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

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CONTENTS

Preamble
Acknowledgements

  1. Introduction
  2. Protection of Study Participants
  3. Responsibility of the Principal Investigator & Participating Investigators
  4. Responsibilities of the Sponsor
  5. Quality Assurance
  6. Data Management and Statistics
  7. Multi-centred Studies
  8. Ethics Committees
  9. Ethical Consideration For HIV/AIDS Clinical and Epidemiological Research

References and Recommended Readings

Appendix A: ICH Guidelines for GCP; Declaration of Helsinki
Appendix B: Clinical Trial Protocol & Protocol Amendments
Appendix C: Details of a MCC inspection
Appendix D: Draft MCC Clinical Trial Evaluation Checklist
Appendix E: Disclosure of Conflict of Interest
Appendix F: Glossary

Writing Team: Ethical Guidelines for HIV Research
Additional Contributors: Clinical Trials Guidelines
Writing Team: Clinical Trials Guidelines

PREAMBLE

This is the first edition of the Guidelines for Good Practice in the Conduct of Clinical Trials in Human Participants in South Africa. The Guidelines are produced as a reference text for researchers, research sponsors, the general public and all those who have an interest in clinical trials research in South Africa. They provide guidance on minimum standards that are acceptable for conducting clinical trials in South Africa.

These guidelines have been compiled by a working group convened by the Director General of the Department of Health and has principally included representatives from the Department of Health, South African Drug Action Programme / World Health Organisation, Medical Research Council, the Medicines Control Council, Universities of Natal and the Witwatersrand and the AIDS Law Project. It has been compiled over a period of a year during which close interaction with major players in the South African research community has been critical.

The purpose of these guidelines is to provide South Africa with clearly articulated standards of good clinical practice in research that are also relevant to local realities and contexts.

These guidelines are closely related to the regulatory requirements of the Medicines Control Council and those of the National Department of Health’s legislative and regulatory framework. It is therefore critical that these guidelines are used by research ethics committees, researchers, trial participants, principal investigators of trials and sponsors alike so as to ensure a standardised and ethical approach to clinical trial activities in South Africa. The guidelines are applicable to both academic and contract clinical research.

The document is not exhaustive. It does however provide references of national and international texts to guide the reader to particular areas of interest. The document is unique in that it provides the first attempt at addressing issues related to clinical trial research in developing countries.

I believe these guidelines would contribute significantly to ensuring good health and promoting the health of South African citizens.

Dr ME Tshabalala-Msimang
Minister of Health

Date: 14 - 09 - 2000

ACKNOWLEDGEMENTS

The national guidelines have been developed to promote good practice and standards in the conduct of clinical trials in South Africa.

The process to develop these guidelines started in 1998 with the formation of a representative expert- writing group which by the end of 1998 had produced a conceptual framework. Subsequently, the process was taken forward by a small task team which has produced the final document.

The drafting team relied on their experiences and knowledge, experts’ advice, available literature, various country experiences and a variety of internationally accepted standards and guidelines. I hereby thank all those who granted us permission to refer to their documents.

I would like to express my sincere gratitude to all those who contributed to the drafting and writing of these guidelines. Thanks to the South African Drug Action Programme/World Health Organisation; Medicines Control Council; Medical Research Council; Universities of Natal and Witwatersrand; Lawyers for Human Rights; Directorate: Health Systems Research, Research Co-ordination and Epidemiology and Directorate: Pharmaceutical Services.

I would also like to sincerely thank all persons and groups that reviewed and made constructive comments and inputs to the guidelines including South African Institute for Medical Research; South African Pharmaceutical Clinical Research Association; Quintiles Clindepharm; MEDUNSA; Medical Research Council; Universities of Cape Town; Free State and Pretoria; Technikon Pretoria; ML Sultan Technikon; Technikon Witwatersrand; Indian Ocean Triangle Quinteles; WHO/EURO Programme for Pharmaceuticals; Health Professions Council of South Africa; Clinical Quality Concepts; WHO Collaborating Centre for Drug Policy; Rand Afrikaans University, SmithKline Beecham (Southern African Region) and all other contributors

Dr Ayanda Ntsaluba
Director-General: Department of Health

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:

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:

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:

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.

________________________________

Footnotes Chapter 1

[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.

2. Protection of Study Participants - Contents

2.1 Guiding Documents
2.2 Ethical Review
2.3 Special Classes of Participants

2.3.1 Children and Adolescents
2.3.2 Women & Pregnancy
2.3.3 Pregnant Women as Participants
2.3.4 Foetuses in utero as Participants
2.3.5 Foetuses ex utero, including Nonviable Foetuses as Participants
2.3.6 Prisoners
2.3.7 People with Mental Disabilities
2.3.8 Vulnerable Communities
2.3.9 Other Special Groups

  1. PROTECTION OF STUDY PARTICIPANTS
2.1 GUIDING DOCUMENTS

The welfare and personal integrity of the participants is the responsibility of the principal investigator. The principal investigator must follow fully the guidelines set out in the Declaration of Helsinki, ICH Guidelines for Good Clinical Practice (Appendix A) and the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS 1993).

2.2 ETHICAL REVIEW

All medical research involving human participants must undergo an independent ethical review. An autonomous accredited ethics committee must ascertain that the protection of the participant is assured in the evaluation of clinical trial applications.

In the evaluation of clinical trials protocols or study applications, these bodies must ensure the protection of participants in accordance with international standards and guidelines.

An ethics committee should consider the following issues when reviewing a proposal for a clinical study:

2.3 SPECIAL CLASSES OF PARTICIPANTS

South African ethics committees must give special consideration to protecting the welfare of special classes of participants, such as children and adolescents, pregnant women, prisoners, people with mental disabilities, people for whom English is not a first language or people from vulnerable communities. The following are guidelines for the inclusion of such populations in a clinical trial.4

2.3.1 Children and Adolescents

Research in children should only be approved if:

  • The research does not place the child / minor at no greater than minimal risk.
  • The research involves more than minimal risk but provides direct benefit for the child / minor. The risk must however be justified by the potential benefit.
  • The research involves greater than minimal risk, with no prospect of direct benefit to the child / adolescent but there is a high probability that it will provide "generalisable knowledge about the subject’s disorder or condition that is of vital importance for the understanding or amelioration of the subject’s disorder or condition" (IRB, 1996:11). In addition the risks must represent only a minor increase over minimal risk and the intervention or procedure "presents experiences to participants that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or education settings" (IRB, 1996:11).
  • In all cases, assent from both child and permission from their parents or legal guardians must be sought. No other caregiver can provide consent on behalf of a child to participate.
  • Child Assent:5 The Ethics committee must ensure that adequate steps are outlined in the protocol to obtain the child’s assent, when in the judgement of the Ethics Committee the child is capable of providing such assent. When the Ethics Committee decides that assent is required, it must also state if and how assent must be documented.
  • Parental Permission: Where the research does not involve greater than minimal risk to the child, or involves greater than minimal risk but presents a likely direct benefit to the child, the Ethics Committee may find that the permission of one parent is sufficient. Permission from both parents is necessary where the research involves greater than minimal risk, no direct benefit to the child but is likely to produce generalisable knowledge about the subject’s condition. "Exceptions would include: 1) one parent is deceased, unknown, incompetent, or not reasonably available, or 2) when one parent has legal responsibility of the care and custody of the child". (IRB Policy and Procedure Manual 1997:4).
2.3.2 Women and pregnancy

Ethics Committees must give extra attention to research that involves women who are or may become pregnant, because of the additional health concerns of mothers during pregnancy and the need to avoid unnecessary risk to the foetus. Reasons for excluding women from trials should be adequately justified both from the point of view of protecting the health of a foetus and from the perspective of whether such exclusion is scientifically supportable. The IRB: Policy and Procedure Manual (1997) states that "No research activities involving pregnant women and foetuses may be undertaken unless:

  • Appropriate studies on animals and non pregnant individuals have been completed;
  • The purpose of the activity is to meet the health needs of the mother of the particular foetus, the risk to the foetus is minimal and, in all cases, is the least possible risk for achieving the objectives of the activity;
  • Individuals engaged in the activity will have no part in 1) any decision as to the timing, method and procedures used to terminate the pregnancy, and 2) determining the viability of the foetus at the termination of the pregnancy; and
  • No procedural changes which may cause greater than minimal risk to the foetus or the pregnant woman will be introduced into the procedure for terminating the pregnancy solely in the interest of the activity.
2.3.3 Pregnant Women as Participants6

No pregnant woman may be involved as a subject in any research activity unless

  • the purpose of the activity is to meet the health needs of the mother and the foetus will be placed at risk only to the minimum extent necessary to meet such needs, or
  • the risk to the foetus is minimal.

Any activity permitted above may be conducted only if the mother is legally competent and have given informed consent after having been fully informed regarding possible impact on the foetus. The father's informed consent need not be secured if

  • the purpose of the activity is to meet the health needs of the mother;
  • his identity or whereabouts cannot reasonably be ascertained;
  • he is not reasonably available; or
  • the pregnancy resulted from rape.
2.3.4 Foetuses in utero as Participants

No foetus in utero may be involved as a subject in any research activity unless

  • the purpose of the activity is to meet the health needs of the particular foetus and the foetus will be placed at risk only to the minimum extent necessary to meet such needs, or
  • the risk to the foetus imposed by the research is minimal and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means.

Any activity permitted above may be conducted only if the mother and father are legally competent and have given their informed consent. The father's informed consent need not be secured if

  • his identity or whereabouts cannot reasonably be ascertained;
  • he is not reasonably available; or
  • the pregnancy resulted from rape.
2.3.5 Foetuses ex utero, Including Nonviable Foetuses, as Participants

Until it has been ascertained whether or not a foetus ex utero is viable, a foetus ex utero may not be involved as a subject in any research activity unless

  • there will be no added risk to the foetus resulting from the activity, and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means, or
  • the purpose of the activity is to enhance the possibility of survival of the particular foetus to the point of viability.

No nonviable foetus may be involved as a subject in any research activity unless

  • vital functions of the foetus will not be artificially maintained;
  • experimental activities which of themselves would terminate the heartbeat or respiration of the foetus will not be employed; and
  • the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means.

Any activity permitted above may be conducted only if the mother and father are legally competent and have given their informed consent, except that the father's informed consent need not be secured if

  • his identity or whereabouts cannot reasonably be ascertained;
  • he is not reasonably available; or
  • the pregnancy resulted from rape.
2.3.6 Prisoners

Ethical review must take cognisance of the impact of a prisoner’s incarceration on their ability to make a truly voluntary and uncoerced decision whether or not to participate as participants in research.

In addition, when reviewing research involving prisoners, ethics committees must meet the following specific requirements:

  • A majority of the ethics committee (exclusive of prison members) shall have no association with the prison(s) involved, apart from their membership on the ethics committee; and
  • At least one member of the ethics committee shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than one ethics committee only one ethics committee need satisfy this requirement.

The following clinical trials involving prisoners is permitted:

Clinical trials conducted or supported in South Africa may involve prisoners as participants only if 1) the research has been registered with the National Health Research Ethics Council, and 2) and in the judgement of the MCC and the relevant approved ethics  committee, the clinical trial involves the following:

  • study of the possible causes, effects, and processes of incarceration, and of criminal behaviour, provided that the study presents no more than minimal risk and no more than inconvenience to the participants;
  • study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the participants;
  • research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) only after appropriate experts have been consulted; or
  • research on practices, both innovative and accepted, that have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the Ethics Committee to control groups that may not benefit from the research, the research may proceed only after appropriate experts have been consulted.
2.3.7 People with Mental Disabilities or Substance Abuse Related Disorders

People with mental disabilities include: those people with psychiatric, cognitive or developmental disorders. The issue with these groupings of people when it comes to research is their capacity for reason regarding participation and comprehend information provided. This issue is also applicable to research on persons with substance abuse related disorders. Institutionalisation may also further compromise a person’s ability to make a truly voluntary decision to participate in a study.

Research in people with cognitive disabilities or with substance abuse related disorders must therefore:

  • Be relevant to mental disabilities or substance abuse related disorders so that it is necessary to involve people who are mentally disabled or with substance abuse related disorders.
  • Provide sufficient justification for involving people with mental disabilities or substance abuse related disorders who are institutionalised as the study population.
  • Ensure appropriate evaluation procedures for ascertaining participants’ ability to give informed consent. If participants are deemed unable to understand and to make a choice, then an appropriate individual, able to consent on their behalf must be sought.
  • Ensure that consent is free from coercion and risk to patients.
  • Ensure that no more than minimal risk is involved, or if minimal risk is involved, the risk is outweighed by the anticipated benefits of the study for the participants and the importance of the knowledge which will emanate from the research.
2.3.8 Vulnerable Communities

South Africa is home to a number of vulnerable communities.7 Particular caution must be practised before undertaking research involving participants in such communities and ethics committees must ensure the following:

  • persons in these communities will not ordinarily be involved in research that could be carried out in populations from developed communities.
  • the research is responsive to the health needs and the priorities of the community in which it is carried out.
  • research participants should know that they are taking part in research and this research should only be carried out with their consent. This implies that particular attention is paid to the content, languages and procedures used to obtain informed consent.
  • the research protocol should not adversely affect the routine treatment of patients, nor disrupt routine management protocols.
2.3.9 Other Special Groups

The discussion on special groups should not be limited to those already mentioned. Other special groups include: Traumatised and comatose patients, terminally ill patients, elderly or aged patients, minorities, students, and employees. Ethics committees must ensure special consideration is given to all these groups, particularly around informed consent. For a more detailed discussion on informed consent please refer to the section 3.5 of this document.

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Footnotes Chapter 2

[4] For further, more detailed discussion on special classes of participants refer to Chapter 5, Institutional Review Board (IRB) Guidebook, 1993, NIH, USA, http://www.nih.gov/grants/oprr/irb/

[5] Worth noting is the following discussion provided by the IRB Guidebook on gaining the assent of children to participate in a trial. “While children may be legally incapable of giving informed consent, they nevertheless may possess the ability to assent to or dissent from participation.  Out of respect for children as developing person, children should be asked whether or not they wish to participate in the research, particularly if the research: (1) does not involve interventions likely to be of benefit to the subjects; and (2) the children can comprehend and appreciate what it means to be a volunteer for the benefit of others.  The [Ethics Committee] must determine for each protocol – depending on such factors as the nature of the research and the age, status and condition of the proposed subjects – whether all or some of the children are capable of assenting to participation.  Where appropriate the [Ethics Committee] may choose to review on a case-by-case basis whether assent should be sought from given individual subjects.  Assent should be sought when, in the judgement of the [Ethics Committee], the children are capable of providing their assent.  [Ethics Committees] are to take into account the ages, maturity and psychological state of the children involved.” (IRB, 1996:12)

[6] Clinical trials involving pregnant women or nursing mothers should ideally involve products where the toxicology in adults is established and is acceptable.  In the case of pregnant women the potential risks associated with using a substance whose short term and long term effects on a foetus and developing infant are unknown, should be outweighed by the benefits.  An example of a positive risk benefit ratio would be the use of anti-retrovirals in mother to child HIV transmission studies.  For nursing mothers, the amount of drug passing into breast milk should be established and the potential impact on a breast fed infant anticipated, and the mother so advised.

[7] UNAIDS define vulnerable communities as having some or all of the following characteristics: Limited economic development; Inadequate protection of human rights and discrimination on the basis of the health status; Inadequate community/cultural experience with the understanding of scientific research; Limited availability of health care and treatment options; Limited ability of individuals in the community to provide informed consent.

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

  1. RESPONSIBILITY OF THE PRINCIPAL INVESTIGATOR (PI) AND PARTICIPATING INVESTIGATORS

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:

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:

  1. That the trial involves research.
  2. The purpose of the trial.
  3. The trial treatment(s) and the probability for random assignment to each treatment (where appropriate).
  4. The trial procedures to be followed, including all invasive procedures.
  5. The subject's responsibilities.
  6. 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.
  7. Those aspects of the trial that are experimental.
  8. The foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant. (Section 2.3.3 refers)
  9. 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)
  10. The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.
  11. The compensation and/or treatment available to the subject in the event of trial-related injury.
  12. The anticipated prorata payment, if any, to the subject for participating in the trial.
  13. The anticipated expenses, if any, to the subject for participating in the trial.
  14. Allow access of sponsor ore regulatory authority to patient records.
  15. Provide a contract name and number of the PI and directly responsible investigator.
  16. 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:

  1. to the ethics committee for review and approval,
  2. to the sponsor for agreement and,
  3. 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.

________________________________

Footnotes Chapter 3

[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.

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:

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:

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):

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 Chapter 4

[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

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 monitor should also:

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:

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:

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 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:

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 Chapter 5

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

6. Data Management and Statistics - Contents

6.1 Protocol
6.2 Randomisation
6.3 Data Management

6.3.1 Data Integrity and Transfer
6.3.2 Case Report Form
6.3.3 Data Quality Control
6.3.4 Code Breaking for Data Analysis

6.4 The Final Study Report
6.5 Preservation of Records
6.6 Archiving by the Principal Investigator
6.7 Archiving by the Sponsor

  1. DATA MANAGEMENT AND STATISTICS

Statistical considerations must be an integral part of study design and the description and analysis of the final results. The aim should be to integrate the clinical and statistical aspects as fully as possible through all phases of a clinical study.

Statisticians and data managers should have advisory and operative functions in the design of clinical studies, in reviewing study protocols, CRFs and manuscripts, and in the design of computer systems for data processing. The operative functions consist of writing or advising on statistical sections in protocols and reports, adapting or developing appropriate methods for the statistical analysis, performing the analysis and making the statistical interpretation of the results.

The protocol and the final study report should be reviewed and commented upon by a statistician.

6.1 PROTOCOL

Statistical considerations in a study protocol should be an integral part of the document and special attention should be paid to the following aspects:

6.