Audit monitoring and inspections cro perspectives

Audits Monitoring & Inspections CRO Perspective

Dr.Prashant Bodhe

[email protected]

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)


Sponsor (Audit of completed data)


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

http://www.fda.gov/ora/cpgm/default.htm

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

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


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

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

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

Thank you!!

???? Any Questions ??? [email protected]

Contact no: +919371069226

Audit monitoring and inspections cro perspectives

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