What is an IND?

1. What is an IND? Keith Wonnacott, Ph.D. Division of Cellular and Gene Therapies Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research FDA

2. Basis for Regulation of INDs • Statutes: THE LAW --- passed by Congress and signed by the President • 42 USC 262 (United States Code) • Regulations: details of the law --- written by the Agency and approved by the Executive Branch • 21 CFR 312 (Code of Federal Regulations) • Guidance: the Agency’s interpretation of the Regulations --- written and approved within the Agency • 68 FR 49488 (Federal Register)

4. Drug and Biologics Law The following is a very brief history of the statutory basis for INDs

6. Biologics Control Act 1901 13 children in St. Louis died of tetanus after receiving diphtheria antitoxin from a horse named Jim. 9 children die of tetanus from contaminated smallpox vaccine 1902 Biologics Control Act authorizes Hygienic Laboratory to issue regulations to ensure purity and safety of serums, vaccines, and similar products 1944 PHS Act incorporates provisions for biologics regulation. Outlines licensing requirements that are independent from pre-marketing requirements for drugs. 1973 Blood, blood products, and allergenics included in the PHS Act

7. Food and Drug Act 1905 Samuel Hopkins Adams published “The Great American Fraud,” a commentary on the patent medicine industry exposing cure-all claims for worthless and dangerous patent medicines. Upton Sinclair publishes “The Jungle” with shocking disclosures of insanitary conditions in meat-packing plants. 1906 Food and Drug Actprohibits interstate commerce in misbranded and adulterated foods, drinks, and drugs.

8. Food, Drug, and Cosmetic Act 1937 Sulfanilimide elixir containing diethylene glycol kills 107 people • Food, Drug, and Cosmetic Act required new drugs to be shown safe before marketing— starting a new system of drug regulation. It also authorized factory inspections and other provisions.

9. Kefauver-Harris Amendments 1962 Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe. Over two million pills distributed in the United States for investigational studies. 1962 Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. It required drug manufacturers to prove the effectiveness of their products before marketing them, gave FDA control over drug advertising, and allowed FDA to regulate investigational studies.

10. Summary A new biologic, drug, or device may not be entered into interstate commerce unless: • It is approved by the FDA as safe and effective (biological license application [BLA], new drug application [NDA], pre-market approval [PMA], or other marketing approval) OR … • An IND is in effect (exempting the study from the premarketing approval requirements that are otherwise applicable)

11. OR…

12. Where do I find IND requirements? 21 CFR 312 Investigational New Drug Application

13. PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS • Subpart A – General provisions • Subpart B – IND application • Subpart C – Administrative action • Subpart D – Responsibilities of sponsors and investigators • Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses • Subpart F – Miscellaneous • Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests

14. PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS • Subpart A – General provisions • Subpart B – IND application • Subpart C – Administrative action • Subpart D – Responsibilities of sponsors and investigators • Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses • Subpart F – Miscellaneous • Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests

15. When do I need an IND? • Anytime you are doing a clinical investigation with a drug or biologic EXCEPT…

16. EXCEPT… If your study is: • An in vitro diagnostics used to confirm the results of an approved test • A study in animals • A placebo study not otherwise requiring an IND (not involving a drug or biologic)

17. EXCEPT… If you are using an FDA approved product AND your study: • Is not intended to support a labeling or advertising change • Is administered so as not to increase the safety risk to the patients • Has institutional review board (IRB) approval • Follows the rules on charging for investigational drugs

18. What are the phases of an investigation? Sponsor Perspective Marketing Preclinical Phase 1 Phase 2 Phase 3 Phase 4 Proof of concept, safety, potential toxicity, dosing strategy Post marketing commitments to monitor safety and efficacy Evaluate safety and side effects Evaluate safety and explore efficacy and dose ranging Obtain efficacy and safety data for approval IND filing BLA filing

19. What are the phases of an investigation? Investigator Perspective Publication Preclinical Phase 1 Extend proof of concept to human Proof of concept IND filing

20. What are the phases of an investigation? FDA Perspective Marketing Preclinical Phase 1 Phase 2 Phase 3 Phase 4 BLA review (6/10 months) IND review(30 days) End of Phase 2 Meeting Pre-IND Meeting Pre-BLA Meeting Amendment Review CONSULTATION

21. How do I label an investigational drug? • “Caution: New Drug – Limited by Federal law to investigational use.” • No false or misleading claims • No statement that the drug is safe or effective for the indication for which it is being investigated

22. Can I promote or charge for my investigational drug? • No promoting drug as safe or effective • No commercial distribution • No charging without the consent of the FDA • For clinical trials, FDA must give written consent after sponsor provides a full written explanation of why charging is necessary and not part of the normal cost of doing business 21 CFR 312.7(d)

23. PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS • Subpart A – General provisions • Subpart B – IND application • Subpart C – Administrative action • Subpart D – Responsibilities of sponsors and investigators • Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses • Subpart F – Miscellaneous • Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests

24. IND Checklist

27. IND Checklist

28. Introductory Statement/ General Investigational Plan • Description of the drug • Summary of previous human experience • Overall plan for investigating the drug

29. IND Checklist

30. Investigator’s Brochure • An investigators brochure contains information and instructions for investigators so that they can properly perform the study. • It is required if a commercial sponsor product is providing product to clinical investigators • It is not required for sponsor-investigators performing a trial at one clinical site

31. IND Checklist

32. Protocols • Protocol for each planned study including: • Statement of objectives and purpose of study • Estimated enrollment • Inclusion & exclusion criteria • Dosing plan (dose, duration, route) • Plan for patient monitoring • Toxicity based stopping/dose adjustment rules • Investigator data (Form FDA 1572)

33. IND Checklist

34. Product Information (CMC) • Physical, chemical, and/or biological characteristics • Manufacturers • Source and method of preparation • Removal of toxic reagents • Quality controls (e.g., identity, assay, purity, impurities profile) • Description of testing and acceptable limits • Sterility (aseptic processing or sterilization process, sterility and endotoxin testing, etc.) • Linkage of pharmacological and/or toxicity batches to clinical trial batches • Stability information

35. IND Checklist

36. Pharmacology and Toxicology Data • Data for studies demonstrating • Safety • Efficacy • Potential toxicities • Optimal dosing • Identification and qualifications of study evaluators • Statement regarding where and how (GLP) studies were performed

37. IND Checklist

38. Previous Human Experience/ Additional Information • Previous human experience is only required when it is relevant • It should be presented as a summary report • Additional information may be submitted if the sponsor feels it is necessary

39. How do I make changes to my IND? Send an amendment • Amendment = Any document, from the sponsor, in support of their IND • An amendment can be made at any time during the life of the IND

40. Types of Amendments • Protocol Amendments • New protocol, Protocol changes, New investigator • Safety reports • Serious and unexpected clinical adverse event or laboratory finding affecting safety • SAE within 15 days, life-threatening within 7 days • Annual reports • A summary report on progress, findings, changes and future plans • Must be submitted within 60 days of anniversary • Information Amendments • Everything else

41. Can I treat patients who don’t qualify for my study? YES, under… • A treatment protocol or IND • Allows access to investigational drugs • Can be for a single patient who doesn’t qualify for existing protocol

42. A treatment protocol or IND is only allowed if: • Serious or immediately life-threatening disease • No comparable or alternative therapy • Actively pursuing market approval • Treatment use may begin 30 days after FDA receives protocol

43. PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS • Subpart A – General provisions • Subpart B – IND application • Subpart C – Administrative action • Subpart D – Responsibilities of sponsors and investigators • Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses • Subpart F – Miscellaneous • Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests

44. What is the objective of regulatory actions? FDA’s primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety. [21 CFR 312.22(a)]

45. Administrative Status and Actions • Exempt – Study does not have to be conducted under IND • Pending– IND is in initial 30-day review period • In Effect– Study may proceed • Hold – FDA orders sponsor to delay or suspend a clinical investigation • Partial Hold– A delay or suspension of part of the clinical investigation • Inactivated – IND is subject to no activity, but may be reactivated • Withdrawal– Sponsor requests to end IND, IND cannot be reactivated • Terminated – FDA orders sponsor to end all clinical investigation, IND cannot be reactivated

46. PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS • Subpart A – General provisions • Subpart B – IND application • Subpart C – Administrative action • Subpart D – Responsibilities of sponsors and investigators • Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses • Subpart F – Miscellaneous • Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests

47. Responsibilities of Sponsors • Select qualified investigators • Provide investigators information needed to properly conduct the study (Investigator Brochure) • Ensure proper study monitoring

48. Responsibilities of Sponsors • Ensure the study is in accordance with the general investigational plan • Maintain an effective IND • Ensure that FDA and all participating investigators are promptly informed of significant new adverse effects or risks.

49. Responsibilities of Investigators • FOLLOW THE PROTOCOL! • Control of the drug • Keep and retain accurate records • Fill out appropriate reports • Ensure IRB protocol review

50. Responsibilities of Institutional Review Boards [21 CFR 56] • Review and approve all research studies involving humans within an institution • Be composed of at least 5 diverse members • at least one scientific member and one non-scientific member • at least one member not otherwise affiliated with the institution • Assure that: • risks to subjects are minimized and reasonable • selection of subjects is equitable • informed consent will be sought and adequately documented