Audit monitoring and inspections cro perspectives
-
Upload
prashant-bodhe -
Category
Business
-
view
4.575 -
download
1
description
Transcript of Audit monitoring and inspections cro perspectives
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
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
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
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
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 and What are Inspected?
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 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
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
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.
Dos and Don’ts
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 Indicated)
Informational
OAI (Official Action Indicated)
Warning
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
QC/ QA, Monitoring, Auditing, Inspection check for compliance
Purpose is same, Objectives and method can be different
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
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)
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)
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)
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
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)
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
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)
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
QC/ QA, Monitoring, Auditing, Inspection check for compliance
Purpose is same, Objectives and method can be different
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
Some Lessons through Humor
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.
Training Bunta
Lessons
Appropriate training is essential
Scope of the training should be defined
Continuous training is essential
Instructions should be clear non-ambiguous
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.
Urgency
Lessons
Do not react to things not happened
But be aware of options and possibilities
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
Guidelines, Rules and Regulations: Interpretation and Compliance
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