1

Overview of Inspections and Audits

Presented by Ashish A

2

Audits

A systemic 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 SOP, GCP and the applicable regulatory requirements. (ICH-GCP; E6 1.6)

Audits are part of Quality Assurance

3

Inspection

An Audit conducted by a Regulatory Body

4

Auditors and Inspectors

Auditors Inspectors

Independent of clinical trial project team

Qualified by training and experienceQualifications should be documented (ICH-GCP 5.19.2)

Are the members of particular regulatory agency

Are appointed by regulatory agencies on the basis of their own defined criteria of qualification, experience and training.

5

Objective of Inspection and Audits is to …..

Determine compliance of IRB, sponsors, clinical investigators and CROs with Protocol, GCP guidelines and applicable regulations

Determine whether data generated and submitted to the regulatory authority are credible and acceptable.

Assure the stake holders and public health agencies that the product is safe and not compromising with the public health.

6

Objective of Inspection and Audits is 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 SOP, GCP and the applicable regulatory requirements.

Determine whether systems and processes are in place to perform the trial related activities.

Provide recommendation and (CAPA) to the sponsor/site, for quality improvement

CAPA = Corrective And Preventive Action

7

Major Regulatory Agencies

DCGI, (Drug Controller General of India) USFDA, (US Food and Drug Administration) MCC, (Medicine Control Council of South Africa) MHRA, (Medicines and Healthcare products Regulatory Agency UK) EMEA, (European Agency for the Evaluation of Medical Products) TGA, (Therapeutic Goods Administration), Australia)

8

Audit Agencies

Can be Sponsor Can be CRO Can be a contracted party

9

Inspection and Audits: An Overview

FDA has (under FD&C Act), the authority to inspect any unit that provided source data in support of an IND/NDA/ANDA.

Applicable to; drugs, biological products, devices, veterinary medicine, food/color additives

Sponsor responsible for QA/QC, as defined in the MSA, has rights to conduct systems/study audits. (ICH-GCP; E6 - 5.1)

10

Types of FDA Inspections

The “Bioresearch Monitoring Program” covers two types of inspections:

“Study –Oriented Inspections”

“Investigator – Oriented Inspection”

Audits can be Study and/or system and processes audits

11

Study – Oriented Inspection

These cover the majority of inspections conducted for a specific application of a drug, device, biological.

To assess compliance of data and procedures with FDA regulations.

12

Investigator – Oriented Inspection

Initiated when questions arise from problems with previous inspections

Questions from the reviewing center during its review of study data

Complaint from a study subject, study monitoring staff or sponsor

13

When Inspector/Auditor Calls

HOW TO FACE …….

14

Preparation

Immediately notify all relevant personals and parties Assign a site escort / facilitator Assemble all study documents in 1 place

Include list of staff responsibilities and training Keep all study related documents ready & up to date Request all patient data (source / hospital notes)

15

Preparation

Train the staff to current procedures Perform adequate QC and be ready with CAPA Reserve adequate work space at the site for entire inspection Assure accessible photocopier

16

When inspector/auditors arrives…….

Upon arrival displays credentials (e.g., photo ID) and Notice of Inspection (482) or Agenda

Requests related trial data and documents during site visit May need copies of documents as exhibits

File all the document asked by inspectors/auditors

17

Conduct of Inspection/Audit includes

Opening interviews with key persons to discuss the agenda Inspection of Facilities and Equipments used/going to be used for

the study and generation of data SDV (source data verification) and IP accountability Review of all essential documents like IRB notifications, Protocol, IB,

ICD, FDA 1572, safety notifications etc. Interviews of site staff directly involved in trial activities and

processes. Exit interview to discuss the observations and clarifications

18

Exit Interview

After completion, investigator/auditor conducts “exit interview" with responsible site personnel to:

Review findings Clarify misunderstandings Describe any deviations from current regulations Suggest corrective action, if appropriate If deviations, FDA inspector leaves a Form 483, (Notice of Inspectional Observations)

Auditors send Audit report

19

Outcome of FDA Inspection

After an inspection the investigator writes .. Establishment Inspection Report (EIR) to Bioresearch

Monitoring Division, where it receives a “final classification”

The EIR is an internal agency document, not provided to the sponsor

Unless requested through the Freedom of Information Act (FOI)

20

Inspection Classification

Establishment Inspection Repot classifies the observations as

Classification Type of Letter NAI (No Action Indicated) Notice of no significant deviations

VAI (Voluntary Action Indicated) Informational

OAI (Official Action Indicated) Warning

Auditors classify observations as; Minor, Major, Critical

21

Inspection Classification

No Action Indicated (NAI) No objectionable conditions or practices found during the inspection

A letter may be issued but no response is necessary

Minor: No significant deviations

22

Inspection Classification

Voluntary Action Indicated (VAI) Objectionable practices that representing departure from regulations

Letter may be issued,

Written response by the investigator is warranted, even if the response to the 483 is complete

Major: Significant deviations if not corrected can lead to rejection of the data. CAPA required

23

Inspection Classification

Official Action Indicated (OAI)

Objectionable practices that represent significant departures from regulations

FDA issues a Warning Letter Must respond to Warning Letters in writing within 15 days Must indicate corrective action and time period for completion May result in rejection of the data, black listing and regulatory

action against investigator, withdrawal of marketing approval.

Critical : presence of exhibits of significant deviation and unacceptability of the data

24

Response to Form 483

Comments to Form 483 should be responded to:

In writing

Within 10 days

Each response with corrective action and timeline

Audit response is required in written and with CAPA as per the time lines agreed with auditor

25

Common Inspection/Audit findings

Problems with consent procedure Non-adherence to protocol/SOPs/Regulations Inadequate or in accurate records Improper drug accountability Problems with EC approval Failure to record Adverse Events and concomitant medications Problems in reconstruction

26

To Get the Approval ……..

Follow the Regulations/Protocol/SOP/GCP Document the activities Accept if done wrong and establish the CAPA

27

Comparison between Audits and Inspections

Audits Inspections

Who conducts? Independent unit of the sponsor company Auditors

Regulatory authorities, IRB/IEC, Data Protection Agencies Inspectors

What do they check?

Trial conduct and compliance withProtocolICH–GCPRegulatory requirements Data generated and reported is reliable, credible and acceptable

When do they occur?

Any time before, during, or after the trial

Why do they take place?

Randomly for cause

28

Thank You