STANDARD OPERATING PROCEDURES - mm3admin.co.za · Participant Information and Informed Consent Requirements 27 22. Placebo Control 28 23. Genetic Research 28 24. Use of Human Tissue

STANDARD OPERATING PROCEDURES

Final, Version 1: 01 March 2012

Pharma-Ethics (Pty)Ltd Registration No. 99/13868/07

PO Box 786 Irene, 0062 123 Amcor Road Lyttelton Manor, 0157 Tel: (012) 6648690 Fax: (012) 6647860

Pharma-Ethics Research Ethics Committee: Standard Operating Procedures Proprietary Information

Standard Operating Procedures Author: M. Haskins, Reviewed by: E Hammann, E Khomo Approved by: C Duvenage,

Final Version 1: 01 March 2012

Page 2 of 32

Pharma-Ethics Standard Operating Procedures

Signature Page

Final Version 1 dated 1 March 2012

Author: M Haskins

Reviewed By: E Hammann, NE Khomo

Approved by: CSJ Duvenage

Signature: ________________________________________________

Date: ____________________________________________________

Title: ____________________________________________________

The information contained in this document is the

property of Pharma-Ethics (Pty)Ltd. The recipient of this

document is responsible for the safekeeping of this

document and for informing other recipients of its proprietary nature.




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TABLE OF CONTENTS

Section Content Page 1. The role of Pharma-Ethics Research Ethics Committee 4

2. The Functions of Pharma-Ethics Research Ethics Committee

4

3. Membership and Administrative Support 5 4. Meetings and Submissions 9

5. Agenda 9 6. Review and Approval Procedures 9

7. New Trial Application 7.1 Submission Requirements

7.2 Review Process

14

14 8. Registry, Post-Marketing Survey or Device Studies

8.1 Submission Requirements 8.2 Review Process

17 18

9. Major Protocol Amendment


19 20

10. Minor Protocol Amendment 20 11. Continuing Review / Annual Re-Approval


21 22

12. Re-submissions 23 13. Expedited Review Procedures 23

14. Recording of Decisions 24 15.

16. 17.

Monitoring

Site Review Ethics Committee Certificate of Compliance

24

24 24

18. Complaints and Suspension or Discontinuation of Research

25

19. Serious Adverse Events and Adverse Drug Reaction

Reporting

25

20. Acknowledgements 27

21. Participant Information and Informed Consent Requirements

27

22. Placebo Control 28 23. Genetic Research 28

24. Use of Human Tissue Samples 29 25. Advertisements 29

26. Epidemiological Research 30 27. Violations and Deviations 31

28. Insurance and Indemnity 31 29. Archiving 31

30. General 31 31. Payments 32




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1. THE ROLE OF PHARMA-ETHICS RESEARCH ETHICS

COMMITTEE

The objective of Pharma-Ethics in reviewing biomedical research is to contribute

to safeguarding the dignity, rights, safety and well-being of all actual or potential

research participants and to ensure that the goals of research do not override the

health, well-being and care of research participants.

It is the aim of Pharma-Ethics to provide independent, competent and timely

review of the ethics of proposed studies.

Pharma-Ethics is multi-disciplinary and multi-sectorial in composition, with

relevant scientific expertise, balanced age and gender distribution and laypersons

representing the interests and the concerns of the community.

2. THE FUNCTIONS OF PHARMA-ETHICS RESEARCH ETHICS COMMITTEE

Reviewing research proposals and protocols to ensure that research conducted

will be in the spirit of endeavouring to promote health, and/or prevent disease

and/or disability and cure disease.

Ensuring that humans involved in research are treated with dignity and that their

well-being is not compromised.

Ensuring that informed consent is obtained.

Granting approval in instances where research proposals and protocols meet

ethical standards.

3. MEMBERSHIP AND ADMINISTRATIVE SUPPORT

Pharma-Ethics (the Committee) consists of members who, collectively, have the

qualifications and experience to review and evaluate the science, health aspects

and ethics of the proposed research.

3.1 Composition

Pharma-Ethics members include:

a chairperson and vice-chairperson

at least nine members, with 60% constituting a quorum

at least one member whose primary area or interest is non-scientific

members of both gender and not more than 70% either male of female

representatives of the communities it serves and, increasingly, reflect the

demographic profile of the population of South Africa




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at least two lay members not currently involved in medical, scientific or

legal work and who are preferably from the community

at least one member with knowledge of and experience in the areas of

research that are regularly considered by the Research Ethics Committee

(REC)

at least one member with knowledge and experience in professional care

or treatment of people

at least one member who has professional training in both qualitative and

quantitative research methodologies

at least one member who is legally trained.

3.2 Appointment of New Members

Members are appointed for a term of five years. For purposes of continuity, the

term can be extended for as long as the member is willing and able to serve on

the committee. When a new member is required to replace a member that

resigns or an additional member is required, a Curriculum Vitae (CV) will be

obtained from potential candidates and distributed to the committee members.

Candidates will be discussed by the members and once the members have

agreed, an appointment will be made. All members are required to sign a service

contract which includes a „Confidentiality Agreement‟ and „Conflict of Interest

Agreement‟. The Chairperson is selected from current committee members for a

minimum period of five years or for as long as the chairperson is willing and able

to perform the required functions.

Pharma-Ethics Independent Research Ethics Committee Members as on 1 January 2012:

Members: Qualification/s: Position:

Dr CSJ Duvenage (F)

(Chairperson)

MBChB, FCP Chief Specialist: Internal Medicine

Dr EHammann (F)

(Vice Chairperson)

MBChB, DOH,

MPharmMed

Clinical Pharmacologist

Prof P Becker (M) PhD Biostatistician

Mr L Scheepers (M) BPharm Pharmacist

Mrs M Haskins (F) BLC, LLB Research Ethicist

Mrs C Grant (F) BA, LLB Human Rights Lawyer

Ms D Masombuka (F) Senior Certificate Lay Member

Prof HS Schoeman (M) BSc, MSc, DSc Biostatistician

Dr L Schoeman (F) BPharm, BA(Hons)(Psy),

PhD, IDRE

Medical Scientist – Medical

Oncology, Psychologist

Dr NE Khomo (F) BSc(Pharm), MBChB,

MMed(Community),

DTM&H, DHSM, DPH

Retired Regional Executive

Manager of Health and Social

Development, Executive Member

of the Medicines Control Council

Mr S Masombuka (M) BA Lay Member

Dr J Strauss (F) MBChB, Postgraduate

Course in Pharmaceutical

Medicine

Non-voting Safety Assessor




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(CV’s of the Committee Members are available on request.)

Only those members who are independent of the investigator and the

Sponsor/Clinical Research Organisation (CRO) of the trial will vote/provide

an opinion on a trial related matter.

Only members who participate in the review and discussion will

vote/provide their opinion and/or advice.

Members who are not able to attend meetings can provide their comments

in writing before the meeting, thereby giving a proxy to one of the

attending members to vote on their behalf.

The investigator may provide information on any aspect of the trial, but

will not participate in the deliberations of the Ethics Committee or in the

vote/opinion of the Ethics Committee.

The Ethics Committee may invite independent consultants with expertise

in special areas for assistance. These consultants may be specialists in

ethical or legal aspects, specific diseases or methodologies, or they may

be representatives of communities, participants or special interest groups.

These consultants will be paid an honorarium on each protocol reviewed

and will be required sign a „Conflict of Interest‟ and „Confidentiality

Agreement‟.

Quorum requirements:

At least 60% of members are required to compose a quorum

No quorum will consist entirely of members of 1 (ONE) profession nor 1

(ONE) gender

A quorum will include at least 1 (ONE) member whose primary area of

expertise is non- scientific

All members must be independent of the institution/site

The committee will ensure that members receive initial and continued education

in research ethics and science, and are kept aware of current issues and

developments in the broad areas of ethics and science. Training will be in the

form of informal discussions during meetings, internet courses such as “TREE for

Africa” and formal certificate courses.

3.3 Functions of Secretariat

1. Organising effective and efficient tracking procedures for each proposal

received.

2. Prepare, maintain and distribute study files.

3. Organise Committee meetings regularly.

4. Prepare, distribute and maintain meeting agendas and arrange meeting

logistics.




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5. Maintain Committee‟s documentation and archive.

6. Provide the necessary administrative support to Committee related activities

to the Managing Director of the Committee, the Chairperson of the Committee

and the Committee members.

7. Perform a pre-review of each submission to ensure adherence to

administrative requirements.

8. Properly distribute and keep files of all correspondence.

3.4 Functions of Managing Director / Administrator

1. In collaboration with the secretariat shall be responsible for the oversight of

Committee documents, records and archives.

2. Undertake all administrative procedures in providing training and education

programs to new and continuing Committee members.

3. Facilitate the provision of training and educational programs to new

Committee and continuing Committee members.

4. Design and disseminate templates for Committee submission documents,

including research protocols, informed consent materials, agreements and

periodic and final reports.

5. Prepare and maintain meeting minutes.

6. Design and maintain a system for collecting and filing all Committee

documents, including meeting minutes, member qualifications, protocol

submissions, etc.

7. Attend Committee meetings, take minutes and verify and distribute minutes

in a timely manner.

8. Correspond with all submitting applicants at all times throughout the

submission and review process, while remaining independent of the

applicant‟s protocol operations.

9. Assist the Chair/Vice-chair to conduct Committee meetings.

10. Create and updated standard operating procedures for the Committee on a

regular basis (at least every 24 months).

3.5 Functions of the Chairperson

1. Chair Committee meetings in accordance with this operating procedure and

relevant regulations.

2. Review and accept revisions that were made as per the committee

recommendation pending protocol approval.




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3. Perform expedited review of research that meets the expedited review

criteria.

4. Assign responsibilities and duties to any other member in his or her absence

and assign responsibilities to other members of the Committee.

5. Evaluate final reports and outcomes.

3.6 Functions of the Vice-Chairperson

1. Assist the Chair in the Committee management.

2. Conduct Committee meetings in the absence of the Chairperson.

3.7 Responsibilities of Members of the Committee

1. Review, discuss and consider research protocols and amendments submitted

for evaluation to safeguard the rights and well-being of study participants.

2. Review progress reports and monitor ongoing studies as appropriate.

3. Support the administrator in the discharge of duties when called upon.

4. Maintain confidentiality of documents and deliberations of the Committee

meetings.

5. Declare conflict of interest.

6. Participate in continuing education activities in biomedical ethics and research.

7. Attend meetings regularly and participate actively during deliberations.

3.8 Conflict of interest

Committee members may have no undisclosed conflict of interest with sponsors

and must disclose actual, apparent or potential conflicts of interest to the

committee. Each member will be required to sign a “Conflict of Interest

Agreement”.

Any member of the committee who presents a conflict of interest with the

protocol submitted must abstain from voting.

3.9 Confidentiality

All issues debated by the Committee are to be kept confidential by all Committee

Members and are not to be distributed to a third party, unless required by law.

Each committee member is obliged to keep confidential the deliberations of

committee meetings and any other information concerning research projects

submitted for the Committee‟s approval.

The Committee shall take care to protect the privacy of individuals involved in the

research project, where applicable. All members will sign a “Confidentiality

Agreement” regarding meeting deliberations, applications and information on

research and related matters.




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4. MEETINGS AND SUBMISSIONS

Meetings are normally held every 2 (TWO) weeks on Wednesday

afternoons, except when the Wednesday falls on a public holiday or where

provision is made for a recess. For more information on meeting and

submission dates refer to www.pharma-ethics.co.za.

All documentation must be submitted NO LATER than 13:00 (1 PM) AT

LEAST 9 (NINE) working days before the scheduled date of the meeting,

as indicated on the list of submission- and meeting dates.

Meetings shall take place at 123 Amcor Road, LYTTELTON MANOR,

CENTURION, Gauteng, South Africa at 16:30.

The Chairperson will conduct all the meetings. If the Chairperson is not

available, the Vice-Chairperson or alternate Chairperson elected from the

members will conduct the meeting.

The Secretariat is responsible for organising the meetings.

5. AGENDA

The Agenda will list the Protocols, Major Amendments, Annual Status Reports and

Responses to Queries to be discussed, and will be sent to the members, together

with the study documents, as they are received from the applicants. The final

Agenda will be sent to members approximately 5 (FIVE) working days before the

meeting.

6. REVIEW & APPROVAL PROCEDURES

The Ethics Committee will consider all aspects of the design of the trial and must

be satisfied of the following:

6.1 Scientific design and conduct of the study

Adequate background information and literature review.

The trial is directed toward answering a specific question, that the

hypothesis is scientifically valid and that the trial medication offers a

realistic possibility of benefit over standard treatment.

The methodology provides a rationale for the selection of appropriate

participants, an appropriate method of recruitment, adequate

understandable information for the purpose of obtaining participants‟

informed consent, a clear description of interventions and observations to

be conducted, and a statistical validation of sample size and outcome.

The justification of predictable risks and inconveniences weighed against

the anticipate benefits of the research participants and the concerned

communities.

The justification for the use of control arms.

The criteria for prematurely withdrawing research participants.

http://www.pharma-ethics.co.za/




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The criteria for suspending or terminating the research as a whole.

The adequacy of provision made for monitoring and auditing the conduct

of the research, including the constitution of a Data and Safety Monitoring

Board (DSMB) or Oversight Committee.

The adequacy of the site including the supporting staff, available facilities

and emergency procedures.

The manner in which the results of the research will be reported and

published.

6.2 Recruitment of research participants

The characteristics of the population from which the research population

will be drawn.

The means by which initial contact and recruitment is to be conducted.

The means by which full information is to be conveyed to potential

research participants or their representatives.

Inclusion/Exclusion criteria for research participants.

6.3 Care and protection of research participants

The competence of the investigator(s) to carry out the proposed study.

Any plans to withdraw or withhold standard therapies for the purpose of

the research and justification for such action.

The medical care provided to research participants during and after the

course of research.

The adequacy of medical supervision and psychological support of

research participants.

The criteria for extended access to, the emergency use of, and/or the

compassionate use of study products.

The arrangement for informing a research participant‟s general

practitioner, including procedures for obtaining the participant‟s consent to

do so.

A description of any plans to make the study product available to the

research participants following research.

A description of any financial costs to research participants.

The rewards and compensation for research participants (money, service,

gifts, etc.).




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The provision for compensation/treatment in the case of

injury/disability/death of a research participant attributable to participation

in research.

The insurance and indemnity arrangement, if required.

6.4 Protection of research participants’ confidentiality A list of people and organisations that will have access to personal data of

the research participants, including medical records and biological

samples.

The measure taken to ensure the confidentiality and security of personal

information concerning research participants.

6.5 Biological specimens and use of human tissue samples

Where biological specimens and human tissue are to be used in research,

researchers and the Committee must be satisfied that the research proposal

conforms to the principles of ethical conduct and the prescribed regulations of the

National Health Act, 61 of 2003.

Approval must be obtained from the Committee for collecting biological

samples for research.

New approval must be obtained for all research on biological samples not

specifically mentioned when approval was originally obtained.

A full description must be provided of any specimens that will be collected

(blood, body fluids, tissue biopsies, etc.).

Plans for obtaining consent and clearance from participants and the

Committee for long-term storage, export and future research must be

specified.

Arrangement for disposal must be specified.

All specimens leaving the country require MTA agreements (See MTA

Template)

In all cases there must be reasonable justification for cross border

transfer/exchange of human biological materials

6.6 Informed Consent Process

The Committee requires a separate document with the following information on

the Informed Consent Process with each New Trial Application:

A description of the process for obtaining informed consent at each site,

including the identification of those responsible for obtaining consent.

The adequacy, completeness, and understandability of written and oral

information to be given to the research participants, and when

appropriate, their legally acceptable representatives.

Clear justification for the intention to include in the research individuals

who cannot consent, and a full account of the arrangements for obtaining

consent for such individuals.




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Assurances that research participants will receive information that

becomes available during the course of the research relevant to their

participation.

The provisions made for receiving and responding to queries and

complaints from research participants or their representatives during the

course of a research project.

A description of how understanding of the information will be assessed

before consent is obtained. Provision can be made for an assessment

document.

Information on how the capacity of vulnerable participants (e.g.

lack/limited decisional capacity, dependence, susceptible to research

harms) to sign informed consent will be assessed.

Information on the continuous efforts that will be made to ensure that the

participants‟ wishes regarding continuation in the study are respected.

6.7 Community considerations

The impact and relevance of the research on the local community from

which the research participants are drawn and the other concerned

communities and the environment.

The steps taken to consult with the concerned communities during the

course of designing the research.

The influence of the community on the consent of the individuals.

Proposed community consultation during the course of the research.

The extent to which the research contributes to capacity-building, such as

the enhancement of local healthcare, research and the ability to respond

to public health needs.

A description of the availability and affordability of any successful study

product to the concerned communities following research.

The manner in which the results of the research will be made available to

the research participants and the concerned communities.

6.8 Vulnerable populations

Special consideration will be given 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. Certain types of research will also require

special attention and the Committee may impose additional measures to protect

the welfare of participants.




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Participants whose involvement needs additional attention include:

Minors

Persons with intellectual or mental impairment

Disabled persons

Persons in dependent relationships

Persons participating in research as groups

Pregnant women

Types of research that need additional attention include:

Research involving indigenous medical systems

Emergency care research

Innovative therapies or interventions

Research necessitating ambiguity of information for participants

For more information, refer to the Department of Health: ‘Ethics in Health

Research Principle, Structures and Processes’ – 2004

6.9 General

The aims of every trial should be precisely stated and every trial should be

conducted by competent South African researchers with suitable experience and

qualifications.

The Ethics Committee may approve, require amendment to, or reject a

research proposal on ethical grounds. Decisions are recorded in writing

and will include reasons for rejection.

In considering a research protocol, the committee may seek assistance

from experts, but the committee must be satisfied that such experts have

no conflicts of interest in relation to the research project under

consideration.

No member of the committee will be allowed to adjudicate on research in

which that member has any conflict of interest in relation to the research

project under consideration.

A research proposal must include a statement of the ethical considerations

involved in the proposed research. The ethics committee must be satisfied

that the research protocol gives adequate consideration to participants‟

welfare, rights, beliefs, perceptions, customs and cultural heritage.

Communication between research sponsors/CRO‟s and the Committee

should be directed through the Principal Investigator unless this

responsibility was delegated in writing to the sponsor/CRO by the

principal investigator.

All documents and other material used to inform potential research

participants must be approved by the Committee, including plain-language

information sheets, consent forms, questionnaires, advertisements and

letters.




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7. NEW TRIAL APPLICATION – PHASE I - III

7.1 Submission Requirements

An application for review of the ethics of proposed biomedical research should be

submitted by a South African qualified researcher responsible for the ethical and

scientific conduct of the research.

Researchers in South Africa have the ethical responsibility to ensure that their

research is relevant both to the broad health and developmental needs of the

country and to the individual needs of those who suffer from the diseases and

concerns under study.

The findings of the research must be translatable into mechanisms for improving

health status of SOUTH AFRICANS.

The following documentation should be submitted to the Secretary of Pharma-

Ethics BEFORE 13:00, no later than 9 (NINE) working days before the next

meeting:

1. Signed and Dated Application Form. (11 copies)

(The application form must be signed by ALL applying principal

investigators)

2. Trial Protocol of the proposed research (clearly identified & dated),

together with supporting documents and annexes. (11 copies)

3. A Summary (as far as possible in non-technical language), synopsis, or

diagrammatic representation (“flow chart”) of the Protocol. (11 copies)

4. Diary Cards and other Questionnaires intended for research participants.

(11 copies)

5. Proposed English Written Informed Consent Forms and Consent Form

Updates in accordance with the requirements set out in the attached PIC

template for all aspects of the research (HIV, Genetic, Minor Assent,

etc.).(Clearly identified and dated.) (11 copies)

6. Participant recruitment procedures (e.g. advertisements) and any other

written information to be provided to participants. (11 copies)

7. Information about payments and compensation available to participants.

(Including costs to participants for study participation.) (11 copies)

8. The process for obtaining Informed Consent at the various sites. (11

copies)

9. Details of Financial Agreements/Study Budget with investigators signed

and dated by the sponsor and the investigator. (11 copies)

10. All significant previous decisions (e.g. those leading to a negative decision

or modified Protocol) by other Research Ethics Committees (REC) or

regulatory authorities for the proposed study and an indication of the

modification(s) to the Protocol made on that account. The reasons for

previous negative decisions should be provided. (11 copies)




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11. A motivation for the use of a placebo control (where applicable). (11

copies)

12. Post Trial Treatment Explanatory Document (where applicable). (11

copies)

13. A list of site details including the name of the site, the site address and

names of the Principal Investigator, Sub-Investigators, Study Co-

ordinators and registered Pharmacists/Dispensers. (11 Copies)

14. Investigator‟s Brochure / registered Package Insert / available safety

information. (4 copies of each document)

15. A delegation letter from all Principal Investigators, delegating their

responsibility to obtain Ethics Committee approval to the Sponsor/CRO,

where applicable. (1 copy)

16. Site Qualification List completed for Principal Investigators, Sub-

investigators, Licensed Dispensers/Pharmacists and other study staff,

evidencing qualifications, capacity, GCP training, etc., including the signed

and dated Declaration by Trialist and GCP Training Certificate. (1 copy)

[See Site Qualification Form Template]

17. A copy of the Sponsor‟s Insurance Certificate covering the Protocol. (1

copy)

18. Medicines Control Council (MCC) Application/Approval/Notification Letter

(if applicable). (1 copy)

19. NHREC Trial Registration Forms. (1 copy)

20. Material Transfer Agreement (if applicable) 1 copy

PLEASE NOTE: Documents must be ring bound (reviewer files 2 – 11) or

filed (master copy) in 11 SEPARATE packs/files, with the following

documents in the various files

FILE 1 - Master File: Documents 1 – 20 (Originals, where applicable)

FILES 2 – 4 (Reviewer Files): Documents 1 – 14

FILES 5 – 11 (Reviewer Files): Documents 1 - 13

Documents not submitted as indicated will be returned to the applicant

without being reviewed.




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7.2 Review Process

All members will be given sufficient time in advance to review the relevant

documentation before the meeting.

A physician will give a brief outline of the disease entity/ies being

investigated in each Protocol under review.

A pharmacist will give a brief outline of the mode of action of the type of

medication/treatment under discussion.

The Protocol, English version of the Participant Information Sheet and

Informed Consent Form will be discussed to assess the Protocol and

participant liability.

The following will be considered, as applicable:

- Scientific Design & Conduct of the Research

- Inclusion Criteria

- Recruitment of Research Participants

- Care & Protection of Research Participants

- Protection of Research Participant Confidentiality

- Informed Consent Process

- Community Considerations

Review of Investigator‟s qualifications and capacity to conduct the

research.

All concerns will be discussed and all members must agree before

approval/conditional approval of a study.

Voting will take place by show of hands.

The applicant will be informed of the approval, conditional approval or

disapproval by facsimile or e-mail. The original documents, as specified

above, will then be mailed to the applicant.

The Committee‟s decision will be known to the applicant within 12

(TWELVE) working days after the meeting, if the application meets

all the requirements set out in this operating procedure.

In instances where these operating procedures are not followed in terms

of submission requirements or where the Participant Information Sheets

and Informed Consent Documents do not comply with our templates, a

PENALTY SYSTEM, whereby applications will be rated, will be put in

place. If an application receives a low rating, a twelve day turnaround

time cannot be guaranteed.




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8. REGISTRY, POST-MARKETING SURVEY, EPIDEMIOLOGICAL

RESEARCH, OBSERVATIONAL RESEARCH OR DEVICE RESEARCH



Ethics BEFORE 13:00 (1PM) no later than 9 (NINE) working days before the

next meeting:

1. Signed and Dated Application Form. (11 copies)

2. Trial Protocol of the proposed research (clearly identified & dated),

together with supporting documents and annexes. (11 copies)

3. A Summary (as far as possible in non-technical language), Synopsis, or

diagrammatic representation (“flow chart”) of the Protocol. (11 copies)

4. Diary Cards and other Questionnaires intended for research participants,

where applicable. (11 copies)

5. Proposed English Written Informed Consent Form and Consent Form

Updates as well as the process for obtaining informed consent.

(Clearly identified and dated.) (11 copies)

6. Participant recruitment procedures (e.g. Advertisements) and any other

written information to be provided to participants. (11 copies)

7. Information about payments and compensation available to participants.

(Including costs to participants for study participation.) (11 copies)

8. List of site details including the site address and names of the Principal

Investigator, Sub-Investigators, Study Co-ordinators and registered

Pharmacists/Dispensers. (11 Copies)

9. Details of Financial Agreements/Study Budget with investigators signed

and dated by the sponsor and the investigator. (11 copies)

10. All significant previous decisions (e.g. those leading to a negative decision

or modified Protocol) by other RECs or regulatory authorities for the

proposed study and an indication of the modification(s) to the Protocol

made on that account. The reasons for previous negative decisions should

be provided. (11 copies)

11. Registered Package Insert / Product Information. (4 copies of each

document)

12. Site Qualification List completed for Principal Investigators, Sub-

investigators, Licensed Dispenser/Pharmacist and other study staff,

evidencing qualifications, capacity, GCP training, etc., including the signed

and date Declaration by Trialist and GCP Training Certificate. (1 copy)

[See Site Qualification Form Template]




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13. A delegation letter from all Principal Investigators, delegating their

responsibility to obtain Ethics Committee Approval to the Sponsor/CRO,

where applicable (1 copy)

14. A copy of the Sponsor‟s Insurance Certificate covering the Protocol. Only

applicable for unregistered medicine/devices (1 copy)

15. Medicines Control Council (MCC) Notification (1 copy)

16. NHREC Trial Registration Forms

PLEASE NOTE: Documents must be ring-bound (reviewers’ files) or filed

(master copy) in 11 SEPARATE packs/files, with the following documents

in the various files:

FILE 1 - Master File: Documents 1 – 16 (Originals, where applicable)

FILES 2 – 4 (Reviewers Files): Documents 1 – 11

FILES 5 – 11 (Reviewers Files): Documents 1 – 10


without review.

8.2 Review Process

All members will be given sufficient time in advance to review the relevant

documentation before the meeting.

A physician will give a brief outline of the proposed registry, survey, device

or observational research being investigated in each Protocol under

review.

A pharmacist will give a brief outline of the mode of action of the type of

medication/treatment/device under discussion.

The Protocol, English version of the Participant Information Sheet and

Informed Consent Form will be discussed to assess the Protocol and

patient liability.

The following will be considered, as applicable:

- Scientific Design & Conduct of the Research

- Inclusion Criteria

- Recruitment of Research Participants

- Care & Protection of Research Participants

- Protection of Research Participant Confidentiality

- Informed Consent Process

- Community Considerations

Principal & co-/-sub-investigator‟s qualifications will be reviewed, if

applicable.




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All queries will be handled and all members must agree before

approval/conditional approval of a study.



disapproval, by facsimile. The original documents will then be mailed to

the applicant.

The Committee‟s decision will be known to the applicant within 12

(TWELVE) working days after the meeting.

In instances where these operating procedures are not followed in terms

of submission requirements or where the Patient Information Sheets and

Informed Consent Documents do not comply with our template, a

PENALTY SYSTEM, whereby applications will be rated, will be put in

place. If an application receives a low rating, a twelve day turnaround

time cannot be guaranteed.

9. MAJOR PROTOCOL AMENDMENT


All Major Protocol Amendments received will be tabled as part of the Agenda

and will be fully discussed and approved or disapproved at a full committee

meeting.

A Major Amendment is an amendment that has an impact on the safety or

integrity of the participants or alters scientific value of the trial or

interpretation of the result or effects validity of data and the design of the

study and planned statistical analyses or significantly alters other aspects of

the trial.

Examples of substantial changes may include, but are not limited to:

Changes to study procedures or design

Changes to measures of efficacy and safety

Alterations to the schedule of samples, addition or deletion of test

measures

Changes to the planned number of participants, the age range or

other entry criteria

Duration or dose of study medication, including comparator.


Ethics before 13:00 (1PM) on or before 9 (NINE) working days before the next

meeting:

1. 11 Copies of the Application Form

2. 11 Copies of the Covering Letter

3. 11 Copies of the Synopsis of the Approved Protocol

4. 11 Copies of the Major Protocol Amendment




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5. 11 Copies of the Rationale for the Amendment

6. 11 Copies of the summary of changes made to the protocol

7. 11 Copies of the English version of the revised Patient Informed Consent (PIC)

(incorporating highlighted changes made to the PIC), where applicable – All

files

PLEASE NOTE: Documents must be ring-bound in 11 SEPARATE

packs/files, with the following documents in the various files:

FILES 1 - 11: Documents 1 – 7 (Originals in file 1 only)


without review.

9.2 Review Process

All members will be given adequate time to review the Amendment before

the meeting.

A physician will give a brief outline of the Amendment.

The Amendment will be discussed and queries will be handled.



disapproval by facsimile within 12 (TWELVE) working days after the

meeting.

10. MINOR PROTOCOL AMENDMENTS

The following documents must be submitted:

1. 1 Copy of the Application From

2. 1 Copy of the Covering Letter

3. 1 Copy of the Major Protocol Amendment

4. 1 Copy of the Rationale for the Amendment

5. 1 Copy of the summary of changes made to the protocol

6. 1 Copy of the English version of the revised PIC (incorporating highlighted

changes made to the PIC) where applicable

Minor amendments will be reviewed and approved by expedited review

procedures and will not be reviewed as part of a formal meeting.




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11. CONTINUING REVIEW / ANNUAL RE-APPROVAL

Continuing review of research will be conducted at appropriate intervals, but

not less than once per year.

The Committee must receive an application for annual re-approval at the

latest ONE YEAR after approval of the research by Pharma-Ethics.

If no participants were enrolled at Pharma-Ethics approved sites

during the first year, the Committee must be informed and no annual

re-approval application will be required. In these instances the date

for annual re-approval will be within 6 months of the first participant

entered at a Pharma-Ethics approved site.

For research that will be completed within a year, no continuing review is

necessary, but the Committee must be supplied with the FINAL STATUS

REPORT for each site upon study completion as well as a summary of the

final study report, once available.

In conducting continuing review all members will receive and review a

protocol summary and a status report on the progress of the research at the

sites approved by the Committee.

Status reports must be completed per site and must be signed and dated by

the Principal Investigator. The status report should include the following

information:

The number of participants screened per site

The number of participants randomised per site

The number of randomized participants withdrawn per site and the

reason for withdrawal. If death was indicated as reason for

withdrawal, the cause of death must be stated.

The number of Serious Adverse Events (SAEs) at the site

A summary of serious adverse events and unanticipated problems

per site, including the outcome of the SAE‟s and their relationship

to the study medication

A statement by the Principal Investigator on the progress of the

research at the site

Any relevant new information.

If the status reports do not contain ALL the above information, the

application will not be reviewed.


The following documentation should be submitted to the Secretary of

Pharma-Ethics on or before 13:00 (1PM) no later than 9 (NINE) working

days before the next meeting:

1. 11 Copies of the Application From

2. 11 Copies of Covering Letter

3. 11 Copies of the Protocol Summary




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4. 11 Copies of the Status Report per Site

5. 3 Copies of all relevant line listings

PLEASE NOTE: Documents must be ring-bound in 11 SEPARATE

packs/files, with the following documents in the various files:

FILES 1 - 3: Documents 1 – 5 (Originals in file 1 only)

FILES 3 - 11: Documents 1 – 4


without being reviewed.

11.2 Review Process

All members will receive a protocol summary and a status report before the

meeting.

The members responsible for safety monitoring will review the line listings.

Members will be given adequate time to review the status report before the

meeting.

A medical doctor will give a brief outline on the status of the study.

The status report will be discussed and concerns will be addressed.

Voting will take place by show of hands


disapproval for the study to continue within 12 (TWELVE) working days of

the meeting.

PLEASE NOTE: A window period of two months between submission for

annual re-approval and receipt of re-approval should be allowed. For

research continuing after the required date of annual re-approval,

Pharma-Ethics approval will expire and research will therefore continue

without ethics approval.

12. RE-SUBMISSIONS

Major inadequacies will usually result in a refusal to approve the Protocol or

Amendment. A new submission will have to be made.

Minor deficiencies in the submission of the Protocol/Amendment will result in

conditional approval with a request for changes or additional information.

The additional or updated information required will be reviewed by a member

of the committee, as well as the chairperson. If found to be satisfactory,

approval will be granted by means of expedited review. Where required,

the re-submission will be discussed at a full meeting.




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13. EXPEDITED REVIEW PROCEDURES

The Committee will review certain categories of research through an expedited

procedure if the research involves no more than minimal risk to the

participants and for review and approval of minor changes to approved

research or conditionally approved research. The expedited review may be

carried out by the Chairperson of the Committee or by one or more designated,

experienced reviewers from among the Committee members. The reviewer has

all the authority of the full committee except that he or she cannot disapprove the

research without going through the review procedures set forth for non-expedited

reviews. A record will be maintained of this review and the approval will be in

writing.

In general, research with potential to cause physical or psychological harm will

not be considered for expedited review. This include medication trials, research

involving invasive procedures and research involving sensitive personal or cultural

issues.

As a rule, the following will be reviewed by expedited procedures and will be

approved by the Chairperson of the Committee or a designated, experienced

reviewer. These approvals will be in writing and records will be maintained. The

full Committee will not be informed of these decisions, unless the opinion of the

full Committee is necessary, in which case it will be discussed at a full committee

meeting:

Minor protocol amendments

Final study approval after conditional approval subject to minor

amendments

Additional sites/investigators

Amended English Informed Consent documents after initial approval

Advertisements

Questionnaires

Changes to patient reimbursement

The applicant will be informed of the approval, conditional approval or disapproval

or the documents submitted for expedited review within 12 (TWELVE) working

days of receipt of the documents.

14. RECORDINGS OF DECISIONS

The Committee maintains a record of all research protocols received and

reviewed.

The Committee will retain on file a copy of each research protocol and application

submitted for approval. The file will include information sheets, consent forms

and relevant correspondence, all in the form in which they were approved. A list

will be kept of the Committee members who were present during discussion of

the application and when the final decision of the Committee was reached.




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15. MONITORING

The Committee has the responsibility to ensure that the conduct of all research

approved by the Committee is monitored. The Committee requires annual

reports from the principal investigator after which annual re-approval will be

given for the study to continue (refer to section 11 for more information).

The Committee has a monitoring plan in place whereby it will adopt any additional

appropriate mechanisms for monitoring, including random inspection of research

sites, data and signed consent forms and records of interviews, with the prior

consent of research participants, where indicated.

It is required that researchers immediately report anything that might warrant a

review of ethical approval of the protocol such as: SAE‟s, proposed changes in the

protocol, protocol violations or unforeseen events that might affect continued

ethical acceptability of the project.

Researchers must inform the Committee, giving reasons, if the research project is

discontinued before the expected date of completion.

The committee may ask to review site monitoring reports on an ad-hoc

basis as part of the monitoring process.

16. SITE REVIEWS

The Committee has the obligation to conduct random site reviews as part of their

responsibilities as specified in the South African Research Ethics Guidelines. The

Committee can also do “for cause reviews” in the following instances:

Complaints from study participants or other relevant parties

Reporting of serious protocol violations at the site

17. ETHICS COMMITTEE CERTIFICATE OF COMPLIANCE

In addition to the above random site inspections, provision is made for Pharma-

Ethics to do compliance visits at sites before or during a clinical trial. These visits

will be voluntary and will be conducted on request of the sponsor or a specific

site.

The purpose of the compliance visits will be to review the sites for compliance

with the relevant ethics principles, structures and processes as required by the

Department of Health. During the compliance visit, the reviewer may make some

suggestions and request corrective action to ensure compliance with the various

guidelines. Upon confirmation of satisfactory corrective action, a certificate of

compliance will be given to the sponsor/investigator by Pharma-Ethics.

Pharma-Ethics personnel should be contacted directly for more information on the

compliance visits.

The costs of these visits will be the responsibility of the sponsor/investigator and

are specified in the Pricing Structure.




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18. COMPLAINTS AND SUSPENSION OR DISCONTINUATION OF

RESEARCH

The contact details of the Committee must be available to all research

participants and researchers in the event that they wish to lodge a complaint. All

complaints will be investigated and parties will receive a response from the

Committee. If the Committee is of the opinion that the compliant warrants a

formal investigation, such an investigation will be launched in the form of a “For

cause” inspection.

Where the Committee is satisfied that circumstances have arisen that a research

project is not being conducted in accordance with the approved protocol and that

the welfare and rights of participants are compromised, the Committee will inform

the regulatory authority and may withdraw Ethics approval.

The Committee will inform the researcher or sponsor of its action and shall

recommend discontinuation or suspension. In such instances, the researcher

must discontinue the research and comply with any special conditions required by

the Committee.

19. SERIOUS ADVERSE EVENTS AND ADVERSE DRUG REACTION

REPORTING

PHASE I – III CLINICAL TRIALS

19.1 Fatal and life-threatening, unexpected adverse drug reactions

All fatal and life-threatening, unexpected adverse drug reactions occurring

at sites approved by Pharma-Ethics must be reported within 7 calendar

days after first knowledge by the applicant.

The initial notification must be followed by a complete report as soon as

possible, within an additional 8 calendar days.

19.2 Serious, unexpected adverse drug reactions which are not fatal or life-threatening

Serious, unexpected adverse drug reactions that are not fatal or life-

threatening, which occur at sites approved by Pharma-Ethics, must be

reported as soon as possible, and not later than 15 calendar days after

first knowledge by the applicant.

19.3 Other

Suspected serious, unexpected adverse drug reactions reports origination

from world-wide clinical sites outside South Africa for clinical trials

conducted with the same product as sites approved by Pharma-Ethics,

should be reported 6-monthly in a line listing format.




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All serious adverse events occurring at sites approved by Pharma-Ethics

should be reported 6-monthly in a line listing format.

All non-serious, unexpected, suspected adverse drug reactions for sites

approved by Pharma-Ethics should be reported 6-monthly in a line listing

format.

The Committee must be notified, within 15 calendar days after first

knowledge by the applicant, when there is a suggestion of a change in the

nature, severity or frequency of expected adverse drug reaction or when

new risk factors are identified.

Any information which may influence the risk-benefit assessment of a

medicine or which would be sufficient to consider changes in the

administration of the medicines or the overall conduct of a clinical trial

must be reported to the Committee within three calendar days of first

knowledge thereof.

A clinical investigator, who has been approved by Pharma-Ethics, must

sign all reports originating from the approved site. A single copy of the

report must be submitted to Pharma-Ethics.

If the sponsor does not agree with the causal association assigned by the

initial reporter or the investigator, the reaction should still be reported.

The following information, as a minimum, should be included when a

Serious Unexpected Adverse Drug Reaction (ADR) is reported (Please

refer to Appendix 8 for a Serious ADR reporting cover sheet):

Protocol number

Protocol title

Participant number

Event onset date – time of onset

Diagnosis (most significant ADR being reported)

Participant’s initials

Date of birth

Investigator’s name

Study product

Description of event

Event outcome

Action taken with regard to study product

Treatment

Causality with study product.

i) A designated member (safety monitor) of the Committee will

review all Serious Unexpected Adverse Drug Reaction Reports.

ii) Line listings will be reviewed by the Chair of the Committee as well

as a designated member (safety monitor) on a 6-monthly basis.

iii) The Ethics Committee will acknowledge receipt of all Serious

Unexpected Adverse Drug Reactions as well as 6-monthly line

listings in writing.

iv) Please address all Serious ADR reports to:

Mrs. Colette Jansen van Vuuren or Ms. Daphne Masombuka




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19.4 POST-REGISTRATION ADVERSE DRUG REACTION

REPORTS

Reactions occurring in South Africa

All serious, suspected adverse drug reactions, occurring in South Africa

related to Phase IV clinical trial approved by Pharma-Ethics, must be

reported by the applicant within 15 calendar days after first notification.

All non-serious, unexpected, suspected adverse drug reactions, occurring

in South Africa with any medicine, must be reported by the applicant

within 15 calendar days after first notification. Do not report non-serious,

expected adverse reactions.

Reactions occurring outside South Africa should not be reported.

20. ACKNOWLEDGEMENTS:

The following documents will only be acknowledged (not approved) by the

Committee:

Translated Patient Information Sheets and Informed Consent

Forms (Certificate of Translation and back translations must be included)

Updated Investigator’s Brochures (a summary of the changes as

well as a rationale for the changes from the previous version must be

included)

Notification of changes in site staff other than principal and sub-

investigators, including resignations and reason for resignation –

includes study co-ordinators and pharmacists. GCP certificate and

dispensing license (where applicable) must be included with the Site

Qualification Form. Information must also be supplied on the capacity of

the site to continue with the trial in case of resignations

Translated Questionnaires and Patient Diary Cards (including

translation certificates)

21. PARTICIPANT INFORMATION AND INFORMED CONSENT REQUIREMENTS:

Separate Patient Information and Informed Consent documents must be

submitted for:

The Main Study

HIV Testing

Pharmacogenetic Research

Assent for minors 7 – 11 years and 12-17 years




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Any other additional research/sub-study that does not form part of

the main research proposal

In all instances verbal and written informed consent should be obtained.

Verbal consent, where the participant is illiterate, should be obtained in

the presence of and countersigned by a literate, independent witness.

Provision must be made for a witness statement.

For minor participants under the age of 18 years, consent from the

parent or legal guardian must be sought. No other caregiver can provide

consent on behalf of a child to participate.

Adequate steps should be outlined to obtain the child‟s assent, when the child

is judged to be capable of providing such assent. Written assent should be

sought, when in the judgment of the parents and investigator the child is

capable of providing their written assent. Maturity, psychological state of mind

and ages should be taken into account.

Informed Consent Documents (ICDs) must comply with the Pharma-Ethics

Patient Information Leaflet and Consent Form TEMPLATES, where applicable.

Refer to APPENDIX 7 for more information.

22. PLACEBO-CONTROL

As a general rule, placebo control will not be allowed by the Committee as

research participants in the control group of a trial of a diagnostic, therapeutic, or

preventative intervention should receive an established effective intervention.

However the Committee will consider applications with placebo-control in the

following circumstances:

i) There is no established effective intervention.

ii) Withholding an established effective intervention would expose

participants to, at most, temporary discomfort or delay in relief of

symptoms.

i) Use of an established effective intervention as comparator would not yield

scientifically reliable results and use of placebo would not add any

risk or serious irreversible harm to the subjects.

In all instances where placebo-control is suggested, the Committee must receive

a separate motivation for the use of placebo for the submitted application.

23. GENETIC RESEARCH

In the case of human genetic research, the Committee requires a sub-protocol or

appendix to the main protocol, outlining the objectives and procedures to be

followed.

The Committee will only allow genetic research within the scope of the protocol

(study medicine toxicity, metabolism, efficacy and specific disease entity studied

within the protocol), i.e. pharmacogenetic research. No open-ended genetic

research will be approved.




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The following will be considered:

Social and cultural significance of the research

The balance between the contribution of knowledge and the potential for

harm to individuals or collectives

The confidentiality and privacy of stored genetic information or research

results relating to identified or potentially identified participants.

Age of participants. Genetic research will not be allowed on minor

participants, unless this research forms part of the selection criteria or

primary objectives of the trial.

23.1 Consent

A separate informed consent for the specific collection of a blood

sample for pharmacogenetic research must be submitted

This document must contain at least the following information:

The genetic research will be limited to the medicine (specify

name) and disease/condition (specify name) under

investigation.

No unspecified research will be conducted without prior consent

from the participant and approval from the Committee.

The costs of the research will be covered by the sponsor.

Information on privacy and confidentiality.

Information on compensation in the event of a trial related

injury.

If samples are to be exported to a central laboratory outside

South Africa, the physical address of this laboratory must be

specified.

The period for which the samples will be stored (maximum 15

years).

In the consent statement, participants must consent to their

samples being shipped to a secure laboratory outside South

Africa.

23.2 Genetic Counseling

If it is anticipated that participants will receive results from the

genetic testing, they should be counseled about the possible

consequences of doing so. Reference must be made to the

counseling in the consent document.

Counseling can be provided at the time of obtaining consent or in

the future, prior to the provision of feedback, where applicable.

24. ADVERTISMENTS

Advertisements for recruitment purposes must be submitted to the Committee for

review and approval before placement and should comply with the following

guidelines:

The following information must be included in the advertisement:




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The general aim of the study.

Essential selection / inclusion criteria required.

A contact telephone number of a person able to answer questions related

to the study.

The name of the Research Ethics Committee that approved the study, the

date on which it was approved and the Ethics reference number for the

study.

The following information should not be included in the advertisement:

The name of a medical practitioner.

Any reference to medicine, which contain a substance appearing in

Schedule 2 and above.

Details of any payment or reimbursement likely to accrue participants.

General:

The advertisement may be published in any medium, printed or

electronic, including the internet and television, provided all the rules

pertaining to advertisements as laid down in this document are

adhered to.

There are no limitations on the size or number of times a notice may

be published.

Details of the clinical trial may be published e.g. “A Phase II Clinical

Trial in Hypertension”.

Direct mailing of advertisements is permissible.

Bulk distribution, for example at shopping malls and to passing

motorists, may be construed as unreasonably drawing attention to the

practice and is not recommended.

Advertisements may be made available for issue individually to existing

patients at the rooms of health care professionals and also at local

information centres such as public libraries and museums.

25. EPIDEMIOLOGIAL RESEARCH

All epidemiological research must be approved by the Committee and should be

conducted according to written protocols that state the aims of the study, the

data that is required and how the data will be collected, used and protected.

When the Committee considers a protocol for epidemiological research it must be

satisfied that:

- The research complies with relevant South Africa legislation or approved

policies dealing with the privacy and confidentiality of data.

- Researchers have the necessary facilities and skills in epidemiology to

conduct the research.

- Access to medical or other records for research should be restricted to

properly qualified researchers.

- There is a scientifically acceptable process for the disclosure of information

and dissemination of research results and, where there is to be selective

disclosure of information, that there are scientifically justifiable reasons for

so doing.

Informed consent of participants should generally be obtained for the use of

Identified or potentially identifiable data for all epidemiological research.




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26. VIOLATIONS AND DEVATIONS

All protocol violations (instances where the selection criteria of the protocol was

not adhered to) and major Good Clinical Practice (GCP) violations must be

reported to the Committee as soon as the applicant becomes aware of the

violation.

Protocol deviations (all other deviations from the protocol) and minor GCP

violations must be reported to the Committee as part of the application for annual

re-approval.

27. INSURANCE AND INDEMNITY

The Committee can only validly examine and issue an opinion on a research

project if the certificate of insurance is enclosed with the application. The

certificate from the insurer serves as presumption of coverage and it is required

to include the following items:

References to the applicable regulatory and legal provisions

Company name of the insurer

The insurance policy number

The name and address of the person/entity, who took out the policy

The exact name of the study that the policy covers.

The duration of the policy. If the policy is not current, it must be renewed

before the study commences.

The policy must show the minimum coverage amount for a biomedical study.

28. ARCHIVING

The Ethics Committee will retain 1 (ONE) set of all submitted documents for a

period of at least 15 (FIFTEEN) years, following the completion of a study.

In those instances where in-house study files for ongoing research are full before

study completion, older documents will be archived and a list of archived

documents will be added to the study file.

In-house files will not be kept for Adverse Event Reports and will be archived on a

daily basis.

29. GENERAL

Pharma-Ethics Research Ethics Committee in granting its approval, is in

compliance with, and must be satisfied that the protocol conforms to the spirit of

the following guidelines:

ICH GCP Harmonised Tripartite Guideline E6: Note for Guidance on Good

Clinical Practice (CPMP/ICH/135/95)

FDA Code of Federal Regulations Parts 50, 56 & 312

The World Medical Association Declaration of Helsinki (current version)




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Guidelines for Good Practice in the Conduct of Clinical Trials in Human

Participants in South Africa, 2006

Council for International Organisations of Medical Sciences (CIOMS):

International Ethical Guidelines for Biomedical Research Involving Human

Subjects (1993)

MRC South Africa: Guidelines on Ethics for Medical Research

Ethics in Health Research: Principles, Structures and Processes, 2004

The Association of the British Pharmaceutical Industry (ABPI)

Compensation Guidelines

No participant may be enrolled in a trial before the Ethics Committee has issued

its written approval.

No deviations from, or changes to the Protocol increasing risk to participants

and/or affecting significantly the conduct of the trial, should be initiated without

prior written approval from the Ethics Committee, except when necessary to

eliminate immediate hazards to participants or when the change(s) involves only

logistical or administrative aspects of the trial.

The Ethics Committee must be informed immediately of any new information that

may adversely affect the safety of the participant or the conduct of the trial.

30. PAYMENTS

After receipt of the submitted documents, a tax invoice will be made out and

faxed or e-mailed and posted to the applicant/sponsor company.

No pro-forma invoices will be necessary as the committee will accept

payment after submission.

Cheques must be made out to Pharma-Ethics or payment can be made directly to

the following account:

- ABSA Lyttelton

- Branch Code: 335045

- Account Number: 600161814

If fees are paid directly into the bank account, the deposit confirmation slip must

be faxed for the attention of Ineke Vermeulen to (012) 664 1721.

PLEASE NOTE: The deposit slip must reference the protocol number and

sponsor.

Refer to www.pharma-ethics.co.za for a list of fees.

http://www.pharma-ethics.co.za/