a surprising finding, given the almost universal availability of information sources, particularly the internet and social media.

These findings suggest that sponsors, CROs and advocacy groups in the rare disease space would be better served by deploying significant resources in three areas with respect to diagnostic tests/procedures:

  • Education – for both physicians and patients
  • Accessibility – working with researchers and the regulatory agencies to enable faster implementation of current and new tests/procedures across communities and institutions
  • Affordability – working with payers, providers and charitable organizations to reduce financial burden

Meanwhile, academia and industry should continue to focus on developing improved testing methodologies and technologies.

Scientific Drivers Improved Understanding of the Pathophysiology and Natural History of the Disease

The U.S. FDA has indicated a strong willingness to be flexible in the application of regulatory standards when it comes to approval of rare disease drugs by offering various programs for expedited drug development. They are:

  • Fast Track Designation – FDAMA 1997/FDASIA 2012
  • Breakthrough Therapy Designation – FD&C Act/FDASIA 2012
  • Priority Review – PDUFA 1992
  • Accelerated Approval – 21CFR314 subpart H, 601 subpart E/FDASIA 2012

Typically, traditional development approaches are defined as a minimum of two Adequate and Well-Controlled (AWC) studies, using endpoints with prior precedents. However, expedited development approvals allow approaches supported by less than two AWC studies and use of a novel endpoint. Data on New Molecular Entity (NME) approvals, between 2008 and 2016, by the FDA’s Center for Drug Evaluation and Research (CDER) indicated that 86 percent of rare disease drugs (n=109) were approved on the basis of an expedited program, compared to 35 percent of non-rare disease drugs (n=193).

The key take-home here is not that the FDA has compromised on the standard of demonstrating substantial evidence of effectiveness. In fact, the FDA may accept other compelling evidence, such as the natural history of the disease in lieu of traditional clinical endpoints.

Speaking of surrogate endpoints, these are markers that are indirect measures of clinical benefit, considered to be reasonably likely to predict clinical benefit. A clinical endpoint, on the other hand, is a direct measure of the therapeutic effect on a patient through objective or subjective measures (e.g. blood pressure, pain, survival, etc.). Fast approval based on surrogate endpoints generally requires a post-approval confirmatory study to demonstrate the direct clinical benefit.

Desirable surrogate endpoints are typically measured sooner, more easily, less invasively, or less expensively. Most surrogate endpoints are biomarkers or composite endpoints involving biomarkers. Among other criteria, predictability of clinical outcome, particularly if linked to cause and effect in a disease pathway, is a key hallmark of a good surrogate. For example, in cardiovascular disease, the level of Low Density Lipoprotein (LDL) is an accepted surrogate, whereas there is insufficient evidence to accept High Density Lipoprotein (HDL).

More recently, in a Phase IIb trial testing lenabasum as a therapy for cystic fibrosis, the FDA has accepted, as a primary endpoint, the event rate of pulmonary exacerbations as a surrogate compared to the gold standard of forced expiratory volume in one second (FEV1) to measure of lung function.

Operational DriversRare Disease Patient Registries and Databases

Rare disease-specific foundations, patient registries and databases, patient advocacy groups, and other support organizations are logical places to start patient outreach and access programs through conventional marketing, communications, and social media.

At a more granular level, patient registries and databases offer a valuable source of patient information and opportunities to recruit for clinical trials. They offer a singular access to a small cohort that is more than likely dispersed very widely across many jurisdictions. They are also a place where a great deal of information may be disseminated and exchanged.

This could be general disease information, patient histories, diagnostic tests / procedures, natural history of the disease, support groups, and so on and so forth. This is the one place where the principle of “patient-centricity” may be truly applied. Provided, of course, sponsors and CROs approach them as a sacred trust, with a great deal of respect, sensitivity to privacy concerns, and with an understanding of the high level of frustration these patients, particularly children and parents, would have suffered through.

This concludes the second and final article in this series.

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

Conducting CTs for Rare Diseases – Patient Recruitment & Retention

Conducting CTs for Rare Diseases – Internet Resources


Global Genes –

Invitae –

Stephanie Gandomi et al. “Rare Disease Diagnosis Obstacles: Patient Perspectives and Physician Findings.” 2016 ACMG Annual Clinical Genetics Meeting,

*BEST (Biomarkers, Endpoints, and other Tools) glossary: