REGISTRATION OF MEDICINES & PROGRESS WITH RESTRUCTURING
THE MCC
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OUTLINEObligations & FunctionsElements of effective regulationRequirements new medicines and
generic medicinesManagement of Clinical TrialsPost registration amendmentsPharmacovigilance & Post Marketing
SurveillanceRestructuring of the MCC
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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 & accountabilityResponsivenessCapacity to regulate
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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
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FUNCTIONSRegistration of medicines based on
quality efficacy and safety Management of post- marketing
amendmentsApproval and monitoring of clinical trialsMonitoring of safetyResponse to signalsLicensing manufacturers, wholesalers
and distributorsProvision of information
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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 MedicinesBiological Medicines
Committee
Names and Scheduling Committee
Veterinary Clinical Committee
Legal Committee
Clinical Committee
Pharmacovigilance Committee
Bio-Therapeutic Committee
Medicines Control Council & Expert Committees
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REGISTRATION REQUIREMENTS OF NEW
CHEMICAL ENTITIES
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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
REGISTRATION REQUIREMENTS OF NEW
ENTITIES cont.
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Clinical trialsPhase 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
REGISTRATION REQUIREMENTS OF NEW CHEMICAL ENTITIES cont.
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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 diseaseWell defined entry criteria & duration of several months
REGISTRATION REQUIREMENTS OF NEW CHEMICAL ENTITIES cont.
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Phase IIITo 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
REGISTRATION REQUIREMENTS OF NEW CHEMICAL ENTITIES cont.
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Phase IV (post-registration)Aim: to monitor ongoing safety in a large
populationFactors to be identified: Epidemiological data,
efficacy and safety within large diverse populations, pharmacoeconomics
Data focus: Efficacy, pharmacoeconomics, epidemiology, adverse events
Design: Uncontrolled, observationalPopulation: Individuals with target disease, new
age groups, genders etc.Risk management plans
GENERIC EVALUATION cont.
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Knowledge of composition of formulation
Confirmation of chemical equivalence with innovator drug
Stability of formulationProportional similarity of different
strengths with innovator comparatorDerived from appropriately designed
bioequivalence protocols
QUALITY
Quality – applies to all evaluationsActive pharmaceutical ingredient ,
excipients, impuritiesManufacturing methodGood Manufacturing Practice
standards Specifications for the final productContainer suitabilityStability for shelf life determination
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QUALITY PILLARS
Pre-registration
Pharmaceutical assessment
GMP inspections Validation Qualification Stability data
GCP inspections
Manufacturing
LicenceResponsible
Pharmacist
GMP compliant
Natural Person
GMP certificates
CPP certificates
Post Registration
GMP inspectionRecalls (Class, Type)AdvertisingQC testing
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MANAGEMENT OF CLINICAL TRIALS
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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
KEY ASPECTS FOR CLINICAL TRIAL APPROVAL
In the approval of Clinical Trials the MCC considers the following aspects:
a. Scientific rationaleb. 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
KEY ASPECTS FOR CLINICAL TRIALS cont.
SCIENTIFIC RATIONALEDoes 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?
KEY ASPECTS FOR CLINICAL TRIALS cont.
SAFETYBalance of risks versus benefitsIs there adequate data from pre-clinical
studies ?Are the animal models used
appropriate?Is there adequate monitoring in place?Pharmacovigilance and GCP inspection
reportsIs safety stipulated as an objective?
POST MARKETING PHASE
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Safety monitoringMarket surveillanceLaboratory testingGood Manufacturing Practice complianceGood Clinical Practice complianceVariations and approval thereof e.g.
Additional or new indicationsChange in source or method of synthesis of Active
Pharmaceutical Ingredient, excipients, packaging etc.
Change of packer, laboratory release, packaging, address, manufacturing site etc.
and PharmaceuticalsHealth Technology Technical Cooperation for Essential
Drugs and Traditional Medicine
Pre-marketing phasePre-marketing phase Post Marketing phasePost Marketing phase
Marketsurveillance
Marketsurveillance
InspectionsInspections
Market distribution
Clinical trialsEthics, GLP;GMP,GCP)
Clinical trialsEthics, GLP;GMP,GCP)
QualityQuality
SafetySafety
EfficacyEfficacy
ProductEvaluation
ProductEvaluation
GMP compliance
GMP compliance
Licensingfacility
Licensingfacility
Laboratory testing
Laboratory testingDossierDossier
Licensing/Registration= evaluation process
Applicants Dossier
Applicants Dossier
Marketing AuthorizationMarketing Authorization
Regulatory Processes
Safetymonitoring
Safetymonitoring
VariationsVariations
ApprovalApproval
PROGRESS
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• Registration, rejections withdrawals
YEAR TOTAL
08/09 541
09/10 748
10/11 970
11/12 Up to October 411
PROGRESS CLINICAL TRIALS
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YEAR 2009 2010 2011
RECEIVED 212 202 254
APPROVED 205 181 154
WITHDRAWN 6 8 2
REJECTED 1 7 3
PENDING 0 6 93
NOTIFICATION 2
RESTRUCTURING OF THE MCC
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Three sets of regulations have been published for public commentComplementary and Alternative MedicinesMedical Devices and In Vitro diagnosticsFood
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 cosmeticsStrengthen governance issues in the statuteStrengthen some elements medical device
regulation in the statute