NEVIRAPINE

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NEVIRAPINE

• THE CONCERNS
• REGISTRAR OF MEDICINES
• 15 AUGUST 2002

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DATES OF FIRST REGULATORY APPROVAL OF ARVs 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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Adverse Drug Reaction Reporting Rates in S. Africa
No. of Reports
Reporting Year
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National DRAs and Pharmacovigilance Centres
Ministry of Health
Complementary Medicines
Clinical Trials
Uppsala Monitoring Centre
Inspectorate
MCC
Industry
Enforcement
NADEMC
UCT teaching hospital
Public health
Clinical Consulting
Pharmnet
SAMJ/SAPJ
Health providers
Medunsa(ARV) Natal (ARV)
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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

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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

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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

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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