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

1. Introduction - Contents

1.1 Why Guidelines?
1.2 Principles
1.3 Scope of these Guidelines
1.4 Guidelines and Legislation
1.5 Roles and Responsibilities

1.5.1 Regulatory Authority (MCC)
1.5.2 The Department of Health
1.5.3 The National Health Research Ethics Council
1.5.4 Ethics Committees
1.5.5 The Principal Investigator
1.5.6 The Sponsor
1.5.7 The Monitor
1.5.8 The Auditor
1.5.9 The Inspector

1.6 Process for Clinical Trials Approval in South Africa

  1. INTRODUCTION

The value of clinical trials as the optimum methodology for the testing and evaluation of new treatments and medicines is well recognised within the South African research community. South Africa provides a particularly unique research environment encompassing high technological medical expertise and infrastructure and a significant burden of disease. The racial - cultural diversity provides an opportunity to investigate racially specific disease traits, whilst the shift from rural to urban areas provides a wealth of patients to investigate emerging and re-emerging diseases lit up by urban deprivation.

Risk inherent in this is the potential for unscrupulous, unethical and unnecessary conduct of clinical research. This is more likely to happen in poor populations with low levels of literacy, an unquestioning acceptance of authority and a need for health services of all descriptions. Currently it is estimated that the clinical trial industry in South Africa has grown by as much as 40% from 1997-1998 (Christley 1998) and yielded an estimated total budget of R826 million during 2000 (Joffe, 2000). In the light of this growth the need to carefully regulate and guide the conduct of clinical trials becomes urgent and necessary.

1.1 WHY GUIDELINES?

In recognition of this necessity a working group convened by the Director General of Health developed the first edition of the Guidelines for Good Practice in the Conduct of Clinical Trials in Human Participants in South Africa. The purpose of these guidelines is to ensure that clinical trials conducted on human participants are designed and conducted according to sound scientific and ethical standards within the framework of good clinical practice. Compliance with these standards provides the public with assurance that the rights, safety and well being of trial participants are protected and that the clinical trial data are credible.

1.2 PRINCIPLES

These guidelines should be read in the context of the Declaration of Helsinki, October 2000 and the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, May 1997 (Appendix A).

Although well designed clinical trials will undoubtedly fit in within these modern ethical sentiments, the potential to violate the rights of trial participants particularly in vulnerable communities necessitates the need to articulate ethical guidelines for clinical trials.

These include the following:

  • Respect for persons
  • Beneficence and non maleficence
  • Justice

The practical application of these principles requires research studies to have distinct components built into them. These include relevant and appropriate study rationale, optimal study design, investigator competence, a balance of risks and benefits for participants, transparency, patient privacy, ethical review and impartial oversight of consent procedures. To follow is a brief discussion on some of these issues as they relate to South Africa.

A. Study Rationale and Motivation

A study rationale and motivation which does not ask relevant and important questions is unethical.1 Whilst maintaining the highest standards of clinical research it is important that clinical trials are based on priority, country specific research questions. Relevant and important questions should also be problems that significantly affect local and regional population. Study rationale should demonstrate that the study question has not been substantially answered and that adequate systematic review of the subject under discussion was done. The findings of which must be translatable into mechanisms for improving the health status of South Africans. Solutions should have the potential for implementation.

B. Study Designs

Appropriate designs are critical in contributing to answering scientific questions. The design must therefore demonstrate a high probability for providing answers to specific research questions. Adequate supporting information and explanation on the study sample size and study population must also be provided. A study on a population comprising a vulnerable group must be able to justify the choice of that population on scientific and social justice grounds. The researchers should be able to say why they have chosen that vulnerable group rather than the other and if a population that is a vulnerable group will stand to benefit in ways that reduce their vulnerability. The design of the drug trial should in no way prejudice the ongoing treatment and care of patients, nor should it anyway undermine or confuse patients with respect to the best available local standard treatment practices and national policy approaches.2 If these are not ensured, then the design is unethical.

C. Investigator Competence

The investigator’s competence is assessed by two major parameters: Technical and humanistic. Technical competence which includes research competence is assessed by education, knowledge, certification and experience. Humanistic parameters require compassion and empathy. This is provided by a proper clinical and research environment, encompassing good research mentoring. In all cases the Principal Investigator must be a South Africa based scientist (resident in South Africa).

D. Balance of Harm and Benefit

A risk benefit analysis of the study should precede the conduct of the research itself. Risk-benefit analysis should take full cognisance of benefits and harms beyond the life of the study itself, particularly in the case of chronic life threatening conditions. Alternative ways of providing benefits to the patients might be available without research; thus the distinction between the probability of harm and the possible benefits of the effects must be made. The principal investigator has the ethical duty of excluding participants who are at undue risks.

E. Transparency

Once the trial has obtained approval, trial information is placed on a central register. The following data items on the trial are recorded in this register: The research question, information on the principal investigator, location of the trial, date of when approval was given, outcomes of the trial, including a summary report, date when trial was commenced/completed and where appropriate, information concerning the premature termination of the trial, the size of funding for trial research and the investment of industry in different aspects of biomedical intervention. The database will serve to promote transparency, good co-ordination and systematic review to prevent unnecessary trials.

F. Privacy

The participants right to privacy must be protected at all costs. This is maintained via the use of appropriate precautions regarding subject identifiers. This will also include electronic / computerised records and access thereof of such information.

G. Ethical Review

This provides an objective appraisal of the research proposal as it affects the potential participants and the general day to day functioning of the health system. Three methods are currently used. (I) Ethics Committees, which are usually made up of lawyers, medical practitioners, bio-ethicists and community representatives, are by far the commonest; (II) Data and safety monitoring committees. These committees oversee ongoing clinical trials with respect to treatment, efficacy and safety. In the advent of clear evidence of efficacy or harm, prior to the end of the trial, premature termination can be recommended on ethical grounds; and (III) The Regulatory Authority (i.e. the Medicines Control Council) which is responsible for reviewing the study design, and in so doing review all significant ethical questions.

H. Informed Consent

Informed consent is a necessary but not sufficient requirement for ethical conduct. Obtaining informed consent implies the provision of information to potential participants regarding the nature of the research procedure, scientific purpose and alternatives to study participation. Participants’ comprehension is addressed by laying out this information in a clear and simple style. In South Africa, this must be achieved via the use of culturally acceptable practices including the use of the participant’s language. The conditions under which the consent is granted must be free of coercion, undue influence or incentives. Treatment for a given condition, which might be an attribute of the clinical trial design should not be denied by the refusal to participate. Withdrawal from the clinical trial at any time will not result in undue clinical penalties to the participant.

I. Safety Monitoring

Safety monitoring of participants during and for defined periods after a clinical trial is an ethical requirement. This involves the prompt reporting of serious adverse events and the appropriate management of such an event.

J. Multi-centre Studies

The number of multi-centred clinical trials being undertaken in South Africa has increased dramatically in recent years. There is a need to ensure that designs are appropriate for the local setting and that particular modifications are made to the local study when required e.g. inclusion / exclusion criteria. It is unacceptable for developed country participants to have better standards of care offered in the study when compared to South African participants. When South Africa is chosen for a clinical trial while the trial is not undertaken in the country of origin an explanation should be sought about why this is the case. In terms of study design, special attention should be paid to the sampling strategy. Other issues in international studies include the appropriateness of incentives packages to trial participants and remuneration packages for investigators.

1.3 SCOPE OF THESE GUIDELINES

These guidelines focus on the management and regulation of drug trials on human participants. These guidelines have not specifically addressed clinical trials on complementary medicines, traditional medicines, non-pharmacological interventions including surgical procedures, medical devices and X-rays. However, these guidelines are such that, in the absence of alternatives, the basic principles outlined in this document may be used to guide any research involving human participants. These guidelines have been guided by and based extensively on the following documents:

  • Declaration of Helsinki, October 2000
  • International Guidelines for Ethical Review of Epidemiological Studies, Council for International Organisations of Medical Sciences (CIOMS), 1991
  • World Health Organisation, WHO Technical Report Series, No. 850, Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, 1995
  • World Health Organisation (2000) Operational Guidelines for Ethics Committees That Review Biomedical Research. Geneva. TDR/PRD/Ethics/2000.1
  • MEDSAFE, New Zealand Regulatory Guidelines for Medicines, Volume 3: Interim Good Clinical Research Practice Guideline, August 1998
  • ICH Guideline for Good Clinical Practice, ICH Harmonised Tripartite Guideline, May 19973
  • Association of the British Pharmaceutical Industry Clinical Trial Compensation Guidelines, Issued January 1991, Reprinted March 1994
  • Institutional Review Board (IRB) Guidebook. Office for the Protection from Research Risks – National Institute of Health, USA, 1993

In the event that these Guidelines differ from any of the above texts, these Guidelines will apply. The responsibility for deviation with any of the above documents lies with the authors of these Guidelines.

1.4 GUIDELINES AND LEGISLATION

These guidelines will be enforced by regulations. In addition, clinical trials to be conducted in South Africa are also required to obtain ethics approval through an approved ethics committee. A process to register clinical trials will be established. Compliance with these guidelines is compulsory under the direction of the Director General of Health. In the event that both a legal requirement and the guideline applies to a particular issue or activity of the clinical trial, the legal requirement will always apply.

1.5 ROLES AND RESPONSIBILITIES

This document outlines the roles and responsibilities of the various parties involved in clinical trials in South Africa. Specifically, these include:

1.5.1 The Regulatory Authority (MCC):

All clinical trials of both non-registered medicinal substances and new indications of registered medicinal substances must be reviewed by the Medicines Control Council (MCC). The MCC has a statutory obligation to ensure that the drugs available in the country fulfil the necessary requirements for safety, quality and efficacy. In the case of an ongoing trial where there are serious breaches of Good Clinical Practice, the MCC can close a trial down. Reference to the regulatory authority in this document refers to the MCC.

1.5.2 Department of Health

All clinical trials to be conducted in South Africa will be required to register and will be issued a study number by the Department of Health through National Health Research Ethics Council. Section 1.6 refers.

1.5.3 The National Health Research Ethics Council:

This body will have the overall responsibility to promote, ensure and monitor compliance by approved ethics committees in South Africa with relevant legislation, regulations and guidelines including Guidelines for Good Practice in the Conduct of Clinical Trials in Human Participants in South Africa. It plays an important role in the issuing study numbers of clinical trials in South Africa and is expected to be established under the National Health Bill. This body reports directly to the Minister of Health and is provided with secretariat support from the Directorate Health Systems Research, Research Co-ordination and Epidemiology (HSRRCE).

1.5.4 Ethics Committees:

The main responsibility of ethics committees in South Africa is to ensure the protection and respect of the rights, safety and well being of participants involved in a trial and to provide public assurance of that protection by reviewing, approving and providing comment on clinical trial protocols, the suitability of investigator(s), facilities, methods and procedures used to obtain informed consent. In the execution of these responsibilities committees should be guided by relevant South African ethical guidelines, professional standards and codes of practice. The performance of ethics committees should be systematically audited in a structured way.

1.5.5 The Principal Investigator:

The principal investigator is a South Africa based scientist who has a sole or joint responsibility for the design, conduct, delegation of trial responsibilities, analysis and reporting of the trial. The principal investigator is accountable to the sponsor and regulatory authorities as required by these Guidelines. The PI should be knowledgeable and have an understanding of the drug, its toxicology and safety. In the case of a multi-centred trial there must be a local principal investigator (PI) attached to each site. It is unacceptable to have an "absentee" PI who is based in another country.

1.5.6 The Sponsor:

An individual, company, institution, or organisation which takes responsibility for the initiation, management, and / or financing of a clinical trial.

1.5.7 The Monitor:

The monitor is appointed by and reports to the sponsor. The monitor is responsible for overseeing the progress of a clinical trial and ensuring that it is conducted, recorded and reported in accordance with protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), Good Laboratory Practice (GLP), Good Pharmacy Practice (GPP), these guidelines and other applicable legislation and regulations.

1.5.8 The Auditor:

The auditors are independent individuals appointed by sponsors to conduct a systematic and in-depth examination of trial conduct and compliance with the protocol, SOPs, GCP, GLP, GPP and the applicable regulatory requirements. An audit is separate from routine monitoring or quality control functions. The regulatory authority may also appoint an auditor to a trial.

1.5.9 The Inspector:

The inspector is a suitably qualified employee of the MCC whose responsibility is to conduct announced or unannounced inspection visits at clinical trial sites as required/instructed by the MCC. Most inspectorate visits will be prearranged but some will not especially where there is suspected serious breaches of the GCP or malpractices.

1.6 PROCESS FOR A CLINICAL TRIAL APPROVAL IN SOUTH AFRICA

The following two steps are required as a standard approval process in South Africa:

  • MCC Approval - PI / Sponsor apply for approval to conduct a Trial of Non-registered drug or registered drug for new indications; and
  • Ethics Committee Approval – ethical approval for all clinical trials

In addition a system to ensure monitoring of all research will be set up through the National Health Research Ethics Council and local ethics committees which will involve each study being registered and issued with a study number. A document will be made available for this registration process during 2001.

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Footnotes

[1] Researchers can seek guidance from the Essential National Health Research (ENHR) committee on relevant and important questions for South Africa.  For further information on the ENHR committee please contact the Minister of  Health, c/o Health Systems Research , Research Co-ordination and Epidemiology Private Bag X828, Pretoria, 0001

[2] Where trials are in contradiction to standard national policy and treatment practices, a motivational statement within the protocol as to why this is the case is required. e.g. testing new vaccines which may disrupt current EPI schedules

[3] Written permission to use the ICH guidelines on a non-commercial basis was given by the ICH secretariat.

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