Orphan Product Development in the US
This article was originally published in SRA
Executive Summary
As the US Orphan Drug Program celebrates its 20th anniversary, Marlene Haffner and Janet Whitley review its history and examine its global reach.
As the US Orphan Drug Program celebrates its 20th anniversary, Marlene Haffner and Janet Whitley review its history and examine its global reach.
Marlene Haffner, MD, MPH, has served the FDA as Director of the Office of Orphan Products Development since 1987, and is responsible for the leadership and management of the FDA Orphan Products Development Program. She is a career Public Health Clinician and Administrator, and holds the rank of Rear Admiral in the US Public Health Service.
Janet Whitley, PhD, is a Reviewing Pharmacologist in the Office of Orphan Products Development and has been with the FDA since 1999. She reviews a variety of orphan product applications, serves as a project officer for a number of orphan grants and monitors international orphan issues.
In 1962, the Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetics Act mandated that all drugs must be demonstrated to be safe and effective by `adequate and well-controlled studies' prior to receiving marketing approval1. This condition not only raised the bar for the protection of public health, but consequently raised the cost of drug development. As a result, industry minimised the risk of drug development investment primarily by focusing on large target populations and utilising patent protection for new molecular entities. Regrettably, drugs for small disease populations became too expensive to develop and were therefore `orphaned' by the pharmaceutical industry.
Following pressure from rare disease support groups, in 1983 President Ronald Reagan signed the Orphan Drug Act (ODA ). This facilitated the development of medical products intended to diagnose or treat the approximately 5 000 rare diseases or conditions that affect over 20 million people in the US. The FDA Office of Orphan Products Development (OPD) administers the ODA and provides assistance and numerous financial incentives for development and approval of orphan products. Financial incentives for orphan product development include seven years of marketing exclusivity, New Drug Application fee waivers, tax credits for clinical research of orphan products and grant funding for the investigation of rare disease treatment.
OPD is located organisationally in the Office of the Commissioner of the FDA - not under the product review centres (Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Food Safety and Applied Nutrition, Center for Devices and Radiological Health). This is because OPD regularly works with sponsors seeking to develop products regulated by each of these centres.
Like all medical products, orphan products are reviewed and evaluated by FDA product review divisions within the review and evaluation centres. OPD serves an important role as a liaison between the product review divisions and orphan product sponsors. OPD maintains awareness of transpiring issues between the FDA and the sponsor, and carefully and objectively monitors the development of a designated orphan product. OPD provides information to the review divisions regarding disease prevalence, issues with enrolment, particulars of orphan drug regulations and institutional information regarding the design of small clinical trials. For sponsors of orphan products who may have limited regulatory experience, OPD provides clarification of the FDA's thinking and regulatory review information.
Orphan Products Grant Program
The Orphan Products Development Grant Program is the largest single source of extramural clinical grants at the FDA. OPD funding is appropriated and made available primarily for investigator-initiated clinical research of drugs, biologics, foods or devices used to treat rare diseases. Over the past 20 years, the OPD Grant Program has funded nearly 400 studies with a total of over $160 million. While the majority of these studies have involved drugs and biological products, studies of medical devices and medical foods are also funded. To date, there are 36 products available on the market, that were supported by OPD grants. Most of these products are significant because, as with many orphan products, they are most often indicated for the treatment of serious and life-threatening conditions and may be the first drug approved for pharmacotherapy for a particular disease (see Table 1).
OPD grants often bridge the critical gap between basic research and early clinical development by funding clinical trials. The goal of the Orphan Product Grant Program is to encourage clinical development of products used for rare diseases or conditions. OPD awards clinical trials $150 000 (for Phase I studies) to $300 000 (for Phase II and III studies) in direct costs for up to three years to approximately 90 currently active grants. OPD awards often go to academic investigators running Phase I and Phase II clinical studies that have not yet gained support of commercial sponsorship. Academic investigators are often involved in early clinical development since pivotal Phase III studies can be onerous to run without the sponsorship of a pharmaceutical firm. A successful Phase II study often attracts the interest of pharmaceutical sponsors that will continue the development of this drug for marketing approval.
The OPD Grant Program publishes a request for applications (RFA) annually in the Federal Register which is also posted on the orphan products website (www.fda.gov/orphan ). There are two closing dates for acceptance of new grants usually in October and April. Nearly all of the grant recipients are from academic institutions, although a few are from industry and those applications are encouraged. Grants are given an initial review for responsiveness, grouped according to disease category, then reviewed by ad hoc committees of experts from outside the FDA. Medical reviewers from the FDA review divisions are also available to provide regulatory feedback to the review committees if such questions arise, but they do not participate in scoring grant applications. All protocols must have either an Investigational New Drug (IND) or Investigational Device Exemption (IDE) unless the product under investigation is considered a medical food. Applications from foreign sponsors are accepted, provided that the protocol has a US IND/IDE.
In November 2002, theRare Diseases Orphan Product Development Act (P.L. 107-281) amended the Orphan Drug Act authorising the appropriation of $25 million of funding for orphan product grants and contracts for fiscal years 2003 through 2006. This authorisation doubles the current authorisation of approximately $12.5 million. This has brought about some confusion among the orphan community because although P.L. 107-281 authorises increased funding for grants and contracts, the amount actually appropriated to the Orphan Product Development Grant Program has remained near $12.5 million. In short, the Congress has approved a budget increase, but at this time no additional funds have been directed to the OPD Grant Program.
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Product: | Indication: |
Adagen® (pegademase bovine) | for enzyme replacement therapy for ADA deficiency in patients with severe combined immunodeficiency |
Xyrem® (sodium oxybate) | treatment of cataplexy in patients with narcolepsy |
CroFabTM (crotalid antivenin) | treatment of minimal and moderate North American Crotalidae envenomation |
Copaxone® (glatiramer acetate) | reduction of frequency of relapses in patients with relapsing-remitting multiple sclerosis |
Remicade® (infliximab) | treatment of moderate to severe Crohn's disease in patients with inadequate response to conventional therapy |
Orphan product designation review
Sponsors developing drugs and biological products to treat rare diseases may apply for orphan product designation. Qualification for orphan product designation is based on disease prevalence (less than 200 000 in the US) and a medically plausible expectation that the product (a drug or biological product) should be effective in that rare disease or condition2. OPD has designated over 1 250 drugs and biological products as orphan products; of these, 242 have been approved for marketing.
Medically plausible subset
Over the past 20 years, an issue that has been a topic of discussion and debate between OPD and applicants seeking orphan designation has been that of defining `medically plausible subsets'. This concept was introduced in the preamble to the proposed orphan product regulations in 1991 and has been discussed in numerous other publications3-5. A `medically plausible subset' is a term used by OPD to differentiate a smaller group of patients from a substantially larger patient population with a particular disease or condition. A product may be designated as an `orphan' if there is a medically plausible basis for limiting the use the product to a subset of patients. For example, it would be reasonable to limit the use of an effective product to only a subset of severely effected patients if its toxicity precluded its use in all patients affected by a particular disease or condition.
Failure to provide a medically plausible rationale for subsetting is frequently why applications for orphan designation are denied. Sponsors often divide larger disease groups into subgroups based on disease stage or response to pharmacotherapy for marketing or drug development purposes. However, unless the sponsor is able to justify why the use of a proposed orphan drug is limited to a particular subset, then OPD will request the entire affected population be included in the prevalence estimate. In many cases, this increases the prevalence estimate above the statutory threshold of 200 000.
Insufficient evidence to expect a positive therapeutic benefit
The second most common reason why applications are not approved is because the sponsor fails to provide sufficient evidence that a drug can be expected to have a positive therapeutic outcome in patients with a particular disease. While OPD prefers to see clinical evidence, pre-clinical data and occasionally strong in vitro data have been adequate to support an orphan application. In such cases, there is usually a well characterised mechanism of action with supporting evidence that the drug would be effective in treatment of the disease. When OPD declines to grant orphan designation based on pre-clinical or in vitro data, it is usually because the sponsor has not provided sufficient data to determine whether the biological activity of the product has a direct effect on the pathogenesis of the disease.
Sponsors must have a tangible product
Numerous applications arrive for review each year, that are good ideas for a medical product. Although there are many theoretical approaches to treating disease, many of which are valid, OPD only designates products, not ideas. Many of these proposed products draw directly from published scientific literature and medical journals and are based on sound science, but the actual product is not necessarily available for use in practice. In other cases a family of compounds, but no particular candidate molecule, is identified. A sponsor applying for orphan designation needs a single identifiable compound that will be further developed for marketing.
Impact of orphan drug incentives on biotechnology development
Over the past 20 years, an increasing number of biotech products have been under development or approved for orphan indications. These products include enzyme replacement therapy, monoclonal antibodies and cell, tissue and gene therapy.
Enzyme replacement therapy involves administration of purified enzyme typically produced using recombinant DNA technology to replace or augment the action of a deficient endogenous enzyme. Short of repairing the defective gene itself, enzyme replacement therapy is often the most direct treatment of disorders of metabolism and their devastating effects. Several severe and life-threatening metabolic disorders can now be treated with enzyme therapy, such as alpha-galactosidase A for the treatment of Fabry's disease, Ceredase® (alglucerase injection) for the treatment of Gaucher's disease or Adagen® (pegademase bovine) for severe combined immunodeficiency disease (SCID) associated with ADA deficiency. Although enzyme replacement therapy is not a cure for these diseases, it is a significant advance because it has allowed treatment of the disease itself rather than simply palliative treatment of disease symptoms.
There are approximately 30 therapeutic antibodies with orphan designation6. Of these, 75% are for oncologic uses. Rituxan® (rituximab), the first monoclonal antibody therapy approved in the US for the treatment of cancer, was approved as an orphan drug in 1997 for the treatment of non-Hodgkin's lymphoma. Mylotarg® (gemtuzumab zogamicin), approved in 2000 for the treatment of CD33-positive acute myeloid leukaemia, is an antibody-targeted chemotherapy that combines an antitumour antibiotic with an antibody that binds to an antigen commonly found on leukaemic cells. CroFabTM Antivenin, approved in 2000 for crotalid snake bites, was the first new entry into the US antivenin market in over 50 years. The development of CroFabTM was also supported by OPD grant funding.
The FDA's regulatory authority extends to any cell and gene therapy. While there are currently no gene therapy products approved for marketing, gene therapy attracts the attention of the rare disease community because many serious and life-threatening rare diseases are a result of a genetic defect. Orphan designations have been given to further the development of gene therapies to treat cystic fibrosis, melanoma, Gaucher's disease and haemophilia. Some advances in cell therapy have also received orphan designation, such as xenogenic hepatocytes for the treatment of severe liver failure.
ODA legislation in 1983 coincided with the founding of several biotech pharmaceutical companies who, stimulated by the incentives of the ODA, focused on the rare disease market. Genentech, Amgen and Genzyme share the distinction of having an orphan drug as their first product to receive marketing approval. These companies have continued to focus on the rare disease market by developing several pharmaceuticals with orphan drug designation. Amgen, established in 1980, has 20 orphan designations of which six are approved for marketing; Genzyme, established in 1981, has 18 designations, of which three are approved for marketing. In addition, other new firms such as Orphan Medical and Rare Disease Therapeutics specialise in the rare disease market sector.
Looking ahead: international orphan development
The past two decades have seen great strides in orphan drug development not only in the US but also worldwide. The OPD has served as a principal resource and provided significant guidance in the development of orphan drug policies and legislation in Europe, Australia and Japan. In this function, OPD has assisted in defining new orphan product policies, reviewing drafts of proposed legislation and discussing issues and progress of orphan legislation with government officials while recognising the unique needs, culture and responsibilities of these regulatory entities.
OPD continues its commitment to the international orphan community and hopes to serve as a primary source of information for the conduct of clinical trials and subsequent drug development utilising resources both in the US and abroad. In addition to assistance in policy development, OPD regularly welcomes exchange of key government personnel between the US and foreign regulatory agencies in an effort to gain mutual understanding concerning orphan product development. In such exchanges, personnel have participated fully in the review process and become well acquainted with the many aspects pertaining to the administration of the OPD Grant Program.
OPD is frequently asked for information and guidance in orphan product development in Europe, Australia and Asia. Sponsors who are developing drugs for rare diseases are often small and may lack the regulatory expertise needed to find readily the information and resources they need to conduct international trials. Improved access to foreign regulatory information and orphan drug policies has significant benefits for patients and manufacturers alike. Not only would patients and healthcare providers have improved access to, and participation in, clinical trials and other research projects, but sponsors of small clinical trials would have access to a larger patient population. The potential market for these products is likely to reflect the results of such regulatory exchange.
Additionally, clinical trials in small populations are fraught with difficulties, the most pervasive of which is patient recruitment. Expanding to multinational trials obviously increases the patient recruitment pool and therefore such trials are a necessity for adequately powered studies to support drug approval. This is particularly the case with clinical trials in diseases that are rare in the US but are more common abroad such as hepatocarcinoma, which is much more prevalent in Asia than in the US and Europe. Moreover, more than 20 orphan drugs have been approved that affect diseases that predominately occur outside the US including clofazimine for leprosy, halofantrine and mefloquine for malaria and rifampin for tuberculosis7.
While the primary focus of OPD both past and present is on drug development in the US, OPD seeks to continue and strengthen its activity in the global community in order to encourage the development of new products for patients with rare diseases. This may be through encouraging the use of orphan product incentives (including grants) and continuing to build a strong international orphan community. Ultimately these activities have an overall net benefit for all those in the orphan community: improved diagnosis and detection of rare diseases and conditions; improved availability of patient services and information on rare diseases and conditions; and increased patient and health care provider access to, and participation in, clinical trials and other research projects on rare diseases.
References
1. Section 505(d), Federal Food, Drug, and Cosmetic Act, as amended by the Kefauver-Harris Amendments, 10 October 1962
2. 21 CFR 316.25
3.Federal Register, 29 January 1991, 56 (19), 3338
4. ME Haffner, Orphan Products - Ten years later and then some, Food and Drug Law Journal, 1994, 49 (4) 593-601
5. ML Butler, KR Karst, Orphan Drugs: subsetting and sameness, December 2001, www.currentdrugdiscovery.com
6. FDA, List of Orphan Designations and Approvals, www.fda.gov/orphan/designat/list.htm
7. Milne, CP, Orphan Drugs: trends, market forces, and future directions, SPECTRUM Pharmaceutical Industry Dynamics, Decision Resources, Inc., 22 June 2001