1. When do I need an IND ? FDA Guidance for Industry – Investigation New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without and IND Procedural Draft for Public Comment October 2010

2. Investigational New Drug – New? The FDA uses the filing requirements of the IND as the primary mechanisms for ensuring the safety of research subjects. The term IND can be misinterpreted, leading researchers to conclude that if the drug they are studying is already approved by the FDA, it is not a “new” drug needing a IND. INCORRECT! The FDA approves a drug as safe with specifications (these indications are spelled out in the Investigational Brochure, labeling, package insert or in the PDR): Route of administration Dose/duration Form of the drug (e.g. capsule vs. tablet) For specific medical conditions With concomitant medications or medical conditions

3. Research Studies that Require and IND Involve a drugdrug The research is a clinical investigationclinical investigation The clinical investigation is not otherwise exempt

4. What is a drug? “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease….” and articles (other than food) intended to affect the structure or any function of the body of man or other animals” Includes: Biologics, compounds administered to healthy subjects to blunt or provoke a physiologic response (vasopressin) or to study the mechanism of action or metabolism of a drug (contrast agents, markers). Dietary Supplements that affect the structure or function of the body and not intended for a therapeutic purpose is not a drug.

5. But …Off-label use is legal…… “In contrast, use of a licensed drug in the course of medical practice involves the use in an individual patient where the primary intent is to treat the patient but not to study the safety or effectiveness of a drug is any systematic way.”

6. Categories Exempt from IND Requirements Otherwise exempt categories There are 3: 1.Certain Research Involving Marketed Drug Products 2.Bioavailablity or Bioequivalence Studies in Humans 3.Radioactive Drugs for Certain uses

7. Exempt from IND Clinical investigation of a drug is exempt if all of the following criteria are met: –The Drug is licensed and marketed in US –No intent to report to FDA in support of a new indication or any other significant change in the product labeling –The investigation is not intended to support a significant change in the advertising for the (licensed) drug

8. Exempt from IND –The investigation does not involve a change in the route of administration, dose, population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product.

9. Exempt from IND –The investigation is conducted in compliance with the requirements for review by an IRB (informed consent) –The investigation is conducted in compliance with the requirements of 312.7(i.e., is not intended to promote or commercialize the drug )

10. Changes to route, population, dosage “ not intended to require that a drug be used in exactly the same dosage form, level, and patient population described in the marketed labeling….but only permit changes…. that do not increase the risk to greater than the risk presented by the use of the product in conformance with its marketed label.”

11. Introducing risk - clarification Low risk modifications : blinding a product by changing its color, scoring or capsule size… Greater risk modifications; Products that are sensitive to conditions in the environment, may create changes to formulation…. or primary packaging. (examples)examples No comprehensive guide - may request consultation with FDA (formal or informal)

12. Introducing risk - clarification Risk assessment of a marketed drug: Oncology setting has been separated out: IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer

13. Consider PI sponsors may have no intent utilize study results for changing labeling or advertising but the research results may have the potential to do so….

14. Example changing the form Example: Coumadin® is very unstable in high humidity, which is why the pills are coated. Crushing of these caplets can change them chemically and result in unanticipated safety risks and a lack of efficacy..

15. Example of Manufacturing change The packaging of some drugs is very important to preserve its chemical composition. Some drugs are in blister packs, because they decompose when they come in contact with air, dark brown glass bottle if photosensitive The IUD was produced and marketed in an insertion kit which was removed and being inserted with a ring forceps. Does this introduce a design control (GMP) risk?

16. Lessons Learned Charging for investigational products under an IND Old rule- rarely permitted, required FDA written permission New rule November 2009 – covers charging for investigational drugs in clinical trials and expanded access use. (FDA has not changed it’s letters to reflect this change) Take home message – PI/ sponsor/ investigator researching an approved drug for unapproved use can have subject obtain drug and bill third party.

17. IND Decision Support tool by the University of Penn http://www.med.upenn.edu/ohr/ind/index.ht ml

18. Investigator/Sponsor Responsibilities MMC HRPP Web Site: http://www.mmcri.org/home/webSubContent.php?subCatID=36&catID=2&headType=h rpp&catLevel=subCat

19. What is a Clinical Investigation? CFR 312.3(b) “,,,[an] experiment in which a drug is administered or dispensed to, or used involving, one or more human subject.” “For the purposes of [the IND regs] an experiment is, any use of a drug [approved or not] except for the use of a marketed drug in the course of medical practice.”