IRB Member Refresher Course
2010
Melissa Epstein, PhD
Senior Education Specialist
melissa.epstein@nyumc.org
1
Thank you for joining us.
We hope to enhance your thinking as
an IRB Member by refreshing your
knowledge of Federal Regulations
and NYU SoM IRB Policies.
Please return your contact information updates.
2
Course Outline
• Specimen banking
• Vulnerable populations
– Pregnant women
– Persons with impaired decision-making capacity
• Data Safety Monitoring Plans
3
Specimen Banking
4
What is a specimen bank?
• A facility for storing and maintaining a
collection of specimens (biospecimens) for
future use that distributes specimens to
multiple investigators and for multiple
projects
5
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Specimen Banking in the News
• Havasupai Indians
– Blood samples collected for diabetes research were used to
study mental illness and migration patterns of American Indians
from Asia.
– The consent document stated that the research was to “study the
causes of behavioral/medical disorders.”
– In 2010 ASU agreed to pay $700,000 to 41 of the tribe’s
members, return the blood samples and provide other forms of
assistance.
– Settlement is significant because it implies that the rights of
research subjects may be violated when they are not fully
informed of the future use of their tissue samples.
7
Specimen Banking in the News
• Henrietta Lacks
– Cells taken from tumor in 1951 formed basis for HeLa
cell line.
– No consent obtained from Ms. Lacks or her family.
– Original PI did not make money from HeLa, but the
line has now been commercialized.
– Family members of Ms. Lacks later participated in
other studies – but thought they were being tested for
cancer.
– Highlights gulf between scientists and research
subjects and the necessity for good communication
8
Specimen Banking in the News
• Texas newborn blood specimens 2010
– Five million blood samples taken from babies without
parental consent and stored indefinitely for scientific
research will be destroyed. The blood samples were
originally collected to screen for birth defects.
– The lawsuit alleged that the state’s failure to ask
parents for permission to store and possibly use the
blood violated constitutional protections against
unlawful search and seizure.
– The plaintiffs cited fears that their children’s private
health data could be misused.
9
Banks have three parts
• Collection system
• Maintenance of specimens
• Sharing of specimens
10
Collection system issues
•
•
•
•
•
Clinical or research specimens
Identifiable or coded or anonymized
Status of informed consent
Number of institutions involved
Vulnerable populations
11
Maintenance of specimen issues
• Single or multiple institutions
• Disease specific or broad number of
conditions
• Who owns it? Who is responsible for it?
Non-profit or for-profit?
• What are the long-term plans for the
bank?
12
Sharing of specimens issues
•
•
•
•
Open or restricted access?
Who determines access?
Identifiable or coded or anonymized
Do you have to return research results?
To the bank? To the subject?
13
Regulatory criteria for a specimen
banking protocol
• Risks to subjects are minimized
• Risks to subjects are reasonable in relation to
anticipated benefit
• Selection of subjects is equitable
• Informed consent will be obtained
• Informed consent will be documented
• Adequate monitoring to ensure safety
• Privacy is protected
• Vulnerable populations have been additionally
safeguarded
14
Risks vs. benefits
• Risks are minimized by anonymizing
samples
• Benefits are often maximized by
maintaining a link between the specimen
and the subject
15
What needs to be in a specimen
banking protocol?
• Purpose of the repository
• Type of specimen to be stored
• Recruitment and consent of subjects
– Subjects have an opportunity to refuse.
• How long will specimens be stored and where
• Procedures for collection of specimens
• Labeling of specimens
– Terms such as “deidentified” or “anonymized” used consistently
•
•
•
•
Other information stored along with specimens
Who has access to the repository
Sample distribution procedures
Method for subject withdrawal of specimens
16
What needs to be in the specimen
banking consent?
• Description of purpose
• How long specimens
will be stored
• Procedures used to
collect specimens
• Information stored
along with specimens
• Labeling of specimens
• Who maintains
specimens and what is
the release process
• Return of research
results
• Withdrawal of
specimens
• Participation is optional
17
Sample specimen banking protocol
18
•Purpose of the bank
•possible future testing specific to the development of
elvitegravir and for possible scientific research relating
to HIV-1 disease, diagnostics or drug safety
•Type of specimen to be stored
•blood
•Recruitment and consent of subjects
•Covered elsewhere in the protocol
•How long will specimens be stored and where
•10 years at Gilead
•Procedures for collection of specimens
•Discussed
19
20
Sample specimen banking consent
21
22
23
24
25
Summary – specimen banking
• Increasingly seen in sponsored clinical
trials.
• Reviewed by the same criteria as any
other protocol
• Protocols and consent information are
often deficient and inconsistent
26
Vulnerable Populations
27
Populations that will be covered
• Pregnant women, fetuses and neonates
(subpart B)
• Persons with mental disabilities or persons
with impaired decision-making capacity
28
Pregnant women and fetuses –
general considerations
• Where scientifically appropriate, preclinical studies,
including studies on animals, and clinical studies,
including studies on non-pregnant women, have been
conducted and provide data for assessing potential risks
to pregnant women and fetuses.
• 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.
29
Pregnant women, fetuses and
neonates – general considerations
• The consent of the father generally does not need
to be obtained if he is unable to consent because of
unavailability, incompetence, or temporary
incapacity or the pregnancy resulted from rape or
incest.
30
Pregnant women and fetuses
• Risks to fetus:
– Risks to the fetus caused solely by interventions or
procedures that have the prospect of direct benefit for
the women or the fetus
OR
– 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
31
Pregnant women and fetuses consent
• Only the consent of the pregnant woman:
– Prospect of direct benefit to the pregnant woman and the
fetus
– Prospect of direct benefit to just the pregnant woman
– No prospect of direct benefit to the woman or the fetus,
when the risk to the fetus is not greater than minimal, and
the purpose of the research is the development of
important biomedical knowledge that cannot be obtained
by other means
• Consent of both the pregnant woman and the father (if
available):
– If the research holds out the prospect of direct benefit
solely to the fetus
32
Consent signature requirements
Direct
benefit to
mother
only
Risk is
more
than
minimal
Risk is
no more
than
minimal
Mother's
consent
Mother's
consent
Direct
benefit
to
mother
and
fetus
Direct
benefit to
fetus only
No direct
benefit or
societal
benefits only
Mother's
consent
Mother
and
father's
consent
NOT
APPROVABLE
BY IRB
Mother's
consent
Mother
and
father's
consent
Mother's
consent
33
Scenario #1
• Description
– An interventional study on the effects of strict control
of maternal diabetes (e.g. insulin requirements, diet,
exercise etc.) on pregnancy outcome.
• Who benefits?
– Pregnant woman and fetus
• Who provides consent?
– Only the pregnant woman
34
Scenario #2
• Description
– An study on the effects of pregnancy on women with
cardiac disease. Data is collected through surveys
and blood tests.
• Who benefits?
– Only the pregnant woman
• Who provides consent?
– Only the pregnant woman
35
Scenario #3
• Description
– A prospective chart review and monthly survey to determine the
optimal gestational age for delivery of post-term pregnancies
(beyond 42 weeks of gestation). Maternal and neonatal
variables are assessed and compared with those of “normal”
pregnancies (37-40 weeks of gestation) to determine at what
gestational age does the benefit of induction outweigh that of
expectant management.
• Who benefits?
– Neither the pregnant woman nor the fetus
• What is the risk level for the fetus?
– Not greater than minimal
• Who provides consent?
– Only the pregnant woman
36
Scenario #4
• Description
– A study about a new technique for fetal transfusion for
Rh incompatibility.
• Who benefits?
– Only the fetus
• Who provides consent?
– Both the pregnant woman and the father
37
Neonates (including uncertain viability,
nonviable and viable) – general considerations
• Where scientifically appropriate, preclinical and
clinical studies have been conducted and
provide data for assessing potential risks to
neonates.
• Each individual providing consent is fully
informed regarding the foreseeable impact of the
research on the neonate.
• Individuals engaged in the research will have no
part in determining the viability of a neonate.
38
Neonates of uncertain viability
• Research can only be conducted if:
– The research holds out the prospect of enhancing the
probability of survival of the neonate to the point of
viability, and any risk is the least possible for
achieving that objective of the research
OR
– The purpose of the research is the development of
important knowledge which cannot be obtained by
other means and there will be no risk to the neonate
resulting from the research.
39
Neonates of uncertain viability
• Consent
– The legally effective informed consent of either
parent of the neonate or, if neither parent is able to
consent because of unavailability, incompetence, or
temporary incapacity, the legally effective informed
consent of either parent's legally authorized
representative is obtained
40
Nonviable neonates
• Research can only be conducted if:
– Vital functions of the neonate will not be artificially
maintained
– The research will not terminate the heartbeat or
respiration of the neonate
– There will be no added risk to the neonate resulting
from the research
– The purpose of the research is the development of
important biomedical knowledge that cannot be
obtained by other means
41
Nonviable neonates
• Consent
– The legally effective informed consent of both parents
of the neonate
• If either parent is unable to consent because of
unavailability, incompetence, or temporary
incapacity, the informed consent of one parent of a
nonviable fetus will suffice to meet the
requirements, except that the consent of the father
need not be obtained if the pregnancy resulted
from rape or incest.
• The consent of a legally authorized representative
of either or both of the parents of a nonviable
neonate will not suffice to meet the requirements.
42
Viable neonates
• Treated the same as children in subpart D.
43
Persons with impaired decisionmaking capacity
• Psychiatric, cognitive or developmental
disorders or conditions; mental disabilities;
substance abusers
• Disorder may compromise ability to make
an informed and reasoned decision
• May be vulnerable to undue influence
44
Persons with impaired decisionmaking capacity
• Approval criteria:
– Only this population is suitable as research subjects
– Evaluation of risks:
• No significant risks
OR
• If there is a probability of harm, there is a greater
probability of direct benefit to the subject
– Procedures developed for obtaining permission from
subjects’ representatives and assent (or consent)
from subject
45
Persons with impaired decisionmaking capacity
• Decision-making capacity may fluctuate –
re-consenting may be required
– Situation vs. disorder-related impairments
• (e.g. emergency room vs. stroke)
– Static vs. progressive vs. episodic vs. time-limited
impairments
• (e.g. severe mental retardation vs. Alzheimer’s
disease vs. manic depressive disorder vs. TBI)
46
Persons with impaired decisionmaking capacity
• Greater than minimal risk research
requirements
– Capacity to consent must be assessed
• Who will assess?
• What procedures?
– Is surrogate consent allowed?
• Direct benefit – yes
• No direct benefit - no
47
Persons with impaired decisionmaking capacity
• Watch out for:
– Research design that includes washout periods,
placebo or symptom provocation
– Research that does not offer direct benefit to the
subjects
48
Summary for vulnerable populations
• Is the risk/benefit profile approvable for
this study?
• Who will be giving consent? What is the
consent process?
49
Data Safety Monitoring Plans
50
Definition of data and safety
monitoring
• The process for reviewing accumulated outcome
data from an ongoing research study to ensure
the continuing safety of current participants and
those yet to be enrolled.
• An effort to ensure the continuing validity and
scientific merit of the research study.
• A data and safety monitoring plan is the strategy
used to conduct data and safety monitoring.
51
Why does the IRB need to see a
DSMP?
• To help the IRB understand how the
overall safety of the trial will be monitored
during the course of the trial.
• 45CFR46.111 (6)
– When appropriate, the research plan makes adequate
provision for monitoring the data collected to ensure
the safety of subjects.
52
When is a DSMP required?
• All studies considered greater than
minimal risk.
• Multi-site research where NYU SoM or its
affiliates is the coordinating site.
• Studies where there is an NIH or FDA
requirement for a plan.
• Studies when requested by the IRB.
53
What does a DSMP include?
• The type of data or events that are to be
captured under the monitoring plan.
• Who will be responsible for monitoring the data
collected and their roles.
– The plan is not required to have a DSMB or DSMC
54
What does a DSMP include?
• The time frames for reporting adverse events
and unanticipated problems to the monitoring
entity.
• The frequency of assessments of data or events
captured by the monitoring plan. This can be
points in time (3 months, 6 months etc.) or after
a specific number of participants are enrolled.
55
What does a DSMP include?
• Definition of stopping rules that will dictate when
some action is required. Stopping rules are
predetermined guidelines that are used to
determine that the study should be altered or
stopped, based on review of study related events
that occur during the conduct of the study.
– Should be specific about the endpoints that will be used and the
decisions that will be made.
• Greater than expected rate of morbidity or mortality.
• When the experimental arm of a head to head comparison
study is shown to be better or worse statistically than the
standard care arm.
56
What does a DSMP include?
• As appropriate, procedures for
communicating to the IRB, the study
sponsor, and other appropriate entities the
outcome of the reviews by the monitoring
entity.
57
What type of DSMP is appropriate?
• The plan should be tailored for:
– the nature, size, and complexity of the research
protocol
– the expected risks of the research
– the type of subject population being studied
58
What is a monitoring entity?
• An identified individual or group assigned to
conduct interim monitoring of accumulated data
from research activities to assure
–
–
–
–
the continuing safety of research participants,
relevance of the study question,
appropriateness of the study,
integrity of the accumulating data.
• Membership should include expertise in the
relevant field of study, statistics and research
design.
59
Who or what can be the monitoring
entity?
• Investigator
• Monitor/Monitoring Group
• Data Safety Monitoring Board (DSMB) /
Data Monitoring Committee (DMC)
60
Who or what can be the monitoring
entity?
• Investigator
– Study involves a small number of subjects
– Study is conducted only at one site
– The range of possible study events that could have
an important impact on the risks and benefits of
research participants is narrow.
61
Who or what can be the monitoring
entity?
• Monitor/Monitoring Group
– A qualified and objective individual or group not directly involved
with the design and conduct of the study
• safety officer
• designated medical monitor or monitoring group
– These individuals may or may not be employees of NYU SoM or
Medical Center or its affiliates or the study sponsor.
• Watch conflict of interest!
62
Who or what can be the monitoring
entity?
• Monitor/Monitoring Group is appropriate for
research studies that involve:
– endpoints that are not serious irreversible events;
– an intervention (for example, to relieve symptoms) that is
not high risk and the effects of which would not generally
be so compelling as to ethically warrant early termination
for effectiveness;
– short term treatments where effects are evaluated over
periods of a few days to a few months
– a smaller number of subjects where the study is
completed quickly and the risk can be adequately
assessed through simple comparisons.
63
Who or what can be the monitoring
entity?
• Data Safety Monitoring Board (DSMB)/Data Monitoring
Committee (DMC)
– A formal committee that is established specifically to monitor data
throughout the life of a study to determine if it is appropriate, from
both the scientific and ethical standpoint, to continue the study as
planned.
– Typically made up of individuals who have expertise in the field,
experience in the conduct of clinical trials, and/or statistical
knowledge, and do not have any serious conflicts of interest.
– Meet at least annually.
– Monitor the timeliness of accrual, the quality of data collection and
management, and the accumulating outcomes.
64
Who or what can be the monitoring
entity?
• DSMB/DMC is appropriate for research
studies involving:
–
–
–
–
–
Large numbers of subjects
Blinded study treatment groups
Multiple clinical sites
High risk interventions
Controlled trials with mortality or major morbidity as a
primary or secondary endpoint
65
Data and Safety Monitoring is not
just Adverse Event review
• The monitor/committee also reviews study
data to decide whether or not to continue
the study
66
Physicians’ Health Study
• Placebo controlled trial of aspirin and beta
carotene
• The trial's Data and Safety Monitoring
Board stopped the aspirin arm of the PHS
several years ahead of schedule because
it was clear that aspirin had a significant
effect on the risk of a first myocardial
infarction.
(http://phs.bwh.harvard.edu/index.html)
67
Trials of Antibiotic Treatment in
Patients with Lyme Disease
• Tested the safety and efficacy of intensive antibiotic
treatment in people with Lyme disease who had
developed chronic symptoms, despite earlier treatments
with antibiotics.
• DSMB recommended the termination of the treatment
component since it had accomplished its objectives.
– Their preliminary analysis showed that after 90 days of continuous antibiotic
therapy there were no significant differences in the percentage of patients who
felt that their symptoms had improved, gotten worse, or stayed the same
between the antibiotic treatment and placebo groups in either trial.
– The DSMB’s review suggested there was only a slight chance that a difference
between the placebo- and antibiotic-treated groups would be found even with
continued accrual of another 131 patients, the number needed to reach full
enrollment.
– (http://www.niaid.nih.gov/topics/lymeDisease/research/Pages/antibiotic.aspx)
68
Coloplast Virtue® Male Sling
The Coloplast Virtue® Male Sling is a Class II, implantable, sub-urethral,
permanent, non-absorbable support sling indicated for the surgical treatment of
male SUI resulting from intrinsic sphincter deficiency (ISD). The sling is
manufactured from polypropylene and is sold for single use only.
The device consists of a knitted monofilament polypropylene mesh. The body of the
device provides surface area for supporting the bulbous urethra. The four arms are
covered with polyethylene sleeves. Extending from the ends of each arm are
braided polyester sutures, which are attached to the mesh arms via heat sealed
polyethylene cones. The sutures provide proper attachment to the introducer and
allow for proper positioning of the sling in the body. The introducer allows for
implanting both the transobturator arms and pre-pubic arms of the mesh sling. The
introducer is sold as single use with the mesh sling in a kit.
This investigation of the Coloplast Virtue® Male Sling device is a prospective,
single-arm, nonrandomized study to assess efficacy and safety of suture fixation in
50 implanted subjects. Implants will not exceed 15 subjects at any particular center.
69
Sample Monitoring Plan
70
No section for a Data Safety Monitoring Plan
The process for reviewing accumulated outcome data from an ongoing research study to ensure the continuing
safety of current participants and those yet to be enrolled.
An effort to ensure the continuing validity and scientific merit of the research study.
*Adverse event reporting and review
*Data quality assurance
71
Types of data or events
•SAEs, Severe Anticipated and
Unanticipated AEs....
Adverse events are reviewed – but
it’s not clear what kind of assessment
is done beyond classification.
72
Responsibilities and roles
for gathering, evaluating and
monitoring the data:
Role of PI, Staff, Sponsor specified for
AE review, but not continuing analysis
for safety.
Verification of data accuracy will be done by
Sponsor (frequency unspecified).
Verification of compliance with protocol will
be done by Site monitor (at least once).
73
Information about monitoring
entity:
Independent Medical Advisor will review
AEs – but this is not a data safety monitor.
74
Reporting adverse events
and unanticipated problems
to the monitoring entity:
Time frames – indicated
Mechanisms – not indicated
Who will prepare – PIs
75
Assessments
No information about a data safety monitor
– just adverse event review.
76
Criteria for action:
No description of triggers for actions or
stopping rules.
77
Procedures for
communicating
Only described for adverse event reporting.
78
DSMP Review Summary
• A data safety monitoring plan is more than
adverse event review.
• Plans are often incomplete or missing.
79
Questions?
80
Thank you.
Melissa Epstein
melissa.epstein@nyumc.org
212-263-4027
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