1. Special Issues in FDA-Regulated Studies: The Good, the Bad, and the Ugly C. Karen Jeans, MSN, CCRN, CIP COACH Program Analyst VA Office of Research & Development

2. What this Talk will Cover  IND Issues Application Issues and the Role of the IRB IND applicability in Special Situations  Oncology?  Nutritional Supplements?  Air?  Clinical Trial Registry

3. FDA Definition: Clinical Investigation Use of a drug other than the use of an approved drug in the course of medical practice (21 CFR §312.3) Use of a medical device other than the use of an approved medical device in the course of medical practice (Food, Drug and Cosmetic Act §530(g)(3)(a)(i)) Gather data that will be submitted to or held for inspection by FDA in support of a FDA marketing permit for a food, including a dietary supplement that bears a nutrient content claim or a health claim, an infant formula, a food or color additive, a drug for human use, a medical device for human use, a biological product for human use, or an electronic product. (21 CFR §50.1(a), or 21 CFR §56.101(a))

4. Investigational New Drug (IND) Application?  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  An IND is required when an unapproved drug or biologic is used in a clinical investigation

5. IND Issues  IND Issues Is it necessary for an IRB to review IND documentation?  Form FDA 1571: Investigational New Drug Application (IND)  IND Application

6. IND Applicability  Problems with determining whether an IND applies Key issue: approved drugs used in unapproved uses  Oncology  Nutritional Supplements  Medical Gases

7. IND Exemptions  Clinical exemption of a drug product that is lawfully marketed in the United States is exempt from 21 CFR 312 if all apply: The investigation is not intended to be reported to the FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling of the drug The investigation is not intended to reported to the FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug  21 CFR 312.2(b)(i-iv)

8. IND Exemptions (cont.)  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  The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50  21 CFR 312.2(b)(i-v)

9. Oncology Drugs  1996 Agency Cancer Initiative Reason: Many sponsor-investigators submitting INDs for exploratory studies of off-label indications  IRBs incorrectly believed IND required  Pharmaceutical manufacturer provided drug free of charge  Majority of sponsor-investigator IND submissions for marketed cancer drugs were exempt

10. Agency Determination  Is risk significantly increased? Examine parts of the protocol:  Dose  Schedule  Route of administration  Patient population

11. Is it exempt from IND requirements?  Phase 1 oncology trial of a marketed drug  Studies of chemotherapy given after surgery to remove cancer  Study of high-dose therapy in cancer patients  Studies of cytotoxic drugs

12. Nutritional Supplements  Regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA)  Do not require FDA approval prior to marketing

13. Is St. John’s Wart a Drug? Scenario: Investigator calls the IRB office stating that she is submitting a protocol for review at the next IRB meeting using St. John’s Wart. She is going to study whether St. John’s Wart reduces cyclosporine levels in patients after kidney transplant. She doesn’t know where to list it on the IRB application. Question: Should the investigator list it on the IRB application as a drug?

14. Is St. John’s Wart a test article?  Test article: Any drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the Food, Drug, and Cosmetic Act or under sections 351 and 354-360F of the Public Health Service Act.  21 CFR 50.3(j)

15. Is Air a Drug?

16. Medical Gases Scenario: During the IRB meeting, the IRB is reviewing a protocol involving the administration of an investigational new drug vs. usual care. The investigator is also going to use supplemental CO2 (carbon dioxide gas) during blood flow scans. They ask you as the IRB Administrator whether they submitted any materials about the IND status of the gas. The investigator did not, and the IRB Chair wants to know why didn’t the IRB Administrative staff didn’t follow-up on this before the IRB convened meeting. Question: Was this a reasonable expectation?

17. IND applicability  Not black and white Regulations Use in protocols  Investigators should communicate with FDA  Sponsor has ultimate responsibility

18. Clinical Trial Registration  1997 – Section 113 of the FDA Modernization Act of 1997 Create a public resource for information on studies of drugs, including biological drug products, to treat serious or life-threatening diseases and conditions conducted under FDA’s IND regulations  September, 2007 – Food and Drug Amendment Act Expanded scope of clinical trials that must be registered Established civil monetary penalties

19. What must be registered?  Federal Law  International Committee of Medical Journal Editors (ICMJE) requirements  FDA, NIH, and ICMJE recommendations

20. FDA requirements Trials of Drugs and Biologics  Controlled clinical investigations, other than Phase 1 investigations, of a product subject to FDA regulation, and Trials of Devices  Prospective clinical studies of health outcomes comparing an intervention with a device against a control in human subjects (other than small clinical trials to determine the feasibility of a device, or clinical trials to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes; and pediatric postmarket surveillance studies, as required under the Federal Food, Drug and Cosmetic Act.  Public Law 110-85, Title VIII

21. FDA requirements Form FDA 3674  Certification of Compliance, under 42 U.S.C. § 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. § 282(j)) When is it filed? Current issues with interpretation

22. International Committee of Medical Journal Editors (ICMJE) Requirements  Any research study that prospectively assigns human participants or groups of humans to one or more health- related interventions to evaluate the effects on health outcomes to be registered. “Health-Related” interventions include any intervention used to modify a biomedical or health- related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). “Health Outcomes” include any biomedical or health- related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.  Includes Phase I investigations and investigations which are not biomedical clinical trials.

23. FDA, NIH, and ICMJE Recommendations  FDA and NIH Registration of all trials, regardless of whether it is required by law.  ICMJE Those who are uncertain whether their trial meets the ICMJE definition should err on the side of registration if they wish to seek publication in an ICMJE journal.

24. Clinical Trial Registration  Who is responsible for ensuring clinical trial registration as required by FDA for the following? Industry-sponsored clinical trials Sponsor-Investigator initiated clinical trials that are not VA funded VA funded programs

25. Summary

26. How to Contact FDA For Questions  1-888-INFO-FDA (1-888-463-6332)  Help Desk: Drugs: http://www.fda.gov/cder/comment.htm http://www.fda.gov/cder/comment.htm Devices: http://www.fda.gov/cdrh/comment4.html Biologics http://www.fda.gov/cber/pubinquire.htm