MONITORING ANDAUDITING IN CLINICAL TRIALS Presented By : Jyotsna Kapoor MSc Clinical Research Sem III
Introduction QC systems are the operational techniques and activities undertaken to verify the requirements for the quality of trial related activities . Monitoring is a part of QC activity QC activities are undertaken by the trial members themselves QA is the planned and systemic action that ensures that the trial is performed and the data is generated , documented , analyzed and reported in compliance with GCP and applicable regulatory requirements. Audit and inspection are part of QA activities and are undertaken by personnel independent of trial.
Monitoring Monitoring is the act of overseeing the progress of a clinical trial , and ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
Purpose of MonitoringTo verify that: The rights and well-being of human subjects are protected. The reported trial data are accurate, complete, and verifiable from source documents. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
Selection and Qualifications ofMonitors Monitors should be appointed by the sponsor. Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsors SOPs, GCP, and the applicable regulatory requirement(s).
Responsibilities of Monitor Acting as the main line of communication between the sponsor and the investigator. Verification of investigator’s qualifications ,expertise and resources and availability throughout the study. Adequate & continued availability of institutional facilities , sufficient IP’s with proper storage facilities. To ensure that the IP’s are supplied to eligible subjects at the specified doses and times and with proper instructions for handling To Ensure documentation of receipt
Contd… To ensure investigator receives current IB To ensure compliance of protocol and maintenance of essential documents by investigator To ensure proper training of the trial team To ensure that any of the trial tasks are not delegated to unauthorized individuals Informing sponsor in case of an unwarranted deviation To follow predetermined written set of SOPs Observing and reporting subject recruitment rate to sponsor To ensure that all CRFs are correctly filled , legible , accurate , complete signed and dated
Contd… To submit a written report to sponsor after each site visit and after all communications Ensuring the documentation of storage , handling , dispensing and return IP as per protocol and SOP
Monitoring Report Submitted to sponsor Reports should include :I. DateII. SiteIII. Name of the monitorIV. Name of the investigator or other individuals contacted during studyV. Summary of monitor review , statements concerning significant findings , deficiencies , deviations , actions to be taken or taken or actions recommended to secure compliance
Audit 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 sop’s, GCP, and Applicable regulatory requirements. (ICH-GCP Sec. 1.6)
Purpose of Audit to evaluate the trial conduct and compliance with:-I. Quality SystemsII. SOPsIII. ProtocolIV. Good clinical practices &V. 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 . Qualification, training and adequacy of staff List of monitors , List of all investigators , Drug supply agreement , clinical trial (site )agreement , other services agreement and material transfer agreement Quality management systems Investigational drug Manufacturing, packaging, labeling and coding of the IP(including placebo and active comparator where applicable) in accordance with applicable GMP standards Labeling requirements, “For Clinical Trial Use Only” to protect blinding where applicable Drug Product Accountability
Contd… IRB/EC Responsibilities Composition, functions and operations Procedures Records
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? )
What to audit (cntd..) Certifications or accreditation of labs 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 reportsI. Pre trialII. During trialIII. Post trial
What to audit ? (Contd) Bio-analytical Laboratories Computerized systems Statistical components
How to execute an audit ? The execution of audit process is divided into three steps :1. BEFORE THE AUDIT2. DURING THE AUDIT3. AFTER THE AUDIT
Before the audit process Auditor contacts the site to arrange for a mutually acceptable date and time for an audit to be conducted A detailed agenda of an audit is informed to the CRC and also about the documents to be checked during an audit Auditor previews the protocol , CRF , local regulations and guidelines , project specific guidelines , relevant SOPs to be aware of the trial.
During the audit process Opening meeting An introductory meeting between the auditor and the site team Auditor briefs the scope and procedures to be followed during the audit An opportunity for trial team members including the investigator to communicate with the auditor Reviewing documents and collating information Audit observations ( documents all observations)
After the audit process Auditor should issue the audit report (an internal and confidential document) within 28 days of the final audit activity He makes clinical research personnel aware of the findings relevant to their activities , and findings are classified as critical , major and minor Prevention/ corrective action list should accompany the report A formal audit response should be prepared and submitted by the trial team to the concerned personnel after the corrective measures have been taken Following the satisfactory responses to the audit , auditor issues an audit certificate confirming that audit has taken place and filed in clinical trial report and also submitted to regulatory authorities
6 Types of audit Sponsor audit of investigative sitea. Routine Auditb. For Cause Audit IRB audit of investigative site System audit of sponsor / CROs Clinical laboratory Audit Clinical study report audit Validation of computer system
1. Sponsor audit of investigative site Aim To assess whether : • the subject’s rights and safety have been maintained • Company procedures satisfactorily implemented • Accurate , reliable and verifiable data has been obtained from the trial Provides assurance to both the sponsor and investigator that if a regulatory inspection occurs , no major problems have remained undetected and unresolved
Routine audit and For cause auditRoutine: For-Cause:To ensure that a site is If the site is out of compliancecomplying with Protocol, SOP, andGCP and the sponsors want to either verifyApplicable regulatory the problem or be reassured thatrequirements. no problem exists.This is referred as “ROUTINE This is referred as “FOR-CAUSEAUDIT” AUDIT”“Study-oriented Audit” “Investigator – oriented Audit”
2. IRB audit of investigativesite To ensure ethical conduct of the trial Ensure subjects enrolled are well informed about the trial and enrolled through a proper informed consent procedure To ensure IRB plan is followed , proper documents are made .
3. System audits To assess the quality and efficiency of the QC systems employed by the sponsor or CRO Policies and procedures audited : SOPs Document access control Security and validation of computers used Personnel record Interviewing of the staff about their job responsibility and description
4. Clinical laboratory audit Involves evaluation of – Contracts , financial agreements and delegation Facilities and environmental conditions Analytical plan , report and results Equipments QC procedures Raw data Labeling and storage Documentation , filing and archiving Methodology , specific tests Reference ranges , alerts for out of range
5. Clinical study report audit To check for :1. Compliance with ICH requirements,2. Consistency of data,3. Accuracy of data ( verifying with the source data )
6. Validation of computersystem Audit of following is done – System setup / installation Data collection and handling System maintenance Data backup , recovery and contingency plans Security Electronic signatures Date/ time stamps Basically done to ensure the authenticity , integrity and confidentiality of the electronic records
Comparison between monitoringand auditing Monitoring AuditingI. Continuous process I. Done either during trial or after the completion of trialII. It controls quality of trial II. It assures quality of trialIII. It is done by monitor who is a part of trial III. It is done by an . independent personnel of trial , e.g. IRBIV. Appointed by the , regulatory sponsor authorities IV. Appointed by the
Inspection 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 sponsors and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).( ICH GCP sec 1.29)
Inspection programdetermines Degree to which sponsor , monitors , clinical investigators , site staff , IRB’s and CROs have fullfilled their trial related obligations The acceptability of resultant clinical data
Difference between Audit andInspectionAUDIT INSPECTIONInspectors are employed of the Inspector are employed bycompany who work for a active government, through the agencyclinical quality assurance (CQA) of the regulatory or competentfunction (i.e. Sponsor/CRO) Authority (i.e. FDA/DCGI)To ensure that a site is complying To ensure that trial relatedwith Protocol, SOP, GCP and obligations and acceptability ofApplicable regulatory resultant clinical data is in supportrequirements. of a new drug approval.
Various global monitoringprograms1. US FDA’S CDER’S BIORESEARCH MONITORING PROGRAM ( BIMO)2. EMEA’S CHMP ,THE GCP INSPECTION PROGRAM3. MHRA GCP COMPLIANCE PROGRAM ( UK )4. PHARMACEUTICAL AND MEDICAL DEVICES AGENCY
BIMO Program Overview Established in 1977 and expanded in 1992 Comprehensive program of on-site inspections and data audits to monitor all aspects of the conduct and reporting of FDA regulated research Each FDA Center has its own BIMO program staff with overall coordination by the Office of Regulatory Affairs Implemented domestically and internationally resulting in over 1000 inspections annually Inspections are Conducted before the approval of drug to be marketed , also called as Pre approval Inspection by FDA
BIMO’S COMPLIANCEINSPECTION PROGRAM1. CLINICAL INVESTIGATOR INSPECTION PROGRAM ( mostly done , provides an indication how well sponsors and IRBs are performing their roles)2. SPONSOR/ MONITOR/ CRO INSPECTION PROGRAM (done mostly in case of suspicion of non compliance with regulations , not done regularly )3. IRB INSPECTION PROGRAM : Conducts routine inspection of 150 IRB’s annually reviews those IRBs with highest volumes of studies or complex studies periodically done , IRB’S with full compliance or minor deficiences are reinspected in 5 years and with major deficiencies within a year Documents auditted : IRB procedures , IRB roster , copies of IRB minutes , records of tracked studies Reveal significant regulatory deviations , which may lead to
Contd..4. NON - CLINICAL INSPECTION PROGRAM ( not done often , inspects GLP are followed or not )5 .IN- VIVO BIOEQUIVALENCE INSPECTION PROGRAM ( inspects both clinical and analytical facilities to ensure safety and quality of generic drugs and safety of subjects participating in BE studies)
Most Common Investigatorinspection Deficiencies Failure to follow the investigational plan Protocol deviations Inadequate recordkeeping Inadequate accountability for the investigational product Inadequate subject protection – including informed consent issues
EIR – establishment inspectedreport After inspection, FDA field inspector writes an establishment inspection report (EIR) After district office review, the completed EIR package is sent to the FDA Once the EIR is received, it is assessed and classified by FDA
Classification of inspection by FDA No Action Indicated (NAI) = the FDA field inspector did not identify objectionable practices or identified only minor issues that did not justify further action Voluntary Action Indicated (VAI) = indicates that objectionable practices were uncovered during the inspection, but were not significant Official Action Indicated (OAI) = inspection uncovered significant objectionable practices, which could affect data reliability or compromise human subject protection. Generally results in the issuance of a Warning Letter or some other higher-level compliance action
FDA Form – 483 f Observation) 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.
EMEA’s CHMP GCP inspectionprogram Focusses largely on clinical trials and clinical data used to support marketing applications. Conducts inspection only at the request of scientific committee of CHMP , to confirm the information provided in the application for marketing authorization
MHRA GCP complianceprogram Assess compliance with requirements of applicable GCP regulations and guidelines , by conducting inspections at sites of sponsor , CRO , trial sites , clinical laboratories , and other facilities involved in clinical research Does not inspect IRB , but assures that related documents are approved by IRB
PMDA Founded in April 2004 , comprises 13 offices Responsible for reviewing and approving new drugs and medical devices , monitoring the reliability of clinical trial data It inspects the site , IRB , sponsor , and laboratories before approving the marketing authorization only when they feel its necessary .
Consequences of Inspection Study may be invalidated ( if there are significant protocol deviations or underreporting of AEs ) Could delay the new drug approval or disapproval of application Investigator may be disqualified or restricted from conducting CTs in future.
Reference ICH GCP guidelines E6 www.fda.gov.in Basic principles of clinical Research and Methodolgy , S.K. Gupta , vol 1