Special Issues in FDA-Regulated Studies: The Good, the Bad, and the Ugly
C. Karen Jeans, MSN, CCRN, CIPCOACH Program AnalystVA Office of Research & Development
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
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))
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
IND Issues
IND Issues Is it necessary for an IRB to review IND
documentation? Form FDA 1571: Investigational New Drug
Application (IND) IND Application
IND Applicability
Problems with determining whether an IND applies Key issue: approved drugs used in
unapproved uses Oncology Nutritional Supplements Medical Gases
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)
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)
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
Agency Determination
Is risk significantly increased? Examine parts of the protocol:
Dose Schedule Route of administration Patient population
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
Nutritional Supplements
Regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA)
Do not require FDA approval prior to marketing
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?
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)
Is Air a Drug?
Medical GasesScenario: 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?
IND applicability
Not black and white Regulations Use in protocols
Investigators should communicate with FDA
Sponsor has ultimate responsibility
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
What must be registered?
Federal Law International Committee of Medical
Journal Editors (ICMJE) requirements FDA, NIH, and ICMJE
recommendations
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
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
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.
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.
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
Summary
How to Contact FDA For Questions
1-888-INFO-FDA (1-888-463-6332) Help Desk:
Drugs:http://www.fda.gov/cder/comment.htm
Devices:http://www.fda.gov/cdrh/comment4.html
Biologicshttp://www.fda.gov/cber/pubinquire.htm