1. MCC presentation to Portfolio Committee on Health -Dr T M Mathivha Vice-Chair MCC Friday 16 August 2002

2. MEDICINES CONTROL COUNCIL Medicines and Related Substances Control Act, (Act 101 of 1965):  Sect 2(1) Establishment, Powers and Functions of MCC  Sect 2(2) “Council may advise the Minister or furnish a report to the Minister on any matter referred to the Council by the Minister for consideration and arising from the application of this Act”  Sect 3(2) Appointment of Council members by the Minister  Sect 9 Council appoints executive committee and other committee members

3. MEDICINES CONTROL COUNCIL Responsibility for approving medicines for use in South Africa and the control thereof Sect 1(3) “In determining whether or not the registration or availability of a medicine is in the public interest, regard shall be had only to the safety, quality and therapeutic efficacy thereof in relation to its effect on the health of man or any animal, as the case may be”

4. MEDICINES CONTROL COUNCIL  24 Council members with well defined expertise and skills  10 Technical Expert Committees  146 members in total  Academic, research and professional backgrounds  Various institutions throughout the country  Range of skills and expertise to the regulatory process

5. MEDICINES CONTROL COUNCIL EXPERTISE Experts in the fields of clinical immunology, clinical pharmacology, virology, toxicology, epidemiology, biochemistry, biostatistics, pharmaceutics, pharmaceutical and analytical chemistry, as well as experts in all specialties of clinical medicine, dentistry, pharmaceutical and veterinary sciences and complementary health

6. COMMITTEES OF COUNCIL 1. Clinical Committee 2. Pharmaceutical and Analytical Committee 3. Clinical Trials Committee 4. Biologicals Committee 5. Veterinary Committee 6. Scheduling Committee 7. Complementary Medicines Committee 8. African Traditional Medicines Committee 9. Pharmacovigilance Committee 10. Veterinary Clinical Committee

7. Registrar of Medicines Sect 12(1) Registrar of Medicines appointed by the Minister after consultation with Council Statutory functions imposed under the Act Secretariat to Council Issues certificates of registration for medicines approved by Council

8. Administration and Technical Support to MCC Provided by the Office of the Registrar of Medicines: A staff complement of 102 with pharmaceutical, clinical, scientific and administrative knowledge and experience. Central activities in Pretoria Two safety monitoring units at MEDUNSA and UCT

9. History of Medicine Regulation in South Africa  South Africa was among the first countries in the world to introduce specific legislation to regulate medicines  Began more than 30 years ago with the Thalidomide disaster in the early 1960’s  Over 200 Council meetings have been held since its inception and approximately 20 000 medicines, including antiretroviral, have been approved to date

10. History of Medicine Regulation in South Africa  Evaluation, approval and registration of medicine for sale in South Africa occurs through expert opinion and peer-review processes of the technical committees of Council  17 antiretroviral agents have been approved by the MCC through these technical processes  Recognition of the regulatory decisions of established regulatory agencies of other countries, namely, USA, UK, Australia, European Union.

11. MEDICINES CONTROL COUNCIL International Co-operation  Since 1979, member of Pharmaceutical Evaluation Review group; an international forum for established regulatory agencies  Also served as chair to this body  Membership and involvement enables exchange of evaluation reports on safety and efficacy of medicines with various regulatory agencies including the the Medicines Control Agency (UK), the Therapeutic Goods Administration (Australia) & Sweden  Regulatory exchanges are also regularly undertaken with the US Food and Drug Administration (FDA)

12. DRUG SAFETY  Continuous and routine reviews of status of all registered medicines  Basis – national and international reporting of adverse drug reactions (ADR’s)  Legal requirement – reports of ADR’s of any medicine approved by Council submitted timeously to MCC  If cause for alarm -registration of the medicine reviewed and if necessary de-registered and withdrawn from the market

13. PHARMACOVIGILANCE UNIT - ANTIRETROVIRAL AGENTS  A new Pharmacovigilance Unit established at the Medical University of South Africa (MEDUNSA).  Primary function - to monitor adverse events related to antiretroviral therapy in South Africa  Works in collaboration with the existing MCC Pharmacovigilance Unit based at the University of Cape Town

14. PHARMACOVIGILANCE UNIT - ANTIRETROVIRAL AGENTS (2)  Already embarked on a survey of the pilot sites where nevirapine is being used to reduce mother to child transmission of HIV.  Other programmes - focus attention on safety monitoring during the conduct of clinical trials with antiretroviral agents.

15. Drug Registration Process  PRE CLINICAL STUDIES  Elucidate hazards & estimate risks  CLINICAL  Data from Clinical Trials –Pivotal study (unequivocal evidence, clinical expert report, appropriate diagnostic & outcome criteria, general applicability)

16. REGISTRATION STATUS IN OTHER COUNTRIES  Detail approvals with indications, deferment, withdrawal,rejection with reasons  Year of approval and conditions, formulations, indications, dosages, copy of PI & registration certificate or particulars  KEY COUNTRIES –MCA OF UK –FDA OF USA –TPP OF CANADA –TGA OF AUSTRALIA –EMEA OF EU

17. Drug Registration :Quality  Manufacturing Procedures –Site master file –Inspection flow diagram –GMP & WHO type certificate –In process controls  STABILITY PROGRAM –temperature, humidity –time points of determination  FINAL PRODUCT SPECIFICATIONS –Identification(salts, isomers) –Assays –Dissolution profile

18. NEVIRAPINE (NVP) RECORD OF EVENTS AND REGULATORY DECISIONS  1996: Submission of application to register nevirapine (NVP) - use with other antiretroviral agents for the treatment of chronic HIV infection was first filed with the MCC.  1998 February: Indication approved, product registered. Subsequently several changes made to package insert of product to address new information on its safety and efficacy, in line with international regulatory decisions.

19.  1999 August: WHO Technical Meeting on nevirapine  1999 November: Application received to fast track the approval of nevirapine as a single agent (monotherapy) for the reduction of HIV transmission from mother to child(MTCT), based on a single study conducted in Uganda (HIVNET012).  2000 January: Clinical Committee of the MCC presented its recommendations for Fast Track Approval to Council.  2000 March: Report of Resistance concerns by the World Health Organisation on the HIVNET012 study.  2000 April: At this stage, Council deferred its decision due to limited evidence of safety and efficacy, concerns of resistance and since an ongoing study (SAINT study) with NVP for this indication was being conducted in South Africa  2000 April : Decision on the applicants request for the inclusion of the claim for the prevention of MTCT be deferred until further clarification on reported Resistance and results of the Saint Study at end on July 2000 is available

20.  2000 July: Post AIDS 2000 Conference, special committee of council established to assess the pronouncement at conference and data submitted, and published data on, safety, efficacy, resistance, breastfeeding.  2000 August: Council requested meeting with researchers and the manufacturer of nevirapine  - discuss NVP and SAINT Study  - request full data and report from SAINT study  2000 September: further meetings of the technical committees of council on NVP for MTCT. Resolved that Council is treating the matter with the urgency it affords by requesting the Clinical committee to hold an extra-ordinary meeting and Council to have a two day meeting in October in order for Council to apply their minds and to debate the issue properly  2000 October: Council decision - refer matter to clinical committee for decision on safety

21.  2000 November: First Council resolution on NVP for MTCT(see handout-A)  2000 December: Executive Committee of Council meeting  2001 February: Further resolutions on NVP(see handout-B)  2001 March- final resolution of MCC with conditions(see handout-C)  2001 April : final package insert and clarity on lack of efficacy  APPROVAL FOR THE INDICATION FOR MTCT  2001July: Due date for submission of SAINT report by manufacturer  2001 October: Reminder to manufacturer to submit SAINT study report and 6 monthly safety report  2001 November: SAINT study report submitted to council by manufacturer  2001 December: Review of report by clinical trial committee

22.  2002 January: MCC discuss SAINT study report  2002 March- letter from manufacturer - problems in Uganda  EXCO had a special meeting, letter to Minister and copy to DG informing him in terms of Section 2 of the Act  2002April: letters to manufacturer, FDA, NIH on HIVNET 012  2002 April: response from FDA and manufacturer  2002 April 26 Special meeting of Council to Discuss Nevirapine  2002 May: further response to manufacturer, FDA and NIH,  2002 May 10 MCC meeting Further discussion on the reports  2002 June: Correspondence from manufacturer, NIH and MCC response to NIH.

23.  June 7 Exco Meeting Further discussion and review of the data and information supplied and decision to invite the applicant to next Council meeting in July 2002  2002 July: Meeting with US official (Health attaché of the US embassy) in MCC offices. Discussion on the conditions in which we can obtain the data from NIH.To sign confidentiality but can only view the data at the US embassy and not obtain a hard copy! Also informed that a re-monitoring of the HIVNET012 site at a significant cost and the results will be available in September 2002  2002 July Meeting with manufacturer at July Council meeting.