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 1987 1987 1989 1991 1992 1992 1992 1992 1994 1994 1996 1998 1995 1996 - 1995 1996 1997 1996 1996 1997 1996 1996 1996 1996 - 1998 1997 1998 1999 1997 1998 1998 1998

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

0

100

200

300

400

500

600

Manufacturer

Direct

No.

of

Rep

orts

Reporting Year

UCT teaching hospital

UCT teaching hospital

NADEMC

UppsalaMonitoring CentreMCC

Public health

Clinical Consulting

National DRAs and Pharmacovigilance CentresComplementary

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