Transcript IRB considerations? - Columbia University Medical Center

IRB 101:
Highlights of the History of
Human Subjects Protections
Columbia University Medical Center IRB
2008 - 2009
Objective
Provide an overview of the events that have led to
the system of protections that are currently in
place to protect individuals who volunteer for
research.
Summarize the applicable regulations for the
protection of human subjects.
Pre-20th Century
• Medical practice developed from medical research
• No formal, widely-accepted codes
• Reliance on morals, ethical principles of culture,
Hippocratic Oath
20th Century
1900: Walter Reed’s Yellow Fever experiments
– 1898: Spanish American War
– 968 soldiers killed in combat
– 5000+ died of disease, mostly Yellow Fever
– United States Army Yellow Fever Commission
– Major Walter Reed
– Conducted experiments outside of Havana
– Proved that the mosquito transmits Yellow Fever
– First systematic use of informed consent in research
Elements present in Yellow Fever Consent Form:

Autonomy (respect for persons): “gives his consent…for the reasons
and under the conditions…”

Voluntary Participation : “being in the enjoyment and exercise of his
own free will”

Risks : “In case of the development of yellow fever in him, that he
endangers his life to a certain extent.”

Benefits : “He will receive from the said commissioner the greatest care
and the most skillful medical service.”

Compensation: “he will receive the sum of $100 in American gold . . .”

Study withdrawal conditions : “The undersigned binds himself not to
leave the bounds of this camp during the period of the experiments and
will forfeit all right to the benefits named in this contract if he breaks this
agreement.”
1932: PHS Study of Syphilis
• Significant health problem
• No initial intent to deny treatment
– Complete physical exam, medical history taken
– Followed for 6-8 months without treatment
• New follow-on study started in late 1933
– New procedures to strengthen scientific validity, control group
– No information provided about true nature of study: “government
doctors” were examining people for “bad blood”
• Penicillin accepted as curative treatment in 1943
– Not provided
– Exemption from draft to keep subjects in study
1939-1944 Nazi Experimentation
Findings of the Tribunal:
– In every single instance appearing in the record, subjects were used who
did not consent to the experiments;…
– In no case was the experimental subject at liberty of his own free choice
to withdraw from any experiment. …
– All of the experiments were conducted with unnecessary suffering and
injury and but very little, if any, precautions were taken to protect or
safeguard the human subjects from the possibilities of injury, disability, or
death.
– In every one of the experiments the subjects experienced extreme pain or
torture, and in most of them they suffered permanent injury, mutilation, or
death, either as a direct result of the experiments or because of lack of
adequate follow-up care.
THE NUREMBERG CODE
[from Trials of War Criminals before the Nuremberg Military
Tribunals under Control Council Law No. 10. Nuremberg,
October 1946–April 1949. Washington, D.C.: U.S. G.P.O,
1949–1953.]
First Tenet - The voluntary consent of the human subject is
absolutely essential.
Nuremberg Code and Voluntary Consent
This means that the person involved should:
– Have legal capacity to give consent
– Situated as to be able to exercise free power of choice, …; and
should have sufficient knowledge and comprehension of the
elements of the subject matter involved as to enable him to make
an understanding and enlightened decision.
• This latter element requires that before the acceptance of an
affirmative decision by the experimental subject there should
be made known to him the nature, duration, and purpose of
the experiment
• The method and means by which it is to be conducted
• All inconveniences and hazards reasonably to be expected;
• The effects upon his health or person which may possibly
come from his participation in the experiment.
Investigator Responsibility
The duty and responsibility for ascertaining the quality of the
consent rests upon each individual who initiates, directs or
engages in the experiment. It is a personal duty and
responsibility which may not be delegated to another with
impunity.
1946, 1950-53 Fernald School
Massachusetts Institute of Technology researchers and Fernald
staff members
Studies with radioisotopes at the school
The first study, in 1946, exposed seventeen students to
radioactive iron.
The second study exposed fifty seven subjects to radioactive
calcium between 1950 and 1953.
Fernald Consent Documents
 Misleading information implies benefits
 No mention of radioisotopes
 Coercive
 Active consent not required
Late 1950’s
•Thalidomide Tragedy
– Approved in Europe as sedative
– Not approved in U.S.
– Samples provided to U.S. physicians paid to study
safety and efficacy
•1962 Amendments to U.S. Food, Drug and Cosmetic
Act (Kefauver-Harris Amendments)
1956-72 Willowbrook
• New York University researchers
• Willowbrook State School for the Retarded, located on
Staten Island
• Residents were injected with a mild form of hepatitis
serum
• The researchers hoped to find a treatment for the virus
by studying the disease in it’s earliest stages
1961 Milgram Obedience Study
 Recruitment by newspaper ad:
 $4.50 for one hour's work
 Psychology experiment investigating learning and memory
 Involved deception
 Individuals were asked to give what appeared to be real electric
shocks to another person
 The researchers wished to test how far subjects would follow the
orders of an experimenter
 Post-experiment interview
1960’s
1964 Declaration of Helsinki – Expansion on Informed Consent
– In any research on human beings, each potential subject must be adequately
informed of the aims, methods, sources of funding, any possible conflicts of
interest, institutional affiliations of the researcher, the anticipated benefits and
potential risks of the study and the discomfort it may entail. The subject should
be informed of the right to abstain from participation in the study or to
withdraw consent to participate at any time without reprisal. After ensuring that
the subject has understood the information, the physician should then obtain
the subject's freely-given informed consent, preferably in writing. If the
consent cannot be obtained in writing, the non-written consent must be
formally documented and witnessed.
1966 NIH Policies for the Protection of Human Subjects issued
– Established the IRB as one mechanism through which human subjects would
be protected.
1970’s
• 1972 Syphilis study exposed
– Study stopped in March 1973 and treatment provided
• 1974 National Research Act passed (raised NIH policy to regulation)
– Required regulations for protection of human subjects
• Informed consent
• Institutional Review Boards
– Created National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research
• 1979 Belmont Report published by National Commission
– Respect for persons (informed consent)
– Beneficence (minimize risk, evaluate risk/benefit ratio)
– Justice (selection of subjects)
Acknowledgement of History of Violation of
Ethical Principles
- Lack of Informed Consent (no respect for persons)
- Convenience sample bearing burden of research (injustice)
- Causing harm to subjects (maleficence)
1981
Based on Commission’s reports and recommendations:
– Significant revisions to HHS and FDA human subject regulations
• Clarified IRB role
• No change in general principles of review
– DHHS regulations codified at Title 45 Part 46 of the Code of Federal
Regulations (45 CFR 46)
• Effective 1/16/81; revised 3/4/83; 6/18/91
• 1991 revision involved adoption of Federal Policy for Protection of HS
– “Common Rule” (Subpart A) – by 16 agencies
• Subparts B,C,D adopted 1978, 1978, 1983 respectively
– FDA regulations codified at Title 21 Parts 50 (1980), 56 (1981)
• Additional regulations for drugs, devices, device classification
Differences between HHS and FDA regulations
Comparison of FDA and HHS Human Subject Protection
Regulations:
http://www.fda.gov/oc/gcp/comparison.html
Consult with IRB staff if uncertain about application.
Summary
• Formal codes for protection of human
subjects relatively recent
• Subsequent to abuses of human
subjects in research
• Limited in extent of protection
IRB 101:
IRB Review Criteria
and
Tips for Submission
Columbia University Medical Center IRB
2008-2009
Objectives
1. Describe how submissions are routed for review;
2. Provide return criteria;
3. Explain the requirements for approval;
4. Demonstrate where in RASCAL information should be entered;
5. Provide tips for a complete and accurate submission.
Facilitate more timely review through a better understanding of the
IRB review process and review criteria.
Submission Process: New Protocols
• Protocol submitted to the
IRB (“submitted”/Log-in
queue);
• Administrative review
conducted by IRB staff:
– Reviewer form guides
review;
– Performance standards
provide timeline;
– Review comments
entered into Notes.
Submission process: New Protocol (2)
Protocol will be accepted (“logged in”/Chair queue) if complete.
PI submits
protocol
“Submitted”
(Log-in queue)
Staff review
“Logged in”
(Chair queue)
Submission process: New Protocol (3)
Return Criteria at log-in stage:
– Cancer Center is not listed in Facilities section, and the research is
cancer-related;
– PI is not qualified;
– Consent and/or Assent is not attached, and a waiver has not been
requested;
– Recruitment material is mentioned, but not attached;
– Study instruments are described, but are not attached;
– Sponsor’s protocol, IDB, or Package Insert is not attached;
– Grant, contract, or other documentation of funding agreement is not
attached;
– There is insufficient information to make required determinations.
Submission process: New Protocol (4)
Correspondenc
e from Chair to
PI
PI revises
protocol
Correspondenc
e from team to
Chair
PI submits
protocol
“Submitted”
(Log-in
queue) Staff
review
Correspondenc
e from logger to
team
“Returned”
(Investigator queue)
PI receives protocol
Protocol will
be returned
(“returned”/
Investigator queue)
if one or more
return criteria
are met.
Submission process: New Protocol (4)
Overview
Correspondenc
e from Chair to
PI
PI revises
protocol
Correspondenc
e from team to
Chair
PI submits
protocol
“Submitted”
(Log-in queue)
Staff review
Correspondenc
e from logger to
team
“Returned”
(Investigator queue)
PI receives protocol
“Logged in”
(Chair queue)
RASCAL tip: Review IRB Submission Manual
Posted on Columbia University’s Office for Clinical Trials website:
http://www.columbiaclinicaltrials.org
RASCAL tip: Clarity
1. Describe clearly and accurately what will be done at this
site or under the direction of a Columbia investigator;
2. Identify related procedures that will be or have been done
elsewhere or previously;
3. Provide clear descriptions of relationships;
4. Accurately describe funding mechanisms;
5. Consistently and precisely describe data collection.
Submission Process: Renewals
Renewals:
• Similar process, different form Return criteria:
– Clean copies of consent documents or study instruments not
attached;
– Enrollment information not provided;
– Documents or fields not updated;
– Conditions of previous approval not satisfied;
– All required attachments not provided.
RASCAL tip: Review attachments
1. Archive superceded, reference,
HIPAA documents;
2. Review content of attachments for
currency, accuracy, outdated
approval stamps, and inclusion of
new requirements;
3. Review correspondence from
previous approval.
Submission Process: Modifications
Modifications:
• Similar process, summary of modification, assessment of revision in all
applicable documents
• Return criteria:
– Clear explanation of changes not provided;
– Description of modification does not match changes in documentation;
– Changes are described but not incorporated;
– Supporting documentation not attached.
Submission Process: Adverse Event Reports
Review New IRB Unanticipated Problems Policy
Unanticipated problem report:
• Similar process, reconciliation of investigator assessment with UP
policy
• Return criteria:
– All required documentation not attached;
– Event does not meet criteria to be reported individually;
– Investigator’s assessment does not comport with supporting information.
RASCAL tip: Name files logically
RASCAL tip: Include Correspondence
1. Cover letter with initial submission.
2. Correspondence or attached
“response” with resubmissions.
3. Attached letter to IRB to explain
unusual or complex collaborations,
centers, affiliations, procedures, etc.
IRB Review
• Low risk protocols may be eligible for exemption (6 categories)
• Minimal risk protocols may be eligible for expedited review (9 categories)
• Protocols that are not exempt or cannot be expedited require review by the full
Board
• Time required for review is dependent upon the type of review, complexity and
risk level of procedures, and other factors
• Chair schedule
• IRB meeting schedule
• Completeness of submission
• Other required approvals
• Recommendation:
• Submit as soon as all protocol materials are available
• Allow 60 days for renewal of full Board protocol
Review Process: Overview
“Logged in”
(Chair queue)
Chair reviews or distributes
Exempt or expedited
“Distributed” then
“Assigned to Meeting”
Full Board
Approve
Approve
Return
Pending
Defer
Return
Disapprove
Criteria for IRB approval of research:
45 CFR 46.111 and 21 CFR 56.111
(a)
In order to approve research covered by this
policy the IRB shall determine that all of the
following requirements are satisfied:
Criteria for IRB approval of research:
1) Risks to subjects are minimized:
(i) by using procedures which are consistent with sound
research design and which do not unnecessarily expose
subjects to risk, and
(ii) whenever appropriate, by using procedures already being
performed on the subjects for diagnostic or treatment
purposes.
New protocol considerations:
– Research versus clinical care?
– Design features?
– Types of risk: physical, social, psychological, economic?
– Risks reduced or managed to the extent possible?
– Safeguards incorporated?
– Potential for statistical validity demonstrated?
– Investigators competent?
– Inclusion and exclusion criteria clearly defined?
Renewal:
– Is it the determination of the IRB, based on an evaluation of reported
enrollment, adverse events, and unanticipated problems, that risks are
still minimized?
Modifications:
– Risks still minimized?
Reports of Unanticipated Problems:
– Unanticipated, related, and suggests increase in risk?
– Change to protocol and/or consent form needed to reflect new risks?
Modifications:
– If another subject group is being added, or inclusion/exclusion criteria
is being revised, does subject selection remain equitable?
Reports of Unanticipated Problems:
– Unanticipated, related, and suggests increase in risk?
– Change to protocol and/or consent form needed, i.e., is risk to a
particular group increased such that inclusion/exclusion criteria need
to be revised or consent documents need to be updated?
RASCAL entry: Research Page
RASCAL entry: Study Description; attachments
1. Study Purpose and Rationale.
2. Study Design and Statistical Procedures.
3. Study Procedures
4. Study Drugs or Devices
5. Study Questionnaires
6. Study Subjects.
7. Recruitment
8. Confidentiality of Study Data
9. Potential Risks
10. Potential Benefits
11. Alternatives
Criteria for IRB approval of research:
(2) Risks to subjects are reasonable in relation to anticipated benefits, if
any, to subjects, and the importance of the knowledge that may reasonably
be expected to result. In evaluating risks and benefits, the IRB should
consider only those risks and benefits that may result from the research (as
distinguished from risks and benefits of therapies subjects would receive
even if not participating in the research).
The IRB should not consider possible long-range effects of applying
knowledge gained in the research (for example, the possible effects of the
research on public policy) as among those research risks that fall within the
purview of its responsibility.
New protocol considerations:
– Acceptable risk/benefit ratio?
– Ethically acceptable to expose participants to risk of harm?
– Available alternatives?
Renewals:
– Is it the determination of the IRB that risks are still reasonable in
relation to anticipated benefits?
– Have any subjects been seriously harmed?
– Should any new information be provided to subjects?
Modifications:
– Risks still reasonable in relation to anticipated benefits?
Reports of Unanticipated Problems:
– Unanticipated, related, and suggests increase in risk?
– Change to protocol needed to ensure that risk/benefit ratio is still
acceptable?
– Change to consent process needed to notify participants of new
risks?
RASCAL entry: Study Description; attachments
1. Study Purpose and Rationale.
2. Study Design and Statistical Procedures.
3. Study Procedures
4. Study Drugs or Devices
5. Study Questionnaires
6. Study Subjects.
7. Recruitment
8. Confidentiality of Study Data
9. Potential Risks
10. Potential Benefits
11. Alternatives
RASCAL tip: 11 Elements
1. Ensure that all 11 elements of a research
protocol are addressed in the Study
Description and/or attached protocol;
2. Study Description may be the “only”
protocol or serve as an overview of a
sponsor’s protocol;
3. Avoid “See attached protocol” as the
Board members will receive the Study
Description but not attached protocols.
Criteria for IRB approval of research:
(3) Selection of subjects is equitable. In making this
assessment the IRB should take into account the
purposes of the research and the setting in which the
research will be conducted and should be particularly
cognizant of the special problems of research involving
vulnerable populations, such as children, prisoners,
pregnant women, mentally disabled persons, or
economically or educationally disadvantaged persons.
New protocol considerations:
– Easy availability, compromised position, or susceptibility to
manipulation a factor?
– If potential benefit, particularly for conditions with no effective
treatment, are recruitment methods and enrollment criteria objective?
– Are ethnic groups neither under- or over-represented?
– Are women and children included where appropriate?
Renewals:
– Has the actual selection/enrollment of subjects represented an
equitable distribution of the benefits and burdens of the research
(versus the anticipated study population)?
RASCAL entry: Subjects Page
RASCAL entry: Subjects Page
RASCAL tip: Subject Selection
1. Select “Special Populations” options
thoughtfully
a. Understand why/when vulnerability
exists
b. Justify inclusion of vulnerable groups
c. Consider and include additional
protections, or exclude group, as
appropriate
2. Select “Recruitment” options accurately
a. Text or documentation must be included
in submission
Criteria for IRB approval of research:
(4) Informed consent will be sought from each prospective
subject or the subject's legally authorized representative,
in accordance with, and to the extent required by 45 CFR
46.116 or 21 CFR 50.
New protocol considerations:
– Are procedures for an ongoing process described?
– When and by whom will consent be obtained?
– How will competency be addressed?
– Is surrogate consent proposed, and if so, is it acceptable?
– Is a waiver of consent* requested, and if so, is justification provided?
*Not permitted under most circumstances by FDA.
Renewals:
– Has consent been obtained from enrolled subjects?
– Is the consent process adequate or are changes required (to the process or
the form/forms) before additional subjects may be enrolled?
– Is there new information that should be, but has not yet been, conveyed to
enrolled subjects so that they may make an informed choice about continuing
their participation?
Modifications:
– Does the consent form need to be revised to reflect change(s)
proposed in the modification?
– Do enrolled subjects need to be advised of the proposed change, e.g.,
if there are new procedures?
Reports of Unanticipated Problems:
– Unanticipated, related, and suggests increase in risk?
– Is there new information that may affect enrolled or prospective
subjects’ willingness to enroll or continue participation, and should be
incorporated into the consent process/form?
Basic elements of informed consent
(1) a statement that the study involves research, an explanation of the
purposes of the research and the expected duration of the subject's
participation, a description of the procedures to be followed, and
identification of any procedures which are experimental;
(2) a description of any reasonably foreseeable risks or discomforts to the
subject;
(3) a description of any benefits to the subject or to others which may
reasonably be expected from the research;
(4) a disclosure of appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the subject;
(5) a statement describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained;
Basic elements of informed consent (2)
(6) for research involving more than minimal risk, an explanation as to
whether any compensation and an explanation as to whether any
medical treatments are available if injury occurs and, if so, what they
consist of, or where further information may be obtained;
(7) an explanation of whom to contact for answers to pertinent
questions about the research and research subjects' rights, and whom
to contact in the event of a research-related injury to the subject; and
(8) a statement that participation is voluntary, refusal to participate will
involve no penalty or loss of benefits to which the subject is otherwise
entitled, and the subject may discontinue participation at any time
without penalty or loss of benefits to which the subject is otherwise
entitled.
Additional elements of informed consent
(1) a statement that the particular treatment or procedure may involve
risks to the subject (or to the embryo or fetus, if the subject is or may
become pregnant) which are currently unforeseeable;
(2) anticipated circumstances under which the subject's participation
may be terminated by the investigator without regard to the subject's
consent;
(3) any additional costs to the subject that may result from
participation in the research;
(4) the consequences of a subject's decision to withdraw from the
research and procedures for orderly termination of participation by
the subject;
(5) A statement that significant new findings developed during the
course of the research which may relate to the subject's willingness to
continue participation will be provided to the subject; and
(6) the approximate number of subjects involved in the study.
RASCAL entry: Consent Form Builder
RASCAL tip: Select Layout; Review Form
Waiver criteria: 45 CFR 46.116(d)
(1) the research involves no more than minimal risk to the subjects;
(2) the waiver or alteration will not adversely affect the rights and welfare
of the subjects;
(3) the research could not practicably be carried out without the waiver
or alteration; and
(4) whenever appropriate, the subjects will be provided with additional
pertinent information after participation.
Waiver criteria: 45 CFR 46.116(c)
(1) the research or demonstration project is to be conducted by or
subject to the approval of state or local government officials and is
designed to study, evaluate, or otherwise examine: (i) public benefit or
service programs; (ii) procedures for obtaining benefits or services
under those programs; (iii) possible changes in or alternatives to those
programs or procedures; or (iv) possible changes in methods or levels
of payment for benefits or services under those programs; and
(2) the research could not practicably be carried out without the waiver
or alteration.
RASCAL entry: Subjects Page
Criteria for IRB approval of research:
(5) Informed consent will be
appropriately documented, in
accordance with, and to the
extent required by 45 CFR 46
46.117 or 21 CFR 50.27.
New protocol considerations:
– Is use of a written consent document proposed?
– Does the consent document contain required elements, exclude
exculpatory language, and include optional elements where
appropriate?
– Is waiver of written documentation of consent requested, and if so, is
justification provided?
– Will a copy of the form be provided to subjects?
– If verbal consent will be obtained, are appropriate procedures
proposed?
Renewals:
– Has consent been appropriately documented for enrolled subjects?
– Have subject complaints about the consent process been received?
Waiver of written documentation criteria:
45 CFR 46.117(c)
(1) The only record linking the subject and the research would be
the consent document and the principal risk would be potential
harm resulting from a breach of confidentiality. Each subject will be
asked whether the subject wants documentation linking the subject
with the research, and the subject's wishes will govern; or
(2) The research presents no more than minimal risk of harm to
subjects and involves no procedures for which written consent is
normally required outside of the research context.
Criteria for IRB approval of research:
(6) When appropriate, the
research plan makes
adequate provision for
monitoring the data collected
to ensure the safety of
subjects.
New protocol considerations:
– Is a data and safety monitoring plan needed?
– Are proposed data and safety monitoring procedures adequate?
– Will the consent process be monitored?
Renewals:
– Has the IRB been informed of any unforeseen problems or accidents
that may have occurred?
– Do reports of adverse events and monitoring bodies reflect that the
data are being adequately monitored?
– Should the IRB request that progress reports be submitted at regular
intervals, more often than annually?
Modifications:
– Does the modification revise procedures in such a way that the data
and safety monitoring plan, or other oversight of the study, needs to be
revised?
Reports of Unanticipated Problems:
– Unanticipated, related, and suggests increase in risk?
– Is more frequent or different monitoring needed as a result of the
unanticipated problem?
RASCAL entry: Study Description; attachments
1. Study Purpose and Rationale.
2. Study Design and Statistical Procedures.
3. Study Procedures
4. Study Drugs or Devices
5. Study Questionnaires
6. Study Subjects.
7. Recruitment
8. Confidentiality of Study Data
9. Potential Risks
10. Potential Benefits
11. Alternatives
Criteria for IRB approval of research:
(7) When appropriate, there are
adequate provisions to protect
the privacy of subjects and to
maintain the confidentiality of
data.
New protocol considerations:
– In what manner will data be gathered and maintained (anonymously,
de-identified, coded, identifiable)?
– Are procedures for collecting and storing identifiable data adequate to
reduce risk of breach of confidentiality?
– If data will be transmitted to another site, are procedures appropriate?
– Does the consent document adequately reflect data confidentiality
issues and potential breaches?
– Are research personnel trained in privacy practices?
Renewals:
– Have there been complaints from subjects, or reports of unanticipated
problems related to privacy and confidentiality?
Modifications:
– Is more sensitive information being collected, such that the measures
in place to protect confidentiality need to be enhanced?
Reports of Unanticipated Problems:
– Unanticipated, related, and suggests increase in risk?
– Has a breach of confidentiality occurred, which requires reassessment
of plans to protect confidential data?
RASCAL entry: Study Description
1. Study Purpose and Rationale.
2. Study Design and Statistical Procedures.
3. Study Procedures
4. Study Drugs or Devices
5. Study Questionnaires
6. Study Subjects.
7. Recruitment
8. Confidentiality of Study Data
9. Potential Risks
10. Potential Benefits
11. Alternatives
IRB 101:
Vulnerable Populations
Columbia University Medical Center IRB
2008-2009
Criteria for IRB approval of research:
45 CFR 46.111 and 21 CFR 56.111
(b)
When some or all of the subjects are likely to
be vulnerable to coercion or undue influence,
such as children, prisoners, pregnant
women, mentally disabled persons, or
economically or educationally disadvantaged
persons,
additional safeguards have been included in
the study to protect the rights and welfare of
these subjects.
New protocols considerations:
– Is information included for the required determinations of Subparts
B (pregnant women, fetuses), C (prisoners), and D (children and
minors) to be made?
– Do consent processes adequately address the needs of vulnerable
subjects, e.g., translations, legally authorized representatives?
– How will competency to provide consent be determined?
– Are procedures in place to address loss of cognitive ability during
the trial?
Renewals:
– Are the determinations required by the Subparts still acceptable?
– Should competency be reassessed?
Subpart B: Pregnant Women & Human Fetuses
(46.204) Assessment of risks made by the IRB
– Where scientifically appropriate, preclinical studies, including studies
on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for
assessing potential risks to pregnant women and fetuses.
– The risk to the fetus is caused solely by interventions or procedures
that hold out the prospect of direct benefit for the woman or the fetus;
or, if there is no such prospect of benefit, the risk to the fetus is not
greater than minimal and the purpose of the research is the
development of important biomedical knowledge which cannot be
obtained by any other means.
– Any risk is the least possible for achieving the objectives of the
research.
In English…
 If the study involves greater than minimal risk to the fetus, there must
be a prospect for direct benefit for the mother or the fetus. There must
also be preclinical studies assessing the potential risk, and the study
must be designed to minimize risk to the extent possible.
 If the study involves no benefit to the mother or fetus, the risk to the
fetus must be minimal and the least possible to achieve the objectives
of the research. Further, the research must be designed to develop
important biomedical knowledge that cannot be obtained any other
way.
Consent Requirements for Research Involving
Pregnant Women & Human Fetuses
– If the research holds out the prospect of direct benefit to the pregnant
woman, the prospect of a direct benefit both to the pregnant woman
and the fetus, or no prospect of benefit for the woman nor the fetus
and the risk to the fetus is minimal, consent of ONLY the pregnant
woman is required.
– If the research holds out the prospect of direct benefit to the fetus only,
then the consent of the pregnant woman AND the father must be
obtained. The father's consent need not be obtained if he is unable to
consent because of unavailability, incompetence, or temporary
incapacity or the pregnancy resulted from rape or incest.
– Each individual providing consent is fully informed regarding the
reasonably foreseeable impact of the research on the fetus or
neonate.
Additional Requirements for Research Involving
Pregnant Women and Human Fetuses
– For children as defined who are pregnant, assent and permission are
obtained in accord with the provisions of subpart D.
– No inducements, monetary or otherwise, will be offered to terminate a
pregnancy.
– Individuals engaged in the research will have no part in any decisions
as to the timing, method, or procedures used to terminate a
pregnancy.
– Individuals engaged in the research will have no part in determining
the viability of a neonate.
Research Involving Neonates
- Non-viable or of Uncertain Viability (46.205)
Research involving, after delivery, the placenta, the
dead fetus or fetal material (46.206)
Additional considerations apply and determinations must be
made.
Consult with the IRB before submitting for tailored guidance.
Research Not Otherwise Approvable (46.207)
The IRB finds that the research presents a reasonable opportunity
to further the understanding, prevention, or alleviation of a serious
problem affecting the health or welfare of pregnant women, fetuses or
neonates; and
The Secretary, after consultation with a panel of experts in pertinent
disciplines and following opportunity for public review and comment,
including a public meeting announced in the FEDERAL REGISTER,
agrees with the above determination or disagrees with the IRB’s
conclusions and finds the research approvable according to current
regulations
Subpart C: Prisoners
Relevant Definitions
Prisoner - any individual involuntarily confined or detained in a penal
institution, including:
– individuals sentenced to such an institution under a criminal or
civil statute;
– individuals detained in other facilities by virtue of statutes or
commitment procedures which provide alternatives to criminal
prosecution or incarceration in a penal institution; and
– individuals detained pending arraignment, trial, or sentencing.
In other words…..
– A resident of a drug rehabilitation center who is in treatment as an
alternative to jail would qualify as a “prisoner”.
– Children in juvenile detention halls qualify as prisoners.
If subjects enroll in the research and are then incarcerated, subpart C
applies.
Subpart C: Prisoners
Relevant Definitions
“Minimal risk" is the probability and magnitude of physical or
psychological harm that is normally encountered in the daily lives, or
in the routine medical, dental, or psychological examination of healthy
persons.
– Minimal risk means that 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.
Prisoners: IRB Review
Prisoner representative must be present.
The majority of the Board must have no association with the prison.
For research funded by DHHS, the institution must certify to the
Secretary that the required findings under subpart C have been
made. The research cannot commence until OHRP has approved
the research.
Prisoners: Approvable Categories of Research
Study of the possible causes, effects, and processes of
incarceration, and of criminal behavior, provided that the study
presents no more than minimal risk and no more than
inconvenience to the subjects.
Study of prisons as institutional structures or of prisoners as
incarcerated persons, provided that the study presents no more
than minimal risk and no more than inconvenience to the
subjects.
Prisoners: Approvable Categories of Research
Research on conditions particularly affecting prisoners as a class
(for example, vaccine trials and other research on hepatitis which
is much more prevalent in prisons than elsewhere; and research
on social and psychological problems such as alcoholism, drug
addiction, and sexual assaults)
provided that the study may proceed only after the Secretary has
consulted with appropriate experts including experts in penology,
medicine, and ethics, and published notice, in the FEDERAL
REGISTER, of his intent to approve such research.
Prisoners: Approvable Categories of Research
Research on practices, both innovative and accepted, which
have the intent and reasonable probability of improving the
health or well-being of the subject.
In cases in which those studies require the assignment of
prisoners in a manner consistent with protocols approved
by the IRB to control groups which may not benefit from the
research, the study may proceed only after the Secretary
has consulted with appropriate experts, including experts in
penology, medicine, and ethics, and published notice, in the
FEDERAL REGISTER, of the intent to approve such
research.
Prisoners: Required findings by the IRB
The research under review represents one of the previously
mentioned categories of research.
Any possible advantages accruing to the prisoner through his or
her participation in the research,
when compared to the general living conditions, medical care,
quality of food, amenities and opportunity for earnings in the
prison,
are not of such a magnitude that his or her ability to weigh the risks
of the research against the value of such advantages in the limited
choice environment of the prison is impaired.
Prisoners: Required findings by the IRB
The risks involved in the research are commensurate with risks that
would be accepted by non-prisoner volunteers.
Procedures for the selection of subjects within the prison are fair to all
prisoners and immune from arbitrary intervention by prison authorities
or prisoners.
Unless the principal investigator provides to the Board
justification in writing for following some other procedures,
control subjects must be selected randomly from the group of
available prisoners who meet the characteristics needed for that
particular research project.
Prisoners: Required findings by the IRB
The information is presented in language which is
understandable to the subject population.
Adequate assurance exists that parole boards will not take into
account a prisoner's participation in the research in making
decisions regarding parole, and each prisoner is clearly
informed in advance that participation in the research will have
no effect on his or her parole.
Prisoners: Required findings by the IRB
Where the Board finds there may be a need for follow-up
examination or care of participants after the end of their
participation, adequate provision has been made for such
examination or care, taking into account the varying lengths of
individual prisoners' sentences, and for informing participants of
this fact.
Children – Subpart D of 45 CFR 46 and 21 CFR 50
•Risk Determination
•Parental Permission Requirements
•Assent Requirements
•Wards?
Research with Children
When children or minors will be subjects, the IRB must determine and
provide the basis for their determination of:
1.
Category of research:
§46.404/§50.51 Research not involving greater than minimal risk.
§46.405 /§50.52 Research involving greater than minimal risk but
presenting the prospect of direct benefit to the individual subjects.
§46.406 /§50.53 Research involving greater than minimal risk and no
prospect of direct benefit to individual subjects, but likely to yield
generalizable knowledge about the subject's disorder or condition.
§46.407 /§50.54 Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious problem affecting
the health or welfare of children.
Research with Children (2)
2.
Requirements for parental permission:
One or both parents may provide permission for research in categories
§46.404/§50.51 and §46.405/§50.52.
Both parents must provide permission for research in categories
§46.406/§50.53 and §46.407/§50.54.
3.
Whether assent should be obtained:
Considering age and maturity of the children
Evaluating whether effective alternatives are available
4.
Whether wards will be involved:
An advocate must be provided for each ward that is enrolled
Subpart D: Minimal Risk Research
“Section 404 Research”
Risk Determination
– In order for a study to be categorized under section 404(DHHS)
or section 51(FDA), the research has to pose minimal risk to
the children involved.
– The regulators define minimal risk as: 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.
• The CUMC IRB’s interpret this to apply to the daily lives of
normal children.
The permission of one parent must be obtained unless consent is
waived by the IRB.
The assent of the child is obtained or the IRB has waived the assent
requirements.
Subpart D: Research presenting Greater than
Minimal Risk with potential for Direct Benefit
“Section 405 Research”
Risk Determination
– The risk is justified by the anticipated benefit to the subjects;
– The relation of the anticipated benefit to the risk is at least as
favorable to the subjects as that presented by available
alternative approaches.
Adequate provisions are made for soliciting the assent of the
children or the IRB has waived the assent requirements.
Permission of one parent is obtained unless waived by the IRB.
Subpart D: Research presenting Greater than
Minimal Risk with No anticipated Direct Benefit
“Section 406 Research”
Risk Determination
– The risk represents a minor increase over minimal risk;
– 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;
– The intervention or procedure is likely to yield generalizable
knowledge about the subjects' disorder or condition which is of vital
importance for the understanding or amelioration of the subjects'
disorder or condition;
Adequate provisions are made for soliciting the assent of the children.
Permission of BOTH parents is obtained unless one parent is deceased,
unknown, incompetent, or not reasonably available, or when only one
parent has legal responsibility for the care and custody of the child.
WARDS
Subpart D: Research Not Approvable according to
Sections 404, 405 or 406 (FDA 51, 52, or 53)
“Section 407 Research”
Risk Determination
– The research presents a reasonable opportunity to further the
understanding, prevention, or alleviation of a serious problem affecting
the health or welfare of children; and
Referral to DHHS for secretarial consultation
– The Secretary, after consultation with a panel of experts in pertinent
disciplines (for example: science, medicine, education, ethics, law)
and following opportunity for public review and comment, agrees with
the above determination or disagrees with the IRB’s conclusions and
finds the research approvable according to current regulations.
Adequate provisions are made for soliciting the assent of the children.
Permission of BOTH parents is obtained unless one parent is deceased,
unknown, incompetent, or not reasonably available, or when only one
parent has legal responsibility for the care and custody of the child.
Inclusion of Wards in Research
If wards are to be enrolled in sections 406 or 407 research:
Detailed information about the proposed informed consent process as well as
detailed information regarding the identity and authority of any individual who
will provide consent must be provided to the IRB.
The research must be:
– Related to their status as wards; or
– Conducted in schools, camps, hospitals, etc. in which the majority of the
subjects involved in the research are not wards.
An advocate for each ward must be appointed to act on behalf of the child. The
advocate must have the background and experience to act in the best interest
of the child throughout the research and cannot be associated in any way with
the research, the investigator or the guardian institution.
In NY, the Administration for Children’s Services (ACS) must agree to the
inclusion of wards in the research and permission must be obtained from the
person designated by ACS for each ward who is enrolled.
Parental Permission – Waiver Options
Parental permission can be waived:
•If the research a) poses no more than minimal risk; b) does not
negatively impact upon the rights and/or welfare of the
subjects; c) renders it impracticable to obtain consent; and d)
provides for informing subjects of any additional pertinent
information upon completion of the research.
•If the research protocol is designed for conditions or for a subject
population for which parental or guardian permission is not a
reasonable requirement to protect the subjects (for example,
neglected or abused children), and an appropriate mechanism
for protecting the children who will participate as subjects in
the research is substituted.
Assent Requirements
In general:
– Applies to children 7 and older who are capable of assenting
• When determining capability, ages, maturity level and
psychological state must be taken into account.
– Ages 7 through 11: Written or verbal
– Ages 12 through 17: Written
• A separate age appropriate assent can be provided or the
child can co-sign the parental consent.
Exceptions from Assent Requirements
Waiver of assent is granted by the IRB in accordance with
46.116.
– The intervention or procedure involved in the
research holds out a prospect of direct benefit that is
important to the health or well-being of the children
and is available only in the context of the research.
IRB Submissions
If your research involves vulnerable subjects:
– RASCAL questions
– Ensure your protocol submission includes adequate information
for the IRB to make the determinations required as outlined in the
previous slides.
– As always, call the IRB office (contact information for individual
staff on website) with any questions.
References
DHHS OHRP - Subpart B (Pregnant women, human fetuses and
neonates)
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#subpar
tb
DHHS OHRP - Subpart C (Prisoners)
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#subpar
tc
DHHS OHRP - Subpart D (Children)
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#subpar
td
FDA - Subpart D (Children)
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cf
m?CFRPart=50&showFR=1&subpartNode=21:1.0.1.1.19.4
Research with Other Vulnerable Individuals
When inclusion of subjects with a specific vulnerability is
proposed:
– Justify selection of this group;
– Include plans for additional protections relative to
vulnerability;
– If status is variable, include plans for periodic assessment;
– Clearly describe any special consent procedures;
– Provide local or expert documentation, as applicable.
IRB Actions
• Approve
• Require modifications
– defer to Chair as “pending” or
– defer to Board as “returned”
• Defer
• Suspend enrollment*
• Suspend the study*
• Terminate*
*Reportable to OHRP and/or FDA, as applicable,
sponsor, subjects, institution
An IRB may also:
Impose additional precautions or
reassess special requirements
previously imposed
– e.g., the IRB has the
authority to observe or have
a third party observe, the
consent process as well as
the research itself [45 CFR
46.109(e) and 21 CFR
56.109(f)]
Summary
IRB Review Criteria
Tips for Submitting
RASCAL
IRB 101:
Case Study
Columbia University Medical Center IRB
2008-2009
Initial submission
Industry-sponsored, Phase III, double-blind, randomized clinical trial to study the
effects of Drug A on Type 2 diabetes mellitus.
The subjects will be patients already in the care of either Dr. PI or Dr. Co-I, or will be
recruited from patients in the care of other endocrinologists at the medical center.
It is anticipated that all subjects will be English-speaking.
Subject compensation: Subjects will be paid $1,500 for the entire study. Payment
will be received at the end of the entire study after all study procedures have been
completed.
In each phase of the study, subjects will receive a radioactive isotope to detect a
newly identified protein that has been shown to affect insulin production in animal
studies.
Six out of seven members of the study team have completed required GCP and
HIPAA training via the RASCAL online testing center.
Level of review?
IRB considerations?
First modification
Revised consent form based on a request from the Radiation Drug
Research Committee that a statement required by the FDA to collect an
additional blood sample to assess a new toxicity that was found in a phase
II study and that is possibly associated with the isotope' regarding the limits
for radiation exposure be included. This change was made in the consent
form under the “Procedures” and "Risks" sections.
Level of review?
IRB considerations?
Second modification
1)
Revision of the blood pressure inclusion criterion to accept patients
with blood pressure < 140/90 mm Hg on blood pressure lowering therapy.
(The current IRB-approved protocol requires a blood pressure < 130/90 on
therapy.)
2)
Submission of a recruitment flyer for IRB approval. The flyer will be
posted at sites accessible to potential study subjects and will be used to
expedite and expand patient recruitment.
Level of review?
IRB considerations?
Third modification
1)
Spanish patient recruitment flyer.
2)
Consent form translated in Spanish.
Each of the Spanish documents has been translated from its approved
English counterpart by the investigator.
Level of review?
IRB considerations?
Fourth modification
1)
Addition of two co-investigators to the study team.
2)
Changes to study inclusion and exclusion criteria in order to:
a.
Require a history of stable diabetes therapy for 6 weeks (instead of 3
months).
b.
Include patients taking metformin only (without a sulfonylurea).
c.
Include patients with cardiovascular disease (except Class III-V CHF).
d.
Include patients taking diuretics
e.
Include patients with stable, treated thyroid disease.
3)
Modification of study protocol and consent to reflect collection of DNA
during study.
Level of review?
IRB considerations?
First renewal
Current Status: Open for enrollment and ongoing review of records/specimens.
Modifications:
Modifications reviewed.
Study Summary 2006 attached.
Subjects:
No Unanticipated Problems (which includes adverse events) reported to date .
Level of review?
IRB considerations?
Fifth modification
Revision of inclusion criteria to include youth ages 16-17.
Level of review?
IRB considerations?
Unanticipated Problem (Adverse Event)
Report
Participant was admitted to (facility) for 4 days, from (dates), as per study protocol.
Participant completed the study and was discharged from the (facility) during the
early afternoon.
Approximately one-half hour after discharge, while at a local restaurant the
participant began having chest pain which radiated to the back and arm. The
participant interpreted the symptoms as being indicative of indigestion and so went
home and took bismuth to obtain relief. The symptoms however worsened, so a
member of the household called 911, and the participant was taken to (hospital) by
ambulance.
Results of initial evaluations are forthcoming. The participant underwent cardiac
catheterization and coronary artery stenting on (date). The participant was
subsequently discharged home in the afternoon on (date) with instructions to follow
up as an outpatient with a particular cardiologist.
Level of review?
IRB considerations?
Second renewal
Current Status: Open for enrollment or ongoing review of
records/specimens.
Change in Literature noted with references.
Oversight Monitoring:
1 Unanticipated Problem (Chest Pain) submitted
Level of review?
IRB considerations?
Noncompliance scenario
Dr. PI incorporates data into the study from five of his own patients who
were taking Drug A before the protocol was approved. Dr. PI did not seek
consent from these patients to enroll in the study.
Issues to consider:
OHRP Reporting requirements: Industry sponsored study ~ Does the FWA
apply to HHS research only, or to all research regardless of funding?
What corrective actions might the IRB consider?
Third renewal
Current status: Closed to enrollment, open for data analysis at main site.
Level of review?
IRB considerations?