1. Investigational New Drug Application 21 CFR Part 312 A Review for OCRA US RAC Study Group September 2005 Ginger Clasby, MS Promedica International gclasby@promedica-intl.com 714-799-1617 x 25

2. IND Application About the Regulation Provides procedures for use of investigational new drugs Exempts products from premarketing approval requirements: – Registration, listing, interstate distribution – Labeling – GMPs Applies to most studies to determine drug safety & effectiveness

3. When IND Application is Not Required Clinical Study Situations Drug legally marketed for indicated use – Study not intended to support new indication or significant labeling change – Study not intended to support significant change in advertising – Study doesn’t involve change in route of admin, dosage, or use that significantly increases patient risks IVD biological for confirmatory diagnostic procedure Intended for tests of in vitro or lab research animals Placebo products

4. “Treatment” IND When Used Drug intended to treat or diagnose serious or life- threatening condition No satisfactory alternative available Controlled clinical trials in progress under IND – Or when trials completed & FDA review of request to market is pending Sponsor actively pursuing device marketing approval with FDA

5. “Emergency Use” IND When Used Need FDA authorization to use experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21 CFR Part 312 May be used for patients ineligible per existing study protocol(s), or if approved study protocol does not exist

6. IND Application Product Labeling Requirements Immediate package must be labeled: – “Caution: New Drug – Limited by Federal (or United States) law to investigational use” No false or misleading statements No representation that drug is safe or effective for indicated use

7. IND Application Promotion & Charging for Investigational Drugs No representation that drug is safe or effective for indicated use No commercial distribution or test marketing No prolongation of study Prior written approval from FDA required to “charge” for drug, unless being used under “treatment” IND

8. IND Application Clinical Study Phases Phase 1 – first time in human – Small number of healthy volunteers – Closely monitored – focus on safety Phase 2 – controlled studies to evaluate effectiveness – Small number of subjects with condition to be treated – Closely monitored – focus on efficacy (& safety) Phase 3 – expanded controlled & uncontrolled studies – Large number of subjects with condition to be treated – Focus on efficacy (& safety)

9. IND Application Contents Administrative Details Sponsor responsibility Submit original & 2 copies of application FDA notifies Sponsor in writing of date application is received IND in effect 30 days after FDA receipt of application, unless FDA notifies Sponsor otherwise

10. IND Review/Approval FDA’s Considerations Subject safety & welfare Rendered  30 days of FDA receipt – Only disapproval or early approval is rendered in writing Clinical hold may be ordered if: – Sponsor fails to comply with applicable regulations – Sponsor is non-responsive to requests for add’l info – Subject risks outweigh benefits – Unreasonable to proceed due to inadequacy of investigational plan, manufacturing or monitoring

11. Clinical Holds To Delay/Suspend A Study Phase I clinical holds – Subject safety concerns Phase II & III clinical holds – Concerns about safety or efficacy Treatment IND clinical holds – Alternative treatment drug now commercially available – Sponsor not diligently pursuing marketing approval – Administrative oversights by Sponsor

12. IND Application Contents An Overview Cover sheet/application form (Form FDA-1571) Table of contents Introductory statement General investigational plan Investigator brochure Protocol(s) Chemistry, manufacturing & control info

13. IND Application Contents An Overview Pharmacology & toxicology info Previous human experience with drug Add’l info as required: – Drug dependence/abuse potential – Radioactive drugs – Pediatric studies Add’l info as requested by FDA

14. IND Application Contents Application Form - FDA 1571 Required for initial IND & all subsequent submissions Provides basic info about Sponsor & submission contents Must be signed & dated – Obligates Sponsor to comply with laws & regs

15. IND Application Contents Introductory Statement Drug name, structure, pharmacological class, development history, foreign testing

16. IND Application Contents General Investigational Plan Summary of studies anticipated in first year Study rationale

17. IND Application Contents Investigator Brochure Package insert Early versions contain more pre-clinical data Later versions more heavily weighted with clinical data

18. IND Application Contents Protocol(s) Must include at least the initial protocol Phase I – protocol outline: – No. subjects planned – Eligibility requirements – Dosing – Safety assessments Phase II & III – detailed protocols

19. IND Application Contents Chemistry, Manufacturing & Controls Manufacturing process Raw materials & finished product testing May refer to drug master file or previous application

20. IND Application Contents Pharmacology & Toxicology Non-clinical study summaries of pharmacological & toxicological effects

21. IND Application Contents Previous Human Experience Foreign trials Data from other INDs, NDAs

22. IND Application Contents Additional Info Other relevant info Minutes of FDA meetings Copies of referenced materials Address issues re: possible drug abuse, dependence, radioactivity, etc.

23. IND Amendments Necessary When: New protocol introduced Changes made to protocol that may affect: – Scientific soundness of study – Rights, safety or welfare of study subjects Addition of new study investigators (FDA Form 1572) New/revised information not related to protocol – New pharmacology, toxicology, chemistry, clinical info – Discontinuance of a study

24. IND Safety Reports FDA Form 3500A Any unexpected, serious adverse experience associated with drug use – 15 calendar days Any finding from animal studies suggesting significant risk for human subjects – 15 calendar days Any unexpected fatal or life-threatening experience associated with drug use – 7 calendar days

25. IND Annual Reports When Required Due within 60 days of IND anniversary Individual study information Summary information for all studies, including: – Summary of safety results & significant changes in product manufacturing, pre-clinical study status – General investigational plan for upcoming year – Any Investigator Brochure revisions – Significant Ph I protocol modifications – Significant foreign marketing developments during prior year – Log of outstanding business

26. IND Review/Approval FDA Meetings Pre-IND Submission – Facilitates planning for IND End of Phase II – Facilitates planning for later studies Pre-NDA or Pre-BLA – Facilitates preparation & review of NDA or BLA

27. Sponsors & Investigators Responsibilities Similar to 21 CFR 812

28. IRB Responsibilities As identified in 21 CFR 50, 56

29. IND Regulation Reference Documents & Links ( www.fda.gov/cder ) www.fda.gov/cder CDER Guidance: IND Application Process (interactive session) http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm

30. IND Regulation Reference Documents & Links (www.fda.gov/cder)www.fda.gov/cder FDA Guidance for Financial Disclosure by Clinical Investigators FDA Guidance for IRBs & Clinical Investigators FDA Guidance for Monitoring Clinical Investigations FDA/ORA Compliance Program Guidance for Bioresearch Monitoring of Clinical Investigations