1. INDs : Does My Study Need One? Edith Paal UAMS Office of Research Compliance 526-6876 August 22, 2003

2. Scenarios  New drug that hasn’t been approved yet – that’s an easy one. Yes, the study needs an IND.  An approved drug used for a new indication – this gets a bit trickier.

3. Using an approved drug for a new indication  It can be prescribed it as part of regular medical care with no problem.  But, say that after trying it in a few patients as part of their standard care, you’ve gotten promising results and you want to formally study it.

4. Does the study need an IND?  21 CFR 312.2(b) (1) lists the circumstances that, if all are met, make an IND unnecessary.  Various guidances and draft guidances also include more details about whether an IND is required.

5. If ALL of these conditions are met, then an IND is NOT required…  The study is not intended to support FDA approval of a new indication or significant change in the product labeling.  The study is not intended to support a significant change in advertising for the product. (continued…)

6. If all of these conditions are met, then an IND is NOT required…  The study is conducted in compliance with IRB and informed consent regulations.  The study is conducted in compliance with 21 CFR 312.7, promotion and charging for investigational drugs.  It does not intend to invoke 21 CFR 50.24, (emergency research). (continued…)

7. One last condition to meet…(and this is the biggie)  The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product).

8. What might increase the risk, or decrease the acceptability of the risk?  Changing the dose level or the route of administration  Is there a chance that subjects in a study might receive a less effective treatment for their condition than the standard of care?

9. The IND criteria for marketed oncology drugs are a bit more flexible.  A draft guidance from the FDA addresses oncology drugs specifically.  The National Cancer Institute’s Cancer Therapy Evaluation Program’s Investigator’s Handbook also has information on INDs http://ctep.cancer.gov/handbook/hndbk_1.html

10. Why are oncology drugs handled a bit differently?  In oncology practice, modifications of ordinary dosing are not uncommon.  Because of the way cancer drugs are used, toxicity, even potentially lethal toxicity, is often described in the approved labeling.  Off-label therapy with cancer drugs is relatively common in practice.

11. One step to take when trying to decide if an IND is necessary  If you are changing the dose, route, or schedule of administration, or you’re trying a new combination of marketed drugs, check the literature. If no safety data of the changed dosage, route, schedule, or new combination are available in the literature, you probably need an IND.

12. Want a second opinion?  Call the FDA and ask for a written opinion.  But before you do that, call the Office of Research Compliance. We can help you put together what you’ll need to tell the FDA.

13. Phone Numbers  FDA Drug Information Branch 301-827-4573 Barry Poole is the current contact there. He’s at 301-827-4570  Phone numbers for other products are in the IRB information sheet titled “Off-Label and Investigational Use of Marketed Drugs, Biologics, and Medical Devices”

14. Sponsor vs. Sponsor-Investigator INDs Carole Hamon ACHRI Research Compliance August 22, 2003

15. Sponsor  The sponsor takes responsibility for and initiates a clinical investigation. 21 CFR 312.50  The sponsor may be a pharmaceutical company, a private or academic organization, or an individual.

16. Sponsor-Investigator  A Sponsor-Investigator is an individual who both initiates and conducts a clinical investigation and under whose immediate direction the investigational drug is being administered or dispensed.

17. Caveats  For administrative reasons, only one individual should be designated as sponsor.  If a pharmaceutical company supplies the drug, but does not submit the IND, the company is NOT the sponsor.  Contract with supplier should define who does what.

18. General Requirements for INDs  FDA Form FD-1571  FDA Form FD-1572  Thirty day waiting period 21 CFR 312.40

19. FDA Form FD-1571  Twenty item form which must be completed and signed by the Sponsor- Investigator.  Willfully falsifying statements on this form is a criminal offense.

20. FDA Form FD-1571- Box 12  HOWEVER, if the investigational drug is prepared or altered in any way after shipment by the supplier, complete manufacturing (or compounding) and controls information, including information on sterility and pyrogenicity testing for parenteral drugs, must be submitted for that process in Box 7.

21. FDA Form FD-1572  This form is required for EVERY physician or sub-investigator who is going to be a part of the study and is obtained BEFORE the release of drug to the physician. This form satisfies the requirements of Box 12, Item 6 b-d.

22. Overview of FDA Requirements for Sponsor-Investigators  Review the applicable federal regulations before performing any sponsor duties  If you are a Sponsor-Investigator, you MUST meet the requirements of both the sponsor and the Investigator.  http://www.access.gop.gov/nara/cfr/wai sidx_00/21cfr312_00.html http://www.access.gop.gov/nara/cfr/wai sidx_00/21cfr312_00.html

23. If you still want to be a Sponsor-Investigator  The following needs to be in place BEFORE you apply for the IND.

24. Monitoring and Compliance  Will select a monitor to oversee the progress of the investigation. 21 CFR 312.53(d)  Will comply with FDA regulations regarding emergency use of test article. 21 CFR 312.54

25. Monitoring and Compliance  Will keep investigators informed on the safety and effectiveness of the drug. 21 CFR 312.55  Need Data Safety Monitoring Board when appropriate.

26. Monitoring and Termination  The Sponsor shall monitor the progress of all clinical investigations being conducted under their IND. 21 CFR 312.56(a)  The Sponsor shall terminate investigator’s participation when investigators fail to follow protocol. 21 CFR 312.56(b)

27. Drug Safety and Effectiveness  The Sponsor shall review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from each investigator. 21 CFR 312.56(c)

28. Drug Safety & Effectiveness  The Sponsor shall discontinue the study if the investigational drug presents an unreasonable and significant risk to subjects  The FDA, IRB, and all investigators must be notified of the discontinuance. 21 CFR 312.56(d)

29. Reporting Requirements  Progress Reports – Your investigators must furnish these to you as the sponsor. 21 CFR 312.64(a )  IND Safety Reports – Adverse Reactions 21 CFR 312.32  Annual Reports – Within 60 days of anniversary of IND 21 CFR 312.33

30. Reporting Requirements  Final Reports – must obtain from your investigators and submit to FDA 21 CFR 312.64(c)  Financial Disclosure Reports from investigators must be received and updated for one year post study completion. 21 CFR 312.64(d)

31. Drug Accountability  The Sponsor must: –Maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug. 21 CFR 312.57 –Assure that investigators return all investigational drugs. 21 CFR 312.59

32. Drug Accountability –Require investigators to maintain adequate drug records. 21 CFR 312.62 –Require investigators to store the investigational drug in a secure area. 21 CFR 312. 69

33. Label and Promotion  “Caution: New Drug – Limited by Federal (or United States) law to investigational use”  Promote and distribute the drug in accordance with FDA regulations 21 CFR 312.7

34. IRB, Case Histories, Payments  The sponsor must: –require investigators to meet local IRB requirements. –maintain complete and accurate records of payments made to clinical investigators.

35. IRB, Case Histories, Payments (cont’d) –require investigators to keep case histories on each individual administered the investigational drug or employed as a control in the investigation.

36. Amendments  Protocol Amendments –New Protocol not already submitted –Changes to a submitted protocol 21 CFR 312.30  Information Amendments – Essential information that is not within the scope of a protocol amendment, IND safety reports, or annual report. 21 CFR 312.31

37. New Protocol  Any study not covered by a protocol already contained in the IND  May begin after two conditions are met –The protocol has been submitted to the FDA for its review –The protocol has been approved by the IRB in accordance with 21 CFR 56 21 CFR 312.30(a)

38. Changes to Submitted Protocol  Phase 1 – any change significantly affecting the safety of subjects  Phase 2 & 3 – any change significantly affecting the safety of subjects, scope of the investigation or the scientific quality of the study. 21 CFR 312.30(b)

39. Information Amendments  New chemistry, toxicology, or other technical information  Report of discontinuation of study  Submit as necessary but, to extent feasible, not more than every 30 days. 21 CFR 312.31 (a-b)