1. REGISTRATION OF MEDICINES & PROGRESS WITH RESTRUCTURING THE MCC 1

2. OUTLINE Obligations & Functions Elements of effective regulation Requirements new medicines and generic medicines Management of Clinical Trials Post registration amendments Pharmacovigilance & Post Marketing Surveillance Restructuring of the MCC 2

3. OBLIGATIONS Public safety & protection through ensuring efficacy, safety & quality of medicines throughout their lifecycle Risk assessment – minimization of harm and maximization of benefit Timely access to medicines & timely action on safety & quality Transparency & accountability Responsiveness Capacity to regulate 3

4. ELEMENTS OF EFFECTIVE REGULATION (WHO) Decisions should be based on scientific evidence and facts Practicable enforcement capacity Accountability and public interest/public good Safeguard against conflict of interest Limit discretionary powers Good regulatory practices and standards Independence from public, commercial and political pressure 4

5. FUNCTIONS Registration of medicines based on quality efficacy and safety Management of post- marketing amendments Approval and monitoring of clinical trials Monitoring of safety Response to signals Licensing manufacturers, wholesalers and distributors Provision of information 5

6. Medicines Control Council Chair Person Medicines Control Council Vice Chair Person Registrar of Medicines Pharmaceutical and Analytical Committee Complementary Medicines Committee Clinical Trials Committee African Traditional Medicines Biological Medicines Committee Names and Scheduling Committee Veterinary Clinical Committee Legal Committee Clinical Committee Pharmacovigilance Committee Bio-Therapeutic Committee Medicines Control Council & Expert Committees 6

7. REGISTRATION REQUIREMENTS OF NEW CHEMICAL ENTITIES 7 Development of a drug starts with the identification of potential drug candidates (early research) Preclinical Development - to determine the safety profile in in vitro and in vivo animal studies Toxicity studies include organs targeted by the drug Any long term carcinogenic effects, toxic effects on mammalian reproduction Choice of animal species based on which one will give the best correlation to human trials

8. REGISTRATION REQUIREMENTS OF NEW ENTITIES cont. 8 Clinical trials Phase I A sample size of 20 - 80 participants (usually healthy individuals) to determine metabolic and pharmacological actions and the maximally tolerated dose Factors to be identified: Bioavailability, dose proportionality, metabolism, pharmacodynamics, pharmacokinetics Data focus: Vital signs, plasma and serum levels, adverse events Duration: up to 1 month

9. REGISTRATION REQUIREMENTS OF NEW CHEMICAL ENTITIES cont. 9 Phase II A sample size of 200 – 300 participants to evaluate effectiveness, determine the short term side effects, identify common risks for a specific population and disease Factors to be identified: Bioavailability, drug-disease interactions, efficacy at different doses, pharmacodynamics, pharmacokinetics, patient safety Data focus: Dose response & tolerance, adverse events, efficacy Design: Placebo controlled or active controlled comparisons Population: Individuals with target disease Well defined entry criteria & duration of several months

10. REGISTRATION REQUIREMENTS OF NEW CHEMICAL ENTITIES cont. 10 Phase III To obtain additional information about the effectiveness of clinical outcomes and evaluate overall risk-benefit ratio in a demographically diverse sample Data focus: Laboratory data, efficacy, adverse events Factors to be identified: Drug - disease interactions, drug-drug interactions, dosage intervals, risk benefit information, efficacy and safety for sub-groups Design: Randomised, controlled, 2-3 treatment arms, broader eligibility criteria Population: Individuals with target disease and hundreds to thousands of participants Duration: Several years

11. REGISTRATION REQUIREMENTS OF NEW CHEMICAL ENTITIES cont. 11 Phase IV (post-registration) Aim: to monitor ongoing safety in a large population Factors to be identified: Epidemiological data, efficacy and safety within large diverse populations, pharmacoeconomics Data focus: Efficacy, pharmacoeconomics, epidemiology, adverse events Design: Uncontrolled, observational Population: Individuals with target disease, new age groups, genders etc. Risk management plans

12. GENERIC EVALUATION cont. 12 Knowledge of composition of formulation Confirmation of chemical equivalence with innovator drug Stability of formulation Proportional similarity of different strengths with innovator comparator Derived from appropriately designed bioequivalence protocols

13. QUALITY Quality – applies to all evaluations  Active pharmaceutical ingredient, excipients, impurities  Manufacturing method  Good Manufacturing Practice standards  Specifications for the final product  Container suitability  Stability for shelf life determination 13

14. QUALITY PILLARS Pre-registration Pharmaceutical assessment GMP inspections Validation Qualification Stability data GCP inspections Manufacturing Licence Responsible Pharmacist GMP compliant Natural Person GMP certificates CPP certificates Post Registration GMP inspection Recalls (Class, Type) Advertising QC testing 14

15. MANAGEMENT OF CLINICAL TRIALS 15 No clinical trial may commence before approval by both MCC and local Ethics Committee Local Ethics Committees registered with The NATIONAL HEALTH RESEARCH COUNCIL Universal principles of autonomy, beneficence and justice must be respected MCC has authority to terminate a clinical trial for reasons of SAFETY or where there is evidence of GCP violations

16. KEY ASPECTS FOR CLINICAL TRIAL APPROVAL In the approval of Clinical Trials the MCC considers the following aspects: a. Scientific rationale b. Safety and c. Contribution to new scientific knowledge  Is it ethical, relevant and can patient safety be assured?  When the trial is undertaken in South Africa the subjects should benefit from the results of the research

17. KEY ASPECTS FOR CLINICAL TRIALS cont. SCIENTIFIC RATIONALE Does the trial contribute to new scientific knowledge? Is it plausible and scientifically appropriate? Is the study design optimal? Should the trial be conducted in the RSA? Is there adequate pre-clinical evidence of safety and efficacy?

18. KEY ASPECTS FOR CLINICAL TRIALS cont. SAFETY Balance of risks versus benefits Is there adequate data from pre-clinical studies ? Are the animal models used appropriate? Is there adequate monitoring in place? Pharmacovigilance and GCP inspection reports Is safety stipulated as an objective?

19. POST MARKETING PHASE 19 Safety monitoring Market surveillance Laboratory testing Good Manufacturing Practice compliance Good Clinical Practice compliance Variations and approval thereof e.g.  Additional or new indications  Change in source or method of synthesis of Active Pharmaceutical Ingredient, excipients, packaging etc.  Change of packer, laboratory release, packaging, address, manufacturing site etc.

21. PROGRESS 21 Registration, rejections withdrawals YEARTOTAL 08/09541 09/10748 10/11970 11/12 Up to October411

22. PROGRESS CLINICAL TRIALS 22 YEAR200920102011 RECEIVED212202254 APPROVED205181154 WITHDRAWN682 REJECTED173 PENDING0693 NOTIFICATION2

23. RESTRUCTURING OF THE MCC 23 Three sets of regulations have been published for public comment  Complementary and Alternative Medicines  Medical Devices and In Vitro diagnostics  Food Legislation however must be amended to:  Separate medicines from the definition of health products to avoid blurring the classification of medicines with the classification of devices  Enable the regulation of food and cosmetics  Strengthen governance issues in the statute  Strengthen some elements medical device regulation in the statute