STANDARD OPERATING PROCEDURES

Transcription

1 STANDARD OPERATING PROCEDURES Final, Version 1: 01 March 2012 Pharma-Ethics (Pty)Ltd Registration No. 99/13868/07 PO Box 786 Irene, Amcor Road Lyttelton Manor, 0157 Tel: (012) Fax: (012)

2 Pharma-Ethics Research Ethics Committee: 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. Page 2 of 32

3 Pharma-Ethics Research Ethics Committee: TABLE OF CONTENTS Section Content Page 1. The role of Pharma-Ethics Research Ethics Committee 4 2. The Functions of Pharma-Ethics Research Ethics 4 Committee 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 8. Registry, Post-Marketing Survey or Device Studies 8.1 Submission Requirements 8.2 Review Process 9. Major Protocol Amendment 9.1 Submission Requirements 9.2 Review Process Minor Protocol Amendment Continuing Review / Annual Re-Approval 11.1 Submission Requirements 11.2 Review Process 12. Re-submissions Expedited Review Procedures Recording of Decisions Monitoring Site Review Ethics Committee Certificate of Compliance Complaints and Suspension or Discontinuation of 25 Research 19. Serious Adverse Events and Adverse Drug Reaction 25 Reporting 20. Acknowledgements Participant Information and Informed Consent 27 Requirements 22. Placebo Control Genetic Research Use of Human Tissue Samples Advertisements Epidemiological Research Violations and Deviations Insurance and Indemnity Archiving General Payments 32 Page 3 of 32

4 Pharma-Ethics Research Ethics Committee: 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 Page 4 of 32

5 Pharma-Ethics Research Ethics Committee: 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) MBChB, FCP Chief Specialist: Internal Medicine (Chairperson) Dr EHammann (F) MBChB, DOH, Clinical Pharmacologist (Vice Chairperson) MPharmMed 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), Medical Scientist Medical PhD, IDRE 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 Page 5 of 32

6 Pharma-Ethics Research Ethics Committee: (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. Page 6 of 32

7 Pharma-Ethics Research Ethics Committee: 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. Page 7 of 32

8 Pharma-Ethics Research Ethics Committee: 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. Page 8 of 32

9 Pharma-Ethics Research Ethics Committee: 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 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. Page 9 of 32

10 Pharma-Ethics Research Ethics Committee: 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.). Page 10 of 32

11 Pharma-Ethics Research Ethics Committee: 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 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. Page 11 of 32

12 Pharma-Ethics Research Ethics Committee: 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. Page 12 of 32

13 Pharma-Ethics Research Ethics Committee: 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 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. Page 13 of 32

14 Pharma-Ethics Research Ethics Committee: 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) Page 14 of 32

15 Pharma-Ethics Research Ethics Committee: 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 Coordinators 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, Subinvestigators, 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. Page 15 of 32

16 Pharma-Ethics Research Ethics Committee: 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 . 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. Page 16 of 32

17 Pharma-Ethics Research Ethics Committee: 8. REGISTRY, POST-MARKETING SURVEY, EPIDEMIOLOGICAL RESEARCH, OBSERVATIONAL RESEARCH OR DEVICE RESEARCH 8.1 Submission Requirements The following documentation should be submitted to the Secretary of Pharma- 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, Subinvestigators, 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] Page 17 of 32

18 Pharma-Ethics Research Ethics Committee: 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 Documents not submitted as indicated will be returned to the applicant 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. Page 18 of 32

19 Pharma-Ethics Research Ethics Committee: All queries will be handled 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. 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 9.1 Submission Requirements 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. The following documentation should be submitted to the Secretary of Pharma- Ethics before 13:00 (1PM) on or before 9 (NINE) working days before the next meeting: Copies of the Application Form Copies of the Covering Letter Copies of the Synopsis of the Approved Protocol Copies of the Major Protocol Amendment Page 19 of 32

20 Pharma-Ethics Research Ethics Committee: Copies of the Rationale for the Amendment Copies of the summary of changes made to the protocol 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) Documents not submitted as indicated will be returned to the applicant 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. Voting will take place by show of hands. The applicant will be informed of the approval, conditional approval or 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. Page 20 of 32

21 Pharma-Ethics Research Ethics Committee: 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 Submission Requirements 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: Copies of the Application From Copies of Covering Letter Copies of the Protocol Summary Page 21 of 32

22 Pharma-Ethics Research Ethics Committee: 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 Documents not submitted as indicated will be returned to the applicant without being reviewed 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 The applicant will be informed of the approval, conditional approval or 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. Page 22 of 32

23 Pharma-Ethics Research Ethics Committee: 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. Page 23 of 32

24 Pharma-Ethics Research Ethics Committee: 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. Page 24 of 32

25 Pharma-Ethics Research Ethics Committee: 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 Serious, unexpected adverse drug reactions which are not fatal or life-threatening Serious, unexpected adverse drug reactions that are not fatal or lifethreatening, 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 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. Page 25 of 32

26 Pharma-Ethics Research Ethics Committee: 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) iii) Line listings will be reviewed by the Chair of the Committee as well as a designated member (safety monitor) on a 6-monthly basis. 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 Page 26 of 32