GUIDELINES FOR GOOD PRACTICE IN THE CONDUCT OF CLINICAL TRIALS IN HUMAN PARTICIPANTS IN SOUTH AFRICA

5. Quality Assurance - C0ntents

5.1 The Monitor

5.1.1 Responsibilities of the Monitor
5.1.2 Prior to the Commencement of the Trial
5.1.3 Contacts with the Principal Investigator
5.1.4 Contacts with Staff
5.1.5 During the Course of the Study
5.1.6 After Completion of the Study

5.2 Audit

5.2.1 Purpose
5.2.2 Selection and Qualifications
5.2.3 Auditing Procedures
5.2.4 Non-compliance
5.2.5 Premature Termination or Suspension of a Trial
5.2.6 Clinical Trial/ Study Reports

5.3 Inspections

  1. QUALITY ASSURANCE

Quality assurance has been defined as, "All those actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with these guidelines … and the applicable regulatory requirements."12 Quality assurance of clinical trials in South Africa is achieved at a number of levels, through monitoring, audits and inspections.

5.1 THE MONITOR

The monitor is appointed by the sponsor and is an important communication link between the sponsor and the investigator(s).

5.1.1 Responsibilities of the Monitor

The main responsibility of the monitor is to oversee and report on the progress of a study. The monitor should follow standard operating procedures (SOPs) to ensure that a study is conducted and reported in accordance with the protocol, SOPs, and appropriate legislation.

The monitor should ideally have adequate medical, pharmaceutical and/or scientific qualifications. Acceptable qualifications for a monitor depend upon the type of study and the investigational product. The monitor should be fully cognisant of the product under investigation, clinical research procedures and the requirements of the protocol and related documents.

A written record should be kept of the monitor’s visits, telephone calls and letters to the investigator.

The monitor or other contact person, appointed by the sponsor and known to the investigator and co-investigator, should be available at any time for consultation or reporting of serious adverse events.

5.1.2 Prior to Commencing the Study

Prior to the start of the study the monitor should visit the principal investigator to verify that the site, staff and facilities for the study comply with the requirements of the protocol and sponsor SOPs. The monitor may be accompanied by the sponsor’s staff during this visit.

Laboratories participating in the study should be checked by the monitor to ensure that they are accredited by an appropriate accreditation organisation and that they have adequate quality assurance.

5.1.3 Contacts with the principal investigator and co-investigator(s)

The monitor should ascertain:

  • the qualifications of the principal and co-investigator(s), i.e. written curriculum vitae;
  • the principal and co-investigator’s understanding of the data on the investigational product, including pharmaceutical, pre-clinical and if appropriate, clinical data (investigator’s brochure);
  • the investigator(s) awareness of their obligations in undertaking the study;
  • that the investigator(s) agree to conduct the clinical study in accordance with the protocol, Declaration of Helsinki, SOPs, relevant legislation and good clinical research practice;
  • that the investigator(s) will accept the relevant controls, including data verification procedures, audit and/or inspection;
  • that each investigator has the means necessary to carry out the study safely with regard to factors such as availability of participants for recruitment, facilities, medical, paramedical staff and clerical support; and
  • the compatibility of the proposed study with the principal and co-investigator's research and other commitments.

The monitor should also:

  • inform each principal investigator of the names of the other principal investigators working on the same protocol in South Africa and other principal investigator(s) overseas;
  • check that storage, dispensing and documentation of the supply of investigational product(s) is safe and appropriate and in accordance with local regulations and SOPs;
  • explain the treatment code and the procedures for breaking of the code, under conditions described in the protocol and how to reach the appropriate person(s) in an emergency;
  • ascertain the membership of the ethics committee and check that it is approved by the National Health Research Ethics Council;
  • confirm that the regulatory requirements, ethics committee review procedures and informed consent procedures are followed and recorded;
  • inform the investigator(s) of the established requirements concerning the retention of records and retrieval of data (see also section 9);
  • discuss in detail the protocol and protocol related documents prior to obtaining the principal investigator’s signed approval;
  • check the descriptions of the methods, normal and reference values for the tests to be performed during the study;
  • provide the principal investigator with written information suitable for developing the patient information package;
  • obtain a copy of the relevant approval(s) from the local ethics committee and, where applicable, clinical institution prior to study commencement;
  • obtain a copy of relevant approval from the regulatory authority; and
  • obtain a copy of the study number issued by the National Department of Health.
5.1.4 Contacts with staff

The monitor should check that all staff involved in the study are informed about its scope and procedures by:

  • obtaining a signed and dated list of names of the staff directly involved in the study and a description of the functions of each person in the study;
  • making contact with the senior doctor or head of department/centre who is responsible for research and receive assurance that the study is compatible with the work at the study site from both medical and administrative points of view; and
  • discussing, preferably at a single meeting, the study protocol and the conduct of the study with the staff involved and their superiors e.g. medically responsible senior doctor or head of department/centre.

Immediately prior to the proposed starting date it is advisable for the monitor to visit the study site to ensure the investigator has all the required materials, e.g. CRFs, investigational product supplies, consent forms and information leaflets.

5.1.5 During the Course of the Study

The monitor should maintain personal contact with the principal investigator by visiting the study site regularly and, if necessary, assemble and meet with the participating staff. The frequency of these visits will depend on the SOPs, the number of participants involved and the nature of the study.

The monitor should ensure:

  • that each investigator has access to a mechanism to identify the treatment of a particular participant;
  • that informed consent for each participant has been obtained prior to commencement of any protocol required activity for that participant;
  • that all investigational products are used according to the conditions in the protocol;
  • that participant compliance is properly documented;
  • that the investigator retains all necessary study documentation;
  • that source data are available, to ascertain the existence of the participant and enable information recorded in the CRFs, e.g. biological results, radiographs, to be verified where possible. The source data should also be checked for correct labelling, dating, signatures, etc. (Source data may be the original or a signed and verified copy, as agreed with the sponsor). Access to source data must take place within the requirements of the privacy legislation and is dependant on the express informed consent of the participant which may be collected at the time of original enrolment into the study ;
  • that any changes to the CRFs are properly documented, signed and dated;
  • that any problems which arise in the course of the study, or may be foreseen, are discussed; and
  • that the investigational product(s) are managed in accordance with Section 4 and that full dispensing or distribution records of the investigational product(s) are maintained.

The monitor must make every effort to maintain confidentiality of information about the participant, including the participant's identity when checking documentation. The monitor should ensure that all information relating to an individual participant is collected and stored by the investigator in compliance with the privacy legislation.

Completed and signed CRFs should be collected during the course of the study or immediately upon their completion or in the event of premature termination of a study.

The monitoring visit should normally include an evaluation of:

  • the progress of the study, determination of recruitment status, number of withdrawals and adverse events;
  • the activities of the principal investigator and his or her staff and the continuing ability of the centre to participate in the study;
  • adherence to the protocol and related documents. In particular the monitor should make an effort to obtain maximum information on any missing or unclear data;
  • the conformity of the data presented in the CRFs with source data;
  • the essential documents to ensure that they are being correctly filled in and stored in compliance with the protocol;
  • monitoring (including observation where appropriate) of the informed consent procedure.

The monitor should check that a report is prepared regularly to fulfil the reporting requirements of the sponsor, ethics committees and regulatory authority.

The monitor should inform and discuss with the principal investigator and co-investigators the possible effects on the safety or ethics of the study of any new data relating to the investigational product(s). All proposed protocol amendments must have the agreement of both the principal investigator and sponsor, and any information which is felt to have a significant effect on the safety or the ethics relating to the study should be presented to the relevant accredited ethics committee by the investigator.

A separate report for the sponsor, the ethics committee and the regulatory authority should be written by the monitor after completion of each visit for each study and each site. This report should be written in accordance with a standard operating procedure and should accurately reflect the discussions with the relevant investigator/personnel stating the findings, conclusions/corrections and actions taken.

5.1.6 After Completion of the Study

When a study is completed the monitor should ensure:

  • that complete documentation of all clinical and laboratory investigations is available in the CRFs;
  • that all CRFs are collected and placed for safe keeping in accordance with regulatory requirements, privacy legislation and the sponsor's operating procedures;
  • that the principal investigator has notified the study participants, ethics committees and, if required, regulatory authorities that the study has been completed;
  • that treatment codes are collected, recording all cases where the treatment code has been broken and the reasons for doing so;
  • that the principal investigator is aware of the archiving requirements for source data and primary records;
  • that the standard operating procedure for unused supplies of the investigational product(s) is followed, i.e. unused supplies are collected or destroyed; that an appropriate record is kept in collaboration with the pharmacist or person designated as responsible for handling the investigational product(s); and
  • that the study information is collated and sent to the reporting centre for multi-national studies.
5.2. AUDIT

If or when sponsors perform audits, as part of implementing quality assurance, they should consider:

5.2.1 Purpose

The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, GPP, Good Laboratory Practices (GLP - where appropriate) and the applicable regulatory requirements.

5.2.2 Selection and Qualifications

The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.

The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.

5.2.3 Auditing Procedures

The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.

The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of participants in the trial, the type and complexity of the trial, the level of risks to the trial participants, and any identified problem(s).

The observations and findings of the auditor(s) should be documented and accessible to the ethics committee and / or the regulatory authority.

The person responsible for auditing must submit a report to the regulatory authority(ies) when evidence of GCP non-compliance exists, or in the course of legal proceedings.

When required by applicable law or regulation, the sponsor should provide an audit certificate.

5.2.4 Non-compliance

Noncompliance with the protocol, SOPs, GCP, GLP, GPP and/or applicable regulatory requirement(s) by an investigator, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.

If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator, the sponsor should terminate the investigator's participation in the trial. When an investigator's participation is terminated because of noncompliance, the sponsor should promptly notify the regulatory authority(ies).

5.2.5 Premature Termination or Suspension of a Trial

If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The ethics committee should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator, as specified by the applicable regulatory requirement(s).

5.2.6 Clinical Trial/Study Reports

Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s).

5.3. INSPECTIONS (Appendix C)

As prescribed by regulations of the MCC (Medicines and Related Substances Act, 1965), the regulatory authority may inspect the conduct of a clinical trial by on-site visits. Inspections are reserved to situations where there is a reason to believe the competency of the clinical trial site needs review, or there is some evidence of GCP non-compliance. Inspectors have the power to conduct both announced and unannounced inspections.

Such an inspection should consist of a comparison of the procedures and practices of the clinical investigator with the commitments set out in the protocol and reports submitted to the regulatory authority by the investigator or the sponsor.

Inspections may be carried out randomly, and /or for specific reasons. MCC inspectors should be given easy access to the trial sites and laboratories at all times, announced or unannounced.

The inspection should determine whether the investigator has custody of the required records or, if not, who has assumed this responsibility. The archives should be tested for retrieval.

Inspections may include a data audit. The regulatory authority should have easy access to all patient files and raw data utilised for and generated during the trial.

All site data and documents must be available for verification. All observations and findings should be verifiable in order to ensure the credibility of data and to assure that the conclusions presented are derived correctly from the raw data. Verification processes must, therefore, be specified and justified.

Sponsor and investigational sites, facilities and laboratories, and all data (including source data) and documentation and reports concerning the data including subject files must be available for inspection by the regulatory authority.

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Footnotes

[12] MRC Guidelines for Good Clinical Practice in Clinical Trials, 1998, 20 Park Crescent, London, W1N 4AL, United Kingdom

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