The Office of Human Subjects Research’s
Compliance Monitoring Program
Educational Seminars:
Projects that Do Not Involve FDA Regulated Products:
Investigator Responsibilities and Compliance
Barbara Starklauf, MAS, CIP
Jenna Schulcz, BA, CCRP
Lea Olverson, MS, CIM
Frederick W. Luthardt, MA, CCRP
September 26, 2006
October 5, 2006
Presentation Topics
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Federal Requirements of the Department of
Health and Human Services (DHHS) and
our Institution’s Federal Wide Assurance
(FWA) responsibilities
Institutional Compliance mechanisms:
Monitoring and Auditing
Organizational strategies for regulatory and
applicable subject documentation
The Power of the FDA…
What we already know
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The FDA regulations are often considered
the “gold-standard” for study organization,
conduct, and oversight.
Researchers and Institutions are aware of
what the FDA can do if the regulations are
not followed.
We’ve seen the painful outcomes of bad
FDA audits… fines, debarment, prison…
Rhetorical Question …
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Should a study not subject to FDA
authority be organized and conducted less
rigorously or with diminished attention to
research integrity and subject safety?
Answer: No. The DHHS and Institutional
authorities are also authorized to regulate,
oversee, and enforce requirements for
research.
Does my study fall under
FDA or HHS authority?
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OHRP recommends that the process for determining whether the HHS
regulations apply should address the following three questions in
order:
(1) Does the activity involve research under 45 CFR 46.102(d)? (If yes,
proceed to the second question.)
(2) Does the activity involve human subjects under 45 CFR 46.102(f)?
(If yes, proceed to the third question.)
(3) Is the activity exempt under 45 CFR 46.101(b)?
If the answer to the first two questions is "yes", and the answer to the
third question is "no", then the HHS regulations apply; otherwise, the
HHS regulations do not apply. To view a chart regarding this decisionmaking process, see OHRP's "Human Subject Regulations Decision
Charts" at
[http://www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm].
DHHS Definitions
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“Research”: a systematic investigation, including research
development, testing and evaluation, designed to develop or
contribute to generalizable knowledge.
“Human Subject”: means a living individual about whom an
investigator conducting research obtains (1) Data through
intervention or interaction with the individual, or (2) Identifiable
private information.
“Research Subject to Regulation” those research activities for which
a federal department or agency has specific responsibility for
regulating as a research activity, (for example, Investigational New
Drug requirements administered by the Food and Drug
Administration).
“Institution”: Any public or private entity or agency [that is engaged
in research].
FDA vs. DHHS
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Not all studies are subject to FDA Regulations, e.g. nonIND studies.
Department of Health and Human Services requires
institutions to assure compliance with regulations (FWA).
Research that is neither conducted nor supported by a
federal department or agency but is subject to regulation
as defined in §46.102(e) must be reviewed and approved,
in compliance with §46.101, §46.102, and §46.107
through §46.117 of this policy, by an institutional review
board (IRB) that operates in accordance with the
pertinent requirements of this policy.
Non-FDA studies must comply with 45 CFR 46: “The
Common Rule.”
45 CFR 46: “The Common Rule”
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Subpart A: Basic HHS Policy for the protection of
Human Research Subjects
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Requirement for assuring compliance with Federal Regulations
for research
Obtaining Informed Consent
Oversight of research by Institutional Review Board
Research institutions will assure the federal government that
it will provide and enforce protections for human subjects of
research.
Subpart B-D: Provide additional protections for Pregnant Women, Human
Fetuses and Neonates (Part B), prisoners (Part C), and Children (Part D)
who are involved in research
DHHS Scope at Johns Hopkins
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45 CFR 46.101: “All research involving human
subjects conducted or supported by HHS or
conducted in an institution that agrees to
assume responsibility for the research in
accordance with 45 CFR 46 regardless of the
source of funding.”
The Institution maintains several Federal Wide
Assurances (FWA), which indicate the above
agreement that the Institution will oversee
research and assure Human Subject Protection.
Federal Wide Assurance (FWA)
Highlights of the terms of the “Agreement”?
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Human Subjects Research Must be Guided by Ethical
Principles
Compliance with the Federal Policy for the Protection of
Human Subjects and Other Applicable Federal, State,
Local, or Institutional Laws, Regulations, and Policies
Written Procedures
Scope of IRB(s)’s Responsibilities
Informed Consent Requirements
Compliance with the Terms of Assurance
Assurance Training
Education Training
FWAs across the Institution
The Institutions had been operating under Multiple Project Assurance # M-1011 for the period of 11/01/98 to
10/31/03. The MPA was replaced by Federal-Wide Assurances associated with each of the organizations linked
to the JHM IRBs. The specific Federal-Wide Assurance numbers and expiration dates are as follows:
• The Johns Hopkins University School of Medicine, FWA00005752-expires 3/16/09
 The Johns Hopkins University School of Nursing, FWA00006088-expires 12/21/08
 The Johns Hopkins Hospital and Johns Hopkins Health Systems, FWA00006087-expires 12/21/08
 Johns Hopkins Bayview Medical Center, FWA00006089-expires 12/21/08
 Howard County General Hospital, FWA00005743-expires 12/21/08
 The Kennedy Krieger Institute, FWA00005719-expires 12/21/08
 Johns Hopkins Community Physicians, FWA00002251-expires 06/14/08
More information on the FWAs can be found at the OHRP website.
For more information on the federal guidelines that determine the kind of research the JHM IRB is
required to approve please visit http://www.hhs.gov/ohrp/policy/index.html.
If you have any comments, questions or suggestions
you may contact the JHM IRB at:
p: 410.955.3008 | f: 410.955.4367 or 443.287.5353 | e: mailto:jhmirb@jhmi.edu?subject=
Examples of Studies that must comply
with HHS regulations
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Studies that receive Federal funding in whole or
in part from any Federal entity:
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Studies receiving NIH Award
Studies funded by specified Federal agencies, e.g.
DOE, DOD, etc.
Studies supported by the VA
Studies that receive no Federal funding
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Investigator initiated protocols
Studies funded by private organizations
Studies receiving internal fellowships/grants
Specific types of studies that fall under
HHS and Institutional (IRB) authority
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Non-IND/IDE: e.g., comparison of
approved treatment modalities
Pilot Studies: e.g., proof of concept
Observational/non-interventional: e.g.,
biomarker assays on stored samples
Quality Improvement: e.g., surveys of
inpatients
Institutional Compliance
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The HHS advises that institutions implement
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“Internal audit procedures [to] assure the institution's
administration that its policies and procedures are being adhered
to and that they are proper in scope and content… [and] that
reporting of noncompliance is accomplished and that appropriate
follow-up measures are taken”
“…internal audit or self-assessment procedures and practices
designed to assure proper protocol and consent document
preparation, protocol submission, review and approval by the
IRB, and timely monitoring of protocol implementation.”
Monitoring is “good policy.”
http://www.hhs.gov/ohrp/irb/irb_chapter1.htm
Monitoring and Auditing
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IRB approved studies can be audited or
monitored by
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A sponsor
A funding agency (NIH, DOE, etc.)
The IRB via the Compliance Monitoring
Program
Per routine selection
 Directed or “for-cause”
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The DHHS (in response to a complaint)
Monitoring Authority of the IRB
4) Only consent forms with a valid approval stamp may be presented to subjects. All consent forms signed by subjects enrolled
in the study should be retained on file. The Office of Human Subjects Research conducts periodic audits of protocol
records, and consent documentation is part of such audits.
What we hear…
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“Why am I being monitored?”
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Implying the following:
 “Nobody died…” or
 “My study is low-risk…” or
 “I’m just collecting samples…” or
 “My study is part of clinical care…”
 Etc.
The Bottom Line
If a study is IRB approved, all
regulatory documents and subject
records must be retained, organized,
retrievable, and available for
inspection.
What do we suggest?
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Develop compliance plans during study design or implement plans
for corrective action, to include the following:
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SOPs: Standard Operating Procedures are “written instructions
to achieve uniformity of the performance of a specific function.”
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CRFs: Case Report Forms are “documents designed to record all
of the protocol-required information…”
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Source Documentation: Maintain all the applicable original
documents, data and records that correspond with the CRFs.
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Checklists: A means to verify the completion of study related
procedures.
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Note-To-File: A means of explaining and correcting unexpected
departures from the protocol.
Consider the following process steps and examples for creating a
compliance plan…
Source: ICH E6: Guideline for Good Clinical Practice
Regulatory Documentation Organization
Recommendations
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The IRB via the Compliance Monitoring Program can
monitor or audit any study approved by the IRB
For example, an investigator initiated study testing
clinical outcomes of two standard therapies:
 Regulatory Binder contents (what to keep…):
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IRB materials (applications, approvals, consent forms,
problem reports, changes to the protocol, correspondence,
etc.) to maintain a comprehensive audit trail
Site responsibility delegation table
The protocol
Sample Regulatory Binder Table of Contents
Protocol
IRB (Submissions, correspondence, amendments, advertisements, reports, approved
consent forms, materials & HIPAA forms)
Investigator Certifications/Licenses
Responsibility Delegation log
Sponsor/Funding agency Communications (written, phone, fax, email)
Monitoring Log (every visit, every report)
Data Safety Monitoring Plan and Reports, if applicable
Subject Screening Log/ Master randomization list
AE, SAE Reports
Protocol deviations and violations
All relevant communications (letters, e-mails, phone notes, meeting minutes)
Study CRFs, data collection forms templates
Documentation of edits (audit trail)
Example Responsibility Matrix
Staff Name/Role
Responsibilities Signature
Jane Doe, M.D.
1, 2, 3, 4, 6, 7,8,9
Principal Investigator
John P. Doe, CRA
2, 3, 4, 5,9
Study Coordinator
Jack Hill, M.D.
1, 2, 7,8
Co-Investigator
IRB Appr. Date
RESPONSIBILITY KEY
1.Consent Designee
2.Evaluates Subject Inclusion/Exclusion criteria
3.Maintains Source Documents
4.Completes Case Report Forms
5.Dispenses Study Drug
6.Administrative
7.Obtains Laboratory Values (sample collection)
8.Interprets Medical Reports and Laboratory Results (i.e. ECGs, MRIs, etc.)
9.Adverse Event Documenting and Reporting
PI Initials
Subject Documentation Organization
Recommendations
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Keep and maintain documentation to
verify
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Consent process
Eligibility assessment
Protocol compliance
Problem and Deviation reporting to the IRB
Quality control (error detection and
correction)
Data Collection and a means to verify data
Informed Consent Process Sample Checklist
INFORMED CONSENT CHECKLIST
Subject initials: ________________
Date of Birth:
________________
Subject study identifier: _________
Consent Version #/Expiration Date: _________________
Consent signed and dated by subject: YES NO 
Date: ____________
Was a copy of the consent given to the subject: YES NO 
Consent signed and dated by parent: YES NO 
N/A 
Date: ____________
Assent signed by minor: YES NO N/A 
Assent NOT signed by minor; reason not obtained:
________________________________________
Verbal assent obtained and assent signed by parent, documenting this
assent
YES NO N/A 
Consent/assent obtained by:
__________________
___________________________
Print name
Signature
________
Date
Eligibility Assessment Sample Checklist
ELIGIBILITY CHECKLIST
Subject initials: __________________
Date of Birth:
__________________
Subject study identifier: ____________
Inclusion criteria:
 “Criterion 1”
 “Criterion 2”
 “Criterion 3”
Exclusion Criteria:
 “Criterion 1”
 “Criterion 2”
 “Criterion 3”
__________________
Print name
__________________
Signature
___________
Date
Protocol Deviations
Date IRB
Take Home Points
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Keep everything organized
There are consequences to non-compliance
Any IRB approved study can be audited
Studies in disarray may lead to
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Data rendered not evaluable
Subject Safety may be compromised
Study delays
Call the Compliance Team with questions
Keep everything organized
How to Get in Touch with
the Compliance Monitoring Team
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Please contact the JHM IRB office at 410-955-3008
if you have questions regarding regulatory guidance.
For general questions and assistance, the monitors may be
contacted at the JHM-IRB office. Please ask for
“Compliance.”
The Monitors may also be contacted directly by email:
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jschulc1@jhmi.edu
lolvers1@jhmi.edu
fluthard@jhmi.edu
References
DHHS: http://www.hhs.gov/
 OHRP: http://www.hhs.gov/ohrp/
 FDA: http://www.fda.gov/ora/
 FDA comparison with DHHS/OHRP:
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http://irb.jhmi.edu/Guidelines/FDAvsOHRP.html
FWA: http://www.hhs.gov/ohrp/humansubjects/assurance/filasurt.htm
 The “Common Rule”:
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http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
JHM-IRB Guidance: http://irb.jhmi.edu/Guidelines/
 Monitoring: http://irb.jhmi.edu/Guidelines/MonitoringVisits.html
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