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

4. Responsibilities of the Sponsor - Contents

4.1 Submission to MCC for Regulatory Authority Approval
4.2 Confirmation of Review by Ethics Committees
4.3 Registration with the Department of Health
4.4 Quality Assurance and Quality Control
4.5 Contract Research Organisation (CRO)
4.6 Medical Expertise
4.7 Trial Design
4.8 Trial Management, Data Handling & Record Keeping
4.9 Investigator Selection
4.10 Allocation of Responsibilities
4.11 Compensation of Participants and Investigators
4.12 Trial Incentives
4.13 Financing
4.14 Information on Investigational Products
4.15 Manufacturing, Packaging, Labelling and Coding of Investigational Products
4.16 Supplying & Handling of Investigational Products
4.17 Record Access
4.18 Safety Information
4.19 Adverse Drug Reaction Reporting
4.20 Premature Termination
4.21 Reporting and Release of Trial Results
4.22 Publication of Trial Results
4.23 Non-compliance Procedures

  1. RESPONSIBILITIES OF THE SPONSOR10

A sponsor is the person or organisation responsible for the initiation, management or financing of a clinical trial (IRB:1993). A sponsor can be a pharmaceutical company, the principal investigator, a funding body or an individual or organisation designated by the funding body or principal investigator. It is important that sponsor’s roles and responsibilities to be undertaken must be clearly articulated in the protocol and related documents.

To follow is a description of the roles and responsibilities of the sponsor in the conduct of clinical trials in South Africa. Some of these roles and responsibilities are repeated in the section on the responsibilities of the PI.

4.1 SUBMISSION TO THE MCC FOR REGULATORY AUTHORITY APPROVAL

Before initiating a clinical trial(s), the sponsor and the investigator, should submit the required MCC application(s) to the regulatory authority for review and permission to begin the trial(s). The protocol should be submitted in triplicate. It is the responsibility of both the sponsor and the PI to ensure that the protocol satisfies the requirements of the protocol checklist (Appendix D). Applicants should note that the MCC review process takes approximately 10 weeks.

In the event that regulatory authority approval is required for a drug trial in less than 10 weeks, fast track approval can be applied for, such approval may be sought when:

  • The trials is for a new chemical entity or new indication which may be life saving or may represent a therapeutic breakthrough for a particular condition;
  • For trials where the season is important and a delay would prevent the trial from progressing;
  • Under exceptional circumstances for reasons of logistics.
4.2 CONFIRMATION OF REVIEW BY ETHICS COMMITTEE

The sponsor should obtain from the investigator the name and address of the investigator's relevant approved ethics committee and documented ethics committee approval.

If the ethics committee conditions its approval upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to participants, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval was given by the ethics committee.

The sponsor should obtain from the investigator documentation and dates of any ethics committee reapprovals/re-evaluations, and of any withdrawals or suspensions of approval.

4.3 REGISTRATION WITH NATIONAL HEALTH RESEARCH ETHICS COUNCIL

The sponsor must also obtain from the investigator a study number issued by the National Health Research Ethics Council. The study number is issued once the National Health Research Ethics Council has received a copy of approvals from an ethics committee, and if required, from the MCC.

4.4 QUALITY ASSURANCE AND QUALITY CONTROL

The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written Standard Operating Procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

The sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.

Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

Agreements, made by the sponsor with the principal investigator and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement.

4.5 CONTRACT RESEARCH ORGANIZATION (CRO)

A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.

The CRO, to which trial related duties have been delegated, must have the required skills, experience and competencies to conduct clinical trials.

Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.

Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.

CROs must be regulated by MCC, registered with MCC, and pay a registration fee.

All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor.

4.6 MEDICAL EXPERTISE

The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose. (See section on PI responsibilities).

4.7 TRIAL DESIGN

The sponsor should utilise qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analysing and preparing interim and final clinical trial reports.

If the study is a multicentre and / or multi-country study, any differences in trial designs between the South African site and other sites, must be clearly documented and explained in the study protocol and related documents. (See section on PI responsibilities)

4.8 TRIAL MANAGEMENT, DATA HANDLING, AND RECORD KEEPING

The sponsor should utilise appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should have written operating procedures and maintain written records of all its meetings.

When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:

  1. Ensure and document that the electronic data processing system(s) conform(s) to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).
  2. Maintains SOPs for using these systems.
  3. Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e. maintain an audit trail, data trail, edit trail).
  4. Maintain a security system that prevents unauthorized access to the data.
  5. Maintain a list of the individuals who are authorized to make data changes.
  6. Maintain adequate backup of the data.
  7. Safeguard the blinding, if any (e.g. maintain the blinding during data entry and processing).

If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.

The sponsor should use an unambiguous subject identification code that allows identification of all the data reported for each subject.

The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial.

The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of South Africa.

If the sponsor discontinues the clinical development of an investigational product (i.e. for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least 5 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).

If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities.

Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).

The sponsor specific essential documents should be retained for not less than 5 years after the last approval of a marketing application and until there are no pending or contemplated marketing applications or at least 5 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.

The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed.

4.9 INVESTIGATOR SELECTION

The sponsor is responsible for selecting the investigator(s). Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected. If the organisation of a coordinating committee and/or selection of coordinating investigator(s) are to be utilised in multicentre trials, their organisation and/or selection are the sponsor's responsibility.

Before entering an agreement with an investigator to conduct a trial, the sponsor should provide the investigator(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator to review the protocol and the information provided.

The sponsor should obtain the investigator's agreement:

  1. to conduct the trial in compliance with GCP, these guidelines, the requirements of the regulatory authority and with the protocol agreed to by the sponsor and given approval by the relevant ethics committee;
  2. to comply with procedures for data recording/reporting;
  3. to permit monitoring, auditing and inspection; and
  4. to retain the trial related essential documents until the sponsor informs the investigator/institution that these documents are no longer needed.

The sponsor and the investigator should sign the protocol, or an alternative document, to confirm this agreement.

4.10 ALLOCATION OF RESPONSIBILITIES

Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions. These must be clearly documented in the protocol related documents.

4.11 COMPENSATION TO PARTICIPANTS AND INVESTIGATORS11

The MCC requires that all participants in clinical trials are covered by comprehensive insurance for injury and damage.

Notwithstanding the absence of legal commitment, the sponsor should pay compensation to patient-volunteers suffering bodily injury, including death, in accordance with these guidelines.

Compensation should be paid when, on the balance of probabilities, the injury was attributable to the administration of a medicinal product under a trial or any clinical intervention or procedure provided for by the protocol that would not have occurred but for the inclusion of the patient in the trial.

Compensation should be paid to a child injured in utero through the participation of the subject’s mother in a clinical trial as if the child were a patient-volunteer with the full benefit of these guidelines.

Compensation should only be paid for the more serious injury of an enduring and disabling character (including exacerbation of an existing condition) and not for temporary pain or discomfort or less serious or curable complaints.

Where there is an adverse reaction to a medicinal product under trial and injury is caused by a procedure adopted to deal with that adverse reaction, compensation should be paid for such injury as if it were caused directly the medicinal product under trial.

Neither the fact that the adverse reaction causing the injury was foreseeable or predictable, nor the fact that the patient has freely consented (whether in writing or otherwise) to participate in the trial should exclude a patient from consideration for compensation under these guidelines.

For the avoidance of doubt, compensation should be paid regardless of whether the patient is able to prove that the sponsor has been negligent in relation to research or development of the medicinal product under trial or that the product is defective and therefore, the sponsor is under strict liability in respect of injuries caused by it.

No compensation should be paid:

  • For the failure of a medicinal product to have its intended effect or to provide any other benefit to the subject.
  • For injury caused by other licensed medicinal products administered to the patient of the purpose of comparisons with the product under trial.
  • To patients receiving placebo in consideration of its failure to provide a therapeutic benefit.
  • (or it should be abated as the case may be) to the extent that the injury has arisen through:
  • a significant departure from the agreed protocol
  • the wrongful act or default of a third party, including a doctor’s failure to deal adequately with an adverse event
  • through contributory negligence by the patient.

The amount of compensation should be paid appropriate to the nature, severity and persistence of the injury and should in general terms be consistent with the quantum of damages commonly awarded for similar injuries by a South African Court in cases where legal liability is admitted.

Compensation should be abated, or in certain circumstances excluded, in the light of the following factors (on which will depend the level of risk the patient can reasonably be expected to accept):

  • the seriousness of the disease being treated, the degree of probability that adverse reactions will occur and any warning given
  • the risks and benefits of the established treatments relative to those known or suspected of the trial medicines.

This reflects the fact that flexibility is required given the particular patient’s circumstances. As an extreme example there may be patient suffering from a serious or life-threatening disease who is warned of certain defined risk of adverse reaction. Participation in the trial is then based on an expectation that the benefit/risk ratio associated with participation may be better than that associated with alternative treatment. It is, therefore, reasonable that the patient accepts the high risk and should not expect compensation for the occurrence of the adverse drug reaction of which he or she was told.

In any case where the sponsor concedes that payment should be made to a patient but there exists a difference of opinion between sponsor and patient as to the appropriate level of compensation, it is recommended that the sponsor agrees to seek at its own cost (and make available to the patients) the opinion of a mutually acceptable independent expert, and that his/her opinion should be given substantial weight by the sponsor in reaching its decision on the appropriate payment to be made.

Claims in pursuant to the guidelines should be made by the patient to the sponsor, preferably via the investigator, setting out details of the nature and background of the claim and, subject to the patient providing on request an authority for the sponsor to review any medical records relevant to the claim, the sponsor should consider the claim expeditiously.

The undertaking given by a sponsor extends to injury arising (at whatever time) from all administrations, clinical interventions or procedures occurring during the course of the trial but not to treatment extended beyond the end of the trial at the instigation of the sponsor. The use of unlicensed products beyond the trial is wholly the responsibly of the treating doctor. The MCC must be informed in writing of any such activities.

The fact that a sponsor has agreed to abide by these guidelines in respect of a trial does not affect the right of a patient to pursue a legal remedy in respect of injury alleged to have been suffered as a result of participation. Nevertheless, patients will normally be asked to accept that any payment made under the guidelines will be in full settlement of their claims. Clinical trials insurance in no way replaces a clinician’s malpractice insurance.

4.12 TRIAL INCENTIVES

The sponsor must ensure that information on incentives offered to participants involved in the trial is included in the protocol. If the study is multi-centered, information on the incentives given to participants at all the different trial sites, irrespective if these are multinational, must also be provided. Differences in the incentives across sites must be explained.

The sponsor must also ensure that participants are reimbursed for all reasonable costs incurred by their participation in the trial.

4.13 FINANCING

The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.

A declaration must be signed by both the sponsor and the principal investigator which states that there are sufficient funds available to complete the study.

4.14 INFORMATION ON INVESTIGATIONAL PRODUCT(S)

When planning trials, the sponsor should ensure that sufficient safety and efficacy data from pre-clinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.

The sponsor should update the Investigator's Brochure as significant new information becomes available.

4.15 MANUFACTURING, PACKAGING, LABELLING, AND CODING INVESTIGATIONAL PRODUCT(S)

The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterised as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. The labelling should comply with MCC requirement(s). (e.g. Labels of materials used in clinical trials should clearly state that it is clinical trial material, provide information on the manufacture and expiry date and give sponsor contact details).

The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. Compliance with the GPP , where applicable, will be required. The sponsor should inform all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations.

The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.

In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.

If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.

4.16 SUPPLYING AND HANDLING INVESTIGATIONAL PRODUCT(S)

The sponsor is responsible for supplying the investigator with the investigational product(s).

The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g. approval from the appropriate ethics committee and regulatory authority(ies)).

The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from participants, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorised by the sponsor and in compliance with the applicable regulatory requirement(s)).

The sponsor should:

  1. Ensure timely delivery of investigational product(s) to the investigator(s).
  2. Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s).
  3. Maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim).
  4. Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition. Disposal must be done according to the regulation of the regulatory authority.

The sponsor should:

  1. Take steps to ensure that the investigational product(s) are stable over the period of use.
  2. Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.
4.17 RECORD ACCESS

The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, ethics committee review, and regulatory inspection.

The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, ethics committee review, and regulatory inspection.

4.18 SAFETY INFORMATION

The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).

The sponsor should promptly notify, in writing all concerned investigator(s) and the regulatory authority and ethics committee of findings that could affect adversely the safety of participants, impact the conduct of the trial, or alter the ethics committee’s approval/favourable opinion to continue the trial.

4.19 ADVERSE DRUG REACTION REPORTING

The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the ethics committee(s), and to the regulatory authority of all adverse drug reactions (ADRs) that are both serious and unexpected.

A serious adverse drug reaction should be reported within 24 hour, whilst unexpected ADRs must be reported without undue delay.

If the study is multi-centred, the sponsor should ensure that all serious and unexpected adverse drug events that occur in other study sites are also reported without delay on six monthly basis to all appropriate parties including, investigator(s), ethics committee(s), and to the regulatory authority.

The sponsor should submit to the regulatory authority and ethics committees all safety updates and periodic reports, as required by applicable regulatory requirement(s). Review of reported serious and unexpected adverse drugs events need to include analysis, evaluation and complete account of the entire body of safety information of the drug, as such data may have emerged during the course of clinical trials by the PI and in the international data set.

4.20 PREMATURE TERMINATION

The sponsor must ensure that the procedures for unblinding on the account of adverse events or by accident, and the premature termination of a trial is clearly documented within the study protocol. Such events must be reported to all concerned investigator(s)/institutions(s), to the ethics committee(s), and to the regulatory authority.

4.21 REPORTING AND RELEASE OF TRIAL RESULTS

The sponsor is responsible for ensuring that trial activities and outcomes are routinely reported to the appropriate ethics committee and the regulatory authority.

The results of all trials must be communicated to the appropriate ethics committee, the regulatory authority and the Director General of Health. The sponsor and the principal investigator are responsible for the appropriate dissemination of the trial findings.

The sponsor must notify the regulatory authority of all Phase IV trials.

4.22 PUBLICATION OF TRIAL RESULTS

The principal investigator has a duty and right to publish trial results, irrespective of the sponsor’s consent. Trial results should always be reported to the appropriate ethics committee, the regulatory authority and the National Health Research Ethics Council.

4.23 NON-COMPLIANCE PROCEDURES

The sponsor has an ethical duty to inform the appropriate ethics committee and regulatory authority of possible instances of serious contravention of GCP during the course of a clinical trial that affect participant’s safety, the credibility of data and/or the ethics of the trial.

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Footnotes

[10] Unless otherwise specified by way of italics, the bulk of this section has been taken directly from the ICH Harmonised Guideline.  Guideline for Good Clinical Practice, May 1996. 

[11] Association of the British Pharmaceutical Industry Compensation Guidelines

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