Making Sense of Reporting Obligations to the IRB

Transcription

Making Sense of Reporting
Obligations to the IRB
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About Quorum Review IRB
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About the Presenters
Regulatory Attorney
Claire Carbary, JD, CIP
IRB Experience
•
•
•
Joined Quorum Review IRB in September 2009
WIRB prior to Quorum
CIP certification since 2010
•
Member of the Northwest Association for Biomedical Research (NWABR) and
Public Responsibility in Medicine and Research (PRIM&R)
Legal Background
•
•
•
9
Juris Doctor from Seattle University
Member of the Washington State Bar Association (WSBA)
Member of the Health and Corporate Law Sections of the WSBA
About the Presenters
Regulatory Attorney
Mitchell Parrish, JD, CIP
IRB Experience
•
•
•
•
Joined Quorum Review IRB in January 2010
Regulatory Counsel with WIRB prior to Quorum
Former Regulatory Advisor to the National Cancer Institute Central IRB
CIP certified since 2009
Legal Background
•
•
•
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Juris Doctor from the University of Oregon School of Law
Member of the Washington State and American Bar Associations
Member of the Health and Corporate Law Sections of the WSBA
Making Sense of Reporting Obligations
to the IRB
11
Webinar Overview
Description of Topic
Page
Role of the IRB
Problems with Reporting
Regulatory Landscape
Obligations for Reporting Safety Information
13
17
20
28
Unanticipated problems that are Adverse Events
SUSAR
UADE
Recommended practices for reporting Safety Information
Obligations for Reporting Non-Safety Information
51
Unanticipated Problems that are not Adverse Events
Recommended practices for reporting Non-Safety Information
Key Take Aways
12
65
Role of the IRB
13
Role of the IRB
“
The primary purpose of both initial and continuing review of [a]
study is ‘to assure the protection of the rights and welfare of the
human subjects’ ( 56.109(f). To fulfill its obligations… an IRB
must have, among other things, information concerning
unanticipated problems involving risk to human subjects in the
study, including adverse events that are considered
unanticipated problems.”
FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs—
Improving Human Subject Protection
(January 2009)
14
15
16
Problems With Reporting
17
Problems with Reporting – Unnecessary Reporting
“
Much of the information that is being reported does not
meet reporting requirements and therefore results in the
unnecessary expenditure of resources by all stakeholders
Specifically, “the way that ‘unanticipated problem’ is
interpreted does not yield information about adverse
events that is useful to IRBs and thus hinders their
ability to ensure protection of human subjects.”
(January 2009)
18
Problems with Reporting – No Explanation Provided
Not only is unnecessary information reported, but also reported information
is not explained:
“
In the years since the IRB and IND regulations issued, changes in the
conduct of clinical trials (e.g., increased use of multi-center studies,
international trials) have complicated the reporting pathways for adverse
event information described in the regulations. IN particular the practice of
local investigators reporting individual, unanalyzed events to IRBs,
including reports of events from other study sites that the investigator
receives from the sponsor of a multi-center study—often with limited
information no explanation of how the event represents an
unanticipated problem—has led to the submission of large numbers of
reports to IRBs that are uninformative.”
(January 2009)
19
20
Regulations (HHS/FDA)
• 45 CFR 46 (Protection of Human Subjects)
• 21 CFR 56 (Institutional Review Boards)
• 21 CFR 312 (Investigational New Drug Application)
• 21 CFR 320 (Bioavailability and Bioequivalence Requirements)
• 21 CFR 812 (Investigational Device Exemptions)
Guidance (HHS/FDA)
• HHS, Guidance on Reviewing and Reporting Unanticipated Problems
Involving Risks to Subjects or Others and Adverse Events, January 15,
2007
• FDA, Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse
Event Reporting to IRBs—Improving Human Subject Protection,
January, 2009
• FDA, Draft Guidance for Industry and Investigators, Safety Reporting
Requirements for INDs and BA/BE Studies, September, 2010
21
From Where is the Obligation to Report Safety
Information to the IRB derived?
• FDA and HHS regulations require the IRB to receive safety and
other information throughout study and during continuing review
to ensure the criteria for approval is still met and to ensure the
safety, rights, and welfare of subjects are protected.
45 CFR 46.109 and 46.111; 21 CFR 56.109 and 56.111
22
From Where is the Obligation to Report Safety
Information to the IRB derived? (continued)
• There is a lot of safety data and other information in
clinical trials, so where in the regulations does it say
exactly what to report to the IRB?
• While the regulations do not contain specifics, they
do provide the term “Unanticipated Problem” (UP)
23
Unanticipated Problem
24
•
21 CFR 312.66 – “The investigator shall . . .Promptly report to the IRB .
. . All unanticipated problems involving risk to human subjects or
others.”
•
21 CFR 56.108(b)(1) – “[E]ach IRB shall: …Follow written procedures
for ensuring prompt reporting to the IRB, appropriate institutional
officials, and the Food and Drug Administration of: (1) Any
unanticipated problem . . . .”
•
45 CFR 46.103(b) (4) – An IRB must have “[W]ritten procedures for
ensuring prompt reporting to the IRB , appropriate institutional officials,
and the department or agency head of (i) any unanticipated problems
involving risks to subjects or others. . . .
Unanticipated Problem = Any incident, experience, or outcome that
meets all of the following criteria:
1. Unexpected (in terms of nature severity or frequency) given(a) the
research procedures that are described in the protocol-related
documents, and (b) the characteristics of the subject population
being studied;
2. related or possibly related to participation in the research; and
3. suggests that the research places subjects or others at a greater
risk of harm (including physical, psychological, economic, or social
harm) than was previously known or recognized.
HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving
Risks to Subjects or Others and Adverse Events (January 15, 2007)
*Note: this general criteria is essentially the same for unanticipated problems under FDA regulations as well
25
Unanticipated Problems and Adverse Events
In addition to defining “Unanticipated Problem,” the HHS Guidance also explains
that there are UPs that stem from adverse events, essentially safety related UPs,
and those that do not stem from adverse events, essentially non-safety related UPs.
Adverse Event: Any untoward or unfavorable medical occurrence in a human
subject, including any abnormal sign (for example abnormal physical exam or
laboratory finding), symptom, or disease, temporally associated with the subject's
participation in the research, whether or not considered related to the subject’s
participation in the research. This encompasses both physical and psychological
harms and can be categorized as “internal” (happening at the site) or “external”
(happening at other locations)
Note: The terms “adverse effect” and “adverse experience” are interchangeable with “adverse event.” FDA
Guidance, Adverse Event Reporting to IRBs – Improving Human Subject Protection (January 2009)
26
• Safety Related:
Do not report
adverse events that
are not UPs
• Safety Related:
Must report adverse
events that are UPs
• Non-Safety Related:
Must report UPs that
are not adverse
events
Adapted from HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to
Subjects or Others and Adverse Events (January 15, 2007); See also FDA Guidance, Adverse Event Reporting to
IRBs – Improving Human Subject Protection (January 2009)
27
Obligations for Reporting Safety
Information to the IRB
28
• Safety Related:
Do not report
adverse events that
are not UPs
• Safety Related:
Must report adverse
events that are UPs
are not adverse
events
29
Reporting Safety Information to the IRB
SUSAR:
Serious and unexpected
suspected adverse reactions
UP
UADE:
Unanticipated Adverse Device
Effect
30
By its very nature,
if an event is an
SUSAR or a UADE
then it is a UP and
must be reported to
the IRB
IRB
Reporting Safety Information - SUSAR
Serious and unexpected suspected adverse reaction (SUSAR) originates from
21 CFR 312 and is designed to guide sponsors on when to submit IND safety
reports to the FDA and investigators
Must report to the IRB all SUSARs that satisfy these three criteria:

Serious (Death, life-threatening, inpatient hospitalization or prolongation of
existing hospitalization, persistent or significant incapacity, substantial
disruption of the ability to conduct normal life functions, and congenital
anomaly/birth defect)

Unexpected (an event not listed in the investigator brochure or not listed at
the specificity or severity observed; or an event not consistent with the risk
information described in the investigational plan)

Suspected Adverse Reaction (“a reasonable possibility that the drug
caused the adverse event”)
 Evidence to suggest a causal relationship between the drug and event
31
Individual Occurrences
A single occurrence of an event that is uncommon and known to be
strongly associated with drug exposure (e.g., angioedema, hepatic
injury, Stevens-Johnson Syndrome)
32
Example:
In a phase II study testing an investigational drug for Hepatitis C, a
subject experiences hepatic injury. In addition to the investigational
drug, the subject was continuing her standard Hepatitis C therapy
at the time of hepatic injury.
Is this reportable to the IRB as an individual occurrence?
33
Example:
In a phase II study testing an investigational drug for Hepatitis C, a
subject experiences hepatic injury. In addition to the investigational
drug, the subject was continuing her standard Hepatitis C therapy
at the time of hepatic injury.
Is this reportable to the IRB as an individual occurrence?
NO
34
One or more Occurrences
One or more occurrences of an event that is not commonly
associated with drug exposure, but is otherwise uncommon in the
population exposed to the drug (e.g., tendon rupture, progressive
multifocal leukoencephalopathy)
35
Example:
A subject with extrapulmonary small-cell carcinoma receiving an
investigational chemotherapy agent experiences a bowel
perforation during his second cycle of chemotherapy.
Is this reportable to the IRB as one occurrence?
36
Example:
A subject with extrapulmonary small-cell carcinoma receiving an
investigational chemotherapy agent experiences a bowel
perforation during his second cycle of chemotherapy.
Is this reportable to the IRB as one occurrence?
NO
37
Aggregate Analysis of Specific Events
An aggregate analysis of specific events observed in a clinical trial
(such as known consequences of the underlying disease or
condition under investigation or other events that commonly occur
in the study population independent of drug therapy) that indicates
those events occur more frequently in the drug treatment group
than in a concurrent or historical control group.
38
Example:
17 oncology sites are participating in a research study
comparing an investigational chemotherapy agent to
standard therapy in subjects ages 60-85. Of those subjects
receiving the investigational drug, an average of 35% of
subjects across the 17 sites experience deep vein
thrombosis.
Is this reportable as an aggregate analysis?
39
Example:
17 oncology sites are participating in a research study
comparing an investigational chemotherapy agent to
standard therapy in subjects ages 60-85. Of those subjects
receiving the investigational drug, an average of 35% of
subjects across the 17 sites experience deep vein
thrombosis.
Is this reportable as an aggregate analysis?
YES
40
Critical to understand the definition of “Suspected
Adverse Reaction” coupled with the examples the
FDA provides:
o Individual occurrence
o One or more occurrences
o Aggregate analysis
41
Without this understanding, the FDA explains that the following
problem occurs:
Reporting of individual events even though unlikely that the event was caused by
the drug. Examples include:
 Serious adverse experiences (e.g. mortality or major morbidity) that
are unlikely to have been manifestations of the underlying disease
 Serious adverse experiences that commonly occurred in the study
population independent of drug exposure (e.g. strokes or acute
myocardial infarction in an elderly population)
 Serious adverse experiences that were study endpoints (i.e. the study
was evaluating whether the drug reduced the rate of these events)
Such reporting causes a “drain on resources” when the FDA, and IRBs are
inundated with “generally uninformative” Safety Information especially when
reported as single events without any context.
42
Reporting Safety Information - UADE
Unanticipated Adverse Device Effect (UADE) originates from 21
CFR 812 and is designed to guide sponsors on when to submit
reports to the FDA and investigators
Must report to the IRB all UADEs that satisfy the following criteria:



43
Serious (death, life-threatening, serious problem)
Not previously identified (an effect not previously identified in
nature, severity, or degree of incidence in the investigational plan
or application)
Caused by, or associated with, a device
Reporting Safety Information - UADE
FDA Guidance for Clinical Investigators, Sponsors, and IRBs,
Adverse Event Reporting to IRBs—Improving Human Subject
Protection (January 2009)

Essentially states that reporting UADEs to the IRB should be treated the
same as reporting SUSARs to the IRB

While not in the device regulations like the drug regulations and while there
are different considerations between safety information for drugs and
devices, take into account whether the effect is a:
•
•
•
44
Individual occurrence
One or more occurrences
Multiple occurrences determined through an aggregate analysis
Recommended Practices for Reporting
Safety Information to the IRB
45
Recommended Practices for Reporting Safety Information
For Multi-center studies:

Even though the FDA regulations indicate it is the investigator’s
responsibility to notify the IRB of unanticipated problems (21 CFR
312.66)—FDA guidance states: “Investigators must rely on the sponsor to
provide them information about AEs occurring at other study sites”

“The sponsor is in a better position to process and analyze the significant
of AE information from multiple sites…and to make a determination about
whether an AE is an unanticipated problem.”

FDA supports an arrangement in which the sponsor prepares UP reports
and submits to the IRB “when the sponsor, investigator, and IRB have
made an explicit agreement for the sponsor to report directly to the IRB.”

“Although the investigator’s view of the causal relationship between an
adverse event and the investigational drug is important, FDA believes that
the sponsor is better positioned than the individual investigator to assess
the overall safety of the investigational drug because the sponsor has
access to serious adverse event reports from multiple study sites and is
able to aggregate and analyze these reports.”
FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs—Improving
Human Subject Protection (January 2009); Draft FDA Guidance for Industry and Investigators, Safety Reporting
Requirements for INDs and BA/BE Studies (September 2010)
46
(continued)

While Investigators may report SUSARs and UADEs to the IRB,
Quorum recommends that Sponsors/CROs submit SUSAR and UADE
information to the IRB on behalf of investigators. This means . . .

The Sponsor/CRO should inform investigators and arrange with the
IRB that it will report on behalf of investigators (arrangement with IRB
should include in what format to report)

The protocol should not state generally that “all adverse events require
reporting the IRB” or include similar language because then if “all
adverse events” are subsequently not reported, investigators run the
risk of being out of compliance with the protocol
 Also it is not appropriate to submit all AEs to the IRB, just AEs that are
SUSARs or UADEs!
47
For single-center or investigator initiated studies:
•
Obviously, the investigator is likely the one reporting to the IRB.
This still means:

The investigator can arrange with IRB in what format to report

The protocol should still not state generally that “all adverse events
require reporting the IRB” or include similar language because then if
“all adverse events” are subsequently not reported, investigators run
the risk of being out of compliance with the protocol.
 Also it is not appropriate to submit all AEs to the IRB, just AEs
that are SUSARs or UADEs!
48
(continued)
TIMING of Reporting to the IRB
Report SUSARs and
UADEs “promptly” to
the IRB
“Promptly” is
generally considered
10 days, which is
supported in the FDA’s
guidance on reporting
AEs to the IRB
This 10-day timeframe exists whether there is an arrangement for the
sponsor to submit on behalf of the IRB or whether the investigator is
responsible for submitting to the IRB
49
(continued)
What to report
QUESTION
ABOUT
Whether to report
How to report
When to report
Contact the IRB!
50
Obligations for Reporting Non-Safety
Information to the IRB
51
Reporting Non-Safety Information to the IRB
• Safety Related:
Do not report
adverse events that
are not UPs
• Safety Related:
Must report adverse
events that are UPs
are not adverse
events
52
Reporting Non-Safety Information to the IRB
Unexpected
Related or Possibly
Related
Greater Risk of
Harm
53
UP
Unanticipated
Problem
Must report all
UPs to the IRB
IRB
Reporting Non-Safety Information
Unanticipated Problems
Examples:
•
Failure to obtain informed consent
•
Omitting study procedure(s) required by the approved protocol
•
•
Study personnel misconduct that adversely impacts the study
Adverse findings by a regulatory agency, medical board, or other relevant body
Are these UPs?
* Whether these are UPs depends on the type of study and the specific factors surrounding each
event or incident.
54
Example:
An investigator is conducting behavioral research and collects individually
identifiable sensitive information about illicit drug use by surveying college students.
The data is stored on a laptop computer that is password protected. The laptop is
stolen from the investigator’s car.
Is this reportable to the IRB as a UP?
55
Example:
An investigator is conducting behavioral research and collects individually
identifiable sensitive information about illicit drug use by surveying college students.
The data is stored on a laptop computer that is password protected. The laptop is
stolen from the investigator’s car.
Is this reportable to the IRB as a UP?
YES
56
Example:
An Investigator is conducting a psychology study evaluating decision making and response
times when persons are listening to music at various decibel levels. In order to perform the
study, participants are placed in a small, windowless, soundproof booth. The IRB-approved
protocol and consent form describe claustrophobic reactions as one of the research risks.
The 12th subject enrolled in the research experiences significant claustrophobia, resulting in
the subject withdrawing from the study.
Is this event reportable to the IRB as a UP?
57
Example:
An Investigator is conducting a psychology study evaluating decision making and response
times when persons are listening to music at various decibel levels. In order to perform the
study, participants are placed in a small, windowless, soundproof booth. The IRB-approved
protocol and consent form describe claustrophobic reactions as one of the research risks.
The 12th subject enrolled in the research experiences significant claustrophobia, resulting in
the subject withdrawing from the study.
Is this event reportable to the IRB as a UP?
NO
58
Example:
As a result of a processing error by a pharmacy technician, a subject enrolled in a
multi-center clinical trial receives a dose of an experimental agent that is 10-times
higher than the dose dictated by the IRB-approved protocol. While the dosing error
increased the risk of toxic manifestations of the experimental agent, the subject
experienced no detectable harm or adverse effect after an appropriate period of
careful observation.
Is this error reportable to the IRB as a UP?
59
Example:
As a result of a processing error by a pharmacy technician, a subject enrolled in a
multi-center clinical trial receives a dose of an experimental agent that is 10-times
higher than the dose dictated by the IRB-approved protocol. While the dosing error
increased the risk of toxic manifestations of the experimental agent, the subject
experienced no detectable harm or adverse effect after an appropriate period of
careful observation.
Is this error reportable to the IRB as a UP?
YES
60
Non-Safety Information to the IRB
61
Non-Safety Information
For multi-center or single-center:
• Generally, UPs that are not an adverse event (i.e. nonsafety related) are typically site or investigator specific
• Therefore, it makes more sense for the investigator, not
the sponsor, to report the UP to the IRB
• The investigator can arrange with IRB in what format to
report
62
Non-Safety Information continued
(
)
TIMING of Reporting to the IRB
Report UPs “promptly”
to the IRB
“Promptly” is
generally considered
10 days, which is
supported in the FDA’s
guidance on reporting
to the IRB
This 10-day timeframe exists whether there is an arrangement for the
sponsor to submit on behalf of the IRB or whether the investigator is
responsible for submitting to the IRB
63
(continued)
What to report
QUESTION
ABOUT
Whether to report
How to report
When to report
Contact the IRB!
64
Key Take Aways
• Know where the obligations to report to the IRB originate
• Understand the term “Unanticipated Problem” (UP) and its three
criteria: Unexpected, Related, Greater Risk of Harm
• Understand the terms SUSAR and UADE, know their criteria,
and know that these are UPs that require reporting to the IRB
• Understand that there are UPs that are not safety-related that
must be reported to the IRB
• Know how and in what timeframe to report to the IRB
• If there are ever any questions relating to reporting to the IRB, talk
to your IRB. The IRB is a resource!
65
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answer your questions in the Q&A we post on
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66
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67
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68
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Thank You for Attending!
69
Making Sense of Reporting
Obligations to the IRB
fully accredited since 2006

Making Sense of Reporting Obligations to the IRB

Transcription

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