OHRP Regulatory Interpretations That You Need To Know But Have Never Been Told

Clinical Research Management Webinar Series:

OHRP Regulatory
Interpretations That You Need To Know
But Have Never Been Told

Wednesday, November 14, 2012
12:00 p.m. - 1:00 p.m. CT

About Our Speakers

Madeleine Williams, MA, CIP
Director, Huron Life Sciences
P 312. 479. 3374
mwilliams@huronconsultinggroup.com

Maddie has over 10 years of research experience and assists clients with
research biorepository design and development, institutional review board (IRB)
assessments and operational support, regulatory compliance evaluations, and
human research protection program evaluation and accreditation.

Frank Conte, MS
Manager, Huron Life Sciences
P 312. 404. 6413
fconte@huronconsultinggroup.com

Frank has more than 10 years of project management experience in higher
education and research compliance. He focuses on assisting higher education and
healthcare organizations with operational analysis, regulatory compliance
evaluations, process improvement and software design and implementation.
© 2012 Huron Consulting Group. All Rights Reserved. Proprietary & Confidential. 2

Agenda

Modifications Research
Expedited Unanticipated Record
Exemptions Engagement to Approved Involving HIPAA
Review Problems Retention
Research Prisoners

In today’s session, we plan to discuss topics including:

• Exempt Determinations
• Category 1
• Category 4
• Expedited Review
• Category 8b
• Institutional Engagement
• Modifications to Previously Approved Research
• Changes in Study Personnel
• Single Subject Exceptions
• Research Involving Prisoners as Subjects
• HIPAA
• Unanticipated Problems Involving Risks to Subjects or Others
• IRB Record Retention

Disclaimer

The information in this webinar is representative of Huron’s
experience and correspondence with OHRP and should not be
interpreted as official guidance. We encourage the audience to
contact OHRP for feedback on specific questions.


Current Environment
Of
Human Research Protections

Human Subjects Protections
Current Environment

• Lots of Regulations
• 45 CFR 46 (Department of Health & Human Services)
• 21 CFR 50 and 56 (Food and Drug Administration)
• 45 CFR 164.512 (HIPAA)

• Interpretation of regulations can be confusing; guidance documents
are helpful .

• Best Practices
• Association for the Accreditation of Human Research Protection Programs (AAHRPP)
• Huron HRPP Toolkit


Scenarios for Discussion
and
Interpretations

Exempt Determinations - Category 1

Expedited Unanticipate Record
Review d Problems Retention
Research Prisoners

 45 CFR 46.101 (b)(1) states:
• (b) Unless otherwise required by department or agency heads, research activities
in which the only involvement of human subjects will be in one or more of the
following categories are exempt from this policy:
(1) Research conducted in established or commonly accepted educational
settings, involving normal educational practices, such as
(i) research on regular and special education instructional strategies, or
(ii) research on the effectiveness of or the comparison among instructional
techniques, curricula, or classroom management methods.



Research Prisoners

Scenarios:
A. Does “involving normal educational practices” to refer to:
(1) The procedures involved in the research are normal educational practices;
(2) The purpose of the research involves normal educational practices; or
(3) Both
B. Suppose a standard practice in a high school current events class is to have a
teacher-led group discussion about how current events affect US society by having
a discussion of how the news of the day has personally affected them and their
families. An investigator/teacher wants to conduct research by facilitating the class
discussion.
1. If the purpose of the research was to improve methods of classroom discussion,
would this be exempt under #1?
2. If the purpose of the research was to understand high school student responses to
current events, would this be exempt under #1?


Research Prisoners

Interpretations:
 Scenario A - In order to qualify for exemption under §46.101 (b) (1), the study would
need to fit BOTH:
- The procedures involved in the research are normal educational practices
AND
- The purpose of the research involves normal educational practices
 Scenario B
• #1 qualifies for exemption under §46.101 (b) (1), because the research is conducted in
an established or commonly accepted setting and the research involves a normal
educational practice
• #2 may be exempt but it would depend on why the investigator wants to understand high
school students’ responses to current events; if it is because the investigator is trying to
better understand the education of high school students, it could be considered exempt
under §46.101 (b) (1)
Email correspondence dated April 2010


Research Prisoners

 45 CFR 46.101 (b)(4) states:
• Research involving the collection or study of existing data, documents,
records, pathological specimens, or diagnostic specimens, if these sources
are publicly available or if the information is recorded by the investigator
in such a manner that subjects cannot be identified, directly or through
identifiers linked to the subjects.



Research Prisoners

Scenario:
An investigator does the following:
1. Creates a data collection form-this is constructed such that the identity of the subject
cannot readily be ascertained by the investigator or associated with the recoded
information. (e.g., the investigator wants to see if there is a relationship between length
of stay for laparoscopic surgery and age, so the data collection form records age and
length of stay. The data collection form contains no other information.)
2. Creates a list of medical record numbers-runs a search to get a list of MRNs of
subjects/potential subjects. This list is separate from the data collection form.
3. Picks a medical record number and get the corresponding medical chart.
4. Checks the chart to see if the individual meets inclusion criteria. If so, complete the
data collection form.
5. Marks the medical record number on the list as complete.
6. Repeats steps #1-#3 until done and then analyzes the data.

Polling Question
Research Prisoners

Polling Question:
Is the described process acceptable for exempt #4 under 45
CFR 46?
A. Yes
B. No
C. Not Sure


Exempt Review - Category 4

Research Prisoners

Interpretation:
 Yes-the described process is consistent with OHRP’s interpretation of exemption 4.

 Exemption 4 applies even if an investigator records a list of identifiable information
(e.g. medical record numbers) for the purpose of linking this list with other records,
provided that: (1) the investigator does not include any private information such as
medical information on this list of identifiers; and (2) does not record identifiers once
the data for the study have been obtained and the analyses begin.

 Note: VA has issued guidance in July 2011 that does not allow exemption 4 to be
applied to such activities.

Email correspondence dated August 2011

Expedited Review - Category 5

Research Prisoners

 Expedited category 5 states:
Research involving materials (data, documents, records, or specimens) that have been
collected, or will be collected solely for non-research purposes (such as medical
treatment or diagnosis). (NOTE: Some research in this category may be exempt from the
HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(4). This listing
refers only to research that is not exempt.)

Scenario:
 Can this category be interpreted to encompass:
• Research involving materials (data, documents, records, or specimens) that have been
collected (for any reasons either for research or for non-research purposes) OR
• Research involving materials (data, documents, records, or specimens) that will be
collected solely for non-research purposes?


Expedited Review - Category 5

Research Prisoners

Interpretation:
 In 2007 OHRP proposed to amend expedited review category 5 to clarify that the
category includes
• Research involving materials that were previously collected for either non-research or
research purposes, provided that any materials collected for research were not collected
for the currently proposed research, OR
• Research involving materials that will be collected solely for non-research purposes.

 http://www.hhs.gov/ohrp/archive/requests/com102607.html


Expedited Review - Category 8b

Research Prisoners

 Expedited category 8 states:
(8) Continuing review of research previously approved by the convened
IRB as follows:
(a) where (i) the research is permanently closed to the enrollment of new
subjects; (ii) all subjects have completed all research-related interventions;
and (iii) the research remains active only for long-term follow-up of subjects;
or
(b) where no subjects have been enrolled and no additional risks have
been identified; or
(c) where the remaining research activities are limited to data analysis.



Research Prisoners

Scenario:
• A study is initially reviewed and approved by the convened IRB on 1/6/12.
• A new risk is identified by the investigator and reviewed by the convened IRB on
6/25/12 where the IRB approves a modification.
• The research then comes up for continuing review on 12/10/12.

If no subjects have been enrolled at the site since initial review and no additional risks
have been identified (at any site) since the convened IRB review on 6/25/12, can the
study undergo continuing review via expedited review under category 8b?



Research Prisoners

Interpretation:
 Yes, the IRB could review the research at the time of continuing review under an
expedited review procedure
• Since there are no additional risks since the last IRB review (the modification on
6/25/12), it would be considered to have “no additional risks identified” and could
be reviewed via expedited procedures.


Guidance on Engagement of Institutions in
Human Subjects Research
Research Prisoners

Scenario:
Dr. Smith at institution A asks individuals at institutions X, Y, and Z to release private
identifiable information to institution A for Dr. Smith’s HHS supported research. The
individuals at institutions X, Y, and Z will review medical records, fill out case report
forms with information extracted from the medical records, and submit them to Dr.
Smith.
• None of the data being abstracted from the medical records was obtained for research
purposes and the individuals would normally have access to these records.
• Individuals at institutions X, Y, and Z will not interact or intervene with subjects and will not
be involved in the analysis of private identifiable data.
• Institutions X, Y, and Z are not awardees through a grant, contract, or cooperative
agreement directly from HHS.
• Institutions X, Y, and Z have ensured that institutional requirements have been satisfied as
well as compliance with other applicable regulations and laws (e.g., HIPAA.)


Research Prisoners

Questions:
1. Are institutions X, Y, and Z engaged in the research?
2. The protocol says that institutions X, Y, and Z are “sites” and that the individuals
providing data to Dr. Smith are “co-investigators.” Does this change the
engagement determination?
3. Dr. Smith says that the individuals at institutions X, Y, and Z will be co-authors
on the paper. Does this change the engagement determination?
4. Dr. Smith will pay institutions X, Y, and Z to reimburse for the work of extracting
the medical records. Does this change the engagement determination?


Research Prisoners

Interpretation:
 Institutions X, Y, and Z are NOT engaged in the research, regardless of whether the
collaborating employees at institutions X, Y, and Z are listed as co-investigators, will
be co-authors on publications related to the research, or will be reimbursed for
extracting medical record data.
 The OHRP guidance on engagement states that if an institution releases private
identifiable data to an investigator conducting research outside the institution,
the institution is not engaged in research.
 The person gathering the data for release needs to have legitimate access to the
data.
• If the individuals at institutions X, Y, and Z did not normally have access to the subjects’
medical records and were accessing them for the purposes of the research, then those
individuals would be doing more than just releasing identifiable private information to
institution A – they would also be obtaining identifiable private information for research
purposes and, thus, institutions X, Y, and Z would be engaged in the research.

Single Subject Exceptions

Review Research Problems Retention
Prisoners

 A common activity in a clinical trial are “protocol exceptions” or “single subject
exceptions.” An exception is when an individual is otherwise eligible for participation in a
protocol but does not meet an inclusion or exclusion criterion or is eligible but one or
more procedures cannot be conducted as specified in the protocol.
 The investigator contacts the sponsor and asks to follow a variation on the protocol for
one subject. The sponsor provides permission provided the IRB approves the plan.
 Examples of exceptions include:
• The protocol specifies that a patient must have a creatinine (kidney function measure) level of
<=1.0. As individual is otherwise eligible for the trial except for a creatinine level of 1.1. The
investigator contacts the sponsor and asks for permission to enroll the subject because the
difference between a creatinine of 1.0 and 1.1 is not clinically significant.
• The protocol specifies that subjects will not be paid for participation nor provided any
reimbursement. The investigator finds an individual who qualifies for the research except that
the subject has insufficient funds for taxi fare to and from the hospital for clinic visits. The
investigator contacts the sponsor and asks for permission to enroll the subject and reimburse
for transportation costs.


Prisoners

 45 CFR 46.103 (b)(4) states:
• (b) Departments and agencies will conduct or support research covered by this policy only
if the institution has an assurance approved as provided in this section, and only if the
institution has certified to the Department or Agency head that the research has been
reviewed and approved by an IRB provided for in the assurance, and will be subject to
continuing review by the IRB. Assurances applicable to federally supported or conducted
research shall at a minimum include:
– (4) Written procedures which the IRB will follow…
(iii) for ensuring prompt reporting to the IRB of proposed changes in a research
activity, and for ensuring that such changes in approved research, during the period
for which IRB approval has already been given, may not be initiated without IRB
review and approval except when necessary to eliminate apparent immediate
hazards to the subject.



Prisoners

Questions:
1. Are these exceptions “proposed changes in a research activity”?
2. If these exceptions are not “proposed changes in a research activity”, what
procedures, if any, does the IRB need in place to grant permission for these
exceptions before they are initiated by the investigator?
3. If these exceptions are “proposed changes in a research activity”, can the IRB
approve these proposed changes in a research activity by any mechanism other
than review by the convened IRB or, if eligible for review using the expedited
procedure, review by the IRB chair or one or more experienced IRB members
designated by the IRB chair?



Prisoners

Interpretation:
 OHRP would consider such circumstances to be changes to the protocol which would
require prior IRB review and approval unless necessary to eliminate apparent
immediate hazards to subjects
 It would be reasonable to review these in an expedited manner by the IRB chair or
one or more experienced IRB members designated by the IRB chair

Email correspondence dated July 2011

Changing Study Personnel

Prisoners

 In many IRB offices, a huge effort goes into tracking the specific study personnel
assigned to a research protocol. For example:
• In cancer centers where there is a large pool of coordinators who cross cover many
protocols. When a new coordinator is hired, the PI is submitting dozens (or more)
modifications to add that coordinator to all possible protocols in which the coordinator
might be involved.



Prisoners

Scenario:
 Can an IRB approve a protocol that describes the qualifications of personnel and the
minimal complement of personnel, without knowing the specific names of the study
personnel, and then allow the principal investigator to change study personnel
provided the qualifications are met?
• A protocol submitted to the IRB indicates that the investigator will have the following study
personnel:
– One or more coordinators who are RNs and CITI trained who will perform specific
study procedures and be involved in the consent process.
– A licensed pharmacist who will dispense study drug.
– One or more physician sub-investigators who will be licensed by the state,
credentialed by the hospital, trained on the study protocol and CITI trained. These
individuals will work under the supervision of the principal investigator.


Polling Question
Prisoners

Polling Question:
Can the IRB approve a protocol without knowing the specific
names of the study personnel, provided that the protocol
indicates specific criteria for selecting study team members?
A) Yes
B) No
C) Not sure


Changing IRB Personnel

Prisoners

Interpretation:
 It is reasonable for the IRB to approve a protocol without knowing specific names of
research personnel, provided that the proposal includes detailed criteria for selecting
research personnel
• Any changes to the proposed criteria would involve a modification to the approved
research, and would need to be reviewed and approved by the IRB.

Email correspondence dated January 2012

Research Involving Prisoners as Subjects

Research Prisoners

 OHRP Guidance states:
• Upon receipt of the investigator's report that a previously enrolled research
subject has become a prisoner, if the investigator wishes to have the prisoner
subject continue to participate in the research, the IRB must promptly re-review
the proposal in accordance with the requirements of subpart C, and the
institution(s) engaged in the research involving the prisoner subject must send a
certification to OHRP and wait for a letter of authorization in reply. Otherwise, the
prisoner subject must stop participating in the research, except as noted
below…



Research Prisoners

Scenarios:
A. An investigator discovers on a follow-up visit that a participant was incarcerated for
two weeks, but at the time of the follow-up visit is no longer incarcerated. The
investigator had no knowledge that the participant was incarcerated at the time of
incarceration, and performed no interventions, interactions, or gathering of private
identifiable information during the time of incarceration. Does Subpart C apply at the
time of the follow-up visit?
B. An investigator attempts to reach out to a subject via phone at the time of his
scheduled follow-up visit and finds out that the subject is now incarcerated. The
investigator wants to keep the subject enrolled in the study. No private identifiable
information is collected while the subject is incarcerated and the investigator makes
a note in the file to follow up with the subject again when he is
released. Does Subpart C apply?



Research Prisoners

Interpretation:
 In both scenarios Subpart C would not apply
• If there is no interaction or intervention with, or collection of private identifiable information
about the incarcerated subject, the research would not involve prisoners as subjects
 Subpart C would not apply if all non-exempt human subjects research activities
associated with this subject were suspended until the subject is no longer a prisoner.

Email correspondence dated November 2011

IRB Review of HIPAA Authorizations

Research Prisoners

 NIH Guidance indicates:
• The HHS Protection of Human Subjects Regulations do not expressly require that Privacy
Rule Authorizations be reviewed or approved by the IRB. However, under HHS regulations
at 45 CFR 46.117(a) and FDA regulations at 21 CFR 50.27(a), IRB review and approval is
required for any document that contains the IRB-approved informed consent document for
human subjects research. Therefore, if the Authorization language is part of the IRB-
approved informed consent document, such as when the Authorization form is combined
with an informed consent, the IRB is required to review such language.



Research Prisoners

Scenario:
 Institutional policy indicates to have the IRB review a consent document, the privacy
officer review and approve a HIPAA authorization (but no IRB review of the
authorization language), and after the investigator goes over both and obtains
consent for the research and authorization for use and disclosure of PHI, ask the
subject to sign a single signature block (indicating that their signature provides
consent to both documents)

Question:
 Does the IRB have to review and approve the authorization language if the consent
document and HIPAA authorization are independent documents except for having a
single common signature block?



Research Prisoners

Interpretation:
 FDA has informally indicated that it would not consider the HIPAA Authorization
document to be a stand-alone document if a joint signature page/block is used for
both a research consent document and a HIPAA Authorization document.
 The IRB should review and approve the HIPAA authorization language if the consent
document and HIPAA authorization have a single common signature block.
 Alternatively, separate signature blocks could be used for both documents, in which
case the IRB would not have to review and approve the HIPAA authorization
language.

Email correspondence dated February 2010

Reporting of Unanticipated Problems Involving
Risks to Subjects or Others
Modifications to Research
Exemptions Engagement Approved Involving HIPAA
Review Research
Problems Retention
Prisoners

 45 CFR 46.103 (b)(5) states:
• (b) Departments and agencies will conduct or support research covered by this policy only
if the institution has an assurance approved as provided in this section, and only if the
institution has certified to the Department or Agency head that the research has been
reviewed and approved by an IRB provided for in the assurance, and will be subject to
continuing review by the IRB. Assurances applicable to federally supported or conducted
research shall at a minimum include:
– (5) Written 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 or any serious or continuing
noncompliance with this policy or the requirements or determinations of the IRB; and
(ii) any suspension or termination of IRB approval.


Risks to Subjects or Others
Review Research
Problems Retention
Prisoners

Scenario:
 A new risk is identified for a federally funded multi-site study. The sponsor modifies
the protocol and informed consent form to add this new risk. A participating site
receives the protocol and informed consent modification and submits it to their IRB
for review. In the process of reviewing the modification, the IRB also determines that
this is an unanticipated problem involving risk to subjects or others because a new
risk that was unexpected and related to the research was identified.


Risk to Subjects or Others – Polling Question
Review Research
Problems Retention
Prisoners

Polling Question:
Who does the IRB need to report this unanticipated problem
involving risk to subjects or others to?
A. OHRP
B. Institutional Official (IO)
C. Both OHRP and the IO
D. None of the above


Risk to Subjects or Others
Review Research
Problems Retention
Prisoners

Interpretation:
 For multicenter research projects, only the institution at which the subject(s)
experienced an event determined to be an unanticipated problem must report the
event to the supporting agency head (or designee) and OHRP (45 CFR
46.103(b)(5)).
• Alternatively, the central monitoring entity may be designated to submit reports of
unanticipated problems to the supporting agency head (or designee) and OHRP.
 In the scenario, the participating site would be responsible for reporting the
unanticipated problem involving risks to subjects or others to the institutional official.
Reporting to OHRP would not be required as there was no local event that was
determined to be an unanticipated problem.

Email correspondence dated July 2010

Retention of IRB Records

Research Prisoners

 45 CFR 46.115 states:
• (b) The records required by this policy shall be retained for at least 3 years, and records
relating to research which is conducted shall be retained for at least 3 years after
completion of the research.

Scenario:
 An IRB reviews a study that is being conducted by the sponsor at 25 sites. The local
investigator enrolls one subject and the investigator closes the study after the one
subject completes all protocol required interactions, interventions, and collection and
analysis of private identifiable data. Three years later, can the IRB dispose of its
protocol records or does the three years start when all 25 sites no longer have
activities that involve human subjects?


Retention of IRB Records

Research Prisoners

Interpretation:
 The requirement for retention of IRB records for at least three years after research is
completed is institution-specific; that is, each institution must retain its records for
three years following the completion of the research study at that institution.
• In the case when an institution is part of a multi-site clinical trial, the institution must retain
records for three years after the subjects’ participation at that institution has ended, even if
the clinical trial continued after that time at some other institutions.
• In the case when a research study is transferred from the original institution to a second
institution, the original institution must only retain records for three years following the date
of the transfer.

Email correspondence dated April 2010

Thank You!

Madeleine Williams, MA, CIP
Director, Huron Life Sciences
P 312. 479. 3374
mwilliams@huronconsultinggroup.com

Frank Conte, MS
Manager, Huron Life Sciences
P 312. 404. 6413
fconte@huronconsultinggroup.com

Visit us online, and download the Huron HRPP Toolkit:
besthrppsops.com

Also stop by the Huron/Click booth at PRIM&R in December!


OHRP Regulatory Interpretations That You Need To Know But Have Never Been Told

OHRP Regulatory Interpretations That You Need To Know But Have Never Been Told

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