NEVIRAPINE THE CONCERNS REGISTRAR OF MEDICINES 15 AUGUST 2002

DATES OF FIRST REGULATORY APPROVAL OF ARV’s IN US,EU,RSA ARV Retrovir (AZT) Videx (ddI) Hivid (ddC) Zerit (d4T) Epivir(3TC) Invirase (INV) Norvir(RTV) Crixivan (IDV) Viramune (NVP) Viracept (NFV) Combivir(AZT/3TC) Sustiva (EFV) USA EU RSA Ô Ô Ô Ô Ô Ô Ô Õ Ô Ô Ô Ô1998

GCP- South Africa & ICH Clinical trials conducted according to sound scientific and ethical standards (good clinical practice) Safety monitoring of participants during a clinical trials an ethical requirement Written and verbal consent should be obtained - countersigning by literate person where required Lack of adherence to standards of GCP (Shalala D. New England Journal of Medicine Sep 2000, Vol. 343, No. 11

GCP-TRIAL DRUG Maintenance of records Inventory at the site Return of unused records Reconciliation of doses List of essential documents and detail on how they are handled and stored

GCP-DATA MANAGEMENT Collection of data, quality recording, maintenance, retrieval of source data Source documentation validity Documentation of all data changes Maintenance of a security system to prevent unauthorized access to the data Source document verification integral to GCP (DIA, Journal 1999) Retention of essential documents for not less than 5 years

Nevirapine-HIVNET012 A study conducted in Uganda Published in Lancet September 1999 Involving 626 women & a pivotal study submitted to MCC for the indication reduction of risk of transmission from mother to child

ISSUE-1 –CONDITIONS OF APPROVAL Submission South African cases of lack of efficacy and other serious adverse reactions submission of 6 monthly periodic safety update reports & information on resistance new local and international information particularly information on resistance information on local utilisation patterns information on resistance from selected pilot sites and SAINT study inclusion of the statement that safety and efficacy in subsequent pregnancy has not been established

Package Insert information Appropriate wording for the indication MTCT- “ to reduce the risk of intrapartum transmission of HIV_1 from mother to child in pregnant women who are not taking antiretroviral therapy at the time of labour Viramune should be only prescribed for the reduction of the risk of intrapartum transmission, of HIV-1 from mother to child for patients who have been tested for HIV and appropriately counseled

Package Insert Information Safety and efficacy has not been established in neonates with birth weight of less than 2,5 kg is contraindicated, should be under the Heading “Contraindicated” Breastfeeding is not recommended if the benefits of the medication in achieving HIV-1 free survival are to be maintained

ISSUE-2 PROBLEMS WITH HIVNET012 STUDY RESULTS IN UGANDA According to company a) reporting and documentation b) deficiencies revealed by the Audit in source documentation c) withdrawal of application from FDA

ISSUE-3 COMMUNICATION WITH FDA,NIH, BI, –Confirmation of concerns by FDA –EMEA,TGA, MCA- (NVP not a drug of choice other regimens used) –NIH (Report confidentiality) –BI ( Data ownership rests with NIH) –Offer from NIH to see report and wait for September Re-monitoring plan report

Adverse Drug Reaction Reporting Rates in S. Africa No. of Reports Reporting Year

UCT teaching hospital UCT teaching hospital NADEMC Uppsala Monitoring Centre MCC Public health Clinical Consulting National DRAs and Pharmacovigilance Centres Complementary Medicines Inspectorate Clinical Trials Ministry of Health Health providers Industry SAMJ/SAPJ Pharmnet Medunsa(ARV) Natal (ARV) Enforcement

RESISTANCE Ongoing trials on ARV resistance including NVP MCC stakeholder congress- regulatory challenges of antimicrobial resistance & public health implications Organizing Committee and call for papers

MCC provincial visits- findings Protocol contradicts Package insert information in terms of paediatric dosing, and breastfeeding Stability profile of the suspension 2 months after opening container Availability of Patient Information Leaflet No process for reporting safety Unresolved breastfeeding issues

MCC-RESPONSE Review of all data (Copy of full submission filed with FDA & Copy of full SAINT report) Evaluation of audit report referred in (March 2002) Provincial visits by MCC team (summary later) Establishment of special MCC team to review all documents submitted Re-monitoring plan report awaited from NIH Ongoing Communication with BI, NIH,FDA Strengthening of Pharmacovigilance New ARV pharmacovigilance established in Medunsa Upgrading of UCT (All medicines) Future unit for ARV in KZN ARV Pregnancy registry (project proposal) for ARV-safety monitoring in pregnant women & babies

IN CONCLUSION Nevirapine is still registered for treatment of HIV/AIDS Nevirapine is not banned Nevirapine is still approved for the indication of “reduction of the risk of intrapartum transmission, of HIV-1 from mother to child” Nevirapine like AZT is one of the available options for the treatment of this indication Review of HIVNET 012 is ongoing