Audit monitoring and inspections cro perspectives

Audits Monitoring & Inspections
CRO Perspective

Dr.Prashant Bodhe

prashant.bodhe@gmail.com

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

CRO types
 Pharmacokinetic (BABE)
 Clinical Research – Phase I, II, III, IV
 Preclinical
 Discovery
 Analytical and Microbiological
 Hospitals, clinics, etc.
 Or any other

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.

Structured compliance plan
 CDSCO  Thailand
 Slovac Republic  EU
 WHO  SA MCC
 Brazil  USFDA
 Zimbabwe  TGA
 Nigeria
CROs need to define their own Objectives and Goals
and Plans to execute according to the business needs

Compliance to
 GLP
 GCP
 GXP
 Applicable Rules, Regulations, Laws and
guidelines of the target regulatory agency
and those of the land

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

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 & Staff Responsibility
 Mandatory
 Safety, Efficacy, Quality

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!!!

To ensure compliance
 Infrastructure & Facilities
 Build Quality systems
 Execute Protocols using these quality
systems
 Quality Control and Assurance
 Monitoring
 Audit
 Review
 Inspection

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
 Assessment and Analysis of the Performance,
Accuracy, Reliability And Integrity Of Quality
Systems through Independent Auditing Activities
 Defines new paradigms, systems, methods

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)

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).

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)

Time of Compliance Check
 Pre-study  Sponsor Site Qualification
 CRO/ Site QA/ QC Unit

 During Study  Sponsor (monitoring)
 Sponsor (Audit of completed data)

 Sponsor (Audit of completed data)
 After Study
 Inspection by RA

Ultimate Aim
 Pass Inspection by regulatory
authority(ies)
 Well this means compliance!!!!
 Audit certification by Sponsor and other external agencies do not
guarantee this, but takes the organization a step closer

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.

Who?
 Sites
 Investigators (Doctors) and Site staff
 IRB, ethics committees
 Sponsor, if applicable (Industry)
 Contract Research Organization
 CPU
 Laboratories (Clinical, Bio-analytical)
 Pharmacy (e.g., Investigational Drug Services)
 Devices (e.g., ECG, Biomedical Engineering)

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)

What studies?
 Usual Emphasis: Bioequivalence studies
for ANDA
 Clinical facilities, procedures, documentation
 Quality Systems
 Analytical facilities, procedures,
documentation
 Clinical investigations laboratory

Impact factor
 Global Importance of data impact on the outcomes
stated in the regulatory filing under consideration
 Suspected for Cause, suspiciously very good data
 Reported for Cause
 Multiple studies from same investigator(s) with
huge no of patients from same or multiple sites
 Data incongruent with experience of RA

QC/ QA, Monitoring, Auditing,
Inspection check for compliance

Purpose is same, Objectives and method
can be different

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)

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

Reasons: “For Cause” Inspections
 Study of “singular  Investigator conducts
importance” in too many studies
product approval  Investigator works
 Study has major outside of specialty
area
impact on medical
practice  Safety or efficacy
findings are
 Sponsor reports inconsistent with other
concerns about investigators
investigator  Lab results are outside
range of biological
 Patient complaint expectations

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)

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.

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

Preparation Tips for Site

 Notify all staff involved in AND/OR
knowledgeable about the study:
 Key staff, “information providers” are on
standby
 Industry sponsor

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

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

Documentation thumb rule
 If not documented means not done
 If documented does not mean that it is
done

FDA Form 482
 FDA written notice of inspection presented
by the investigator at the beginning of an
inspection.

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

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

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

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

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

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.

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

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

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

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

Dos and Don’ts
 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
 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
 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
 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.

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

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.

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

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 Informational
Indicated)
OAI (Official Action Warning
Indicated)

FDA Inspection Process

FDA Office Site Location

1. Select Site 4. Arrive (482)

2. Contact Site 5. Review Records

3. Schedule Site 6. Interview Staff

9. Write Report (EIR) 7. Present Findings

10. Classify Inspection 8. Depart (483)

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

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

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

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

What to audit

 IRB/EC
 Responsibilities
 Composition, functions and operations
 Procedures
 Records
 Investigators and sub-investigators
 Qualifications and agreements
 Essential documents

What to audit (Essential documents)
 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)

 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

 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)


 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

 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

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

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

Computerized systems (used to create, modify,
maintain, archive, retrieve or transmit data)

 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

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

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

Participants in compliance
 Sponsors
 CROs
 Management of all the organizations
 All the employees, contractors,
subcontractors

Key to Success for all - 01
 Compliance is Organizational responsibility & mandatory act

Key to Success for all -02
 Compliance is not a individual responsibility

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

Training Bunta

Master Bunta, how much did you spend on the groceries today?
Bunta I spent Rs.99 and 50 paise.
Master Why don't you round it off to Rs.100. Rounding off figures is very
convenient
Then one day-
Master Bunta, go and get me a ticket to Mumbai.
Bunta Buys tickets and When he came back
Master What time does the train leave tomorrow?
Bunta 4 p.m.
Then the next day- Mater reaches station at 3:55 with Bunta
Master Its 4 p.m., and the train to Mumbai hasn't arrived, I think it is late.
A passer by No sir, the train left at 3.45.
Master Bunta, you told me the train is leaving at 4.00 p.m
Bunta The time was 3. 45 but I rounded it off to 4p.m.

Lessons
 Appropriate training is essential
 Scope of the training should be defined
 Continuous training is essential
 Instructions should be clear non-ambiguous

Urgency

Master Bunta, why are you holding the receiver of
the phone to your ear? Did it ring?

Bunta No, I am expecting an urgent call from my
brother.

Lessons
 Do not react to things not happened
 But be aware of options and possibilities

Guidelines, Rules and Regulations: Interpretation and Compliance

Bunta starts working as a guard in Bank
Bank manager Bunta, you will watch and frisk if necessary all the people coming
inside branch. Do not allow any person with arms inside the branch
Bunta Yes Sir
Branch manager is happy that he has obedient guard. After an hour after opening a branch
manager does not see any customer inside branch but there is lot of noise outside branch.
Manager comes out of the branch and sees many customers arguing with Bunta
Customer to Manager Sir, this new guard is not allowing us to go in
Manager angrily Bunta, why are you not allowing customers to go in
Bunta Yes Sir, I am complying to your orders
Manager Bunta, I did not tell you not to let customers in
Bunta Yes Sir, but you told me anyone with arms should not be allowed
to come in. See everyone here has two arms and that is why I am
not allowing them to come in

Lessons
 Interpretation is not just to letter but to
letter and spirit
 Compliance should be to Spirit and Letter
 Common sense prevails all the time

Thank you!!

???? Any Questions ???
prashant.bodhe@gmail.com
Contact no: +919371069226

Audit monitoring and inspections cro perspectives

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