1. Regulatory Requirements for Orphan Drugs Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Professor of Pharmaceutics KLE University, Belgaum, India E-MAIL: bknanjwade@yahoo.co.inbknanjwade@yahoo.co.in Cell No: 00919742431000

2. What is an Orphan Drug?  A drug to test a rare disease or condition affecting <200,000 people in the U.S.  A vaccine, a preventive drug, or a diagnostic drug to be administered to <200,000 persons per year  A drug with no expected profitability within years even if prevalence > 200,000 people in the U.S. 02/03/20102BIOBIO-2010, Hyderabad

3. Orphan Drug Act Incentives  Marketing Exclusivity-7 years  Tax Credits-50% of Clinical Investigations Expenses  Exemption from PDUFA Application Fees  Protocol Assistance in Drug Development Process 02/03/20103BIOBIO-2010, Hyderabad

4. Orphan Drug Act Incentives  Grant Support-Medical Foods and Medical Services also  Open Protocols to increase drug availability for patients  Establish DHHS orphan products board 02/03/20104BIOBIO-2010, Hyderabad

5. Orphan Drugs  Among orphan drugs, 15-20% are for diseases only affecting children, 55% for diseases affecting both adult and children  Orphan drugs receive 10 years of market exclusivity in EU  Orphan drugs must submit a Pediatric investigation plan  Orphan drugs can get 2 additional years of exclusivity when they comply with PIP 02/03/20105BIOBIO-2010, Hyderabad

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7. Paediatric Investigation Plan (PIP)  Paediatric investigation plan proposed by company  By end of phase 1 for new products  Plan is discussed, modified, and agreed/refused by paediatric committee  Followed by EMEA decision  Binding on company 02/03/20107BIOBIO-2010, Hyderabad

8. Paediatric Investigation Plans  Define necessary data on Quality, Safety and Efficacy for use in the paediatric population (0 – 18 years)  No explicit link with adult indication  Specify development timelines, including deferral of studies  Define age-appropriate formulation  Results according to agreed plan serves as basis for approval 02/03/20108BIOBIO-2010, Hyderabad

9. PIP Waivers/Deferrals On request from applicant or initiative of Paediatric Committee, for all or part of the paediatric population:  Waiver of development for ‘classes’ of indications, or for a specific product  Deferral of initiation of studies and/or completion Development is most often a combination of a plan with deferrals and waivers (population subset) 02/03/20109BIOBIO-2010, Hyderabad

10. Life cycle of a Paediatric Investigation Plan 1 Phase 1Phase 2Phase 3Post Approval Modifications MAPIP Compliance Paediatric Committee Non-clin 02/03/201010BIOBIO-2010, Hyderabad

11. Life cycle of a Paediatric Investigation Plan 1 Non-clinPhase 1Phase 2Phase 3 Compliance Modifications MA PIP With deferral Paediatric Committee Post Approval 02/03/201011BIOBIO-2010, Hyderabad

12. Applications and Indications  Each PIP corresponds to an active substance (or a combination) from a company  Each PIP usually covers more than one indication (e.g. high grade glioma and neuroblastoma) 02/03/201012BIOBIO-2010, Hyderabad

13. PIP Therapeutic areas (%) -CNS 6 -Cardiovascular 10 -Oncology 14 -Anti-infectives 10 -Endocrinology/metabolism 21 -Immunology/vaccines 11 -Other 28 02/03/201013BIOBIO-2010, Hyderabad

14. Tips for Applying for Orphan Product Designation 1.The required information to be included in the application is found under 21 CFR 316.20(b), shown as (9) items. -Number the items in your application 1 though 9 and respond to the nine items as described. -Creative numbering is not helpful 02/03/201014BIOBIO-2010, Hyderabad

15. Tips for Applying for Orphan Product Designation 2. While all nine items will be reviewed, the application will be reviewed most critically in two areas: scientific rationale (Item 4) and population prevalence (Item 8). -Do not confuse prevalence with incidence -They are different entities and can’t be substituted for one another 02/03/201015BIOBIO-2010, Hyderabad

16. Tips for Applying for Orphan Product Designation 3. Information provided by the sponsor relating to Item 7 is often incomplete - Provide the IND or NDA/BLA numbers if they are available to you 02/03/201016BIOBIO-2010, Hyderabad

17. Tips for Applying for Orphan Product Designation 4. Format your application so that it is user friendly -After addressing the nine required items, provide a bibliography displayed in a related fashion as shown in the text of your document. -Usually references within the application are cited numerically with superscripts 02/03/201017BIOBIO-2010, Hyderabad

18. Tips for Applying for Orphan Product Designation 5. Submit the original and one photocopy of the application in separate binders or report covers to the office of Orphan Products Development -The photocopy needs to be an exact duplicate of the original application. 02/03/201018BIOBIO-2010, Hyderabad

19. Tips for Applying for Orphan Product Designation -If there is a cover letter with the original, there needs to be a copy of the cover letter with the duplicate -No correspondence should arrive loose or out of the binder or report cover -They are inexpensive and readily available, plus they fit in standard filing cabinets nicely 02/03/201019BIOBIO-2010, Hyderabad

20. Tips for Applying for Orphan Product Designation 6. Submit the application (one original and one photocopy) for orphan designation to: Director, Office of Orphan Products Development Food & Drug Administration, HF-35 5600 Fishers Lane, Room 6A55 Rockville, MD 20857 02/03/201020BIOBIO-2010, Hyderabad

21. How to Apply for Designation as an Orphan Product (a)A sponsor that submits a request for orphan drug designation of a drug for a specified rare disease or condition shall submit each request in the form and containing the information required in paragraph (b) (b)A sponsor shall submit two copies of a completed, dated, and signed request or condition that contains 02/03/201021BIOBIO-2010, Hyderabad

22. How to Apply for Designation as an Orphan Product 1.A statement that the sponsor requests orphan drug designation for a rare disease or condition, which shall be identified with specificity 02/03/201022BIOBIO-2010, Hyderabad

23. How to Apply for Designation as an Orphan Product 2. The name and address of the sponsor; the name of the sponsor’s primary contact person and/or resident agent including title, address, and telephone number; generic and trade name 02/03/201023BIOBIO-2010, Hyderabad

24. How to Apply for Designation as an Orphan Product 3. A description of the rare disease or condition for which the drug is being or will be investigated, the proposed indication or indications for use of the drug, and the reasons why such therapy is needed 02/03/201024BIOBIO-2010, Hyderabad

25. How to Apply for Designation as an Orphan Product 4. A description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease or condition - Copies of pertinent unpublished and published papers are also required 02/03/201025BIOBIO-2010, Hyderabad

26. How to Apply for Designation as an Orphan Product 5. Where the sponsor of a drug that is otherwise the same drug as an already approved orphan drug seeks orphan drug designation for the subsequent drug for the same rare disease 02/03/201026BIOBIO-2010, Hyderabad

27. How to Apply for Designation as an Orphan Product 6. Where a drug is under development for only a subset of persons with a particular disease or condition, a demonstration that the subset is medically plausible 02/03/201027BIOBIO-2010, Hyderabad

28. How to Apply for Designation as an Orphan Product 7. A summary of the regulatory status and marketing history of the drug in the US and in foreign countries, e.g., IND and marketing application status and dispositions 02/03/201028BIOBIO-2010, Hyderabad

29. How to Apply for Designation as an Orphan Product 8. Documentation, with appended authoritative references, to demonstrate 02/03/201029BIOBIO-2010, Hyderabad

30. An orphan disease has an incidence fewer than 5 patients per 10,000 population (EU) or <200,000 patients (US). 02/03/201030BIOBIO-2010, Hyderabad

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32. THANK YOU 02/03/201032BIOBIO-2010, Hyderabad