Human Research Protection Program
(HRPP)
DOMAIN II: RESEARCH COMPLIANCE OFFICE, INCLUDING IRBs
STANFORD* has the following written policies and procedures requiring
informed consent from participants or their legally authorized representatives (sometimes
referred to as “surrogates”),
and it verifies this requirement is met. (AAHRPP Standard II-7) The purpose is to
assure knowledgeable decision-making and voluntary participation.
The
IRBs evaluate compliance with policies and procedures on seeking informed
consent from participants, and assent, when possible, from participants who
cannot give consent. (AAHRPP Element II.7.A) The
IRBs review the content of the consent process, including the consent document,
and the process through which informed consent is obtained from each
participant, focusing on measures to improve participant understanding and
voluntary decision-making. (AAHRPP Element
II.7.C)
Protocol
Director Prepares and Submits Consent Information
The IRBs require
that the Protocol Director (PD) submit consent information, including any
consent document and explanation of the circumstances under which informed
consent will be sought, with his or her protocol application at initial,
continuing, or revision review times. The IRBs maintain electronic informed consent
templates (Documents F.3.e.-g.), including VA specific templates (Documents
F.3.h. and F.3.i.) and other specific consent situations (Documents F.3.f. and
F.3.m.-o.), for use by and guidance to investigators. To assist PDs in preparing consent documents
comprehensible to lay persons (i.e., approximately 8th grade level), the IRBs
maintain an electronic Glossary of Lay Terms (Document F.3.d.).
In addition to covering the eight basic informed
consent elements and six optional elements (as described in Section 12.1.1),
the PD may also need additional information (as described in Section
12.1.2). Examples include a statement
that participants do not waive liability rights for personal injury by signing
the consent, an examination of the consent to eliminate exculpatory language,
and inclusion of financial assistance for the costs of medical treatment of
complications. The IRB informed consent templates
address these elements as well as other specific consent situations in which
certain additional information may need to be disclosed to participants.
The PD also must address the circumstances under
which consent will be sought. The
protocol application requires information that enables the IRB to determine
whether the proposed consent process adequately protects participants, such as
whether they will have sufficient time to discuss and decide whether to
participate in the research, and whether the possibility of coercion and undue
influence is minimized.
A guidance in the form of an informed consent
checklist is also made available by the IRB to investigators (Document F.3.a.).
IRB Checklist and Other Substantive Review
Once
submitted, the consent information is reviewed by IRB staff using the Informed
Consent Checklist (Document F.3.a.). If
needed, the IRB staff contacts the PD with questions and requests for
revisions. (See comment codes at
Document F.5.f.). The IRB staff gives
the completed IRB checklist to the primary member reviewer(s). The primary member reviewer(s) examines the
consent in conjunction with the protocol and, where applicable, the
Investigator’s Brochure or the federal grant, regarding the purpose, risks, and
benefits of the research. During
continuing or revision reviews, any new information that could impact
participants’ risks (e.g., adverse events) or procedure changes are also
examined to ensure any updated language is appropriately contained in the
consent document. If needed, the primary
reviewer(s) submit further questions and requests for revisions, until
satisfied that the protocol and consent document can be approved as expedited
or submitted to a convened IRB meeting for consideration.
The IRB review also considers the relationship
between the person who will solicit and obtain consent and the person giving
consent, and pays attention to the person who explains the consent document to
the potential participant. See the New Protocol
Application Forms (Documents F.1.a.-c.) for questions regarding how consent is
obtained. The IRBs require that the
circumstances of the consent process be culturally and linguistically
appropriate for the intended participants, and protective of participants
through minimizing the possibility of coercion and undue influence and allowing
adequate time for them to discuss and decide whether to participate in the
research. The IRBs require this to be
delineated before protocol approval.
Additionally, the IRBs review any direct advertising (Document F.4.r.)
(e.g., newspaper, TV or radio ads, posters, flyers, letters or postcards,
e-mails, postings on bulletin boards/ internet/ world wide web), since it is
considered by the FDA “to be the start of the informed consent and subject
selection process.” In order to approve
them, the IRBs determine that the direct advertising is not unduly coercive and
does not promise a certainty of cure or favorable outcome or other benefits
beyond what is outlined in the consent and the protocol. (This is discussed in more detail in Chapter
10.)
IRB Criteria
for Approval of Consent Information
The IRBs must find that all the relevant requirements in the Common
Rule in 45 CFR 46.111 and 46.116, and in the FDA regulations in 21 CFR 50.20 and
50.25, that are applicable to the consent process and the consent document, are
satisfied in order to approve them.
Consideration at Convened Meeting or Under Expedited Review
At a
convened meeting, if minor revisions to the consent document are necessary and
able to be dictated verbatim at that time, the protocol is approved contingent
upon the revisions being made. This is
subject to an assigned IRB member reviewer confirming the dictated minor
revisions in the consent document. If
the PD objects to the dictated revisions, he or she submits a new consent
document for consideration at a future convened meeting. If revisions are greater than minor or cannot
be dictated verbatim at the convened meeting, the protocol is tabled, and the
consent document is referred back to the PD for the drafting of the revisions
and submission at a future convened meeting.
The PD puts two dates on the consent form, as
instructed by the IRB staff - the approval date and the expiration date. These instructions are given on the New
Protocol Application Regular Medical and Nonmedical (Documents F.1.a.-b.). See Approval Period and Determination of
Expiration Date in Chapter 7.1.
Consent Form Audits
The IRB staff evaluates
the accuracy of the approved consent forms by comparing signed consents to
approved consent forms for a specific period of time. This process is described in Documents D.3.f.i.-ii.
and D.3.f.iv. See also 12.10,
Observation of Consent Process.
Eight Basic Requirements of Consent
The IRBs require that the consent document and
information given to participants include the eight basic informed consent
elements mandated by the Common Rule at 45 CFR 46.116(a) and the FDA regulations
at 21 CFR 50.25(a), outlined below, and explained in more detail in the Guidance
on Basic Research Consent Requirements in Document F.4.cc. The IRBs have a poster with the basic and
additional elements of informed consent on display in its conference room as a
part of its educational tools for IRB members and staff (Document C.1.c.ii.).
Research Statement (Requirement #1)
Consents should not say
"treatment." They may describe
a goal as determining if the item or procedure is an effective treatment for a
disease or condition.
FDA
Investigational Drugs, Devices, or Biologics: If the test article is an investigational
drug, device or biologic, the IRBs require that the consent disclose that it
has not been approved by the FDA. If the
drug/device has been approved in certain situations but is being investigated
for different situations, the consent document should disclose that also. E.g.,
"Drug X has been approved for the treatment of bone cancer, but not for
the treatment of brain cancer. We are investigating
if Drug X is safe and effective for the treatment of brain cancer."
The IRBs require
that all consent forms for studies of investigational drugs, biologics and
devices include a statement that a purpose of the study is to evaluate the
safety of the test article. In studies
that also evaluate the effectiveness of a test article in addition to safety,
consent documents should include both purposes, but should not contain claims
that the article has been proven to be effective.
Phase 1 drug studies
often have the exclusive purpose of determining the pharmacological activity of
the investigational drug and how high a dosage can be administered before
unacceptable toxicity is reached. The
IRBs do not permit the consent document for such phase 1 studies to describe
the evaluation of effectiveness as a study purpose. If, however, a phase 1 protocol includes the
collection of data relating to possible effectiveness, the IRBs may permit the
consent document to list this as a secondary purpose. In such situations, the IRBs require the
consent document to be explicit in describing the limited experience to date in
administering the investigational drug to humans (e.g., "this is the first
time use in humans of drug X" or "To date, drug X has been administered
to 10 human beings"). Moreover, in
such situations the benefits section should include a statement to the effect
that most phase 1 drug studies do not result in benefit to the participants. (E.g., "It is possible that you will
(describe potential benefits). However,
you should be aware that most phase 1 studies do not result in benefit to
participants.")
Reasonably Foreseeable Risks or Discomforts
(Requirement #2)
Risks should be listed
in descending order of probability and magnitude (risk of death, even if
remote, before risks associated with blood draw, for example). For a fuller description of risk, see Chapter
9.
Reasonably Expected Benefits to Participants or
Others (Requirement #3)
If no direct benefit to the
participant is anticipated, the IRBs require this be clearly stated in the
informed consent discussion and consent document. An example is a phase 1 drug study, whether
in healthy or ill participants, directed solely at investigating the
pharmacological activity or safety of the investigational drug.
FDA Phase I: The
protocols for some phase 1 drug studies include the evaluation of effectiveness
as a secondary purpose of the study. In
such situations, the IRBs may allow the consent document to describe potential
benefits, together with a statement to the effect that most phase 1 drug
studies do not result in benefit to the participants.
Clinical Trial with
a Placebo:
If the research involves a placebo-controlled trial in which some
participants never receive the investigational item, the consent document
should include a statement about the placebo arm and that if the participant is
assigned it, it is not anticipated that he or she will receive any direct
benefit from participation in the research.
Appropriate Alternatives (Requirement #4)
Enough detail must be
presented so that the participant can understand and appreciate the nature of
alternatives and their relative risks and benefits. It is not sufficient simply to state, “the
doctor will discuss alternatives to participating.”
Extent of Confidentiality (Requirement #5)
In some research, loss of
privacy may be the greatest risk of participation. For example, during the course of research an
investigator may learn about incidents of child or elder abuse that the
investigator is required by law to report to public authorities. This is addressed in greater detail in
Chapter 11.
Agency Audit
Statement.
The substance of the following statement is required for FDA-regulated
research:
Because this research involves articles regulated by
the Food and Drug Administration (FDA), the FDA may choose to inspect and copy
medical or research records that identify individual research participants.
A comparable statement
is recommended for research subject to audit or inspection by any funding
agency or sponsor.
Compensation or Treatment for Injury (Requirement #6)
In accordance with VA
policy, the IRBs require a statement that veteran-participants shall receive
medical care and treatment for injuries suffered as a result of participating
in a VA research program. That language
is included in the VA consent form template in Documents F.3.h.-i. This requirement is discussed in more detail
in Chapter 16.2.
When questions arise regarding
research-related injuries at
See Chapter 16.2 for a more detailed
discussion of STANFORD policies and practices about compensation or medical
treatment for a research-related injury.
Contact Information (Requirement # 7)
Information must include
opportunities for potential participants to ask questions at all times during
the consent process and throughout the duration of the research. The information must include details,
including telephone numbers, about whom to contact in specific situations:
Voluntary Participation Statement (Requirement #8)
For example, when research
is conducted within the prison system, in the classroom or other setting, the
IRBs ensure that the informed consent information explains to participants that
they are free to decline participation or to withdraw at any time without
negative consequences. (This is also
covered in Chapter 10.)
Six Possible Additional Requirements of Consent
The following six additional
elements must be included in the informed consent information unless it is not
appropriate. See the Common Rule, 45 CFR
46.116(b), the FDA regulations, 21 CRF 50.25(b), and the Guidance on Basic
Research Consent Requirements (Document F.4.cc.).
Unforeseeable Risks to Participants,
Embryos, or Fetuses (Additional
#1)
If the research involves any
investigational drugs or devices or the risk profile of all research-related
interventions is not well known, the consent process must disclose that the
particular treatment or procedure may involve risks to the participant which
are currently unforeseeable. If the
research includes women of child bearing potential or includes pregnant women,
AND the risk profile of any research interventions or interactions on embryos and
fetuses is not well known, the consent process must disclose that the
particular treatment or procedure may involve risks to the embryo or fetus, if
the participant is or may become pregnant, which are currently
unforeseeable.
Investigator-Initiated Termination of
Participation (Additional
#2)
Additional Costs (Additional #3)
If there are any costs to
the participant that may result from participation in the research, the consent
process must disclose those additional costs to the participant.
If veteran participants are
involved, any such costs must be consistent with VA policy concerning veterans'
eligibility for medical care and treatment.
Those policies are discussed in Chapter 16.2 and explained in the VA
informed consent template (Documents F.3.h.-i.).
If the research is taking
place over a span of time in which it is possible that significant new findings
may occur during the course of the research which may relate to the
participant’s willingness to continue participation, the consent process must
disclose that significant new findings developed during the course of the
research which may relate to the participant’s willingness to continue
participation will be provided to the participant.
Approximate
Number of Participants (Additional #6)
If the approximate number
of participants involved in the study (locally and in total) might be important
to a decision to take part in the research, the consent process must discloses
the approximate number of participants (locally or in total) involved in the
study. For example, the number of
anticipated participants might be relevant to an individual enrolling in a
clinical trial for an investigational drug or devices, particularly if the
numbers are very small or very large.
Other Additional Requirements
The IRBs may also require
that information in addition to these six additional elements be given to
participants when in the IRBs judgment the information would meaningfully add
to the protection of the rights and welfare of participants. This requirement is addressed in the Common
Rule in 45 CFR 46.109(b) and in the FDA
regulations at 21 CFR 56.109(b) and is discussed in the Guidance on Basic
Research Consent Requirements.
Two such situations are:
In addition to the basic
and additional elements of informed consent described above, the IRBs require
that participants be given a list of their rights, if participating in a
“medical experiment” under
PHS Funded Research: If the
protocol is supported by funding from the Department of Health and Human
Services and includes testing for HIV, the consent documentation must state
that identifiable participants will be informed of their results and provided
with the opportunity for counseling. The
IRBs require this except in cases where it is not required by PHS policy.
AIDS Records: In addition, the IRBs require,
consistent with California Health & Safety Code § 121080, that individually
identifiable research records generated by AIDS-related research are
confidential and may only be disclosed with the prior written consent of the
participant. Any authorized disclosure must
include a written statement similar to:
This information has been disclosed to you from a
confidential research record, the confidentiality of which is protected by
state law and any further disclosure of it without specific prior written consent
of the person to whom it pertains is prohibited.
If a
protocol includes genetic testing, the IRBs require that the informed consent
information disclose the risks specific to this type of testing. Genetic testing includes research that
studies the characteristics, genes, and gene versions that are transmitted by
parents to offspring. This may include
many types of information, such as personal appearance and biochemistry, gene
sequences, genetic landmarks, individual or family medical histories, reactions
to medication, and responses to treatment.
The IRBs include detailed provisions and issues in its informed consent
template (Documents F.3.e. and F.4.g.) that should be considered by the
protocol director for his or her consent document that includes genetic
testing. The template is also used by IRB
staff and members as a guide for their review of such a consent document.
The IRBs make available its Guidance on Data and Tissue Repositories (Document F.4.dd.) to investigators who collect data or tissues of participants for repositories, and IRB staff and members who review such protocols. The guidance includes an exemplary consent for a pathology tissue bank (as exhibit #1) that also identifies the type of provisions, information and issue that should be covered in a consent document.
When such repositories collect individually identifiable health
information of participants, the HIPAA privacy regulations in 45 CFR Parts 160
and 164 must also be satisfied (Document F.4.i.). This may require either a written HIPAA
authorization from the participants or a waiver of authorization by the IRBs. These requirements are discussed in Chapter
11.
In
reviewing protocols and informed consent involving xenotransplantation, the IRBs
act in accordance with the Guideline on Infectious Diseases Issues in
Xenotransplantation issued by the federal Public Health Service (PHS) on
Xenotransplantation is defined as any procedure that involves the
transplantation, implantation, or infusion into a human recipient of either (A)
live cells, tissues, or organs from a nonhuman animal source or (B) human body
fluids, cells, tissues or organs that have had ex vivo contact with live
nonhuman animal cells, tissues, or organs.
(As of
The PD
should consult the PHS Guideline prior to drafting the consent document, since
they contain detailed guidance about the content of the informed consent
information provided to potential xenotransplantation product recipients. For example, they must be informed of the
importance of complying with long-term or life-long surveillance necessitating
routine physical evaluations and the archiving of tissue or body fluid
specimens.
Furthermore, the IRBs will require that individuals
whose excess embryos, originally created for fertility purposes, are to be utilized
to derive new stem cell lines consent to such use and receive the information
that
·
That the early
human embryos will be used to derive human pluripotent stem cells for research
and that the cells may be used, at some future time, for human transplantation
research
·
That all
identifiers associated with the embryos will be removed prior to the derivation
of human pluripotent stem cells
·
That the donors
will not receive any information about subsequent testing on the embryo or the
derived human pluripotent stem cells
·
That derived
cells or cell lines, with all identifiers removed, may be kept for many years
·
That it is
possible that the donated material may have commercial potential, and that the
donor will not receive financial or any other benefits from any future
commercial development
·
That the
research is not intended to provide direct medical benefit to the donor
·
That early human
embryos donated will not be transferred to a woman's uterus, will not survive
the stem cell derivation process, and will be handled respectfully, as is
appropriate for all human tissue used in research.
The IRBs recognize
that