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FDA Regulations Pertaining to Good Clinical Practice and Clinical Trials

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FDA Regulations Pertaining to Good Clinical Practice and Clinical Trials Steven Hirschfeld, MD PhD Office of Cellular, Tissue and Gene Therapy Center for Biologics ... – PowerPoint PPT presentation

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Title: FDA Regulations Pertaining to Good Clinical Practice and Clinical Trials


1
FDA Regulations Pertaining to Good Clinical
Practice and Clinical Trials
  • Steven Hirschfeld, MD PhD
  • Office of Cellular, Tissue and Gene Therapy
  • Center for Biologics Evaluation and Research
  • FDA

2
Fundamentals of Government
  • Law (Act, Statue)- developed and passed by
    Legislative Branch, signed by President.
    Published in the United States Code (USC)
  • Regulation (Rule)- developed and published by
    Executive Branch. Published in the Code of
    Federal Regulations (CFR)

3
FDA Authority
  • Derived from multiple laws and regulations
  • Focus is on product and product use

4
Some Applicable Regulations for Good Clinical
Practice
  • Human Subject Protection 21 CFR Part 50
  • Financial Disclosures by Clinical Investigators
    21 CFR Part 54
  • Institutional Review Boards 21 CFR Part 56
  • Investigational New Drugs 21 CFR Part 312

5
21 CFR Part 50 Human Subject Protection
  • Part A- General Provisions
  • Part B- Informed Consent of Human Subjects
  • Part C- (Reserved)
  • Part D- Additional Safeguards for Children in
    Clinical Investigations

6
21 CFR 50 Subpart D-Additional Safeguards for
Children in Clinical Investigations
  •  50.50 - IRB duties.   50.51 - Clinical
    investigations not involving greater than minimal
    risk.   50.52 - Clinical investigations
    involving greater than minimal risk but
    presenting the prospect of direct benefit to
    individual subjects.   50.53 - Clinical
    investigations involving greater than minimal
    risk and no prospect of direct benefit to
    individual subjects, but likely to yield
    generalizable knowledge about the subjects
    disorder or condition.   50.54 - Clinical
    investigations not otherwise approvable that
    present an opportunity to understand, prevent, or
    alleviate a serious problem affecting the health
    or welfare of children.   50.55 - Requirements
    for permission by parents or guardians and for
    assent by children.   50.56 - Wards.

7
Relationship of 21 CFR 50 Subpart D to 45 CFR 46
Subpart D
  • The FDA regulations apply to all research
    utilizing FDA regulated products
  • The HHS regulations apply to all research that is
    supported by HHS
  • Research supported by HHS using FDA regulated
    products is subject to both sets of regulations
  • The regulations are harmonized

8
Subpart D Adaptation-Definitions
  • children at Sec. 50.3(o) includes persons who
    have not attained the legal age for consent to
    treatments or procedures involved in clinical
    investigations as determined under the applicable
    law of the jurisdiction in which the research
    will be conducted. This provision means that the
    law of the site of the research will determine
    the legal age of consent of the participant.

9
Subpart D Adaptation-Definitions
  • Parent is defined as a child's biological or
    adoptive parent.
  • The term Ward is used in HHS subpart D but is not
    defined. In Sec. 50.3(q), FDA has developed a
    definition for ward that is consistent with the
    use of the term in HHS subpart D. Under Sec.
    50.3(q), a ward is a child who is placed in the
    legal custody of the State or other agency,
    institution, or entity, consistent with
    applicable Federal, State, or local law.

10
Subpart D Adaptation-Definitions
  • Guardian is an individual who is authorized
    under applicable State or local law to consent
    on behalf of a child to general medical care. FDA
    is adopting this definition and is adding text
    to clarify that authorization to consent to
    general medical care must include participation
    in research and, for purposes of this rule, a
    guardian is also an individual authorized to
    consent to a child's participation in research.

11
Subpart D Adaptation-Definitions
  • The definition of permission'' at Sec. 50.3(r)
    is adopted from 45 CFR 46.402(c) of HHS subpart D
    with a minor change to clarify that permission
    applies to participation in clinical
    investigations involving FDA-regulated products.
    FDA's definition at Sec. 50.3(r) generally adopts
    the HHS definition and states that permission is
    the agreement of parent(s) or guardian to their
    child's or ward's participation in a clinical
    investigation.
  • FDA's regulation at Sec. 50.3(r) adds a sentence
    clarifying that permission must be obtained in
    compliance with part 50, subpart B and must
    include the elements of informed consent
    described in FDA's regulations at Sec. 50.25.

12
Subpart D Adaptation-Definitions
  • FDA's regulation, like the HHS regulation,
    defines assent as a child's affirmative agreement
    to participate in research. FDA's definition also
    states that mere failure to object to
    participation in clinical investigations should
    not, absent affirmative agreement, be considered
    assent.

13
IND Regulations 21 CFR 50 Subpart D Section 50.50
IRB Duties
  • In addition to other responsibilities assigned to
    IRBs under this part and part 56 of this chapter,
    each IRB must review clinical investigations
    involving children as subjects covered by this
    subpart D and approve only those clinical
    investigations that satisfy the criteria
    described in Sec. 50.51, Sec. 50.52, or Sec.
    50.53 and the conditions of all other applicable
    sections of this subpart D.

14
Subpart D Adaptation-Minimal Risk
  • FDA anticipates that among the types of
    procedures that might be used in a clinical
    investigation that would present no more than
    minimal risk to children would be clean-catch
    urinalysis, obtaining stool samples,
    administering electroencephalograms, requiring
    minimal changes in diet or daily routine, or the
    use of standard psychological tests. Examples of
    the types of clinical investigations that would
    present no more than minimal risk would include a
    taste test of an excipient or tests of devices
    involving temperature readings orally or in the
    ear.

15
When May IRBs Approve a Clinical Investigation
Not Involving Greater than Minimal Risk?
  • Under Sec. 50.51, an IRB may approve a
    clinical investigation in which no greater than
    minimal risk is presented only if an IRB finds
    and documents that adequate provisions are made
    for soliciting the assent of the children
    involved and the permission of their parents or
    guardians as set forth in Sec. 50.55.

16
When May IRBs Approve Clinical Investigations
Involving Greater Than Minimal Risk But
Presenting the Prospect of Direct Benefit to the
Individual Subjects?
  • Under Sec. 50.52, an IRB may approve a
    clinical investigation in which an IRB finds more
    than minimal risk to children but that presents
    the prospect of direct benefit to individual
    subjects only if the IRB finds and documents
    that
  • (1) The risk is justified by the anticipated
    benefit to the
  • subjects,
  • (2) The relation of the anticipated benefit
    to the risk is at least as favorable to the
    subjects as that presented by available
    alternative approaches, and
  • (3) Adequate provisions are made for
    soliciting the assent of the children and
    permission of their parents or guardians, as set
    forth in Sec. 50.55. . These clinical
    investigations generally are performed in
    children with the disease or condition for which
    the product is intended.

17
When May an IRB Approve a Clinical Investigation
Involving Greater Than Minimal Risk and No
Prospect of Direct Benefit to Individual
Subjects, But Likely to Yield Generalizable
Knowledge About the Subjects' Disorder or
Condition?
  • Section 50.53 provides that in certain
    circumstances an IRB may approve a clinical
    investigation in which the IRB finds that more
    than minimal risk to children is presented
  • (1) By an intervention or procedure that does
    not hold out the prospect of direct benefit for
    the individual subject, or
  • (2) by a monitoring procedure that is not likely
    to contribute to the well-being of the subject.
    The clinical investigation may be approved only
    if the IRB finds and documents that
  • (1) The risk represents a minor increase over
    minimal risk
  • (2) The intervention or procedure presents
    experiences to subjects that are reasonably
    commensurate with those inherent in their actual
    or expected medical, dental, psychological,
    social, or educational situations
  • (3) The intervention or procedure is likely
    to yield generalizable knowledge about the
    subjects' disorder or condition that is of vital
    importance for the understanding or amelioration
    of the subjects' disorder or condition and
  • (4) Adequate provisions are made for
    soliciting the assent of the children and
    permission of their parents or guardians as set
    forth in Sec. 50.55.

18
Subpart D Adaptation-IRB Approval Criteria
  • FDA regulations set out criteria to be satisfied
    if an IRB is to
  • approve research (Sec. 56.111). These criteria
    are the same for initial
  • review and continuing review and include a
    determination by the IRB
  • that
  • (1) Risks to subjects are minimized,
  • (2) Risks to subjects are reasonable in
    relation to anticipated
  • benefits,
  • (3) Selection of subjects is equitable,
  • (4) Informed consent is adequate and
    appropriately documented,
  • (5) Where appropriate, the research plan
    makes adequate provision
  • for monitoring the data collected to ensure the
    safety of subjects,
  • (6) Where appropriate, there are adequate
    provisions to protect the
  • privacy of subjects and to maintain the
    confidentiality of data, and
  • (7) Appropriate safeguards have been included
    to protect vulnerable
  • subjects.

19
Subpart D Adaptation-Monitoring
  • While the level of risk in a clinical
    investigation may change during the course of a
    study, appropriate strategies may be included in
    the study design that may mitigate risks. These
    might include exit strategies in the case of
    adverse events or a lack of efficacy, or
    establishing a data monitoring committee (DMC) to
    review ongoing data collection and recommend
    study changes, including stopping a trial on the
    basis of safety information.

20
21 CFR Part 56-Institutional Review Boards
  • Subpart A--General Provisions   56.101 - Scope.
      56.102 - Definitions.   56.103 -
    Circumstances in which IRB review is required.
      56.104 - Exemptions from IRB requirement.
      56.105 - Waiver of IRB requirement.
  • Subpart B--Organization and Personnel   56.107
    - IRB membership.

21
21 CFR Part 56-Institutional Review Boards
  • Subpart C--IRB Functions and Operations
      56.108 - IRB functions and operations.
      56.109 - IRB review of research.   56.110 -
    Expedited review procedures for certain kinds of
    research involving no more than minimal risk, and
    for minor changes in approved research.
      56.111 - Criteria for IRB approval of
    research.   56.112 - Review by institution.
      56.113 - Suspension or termination of IRB
    approval of research.   56.114 - Cooperative
    research.

22
21 CFR Part 56-Institutional Review Boards
  • Subpart D--Records and Reports   56.115 - IRB
    records.
  • Subpart E--Administrative Actions for
    Noncompliance   56.120 - Lesser administrative
    actions.   56.121 - Disqualification of an IRB
    or an institution.   56.122 - Public disclosure
    of information regarding revocation.   56.123 -
    Reinstatement of an IRB or an institution.
      56.124 - Actions alternative or additional to
    disqualification

23
IND Regulations 21 CFR 312 Subpart A General
Provisions
  •  312.1 - Scope.   312.2 - Applicability.
      312.3 - Definitions and interpretations.
      312.6 - Labeling of an investigational new
    drug.   312.7 - Promotion and charging for
    investigational drugs.   312.10 - Waivers.

24
IND Regulations 21 CFR 312 Subpart
B Investigations New Drug Application (IND)
  •   312.20 - Requirement for an IND.
      312.21 - Phases of an investigation.
      312.22 - General principles of the IND
    submission.   312.23 - IND content and format.
      312.30 - Protocol amendments.   312.31 -
    Information amendments.   312.32 - IND safety
    reports.   312.33 - Annual reports.   312.34
    - Treatment use of an investigational new drug.
      312.35 - Submissions for treatment use.
      312.36 - Emergency use of an investigational
    new drug.   312.38 - Withdrawal of an IND.

25
IND Regulations 21 CFR 312 Subpart
C Administrative Actions
  • 312.40 - General requirements for use of an
    investigational new drug in a clinical
    investigation.   312.41 - Comment and advice on
    an IND.   312.42 - Clinical holds and requests
    for modification.   312.44 - Termination.
      312.45 - Inactive status.   312.47 -
    Meetings.   312.48 - Dispute resolution.

26
IND Regulations 21 CFR 312 Subpart
D Responsibilities of Sponsors and Investigators
  •    312.50 - General responsibilities of
    sponsors.   312.52 - Transfer of obligations to
    a contract research organization.   312.53 -
    Selecting investigators and monitors.   312.54
    - Emergency research under Sec. 50.24 of this
    chapter.   312.55 - Informing investigators.
      312.56 - Review of ongoing investigations.
      312.57 - Recordkeeping and record retention.
      312.58 - Inspection of sponsors records and
    reports.   312.59 - Disposition of unused
    supply of investigational drug.   312.60 -
    General responsibilities of investigators.
      312.61 - Control of the investigational drug.
      312.62 - Investigator recordkeeping and
    record retention.   312.64 - Investigator
    reports.   312.66 - Assurance of IRB review.
      312.68 - Inspection of investigators records
    and reports.   312.69 - Handling of controlled
    substances.   312.70 - Disqualification of a
    clinical investigator.

27
IND Regulations 21 CFR 312 Subpart E Drugs
Intended to Treat Life Threatening and Severely
Debilitating Illnesses
  •  312.80 - Purpose.   312.81 - Scope.
      312.82 - Early consultation.   312.83 -
    Treatment protocols.   312.84 - Risk-benefit
    analysis in review of marketing applications for
    drugs to treat life-threatening and
    severely-debilitating illnesses.   312.85 -
    Phase 4 studies.   312.86 - Focused FDA
    regulatory research.   312.87 - Active
    monitoring of conduct and evaluation of clinical
    trials.   312.88 - Safeguards for patient
    safety.

28
Section 312.87 Active Monitoring of Conduct and
Evaluation of Clinical Trials
  • For drugs covered under this section, the
    Commissioner and other agency officials will
    monitor the progress of the conduct and
    evaluation of clinical trials and be involved in
    facilitating their appropriate progress.

29
Sec. 312.88 Safeguards for patient safety.
  • All of the safeguards incorporated within parts
    50, 56, 312, 314, and 600 of this chapter
    designed to ensure the safety of clinical testing
    and the safety of products following marketing
    approval apply to drugs covered by this section.
    This includes the requirements for informed
    consent (part 50 of this chapter) and
    institutional review boards (part 56 of this
    chapter). These safeguards further include the
    review of animal studies prior to initial human
    testing (Sec. 312.23), and the monitoring of
    adverse drug experiences through the requirements
    of IND safety reports (Sec. 312.32), safety
    update reports during agency review of a
    marketing application (Sec. 314.50 of this
    chapter), and postmarketing adverse reaction
    reporting (Sec. 314.80 of this chapter).

30
Conclusions
  • FDA has authority to regulate clinical studies
    using FDA regulated products
  • FDA regulations incorporate IRB and FDA oversight
    of studies
  • Regulations exist for studies using products
    intended to treat life threatening illnesses
  • Regulations exist for providing additional
    safeguards for children enrolled in clinical
    investigations
  • HHS and FDA regulations are intended to be
    harmonized
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