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!!