Human Research Protection Program 101

March 19-20, 2007Cincinnati, Ohio

The Drug Side of FDA Regulations, with a Few Mechanics

C. Karen Jeans, MSN, CCRNCOACH Project Analyst

What This Talk Will Cover

• The mystique of the Investigational New Drug Application (IND)

• IND• Emergency IND• Treatment IND• Off Label

• What is FDA looking for when Auditing Clinical Investigations?

Introduction to FDA

• U.S. Food and Drug Administration

• Over 10,000 employees

• Key Branches• Center for Drug Evaluation & Research (CDER)• Center for Biologics Evaluation & Research (CBER)• Center for Devices and Radiological Health (CDRH)

FDA Regulates Products

• Drugs, biologics, medical devices (diagnostic and therapeutic), foods: nearly 25% of the U.S. economy

• FDA has responsibility for clinical investigations of FDA-regulated products• Irrespective of study funding (unlike OHRP)• Irrespective of study location within the U.S.• Irrespective of whether for

commercialization/marketing or for scientific knowledge

How Did it All Begin?

• 1937: Sulfanilamide – the first “wonder drug” for strep throat and gonorrhea

• Made into Elixir of Sulfanilamide

• Resulted in 107 deaths

• No laws regarding safety

• Congress got involved

Levels of Authority at FDA

• Law: Passed by Congress; Governs the U.S. Public AND FDA• Federal Food, Drug, and Cosmetic Act

• Regulation: Promulgated by FDA to implement the law; Carries the force of law

• Guidance: FDA’s best advice; Alternate methods may be used to meet regulation

Key FDA Regulations Governing the

Conduct of Clinical Trials

• FDA regulations directed towards protection of human research subjects• 21 CFR Part 50: Informed Consent• 21 CFR Part 56: IRB Regulations

• These regulations are near-identical to the “Common Rule” which governs protection of subjects in federally funded research

Key Regulations Governing the Conduct of Clinical Trials

Regulations supporting FDA’s unique product application review responsibilities and the Agency’s broad public protection mission

• 21 CFR Part 312: IND Regulations (drug)• 21 CFR Part 812: IDE Regulations (device)• 21 CFR Part 314: NDA Regulations (drug)• 21 CFR Part 814: PMA Regulations (device)• 21 CFR Part 11: Electronic Records/Signatures• 21 CFR Part 54: Financial Disclosure

Which Regulations Apply? All three: if VA research involves a FDA regulated product in

a project supported or conducted by HHS or conducted in an institution that agrees to review all research under HHS regulations

HHS

FDA

VA

A Few Differences and Quirks

Definitions• Research (HHS and VA) vs. Clinical Investigation

(FDA)• Human Subject: Recipient of test article or control

(FDA) vs. DHHS and VA• Principal Investigator vs. Sub-Investigator: FDA vs.

DHHS and VA• Investigational New Drug: FDA vs. VA

What is an 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

What Does it Mean?

Is an IND always required?

• No IND is needed when an approved product is used in the course of medical practice (even for an indication different from the approved indication)

• But an IND may be required when an approved product is used in a clinical investigation based on use of the study information or based on increased risk

• Even when exempt from an IND, IRB review and Informed Consent are required

FDA Regulations: Off-Label Use

• FDA-approved products (i.e. marketed products) may be used by authorized prescribers outside of labeled indications for the practice of medicine

• Such use in research (i.e., as part of a systematic investigation designed to contribute to generalizable knowledge) requires IRB review

• Such use intended to support a change in labeling requires IRB review and an IND

How Does One Get an IND?

• Submit an Application to FDA with 8 components:• Cover Sheet and Form FDA 1571• Table of Contents• Introductory Statement and General Investigational

Plan• Clinical Protocol• Chemistry, Manufacturing and Control Information• Pharmacology and Toxicology Information• Previous Human Experience• Additional Information

When Does the IND Go Into Effect?

• FDA notifies sponsors in writing the date it receives the IND application

• 30-day rule• Earlier notification• Clinical hold

21 CFR 312.40(b)

The Special INDs: Emergency and Treatment

• Emergency INDs are used for emergency use of a test article regulations

21 CFR 50.23, 56.102(d), 56.104(c), 312.36

• Treatment INDs are used for treatment protocols or treatment IND

21 CFR 312.34

• Neither of these are INDs used to support marketing

Emergency IND

• Intended subject does not meet the criteria of an existing study protocol

• Approved study protocol does not exist• Manufacturer cannot make the

unapproved investigational drug or biologic available under the company’s IND

• FDA request by telephone or other rapid communication means

Now that you have the Emergency IND, What do you do with it?

• Emergency use of a Test Article Regulations• Use of a test article on a human subject

• in a life-threatening situation • no standard treatment is available• there is not sufficient time to obtain IRB

approval

21 CFR 56.102(d)

Human Subject Severely debilitated or life-threatening conditionStandard acceptable treatment unavailable, and

Sufficient time not available to obtain IRB approval

IND obtained by investigator

from sponsor or authorized by FDA

Informed Consent obtained from participant

No Informed Consent can Be obtained from participant

Test Article administered

Written certification by investigator and

non-study participating physician or independent determination of investigator

IRB Report within 5 working days

FDA Regulations Usually Involved with Emergency IND

• Emergency IND regulations

• Emergency Exemption from Prospective IRB Approval

• Exception from Informed Consent Requirements

• Targeted to Investigators

• Not to be confused with Planned Emergency Research

Why Does One Need a Treatment IND?

The investigational drug• intended to treat a serious or immediately

life-threatening disease;• no comparable or satisfactory alternative drug or

other therapy available to treat that stage of the disease in the intended patient population;

• under investigation in a controlled clinical trial under an IND or the clinical trials have been completed;

• sponsor is actively pursuing marketing approval of the investigational drug with due diligence.

• Confusion about terminology: “humanitarian use”

Treatment INDs

• Require IRB approval• Sponsor may apply for a waiver of

local IRB review• Require informed consent unless the

requirements for exception from informed consent requirements are met as described in 21 CFR 50.23(a)

• Protocols for one or thousands of potential subjects

What’s the Major Difference Between:

An IRB-approved protocol with a IND that will be used for marketing the investigational drug or biologic

vs.

An IRB-approved protocol with a treatment IND?

Review of three INDs

• IND• Most common

• Treatment IND• Designed so that subjects may continue to

receive the benefits of the investigational drug until marketing approval is obtained

• Emergency IND• Obtained by calling FDA• Applied with emergency exemption from

prospective IRB review

IRB Issues

• Does the IRB need to review the IND application?

• What is the IRB’s role in validating the IND?

• What is the IRB ‘s role in emergency use of a test article?

IRB Issues

• Does the IRB need to review the IND application?

NO (with a caveat)

IRB Issues

• What is the IRB’s role in validating the IND?• Applies to portion of AAHRPP element

1.5.A• Policies and procedures describe how the

organization decides whether an IND or IDE is required.

• When an IND or IDE is required, policies and procedures describe how the organization determines that a valid IND or IDE is present before approval of the research.

IRB Issues • Validation of the IND or IDE (Investigational Device

Exemption)• More than making sure a number is on an IRB

application• Source document:

• Industry-sponsored clinical trials:• Clinical Protocol• Investigator’s Brochure (for investigational drugs)• Sponsor correspondence or e-mail• FDA correspondence

• Investigator-initiated• FDA correspondence

• AAHRPP does not define who or what entity must conduct the validation

IRB Issues

• What is the IRB ‘s role in emergency use of a test article?• FDA regulations only require

retrospective IRB notification• Did the use meet the criteria for an

emergency exemption from prospective IRB approval?

• If informed consent was not obtained, did the investigator meet the requirements for exception from informed consent requirements?

FDA Regulations for IRBs – Most Common Warning Letters (483)

• What is a 483?

• What is a warning letter?

• FDA’s Bioresearch Monitoring Program

• Current philosophy of FDA audits of IRBs

• Triggers

FDA Inspections- Triggered by Investigator Action

• “You deprived the IRB of its oversight role by failing to report, for time periods ranging from four years to five and half years, the following serious adverse events to the IRB as required by Standard Procedure 00-701/1.00-201.”

• “You involved human beings as subjects in this research before you obtained their legally effective informed consent, when study-required skin tests were performed on subjects before they signed the informed consent document.”

FDA Inspections- Triggered by Investigator Action

• “You stated that you were not provided with a specific chart by the sponsor to determine exclusion. As a result, this issue was overlooked at the time of the consent. This response is inadequate because as a clinical investigator, it is your responsibility to follow the protocol, including its exclusion criteria.

• “You stated that the unapproved versions of the informed consent forms had a much clearer description of the PURPOSE OF THE STUDY. This response is not adequate. . . . It is your responsibility to use informed consent forms that have been approved by the reviewing IRB prior to initiating any study related procedures.”

FDA IRB Findings

• “The IRB approved an informed consent form that did not contain the basic elements described in 21 CFR 50.25.”

• “The IRB failed to follow some of its own written procedures.”

• “The IRB Coordinator stated that that the IRB approved a protocol required full board approval and issued an approval letter even though it had not been presented to the full board. Review of the approval letter and IRB minutes indicate that the protocol was not presented at the meeting.”

FDA Warning Letters – Key Phrases

• “The above-described deviations are not intended to be an all-inclusive list of deficiencies that may exist.”

• “Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you.”

• “These corrections may be verified during future inspections.”

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