Clinical research for rare disease: Opportunities, challenges, and solutions

https://doi.org/10.1016/j.ymgme.2008.10.003Get rights and content

Abstract

Over 7000 rare diseases, each <200,000 US residents, affect nearly 30 million people in the United States. Furthermore, for the 10% of people with a rare disease and for their families, these disorders no longer seem rare. Molecular genetics have characterized the cause of many rare diseases and provide unprecedented opportunities for identifying patients, determining phenotypes, and devising treatments to prevent, stabilize, or improve each disease. Rare disease research poses challenges to investigators requiring specific approaches to: (1) the design of clinical studies; (2) the funding of research programs; (3) the discovery, testing, and approval of new treatments, and (4) the training of clinical scientists. Rigorous, statistically-valid, natural history-controlled, cross-over, and n-of-1 trials can establish efficacy and support regulatory approval of new treatments for rare diseases. The U.S. Orphan Drug Act of the U.S. FDA has stimulated industry investment in clinical trials to develop treatments for rare diseases. For trainees interested in finding a treatment for a rare disease, a commitment to longitudinal care of patients provides a base for the characterization of phenotype and natural history, a stimulus for innovation, a target population for research and helps fund training and research. The scientific methodology, financial resources, and logistics of clinical research for rare diseases have changed dramatically in the past two decades resulting in increased understanding of the pathophysiology of these disorders and direct benefit to patients.

Introduction

The clinical presentation, natural history, pathophysiology, and often mysterious nature of rare diseases have fascinated physicians for centuries. Rare diseases provide opportunities to study human physiology and biomedical science from unique perspectives. Major scientific breakthroughs resulting from investigation of rare diseases have often provided insight into more common disorders. The satisfaction of diagnosing a patient with a rare disorder successfully is often rapidly countered by the realization that the ability to understand and treat the patient’s condition is limited by ignorance and the difficulties of studying the disease. Moreover, for the “interesting” patient with a rare disease, being a “fascinoma” to physicians may intensify suffering. Patients may feel that their physicians are in league with the “interesting” disease. Furthermore, for patients with a rare disorder, the disease is no longer rare—it is a constant part their lives and the life of their families.

There are several definitions of “rare” or “orphan” diseases and these definitions may differ among countries. Common to all definitions is the low prevalence of a disease and the perception that treatments and research related to a specific disease are inadequate. In 1983 the United States (U.S.) Congress passed the “Orphan Drug Act” (since amended several times). This landmark act instructs the U.S. Food and Drug Administration to label a disease as “rare” if it has a prevalence of <200,000 persons in the U.S. Using this definition, it is estimated that over 7000 rare diseases affect an estimated 25–30 million people with a rare disease in the U.S. (8–12% of population). The Orphan Drug Act also designates diseases as “rare” if they affect more than 200,000 persons in the U.S. if “…there is no reasonable expectation that the cost of developing and making available in the U.S. a drug for such disease or condition will be recovered from sales in the U.S. of such drug” [1].

The awareness of rare diseases by the general public has grown over the last three decades. This increased awareness is the result of changes in society including: the marked expansion in the size, number, and influence of patient advocacy groups focused on a specific rare disease; groups promoting awareness of rare diseases in general (e.g. the National Organization for Rare Disorders [2]; the ability of the internet to allow patient groups to organize and educate and reach millions of people world-wide inexpensively; the growing interest by mainstream media in human interest stories about people, especially celebrities, with rare diseases; increased government attention to, and funding of, rare disease research and targeted drug development; and academic medical institutions’ support of specialized centers organized to treat patients with rare diseases and conduct research on these disorders. This paper reviews important issues facing clinical investigators studying or training to study rare diseases.

Section snippets

Pursuing a career in rare disease research

Once interested and engaged in research into a rare disease, an investigator faces a number of opportunities and challenges. The scientific and career opportunities for researchers specializing in rare diseases are excellent. Unanswered questions about the pathophysiology of many rare diseases have the potential to make possible a major impact on a clinically and scientifically underserved population. The advances and availability of powerful tools for studying genetics has been of particular

Orphan-drug designation program

The Orphan Drug Act (Public Law 97-414) was enacted in 1983 to provide sponsors incentives to develop promising drugs to treat, prevent, or diagnose rare diseases or conditions affecting less than 200,000 persons in the United States (US). These incentives include: protocol assistance (written recommendations from the US Food and Drug Administration (FDA) on the preclinical and clinical studies necessary for marketing approval); tax credits equal to 50 percent of the qualified clinical testing

Humanitarian use device designation program

The Safe Medical Devices Act of 1990 (Public Law 101-629) authorizes the FDA to exempt makers of medical devices developed for the diagnosis or treatment of diseases or conditions affecting a relatively small number of people in the US from the requirements to show effectiveness prior to marketing approval. This provision is also known as the humanitarian device exemption (HDE). As a prerequisite to HDE approval, the sponsor must submit to OOPD a request for humanitarian use device (HUD)

Orphan product development grants

The aim of the orphan product development (OPD) grant program is to assist sponsors in defraying the costs of clinical trial expenses incurred in the development of drugs, medical devices, and medical foods for rare diseases and conditions [8]. The program has an annual budget of approximately $14 million. Domestic or foreign, public or private, non-profit or for-profit entities (excluding those engaging in lobbying activities), state and local units of government, and non-HHS federal agencies

Academic partnerships with industry for orphan diseases

Probably the first question an academician interested in orphan disease should ask before dealing with a biotechnology or pharmaceutical company is “why should a biopharmaceutical company be interested in a rare disease?” The answer relates to some of the history of orphan diseases. The Orphan Drug Act gave financial incentives for companies to consider working in the rare disease field. There was also the incentive of ‘less competition’ and the more likely probability to demonstrate ‘proof of

Working with patient advocacy groups for rare diseases

Patients with rare diseases often form advocacy groups as a way of sharing information and encouragement, supporting research, and helping patients and their families obtain needed services. These groups have played an important role in the history of the orphan product movement and they continue to provide substantial support to rare disease researchers today. Patient advocacy groups often help with patient recruitment, research funding, administration of patient assistance programs, and

Clinical trial design

Trial designs for rare diseases must meet the same rigorous standards as those for trials for more prevalent diseases [11]. They must ask important scientific questions, minimize bias and have appropriate likelihood of achieving a scientifically acceptable answer. Indeed, designs for rare diseases are equally applicable to any other category of diseases. However, many different types of study designs exist, some of which require only a fraction of the number of subjects required to conduct a

IRB and HIPAA issues regarding research in rare diseases

Navigating the requirements of domestic Institutional Review Boards (IRB’s), international ethics boards, and the U.S. Health Insurance Portability and Accountability Act (HIPAA) regulations are daunting for both new and experienced investigators in rare disease as the complexity of adherence to HIPAA regulations is amplified when conducting clinical trials in rare diseases. An understanding of the fundamentals of human subjects protection regulations relevant to clinical research and the role

Research training for rare disease research

Research training strategies, including curricula and mentoring requirements for clinical investigators in rare diseases do not necessarily differ from those employed for other clinical research. However, the absolute requirement that training prepares the investigator for the challenging task of supporting a research program mandates distinct considerations for rare disease research (Table 3). It could be argued that those interested in a rare disease should consider the option of studying

Conclusion

The scientific methodology, financial resources, and logistics of clinical research for rare diseases have changed dramatically in the past two decades with these changes resulting in substantially increased understanding of the pathophysiology of these disorders, many new treatments, and direct benefit to patients with many of these diseases. There are many other resources which can be brought to bear on rare disease research (Web Table 1). Although challenges specific to studying rare

Acknowledgments

R13 RR024337 Merkel, Peter A., Boston University, Boston, MA.

U54 NS059065 Griggs, Robert C., University of Rochester, Rochester, NY.

U54 RR019497 Merkel, Peter, Boston University, Boston, MA.

U54-RR019453 Batshaw, Mark, National Children’s Hospital, Washington, DC.

U54-RR019478 Beaudet, Arthur, Baylor College of Medicine, Houston, TX.

U54-RR019480 Knowles, Michael, University of North Carolina, Chapel Hill, NC.

U54-RR019397 Maciejewski, Jaroslaw, Cleveland Clinic College of Medicine-CWRU, Cleveland,

References (28)

  • H. Sacks et al.

    Randomized versus historical controls for clinical trials

    Am. J. Med.

    (1982)
  • Orphan Drug Act, Pub. L. No 97-414, 96 Stat. 2049 (1984 as...
  • Available from:...
  • The tax provisions are administered by the Internal Revenue Service (see Title 26, Code of Federal Regulations, Section...
  • See Title 21, Code of Federal Regulations, Part...
  • J. Mitsumoto, E.R. Dorsey, J. Thompson, R.C. Griggs, Impact of the Orphan Drug Act on Drug Development. Presented at...
  • Available from:...
  • See Title 21, Code of Federal Regulations, Parts 20 and...
  • Available from:...
  • E.M. Shore et al.

    A recurrent mutation in the BMT type 1 receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

    Nat. Genetics

    (2006)
  • Available from:...
  • L.J. Appel

    A premier on the design, conduct, and interpretation of clinical trials

    Clin. J. Am. Soc. Nephrol.

    (2006)
  • B. Wilcken

    Rare diseases and the assessment of intervention: what sorts of clinical trials can we use?

    J. Inherit. Metab. Dis.

    (2001)
  • S.J. Edwards et al.

    Why underpowered trials are not necessarily unethical

    Lancet

    (1997)
  • Cited by (288)

    • Uncovering key clinical trial features influencing recruitment

      2023, Journal of Clinical and Translational Science
    View all citing articles on Scopus
    View full text