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