Clinical Trial Monitoring Standard Operating Procedure.docx

8/13/2019 Clinical Trial Monitoring Standard Operating Procedure.docx

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Clinical Trial Monitoring Standard Operating Procedure

Version1.0

Effective From01 July 2013

Review Date01 July 2016

OwnerEpsilon Clinical Research Private Limited

Prepared By

Approved by


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Table of Contents

Sl No Title Page Number

1 Glossary 3

2 Objective 5

3 Background 5

4 Process 5

5 Reference 10

6 Study Site Monitoring Visit Checklist 11


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Glossary

Adverse Event (AE): Any untoward medical occurrence in a subject to whom a medical product

has been administered, including occurrences which are not necessarily caused by or related to

that product.

Case Report Form (CRF): A printed, optical, or electronic document designed to record all of the

protocol required information to be reported to the sponsor on each trial subject.

Clinical Trial: Any investigation in human subjects, other than a non-interventional trial

intended to discover or verify the clinical, pharmacological or other pharmacodynamic effects

of one or more medical products or to identify any adverse reactions to one or more such

products and to study absorption distribution, metabolism, and excretion in one or more such

products with objective of ascertaining the safety or efficacy or those products.

Clinical Research Associates (CRAs): Part of quality team who ensure compliance with GCP,

other regulatory requirements, protocol, and SOPs, by monitoring clinical trial.

Informed Consent Form (ICF): The document which is signed by the participant/legal

representative as well as the person who conducted the informed consent discussion

confirming the volunteers willingness to participate in the particular trial after having been

informed of all aspects of the trial that are relevant to their decision.

Investigator Site File (ISF): A standard filing system which allows the effective storage and

location of essential documents related to an individual trial site.

Investigational Medicinal Products (IMP): A pharmaceutical form of an active substance or

placebo being tested, or used as a reference in a clinical trial. This includes a medicinal product

which has a marketing authorization but is, for purpose of the trial


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(a) Used or assembled (formulated or packaged) in a way different from the form of the

product authorized under the authorization.

(b)Used for a indication not included in the summary of product characteristics under the

authorization for that product, or

(c) Used to gain further information about the form of that product as authorized under theauthorization.

Standard Operating Procedure (SOP): Detailed, written instructions to achieve uniformity of

performance of a specific function. SOPs are the base on which Quality System and Processes

are conducted and monitored against.

Quality Team: Comprises the Manager, Clinical Research Associates (CRAs), and trainingexecutives.

Monitoring Plan: A document detailing how all the monitoring activities for the trial will

carried out based upon the trial risk assessment.

Monitoring Visit Report (MVR): A report written by CRA to the sponsor (or representative)

after each site visit.

Principal Investigator (PI): A registered physician, who has the responsibility for conduct of the

trial at the site.

Trial Master File (TMF): A standard filing system which allows the effective storage and location

of essential documents. The filing system can be in the form of a single project file or a number

of files, depending on what are deemed most appropriate for a particular clinical trial given its

size and complexity. The regulatory documents and approvals within the TMF will be

maintained alongside case report forms and source documentation.


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1 Objectives

The objective of this SOP is to establish quality standards for the preparation, conduct and follow-up of

monitoring visits during a clinical trial.

Monitoring is defined as the act of overseeing the progress of clinical trial and of ensuring that it is

conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and the applicable

regulatory requirements.

The purpose of monitoring is to verify that

The rights and well beings of the 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/amendments,

GCP and the applicable regulatory requirements.

Monitoring has an integral role in the QC of the clinical trial and is designed to verify the ongoing quality

of the study.

2 Background

In accordance with the Good Clinical Practice Guideline ICH-GCP E6 (Sections 5.1 and 5.18), continuous

monitoring is an indispensable instrument in the quality assurance of a clinical trial.

Regular visits to the trial site, as well as telephone and written contact with the trial staff at the site are

conducted to ensure that: the trial is conducted in accordance with the trial protocol and GCP and above

all, the safety and rights of the trial subjects are verified. Problems at a trial site can be recognised at an

early stage and solved. Monitoring will be conducted by CRA team and overseen by Manager or

delegate.

3 Process

The quality team can assume responsibilities on behalf of the sponsor/CRO for the clinical trail activities

provided this is agreed in advance. (e.g. by contract or authorisation)

3.1 Determination of Time of Visit

Dates and frequency of visits depend on the trial and site (e.g. depending on the recruitment rate, data

quality) or is determined by contractual agreements, the protocol or definitions in the monitoring

manual from sponsor/CRO.

It is recommendable to perform the first monitoring visit after initiation of the trial site as early aspossible, usually after enrolment and documentation of the first subject. This enables identification of

site-specific problems with trial conduct at an early stage and avoids errors.

3.2 Preparation

The following points should be covered when making an appointment:


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At least one person from the trial site involved in the conduct of the trial, who is qualified to make

changes or additions to the CRF, must be present.

Time required for pure monitoring activities/for discussions with the investigator/site staff

Current status of site (enrolled/withdrawn/completed subjects) and site-specific problems Trial materials required, including trial medication

Documents that the site should provide

The appointment should be confirmed in writing with the trial site, and if appropriate, for a second time

shortly before the planned visit.

The monitor should familiarise himself or herself with the content of the following documents to

prepare for special situations or requirements at the site:

Monitoring report of the previous visit

Any follow-up correspondence, deficiency lists from previous visit

Correspondence since the last visit

Reports on serious adverse events requiring follow-up or which have to be reported at definedintervals to the ethics committee or competent higher federal authority.

Status of documents (CRF, queries).

All documents and materials to be given to the investigator are put together.

3.3 Conduct

3.3.1 General Activities

Based on the study site monitoring visit checklist (see Appendix 1), the following points are to be revised

during the monitoring visit:

CRA/delegate will ensure that investigator provides all required reports, notifications, applications

and submissions and that these documents are accurate, complete, timely, legible, dated and

identify the trial

The ISF/TMF including all essential documents

Investigator and other team members have adequate qualifications, resources and facilities,

including laboratories, equipment and staff and these remain adequate throughout the study

period.

All trail functions are performed as designated and not delegated to unauthorised individuals. Informed consent was obtained and documented prior to subject participation in the trial.

Inclusion/Exclusion criteria

Documentation of subject status

CRFs (review and CRF status)

Protocol compliance

Staff changes


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Documentation of adverse events and serious adverse events as well as reporting of these in

accordance with regulations

Documentation of source data

Trial medication (if applicable)

Logistics of laboratory samples (if applicable)

Documentation of trial site status Investigator site file

Status of pending points of previous monitoring visits

Documentation of protocol deviations

Adverse events, concomitant medications and concurrent illness are reported in accordance with

protocol.

All SAEs are appropriately reported within the time period required by GCP, protocol and other

applicable regulatory requirements.

All withdrawals and dropouts of enrolled subjects from the trial are reported and explained

properly.

3.3.2 Source Data Verification

CRF entries to source documents such as medical records, laboratory reports, ECGs, patient diaries, etc

will be monitored by monitor. The monitor checks that all relevant source data have been properly

transcribed to the CRF.

3.3.3 Data Corrections

If the monitor finds errors in the CRF entries or source data that require correction, additions or

deletions, these must be clarified with the investigator or an authorised delegate at the trial site.

The monitor is responsible for instructing the investigator or delegates in the correct way ofperforming corrections according to GCP.

Entries/corrections on the CRF may only be made by the investigator or an authorised staff member

at the trial site. The authorisation must be documented (authorized signatory log)

A single line must be drawn through the original entry (must still be legible)

The correct entry is written next to it

The correction/addition must be initialled and dated by the investigator or the authorised member

of the trial site staff

If the reason for the correction is not obvious based on the documentation available, a reason must

be given by investigator or trial site staff.

3.3.4 Queries

Unclear entries detected by data management are queried. These queries can be listed and taken to the

regular monitoring visits, sent by post/fax to the trial site or marked in the e-CRF, respectively. Monitors

must have a list of open queries for each trial site.


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Queries must be answered in writing by the investigator or an authorised staff member (authorized

signatory log).

3.3.5 Drug Accountability

In order to ensure the correct handling of medication during clinical trials and to supervise the

whereabouts of the trial medication, the monitor verifies the correctness and integrity of the data in the

ISF provided by the trial site and/or pharmacy. Reception and return of trial medication by the trial site

must be confirmed in writing by the investigator or an authorised person (e.g. pharmacist). This must be

checked by the monitor. CRA will also check storage conditions are acceptable and supplies are

sufficient.

3.3.6 Notification of serious breach

Minor deviations from clinical trial protocols and GCP occur commonly in clinical trials. The majority of

these instances are technical deviations that do not result in harm to the trial subjects or significantly

affect the scientific value of the reported results of the trial. These cases should be documented e.g. in

the case report form for the trial or trial master file, in order for appropriate corrective and preventative

actions to be taken. In addition, these deviations should be included and considered when the clinical

study report is produced, as they may have an impact on the analysis of the data. However, not every

deviation from the protocol needs to be reported as a serious breach.

What needs to be reported?

Any serious breach of:

(a) the conditions and principles of good clinical practice in connection with that trial or

(b) the protocol relating to that trial.

For the purposes of this regulation, a serious breach is a breach which is likely to effect to a

significant degree:

(a) the safety or physical or mental integrity of the subjects of the trial or

(b) the scientific value of the trial.

The judgment on whether a breach is likely to have a significant impact on the scientific value of the trial

depends on a variety of factors e.g. the design of the trial, the type and extent of the data affected by

the breach, the overall contribution of the data to key analysis parameters, the impact of excluding the

data from the analysis etc.


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3.3.6.1 Examples illustrating breaches classified as serious

1. A breach of GCP or the protocol leading to the death, hospitalization or permanent disability of a

trial subject. Please note, not every serious adverse event (SAE) or suspected unexpected serious

adverse reaction (SUSAR) would routinely be classified as a serious breach, but SAEs/SUSARs

resulting from a breach of the conditions and principles of GCP or a breach of the protocol may

constitute a serious breach.

2. Proof of fraud relating to clinical trial records or data, if the fraud is likely to have a significant

impact on the integrity of trial subjects or the scientific value of the data.

3. Persistent or systematic non-compliance with GCP or the protocol that has a significant impact on

the integrity of trial subjects or on the scientific value of the trial. For example, widespread and

uncontrolled use of protocol waivers affecting eligibility criteria, which leads to harm to trial

subjects or which has a significant impact on the scientific value of the trial. Another example wouldbe of an investigator repeatedly failing to reduce or stop the dose of an IMP in response to a trigger

(e.g. abnormal laboratory results) defined in the protocol.

4. Failure to follow protocol specific instructions about investigational medicinal product(s) such that

trial subjects are put at significant risk or the scientific value of the trial is compromised.

5. Failure to report adverse events, serious adverse events or SUSARs in accordance with the

regulatory requirements.

3.3.7 Documentation of the Monitoring Visit

A detailed monitoring report should be prepared shortly after every visit to document the status at the

site at the time of the monitoring visit (subject status, informed consent forms, protocol deviations,

problems/difficulties, open questions, trial materials needed etc.), and the activities of the monitor at

the trial site.

Review and approval of monitoring reports is done by the person responsible designated for each

clinical trial. To ensure that any necessary measures are taken, the report must be given to the person

responsible for the trial. In critical cases, findings of a monitoring visit must be passed on to the personresponsible before finalising the monitoring report.

The Investigator will be informed in writing of any problem(s) that were identified during the monitoring

visit. If there is evidence of systematic failure to comply with GCP retraining will be given and

management informed


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The monitoring reports should reflect the course of the clinical trial and, as original documents, must be

archived in the Trial Master File (TMF).

Any deficiencies recorded in the monitoring report, future strategies for avoidance, problems and their

solutions, and any outstanding points to be dealt with at the trial site within a defined period of time

should be set out in a follow-up letter to the trial site shortly after the monitoring visit.

3.3.8 Status Updates between Monitoring Visits

Depending on the agreement, the status at the trial site should be regularly inquired by telephone and

updated in writing. At the minimum, the following points should be discussed by telephone:

Subject status

Serious adverse events

Changes in staff (changes in responsibilities)

Problems/ questions/difficulties

Telephone calls should be documented.

4 References

WHO Operational Guidelines for Ethical Review Committee that Review Biomedical Research(Geneva

2000). Retrieved from -www.who.int/tdr/publications/publications /

International Conference on Harmonization, Guidance on Good Clinical Practice (ICH GCP) (1996).

Retrieved from -http://www.ich.org/LOB/media/MEDIA482.pdf

ICMR Ethical Guidelines for Biomedical research on Human Participants, ICMR (2006), Retrieved from -

http://www.icmr.nic.in/ethical guidelines.pdf

Schedule Y (Drugs and Cosmetic Act 1940 Retrieved from - http://cdsco.nic.in/html/schedule-

y%20%28amended%20version-2005%29%20original.htm
http://www.who.int/tdr/publications/publications%20/http://www.who.int/tdr/publications/publications%20/http://www.who.int/tdr/publications/publications%20/http://www.ich.org/LOB/media/MEDIA482.pdfhttp://www.ich.org/LOB/media/MEDIA482.pdfhttp://www.ich.org/LOB/media/MEDIA482.pdfhttp://www.icmr.nic.in/ethical%20guidelines.pdfhttp://www.icmr.nic.in/ethical%20guidelines.pdfhttp://cdsco.nic.in/html/schedule-y%20%28amended%20version-2005%29%20original.htmhttp://cdsco.nic.in/html/schedule-y%20%28amended%20version-2005%29%20original.htmhttp://cdsco.nic.in/html/schedule-y%20%28amended%20version-2005%29%20original.htmhttp://cdsco.nic.in/html/schedule-y%20%28amended%20version-2005%29%20original.htmhttp://cdsco.nic.in/html/schedule-y%20%28amended%20version-2005%29%20original.htmhttp://www.icmr.nic.in/ethical%20guidelines.pdfhttp://www.ich.org/LOB/media/MEDIA482.pdfhttp://www.who.int/tdr/publications/publications%20/


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Study Site Monitoring Visit Checklist

Study Details

Study Title:

Investigator Name:

Site:

Sponsor:

Protocol Number:

Visit Summary

Date of Visit(s):

Report Produced on:

Follow-up Correspondence Sent:

Study Site Staff Present:

Monitoring Team Present:

Patient Recruitment Status

Planned Confirmed

Entered Screening:Dropped Screening:Entered Treatment:

Dropped Treatment due to Adverse Events:

Dropped Treatment due to Other:Completed Treatment:

Entered Follow-up:Dropped Follow-up:

Completed Follow-up:


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YES NO NA*

1. DETAILS OF CURRENT VERSIONS OF STUDYDOCUMENTATION

Protocol:ICF:

2. STUDY FILE2.1. Are all required documents filed in the Trial Master File (TMF) / Investigator

Study File (ISF) and available for review including updated regulatorydocuments?

Comments:

2.2. Does the Investigator maintain logs of screened and enrolled subjectsincluding identification code list?

Comments:

3. FACILITIES / STUDY SITE STAFF3.1. Have all study staff been documented in the Delegation of Duties &

Authorised Signatures Form and up to date signed and dated curriculumvitae filed?

Comments:

3.2. Have all study staff had up to date GCP and all other applicable trainingcertificates?

Comments:

4. GCP, ETHICAL & REGULATORY REQUIREMENTS4.1. Are all Ethics approvals in place for the study?

Comments:

4.2. Have annual safety update report and any other required documents beenprovided by the Investigator/Sponsor to the EC appropriate?

Comments:

5. PROTOCOL ADHERENCE

5.1. Have there been any significant deviation(s) from the final version of theprotocol and Protocol Amendment(s) (if any)?

Comments:

5.2. Is the enrolment/recruitment rate acceptable in accordance with study planand timelines?

Comments:

5.3. Has/have there been any subject (s) lost to follow-up (according to theProtocol) since the last monitoring visit report?

Comments:

5.4. Has there been any subject discontinued from treatment phase or from theclinical study (include details of any discontinuation for non-seriousadverse events)?

Comments:

6. Patient Consent and Source Data Verification6.1. Is the Informed Consent Form (including any pharmaco-genomic ICF) or

Amended Informed Consent Form (if any) properly obtained anddocumented?

Comments:

6.2. Is there appropriate source documentation of each subjectsconsent andparticipation in the clinical study?

Comments:

6.3. Were all CRFs consistent with source documents ?


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YES NO NA*

Comments:

6.4. Is the study site maintaining an acceptable rate of CRF completion andquery resolution?

Comments:

6.5. Were all corrections and clarifications discussed with and obtained from

Investigator / designate?Comments:

7. PHARMACOVIGILANCE7.1. Have there been any new Serious Adverse Event / SUSAR (s) since the

last monitoring visit report?

Comments:

7.2. Have all Serious Adverse Events been appropriately reported to theSponsor and followed up?

Comments:

8. LABORATORY + DIAGNOSTIC SAMPLES8.1. Are the labelling, storage and shipment of laboratory specimens/diagnostic

material adequate?

Comments :

9. INVESTIGATIONAL MEDICINAL PRODUCT (IMP)9.1. Are all IMPs correctly stored and dispensed in accordance with

Investigator Brochure?

Comments:

9.2. Are all IMPs correctly stored and dispensed in accordance with theprotocol requirements (including randomisation schedule/IVRSprocedures)?

Comments:

9.3. Are the IMP accountability performed and documented?

Comments:

9.4. Do the expiry dates of IMPs remain compatible with the study duration?

Comments:

9.5. Are there sufficient IMP supplies available for continuation of the study?Comments:

9.6. Has the blind been maintained?

Comments:

10. ACTION TO BE TAKEN / FOLLOW-UP10.1. Are there any action(s) required and/or any follow-up needed (provide

details below)?

Comments:

10.2. Has follow-up of all previous action points been documented andappropriately filed?

Comments:*NA : Not Applicable / Not done

Issues:

Documents Collected/Copied:


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Form completed by:

Function:

Date:

dd-mmm-yy

Reviewed by:

Function:

Date:

dd-mmm-yy

Signature:

Signature:

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