How to Conduct GCP Inspections/Audits atthe Clinical Investigator SiteContents

1. Contents2. Course Contents3. Course Objectives4. Introduction to GCP

1. The 13 Basic Principles of ICH-GCP2. What is a GCP Inspection/Audit?3. Regulatory Framework

5. Characteristics of an Inspector/Auditor1. Characteristics of an Inspector/Auditor (a)

6. Inspection Programme - Points to Consider1. Inspection Programme - Points to Consider (a)2. Inspection Programme - Points to Consider (b)

7. Audit Programme - Points to Consider1. Audit Programme - Points to Consider (a)

8. Preparation of a GCP Inspection/Audit1. Appointment of the Inspection/Audit Team2. Announcement of the Inspection/Audit to the Inspectee/Auditee3. Travel Arrangements4. Documents to be Reviewed Before the Inspection/Audit5. Inspection/Audit Plan

9. Conduct of GCP Inspection/Audit at the Clinical Investigator Site1. Opening Meeting with the Investigator and Study Team2. Interviews with the Study Team3. Informed Consent of the Trial Subjects4. Source Data Documents and CRFs5. IMP Records6. Review of Essential Documents7. Monitoring and Auditing8. Use of Computerised Systems9. Facilities

10. Closing Meeting10. Reporting and Follow-up of the GCP Inspection/Audit

1. Inspection/Audit Report2. Inspection/Audit Findings3. Inspection/Audit Follow-up

11. Common Findings1. Common Findings (a)2. Common Findings (b)

12. Case Studies1. Case Study 12. Case Study 23. Case Study 3

13. Appendices14. References15. Resources16. Quiz

Course Contents

This course is intended to benefit regulatory good clinical practice (GCP) inspectors and sponsorauditors who audit clinical trials and in particular:

1. regulatory authorities or sponsors in the process of building up their GCP inspection/auditteam and an inspection/audit programme

2. regulatory authorities or sponsors which require further, up to date training in the planning,conduct and reporting of GCP inspections/audits for their inspection/audit team.

This course describes the procedures involved in planning, conducting and reportinginspections/audits, specifically at clinical investigator sites. However, some of the generalprinciples described could be used when conducting inspections at other sites e.g. those of thesponsors and contract research organisations (CRO).

It is recommended that before commencing this course, participants may find it valuable tocomplete the course ‘ ICH Good Clinical Practice’ available on the Global Health Trials website(https://globalhealthtrainingcentre.tghn.org/elearning/short-courses/)

There is the possibility for this course to be offered as a face to face training course inconjunction with an onsite national inspection at a clinical investigator site. This would providethe opportunity to gain hands-on experience in the conduct of an inspection by implementingthe theoretical aspects of the course, into real life practice. For further information and detailsplease contact training@theglobalhealthnetwork.org

Course ObjectivesParticipants who complete this course will have a good understanding of:

1. What GCP is2. The 13 basic principles of ICH GCP3. Which points to consider when preparing a GCP inspection or audit programme of clinical

trial sites4. The roles and responsibilities of GCP inspectors/auditors5. How to perform a GCP inspection/audit at a clinical investigator site6. How to report the outcome of a GCP Inspection/audit at a clinical investigator site7. How to communicate and follow up the inspection/audit findings8. How to use and develop templates for:

An inspection/audit planAn inspection/audit checklistAn inspection/audit report

The ultimate aim of this course is to equip inspectors/auditorswith the necessary skills for improving GCP compliance of clinicaltrials conducted in their country/by their company:

through the implementation of a clearly thought outinspection/audit programme,by preparing, conducting and reporting high quality inspections/audits,by monitoring the follow-up of the inspections/audits,by making clear to the inspectee/auditee the regulatory requirements and GCP principlesthat must be followed.

It is important to note that on completion of this course, a junior inspector/auditor will not bequalified to lead an inspection/audit. In order to become a lead inspector/auditor, additionalestablished training courses combined with training on site with senior inspectors/auditors, isnecessary.

Introduction to GCP

What is GCP?

- Definition

Good Clinical Practice (GCP) is an internationalethical and scientific quality standard fordesigning, conducting, recording and reportingtrials that involve the participation of humansubjects. Compliance with this standard providespublic assurance that the rights, safety and well-being of trials subjects are protected, consistentwith the principles that have their origin in theDeclaration of Helsinki and that the clinical trialdata are credible. ICH Harmonised TripartiteGuideline. Guideline for Good Clinical PracticeER6(R1) (ICH-GCP 1996)

- Purpose

Compliance with GCP provides public assurancethat:

the rights, safety and wellbeing of trial subjectsare protectedthe data collected during the clinical trial arecrediblethe applicable laws and regulations are complied with

GCP therefore protects trial subjects who will be and are currently participating in clinical trialsand anyone who will be treated with marketed medicinal products.

The 13 Basic Principles of ICH-GCPThe principles of GCP are defined in the International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use: ICH-GCP (1996) which aimsto provide a unified standard for the European Union, Japan and the United States to facilitatethe mutual acceptance of clinical trial data by the regulatory authorities. The guidelines relate tothe protection of the rights, safety and wellbeing of trial subjects as well as the credibility of theclinical trial data.

The 13 basic principles are as follows:

1. Clinical trials should be conducted in accordance with the ethical principles that have theirorigin in the Declaration of Helsinki, and that are consistent with GCP and the applicableregulatory requirement(s).

2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed againstthe anticipated benefit for the individual trial subject and society. A trial should be initiatedand continued only if the anticipated benefits justify the risks.

3. The rights, safety, and well-being of the trial subjects are the most importantconsiderations and should prevail over the interests of science and society.

4. The available nonclinical and clinical information on an investigational product should beadequate to support the proposed clinical trial.

5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.6. A trial should be conducted in compliance with the protocol that has received prior

institutional review board (IRB)/independent ethics committee (IEC) approval/favourableopinion.

7. The medical care given to, and medical decisions made on behalf of, subjects shouldalways be the responsibility of a qualified physician or, when appropriate, of a qualifieddentist.

8. Each individual involved in conducting a trial should be qualified by education, training, andexperience to perform his or her respective task(s).

9. Freely given informed consent should be obtained from every subject prior to clinical trialparticipation.

10. All clinical trial information should be recorded, handled, and stored in a way that allows itsaccurate reporting, interpretation, and verification.

11. The confidentiality of records that could identify subjects should be protected, respectingthe privacy and confidentiality rules in accordance with the applicable regulatoryrequirement(s).

12. Investigational products should be manufactured, handled, and stored in accordance withapplicable good manufacturing practice (GMP). They should be used in accordance with theapproved protocol.

13. Systems with procedures that assure the quality of every aspect of the trial should beimplemented.

What is a GCP Inspection/Audit?Definition of a GCP inspection/audit

A GCP inspection is the act by a regulatory authority(ies) of conducting an official review ofdocuments, 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 thesponsor’s and/or CRO’s facilities or at any other establishment deemed appropriate by theregulatory authority(ies). (ICH-GCP 1.29)A GCP audit is a systematic and independent examination of trial-related activities anddocuments to determine whether the evaluated trial-related activities were conducted andthe data recorded, analysed and accurately reported according to the protocol, sponsor’sSOPs, GCP and the applicable regulatory requirements.(ICH-GCP 1.6)

Purpose of a GCP inspection/audit

The purpose of a GCP inspection is to verify compliance with the provisions of GCP and theapplicable regulatory requirements.

The purpose of a sponsor’s audit, which is independent of and separate from routinemonitoring and quality control functions, should be to evaluate trial conduct and compliancewith the protocol, company’s SOPs, GCP and the applicable regulatory requirements (ICH-GCP 5.19.1)

The main differences between an audit and an inspection are summarised in the followingtable:

Audits Inspections

Conducted by Sponsor/ CRO Regulatory agency

Focus on Compliance and processreview Patient safety and data credibility.

Checkedagainst Regulations and sponsor SOPs Legislation and guidance. Sponsor SOPs usually

irrelevant

Vested interests Enuring study success Public safety. Study success "irrelevant".

Despite the differences between the two processes, a series of inspections/audits of high qualitywill ultimately result in an improvement in GCP compliance. This course aims at providing thenecessary tools for inspectors/auditors to be able to perform inspections/audits of a highstandard. This will lead to an assurance of the quality of clinical trials performed in theircountry/company, which is the ultimate purpose of inspections/audits.

Regulatory FrameworkGCP inspections/audits are carried out to verify compliance with applicable regulatoryrequirements such as

International agreements and guidelines:The Declaration of HelsinkiGCP

- ICH Topic E6 Note for Guidance on Good Clinical Practice- WHO Guidelines for GCP

CIOMS Ethical Guidelines for Biomedical Research Involving Human Subjects

European legislation and guidelines:the 'Clinical Trial Directive' (Directive 2001/20/EC )the 'GCP Directive' (Directive 2005/28/EC )Volume 10: Clinical Trial Guidelines “The Rules Governing Medicinal Products in theEuropean Community”;Reflection Papers and Q&As are placed onthe GCP Inspectors Working Group webpageof the EMA website.

National requirements:LawsGuidelinesProcedures

see: http://globalhealthreviewers.tghn.org/resources/guidance-and-regulation for more detail ofnational regulations and guidelines.

Characteristics of an Inspector/AuditorQualifications and Competence

Inspectors are officials appointed by theircountry’s competent authority to carry outinspections. In order to be competent to carryout their duties they should receive appropriatetraining before and during their time of service.The inspectors should be educated at universitylevel with a degree in a scientific/medicaldiscipline or quality-related field, or equivalentcombination of education, training andexperience. The inspector should be competentin expressing concepts both verbally and in

writing and be familiar with basic medicalterminology.

Inspectors should systematically follow established training courses in order to maintain andimprove their knowledge, skills and competence. A basic training course could include but doesnot have to be limited to:

Information about the process of drug development Information about drug regulation and approval processes in the local regulatory body(ies)Information about application of GCPInformation about and application of relevant national and international legislation andguidanceInformation about the conduct of a clinical trialUp to date information about technology, computer systems, information technology anddata managementInformation about the handing of investigational medicinal products including labelling,storage and administrationInformation about the structure and content of a protocol, CRF and clinical study reportInformation about SOPs related to the planning, conduct and reporting of nationalinspections

All training received should be documented.

It is essential that before taking up any responsibility as an independent inspector, a juniorinspector should initially observe inspections and gradually take over responsibilities ininspections led by experienced inspectors. He/she should be able to demonstrate the ability tomanage an inspection and to write inspection reports according to national requirements beforehe/she takes up the role of lead inspector. A junior inspector should preferably be ‘mentored’ fora period of time by a more experienced inspector who will guide the junior inspector andevaluate his/her progress.

In the case of auditors, it is the sponsor who is responsible for appointing individuals who areindependent of the clinical trials/systems, to conduct audits. The sponsor should ensure that theauditors are qualified by training and experience to conduct audits properly and according tothe sponsor’s SOPs (ICH-GCP 5.19.2).The basic training/qualification requirements for auditors are in most respects similar to those ofan inspector (see above). Auditors are likely to receive additional training on topics such asspecific company processes.

Characteristics of an Inspector/Auditor (a)Personal characteristics

Inspectors and auditors are just like any other human being - each with his/her personalcharacteristics and qualities. However, inspectors and auditors should all possess the followinggeneral characteristics:

Integrity; show professionalism and reasoned judgementFairness; report in a truthful, accurate, objective, complete and timely mannerConfidentiality; be discreet and handle information correctlyOpen-mindedness; be open to different personalities and culturesStrong communication skills; good listener and observerDiscipline and leadership qualities

The following characteristics should be avoided: aggression, intimidating and/or uncooperativebehaviour, stubbornness, sneakiness and over-attention to minute and trivial faults.

The quality of an inspection/audit does not depend only on the inspector’s/auditor’s expertise

but also on his/her communication skills. In this sense, an inspection/audit is the “art” of knowinghow to send and receive signals, knowing when to go deeper into an issue, how to deal withdifficult situations and personalities, etc. Poor inspection technique is unprofessional and candamage a regulatory authority’s reputation.

Inspection Programme - Points to Consider

The scheduling and conduct of inspections should be driven by the preparation of inspectionprogrammes in order to ensure that inspection resources are used as efficiently as possible anda wide range of key players in clinical trials is routinely inspected.

Each competent authority is responsible for preparing a periodic (e.g. quarterly/six-monthly/yearly) national programme with the scope to establish:

1. The routine surveillance of national clinical trials2. The quality assessment of clinical trials submitted as part of a marketing authorisation

application (MAA)

For the routine surveillance of clinical trials, the focus is on the protection of the rights, safety,and well-being of the trial subjects as well as the GCP compliance of the trial. The inspection ismainly process-driven in order to achieve quality during on-going trials rather than finding faultsin completed trials.

Inspections carried out in clinical trials submitted as part of a MAA, are conducted after thecompletion of the trial when clinical trial results are available. These inspections are focused onquality of the data submitted as part of a MAA as well as the protection, safety and wellbeing ofthe participants. Communication between inspectors and assessors of marketing authorisationapplications is important to ensure successful prioritisation and targeting of such inspections.

It is clear that an inspection programme is based on the planning of routine inspections. Theseare scheduled inspections which are performed in the absence of a particular concern and arecarried out as a routine surveillance of GCP compliance based on pre-defined criteria.

Inspection Programme - Points to Consider (a)“For cause” inspections, on the other hand, which can be conducted on on-going or completedtrials, are inspections that have been triggered due to some specific concern such as:

reporting to the authorities of GCP non-compliancenon-adherence to legal requirementshigh number of protocol deviations

under/ over-reporting of AEs / SAEsuncommon / inconsistent study resultsunusual study conduct, e.g. no screen failuresdata “too good to be true”

In order to identify triggers from the data collected by the authority, close cooperation isneeded between the different departments of the authority.

If the need for a “for cause” inspection is identified, and inspection resources are limited, it willreplace the planned routine inspection and so the inspection programme will have to be revisedto reflect the new time frame.

An inspection programme should also include any necessary re-inspections to be conducted as aresult of previous non-compliant inspections.

Before planning the details of an inspection programme the following general points should betaken into consideration:

How many trials are currently being conducted in your country?What percentage do you want to inspect?What types of trials are conducted?

1. Commercial/non-commercial2. Early phase/late phase3. Healthy volunteers/patients4. Completed/on-going

What percentage of sponsors has offices in your country?What resources will be required to fulfil the agreed inspection programme?How will inspections be financed?

- By sponsor e.g. inspection fee, clinical trial application fee- By marketing application authorisation holders- Government funding

Inspection Programme - Points to Consider (b)A risk based approach should be used by competent authorities when establishing inspectionprogrammes. This will enable:

targeted decision making based on factual informationprioritisationeffective and efficient use of available resourcesa risk assessment of the clinical trials

Factors which may be taken into consideration, as appropriate, by the competent authoritieswhen establishing inspection programmes using a risk-based approach are described below:

Number of clinical trials (or a substantial increase in the number of trials) sponsored ormanaged by a given organisationNumbers of patients and the nature of the trial participants (e.g. vulnerable populations)Risks associated with the IMP or its applicationNature of indication i.e. the disease for which the drug is usedTrial phase (for first in human trials, a pre-evaluation of the facilities could be conductedwith a particular emphasis on patient safety)Non-compliance with reporting requirements (intelligence from other departments of theauthority)Number of subjects to be enrolled versus number of site staffNumber of trials conducted by the investigator

Experience of the investigator / site with the:

- indication / IMP- special efficacy measurement i.e. the methods used to measure the therapeutic effectof the IMP.- protocol specific responsibilities to be taken over in the trial

Organisations that have not previously been inspected or have not been inspected for along periodPrevious inspection history of the organisation/investigator including possible unresolvedissuesSites where issues have been identified: including safety issues, ethics committee concerns,GCP non-compliance, high drop-out rate etc.

The specific trials or sites to be inspected will be selected based on the prioritisation of theabove criteria, and will be scheduled into the inspection programme. Sometimes specific sitescan be chosen following a sponsor inspection, based on issues identified during that inspection.It is important that regulatory authorities develop inspection programmes that are practical, wellfocused and can be implemented with the available resources. A small number of high qualityinspections of key selected sites, can be very useful. Organisations may become aware of yourpresence, not only as a regulator, but also as a source of information and support in improvingthe quality of clinical trials.

Audit Programme - Points to Consider

An audit programme should aim at a general surveillance and quality control of the clinical trialsconducted as part of the clinical development programme(s) of the company. In particular, theroutine audit programme should aim at checking the quality of the trials in terms of adherenceto applicable regulations and GCP.

Audits selected to be included in an audit programme should come from:

a range of clinical trials within each project, i.e. phase I to phase III/IV trials

a range of territories within which these trials are being conducted

as many of the service providers (CROs/laboratories etc) as possible, based on a riskassessment and other measures of evaluating the work of the CRO, such as databasereconciliation (e.g. IVRS and eCRF databases), etc.

As for an inspection programme, an audit programme is also based on the planning of routine

audits. However, when the need for “for cause” audits is identified, the audit programme willhave to be revised in order to accommodate these.

Audit Programme - Points to Consider (a)Before planning the details of an audit programme some general points should be taken intoconsideration such as:

What percentage of the trials do you want to routinely audit?What resources will be required to fulfil the audit programme?What have previous audit programmes already covered?Which trials are important for the sponsor i.e. pivotal trials?

The specific trials/sites to be included in an audit programme (as for an inspection programme)should be chosen based on a risk-based approach.

The selection of trials to be audited should be based on factors similar to those listed for theinspection programme, such as the:

size of the trialtype of trialcomplexity of the triallevel of risk for trial participantsrisks associated with the IMPprevious experience with the site/vendorgeographical location of the sitespreviously identified problemssubmission as part of a MAA application

Finally, it is important that audit programmes are practical, well focused and can beimplemented with the available resources.

Preparation of a GCP Inspection/AuditAll inspection and audit processes should be covered by written procedures.The preparation of an inspection/audit should include the steps described in the followingsections and should generally be completed within one to two weeks depending on the nature ofthe inspection/audit, the amount of data and number of documents to be reviewed and theexperience of the inspection/audit team.

Appointment of the Inspection/Audit TeamThe size of the inspection/audit team may vary depending on the available resources and thescope of the inspection/audit. However an inspection/audit team should preferably consist of atleast two inspectors/auditors one of whom should be an experienced inspector/auditor.

For each site to be inspected/audited, one of the inspectors/auditors is assigned the role of leadinspector/auditor. The lead inspector/auditor is responsible for:

Organising the practicalities of the inspection/audit and communicating them to theinspectee/auditee (e.g. announcing the inspection to the inspectee)Ensuring that all members of the inspection/audit team are informed and prepared for theinspection/auditPreparing the inspection plan and checklistsSetting the timelines for the various steps of the inspectionLeading and coordinating the conduct of the inspection/audit on-siteWriting and signing the inspection/audit reportFollowing-up any issues resulting from the inspection/audit

Archiving the inspection/audit documentsThe lead inspector/auditor may also choose to appoint additional experts with specialisedskills for specific inspections/audits and permit the attendance of trainees in the inspectionteam, subject to consideration of the size of the inspection team.

Announcement of the Inspection/Audit to the Inspectee/AuditeeThe majority of inspections/audits will be announced inadvance to the inspectee/auditee. In some cases of “forcause” inspections/audits, the inspection/audit may beunannounced.As already mentioned, it is the responsibility of the leadinspector/auditor to announce the inspection/audit to theinspectee/auditee. This should be done in writing using atemplate letter.

An example of the kind of information to be included in thetemplate letter is given below:

1. The type of inspection/audit to be conducted, i.e. routine/“for cause”2. The scope of the inspection/audit3. The names and affiliation of the inspection/audit team4. The address at which the inspection/audit is to be carried out5. The proposed dates of the inspection/audit6. The length of the inspection/audit7. A very brief overview of the inspection/audit plan8. A request for ensuring that:

All members of the clinical trial team are available, on occasion, during theinspection/auditAll relevant departments and personnel are notified of the inspection/audit by theinvestigatorAll relevant documentation is available for inspection/auditAll relevant facilities are ready for inspection/auditA room is allocated for the inspectors/auditors to conduct the inspection/audit

9. Asking the principal investigator to confirm the address of the site and the datesproposed

Travel ArrangementsTravel and accommodation arrangements should be made well in advance. For regulatoryauthorities, reimbursement of the expenses (daily allowance, travel and accommodation) shouldalso be taken into consideration. These could, for example, be covered by charging the sponsoran inspection fee (where permitted by national law).

Where inspections are conducted in foreign countries a translator may be needed. The sponsormay be required to provide a translation service.

Documents to be Reviewed Before the Inspection/AuditThe quality of an inspection/audit depends very much upon the extent to which theinspection/audit team is prepared. As mentioned above, the lead inspector/auditor shouldcoordinate the preparation of the inspection/audit and make sure that the inspection/audit teamhas been provided with all the necessary documentation and information.

The lead inspector/auditor should identify what essential information and documentation isneeded in preparation for the inspection/audit and make sure it is obtained in advance. Thisinformation can be obtained from various sources such as the marketing authorisation dossier(if applicable), local legal requirements, regulations, guidelines, policies, regulatoryauthority/sponsor organisation procedures and additional documents requested from thesponsor (or applicant for trials submitted as part of a marketing authorisation application).Below is a list of the documentation that could be used for review as part of the preparation foran inspection/audit at a clinical investigator’s site. The precise number and nature of documentsto be reviewed prior to an inspection/audit will be decided on a case by case basis and does notneed to include all the items on this list.

1. The protocol and any amendments2. A sample of the CRF and diaries3. A sample of the information sheet/informed consent form (with local translations when

applicable)4. CRF guidelines provided to the research team5. The monitoring manual/plan6. The investigator brochure7. Any study specific documents/manuals8. Contracts/agreements9. Information on the site including whether other departments e.g. pharmacy, clinical

laboratories were used10. Information on any providers such as CROs, central technical facilities which were

subcontracted by the sponsor to carry out specific tasks ( a list of the specific tasks couldbe included)

11. Monitoring reports12. Listings of SAEs13. Trial medication documents such as blinding procedures, certificates of analysis for new

batches of IMP etc.14. Insurance documents15. CVs, qualifications and professional licences of the clinical trial team and training material16. Selected data listings from the clinical study report (for completed trials)

Electronic or paper copies of documents may be requested. A mixture may be preferred:electronic copies of all patient data in sortable excel files for the preparation of the inspectionand paper copies of particular ‘patient profiles’ which are useful for source data verificationprocess for individual subjects at the site.The documents requested should be reviewed carefully in order for the inspectors/auditors to:

Have a good understanding of the protocol and study specific proceduresIdentify any inconsistencies/unusual patternsMake note of any protocol deviationsCheck whether the data are “ too perfect”Make a list of questions to be addressed during the inspection

For audits it is important, in addition to the above, to review the organizational chart and identifythe roles, responsibilities and reporting lines of the relevant personnel. The overall managementof the trial should be reviewed and questions asked about issues such as cover provided duringthe absence of key personnel. In addition, a sample of training records, the training plan, andqualifications, CVs and job descriptions of the relevant personnel should be checked. The systemin place to archive and update these documents should be reviewed.

Inspection/Audit PlanAn inspection/audit plan should be drafted by the lead inspector/auditor and agreed by theinspection team members. The inspection/audit plan should reflect the scope of theinspection/audit and so the extent of detail included will vary. Generally, for routineinspections/audits the inspection plan will follow a standard format. “For cause” inspection/auditplans may require more detail and specificities.

An example of the content of a template inspection/audit plan is given below:

1. Inspection/audit site- name and address of inspection/audit site and principal investigator2. Inspection/audit reference number-include the local reference number3. Place and date of inspection/audit4. Names and affiliation of inspectors/auditors5. Reference documents e.g. Local regulations ( Directive 2001/20/EU and 2005/28/EU for

inspections in the EU), ICH-GCP and other applicable guidelines, sponsor organisation SOPs(for audits)

6. Inspection/audit scope7. Opening meeting with clinical trial team (duration approximately 1 hour)8. Interviews- list names of people to be interviewed and approximate duration9. Visit to facilities- list the facilities to be inspected/audited and approximate duration

10. Review of documentation- list documents to be made available and approximate time ofreview

11. Closing meeting- state the main points to be covered e.g. findings identified and inspectionfollow-up process as well as approximate time and duration

The inspection/audit plan should be followed as much as possible, however both parties shouldbe flexible in adjusting the plan when considered appropriate. It should be sent to theinspectee/auditee in advance of the inspection/audit.

Conduct of GCP Inspection/Audit at the Clinical Investigator SiteAn inspection/audit of an investigational trial site should on average last between two to threedays, but the time taken will depend on the nature of the inspection/audit, the amount of data tobe reviewed, the complexity of the trial and the size of the inspection/audit team.In order to ensure that all aspects of the inspection/audit are covered as originally planned, it isrecommended that an inspection/audit checklist is used which can be filled in as theinspection/audit progresses. The checklist should include a summary of all aspects of theinspection/audit (see below and refer to appendix 1 for an example of an inspection checklisttemplate). Parts of the checklist can be filled in during the preparation of the inspection/auditand focus points can be indicated on the checklist for attention during the inspection/audit.During the inspection/audit the inspectors/auditors may request copies of any of the documents(apart from any which include patient identification data). It is especially important to collectevidence for observed deviations from GCP.

Opening Meeting with the Investigator and Study TeamA meeting of the inspectors/auditors and the inspectees/auditees should take place at the startof the inspection/audit. It should last between 60 and 90 minutes and should cover the followingpoints:

Introduce the inspectors/auditors and the research team membersExplain the legal basis for conducting the inspection/audit and describe its scope andobjectivesProvide an overview of the inspection procedure and briefly introduce the inspection/auditplanGive an opportunity for the inspectee/auditee to ask any questionsConfirm the availability of people/documents/facilitiesAsk the principal investigator to outline his/her responsibilities, to describe staff training, toexplain the conduct of the trial, procedures followed and documentation filed

Refer to Appendix 2 for examples of opening meeting questions.

Interviews with the Study TeamInspectors/auditors should try and interview the staff to whom the principal investigator hasdelegated key responsibilities: e.g. study nurses, sub-investigators, pharmacists. Theseinterviews can take place at any time during the inspection, but should preferably be carried outat the times stated in the inspection plan.

When conducting interviews the inspector/auditor should:

Put the person being interviewed at easeExplain the reason for being interviewedAsk the interviewee to describe his/her role in the trial, to describe his/her tasks, todescribe any problems encountered and if so how they were resolvedAsk the person to clarify/explain any serious issues identified during the inspection/auditUse mostly general, open-ended questions such as who? when? where? how? and avoidclosed (yes/no) questionsThank the interviewee at the end of the interview.

Informed Consent of the Trial SubjectsThe inspectors/auditors should verify the informed consent procedure was carried out accordingto applicable regulations and guidelines by:

Carefully reviewing the information sheets/informed

consent forms (signed and dated by investigator andparticipant) and approved by the REC/IRB at the time ofinclusion of the participantsand cross checking them withthe subject screening/enrolment/identification list/notes inmedical recordsInterviewing the person(s) responsible for obtaining consentfrom the trial participants in order to clearly understand theprocess for obtaining informed consent.

It is important to note here that the inspectors/auditors should check that the informed consentform includes a statement on access to medical records by the authorities /auditors.

Source Data Documents and CRFsInspectors/auditors should carefully review a sample of source data and CRFs during the processof source data verification. Source data verification aims at determining whether the trial hasbeen conducted according to the protocol and whether the data recorded in the CRFs isconsistent with the source documents. In some cases, it may not be possible to performcomplete source data verification on all selected participants. The lead inspector/auditor shoulddetermine the sample of patient data that should be examined, (√n+1) is often used, but forlarge studies, it may not be possible to review all records. A focus on the following aspects isrecommended, when a complete chart of the selected patients cannot be reviewed:

Verification of the existence of the trial participants Adherence to the inclusion and exclusion criteriaAdherence to the protocol schedule of assessmentsVerification of key efficacy and safety data (e.g. alertlaboratory values)Verification of management of concomitant medicationAdverse event reporting (e.g. time lines for reportingSAEs), quality of SAE reports, SAE follow-up reports)Investigational product compliance (administration andreturns)

Verification of source data is a considerable part of the workof monitors, auditors and inspectors. During GCP inspections,it is frequently noted that data are recorded in multiple locations at a site. It is essential todetermine where the original record is documented in order to clearly reconstruct the clinicaltrial. The location of the source data should be described in a source data location list whichshould be generated prior to the initiation of the trial and agreed between the site and thesponsor. The identification list of where source data is documented is primarily intended as atool for monitors, auditors and inspectors in their work of verifying that the trial is performed inkeeping with the ICH GCP guidelines, current legislation and guidelines as well as the trialprotocol.

Source data is documented in electronic and/or paper source documents. Source data may belocated in the following documents for example: medical records, laboratory reports, subjectdiaries, nurses’ notes, dispensing logs, electrocardiogram (ECG) print-outs, CRFs, X-ray images,radiological reports, etc.

If, during the inspection/audit preparation, inspectors/auditors have identified anyinconsistencies, unusual patterns or protocol deviations, this is the point when they should bechecked/confirmed against the available source data.

IMP RecordsThe inspectors/auditors should verify whether the IMP was managed according to the protocoland other study documents. In particular they should review:

Instructions for handling the IMP and trial related materialsThe IMP shipping, receipt, return and destruction recordsIMP accountability recordsDocumentation regarding allocation, randomisation andunblinding (if applicable)The IMP storage and access conditions (temperature logs ifapplicable, thermometer calibration records)The IMP label for compliance with applicable requirements

The inspectors/auditors should check that all the abovedocuments have been signed and dated by the responsible person.

Review of Essential Documentsi. Legal and administrative documentsThe inspectors/auditors should check whether the trial has been notified and approved by theregulatory authorities as required by local regulations and ICH-GCP before the commencementof the trial. They should also check whether protocol amendments and any other reports suchas information about adverse events have been notified and where applicable approved by theregulatory authorities before their implementation. This could often be checked prior to theinspection in the authority’s files.The inspectors/auditors should check that the trial has received approval/favourable opinion bythe REC/IRB before commencing and before implementing any protocol amendments, ifapplicable. They should also check the status of the REC/IRB and whether it functions accordingto GCP and applicable laws and regulations.

ii. Organisation and personnelThe inspectors/auditors should review the following documents in order to understand how theclinical trial team is organised and trained. These documents should normally verify what thetrial staff say during the interviews with the inspectors/auditors (any inconsistencies should beclarified):

Delegation/signature list recording the responsibilities of the trial teamQualifications, experience, CVs of trial personnelTraining documents for the trial team; including study specific and GCP training

iii. Other essential documentsFinally, the inspectors/auditors should review the following essential documents:

Signed and dated protocol, and amendments (if applicable)Contract between the sponsor and the principal investigatorAnnual reports to REC/IRBNormal values for laboratory testsInvestigator brochure(s)Relevant communicationsInsurance statementShipping documents and correspondence for biological samples/specimens sent for testingby external laboratories (if applicable)

Monitoring and AuditingThe inspectors/auditors should evaluate the quality of the monitoring of the trial at the site by,for example:

checking compliance of the monitor with the monitoring planreviewing the monitoring logreviewing the monitoring visit reports (and audit certificates) which have been requestedprior to the inspection/audit

evaluating the ability of the monitor to verify that the site is GCP compliantreviewing escalation and follow-up by the sponsor of issues identified during monitoringvisits

Use of Computerised SystemsThe

validation status of any computerised systems used on site should be examined by theinspectors/auditors. Controlled access to computerised system should also be verified.There are specific requirements for electronic systems used in clinical trials. Theserequirements are described in ICH GCP section 5.5.3.

FacilitiesThe inspection/audit team should ask to begiven a tour of the hospital facilities used, inaccordance with the inspection/audit plan.These will include the hospital departmentwhere the participants’ visits take place, thepharmacy or area where the IMP is stored,the clinical laboratories where patientsamples are analysed (if applicable) and thearchive facilities. Inspectors/auditors shouldcheck that the facilities used are suitable forthe conduct of the clinical trial (e.g. that theequipment used is appropriate, that it hasbeen calibrated and that the applicable SOPshave been followed etc.) and that theprotocol procedures and applicableguidelines are being followed by the relevant staff.

Closing Meeting

The closing meeting takes place at the end of the inspection/audit, and normally lasts between30 and 60 minutes, depending on the number of findings identified and the issues which requirediscussion.

During this meeting, the inspectors/auditors should:

Give an overview of the conduct of theinspection/audit, describing briefly what hasbeen inspected/audited.Present the main findings identified, startingwith the most important and ending with themore minor. In cases when there is a largenumber of findings to discuss, there may notbe time to discuss all the minor findings. Atthis stage, it is not necessary to commit to thefinal number or grading of findings.Inspectors/auditors are able to think over theinspection findings once back in the officewhere they are given the chance to review their notes and all documents collected duringthe inspection. It is also a good opportunity to discuss any inspection findings and theirgrading, with colleagues and line managers.Highlight the positive aspects of the trial that have been identified and praise the researchteam for their effort and hard work, as considered appropriate.Address any issues to be followed-up by the inspectees/auditees, including any additionaldocuments that may need to be sent to the inspectors/auditors.Explain to the inspectees that their responses are expected to include not only corrective,but also preventative actions.Inform the inspectees/auditees of the timelines and procedure for issuing theinspection/audit report, the responses to the findings and the completion of theinspection/audit.

Some inspectees/auditees can get quite offended and thus defensive during the closingmeeting. It is therefore important that the closing meeting is conducted and led by theinspectors/auditors in a friendly and professional manner without the use of aggressivelanguage and negative emotions. Messages should be put across clearly and constructively,emphasising the importance of compliance and explaining the reason for giving a finding, ratherthan pointing out personal faults and misgivings.

Reporting and Follow-up of the GCP Inspection/AuditThe following three sections detail what is required after the audit/inspection at the clinicalinvestigator site is complete, this includes:

ReportingFindingsFollow up

Inspection/Audit ReportFollowing completion of the inspection/audit, the lead inspector/auditor is responsible for writingup the inspection/audit report (IR/AR). This should be reviewed by the inspection team and anyother relevant peers (for example the quality assurance department for an audit report).

The IR/AR should:

be of high qualitybe clear, concise and understandablereflect the conduct of the inspection/audit

evaluate the compliance with local regulations, ICH-GCP, WHO-GCP, ethical andscientific standardsevaluate the validity and reliability of the data recorded according to the scope of theinspection/auditlist observations related to non-compliance with GCP and regulatory requirements andattribute responsibility (with clear references to the relevant legislation for eachdeviation)Contain comments to improve the quality of the trialInclude recommendations for corrective actions and suggestions for improvement(only for audit reports)

For inspection reports, a conclusion could be included at the end of the report stating whetherthe conduct, recording and reporting of the trial is acceptable/non-acceptable according to theprinciples of GCP and applicable regulatory requirements. If the inspection is related to amarketing authorisation or a completed trial, a recommendation should be given on whetherthe quality of the reported data allows its use in a marketing authorisation application.

An inspection/audit template report should be used when writing up a report. An example of thecontent of such a template is given below:

Inspection report template content

1. Administrative information (details of inspected site, date of inspection, names ofinspectors, inspection reference number, product, trial code etc.)

2. References3. Objectives and scope of inspection4. Trial documents5. Conduct of trial6. Documentation and reporting of data7. Accountability of medicinal products8. Laboratories, technical departments9. Monitoring and auditing

10. Summary, discussion and conclusions11. Dates and signatures of lead inspector and other inspector(s)12. Appendices; responses from investigator/sponsor, others as required

Audit report template content

1. Administrative information (details ofthe site that was audited, date ofaudit, names of auditors, trial code,etc)

2. References3. Objectives and scope of audit4. Executive summary5. Relevant background information6. Observations and recommendations7. Date and signature of lead auditor8. Appendices; responses from auditees

Inspection/Audit FindingsAny findings/observations identified during theinspection/audit should be included under the relevantreport section and should:

briefly be described and substantiated by facts

briefly be described and substantiated by factsinclude the relevant regulatory/GCP referencebe classified as critical, major, minor, comments(see below)attribute responsibility (e.g. tosponsor/investigator)

How are findings classified? There are different waysof classifying inspection/audit findings. Here, theclassification system used by the European GCPinspectors is described:

1) Critical: Conditions, practices or processes that adversely affect the rights, safety orwell being of the subjects and/or the quality and integrity of data.Critical observations are considered totally unacceptable.Possible consequences: rejection of data and/or legal action required.Remark: observations classified as critical may include a pattern of deviations classified asmajor, bad quality of the data and/or absence of source documents. Fraud belongs to thisgroup.2) Major: Conditions, practices or processes that might adversely affect the rights,safety or wellbeing of the subjects and/or the quality and integrity of data.Major observations are serious deficiencies and are direct violations of GCP principles.Possible consequences: data may be rejected and/or legal action requiredRemark: observations classified as major may include a pattern of deviations and/ornumerous minor observations.3) Minor: Conditions, practices or processes that would not be expected to adverselyaffect the rights, safety or well being of the subjects and/or the quality and integrity of data.Possible consequences: observations classified as minor indicate the need for improvementof conditions, practices and processes.Remark: many minor observations might indicate a bad quality and the sum might be equalto a major finding with its consequences.4. Comments: The observations might lead to suggestions on how to improve quality orreduce the potential for a deviation to occur in the future.

INS-GCP-4 procedure for reporting of GCP inspections requested by the Committee for MedicinalProducts for Human Use (CHMP) (17 June 2013) European Medicines Agency

Inspection/Audit Follow-upThe inspection/audit report should be sent to the inspectee/auditee within a month of the date ofthe inspection/audit. The inspectee/auditee will have the opportunity to respond to any findings(mainly critical/major) and describe a corrective and preventative actions (CAPA) plan if relevantwithin a set time (usually no more than a month) from receiving the report. It is important thatthe timing and responsibility for any CAPA plan is clearly indicated in the inspectee’s/auditee’sresponses.

The responses should include:

An analysis of the cause of the findingAny corrective actions to rectify the specific non-compliance

Any preventative actions necessary i.e. changes to systems and proceduresThe party responsible for each CAPAAn agreed deadline by which the CAPA will be completed

The inspectors/auditors should review the responses and attach them as an appendix to theinspection/audit report. An evaluation of the responses should be included in the final report,indicating whether or not the CAPA are acceptable and what impact, if any, they have on theoriginal inspection/audit findings.

Where required by applicable law or regulation, the sponsor should provide an audit certificate(ICH-GCP 5.19.3e)The lead inspector/auditor is responsible for tracking any follow-up actions agreed with theinspectees/auditees e.g. follow-up of action plan for audits, scheduling a re-inspection/audit.

Common FindingsA list of common findings identified during inspections/audits is given below. The exampleschosen provide an indication of the kind of detailed review/investigation that should be carriedout during an inspection/audit.

Legal and administrative documents

Contacts with regulatory authority and ethics committee (REC/IRB):

Unclear if the approval covers the relevant clinicChange of investigator not reportedAnnual safety report not submittedEnd of study letter not submittedProtocol amendments not submitted (non-approved version or unsigned version used)

Informed consent procedure

Informed consent has been obtained after the start of the trialThe wrong version has been usedTrial staff have dated the form on behalf of the patientInformed consent has been taken by non-trial staffAmended informed consents have been introduced lateA copy of the ICF has not been given to participant

Conduct of the trial

Deviations from the protocol

- Patients who do not fulfil the eligibility criteria have been included in the trial

- Patient visits are outside the window defined in the protocol

- The sponsor prospectively approves deviations from the protocol

Amendments not handled correctly

- Protocol amendments have been introduced too early or too late

Common Findings (a)Source data

Location of source data unknown

- Location of source data document missing- Double set of source data

Hospital records incomplete

- No record that the patient is participating in a clinical trial- Not all visits have been recorded- Confirmation of subject eligibility by investigator missing

Inconsistencies between source data and data recorded in the CRF

Organisation and personnel

Delegation log incomplete

- Not all staff involved have been mentioned- Delegated tasks have not been specified- The tasks assigned are not in accordance with the actual conduct of the trial

Curriculum vitae incomplete

- Previous experience in clinical trials is not mentioned- Evidence of GCP is missing- Has not been recently updated and signed

Training records are incomplete

- No records of GCP training for the trial staff are available- No study specific training records are available

IMP handling

IMP handling is incorrect

- IMP accountability is incomplete; delivered and returned IMP do not match- IMP inventory is missing

IMP is incorrectly stored

- The IMP storage area is not secure- The temperature log is missing or not followed-up

Breaking of the treatment code can only be done via the sponsor

Common Findings (b)Adverse event reporting

The time lines for reporting SAE have not been complied withThe SAE reports are incomplete e.g. date missingSAE follow-up reports are missing

Essential documents

Essential documents incomplete

- The lists and logs are incomplete- They contain irrelevant information or are missing required information

Organisation and content of the investigator file difficult to assessArchiving facilities not appropriate and retention period not decided

CRF

Not always accurately filled inMany corrections doneNot filled in in a timely manner

Laboratory and good quality control laboratory practice

(Quality assurance of testing and testing procedures is key not only to results during trials butalso to correct enrolment of participants in studies where inclusion criteria rely on certainlaboratory tests. Quality assurance ensures consistent, accurate and traceable test reports andresults)

Inappropriate equipment usedCalibration of equipment incomplete or not doneSOPs on receipt of samples or specimens, calibration, documentation of samples receivedetc. not followed (if available)

Monitoring

Initiation visit missing or too early. Sometimes the investigators’ meeting replaces the siteinitiation visitThe trial is inadequately monitored

- The monitoring plan is not being followed- Identified issues are not being followed up- Obvious mistakes have not been identified- The monitor only conducts source date verification during the visits- The monitoring reports are inadequate and not informative- Not all available documentation is being verified by the monitor

Case StudiesThe following case studies are provided in order to stimulate discussionwithin your inspectorate/company on how to identify findings and decide onhow to grade and reference them. You will notice that the final decision isnot always black and white and opinions will vary. Remember that theimpact and therefore the severity of each issue identified should bediscussed and decided within the actual context of the clinical trial. Don’tforget that your focus should be on verifying the safety and wellbeing of thetrial participants as well as the integrity of the trial data.

Case Study 1The protocol sets as an inclusion criterion ‘Screening of hormone ‘HAPPY’ between 20 and45mg/dl based on an average of at least 2 ‘HAPPY’ readings taken within the screening period(and day of randomisation) with a minimum of 5 days and a maximum of 2 weeks betweenvalues.”

Participant x has an average ‘HAPPY’ value of 46.5mg/dl. The subject is recruited despite thisvalue.

List the number of findings you would give (if any), grade them and indicate the references youwould use.

Case Study 2During the review of the delegation list the inspectors noticed that the principal investigatordelegated all her tasks to sub-investigators whereas the study nurse had been delegated onlythe following tasks: drug dispensing and organisation of patient visits. However, during theinspection, the study nurse explained to the inspectors that she also carried out tasks such asphysical examination of subjects (vital signs), took blood samples, centrifuged the blood samplesand filled in (but never signed) most CRFs apart from the AE/SAE and hospitalization parts.Based on the nurse’s CV found on site the inspectors noticed that the study nurse had noprevious experience in conducting clinical trials. There was no documented evidence showingthat the study nurse or any of the sub-investigators completed the GCP video training providedby the sponsor or any kind of GCP training.

List the number of findings you would give (if any), grade them and indicate the references youwould use.

Case Study 3All MRI scans at the inspected site were sent with full names of the participants to the centralfacility analysing the MRIs. The site staff explained that they had not been asked by the sponsorto send the MRIs without the full names attached. In contrast to this, the sponsor explained that

the site staff were trained during the initiation visit to blind the MRIs before sending them.

List the number of findings you would give (if any), grade them and indicate the references youwould use.

Appendices1. Inspection checklist template2. Opening meeting Topics

References1. ICH Topic E6 Note for Guidance on Good Clinical Practice (ICH-GCP)2. WHO Guidelines for GCP3. INS-GCP-4 Procedure for Reporting of GCP Inspections Requested by the Committee for

Medicinal Products for Human Use (CHMP)

ResourcesDeclaration of HelsinkiDirective 2001/20/ECDirective 2005/28/ECVolume 10: Clinical Trial Guidelines “The Rules Governing MedicinalProducts in the European Community”.

i. Guidance for the Preparation of GCP Inspectionsii. Guidance for the Conduct of GCP Inspectionsiii. Annex I to Guidance for the Conduct of GCP Inspections -Investigator Siteiv. Guidance for the Preparation of Good Clinical Practice InspectionReportsv. Recommendations on the Qualifications of Inspectors VerifyingCompliance in Clinical Trials with the Provisions of Good ClinicalPractice

INS-GCP-2 Procedure for Preparing GCP Inspections Requested by theEMEAINS-GCP-3 Procedure for Conducting GCP Inspections Requested by theEMEAAnnex I to Procedure for Conducting GCP Inspections Requested by the EMEA: InvestigatorSite

INS-GCP-4 Procedure for Reporting of GCP Inspections Requested by the Committee forMedicinal Products for Human Use (CHMP)

Quiz

Summary1. A GCP audit is a systematic and independent examination of trial related activities and

documents to determine whether the evaluated trial related activities were conducted andthe data recorded, analysed and accurately reported according to the protocol, GCP andthe applicable regulatory requirements. The sponsor’s standard operating procedures(SOPs) are not taken into account.

True False

2. What is the purpose of compliance with GCP?(Please select all that apply)

It provides public assurance that the rights, safety and wellbeing of trial subjectsare protected

It provides public assurance that the data collected during the clinical trial arecredible

It provides public assurance that clinical trials will always result in the discovery ofnew therapies

It provides public assurance that the applicable laws and regulations are compliedwith

3. Which of the following is not one of the 13 principles of GCP? Clinical trials should be conducted in accordance with the ethical principles that

have their origin in the Declaration of Helsinki, and that are consistent with GCP andthe applicable regulatory requirement(s)

Each individual involved in conducting a trial should be qualified by education,training, and experience to perform his or her respective task(s)

Freely given informed consent should be obtained from every subject prior toclinical trial participation, unless decided otherwise by the investigator responsible forthe clinical trial

Clinical trials should be scientifically sound, and described in a clear, detailedprotocol.

4. Competent authorities are responsible for preparing national inspection programmes withthe scope to establish:(Please select all that apply)

The quality assessment of clinical trials submitted as part of a marketingauthorisation application (MAA)

A list of GCP compliant clinical investigator sites The routine surveillance of national clinical trials None of the above

5. ‘ For cause’ audits are only conducted on on-going clinical trials. True False

6. For which of the following is the lead inspector not responsible? Photocopying the documents requested for during the inspection Organising the practicalities of the inspection/audit and communicating them to the

inspectee/auditee Preparing the inspection plan Writing and signing the inspection report

7. It is important that before the inspection/audit, the inspection/audit team have carefullyread and understood the clinical trial protocol and any amendments.

True False

8. During an inspection/audit opening meeting:(Please select all that apply)

The inspectors/auditors and the research team members should introducethemselves

The scope and objectives of the inspection/audit should be clearly explained butthe inspectees/auditees should not be permitted to ask questions

An overview of the inspection/audit procedure should be provided and theinspection/audit plan should be briefly introduced explaining that no adjustments canbe made to it after this meeting

The inspectors should try to ask ‘open questions’ rather than ‘closed questions’9. The inspectors should check:

(Please select all that apply) The IMP price The IMP storage conditions The IMP access conditions None of the above

10. It is not the job of an inspector/auditor to check the validation status of computerisedsystems used on site. This is the job of IT experts:

True False

11. The lead inspector/auditor should determine the sample of data that should be examinedduring the inspection/audit following consideration of the following issues:

Verification of the existence of the trial subjects and adherence to the inclusion andexclusion criteria

Adherence to protocol visits Verification of key efficacy and safety data All of the above

12. Which of the following is incorrect: The closing meeting should last as long as it takes for the inspectors/auditors to

describe all findings in detail and discuss at length their classification The inspectees/auditees should be informed of the timelines and procedure for

issuing the inspection/audit report The inspection/audit team should ask to be given a tour of the hospital facilities

used, in accordance with the inspection/audit plan Controlled access to computerised system should also be verified during an

inspection/audit13. Inspectors/auditors are not allowed to ask for any documents to be copied during an

inspection/audit for them to take away. This is to ensure patient confidentiality. True False

14. The inspection report/audit report should: Evaluate compliance with local regulations only Evaluate the validity and reliability of the data recorded according to the scope of

the inspection/audit Evaluate compliance with ICH-GCP and other international ethical and scientific

standards only15. Inspection/audit reports should not contain comments to improve the quality of the trial.

True False

16. The findings described in an inspection/audit report should: not be classified briefly be described and substantiated by facts never include the relevant regulatory/GCP reference attribute responsibility to a specific person

17. Findings classified as ‘Major’ include: Conditions, practices or processes that adversely affect the rights, safety or

wellbeing of the subjects and/or the quality and integrity of data Conditions, practices or processes that might adversely affect the rights, safety or

wellbeing of the subjects and/or the quality and integrity of data Conditions, practices or processes that would not be expected to adversely affect

the rights, safety or wellbeing of the subjects and/or the quality and integrity of data18. The following finding was reported: ‘The trial related documents were stored in the

investigator’s offices in unlocked cupboards. Even though the offices are locked at night,study related documents should be protected from inappropriate access ’. Which of thereferences listed below is the most appropriate?

ICH-GCP 4.9.4 ICH-GCP 2.10 ICH-GCP 4.9.5 ICH-GCP 5.1.3

19. The following finding was reported: ‘The protocol stated that in case of an emergency, thetreatment code could be broken after communication with the assigned monitor. In anemergency situation this could be very time consuming. The investigator should be the onlyperson to decide if the treatment code needs to be broken’. Who should be attributedresponsibility?

The investigator The sponsor Both the sponsor and the investigator Neither the sponsor nor the investigator

20. A CAPA plan:(Please select all that apply)

Should be written by the principal investigator and not the sponsor Includes any corrective actions to rectify the specific non-compliance and any

preventative actions necessary Should be reviewed by the supporting inspector(s) before passing on to the lead

inspector Should be completed within 2-3 weeks Should be followed by the inspectee/auditee in line with timelines agreed with the

inspectors

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