2. What is a CRO
Contract Research Organization
A person or an organization (commercial,
academic, or other) contracted by the
sponsor to perform one or more of a
sponsor's trial-related duties and
functions
3. CRO types
Pharmacokinetic (BABE)
Clinical Research – Phase I, II, III, IV
Preclinical
Discovery
Analytical and Microbiological
Hospitals, clinics, etc.
Or any other
4. Our Focus
Site
Where actual work will get executed
Clinical Trials
Any investigation in human subjects intended to
discover or
verify the clinical, pharmacological, and/or other
pharmacodynamic effects of an investigational
product(s), and/or
to identify any adverse reactions to an
investigational product(s), and/or
to study absorption, distribution, metabolism, and
excretion of an investigational product(s) with the
object of ascertaining its safety and/or efficacy.
5. Structured compliance plan
CDSCO
Slovac Republic
WHO
Brazil
Zimbabwe
Nigeria
Thailand
EU
SA MCC
USFDA
TGA
CROs need to define their own Objectives and Goals
and Plans to execute according to the business needs
6. Compliance to
GLP
GCP
GXP
Applicable Rules, Regulations, Laws and
guidelines of the target regulatory agency
and those of the land
7. Controlled regulated environment
US: CFR and guidelines
ICH Guidelines, including E6: GCP
GXPs: GCP, GLP, GMP
EU: Clinical trials directive and guidelines
CIOMS guidelines (council for international
organizations of medical sciences WHO Geneva)
National regulations & guidelines
8. Why Compliance?
Promote quality and validity of test data
Help scientists to obtain Reliable,
Repeatable, Auditable, Acceptable results
Necessary intrinsic scientific value
Organizational requirement
Management responsibility
Mandatory
Safety, Efficacy, Quality
9. Meeting Phenomenon
We all are in a marathon meeting to
discuss why work is not being done
We are conducting an Audit to check for
compliance to the remarks in the Audit
conducted to check compliance…….
Vicious cycle?? Or routine and sincere
practice!!!
10. To ensure compliance
Build Quality systems
Execute Protocols using these quality
systems
Quality Control and Assurance
Monitoring
Audit
Review
Inspection
11. Quality Control / Quality Assurance
Quality Control / Operational Units
Responsible for inspecting and certifying
predefined quality expected in a product or
process through Quality Control Systems
Quality Assurance / Audit Group
Assesses the Performance, Accuracy,
Reliability And Integrity Of Quality Systems
through Independent Auditing Activities
12. Monitoring (ICH-GCP)
The act of overseeing the progress of a
clinical trial, and of ensuring that it is
conducted, recorded, and reported in
accordance with
the protocol,
standard operating procedures (SOPs),
GCP, and
the applicable regulatory requirement(s)
13. Audit (ICH-GCP)
A systematic and independent examination of
trial-related activities and documents to
determine
whether the evaluated trial-related activities
were conducted, and
the data were recorded, analyzed, and accurately
reported according to
the protocol,
sponsor's standard operating procedures (SOPs),
good clinical practice (GCP), and
the applicable regulatory requirement(s).
14. Inspection (ICH-GCP)
The act by a regulatory authority(ies),
of conducting an official review of documents,
facilities, records, and any other resources that
are deemed by the authority(ies) to be related to
the clinical trial and
that may be located at the site of the trial, at the
sponsor's and/or contract research organization’s
(CROs) facilities, or
at other establishments deemed appropriate by
the regulatory authority(ies)
15. Time of Compliance Check
Pre-study
During Study
After Study
Sponsor Site Qualification
CRO/ Site QA/ QC Unit
Sponsor (monitoring)
Sponsor (Audit of completed data)
CRO/ Site QA/ QC Unit
Sponsor (Audit of completed data)
CRO/ Site QA/ QC Unit
Inspection by RA
16. Ultimate Aim
Pass Inspection by regulatory
authority(ies)
Well this means compliance!!!!
17. Compliance Certification
Audit certificate: A declaration of confirmation
by the auditor that an audit has taken place.
Audit report: A written evaluation by the
sponsor's auditor of the results of the audit
A written report from the monitor to the sponsor
after each site visit and/or other trial-related
communication according to the sponsor’s
SOPs.
19. Who?
Sites
Investigators (Doctors) and Study Coordinators
IRB (IRBMED)
Sponsor, if applicable (Industry)
Contract Research Organization, if involved
Laboratories
Pharmacy (e.g., Investigational Drug Services)
Devices (e.g., ECG, Biomedical Engineering)
20. What studies?
Usual Emphasis: Phase 3
Adequate and well controlled
Blinded
Safety and Efficacy
Multi-site
High patient enrolling sites
Recent marketing application (e.g. New Drug
Application) filed to an Investigational New
Drug (IND)
21. What studies?
Usual Emphasis: Bioequivalence studies
for ANDA
Clinical facilities, procedures, documentation
Quality Systems
Analytical facilities, procedures,
documentation
Clinical investigations laboratory
22. QC/ QA, Monitoring, Auditing,
Inspection check for compliance
Purpose is same, Objectives and method
can be different
23. When will inspection Occur?
At any time during the study
After the study is complete prior to
regulatory approval for the product
At any time after regulatory approval (15
years) if a safety concern with the product
(rare)
24. FDA selects Site(s)
• FDA selects site for inspection:
• Usually within 6 months of marketing
application [NDA] (Data Audit) or ANDA
• Selects 3 sites (average) per study, if multi-
site
• May concurrently inspect the associated IRB:
• If no previous inspection; or
• Last inspection >5 years
OR
• May conduct a “For Cause” Audit
25. Reasons: “For Cause” Inspections
Study of “singular
importance” in
product approval
Study has major
impact on medical
practice
Sponsor reports
concerns about
investigator
Patient complaint
Investigator conducts
too many studies
Investigator works
outside of specialty
area
Safety or efficacy
findings are
inconsistent with other
investigators
Lab results are outside
range of biological
expectations
26. FDA Inspection
• May give sufficient or very short advance
notice or no notice of visit
• Becomes suspicious on attempts to delay
visit (e.g., >10 days without valid reason)
• Previews internally following subject
related data:
• Number of total subjects, dropouts and evaluable
subjects
• List of AEs and deaths (with description and cause)
27. Objectives of Inspecting In-vivo BE
To verify the quality and integrity of
scientific data from bioequivalence
studies submitted
To ensure that the rights and welfare of
human subjects participating in drug
testing are protected; and
To ensure compliance with the
regulations (21 CFR 312, 320, 50, and 56)
and promptly follow-up on significant
problems, such as research misconduct or
fraud.
28. Objectives of Inspecting In-vivo BE
Clinical laboratories are usually certified
under programs based on the Clinical
Laboratories Improvement Act (42 USC
263a), and are not routinely inspected by
the FDA.
A clinical laboratory may be visited
during a bioequivalence study audit to
confirm that reported screening or
diagnostic laboratory work was indeed
performed
29. Preparation Tips for Site
Notify all staff involved in AND/OR
knowledgeable about the study:
Key staff, “information providers” are on
standby
Industry sponsor
30. Preparation Tips for Site
Assign a site escort/facilitator
Define “SOP” for Interacting with inspectors
from welcome to exit and do not underplay or
overplay
Assemble all study documents in One place
Include list of staff responsibilities and training
Request all patient charts
Prepare a list of investigator’s studies
Reserve adequate work space for field
investigator for entire inspection
Assure accessible photocopier provide a back up
if necessary
31. You have 3 to 5 minutes
To provide documents requested by
Inspector
If not available be truthful
Beyond five minutes inspector may
assume that it has been fabricated
32. Documentation thumb rule
If not documented means not done
If documented does not mean that it is
done
33. FDA Form 482
FDA written notice of inspection presented
by the investigator at the beginning of an
inspection.
34. Tips on Document Requests
Do not provide or copy these information
for FDA:
Financial data (salary information, budgets)
(except financial disclosure of clinical
investigators)
Personnel data (performance appraisals)
(except qualifications [job descriptions] and
training records)
Remember 3-5 minute rule
35. FDA interviews Site Staff
• FDA investigator interviews site staff
directly involved in trial activities and
processes
• May question any staff member during
inspection
• May use Compliance Program Guidance
Manual as interview guide
36. Tips for Anticipating FDA Questions
Compliance Program Guidance Manuals
(CPGMs)
http://www.fda.gov/ora/cpgm/default.htm
In Vivo Bioequivalence 7348.001
IRBs 7348.809
Sponsors, CROs and Monitors 7348.810
Clinical Investigators 7348.811
37. FDA investigative techniques for
Gathering evidence
Questioning employees at home at night
or on the weekend, permitted under
FDCA Sec. 704
Can go through trash, obtain grand jury
subpoenas and search warrants for
telephone and business records
Collaboration with FBI
38. Tips for Handling FDA Questions
Answer
Politely, cooperatively, understanding them
(ask for clarification), factually, briefly, within
one’s expertise (seek expert), directly (remain
within scope), without speculation or
guesswork
Avoid
Unsolicited questions, hypothetical questions,
long delays to requests, affidavits
39. Dos and Don’ts
Effective inspection preparation requires
a multi-faceted approach.
But communication issues can be just as
critical, as these dos and don'ts suggest.
40. What should you do for preparation?
Review regulatory site files
Confirm audit dates with all site staff
Ensure all patient notes and other source
data are in good order.
Ensure familiarity with the protocol and
the conduct of the study
41. Preparing for an inspection
Have a written corporate policy for
regulatory inspections
Conduct independent audits and internal
audits
Establish attitude of the company
Designate an inspection coordinator have
back up
42. Training personnel for inspections
Every employee must know his/her job function
and regulatory obligations
Document employee credentials, training and
knowledge
Study related documents
FDA program and inspection guidance
documents
43. Personnel interacting with inspector (s)
confirm that they are at correct name and
institution, record inspector’s badge number
Never leave investigator unattended
List of inspection team members and alternate
persons:
Clinical Director/Study Coordinator/Principal
Investigator
Production V.P./Quality Control Manager
Executive V.P./ President
Legal Counsel
44. Do be professional and confident
Don't become argumentative or at worst
hostile
Attitudes are important
If management is seen as "uncooperative,"
the investigator may well become
suspicious and more zealous
Dos and Don’ts
45. Don't tell the investigator that an
inspection isn't possible that day because
the owner is on vacation, and suggest
they return next week.
Dos and Don’ts
46. Do balance cooperation with wariness.
initial presentation about the facility's operations
and a tour can be useful in setting a positive tone
wait for the investigator to make specific requests
before providing records, samples, labels and the
like.
Respond to requests appropriately
do not offer other materials that might relate to
another matter pending with FDA but are
unrelated to the request.
Dos and Don’ts
47. Do provide timely and carefully prepared
written responses to 483s, and to any
letters issued by FDA regarding
violations identified as a result of the
inspection. Often, it is appropriate to
include a plan for corrective action.
FDA wants to see that management is
taking these issues seriously.
Dos and Don’ts
48. FDA conducts “Exit Interview”
• [Review findings with FDA investigator at
end of each inspection day]
• At site visit completion, FDA investigator
conducts “exit interview” with responsible
site personnel to:
• Review findings
• Clarify misunderstandings
• Describe any deviations from current regulations
• Suggest corrective action, if appropriate
49. FDA Form 483
A summary report of inspectional
observations. It is a list of objectionable
conditions or practices observed during
the inspection, prepared by the FDA
investigator and presented to the auditee
at the conclusion of an inspection.
50. Most Common Observations
(for Investigators)
Protocol non-adherence
Inadequate and inaccurate records
Failure to report adverse events
Failure to report concomitant therapy
Inadequate drug accountability
IRB/IEC problems
Informed consent issues
51. FDA classifies Inspection
• When evaluation is completed, FDA
classifies inspection and sends a letter to
site
Classification Type of Letter
NAI (No Action Indicated) Notice of no significant
deviations
VAI (Voluntary Action
Indicated)
Informational
OAI (Official Action
Indicated)
Warning
52. 1. Select Site
2. Contact Site
3. Schedule Site
4. Arrive (482)
5. Review Records
6. Interview Staff
7. Present Findings
8. Depart (483)
9. Write Report (EIR)
10. Classify Inspection
FDA Office Site Location
FDA Inspection Process
53. QC/ QA, Monitoring, Auditing,
Inspection check for compliance
Purpose is same, Objectives and method
can be different
54. Audit : purpose
The purpose of a sponsor’s audit is to evaluate
the trial conduct and compliance with:-
Quality Systems and SOPs
Protocol
Good clinical practices & other applicable
regulatory requirements
Auditors are independent of the clinical trial/
data collection system(s)
Sponsor or CRO or Site
55. What to audit
Organization and personnel
Responsibilities and functions - Ensure clear
responsibilities exist so as to minimize ambiguity
between:-
Investigator and sub-investigator
Sponsors and contractors
Contractors/suppliers (CROs, Labs, IRBs) –
audit suppliers!
Qualification, training and adequacy of staff
List of monitors
List of all investigators
56. What to audit?
Quality management systems
Management responsibilities
Procedures and their adequacy
Training
Documentation control
Change control
Deviations and non conformities
management
QC, QA
Internal Monitoring Program
Internal Auditing Program
57. What to audit? Investigational drug
Manufacturing, packaging, labeling and coding of the
investigational product (including placebo and active
comparator where applicable)
In accordance with applicable GMP standards
Labelling requirments, “For Clinical Trial Use Only”
to protect blinding where applicable
Drug Product Accountability
Control Quantity
58. What to audit
IRB/EC
Responsibilities
Composition, functions and operations
Procedures
Records
Investigators and sub-investigators
Qualifications and agreements
Essential documents
59. Investigator’s brochure
Has all current info been provided to the investigator?
Signed protocol and amendments
How are changes and deviations to the protocol
handled?
Advertisements for subject recruitment
Informed consent forms
Approved by IRB/IEC?
All been signed off according to requirements?
Financial aspects of the trial
Approved by IRB/IEC?
Insurance statement (where required)
What to audit (Essential documents)
60. Subject Databank
Subject screening log
Subject identification code list
Subject Enrollment log
Case report forms
Documentation of CRF corrections
Serious adverse events reporting
Signature sheet
Signed agreements between parties
IRB/IEC approval/favorable opinion
IRB/IEC composition
What to audit (Essential documents)
61. Regulatory authorities authorization/approval/
notification of the protocol
Normal value(s)/ranges for medical/laboratory
tests
Certifications or accreditation of labs (or other
means that establishes competency of lab)
What to audit (Essential documents)
62. What to audit (Essential documents)
At the clinical site:- investigational
product and trial related materials
Instructions for handling
Shipping records
Certificates of analysis of product shipped
Accountability at the trial site
Decoding procedures for blinded trials
Master randomization list and method
63. Records of retained body fluids/tissue samples
(if any)
Monitoring visit reports
Pre trial
During trial
Post trial
Final report by investigatory
Clinical study report
Archiving
What to audit (Essential documents)
64. Bio-analytical Laboratories
Documentation control including archiving
Qualification of instruments
Qualifications and Training of staff
Bio-analytical method validation
Receipt and storage of samples
Handling of reagents and solution
Testing conducted as outlined in protocol
CFR 11 compliance
65. Computerized systems (used to create, modify,
maintain, archive, retrieve or transmit data)
Identify software and hardware used, when and where?
Check security of the system (individual Login,
secure passwords)
Check traceability
Check audit trail capabilities where applicable:-
Who made the changes?
When and
Why, Certification of changes by appropriate authorites
Check validation status where applicable
Check record retention capabilities
66. Adequate procedures that need to be in place:-
System setup/installation
Data collection and handling
System maintenance
Data backup, recovery and contingency plans
Security
Change control
Alternative recording methods
Personnel training
Computerized systems (used to create, modify,
maintain, archive, retrieve or transmit data)
67. Statistical component
Check statistical procedures and methods used
are according to protocol
Check statistical package used has been
validated
Review statistical analysis and results
Check integrity of data and timely locking of
database
68. QC/ QA, Monitoring, Auditing,
Inspection check for compliance
Purpose is same, Objectives and method
can be different
69. Temperature Reading
Display is one digit -67.8
In log book entries are -67.80, -70.50 etc
Subsequently recording style changed to
single digit -56.7, etc.
Sponsors Monitor’s View
Sponsors Auditors View
Inspectors View
70. Participants in compliance
Sponsors
CROs
Management of all the organizations
All the employees, contractors,
subcontractors
71. Key to Success for all - 01
Compliance is Organizational
responsibility & mandatory act
72. Key to Success for all -02
Compliance is not a individual responsibility
73. Key to Success for all -03
Compliance is Organizational
responsibility & mandatory act
Compliance is not a individual responsibility
Integrity as a culture
Document properly what you do
Do not document what you do not do
Do it right at for the first time, at right time,
in right manner
GLP (animal laboratories) GMP (manufacturing facilities) Are also inspected with regards to research and new products
Main target is the investigator, then IRBs, then sponsor /CRO (very small numbers) US and International based Other groups listed on overhead usually are ancillary dependent on the questions and needs posed by FDA investigators
Other: IND Drugs, Biologics, Devices, combinations Bioequivalence (I.e., pharmacokinetics) For cause changes the whole mix, then any study is fair inspection game
Other: IND Drugs, Biologics, Devices, combinations Bioequivalence (I.e., pharmacokinetics) For cause changes the whole mix, then any study is fair inspection game
Inspectors manual cites these metrics….
Will cover some case studies in the last of the series However, do not want the NIH folks to get to comfortable. Just this year, a patient complained about an NIH study to FDA and they visited for 3 weeks.
Be in a state of readiness at all times. Eg: files organized and accessible No notice = “for cause” inspection. Example: One UM investigator (and study coordinator) arrived after FDA who already visited the IRB, then stayed 6 weeks. Be ready to validate patient existence. One study coordinator had this question posed….and had to generate lists of the screened patients, too (who did not get on study)
OGC Rachel Nosowsky IRBMED: Send email to general mailbox (June Insco and/or Pat Ward) Want to start tracking centrally what is happening. Have not been so good about this to date In case problems, need to address together. Do not have the sponsor present at the inspection
Data needs to be directly related to the study generated data
Target the expert, and the level headed and the knowledgeable ones
Clinical Investigator CPGM Headers: Authority and Administration Protocol Subjects’ Records Other Study Records Consent of Human Subjects Institutional Review Board Sponsor Investigational Product Accountability Records Retention Electronic Records and Signatures Animal Clinical Studies (if applicable) Device Studies (if applicable) Report Format Sample Collection (if applicable)
Be cool, calm, collected and concise! FDA inspector from Detroit nicknamed “Columbo” Self effacing, same question for numerous people, tenacious until satisfied with the answer (oh yes, also wore a rumpled lab coat that he brought along)
Daily summaries for next day preparation and information gathering Exit interview: Management/Investigator and key person, study coordinator Important piece of discussion especially if a written response is needed in the future
Does not discriminate between minor and major (misspelled words in a consent versus many missing consents)
Describe classifications, can view on line, that the problem situations and warning letters are subject of future date in this series
Included in packet Green = FDA office activities Purple = Site activities Remind about CME cards Remind about feedback Remind about next class: Oct 20, 2003 Q and A Remind about speaking into microphone