cro perspectives
TRANSCRIPT
Audits & InspectionsCRO Perspective
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 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
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 Assesses the Performance, Accuracy,
Reliability And Integrity Of Quality Systems through Independent Auditing Activities
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!!!!
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 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)
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
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
Thank you!!