The Office of Human Subjects Research’s
Compliance Monitoring Program Educational Seminar:
Audit Preparation Suggestions and Strategies
Barbara Starklauf, MAS, CIP
Jenna Schulcz, BA, CCRP
Lea Olverson, MS, CIM
Frederick W. Luthardt, MA, CCRP
June 16, 2006
Presentation Topics
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•
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•
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Review of the Compliance Monitoring
Program
What’s happening out there?
Why does the FDA audit studies? What
happens in a FDA audit? What is the FDA
finding?
What concerns are we observing?
How to organize regulatory and subject
information, and what to do in advance of a
visit from the OHSR or the FDA.
Overview: The Activities of the Monitoring Program



Examining IRB approved studies for
compliance with applicable regulations to
assure the protection of human subjects in
research.
Evaluating a study’s progress in both
regulatory documentation maintenance and
overall study conduct.
Educating Investigators and staff about
regulatory requirements and study
organizational strategies.
Research Misconduct makes the News


“Ripped from the Headlines…”
Research Misconduct Examples…
Test Case: Drug Makers Relied On
Researchers
Who NowTurn
AClinical
Doctor's
Drug Trials
Await Trial --- Two Professors Are Accused Of Endangering Patients
By KURT EICHENWALD AND GINA KOLATA
And Stealing $10 Million --- `Checks
and May
Balances'
Published:
17, 1999 Failed
Into Fraud
Practice Manager Who Lied about Subjects
in Clinical Study Gets Probation, Small Fine
By By Steve Stecklow and Laura Johannes, The
Wall Street
3164Records,
words
…The
FraudJournal,
- Falsifying
Endangering Patients
Aug 15, 1997
Georgia state investigators accuse the two men of running a secret, renegade
drug-testing operation, recklessly endangering patients and stealing from
Georgia's only state medical school more than $10 million in drug-company
payments. They contend that Dr. Borison, a 47-year-old medical doctor, was
rarely around the test sites and left unqualified employees to treat patients and
that Dr. Diamond, 52, a pharmacologist, routinely forged Dr. Borison's signature
on patient and test records…
When the FDA means business!

FDA 483
EIRs/Warning Letter
An FDA Audit: Are you next?
The FDA may conduct announced or unannounced inspections
of clinical investigator sites for various reasons such as:

Routinely to verify data that has been submitted to the Agency

As a result of a complaint to the Agency about the conduct of the
study at the site [i.e., “for cause”]

In response to sponsor concerns or termination of the clinical site

At the request of an FDA review division

And related to certain classes of investigational products that the
FDA has identified as products of special interest in its current work
plan (i.e. targeted inspections based on current public health
issues).
http://www.fda.gov/oc/ohrt/irbs/investigator.pdf
The FDA Audit: What happens?
During an inspection at the site of a clinical investigator, FDA
personnel all aspects of a study, for example:

Who performed various aspects of the protocol (e.g., who verified
inclusion and exclusion criteria, who obtained informed consent,
etc.)

Signed and dated Informed Consent Forms

Medical and study records to confirm subject eligibility

Case-Report-Forms (study data)

Accountability for the investigational product
http://www.fda.gov/oc/ohrt/irbs/investigator.pdf
An FDA Audit: The Aftermath…
After the Inspection, the Clinical Investigator may receive
one of the following:
1.
A letter that generally states that FDA observed no significant
deviations from the regulations. Note that a letter is not always
sent when FDA observes no significant deviations. [NAI]
2.
An informational or untitled letter that identifies deviations from
statutes and regulations for which voluntary corrective action is
sufficient. Occasionally, such letters request a response from the
clinical investigator. [VAI]
3.
A Warning Letter that identifies serious deviations from applicable
statutes and regulations. A Warning Letter generally requests
prompt correction by the clinical investigator and a formal written
response to the agency. [OAI]
http://www.fda.gov/oc/ohrt/irbs/investigator.pdf
What the FDA Typically Finds
100
90
85
82
74
80
67
% Identified Findings
70
60
44
50
40
30
20
10
0
Documentation
Protocol Violations
Reporting Violations
Human Subject Safety
Device/Drug Control
What we are finding…
100
95
90
80
% Identified Findings
70
60
60
50
40
30
25
30
15
20
10
0
Documentation
Protocol Violations
Reporting Violations
Human Subject Safety
Device/Drug Control
Specifically, we are observing…

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Disorganized or missing regulatory documentation
Unclear study personnel responsibility delegation
Consent form signature/date anomalies
Inadequate or unverifiable Subject eligibility
assessment procedures
Inadequate Drug or Device accountability
What do we suggest?


Develop compliance plans during study design or implement plans
for corrective action, to include the following:

SOPs: Standard Operating Procedures are “written instructions
to achieve uniformity of the performance of a specific function.”

CRFs: Case Report Forms are “documents designed to record all
of the protocol-required information…”

Source Documentation: Maintain all the applicable original
documents, data and records that correspond with the CRFs.

Checklists: A means to verify the completion of study related
procedures.

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 Binder Organization
Suggestions
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Three-Ring Binder(s) to minimize loss
Arrange documents chronologically
Tab or divide documents by IRB Approval year
Maintain audit trail of all IRB approved and study
related documentation
Sample Regulatory Binder Table of Contents
Protocol
IRB (Submissions, correspondence, amendments, advertisements, reports, approved
consent forms, materials & HIPAA forms)
Investigator’s Brochure
FDA Form 1572 (Investigator’s Statement)
Sponsor Communications (written, phone, fax, email)
Monitoring Log (every visit, every report)
Subject Screening Log/ Master randomization list
Study Drug (shipping, accountability, storage, batch numbers, dates)
AE, SAE Reports / protocol deviations and violations, IND Safety Reports
All relevant communications (letters, e-mails, phone notes, meeting minutes)
Study CRFs, data collection forms
Documentation of edits (audit trail)
Delegation of Responsibility Process
Compliance Suggestions
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List all personnel involved in study procedures
Assure training and applicable certifications
Submit to IRB for approval
Check and update as necessary
Source: 21 CFR 312: Code of Federal Regulations; Form FDA 1572
Example Responsibility Matrix
Staff Name/Role
Responsibilities Signature
Jane Doe, M.D.
1, 2, 3, 4, 6,
Principal Investigator 7,8,9
John P. Doe, CRA
Study Coordinator
Jack Hill, M.D.
Co-Investigator
Date
PI Initials
2, 3, 4, 5,9
1, 2, 7,8
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
Informed Consent Process
Compliance Suggestions
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Identify who obtained consent and when
Specify that subject comprehended the consent
and all questions were addressed
Indicate that assent and/or proxy consent was
obtained and when
Note Witness signature and date (if needed)
Verify that a copy was given to the subject
Source: 21 CFR 50.20: FDA Code of Federal Regulations; ICH E6: Guideline for Good Clinical Practice
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 Determination Process
Compliance Suggestions
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Indicate that specific Inclusion and Exclusion
criteria were assessed
File applicable source documentation with the
I/E checklist or case report form
Report any exceptions to the IRB, sponsors (if
applicable), etc.
Source: 21 CFR 56: FDA Code of Federal Regulations; ICH E6: Guideline for Good Clinical Practice
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
Drug Accountability
Compliance Suggestions
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Remember: it is mandatory if the IND is held by
the Investigator
Develop log sheets to track drug receipt,
dispensation, return
Keep shipping invoices
If applicable, submit annual FDA progress
reports
Consider utilizing Investigational Drug Service
Source: 21 CRF 312.50, 312.56, 312.57, 312.59-62, 312.68: Code of Federal Regulations
Drug Accountability Sample Worksheet
Protocol Number:
Location Drug:
PI:
Study Title:
Recorder Initials ____Recorder Name_______________
Date Received/ Subject
Returned/
Initials
Dispensed
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Notes / Comments:
Subject #
Drug Administered:
Drug Administered:
Lot # Dose Quantity Balance Recorder Initials of
Received/ Forward Initials
personnel
Dispensed
Device Accountability
Compliance Suggestions
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Remember: it is required for the holder of the
IDE
Develop log sheets to track the receipt,
condition, dispensation, serial/lot numbers, and
return of a device
Keep shipping invoices
As mandated, submit progress reports to FDA at
least annually.
Source: 21 CRF 812 Subpart G (812.140, 145, and 150): Code of Federal Regulations
Device Accountability Sample Worksheet
DEVICE ACCOUNTABILITY LOG
Principal Investigator:
Study Title:
From Label
Date
Received by Model#
Received (initials)
Serial# Lot#
Device Disposition
Subject Date Used Date
ID#
Destroyed
(Initials)
Date Returned
(Initials)
Principal Investigator Signature: _________________________________ Date: _____________
How to Get in Touch with
the Compliance Monitoring Team
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
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Please contact the JHM IRB office at 410-955-3008
if you receive a notice from any federal or grant
agency, including the FDA and NIH Ask for
“Regulatory.”
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
In Conclusion…
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Preventative Maintenance: Or an ounce of
Prevention is Worth .453 kg of Cure…
Keep in contact with IRB, sponsor, and
FDA
Suggestions are pertinent for assembling a
study as well as in preparation for a visit
from the FDA or the OHSR
Reference Information & On-line Resources
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JHM-IRB Guidance: http://irb.jhmi.edu/Guidelines/MonitoringVisits.html
FDA Regulations: http://www.fda.gov/cder/regulatory/default.htm
FDA Audit Details: http://www.fda.gov/oc/ohrt/irbs/investigator.pdf
FDA Information for Human Subject Safety:


http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
ICH GCP Principles:
 http://www.fda.gov/cder/guidance/959fnl.pdf
 http://www.fda.gov/oc/gcp/regulations.html
Questions??
Suddenly, it all made sense. Late at night, in a nest of manila folders in
the middle drawer of the filing cabinet, the paperwork had been mating.