Human Research Protection Program 101

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Human Research Protection Program 101

• September 18-19, 2007
• Little Rock, Arkansas

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The Drug Side of FDA Regulations
C. Karen Jeans, MSN, CCRN COACH Project Analyst
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What This Talk Will Cover

• Institutional responsibilities for IRB review of
  protocols involving human research and
• Drugs with an Investigational New Drug
  Application (IND)
• Emergency Investigational New Drug Application
  (IND)
• Treatment Investigational New Drug Application
  (IND)
• Off Label
• FDA regulatory findings

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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)

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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
• Irrespective of study location within the U.S.
• Irrespective of whether for commercialization/mark
  eting or for scientific knowledge

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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

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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 FDAs best advice Alternate methods
  may be used to meet regulation

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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

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Key Regulations Governing the Conduct of
Clinical Trials

• Regulations supporting FDAs unique product
  application review responsibilities and the
  Agencys 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

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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

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A Few Differences and Quirks

• Definitions
• Research (HHS and VA) vs. Clinical Investigation
  (FDA)
• Human Subject FDA vs. DHHS and VA
• Principal Investigator vs. Sub-Investigator FDA
  vs. DHHS and VA
• Investigational New Drug FDA vs. VA

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FDA Definitions

• Human Subject An individual who is or becomes a
  participant in research, either as a recipient of
  the test article or as a control. A subject may
  be either a healthy individual or a patient.
• 21 CFR 50.3(g)
• If the research involves a medical device,
  individuals are considered subjects when the
  participant is in an investigation either as an
  individual or on whose specimen an
  investigational device is used on or as a
  control.
• 21 CFR 812.3(p)

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FDA Definitions

• 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))

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FDA Definitions

• Investigator
• An individual who actually conducts a clinical
  investigation (i.e., under whose immediate
  direction the test article is administered or
  dispensed to, or used involving, a subject) or,
  in the event of an investigation conducted by a
  team of individuals, is the responsible leader of
  that team.
• 21 CFR 56.102(h)

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FDA Definitions

• Investigational New Drug
• A new drug or biological drug that is used in a
  clinical investigation. The term also includes a
  biological term that is used in intro for
  diagnostic purposes. The terms investigational
  drug and investigational new drug are deemed
  to be synonymous for purposes of this part.
• 21 CFR 312.3(b)

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Who determines which set(s) of regulations apply?

• Policies and procedure describe which activities
  meet the regulatory definitions of research
• The entity or office that can provide a
  determination
• Criteria used to make determinations
• The process used to communicate definitions
• AAHRPP Element 1.3.A.

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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

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• What Does it Mean?

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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

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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)

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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)

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Determination of IND Exemption

• Institution is responsible for having a policy
  and procedure to confirm that the drug has an IND
  or the protocol meets one of the FDA exemptions
  from the requirements to have an IND
• AAHRPP Accreditation Standard 1.5.A

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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

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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
• Investigators Brochure
• Clinical Protocol
• Chemistry, Manufacturing and Control Information
• Pharmacology and Toxicology Information
• Previous Human Experience
• Additional Information
• 21 CFR 312.23

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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)

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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

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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 companys IND
• FDA request by telephone or other rapid
  communication means

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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)

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Human Subject Severely debilitated or
life-threatening condition Standard 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
Written certification by investigator and
non-study participating physician or
independent determination of investigator
Test Article administered
IRB Report within 5 working days
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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 (21 CFR 50.24)
• Planned Emergency Research Not Allowed by VA

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Emergency Use of a Test Article

• Policies and procedures
• Criteria for emergency use
• Informed consent
• Prior notification of intent
• IRB review of 5-day reports
• AAHRPP Element 1.5.c.

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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

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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

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Whats 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?

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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

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IRB Issues

• Does the IRB need to review the IND application?
• What is the IRBs role in validating the IND?
• What is the IRB s role in emergency use of a
  test article?

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IRB Issues

• Does the IRB need to review the IND application?
• NO

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IRB Issues

• What is the IRBs 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.

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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
• Sponsor correspondence or e-mail
• FDA correspondence
• Investigator-initiated
• FDA correspondence
• AAHRPP does not define who or what entity must
  conduct the validation (Element 1.5.C.)

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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?

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FDA Regulations for IRBs Most Common Warning
Letters (483)

• What is a 483?
• What is a warning letter?
• FDAs Bioresearch Monitoring Program
• Current philosophy of FDA audits of IRBs
• Triggers

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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.

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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.

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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.

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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.

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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
• Biologics
• http//www.fda.gov/cber/pubinquire.htm

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QUESTIONS