From Bench to Bedside to Practice: a Practical Course Genetic Alliance Annual Conference July 28, 2006

1. FDA Office of Orphan Products Development From Bench to Bedside to Practice: a Practical Course � Genetic Alliance Annual ConferenceJuly 28, 2006 How do We Get to Treatments? The Orphan Drug Act Incentives to Drug Development Marlene E. Haffner, M.D., M.P.H. Director, FDA Office of Orphan Products Development

2. FDA Office of Orphan Products Development To assist and encourage the identification, development, and availability of safe and effective products for people with rare diseases/disorders. The Mission of The Office of Orphan Products Development (OOPD) Since 1983, the mission of the Office of Orphan Products Development has been to facilitate the availability of products to treat and/or diagnose rare diseases and disorders. Unlike other research programs that focus primarily on science, OPD�s goal is getting products to patients.Since 1983, the mission of the Office of Orphan Products Development has been to facilitate the availability of products to treat and/or diagnose rare diseases and disorders. Unlike other research programs that focus primarily on science, OPD�s goal is getting products to patients.

3. Why is our mission important? Millions of Americans suffer from one of the approximately 6,000 identified rare diseases. The same is true in Europe. No effective treatment is available. 85% are Serious/Life Threatening. 50% are Pediatric.

4. How do we Achieve our Mission? Orphan Drug Designation Program Grants Program Humanitarian Use Device Designation Program Interacting with government agencies, medical and research communities, pharmaceutical and device industries, professional organizations, rare disease groups, and concerned citizens

5. What Are Orphan-Drug Designation Incentives? Seven-year marketing exclusivity upon FDA approval Other incentives: Tax credit equal to 50% of clinical investigation expenses Exemption of PDUFA application fees Assistance in drug development process Orphan products grant funding OOPD assistance

6. Marketing Exclusivity - Most Sought Incentive 7 years following FDA market approval FDA cannot approve same drug for same indication during exclusivity period Except with consent of sponsor If sponsor cannot provide sufficient quantities Through the Orphan Drug Act, market exclusivity is awarded to sponsors of designated orphan products when their product receives FDA marketing approval for that specific product, for that specific orphan disease indication. After approval of a sponsor�s marketing application for a designated orphan drug product for the treatment of the rare disease or condition for which orphan drug designation was granted, FDA will not approve another sponsor�s marketing application for the same drug for that indication for 7-year period from the date of approval. This then becomes a 7- year period of marketing exclusivity for the sponsor. Market exclusivity has been by far the most motivating incentive of the U.S. Orphan Drug Act. Because of the tremendous resources and expenditures necessary for drug research pharmaceutical manufacturers tend not to invest in developing drugs for which personal property protection is not assured, and which therefore will not recover costs. In a market-driven industry, 7 years� market exclusivity will entice small-medium sized firms to develop products to treat very few patients, offering a possibility for return on their investment. Through the Orphan Drug Act, market exclusivity is awarded to sponsors of designated orphan products when their product receives FDA marketing approval for that specific product, for that specific orphan disease indication. After approval of a sponsor�s marketing application for a designated orphan drug product for the treatment of the rare disease or condition for which orphan drug designation was granted, FDA will not approve another sponsor�s marketing application for the same drug for that indication for 7-year period from the date of approval. This then becomes a 7- year period of marketing exclusivity for the sponsor. Market exclusivity has been by far the most motivating incentive of the U.S. Orphan Drug Act. Because of the tremendous resources and expenditures necessary for drug research pharmaceutical manufacturers tend not to invest in developing drugs for which personal property protection is not assured, and which therefore will not recover costs. In a market-driven industry, 7 years� market exclusivity will entice small-medium sized firms to develop products to treat very few patients, offering a possibility for return on their investment.

7. Eligibility for incentives of the Orphan Drug Act = Designation Two of the criteria applied: - Prevalence < 200,000 - Rationale for use of the drug for the proposed indication.

8. The Orphan Designation Process Sponsor submits application to OOPD for specific product/specific disease indication. Designation must be received prior to New Drug Application (NDA) Does not affect timing of investigational new drug (IND).

9. Since 1983 1619 active designated orphan products 294 approved orphan products: 227 drugs 67 biologics Potentially treat 15 million patients

10. Unanticipated Positive Outcomes of the Orphan Drug Act Profitability of the product: chronicitiy of disease. Building Biotech science. Building large and small pharmaceutical firms. Support to the U.S. economy. Development of cutting-edge technology.

11. Development of �Orphan Industry� Many Small-to-Medium Sized Pharmaceutical Companies have been established to develop rare disease therapies. A large number of biotechnology firms have prospered as a result of the U.S. Orphan Drug Act. Major pharmaceutical organizations have subsidiaries devoted to the development of orphan drugs.

12. Trends in Orphan Product Development Targeted therapies Recombinant therapies Monoclonal antibody therapies Addressing the Human Genome

13. Grant Support for Investigation of Rare Disease Treatment Supports mainly early trials Primarily awarded to academic researchers FDA funds approximately 20 new grants per year Provides $200,000 to $350,000 in total costs per year -- up to 3 years Through the Orphan Drug Act, FDA provides grants to fund clinical trials of products for rare diseases or conditions -- studies that produce data acceptable to the agency that result in or substantially contribute to approval of these products. This incentive of the Act provides financial support for clinical studies to determine the safety and efficacy of products to treat rare disorders, and achieve marketing approval from the FDA under the Federal Food, Drug, and Cosmetic Act. Most orphan drugs are originally studied by academic researchers. The early-- Phase I and Phase II -- studies by these investigators provide the initial data necessary to interest commercial sponsorship for further development, and for preparation of a new drug approval application leading to market approval. FDA awards between 20 and 30 grants each year, funded through the orphan products grants program. Early clinical trials are eligible to receive $100,000 in direct costs for up to 3 years; later stage trials may receive up to $200,000 per year, also for 3 years. The products to be tested must be intended to treat conditions affecting fewer than 200,000 people in the United States. Through the Orphan Drug Act, FDA provides grants to fund clinical trials of products for rare diseases or conditions -- studies that produce data acceptable to the agency that result in or substantially contribute to approval of these products. This incentive of the Act provides financial support for clinical studies to determine the safety and efficacy of products to treat rare disorders, and achieve marketing approval from the FDA under the Federal Food, Drug, and Cosmetic Act. Most orphan drugs are originally studied by academic researchers. The early-- Phase I and Phase II -- studies by these investigators provide the initial data necessary to interest commercial sponsorship for further development, and for preparation of a new drug approval application leading to market approval. FDA awards between 20 and 30 grants each year, funded through the orphan products grants program. Early clinical trials are eligible to receive $100,000 in direct costs for up to 3 years; later stage trials may receive up to $200,000 per year, also for 3 years. The products to be tested must be intended to treat conditions affecting fewer than 200,000 people in the United States.

14. 40 Products Approved Through Research Funded By Orphan Grants Program

15. Challenges in Clinical Trial Design for Rare Diseases Getting usable clinical data early Population Size Geographic Distribution Disease Severity Informed Consent Data Anecdotal Case Reports Again, the same obstacles to orphan product development occur in trial design for orphan products clinical studies. Again, the same obstacles to orphan product development occur in trial design for orphan products clinical studies.

16. Orphan Products Must Be Just as Safe and Effective Orphan products have same review standards as non-orphans. The U.S. Orphan Drug Act did not change the legal requirements for testing and marketing drug products to be used in treating rare disease. Orphan designated products must be proven safe and effective before FDA will approve them for commercial use. They undergo the same FDA review process as any non-orphan product. Despite the uncommon occurrence of a disease, the parameters for approval of a drug to treat it must not be compromised. Therefore, there has been a need to provide sponsor assistance in order that studies may be devised that are adequately controlled to show safety and efficacy even with small numbers of patients. FDA clinical testing requirements are designed to determine the effectiveness of the drug, and its safety to patients.The U.S. Orphan Drug Act did not change the legal requirements for testing and marketing drug products to be used in treating rare disease. Orphan designated products must be proven safe and effective before FDA will approve them for commercial use. They undergo the same FDA review process as any non-orphan product. Despite the uncommon occurrence of a disease, the parameters for approval of a drug to treat it must not be compromised. Therefore, there has been a need to provide sponsor assistance in order that studies may be devised that are adequately controlled to show safety and efficacy even with small numbers of patients. FDA clinical testing requirements are designed to determine the effectiveness of the drug, and its safety to patients.

17. OPD Web Site Overview of the FDA Office of Orphan Products Development Guidelines for designation application List of designated and approved orphan products Grant application information List of ongoing orphan grant studies

18. Meet the OOPD Staff

19. Questions