GUIDELINES FOR GOOD PRACTICE IN THE CONDUCT OF CLINICAL TRIALS IN HUMAN PARTICIPANTS IN SOUTH AFRICA
3. Responsibility of the Principal Investigator & Participating Investigators - Contents
3.1 Competencies & Responsibilities of the Principal Investigator
3.2 Qualifications and Availability
3.3 Adequate Resources
3.4 Medical Care of Trial Participants
3.5 Informed Consent
3.6 Investigational Products
3.7 Compliance with Protocol
3.8 Monitoring and Auditing
3.9 Change of Principal Investigator
3.10 Data Management
3.11 Safety Issues
3.12 Reporting of Serious Adverse Events
3.13 Premature Termination – Breaking the Treatment Code
3.14 Progress Reports
3.15 Trial Outcome
In most cases, clinical trials are conducted by a principal investigator (usually, but not limited to, a medical doctor with appropriate qualifications to undertake the study) who has entered an agreement with a sponsor to conduct a clinical trial. She/he is the person responsible for the conduct of the clinical trial at the trial site/s. Clinical trials, including multicentre studies, must be undertaken by local PI resident in South Africa.
A clinical trial can however be conducted with or without a sponsor. If a sponsor is involved in the clinical trial, the trial must be designed, conducted and reported in collaboration with both the sponsor and the principal investigator. If there is no sponsor, the principal investigator must clearly state in the protocol who takes on the role of the sponsor in the initiation, management and / or funding of the clinical trial.
The following section outlines the responsibilities of the principal investigator and other investigators designated by the principal investigator to undertake certain trial related activities in the conduct of clinical trials.
3.1 COMPETENCIES AND RESPONSIBILITIES OF THE PRINCIPAL INVESTIGATOR
Prior to commencement of the trial, the PI must:
- be a South African based scientist;
- ensure that approval(s) from the relevant approved local ethics committee, and, if applicable, the MCC are obtained and that the trial is issued a study number by the National Health Research Ethics Council;
- have read and accepted the relevant information package developed by the sponsor for clinical studies;
- have good knowledge of the protocol, related documents and the regulatory requirements of the regulatory authority(ies) and other relevant legislation;
- have read, understood and agreed to work according to the protocol, the Declaration of Helsinki, ICH Guideline for Good Clinical Practice, these Guidelines and other relevant legislation;
- undertake to use the investigational and comparator product(s) only for the purposes of the study as described in the protocol;
- take responsibility for accountability of the investigational product(s);
- document clearly the sequence of events to be followed in the conduct of the clinical trial, including timeframes, roles and responsibilities;
- ensure the availability of all necessary facilities, equipment, and finance to conduct the trial;
- develop proper mechanisms to ethically obtain informed consent of participants;
- accept the involvement of monitors to review and verify the quality control procedures and conduct data verification;
- accept the possibility of audit and/or inspection by an independent auditor appointed by the sponsor, regulatory authority or ethics committee;
- obtain the right to publish; it is unethical for the sponsor to reserve to right to publish;
- generate the information package for the participant, and where applicable with the sponsor;
- ensure proper safety reporting procedures.
3.2 QUALIFICATIONS AND AVAILABILITY
The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through an up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the ethics committee, and/or the regulatory authority(ies).
The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator's Brochure,8 in the product information and in other information sources provided by the sponsor.
The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).
The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.
3.3 ADEQUATE RESOURCES
The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable participants within the agreed recruitment period.
The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.
The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.
The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions.
3.4 MEDICAL CARE OF TRIAL PARTICIPANTS
A qualified physician (or dentist, when appropriate), who may be the PI or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
During and after a subject's participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.
It is recommended that the investigator informs the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
3.5 INFORMED CONSENT
The PI is responsible for ensuring that an adequate information package, in an acceptable format, is available for use in the process of seeking informed consent from participants to participate in the study. In all instances both written and verbal informed consent should be obtained. Verbal consent, where the participant is illiterate, should be obtained in the presence of and countersigned by a literate witness.
The PI, co-investigator, or designated person as defined in the protocol, should then seek the participant's informed consent to participate in the study in accordance with the principles outlined in the Declaration of Helsinki, and in these guidelines.
If the trial is a multi-site, and/or multi-country study, the site PI must ensure that informed consent procedures take cognisance of the characteristics of the site participants and tailor the informed consent content and procedures accordingly.
Both the informed consent discussion and the written informed consent form and any other written information to be provided to participants should include explanations of the following:
- That the trial involves research.
- The purpose of the trial.
- The trial treatment(s) and the probability for random assignment to each treatment (where appropriate).
- The trial procedures to be followed, including all invasive procedures.
- The subject's responsibilities.
- The fact that participation in the trial is voluntary and refusal to participate or withdrawal from the trial will not prejudice the ongoing care of the person in any way.
- Those aspects of the trial that are experimental.
- The foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant. (Section 2.3.3 refers)
- The expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this. (e.g. Phase I Clinical Trial)
- The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.
- The compensation and/or treatment available to the subject in the event of trial-related injury.
- The anticipated prorata payment, if any, to the subject for participating in the trial.
- The anticipated expenses, if any, to the subject for participating in the trial.
- Allow access of sponsor ore regulatory authority to patient records.
- Provide a contract name and number of the PI and directly responsible investigator.
- The identity of a sponsor and any potential conflict of interests.
Once consent to participate in the study has been obtained, a copy of the signed informed consent form and a source document identifying the study and recording the dates of participation should be placed in the participant's medical record. The original signed informed consent form should be kept with the trial records and a copy of signed informed consent form should be provided to the participant.
If the participant can identify a usual medical practitioner, the principal investigator, should seek consent from the participant to inform their usual medical practitioner of their entry into the study. The principal investigator should only inform the medical practitioner on approval from the participant.
Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
3.6 INVESTIGATIONAL PRODUCT(S)
Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator.
Investigational products which are unregistered medicines may only be brought into the country after the protocol has been approved by the regulatory authority. Samples of the investigational product imported before trial approval require a permit from the regulatory authority.
Where allowed/required, the investigator may/should assign some of the investigator's duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution.
The investigator and/or a pharmacist or other appropriate individual, who is designated by the investigator, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s).9 These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial participants. Investigators should maintain records that document adequately that the participants were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.
The investigational product(s) should be stored as specified by the sponsor, and in line with Good Pharmacy Practice (GPP) in South Africa, and the regulatory authority regulations and conditions.
Investigational products unused at the conclusion of a trial should be disposed of in line with the guidelines established by the regulatory authority.
The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.
The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.
3.7 COMPLIANCE WITH PROTOCOL
The investigator should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval by the ethics committee. The investigator and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.
The investigator should not implement any changes to the protocol without agreement by the sponsor and prior review and documented approval from the ethics committee and the MCC of such amendment. An exception to this would be where it is necessary to eliminate an immediate hazard(s) to trial participants, or when the change(s) involve only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)). The regulatory authority and the ethics committee should be informed of any such changes in retrospect.
The investigator, or person designated by the investigator, should document and explain any changes to the approved protocol.
Where necessary, the investigator may implement a change to, the protocol to eliminate an immediate hazard(s) to trial participants without prior ethics committee/MCC approval. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be documented and submitted:
- to the ethics committee for review and approval,
- to the sponsor for agreement and,
- to the regulatory authority(ies).
For more detailed information on clinical trial protocol refer to Appendix B.
3.8 MONITORING AND AUDITING
The relationship between the principal investigator, the monitor and the sponsor must be clearly defined and stated in writing in the study protocol or related documents. These documents should also define a list of essential documents and detail how they are to be handled and stored. The investigator(s) should attend the initial briefing between the monitor and all staff involved in the study and be available for periodic visits by the monitor(s).
In addition, the investigator(s) should accept the possibility of audit and/or inspection by the sponsor, regulatory authority or ethics committee.
3.9 CHANGE OF PRINCIPAL INVESTIGATOR
If the principal investigator withdraws for any reason(s) before completion of the study, a suitably qualified successor should be appointed by the sponsor to take over responsibility for the conduct of the study.
Before the study continues, information about the new principal investigator (in similar form to that submitted for the original investigator) should be presented for approval to the relevant ethics committee. If practicable the change in principal investigator should also be notified to the participants in the study and the regulatory authority.
3.10 DATA MANAGEMENT
The principal investigator is responsible for the collection, quality, recording, maintenance and retrieval of source data arising from the clinical study. A fully comprehensive collection of information on the participant, the administration of the investigational product(s) and the outcome of the protocol procedures should be developed using Case Report Forms (CRF). The design of the CRF should facilitate observation of the participant and should be consistent with the protocol for the study. The protocol should specify which data will be entered directly into the CRF and will not be supported by other source data. The source document must be signed and dated by the clinician identified in the procotol, or designated person, on a visit by visit basis and then stored securely.
The principal investigator should make the data available to the sponsor/nominee to enable the conduct of data editing and audit according to the protocol/contract.
Corrections to CRFs can only be made by the principal investigator, co-investigator or designated person. Where existing data are incorrect, a single line should be drawn through the data in such a way that the original entry is not obscured, and the correct data inserted nearby. All corrections should be initialled and dated by the corrector.
Data collected by direct entry onto a computer should only be entered by the investigator and or a designated person. The computer system should be virus proofed, access restricted and should ideally record a data trail of all changes made to CRFs. The system should be designed in such a way that the data changes are documented and that there is no deletion of entered data in order to maintain, audit and edit data trail. Once a hard copy of the computer stored data has been made, procedures for editing are as for paper CRFs.
The sponsor may maintain a separate record of requests for clarification and correction (monitor's notes).
The investigator must be available for agreed visits by the monitor during the study and also co-operate in the data editing, quality control and audit.
3.11 SAFETY ISSUES
Decisions and actions relevant to the clinical management and safety of the participant in acute situations are the responsibility of the investigator. The investigator is responsible for ensuring that adequate provisions are made for dealing with any unexpected adverse events that may occur in the study participants. In some situations it may be appropriate for the sponsor to develop standard operating procedures for the clinical management of some adverse events. These operating procedures should be included in the protocol and its related documents.
During the progress of the study the investigator is obliged to be acquainted with, and consider, new data on the investigational product, either supplied by the sponsor or published.
3.12 REPORTING OF SERIOUS ADVERSE EVENTS
The principal investigator must inform the sponsor, within the time specified in the protocol, of any serious or unexpected adverse events occurring during the study. A serious adverse event initial report form and any relevant follow-up information should be sent to the sponsor, who in turn should forward the relevant information to the appropriate ethics committee, and regulatory authority. A serious adverse event should be reported within 24 hour, whilst unexpected AEs must be reported without undue delay. (Section 4.19 refers)
3.13 PREMATURE TERMINATION - BREAKING THE TREATMENT CODE
The investigator should follow the trial's randomisation procedures, if any, and should ensure that the code is broken only in accordance with the protocol. In blinded studies the circumstances under which the code would be broken and the procedure for unmasking the identity of the treatment received by each participant should be stated in the protocol and known by the staff involved in the clinical management of the participants.
The principal investigator and/or a designated person should keep the treatment code list, code-break envelopes or code-break cards accessible 24 hours a day at the study site in the event of an emergency.
If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s).
Reporting of accidental unblinding or unblinding due to a serious adverse event should be reported to the regulatory authority by the principal investigator via the sponsor where there is a sponsor, in writing and within 24 hours of the incident.
3.14 PROGRESS REPORTS AND FINAL STUDY REPORTS
The investigator is obliged to submit progress reports as required by the sponsor, the regulatory authority and/or the relevant ethics committee(s). These reports should contain information on how the study is progressing, the number of participants included in relation to the number expected, the number of dropouts and withdrawals and if the planned time schedule is still appropriate. A final report on completion of the study should also be submitted. The format and frequency of reporting shall be as prescribed.
3.15 TRIAL OUTCOME
All trials should be analysed. The results of trials must be submitted to the Department of Health via National Health Research Ethics Council irrespective of the outcome of the trial. This is a condition of approval for any clinical trial being undertaken in South Africa.
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Footnotes
[8] See ICH Guidelines:- Section 7: Investigator’s Brochure for a more detailed discussion of the contents of the Investigator’s Brochure.
[9] If it is a new investigational product, the MCC will specify the conditions under which the product is made available in South Africa.