APPENDICES

1. Review Team

The Review Task Team comprised four members independent of the Department of Health and current medicines regulatory system and three support and resource staff from the Department and Ministry:

Prof Graham Dukes (Norway/The Netherlands/ United Kingdom)
Prof Rob Summers (Medical University of South Africa-MEDUNSA)
Dr Suzanne Hill (University of Newcastle/ Australia)
Dr Wilbert Bannenberg (SADAP coordinator)

Mr Bada Pharasi (Chief Director, DOH)
Dr Ayanda Ntsaluba (Deputy Director-General, DOH)
Dr Ian Roberts (Special Adviser to the Minister of Health)

The Review Team met in Pretoria on January 20, 1998 and reviewed the Terms of Reference and the background material provided. The two international consultants (Prof Dukes/ Dr Hill) spent the subsequent 10 days gathering information, including interviewing staff of the Directorate, members of the MCC and other interested parties, and reviewing additional documents. A meeting with representatives of the pharmaceutical industry took place on 27 January 1998, and attendees were invited to submit formal written submissions for the consideration of the Review Team.

The Review Team reconvened in Cape Town on 9 March 1998, when Prof Dukes and Dr Hill returned to South Africa. The following two weeks were spent in preparing and revising the draft report and presenting it to the Department and Minister.

CURRICULA VITAE OF CONSULTANTS

MAURICE NELSON GRAHAM DUKES

Prof. Dukes is Emeritus Professor of Drug Policy Studies at the University of Groningen (The Netherlands) and Adviser on Drug Policy Studies to the Institute of Pharmacotherapy, University of Oslo, Norway. He is Editor-in Chief of the standard international reference work Meyler's Side Effects of Drugs (13th Edition, 1996, Compact Disk 1998) and of the International Journal of Risk and Safety in Medicine.

He qualified in law and medicine at St. John's College, University of Cambridge and holds a higher degree in medicine from the University of Leiden, The Netherlands. His formal qualifications are MD, MA, LLM.

Dr Dukes held two senior positions in the international pharmaceutical industry, latterly as Research Manager, up to 1972. From 1972 to 1982 he was Medical Director of the Netherlands Drug Regulatory Agency and a member of the corresponding European Committee Products. From 1982 to 1991 he served as head of the Regional Programme for Pharmaceuticals of the World Health Organization (Europe) at Copenhagen.

In addition to his academic work, Prof. Dukes has since 1991 served as pharmaceuticals policy consultant to the World Bank, The World Health Organization, and the bilateral aid agencies of Sweden, Denmark and The Netherlands; this has involved his advising on the reform of national regulatory systems and laws, including those of Spain, Ukraine, Romania, The Netherlands, Laos, Mongolia, Macedonia and Uganda. In addition he has advised in major litigation involving drug safety and efficacy in the USA, the United Kingdom and The Netherlands.

Prof.Dukes has published some 250 papers, many of these relating to drug policy and regulatory management; he is author of 12 books, including the medicolegal volume "Responsibility for Drug-Induced Injury" (Second edition in press).

SUZANNE ROSE HILL

Dr Suzanne Hill (B.Med, Grad.Dip Epi, Ph.D, FAPHM) is a public health physician and clinical pharmacologist and epidemiologist currently appointed as Research Academic in the Discipline of Clinical Pharmacology, Faculty of Medicine and Health Sciences, University of Newcastle, NSW, Australia. Her current position involves postgraduate teaching and research, particularly in the fields of pharmaceconomics and pharmacoepidemiology, as well as clinical work as a physician in the Accident and Emergency Department of the Newcastle Mater Hospital.

Prior to taking up her current post in 1996, Dr Hill was a Senior Medical Officer in the Therapeutic Goods Administration, Commonwealth Department of Health and Human Services. She held a number of senior positions in the Drug Evaluation Branch, responsible for the evaluation and regulation for prescription medicines. She was particularly involved in implementing the changes in the Australian drug regulatory system arising from the Baume Report of 1991.

Dr Hill’s current research and training interests include

• development of methods of applying the results of clinical trials to clinical practice
• analysis of the effects of changes in health policy
• methods for economic evaluation of pharmaceuticals and health care technologies
• training government and industry personnel in methods of economic evaluation
• assessing needs of consumers for information about methods and how best to meet those needs.

Dr Hill has published a number of scientific papers, and has presented papers and lectures at national and international meetings on these and related topics.

ROBERT STANLEY SUMMERS

Professor Summers is currently Head of the School of Pharmacy in the Faculty of medicine at the Medical University of Southern Africa (MEDUNSA). He was educated in Zimbabwe, South Africa and the UK. His formal qualifications are: BSc (Pharm), BSc(Honours)(Pharm), MSc( all Rhodes), PhD(Bradford, UK).

Prior to taking up his current position at MEDUNSA in 1983, he was Head of the School of Pharmacy at the University of Zimbabwe, where he was also Deputy Dean of Medicine. While at MEDUNSA, and in his previous positions, he has contributed to many institutions and organisations, both at management level and in honorary positions.

Professor Summers has a number of research and training interests, which include the following:

• Pharmacy practice in health care, including pharmacy manpower, rational drug use, hospital and clinical pharmacy and pharmacotherapy, especially in children.
• Therapeutic drug monitoring and clinical pharmacokinetics, with special reference to aminoglycosides, theophylline and anticonvulsants
• Photobiology, including UV effects on humans, sun screen preparations and Sun Protection Factor testing
• Extension, outreach and distance learning programmes for pharmacists, pharmacists’ assistants and primary clinical nurses.

Professor Summers has published >50 refereed, scientific research papers, and almost 100 other papers and book contributions on the above topics locally and internationally. He has presented >90 research papers and >50 other lectures at congresses and meetings in South Africa, European countries, Japan, and the USA

WILBERT J. BANNENBERG

Dr Wilbert Bannenberg (MD, MPH) is currently co-ordinator of the South African Drug Action Programme, which is executed by the Action Programme on Essential Drugs of the World Health Organisation to assist the Department of Health in implementing the National Drug Policy.

He qualified in medicine from the Free University, Amsterdam, The Netherlands and then obtained Masters degrees in Community Health in Developing Countries (London School of Hygiene and Tropical Medicine, UK) and Epidemiology (Netherlands Epidemiological Society).

Prior to his appoinment as WHO staff member in South Africa in December 1996, he was a freelance consultant for 12 years with Consultants for Health and Development (CHD, The Netherlands). He completed more than 50 missions to developing countries in the field of essential drugs and national drug policies, for development agencies of The Netherlands (DGIS), United Kingdom (ODA, now DFID), Denmark, WHO, the World Bank and European Union.

In the area of drug regulation, Dr Bannenberg assisted the Peruvian and Zimbabwean Drug Regulatory Authorities to computerise their drug registration; organised 8 training courses for drug regulation in Africa and Asia for the German Foundation for International Development (DSE) and co-ordinated the first two conferences of the African Drug Regulatory Agencies Network (AFDRAN).

2. Terms of reference

EXTERNAL REVIEW OF THE MEDICINES REGULATORY PROCESS

TERMS OF REFERENCE

Finalised January 20th 1998

The Review Task Team, consisting of 2 international and 4 national experts, will investigate and describe the status quo in relation to the following issues, analyse the strengths, weaknesses, opportunities and threats to each topic, and make, where necessary, recommendations for improvements. In doing so, the experiences of comparable regulatory systems around the world should be taken into consideration. The Review Task Team will also review the mission, vision and purpose of the MCC and the Directorate Medicines Administration.

MCC-DOH/Minister Relationship

DOH considers splitting the posts of Registrar of the MCC and Director: Medicines Administration (which are currently joined in one person). Consultants are asked to list (dis)advantages of both scenarios. If split, how are the responsibilities to be split? Should the Registrar continue to be a civil servant What will be the role of the director Medicines Administration viz-a-viz MCC matters? Would the MCO's be responsible to the Director or to the Registrar?

If the MCC is to retain its revenue, what should be the extent of its autonomy with regard to the utilization of such funds and incidental matters? Who should have responsibility for the budget?

The processes and procedures of medicines control and registration

Drug evaluation: review of procedure and strategies chosen in the review of applications; priorities in view of workload; performance measurement and internal quality control systems and indicators; role of Medicines Control Officers (MCO's) and their interaction with Council committees; transparency of decisions; confidentiality of data versus public interest.

Clinical trials: are the guidelines for good clinical practice of good enough a standard? Should responsibility for clinical trials be located within the MCC, or should there be a separate body?

Bioavailability studies and dissolution tests: what are the Guidelines; procedures for exemption from registration requirements; role of Director/Registrar in granting exemptions.

Fast-tracking of registration: which drugs should qualify for fast-tracking? Review of the drafted guidelines.

Appeal process: review in line with changes to Act 101 (Medicines Control Act; recently revised).

Council appointments: procedures for nominations; core skills; to what extent are members orientated?

Relationship of MCC with institutions carrying out certain functions on its behalf, laboratories doing testing and quality control, institutions doing drug surveillance / pharmacovigilance, etc. What is the nature of relationship / contract? What are the funding arrangements?

What is the situation regarding review or call-up procedures for unregistered, "old" medicines, traditional medicines? How best to incorporate the 5-year review process? Would the principle of "pharmacological norms" be helpful?

The processes and procedures of the technical committees of the Council

Criteria and process of appointment of members.

Accountability of committees to Council.

Training programmes for committee members and MCOs.

How are/should the committees be funded?

Administrative support by the Medicines Administration Directorate

What are the decision-making mechanisms in between Council meetings? Are such decisions taken by the executive, the Registrar, the chairman or a special  committee appointed for the purpose? To what extent are decisions referred to Council for ratification? What do the consultants recommend?

What are the international norms regarding qualifications and training requirements for MCOs?

How do the skills of the MCOs compare to international norms? Is the training received adequate for their functions?

Revise staffing norms for MCOs doing registration/evaluation.

Revise staffing norms for MCO's doing inspections.

Considering shortage of pharmacists in the public sector, should health professionals other than pharmacists be used for inspections? If so, what should be
the minimum qualifications / training requirements?

International collaboration and commitments

What are the country's international obligations in terms of drug regulation and related matters? (Conventions, treaties, etc.)

Subsequently, how should the Council's participation in international and regional meetings/conferences/agreements be classified in terms of importance, i.e. i) which are statutory requirements and therefore a "must", ii) simply "nice to attend"?

Is it necessary for the MCC to do overseas inspections of all factories supplying drugs to the SA market? Is there or could there be an arrangement for exchange of information with other regulatory authorities which would shorten the registration procedures? Are there any precedents?

Is it necessary for a product to go through the full registration process if it is already registered with a reputable regulatory authority?

Pharmaceutical companies often offer to pay for the expenses of inspections that have to be done in their factories overseas by MCC's inspectors. It would seem that there is provision for this in some of the statutes, yet policy is largely against this practice. How is this to be viewed?

Definition of a medicine

Review appropriateness of the Medicines and Related Substances Act's definition of a medicine. This is with regard to the viewing of products (including nutrients, herbal products and cosmetics) on the fringe of medicines but making claims for medicinal properties. Should there be special registration categories for such products?

Medical devices

Is the Medicines and Related Substances Act the most appropriate act for the regulation of medical devices. Are there any duplications with the regulatory and licensing functions of the Directorate: Health Technology.

Other matters

The report of the MCC workshop held on 24 November 1997 contains several proposals relating to many of the TOR's. Consultants are requested to study the report and comments on its conclusions and recommendations.

3. Income and expenditure summary

FINANCE - 1 APRIL - 31 DECEMBER 1997

EXPENDITURE (listed under a number of entities which provide funds for the various activities performed by the Council)

Items which are covered under expenditure.

Personnel Expenditure
Salaries via persal
Other salaries : recurring
House Owner’s allowance
Motor allowances snr officials
Service bonus
Merit awards
Medical funds
Pension fund

Administrative Expenditure
Subsistence
Government Garage transport
Contractors and private agencies
Public transport of persons
Motor fin scheme claim > 500km
Private motor transport (staff)
Air tickets
Telephones and phonograms - also under 4. below
Other communication expenses
Training fees : computer person
Entertainment : departmental
Membership/registration fees
Incidental expenditure
Toll road fees
Hire of parking/garages
Regional service council levy

Stores and livestock
Book, journals etc
Printing : government printer
Maintenance materials and spares
Medicines

Professional and Special Services
Mechanical and technical services
Computer maintenance service
Rent of parking/garages
Telephone expenses - also under 2. above
Transport : private agencies
Conference and meetings
Other professional services

Sundry Expenditure
Stabilisation fund contribution

4. Documents consulted

Throughout its work, the Review Team has been provided with many documents. This list does not necessarily all documents sighted by the Team.

1. Background documents provided

Report of meeting of November 24th, 1997.

Skeleton regulations, which were to have been part of the MCC meeting, held in January 1998, including:

1. Therapeutic equivalence.
2. Internal rules of conduct of the Medicines Control Council.
3. Small-scale manufacturing.
4. Re-packaging of medicines in patient-ready packs in a pharmacy.
5. Clause 4 (d)
6. Fast-track registration procedure.
7. Parallel importing.
8. Labelling of medicines.
9. Use of medicine or scheduled substances for exhibition purposes.
10. Criteria relating to the advertising and marketing of medicines intended for administration to humans and medicines for veterinary use.
11. Control of medicines and scheduled substances.
12. Licenses for dispensing.
13. Licenses for manufacturers and wholesalers.
14. Purchase and sale of medicines by wholesalers.
15. Period and manner of appeal.
16. Clinical trials.

Copies of correspondence:

1. From the Chiropractors, Homeopaths and Allied Health Service Professions Council of SA regarding the regulation of complementary medicines (dated 22 January 1998).
2. From the Chiropractors, Homeopaths and Allied Health Service Professions Council of SA to Mr Anthony Rees of Pharmapact, dated 21 November 1997.
3. From the National Association of Pharmaceutical Manufacturers to Mr Pharasi before the Regulatory Affairs meeting of 27 January 1998.(dated 26 January 1998)
4. From Mr D Frank, General Manager of Safeline Pharmaceuticals, to Dr Ian Roberts, date 14 July 1997.
5. From Mr Pharasi to Prof Folb, undated , including copy of letter from Mr Nicolaou (General Manager of Garec Pharmaceuticals) to Mr Pharasi, dated 21 August 1997.
6. From The South African Reflexology Society to Dr Shisana, 31 December 1997 and reply from Mr Pharasi, 11 February 1998
7. Fax from Prof P Eagles to Ms P Matsoso, 6 November 1997

Copies of departmental documents:

1. Registration of "old" medicines from Directorate at Medicines Administration to the Minister, dated 7 October 1997.
2. Complementary medicines : from Director, Medicines Administration to Director- General (DOH) dated 4 December 1997.
3. The control of medicine manufacture as practised by the Registrar of Medicines, Status Report to MCC: 1997.
4. Remuneration of highly specialised specialists/scarce groups. From Director Medicines Administration to Chief Directorate, 25 August 1997.
5. Complementary medicines. From Director of Medicines Administration to Director-General, 4 December 1997
6. Medicines Control Council : Conflicts of interests : Version 3 : Approved implementation 1996.05.31 (R161).
7. List of trials since 1995, which was distributed by e-mail to the Review Team members on 13 February 1998.
8. Contracting-out of a service: National Control Laboratories (NCL) for biological medicines and vaccines (Tender no. RT9091ST).
9. The Tender : Laboratory and related services for the Directorate of Medicines Administration (DOH) (Tender no. RT9372ST).
10. Standard operating procedure (SOP) describing activities that comprise the medicines registration and control process : from Directorate, Medicines  Administration to members of the Medicines Control Council (document undated).
11. Circular 26/93, regarding "Applications to conduct clinical trials", date October 1993.
12. List of all "Dear Applicant Letters" circulated since 1995.
13. Circular 09/97, "Up-to-date list of persons, functions and e-mail", 12 February 1998.
14. Memo, from J.Schlebusch to Chief Director, "Initiative to discredit the MCC and this office", 4 March 1998.
15. Copy of correspondence between Department and Garec, with covering memo from J. Schlebusch to Chief Director, date 27 February 1998.
16. Memo to the Task Team from Directorate, Medicines Administration concerning the process in developing bioequivalence requirements, 3 March 1998.
17. Circular 5/96, concerning "Increased tariffs....", 21 February 1996.
18. Monthly Report, Directorate Medicines Administration, 27 February 1998
19. Memorandum from Director: Medicines Administration on Leave and Vacation Policy, 12 January 1998
20. Tabular overviews of Departmental Expenditure, Department of Health (various tables).
21. Draft Regulation pertaining to the constitution of the MCC and the Executive Committee, 19 January 1998.
22. National Drug Policy for South Africa. Department of Health publication, January 1996.
23. Report from Inspectorate (sub-directorate Medicines Control) to the Review Team, January 27th 1998, comprising inspection repots, operational plans, overviews of activities, training week agenda and current planning.
24. Old Medicines Evaluation Program: Sample Monographs (Antihistamines, Analgesics and Antipyretics, Antacids, Gripewaters).
25. Duty Sheet for Dr B.S. de Wet, 13 January 1997.

Miscellaneous other information

1. Draft of the National Veterinary Medicines Policy.
2. Code of practice for the pharmaceutical industry 1998, prescription medicines: ABPI
3. Sample list of Old Medicines, provided to the Review Team during the week of January 26 1998.
4. List of reports requested and received from PER-countries, 1995-1997
5. List of Expert Committees and current members, but excluding affiliations/addresses.
6. "Difficulties with MCC Applications" from Dr K.A.Payne, dated 1990 and 1996.
7. Inspection : How to do an inspection for compliance with current good laboratory practice (GLP) at an analytical laboratory.
8. University of Witwatersrand (Department of Pharmacy): Timetable and Module 2 of M.Pharm Course in Industrial Pharmacy (Regulatory Affairs and Medicine Registration), October 1997.
9. Medicines Control Agency (London): Internet Home Page, Updated November 18th 1997
10. Annual Report (1997) of the National Adverse Drug Event Monitoring Centre.
11. Provision Draft: National Health Bill, 17 December 1997, Sections 143 (Research on Human Subjects), 144 (The National Ethics Council) and 145 (Ethics Committees).
12. Draft Essential Drug List for Hospitals. 5 January 1998.

5. Persons consulted

The list of persons consulted was determined in part by the limited time available during the consultancy. All persons who themselves requested a meeting were personally consulted. Not all informal or brief discussions that took place may necessarily be included in the list below.

1. Department

2. Medicines Control Council and its Committees

3. Other

Mr Ivan Kotze, Executive Director, Pharmaceutical Society of South Africa
Dr W Prozeskey, President, Medical Research Council
Dr Anthony Mbewu, Executive Director of Research, MRC
Prof Dent, Sis. Matiswa, Prof van Nierkerk - University of Capetown Ethics Committee
Mr Stuart Thompson, Pharmapact
Dr H Mateme, MEC, Northern Province

6. Submissions received

1. The South African Association of Pharmaceutical Physicians, 27 January 1998.
2. The South African Pharmaceutical Regulatory Affairs Association, January 1998.
3. The Direct Sales Association, 18 February 1998.
4. Cape Lobby for Health Freedom, 26 February 1998.
5. Adcock Ingram, 12 February 1998.
6. Ranbaxy (SA) (Pty) Ltd, 19 February 1998.
7. Be-tabs registration department, 16 February 1998.
8. Garec (Pty) Ltd, undated.
9. The Health Products Association of SA (HPA), 12 February 1998.
10. Medical Supplies International (SA) (Pty) Ltd, 16 February 1998.
11. Pharmapact; facsimile dated 13 February 1998, including copy of facsimile dated 2 February 1998 to Dr O Shisana, plus fax to Prof Dukes/Dr Hill,
    6 March  1998, and revised submission received 9 March 1998
12. Natal Bioproducts Institute, 22 January 1998.
13. Pharmaceutical Manufacturers Association, undated.
14. The Chiropractors, Homeopaths and Allied Service Professions Interim Council, 16 February 1998.
15. Apotex S.A., 16 February 1998.
16. GR Pharmaceuticals (Pty) Ltd., 3 February 1998.
17. National Association of Pharmaceutical Manufacturers, 4 March 1998.
18. Mrs W.H.Maritz: (a) job description (b) update on medical device registration.