Download FDA Guidance for IRBs

Guidance for IRBs
Barbara D. Wright
Bioresearch Monitoring Specialist
New Orleans District
Baton Rouge Resident Post
Objectives
• Define key IRB terms
• Define IRB Exempt Studies
• Identify research eligible for Expedited
Review
• Define IND, IDE and Expanded Access
• Identify the Categories of Expanded Access
• Identify the Types of Regulatory
Submissions for Expanded Access
2
Objectives
• Identify the Responsibilities of
Investigators, Sponsors and IRB with
Regard to Expanded Access to
Investigational Drugs
• Identify the IRB’s Responsibilities in
Regard to IND or IDE Exempt Research
• Informed Consent Waivers
3
21 CFR 56
Institutional Review Boards
Objective:
To protect the rights and welfare of human
subjects involved in clinical investigations.
4
FDA Authority: 21 CFR 56.101
• IND & IDE research [FD&C Act 505(i) & 520(g)]
• Investigations submitted in support of
research or marketing applications
This may include foods that bear a nutrient
content or health claim (including dietary
supplements), infant formulas, food & color
additives, drugs or biologicals for human
use, medical devices for human use and
electronic products.
5
Definitions
Institutional Review Board – any board,
committee, or other group formally designated by
an institution to review, to approve the initiation
of, and to conduct periodic review of, biomedical
research involving human subjects.
Human Subject – an individual who is or
becomes a participant in research, either as a
recipient of the test article or control. A subject
may be either a healthy individual or a patient.
6
Definitions
Test article – any drug for human use,
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 FD&C
Act or under sections 351 or 354-360F of the
PHS Act.
7
Definitions
Minimal Risk – the probability and magnitude
of harm or discomfort anticipated in the
research are not greater in and of themselves
than those ordinarily encountered in daily life
or during the performance of routine physical
or psychological examinations or tests.
8
Definitions
Emergency use – the use of a test article on
a human subject in a life-threatening situation
in which no standard acceptable treatment is
available, and in which there is not sufficient
time to obtain IRB approval.
9
Definitions
IND – Investigational New Drug application
• required to legally ship an unapproved new
drug in interstate commerce
• establishes conditions for use
IDE – Investigational Device Exemption
• required to legally ship an investigational
medical device
10
IRB Review Exemptions - 21 CFR 56.104
• (a) Any investigation which commenced before July
27, 1981 and was subject to requirements for IRB
review under FDA regulations before that date,
provided that the investigation remains subject to
review of an IRB which meets the FDA requirements
in effect before July 27, 1981.
• (b) Any investigation commenced before July 27,
1981 and was not otherwise subject to requirements
for IRB review under Food and Drug Administration
regulations before that date.
11
IRB Review Exemptions - 21 CFR 56.104
• (c) Emergency use of a test article, provided that
such emergency use is reported to the IRB within 5
working days. Any subsequent use of the test article
at the institution is subject to IRB review.
• (d) Taste & food quality evaluations and consumer
acceptance studies, if wholesome foods without
additives are consumed or if a food is consumed
that contains a food ingredient at or below the level
and for a use found to be safe, or agricultural,
chemical, or environmental contaminant at or below
the level found to be safe, by FDA or approved by
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the EPA or FSIS/USDA
Categories of Research Eligible for
Expedited Review
(A) Research activites that (1) present no more than mimimal
risk to human subjects, and (2) involve only procedures listed
in one or more of the following categories, may be reviewed
by the IRB through the expedited review procedure
authorized by 45 CFR 46.110 and 21 CFR 56.110. The
activities listed should not be deemed to be of minimal risk
simply because they are included on this list. Inclusion on this
list merely means that the activity is eligible for review
through the expedited review procedure when the specific
circumstances of the proposed research involve no more
than minimal risk to human subjects.
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Categories of Research Eligible for
Expedited Review
(B) The categories in this list apply regardless of the age of
subjects, except as noted.
(C) The expedited review procedure may not be used where
identification of the subjects and/or their responses would
reasonably place them at risk of criminal or civil liability or be
damaging to the subjects’ financial standing,employability,
insurability, reputation, or be stigmatizing, unless reasonable
and appropriate protections will be implemented so that risks
related to invasion of privacy and breach of confidentiality are
no greater than minimal.
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Categories of Research Eligible for
Expedited Review
(D) The expedited review procedure may not be used
for classified research involving human subjects.
(E) IRBs are reminded that the standard requirements
for informed consent (or its waiver, alteration, or
exception) apply regardless of the type of review—
expedited or convened— utilized by the IRB.
(F) Categories one (1) through seven (7) pertain to
both initial and continuing IRB review.
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Categories of Research Eligible for
Expedited Review
(1) Clinical studies of drugs and medical devices only when
condition (a) or (b) is met.
(a) Research on drugs for which an investigational new drug
application (21 CFR Part 312) is not required.
(b) Research on medical devices for which (i) an
investigational device exemption application (21 CFR Part
812) is not required; or (ii) the medical device is
cleared/approved for marketing and the medical device is
being used in accordance with its cleared/approved labeling.
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Categories of Research Eligible for
Expedited Review
(2) Collection of blood samples by finger stick, heel stick, ear
stick, or venipuncture as follows:
(a) From healthy, non-pregnant adults who weigh at least 110
pounds. Amounts drawn NTE 550 ml/8 weeks and no
more frequently than 2 times/week; or
(b) (b) from other adults and children, considering the age,
weight, and health of the subjects, the collection
procedure, the amount of blood to be collected, the
frequency with which it will be collected. Amounts drawn
NTE the lesser of 50 ml or 3 ml per kg/8 weeks and no
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more frequently than 2 times/week.
Categories of Research Eligible for
Expedited Review
(3) Prospective collection of biological specimens for
research purposes by noninvasive means.
(4) Collection of data through noninvasive procedures (not
involving general anesthesia or sedation) routinely employed
in clinical practice, excluding procedures involving x-rays or
microwaves. Where medical devices are employed, they
must be cleared/approved for marketing. (Studies intended to
evaluate the safety and effectiveness of the medical device
are not generally eligible for expedited review, including
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studies of cleared medical devices for new indications.)
Categories of Research Eligible for
Expedited Review
(5) Research involving materials (data, documents, records,
or specimens) that have been collected or will be collected
solely for nonresearch purposes (such as medical treatment
or diagnosis).
(6) Collection of data from voice, video, digital, or image
recordings made for research purposes.
19
Categories of Research Eligible for
Expedited Review
(7) Research on individual or group characteristics or
behavior (including, but not limited to, research on
perception, cognition, motivation, identity, language,
communication, cultural beliefs or practices, and social
behavior) or research employing survey, interview, oral
history, focus group, program evaluation, human factors
evaluation, or quality assurance methodologies.
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Categories of Research Eligible for
Expedited Review
(8) Continuing review of research previously approved by the
convened IRB as follows:
(a) Where (i) the research is permanently closed to the
enrollment of new subjects; (ii) all subjects have
completed all research-related interventions; and (iii) the
research remains active only for long-term follow-up of
subjects; or
(b) Where no subjects have been enrolled and no additional
risks have been identified; or
(c) Where the remaining research activities are limited to data
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analysis.
Categories of Research Eligible for
Expedited Review
(9) Continuing review of research, not conducted under an
investigational new drug application or investigational device
exemption where categories two (2) through eight (8) do not
apply but the IRB has determined and documented at a
convened meeting that the research involves no greater than
minimal risk and no additional risks have been identified.
[Federal Register Vol. 63, No. 216 Monday, November 9, 1998 pp 60353-60356]
22
More Definitions – Drug Research
Expanded Access
vs.
Access
vs.
Treatment Use
Use of an investigational drug when the
primary purpose is to diagnose, monitor or
treat a patient’s disease or condition.
23
Expanded Access for Treatment Use
FDA has had rules in place since 1987 that
have allowed patients to have access to
investigational drugs under certain
circumstances, even though the safety and
effectiveness of the drug has not been fully
established.
Treatment use is not primarily intended to
obtain safety or effectiveness data.
24
Changes to Federal Regulations
On August 12, 2009, FDA announced
changes to the rules to make them broader
and clearer for the patient and the treating
physician, while still preserving the integrity
of clinical trials designed to find out whether
a drug has a desired effect on some disease
or condition.
25
Expanded Access Rule
In order to permit treatment of a patient with an
investigational drug under an expanded access
program, FDA generally must be satisfied that:
• The patient’s disease or condition has no
satisfactory approved therapy. An example of this
is a rare type of cancer that has no known or
approved treatment. Or, it may be the case that
the available treatments did not work for the
patient.
[21 CFR 312.305(a)]
26
Expanded Access Rule
• The potential benefit for the patient justifies the
potential risks. An example of this is the
potential for longer survival with a disease or
condition.
• The expanded availability of the untested drug
will not interfere with that product’s
development. For example, access to an
investigational drug shouldn’t interfere with
enrollment in clinical trials needed to
demonstrate the drug's safety and
effectiveness.
[21 CFR 312.305(a)] 27
The Expanded Access Rule:
• Explains the several different kinds of
access that are possible, including access
for individual patients, for small numbers of
patients, and for large numbers of patients
in what are called “treatment protocols”
• Ensures safeguards to protect patients
• Preserves the ability to develop meaningful
data on the drugs available under
expanded access
28
Categories of Expanded Access
• Access for Individual Patients, including for
Emergency Use (21 CFR 312.310)
• Access for Intermediate-Size Patient
Populations (21 CFR 312.315)
• Access for Large Patient Populations under
a Treatment IND or Treatment Protocol (21
CFR 312.320)
29
Types of Regulatory Submissions
Access Protocol
• submitted as an amendment to an existing IND
• preferred method when an existing IND is in effect
New IND (Access IND/Treatment IND)
• for treatment use only
• when there is no existing IND in effect or the
current sponsor declines to sponsor the treatment
access
Submissions under an existing IND may be made by either
the sponsor or a licensed physician.
30
Content of Submissions
The different types of submissions have some
differences in content requirements. All must
contain information required by 21 CFR
312.305(b). However,
• Additional requirements for Individual patient
and Emergency submissions are outlined in 21
CFR 312.310(b);
• Requirements for Intermediate-size patient
populations are in 21 CFR 312.315(c); and
• Treatment IND/protocols are addressed in 21
CFR 312.320(b).
31
Role of the Physician
• Determine that the probable risk to the
patient from the investigational drug is not
greater than the probable risk from the
disease or condition [21 CFR 312.310(a)]
• The decision should be based on the
physician’s knowledge of the patient’s
clinical situation and based on available
information regarding the drug.
32
Role of FDA
• Determine that the potential benefit justifies
the risks of treatment use and that those
risks are not unreasonable in the context of
the disease or condition [21 CFR 312.305(a)(2)]
• Determine that the patient has a serious or
life-threatening disease or condition and no
other comparable/satisfactory therapeutic
options exist [21 CFR 312.305(a)(1)]
33
Role of FDA
• Determine that providing access will not
interfere with development of the drug for
the expanded access use [21 CFR
312.305(a)(3)]
• Determine that the patient may not obtain
the drug under another IND or protocol
(e.g., in a clinical study) [21 CFR 312.310(a)(2)]
34
Role of the IRB
Full board approval is required for all
expanded access uses, including individual
patient access uses. [21 CFR 312.305(c)(4)]
35
Emergency Authorizations
[21 CFR 312.310(d)]
• FDA may authorize expanded access for an
individual patient without a written submission if
there is “an emergency that requires the
patient to be treated before a written
submission can be made.” (e.g., treatment is
needed within a very limited # of hours/days)
• The licensed physician/sponsor must agree to
submit an expanded access IND or protocol within
15 working days
• Reporting to IRB within 5 days [21 CFR 56.104(c)]
36
IND Exempt Research
What are the IRB’s responsibilities with
respect to verifying the determination of
whether an IND is required for an FDAregulated investigation?
The IRB should ask the clinical investigator
whether the sponsor determined that an IND is or
is not required and the basis for the
determination. The IRB may request supporting
documentation (e.g., letter from sponsor or FDA).
37
IND Exemptions [21 CFR 312.2(b)]
(1) The clinical investigation of a drug product that is
lawfully marketed in the United States is exempt
from the requirements of this part if all the following
apply:
• (i) The investigation is not intended to be reported
to 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;
38
IND Exemptions [21 CFR 312.2(b)]
• (ii) If the drug that is undergoing investigation is
lawfully marketed as a prescription drug product,
the investigation is not intended to support a
significant change in the advertising for the
product;
• (iii) 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;
39
IND Exemptions [21 CFR 312.2(b)]
• (iv) 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; and
• (v) The investigation is conducted in compliance
with the requirements of 312.7 (promotion).
(2)(i) A clinical investigation involving an in vitro
diagnostic biological product listed in paragraph
(b)(2)(ii) of this section is exempt from the
requirements of this part if
40
IND Exemptions [21 CFR 312.2(b)]
(a ) it is intended to be used in a diagnostic
procedure that confirms the diagnosis made by
another, medically established, diagnostic product
or procedure and
(b ) it is shipped in compliance with 312.160.
(ii) In accordance with paragraph (b)(2)(i) of this
section, the following products are exempt from the
requirements of this part: (a ) blood grouping
serum; (b ) reagent red blood cells; and (c ) antihuman globulin.
41
IND Exemptions [21 CFR 312.2(b)]
(3) A drug intended solely for tests in vitro or in
laboratory research animals is exempt from the
requirements of this part if shipped in accordance
with 312.160.
(4) FDA will not accept an application for an
investigation that is exempt under the provisions of
paragraph (b)(1) of this section.
42
IND Exemptions [21 CFR 312.2(b)]
(5) A clinical investigation involving use of a
placebo is exempt from the requirements of this
part if the investigation does not otherwise require
submission of an IND.
(6) A clinical investigation involving an exception
from informed consent under 50.24 of this chapter
(i.e., emergency research) is not exempt from the
requirements of this part.
43
When in IND Doubt
If the Sponsor is uncertain whether an IND is
required, the Sponsor should contact the
appropriate review division within FDA.
If the review division is not known, contact CDER at:
Office of Communications, Division of Drug
Information, Center for Drug Evaluation and
Research, Food and Drug Administration
10001 New Hampshire Avenue, 4th Floor
Silver Spring, MD 20993
(301) 796-3400
44
When in IND Doubt
Contact CBER at:
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448
(800) 835-4709 or (301) 827-1800
45
Investigational Drug Charging Rule
The charging rule permits drug
manufacturers to charge patients for an
investigational drug in clinical trials or that's
being made available for expanded access.
Charging in clinical trials will be allowed
under very limited circumstances, but will be
permitted for most expanded access uses.
46
Expanded Access Mechanisms for
Medical Devices
• Compassionate Use – IDE Supplement
(deviation/change in the investigation)
• Emergency Use – IDE Supplement
(Notification within 5 days)
• Treatment IDE (must be for the same use as
an approved IDE)
• Continued Access Policy / Extended
Investigations – IDE Supplement (does not require
life-threatening or serious condition)
47
48
Expanded Access Mechanisms for
Unapproved Devices
Expanded
Access
Mechanism
Regulatory
Authority
Emergency
Use
“Guidance for the Emergency Use of 1. Life-threatening condition‡;
Unapproved Medical Devices”
2. No alternative;
and
50 FR 42866
3. No time to obtain
21 CFR 812.35(a)
FDA approval.
Before or after initiation of
clinical trial
Compassionate
Use
21 CFR 812.35(a)
During clinical
trial
Treatment IDE
Continued
Access
Criteria for Use
1. Serious disease
or condition and
2. No alternative.
21 CFR 812.36
1. Life-threatening
or serious disease;
2. No alternative;
3. Controlled clinical trial; and
4. Sponsor pursuing
marketing approval.
“Continued Access to Investigational 1. Public health need; or
Devices During PMA Preparation
2. Preliminary evidence that device will be
and Review”
effective and no significant
safety concerns.
ODE Blue Book
IDE Memorandum
#D96-1
When Can It
Be Used?
During clinical
trial
After completion of clinical trial
49
Expanded Access Mechanisms for
Unapproved Devices
Expanded
Number of
Access
Patients to be
Mechanism Treated
FDA Approval
Needed?
How is FDA Approval
Obtained?
Patient Protection
Measures
Emergency
Use
Limited to few patients
No; submit report to FDA
following device use
Not applicable
Compassionate
Use
Individual
patient or small groups of
patients
Yes
IDE supplement with:
1. Explanation of circumstances
constituting need for the device;
2. Reasons alternatives not
acceptable;
3. Deviations from protocol, if any;
and
4. Patient protection measures.
1. Independent assessment
by uninvolved doctor;
2. IRB chairperson’s
concurrence;
3. Institutional clearance;
and
4. Informed consent
1. Independent
assessment by uninvolved
doctor;
2. IRB chairperson’s
concurrence;
3. Institutional clearance;
and
4. Informed consent.
50
Expanded Access Mechanisms for
Unapproved Devices
Expanded
Number of
Access
Patients to be
Mechanism Treated
FDA Approval
Needed?
How is FDA Approval
Obtained?
Patient
Protection
Measures
Treatment IDE
Wide access;
depends on patient/physicia
n need
Yes
1. IRB approval and
2. Informed consent.
Continued
Access
Same rate of enrollment as
study
Yes
Treatment IDE supplement with:
1. Intended Use, protocol, and patient
selection criteria;
2. Rationale for treatment use
3. Methods used to evaluate device use
and minimize risks;
4. Monitoring plan;
5. Summary of Safety & Efficacy data
6. Instructions for use and device
labeling;
7. Commitment to patient protection;
8. Investigator agreement; &
9. Price, if will be sold.
IDE supplement with:
1. Justification for extended study;
2. Summary of Safety & Efficacy
data and risks posed by the device;
3. Proposed enrollment rate;
4. Clinical protocol; and
5. Progress towards marketing
approval.
1. IRB approval and
2. Informed consent.
51
Treatment vs. Continued Access
• Both are intended to provide additional
access to an unapproved device, once
preliminary evidence regarding safety &
efficacy is available to FDA
• Treatment IND regulation has a more
narrow application – immediately lifethreatening or serious disease or condition
• Continued Access – may be considered for
any clinical investigation
52
Compassionate Use vs. Continued
Access
• Compassionate Use – patients do not meet
eligibility criteria for open trial & must have
immediately life-threatening or serious
disease or condition
• Continued Access / Extended Investigation
– may be considered for any clinical
investigation after IDE trial enrollment has
been closed
53
IDE Exempt Research
What are the IRB’s responsibilities with
respect to verifying the determination of
whether an IDE is required for an FDAregulated investigation?
For investigational device studies, the sponsor
is responsible for determining whether
submission of an IDE application to FDA is
required before a study may proceed.
54
Types of Device Studies
• Significant Risk (SR) – must have an IDE
application approved by FDA and IRB approval
• Nonsignificant Risk (NSR) – must follow
abbreviated IDE requirements in 21 CFR
812.2(b), including informed consent and IRB
approval, but no IDE application is required to
be filed with FDA (IRB may refer back for IDE)
• Exempt – not subject to IDE regulations (21
CFR 812) - must comply with 21 CFR 50 & 56
55
21 CFR 812.2(c)
Exempted investigations. This part, with the
exception of 812.119, does not apply to
investigations of the following categories of
devices:
(1) A device, other than a transitional device, in
commercial distribution immediately before May 28,
1976, when used or investigated in accordance
with the indications in labeling in effect at that time.
56
21 CFR 812.2(c)
(2) A device, other than a transitional device,
introduced into commercial distribution on or after
May 28, 1976, that FDA has determined to be
substantially equivalent to a device in commercial
distribution immediately before May 28, 1976, and
that is used or investigated in accordance with the
indications in the labeling FDA reviewed under
subpart E of part 807 in determining substantial
equivalence.
57
21 CFR 812.2(c)
(3) A diagnostic device, if the sponsor complies with
applicable requirements in 809.10(c) and if the
testing:
• (i) Is noninvasive,
• (ii) Does not require an invasive sampling procedure that
presents significant risk,
• (iii) Does not by design or intention introduce energy into a
subject, and
• (iv) Is not used as a diagnostic procedure without
confirmation of the diagnosis by another, medically
established diagnostic product or procedure.
58
21 CFR 812.2(c)
(4) A device undergoing consumer preference
testing, testing of a modification, or testing of a
combination of two or more devices in commercial
distribution, if the testing is not for the purpose of
determining safety or effectiveness and does not
put subjects at risk.
(5) A device intended solely for veterinary use.
59
21 CFR 812.2(c)
(6) A device shipped solely for research on or with
laboratory animals and labeled in accordance with
812.5(c).
(7) A custom device as defined in 812.3(b), unless
the device is being used to determine safety or
effectiveness for commercial distribution.
60
IRB Review of IDE Determinations
• When the Sponsor has determined that a
device study is NSR, the IRB must review
that determination.
• If the IRB disagrees with the sponsor’s NSR
assessment and decides the study is SR,
the IRB must inform the clinical investigator
and, where appropriate, the sponsor.
• The IRB should document its NSR/SR
determination in the meeting minutes.
61
When in IDE Doubt
Sponsor should contact:
IDE Staff, Office of Device Evaluation
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002
(301) 796-5640
62
Informed Consent Waivers
• FDA regulations do NOT allow the IRB to
modify or waive any of the basic elements of
informed consent (with the exception of
emergency situations or for emergency
research as described in 21 CFR 50.23 and
21 CFR 50.24)
• The IRB may waive the requirement that the
subject sign a written consent form under the
circumstances described in 21 CFR 56.109(c)
63
References & Resources
• “FDA Expands Access to Investigational Drugs”
FDA Consumer Health Information, August 2009
• http://www.fda.gov/ForConsumers/ByAudience/F
orPatientAdvocates/AccesstoInvestigationalDrug
s/default.htm
• Draft Guidance for Industry – Expanded Access
to Investigational Drugs for Treatment Use – Qs
& As, May 2013
• 74 Federal Register 40900, August 13, 2009
References & Resources
• 74 Federal Register 40872, August 13, 2009
• Guidance for IRBs, Clinical Investigators, and
Sponsors – IRB Responsibilities for Reviewing
the Qualifications of Investigators, Adequacy of
Research Sites, and the Determination of
Whether an IND/IDE is Needed, August 2013
References & Resources
• Guidance for Industry – IND Exemptions for
Studies of Lawfully Marketed Drug or Biological
Products for the Treatment of Cancer, January
2004
• Draft Guidance for Industry, Clinical Investigators,
Institutional Review Boards, and Food and Drug
Administration Staff – FDA Decisions for
Investigational Device Exemption (IDE) Clinical
Investigations, June 14, 2013
References & Resources
• IDE Guidance Memorandum - Procedures for
Handling Inquiries Regarding the Need for an
Investigational Device Exemptions Application for
Research Involving Medical Devices, October 26,
2001