Title: Special Issues in FDA-Regulated Studies: The Good, the Bad, and the Ugly
1Special 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
2What 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
3FDA 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))
4Investigational 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
5IND Issues
- IND Issues
- Is it necessary for an IRB to review IND
documentation? - Form FDA 1571 Investigational New Drug
Application (IND) - IND Application
6IND Applicability
- Problems with determining whether an IND applies
- Key issue approved drugs used in unapproved
uses - Oncology
- Nutritional Supplements
- Medical Gases
7IND 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)
8IND 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)
9Oncology 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
10Agency Determination
- Is risk significantly increased?
- Examine parts of the protocol
- Dose
- Schedule
- Route of administration
- Patient population
11Is 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
12Nutritional Supplements
- Regulated under the Dietary Supplement Health and
Education Act of 1994 (DSHEA) - Do not require FDA approval prior to marketing
13Is St. Johns 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. Johns Wart. She is
going to study whether St. Johns Wart reduces
cyclosporine levels in patients after kidney
transplant. She doesnt know where to list it on
the IRB application. - Question Should the investigator list it
on the IRB application as a drug?
14Is St. Johns 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)
15Is Air a Drug?
16Medical 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 didnt the IRB
Administrative staff didnt follow-up on this
before the IRB convened meeting. - Question Was this a reasonable
expectation?
17IND applicability
- Not black and white
- Regulations
- Use in protocols
- Investigators should communicate with FDA
- Sponsor has ultimate responsibility
18Clinical 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 FDAs IND
regulations - September, 2007 Food and Drug Amendment Act
- Expanded scope of clinical trials that must be
registered - Established civil monetary penalties
19What must be registered?
- Federal Law
- International Committee of Medical Journal
Editors (ICMJE) requirements - FDA, NIH, and ICMJE recommendations
20FDA 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
21FDA 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
22International 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.
23FDA, 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.
24Clinical 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
25Summary
26How 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
- Biologics
- http//www.fda.gov/cber/pubinquire.htm