The IND Process

1. THE UNIVERSITY OF NEW MEXICO ▪ HEALTH SCIENCES CENTER The IND Process Clinical and Translational Science Center (CTSC) http://hsc.unm.edu/research/ctsc/ 4/2009

2. What is an IND/IDE ? • An exemption from the law which otherwise requires that a drug (biologic, device) be approved before it can be transported across state lines • The standard for approval is evidence of safety and efficacy • The IND exemption is granted for purposes of clinical investigation (research)

3. Importance of the IND • Affirms a body of knowledge about the manufacturing, pharmacology, and toxicology of the drug to support its use in human testing • Requires that the clinical investigation(s) be performed in accordance with Good Clinical Practice (GCP) • Provides an additional level of protection through FDA oversight

4. The FD&C Act Defines “Drug” Very Broadly • Any of: • Article recognized in the U.S. Pharmacopeia, official Homeopathic Pharmacopeia of the US, or official National Formulary, or any supplement • Article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals

5. The FD&C Act Defines “Drug” Very Broadly • Any of: • Article (other than food) intended to affect the structure or any function of the body of man or other animals • Article intended for use as a component of any article specified in clauses above Section 201(g) of the FD&C Act

6. “Clinical Investigation” is also Defined Broadly • Any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice 21 CFR 312.3

7. So When Is an IND Required ? • In general: An IND is required when an unapproved drug (or biologic) is used in a clinical investigation

8. What About Approved Products • No IND is needed when an approved product is used in the course of medical practice (even for an indication different from the approved indication) • But an IND may be required when an approved products is used in a clinical investigation

9. What About Approved Products • An IND is needed if: • The clinical investigation is intended to be reported to FDA as a well-controlled study in support of a new indication or a significant change in the labeling of the drug • The clinical investigation is intended to support a significant change in advertising for the product

10. What About Approved Products • With the above caveats, clinical investigation of an approved product may be exempt from IND requirements if: • The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases risks AND • The investigation is conducted in accordance with IRB and informed consent requirements

11. What About Approved Products • FDA has generally allowed the IRB to assess whether risk of an approved product is increased for a given protocol • But FDA retains final authority for such determinations

12. What About Approved Products • It is also important to note that shelf chemicals which bear the same “name” as an approved product are not considered as “lawfully marketed” equivalents of the approved product • Approval is specific to dose, formulation, and applicant

13. Need for an IND/IDE:Who to Contact with Questions • Drugs (CDER) • Drug Information Branch: (301) 827-4573 • Biological Products (CBER) • (301) 827-0373 • Medical Devices (CDRH) • IDE Staff: (301) 594-1190 • Food Safety (CFSAN): (202) 418-3126

14. Related Information • GCP Regulations • IND/IDE Regulations: 21 CFR Part 312/812 • IRB Regulations: 21 CFR Part 56 • Informed Consent Regs: 21 CFR Part 50 • All are accessible at: • www.fda.gov/oc/gcp

15. Related Information • IND Forms • Available on-line through: (ADD LINK)

16. IND: What is Required -1- • General Investigation Plan • Investigator’s Brochure • Protocol(s): Later protocols submitted as amendments • Chemistry, manufacturing and control information • Animal pharmacology and toxicology information

17. IND: What is Required -2- • Previous human experience • Additional information • Dependence and abuse potential • Plans for pediatric studies • Amount of information required in each section depends on novelty of the drug, extent studied, and known or suspected safety concerns

18. The FDA Form “1572” • IND sponsors are required to obtain a signed FDA Form “1572” from each clinical investigator, containing: • Name and address of CI • Name and code number of any protocol(s) • Name and address of research facility and any clinical labs • Name and address of responsible IRB • Names of co-investigators • Signed commitment by the investigator

19. Clinical Investigator Responsibilities* • Personally conduct or supervise investigations • Ensure all persons assisting in conduct of studies are informed of their obligations • Ensure informed consent (21 CFR 50) and IRB review, approval , and reporting (21 CFR 56) requirements are met *(Form FDA 1572: #9. Commitments)

20. Clinical Investigator Responsibilities* • Conduct studies according to relevant, current protocol • Make changes in a protocol only after notifying the sponsor • Maintain adequate and accurate records • Make records available for inspection • Agree to comply with all other requirements in 21 CFR 312 *(Form FDA 1572: #9. Commitments)

21. Review of IND Application • FDA also has responsibilities under GCP • The focus of FDA’s IND Review is on safety for human research subjects and ensuring that the studies will produce useful information to assess safety and efficacy of the test product

22. Reviews are Conducted by Teams of Specialists • Medical Officer • Consumer Safety Officer/Project Manager • Statistician • Chemist • Pharmacologist • Human Biopharmaceutics • (Microbiologist)

23. Review of IND Application • Review team has 30 days to review • Focus of review is always on safety/ human subject protection • No News = Good News

24. IND Application: If Problems.. • “Clinical Hold” • Legal order to delay or stop the study in the U.S. • Subjects may not be given the investigational drug • May be imposed if: • Exposure of subjects to unreasonable risk (includes manufacturing problems) • Investigator brochure is misleading, erroneous, or materially incomplete • Investigator is not qualified

25. Drug Development Under an IND • Review Team Monitors • New Protocols (IND amendments) • Safety reports • Annual reports • Additional chemistry, animal toxicology, microbiology data • Review team is available to consult/meet with sponsors: advise on protocol design, advise on drug development plan

26. IND and Non-US Studies • Studies performed outside of the U.S. may be conducted with or without IND • With an IND: • Test article can be exported from the U.S. • Study must conform to U.S. IND regulations (including U.S. IRB and informed consent rules)

27. IND and Non-US Studies • Studies performed outside of the U.S. may be conducted with or without IND • Without an IND • May be acceptable for FDA review in support of a marketing application • Export of the test article from the U.S. must conform to FDA regulations

28. Export of an Investigational Drug • Mechanisms (21 CFR 312.110) • FDA authorization of a written request from the person that seeks to export • Adequate information; investigational purposes only; can be legally used in the importing country for investigation; specifies quantity/frequency of shipment • FDA authorization of a formal request from the government of the receiving country

29. Export of an Investigational Drug • 1996 law also allows drug export for investigational use without prior FDA approval if intended for use in one of 25 countries • Australia; Canada; Israel; Japan, New Zealand; Switzerland; European Union Member States (15), Iceland, Norway, and Liechtenstein

30. IND Content/Submission:Who to Contact with Questions • Center for Drugs ODE I • Cardio-Renal (110) • 301-594-5300 • Neuropharm (120) • 301-594-2850 • Oncology (150) • 301-594-2473 • Center for Drugs ODE II • Anesthetic, Critical Care & Addiction (170) • 301-827-7410 • Metabolic/Endocrine (510) • 301-827-6430 • Pulmonary (570) • 301-827-1050

31. IND Content/Submission:Who to Contact with Questions • Center for Drugs ODE III • Medical Imaging & Radiopharm (160) • 301-827-7510 • GI & Coagulation (180) • 301-827-7310 • Repro/Urologic (580) • 301-827-4260 • Center for Drugs ODE IV • Anti-Infective (520) • 301-827-2120 • Antiviral (530) • 301-827-2330 • Special Pathogens & Immunologic (590) • 301-827-2336

32. IND Content/Submission:Who to Contact with Questions • Center for Drugs ODE V • Derm/Dental (540) • 301-827-2021 • Anti-Inflammatory, Analgesic & Ophthalmic (550) • 301-827-2040 • Over-the-Counter (OTC) (560) • 301-827-2222

33. IND Content/Submission:Who to Contact with Questions • Center for Biologics (CBER) • Office of Vaccines Research and Review • (301) 827-0654 • Office of Blood Research and Review • (301) 827-3524 • Office of Therapeutics Research and Review • (301) 827-5099

34. Office of Generic DrugsWho to Contact with Questions • OGD Regulatory Support Branch • (301) 827-5862

35. IDE Content/Submission:Who to Contact with Questions • Center for Devices and Radiological Health (CDRH) • General, Restorative, and Neurological Devices: (301) 594-1184 • Clinical Laboratory Devices: (301) 594-3084 • Cardiovascular and Respiratory Devices: (301) 443-8320

36. IDE Content/Submission:Who to Contact with Questions • Center for Devices and Radiological Health (CDRH) • Ophthalmic and ENT Devices: (301) 594-2205 • Reproductive, Abdominal, and Radiological Devices: (301) 594-5072 • Dental, Infection Control, and General Hospital Devices: (301) 443-8879

37. Reporting to FDA • IND sponsors/researchers are required to report serious non-compliance • But anyone can report complaints in FDA-regulated clinical trials to FDA • FDA’s GCP website (www.fda.gov/oc/gcp) highlights where to report complaints in clinical trials