Investigational New Drug Application 21 CFR Part 312

1. A Review for OCRA US RAC Study Group September 2005 Ginger Clasby, MS Promedica International gclasby@promedica-intl.com 714-799-1617 x 25 Investigational New Drug Application21 CFR Part 312

2. IND ApplicationAbout 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 RequiredClinical 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” INDWhen 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” INDWhen 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 ApplicationProduct 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 ApplicationPromotion & 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 ApplicationClinical 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 ContentsAdministrative 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/ApprovalFDA’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 HoldsTo 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 ContentsAn 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 ContentsAn 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 ContentsApplication 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 ContentsIntroductory Statement • Drug name, structure, pharmacological class, development history, foreign testing

16. IND Application ContentsGeneral Investigational Plan • Summary of studies anticipated in first year • Study rationale

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

18. IND Application ContentsProtocol(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 ContentsChemistry, Manufacturing & Controls • Manufacturing process • Raw materials & finished product testing • May refer to drug master file or previous application

20. IND Application ContentsPharmacology & Toxicology • Non-clinical study summaries of pharmacological & toxicological effects

21. IND Application ContentsPrevious Human Experience • Foreign trials • Data from other INDs, NDAs

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

23. IND AmendmentsNecessary 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 ReportsWhen 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/ApprovalFDA 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 & InvestigatorsResponsibilities • Similar to 21 CFR 812

28. IRBResponsibilities • As identified in 21 CFR 50, 56

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

30. IND RegulationReference Documents & Links (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