Good Clinical Practice and
Audit Preparedness
IUPU Symposium - October 2010
Michael R. Hamrell, Ph.D.
MORIAH Consultants
What is Clinical Research?

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The essential piece to demonstrate that
a new product is safe and effective
The most costly part of development
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60% of cost spent on clinical
The most time-consuming part of
product development
2
Quality Concepts in Clinical Trials
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Sponsor Responsibilities:
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Ensure proper monitoring of investigations
(21 CFR 312.50)
Monitor the progress of all clinical
investigations being conducted under its
IND (21 CFR 312.56(a))
Correct and/or report serious noncompliance to the FDA (812.46(a))
3
Quality Concepts in Clinical Trials

Clinical Investigator Responsibilities

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Conduct study according to the protocol
(21 CFR 312.60 & 812.100)
Maintain adequate and accurate case
histories (21 CFR 312.62(b) & 812.140)
4
Role of the Coordinator
Clinical Research Coordinator (CRC)
 Works under the direction of the Principal
Investigator
 Expected to perform many of the tasks in
the clinical study

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need to be qualified (and trained) to perform
the task
PI still responsible for all patients
5
Role of the Coordinator
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Often is the key person for the successful
conduct of a trial
Typically has the most patient contact and
direct role in many key tasks
Usually the person who fills out the CRFs,
lab slips, etc.
Tasks will depend on professional
qualifications and training
6
Safety Reports

Investigator is required to report all
adverse events to Sponsor
timing depends on nature and
severity
 has major impact on subject safety

21 CFR §312.64(b) & 812.150
7
Quality Concepts in Clinical Trials

IRB Responsibilities
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Organization and Personnel through review
of IRB membership list (21 CFR 56.107)
Functions and Operations through evidence
of written SOPs (21 CFR 56.108)
Review of Research through sufficient
details of IRB meeting minutes (21 CFR
56.109)
8
Product Accountability

Focus on complete picture

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Shipping
Receipt
Use
Returns
Reconciliation
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Product Accountability
Sponsor
Test Article
Received
1
4
Test Articles
Reconciled
By Sponsor
By Investigator
2
3
Test Articles
Dispensed
To Patient
Test Articles
Returned
To Investigator
Investigator
Timepoint A
Investigator
Timepoint B
Patient
10
Test Article – FDA Comment

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“Although the site’s personnel have been
delegated the responsibility for test article
accountability, it is the Principal Investigator
who is ultimately responsible for the this
task….
Even when a research pharmacist is involved
in a study at a site, the clinical investigator
retains responsibility for ensuring that the
test article was appropriately prepared,
dispensed and administered.”
11
FDA Viewpoint on Auditing
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FDA takes no official position on whether
companies should conduct clinical audits
FDA viewpoint on sponsor responsibilities:
“Sponsors are responsible for selecting
qualified investigators… ensuring that the
investigation(s) is conducted in accordance
with the general investigational plan and
protocols contained in the IND…” 21 CFR
312.50 & 812.40
12
What’s the Chance of an Audit
According to the Inspector General’s
Report: on ‘The FDA Oversight of
Clinical Trials’ (Sept 2007)
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FDA only inspects less than 1% of all
clinical trial sites
75% of inspections overall were routine
(surveillance)
http://oig.hhhs.gov/oei/reports/oei-01-06-00160.pdf
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How would you characterize
your site?
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How would you characterize the staff
What is the commitment/focus to
research relative to medical practice
How is their research performance
perceived?
14
Some fun examples
15
Reality Check
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How many of you do multiple clinical trials each
year?
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Investigator initiated vs. sponsor
How many of your sites/groups have SOPs?
How many of your sites use electronic medical
records?
How many of you have experience with eCRFs?
How do you communicate with your IRB (paper
or electronic)?
16
Should a Site have SOPs?
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Reiterates role of PI in all
studies; including delegation
of responsibilities to study
staff and supervision
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Defines role of PI and staff in
study oversight
Suggests the need for site
SOPs
17
From Guidance Document
‘The investigator should develop a plan for the supervision and oversight of the clinical
trial at the site. Supervision and oversight should be provided even for individuals who are
highly qualified and experienced. A plan might include the following elements, to the
extent they apply to a particular trial:’
18
ICH GCP Viewpoint

“The auditing of clinical trials is
conducted in accordance with the
Sponsor’s written procedures of what to
audit, how to audit, the frequency of
audits and the form and content of
audit reports.” Section 5.19.3
19
FDA Role in GCP Compliance
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Determine compliance
with regulations
Verify integrity of data
20
FDA GCP Inspections
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FDA will routinely inspect some or all of the
data for pivotal studies in support of an
application
FDA choice of sites are based on a variety of
factors
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number of sites
Number of studies at site
importance of data
type of study
Geographic location
21
Role of FDA Inspection
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Essential part of PMA/510K/NDA/BLA
review process
Know your rights
Use sponsor/CRO/consultants help to
prepare
Build quality into your work
22
FDA Role in Clinical
Investigations

Bioresearch Monitoring Program
 An on-going audit program managed by the
Division of BIMO in each Center
 To determine the adherence of sponsors,
CROs, monitors, IRBs and clinical
investigators to current regulations and
official guidelines
 To assess through audit procedures whether
data submitted to FDA are substantiated by
records
23
FDA Inspection of Clinical Research
FDA Conducts Two Types of Inspections
 Routine data audits (study oriented)
 Audit of key pivotal data from NDAs, BLAs,
510(k)s, PMAs, etc. to verify data and
procedures
 'For-cause' audits (investigator oriented)
 Targeted audit of data or investigators as
a result of prior knowledge or suspicion or
alleged violations of the regulations
24
The Facts About Source
Documents
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FDA Requirements Related to source
documents in clinical trials
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312.62(b) An investigator is required to
prepare and maintain adequate and
accurate case histories that record all
observations and other data pertinent to
the investigations on each individual
administered the investigational drug or
employed as a control
Similar requirement in 812.140 for devices
25
Preparing for the Inspection
Before you start, make sure you are
prepared
 (re)Familiarize with protocol, CRFs,
other study documents
 Review Study archives
 Check FOI for other inspection results
26
Plan for FDA Inspection
FDA Arrival
 Who is to be called
 Check FDA inspector credentials
 Accept Notice of Inspection (Form 482)
 Confirm purpose of FDA inspection
27
FDA Form 482
Site Policy
Main Contact
 Identify who is to be notified at the
time inspection commences and how
 Identify who is authorized to receive
and accompany FDA inspector
 Plan how oral inquiries and requests for
documents are processed
29
General Do’s and Don’ts
DO !
 Greet FDA and ask for identification and FDA Form
482
 Provide work area that affords privacy
 Make available phone/internet/power
 Offer coffee, tea, water, bathroom
 Provide visitor pass or parking pass
 Keep conversation polite and professional
 Extend common courtesy
30
General Do’s and Don’ts
Don’t even think about: !
 Pay for meals
 Offer any monetary compensation
 Offer gifts (even at holiday time)
 Photograph, record or tape things
 Socialize with FDA after work hours
 Ask personal questions
 Look over the inspector’s shoulder
 Complain about government, taxes, FDA
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Company/Site Policy
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Document Production
32
Company/Site Policy
Document Marking and Duplication
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Do not permit marking of documents by
FDA Inspector
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Make copies for FDA and retain a copy of each
document provided to FDA
Mark documents containing trade secret or
confidential information before providing
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If confidential information is conveyed orally,
establish these facts to FDA; use witness
33
Company/Site Policy
Affidavits
 Establish policy on whether to review
FDA prepared affidavits
 Circumstances under which
an affidavit could be signed
 Do not sign affidavit or volunteer any
information unless such disclosure is
consistent with company policy
34
Plan for FDA Inspection
During Inspection
 Company/site representative should
accompany FDA Inspector at all times,
to ensure access only to information
and those parts of the premises under
the FD&C Act
35
Plan for FDA Inspection
Keep an accurate written record of:
 Areas of the site visited and to whom he/she
spoke
 Accurate and complete record of all
comments and suggestions made by
inspector, unanswered questions and site
commitments
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Any commitments made to FDA should have
concurrence of top management
36
Plan for FDA Inspection
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A daily summation with FDA, and
separately with site staff is helpful
If additional inspection days are
required, prepare an agenda for next
day with FDA
Prepare daily report to management
37
Company/Site Policy
Corrections during Inspection
 If a change is made during the
inspection, decide whether the
change/correction will be conveyed to
the FDA inspector and, if so, in what
manner
38
Correction to 483
39
The Inspection Process
40
“What will the Inspectors ask me
to produce for the audit”
Source Documentation
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All of the source documents should cover
the entire period of the study and be
present at the time of the audit to allow
the auditor(s) to properly conduct the
audit
A ‘standard’ GCP site inspection will
include a tour of the facility and a
thorough review of the documentation
41
“What will the Inspectors ask
me to produce for the audit”
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Documents in the project notebook filed
during the course of the trial
List of the study subjects and their
corresponding study numbers
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Should the FDA investigator ask for the
identities and demographics of your study
subjects because of some concern, you are
required to comply with the request
42
Warning Letter
07-HFD-45-0601
“What will the Inspectors ask me
to produce for the audit”
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Two-way correspondence with the IRB,
sponsor/monitor
Original signed consent forms for all the
patients
Case Report Forms (CRFs) for all the
patients
Source Documentation (Patient medical
records, clinic and hospital charts)
44
“What will the Inspectors ask me
to produce for the audit”
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Records of patients who were study
drop outs
Product storage facilities and
accountability records
Serious Adverse Event Reports and
documentation
Monitor visit log
45
Data Inspection Process
Subject Records
 Did the Investigator maintain records
that are supportive of each entry in
CRFs for each subject
 Were all CRFs completed in a timely
fashion
Could you recreate CRF from source?
46
Data Inspection Process
For eCRF situations
 Were all regulations and requirements
followed relative to 21 CFR §11
 Do source documents support any
changes/corrections to the e-CRF
47
Data Inspection Process
Reporting of Study Progress
 Did investigator terminate or
discontinue the study before completion
 Incidence and reports of SAEs to
Sponsor and IRB handled properly
 Did Investigator maintain copies of all
reports submitted to sponsor and IRB
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Data Inspection Process
Records Retention
 Who maintains custody of required
records
 Data storage media
 Record storage conditions
 Investigator aware of FDA record
retention regulations
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Data Inspection Process
Data Audit Procedures
 Subject study data
 Number and type of subjects
 Existence and availability of subjects
 Documentation of prior conditions
 Subject inclusion/exclusion criteria
 Screen log/failures
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Data Inspection Process
Protocol Adherence
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Enrollment of subjects who did not
meet the inclusion/exclusion criteria
Changes in the protocol in dosage,
frequency, time of dosing, or method of
dosing of the ‘test article’
Failure to report serious adverse events
promptly to the IRB and the sponsor
51
Data Inspection Process
Protocol Adherence
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Failure to document illnesses,
hospitalizations, and other significant
problems concurrent with the study
Failure to perform critical tests,
examinations, or assessments at the
protocol-specific time or visit
52
Data Inspection Process
Protocol Adherence
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Administration of concomitant therapy that
could compromise the study results
Failure to report concomitant therapy
Entering more subjects into the study than
originally approved by the IRB or the
sponsor
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Data Inspection Process
Product Accountability
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Did the sponsor maintain accounting
procedures for the test article
Were all unused supplies returned to
sponsor or disposed of properly
Limitations of test article access and
distribution
Route of administration and proper use
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Data Inspection Process
Medical/Clinical Laboratory Facilities
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Are the facilities adequate, and proper diagnostic
equipment available, to fulfill protocol requirements?
Is the equipment in good working order?
Does the equipment require calibration and are there
records documenting the required equipment
calibration?
Is the laboratory accreditation/license documentation
current?
Is there proper documentation and storage of trial
samples?
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Data Inspection Process
Safety Information
 How does sponsor assure that the
Investigator notifies promptly of SAEs
 Is monitor involved in reporting
 Is timeframe consistent with regulations
 Does source data support SAEs
 Any deaths or dropouts due to SAEs
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Data Inspection Process
IRB Communication
 Proper approval and documentation for
protocol and informed consent
 Documentation of IRB qualifications
 Communication/correspondence
between Investigator and IRB
 Continuing review performed
57
It’s Over – Now What??
58
FDA Inspection Follow-up
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At the end of the inspection a discussion
is scheduled with key personnel to
discuss the findings (exit interview)
May issue Form 483
May note observations (annotate)
Will record any verbal responses and
promised corrections
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What is a 483 Observation?
60
Plan for FDA Inspection
Exit Interview
 Report of FDA inspector findings with
appropriate site management
 Opportunity for site to correct any
misunderstandings; incorrect deficiencies
 If Form 483 is issued, each observation should
be reviewed with the Inspector and understood
 Commitment to FDA
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Plans to correct deficiencies
Timetable for future actions (answer will be
recorded by FDA)
61
Plan for FDA Inspection
After Inspection
 All items on FDA 483 should be
responded to in a letter to appropriate
FDA Office
 Follow-up report to appropriate
company/site employees
62
Plan for FDA Inspection
After Inspection
 Form 483 items should be reviewed by
company/CRO regulatory, technical, or
legal personnel
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work with Sponsor to address issues
State how and when you expect to
make corrections to FDA
63
Some items can appear in a letter that
were not on the 483
Warning Letter
g4841d
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What Happens to Inspection
Findings?
65
FDA Inspection Follow-up
FDA Follow-up
 Investigator reviews notes, observations,
documents collected, etc.
 All records collected during inspection are
attached as exhibits
66
FDA Inspection Process
Completion of Inspection
 Inspector returns to office and prepares
written report of findings [an
Establishment Inspection Report (EIR)]
 Audit classification is determined and
submitted to FDA Headquarters for
concurrence
67
FDA Inspection Follow-up
FDA Follow-up
 A recommendations for classification is
made
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Headquarters agrees with Field most of
the time
EIR and exhibits are forwarded to
assigning office at HQ (BIMO) for final
review and classification
68
FDA Inspection Process
Completion of Inspection
 Based on Classification of Inspection
follow-up letter usually sent
 Additional Courses of Action
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as needed or required
69
FDA Inspection Follow-up
Follow-Up Letters
 Acknowledgement Letter – NAI
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No problems – thank you for cooperation
Information Letter - VAI
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letter may point out deviations from the
regulations and a written response may or
may not be requested
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FDA Inspection Follow-up
Follow-Up Letters
 Warning Letter - OAI
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Significant deviations from the regulations
and written response is required within 15
days
Letter may also include an invitation to an
informal conference if deviations are major

may be signal of other regulatory action
71
FDA New Policy on WL
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More rigid internal timelines for issuing 483
and follow-up letters
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Send response to 483 within 15 days
Speedier enforcement following an
inspection, if needed
A Warning Letter response can be followed
with a Closeout Letter, after evaluating the
corrective action taken, not based on just
promised action
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FDA Inspection Follow-up
Other Follow-Up Letters
 NIDPOE Letter - Notice of Initiation of
Disqualification Proceeding and Opportunity to
Explain
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Most serious deviations from the regulations where
additional administrative actions are being considered
No further use in studies while under investigation
73
BIMO Inspections Completed
FY 2009
Center
CI
IRB
Spon/Mon
GLP
CBER
83
15
11
6
115
CDER*
458
102
73
36
669
CDRH
163
79
59
4
305
CFSAN
0
0
0
1
1
CVM
26
na
4
15
45
All Centers
730
196
147
53
1135
* + 137 BEQ inspections (CDER specific) = 1272 total
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Total
International Inspections - 2009
Center
CBER
CDER
CDRH
CVM
Total
total
3 (2 CI, 1 sponsor)
119
12 (10 CI, 2 sponsor)
0
134
75
FY’09 CI Inspection Classified
– All Centers
6%
48%
46%
n = 867
76
FY’09 Sponsor/Monitor Inspection
Classified – All Centers
8%
28%
64%
n = 116
77
CDRH BIMO Compliance Rates
70%
NAI
VAI
OAI
60%
50%
40%
31%
30%
20%
20%
18%
16%
15%
11%
11%
14%
10%
0%
10
FY01 FY02 FY03 FY04 FY05
Years
10-Year CDER OAI rate = 3-5%
78
FY06
FY07
2/08
FY’09 IRB Inspections Classified
– All Centers
7%
43%
50%
n= 179
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Top ten ways to tell your FDA
inspection is going badly
10. FDA sets up temporary housing in your parking
lot
9. The FDA inspector mutters “uh-oh” each time
he enters a different department, or opens a
different folder
8. A “60 Minutes” crew asks to film the inspection
7. The FDA inspector won’t even enter the room
where the test article is stored
6. The Congressman you called for help won’t
return your call, but returns your campaign
contribution
80
Top ten ways to tell your FDA
inspection is going badly
5. Instead of a Form 482, the FDA Inspector
begins with, “You have the right to remain
silent….”
4. The FDA inspector comes to audit a specific
study, but its not one you completed
3. The FDA inspector knows all of your employees
by their first names
2. The FDA inspector is a former employee; that
you fired
1. The FDA Commissioner conducts the exit
interview
81
FDA’s Purpose for Inspections


Remember, the FDA is both a Public
Health & Consumer Protection Agency
and must assure the people that the
products it approves meet the required
standards
For the government, that means they
and you) need to AUDIT!
82
Any Questions ?
Michael Hamrell, Ph.D.
MORIAH Consultants
714-970-0790
michael@moriahconsultants.com
83