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The Office of Orphan Products Development (OOPD) located in the Office of the Commissioner, Food and Drug Administration (FDA), administers the orphan products development program. This program is essentially involved in the identification of orphan products and the facilitation of their development. Although the OOPD Grants Program has been expanded to include clinical studies for medical foods and devices that meet the "orphan" criteria established by Congress, the Orphan Drug Act pertains primarily to drug and biological products.
This introduction will provide a general overview of the organization and operation of the orphan products program at FDA. For further guidance and direction, additional and more specific information is available on the topics covered here.
Congressional Action
The Orphan Drug Act (P.L. 97-414) amended the Federal Food, Drug and Cosmetic Act (FFDCA) as of January 4, 1983. Additional orphan drug amendments were passed by Congress in 1984, 1985 and 1988 The use of the term "orphan", as in "orphan drug", "orphan" disease, etc., does not actually appear in the text of the law which focuses upon definitions of and treatments for "rare diseases and conditions".
The 1983 Orphan Drug Act guarantees the developer of an orphan product seven years of market exclusivity following the approval of the product by the FDA. As a result of the Orphan Drug Act, the following procedures are administered by the Office of Orphan Products Development:
The original definition of "rare disease or condition" in the Orphan Drug Act was amended in October 1984 by P.L. 98-551 to add a numeric prevalence threshold to the definition:
"...the term rare disease or condition means any disease or condition which (a) affects less than 200,000 persons in the U.S. or (b) affects more than 200,000 persons in the U.S. but for which 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."
Prior to this revision of the Orphan Drug Act, every sponsor was required to provide financial information regardless of the size of the proposed target patient population. A product may still be designated as an orphan by demonstrating that the financial criteria of the law are applicable, regardless of the number of patients affected.
P.L. 100-290 amended the Orphan Drug Act on April 18, 1988, and requires that the application for designation be made prior to the submission of an application for marketing approval, New Drug Application (NDA) or Product License Application (PLA). Prior to this amendment, the designation request could be filed at any time prior to FDA's approval to market the product.
Section 1205 of P.L. 104-188 reinstated the tax credits for clinical testing expenses of orphan drugs for the period July 1, 1996 to May 31, 1997 and allows these credits to be carried forward/back like some other business tax credits.
The Orphan Drug Final Regulations were published in the Federal Register on December 29, 1992, and became effective thirty days thereafter.
In order for a sponsor to obtain orphan designation for a drug or biological product, an application must be submitted to OOPD, and the designation approved. The approval of an application for orphan designation is based upon the information submitted by the sponsor. A drug that has obtained orphan designation is said to have "orphan status." Each designation request must stand on its own merit. Sponsors requesting designation of the same drug for the same indication as a previously designated product must submit their own data in support of their designation request. The approval of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval. Safety and efficacy of a compound must be established through adequate and well-controlled studies.
Incentives of the Orphan Drug Act
The Orphan Drug Act (P.L. 97-414, as amended) includes various incentives that have stimulated a considerable amount of interest in the development of orphan drug and biological products. These incentives include tax credits for clinical research undertaken by a sponsor to generate required data for marketing approval, and seven years of marketing exclusivity for a designated drug or biological product approved by the FDA.
Section 527 of the Orphan Drug Act provides a seven-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan drug or biological product. Exclusivity begins on the date that the marketing application is approved by FDA for the designated orphan drug, and applies only to the indication for which the drug has been designated and approved. A second application for the same drug for a different use could be approved by FDA.
Final regulations on the tax credits were published in the Federal Register on October 3, 1988 (53 FR 38708), and the current version of these regulations are in Title 26, Code of Federal Regulations, Section 45c. The Internal Revenue Service administers the tax credit provisions, and specific questions about the interpretation of the law or regulations affecting the applicability of the tax credit provision of the Act should be directed to IRS. If more information on tax credits is needed, contact Pass Through and Special Industries Division, Office of the Chief Counsel, Internal Revenue Service, 1111 Constitution Avenue, NW, Washington, DC 20224; telephone is (202) 622-3120.
Protocol Assistance
Section 525 of the Orphan Drug Act provides for formal protocol assistance when requested by the sponsors of drugs for rare diseases or conditions. The formal review of a request for protocol assistance is the direct responsibility of the Center for Drug Evaluation and Research (CDER) or the Center for Biologic Evaluation and Research (CBER), depending on which Center has authority for review of the product. The Office of Orphan Products Development (OOPD) is responsible for insuring that the request qualifies for consideration under section 525 of the FFDCA. This includes determining "whether there is reason to believe the sponsor's drug is a drug for a disease or condition that is rare in the United States." A sponsor need not have obtained orphan drug designation to receive protocol assistance.
Once OOPD determines that the proposed compound is for a disease or condition that is rare in the U.S., the request will be forwarded to the responsible reviewing division for formal review and direct response. OOPD monitors the review process within the respective CDER/CBER reviewing division and, where possible, assists in resolving specific issues that may arise during the review process. It should be understood that protocol assistance provided under the Act does not waive the necessity for the submission of an Investigational New Drug Application (IND) by sponsors planning to conduct clinical trials with the product.
The FDA, through OOPD, funds the development of orphan products through its grants program for clinical studies. The Request for Applications (RFA) announcing availability of funds is published in the Federal Register each year - usually in June. Eligibility for grant funding is extended to medical devices and medical foods for which there is no reasonable expectation of development without such assistance. Applications are reviewed by panels of outside experts and are funded by priority score.