KEMRI/CDC RESEARCH AND

PUBLIC HEALTH COLLABORATION

AND THE INDEPTH NETWORK IN

INTERNATIONAL COLLABORATIVE

STUDIES OF

PHARMACOVIGILANCE

Kayla Laserson, ScD, and Stephanie Dellicour KEMRI/CDC Research and Public Health Collaboration

CDC IN KENYA

• CDC collaboration began with the Kenya Medical Research Institute (KEMRI) in 1979

• KEMRI is part of the Ministry of Health

• Mandated to conduct clinical and public health research (similar to NIH and CDC [in particular surveillance and operational research] in US)

• Malaria research was initial focus of collaboration

• Today, comprehensive public health program and multi-disease research activities

• Integral component of Kenya’s and USG’s efforts to improve public health and build capacity of institutions and people

• CDC’s largest overseas presence

CDC-KENYA GOALS

• Conduct collaborative surveillance, research, and program implementation

• Conduct population-based surveillance, including new initiatives and unexpected events

• Conduct cutting-edge clinical research/trials • Provide technical assistance and strengthen service delivery,

including national and regional outbreaks • Link research to service delivery and conduct impact

evaluations • Translate science to policy to implementation

• Promote training and strengthen capacity of Kenyan government staff and institutions

HEALTH AND DEMOGRAPHIC

SURVEILLANCE SYSTEMS

INDEPTH

• International Network for the Demographic Evaluation of Populations and their Health in Developing Countries (INDEPTH) is a global network of 43 member health and demographic surveillance systems (HDSSs) in 20 low- and middle-income countries (Africa, Asia, Oceania) that conducts longitudinal health and demographic evaluations

• In Kenya, INDEPTH was operational in Kisumu, Kombewa, Kilifi, Kibera, Mbita, Nairobi slums, and Eldoret

HOW DOES AN HDSS OPERATE?

• Household surveys every 4 months: 50-200,000 persons

• Collect standardized information

• Pregnancies, births, migrations, and deaths

• SES and educational status

• Immunization status for children <2 years old (home and at health facilities)

• Cause of death using verbal autopsy

• Surveillance of use of bed nets, other interventions

• Household data linked to continuous health facility/morbidity surveillance (e.g., immunization status collected at homes and facilities)

• At health facilities, specimens collected, e.g., malaria, influenza, and rotavirus surveillance (“wet” HDSS)

• Home-based HIV counselling and testing

TWO INTERNATIONAL POPULATION-BASED SURVEILLANCE PLATFORMS FOR

INFECTIONS

• Rural western Kenya (Asembo) and Kibera (informal settlement)

• 25,000 - 30,000 people per site

• Biweekly home visits

• Referral clinics with project clinicians and diagnostics

• Defines burden and causes of pneumonia, febrile illness, diarrhea; new focus on TB

• Data available on HIV status, care, and treatment

METHODOLOGY FOR EMERGING

INFECTIONS SURVEILLANCE (1)

• Household visits every two weeks

• Illnesses in household identified for each resident

• If illnesses during last 2 weeks, detailed questions asked

• Free use of field clinic

• Clinicians trained in diagnostic treatment algorithms

• Essential medicines always in stock

METHODOLOGY FOR EMERGING

INFECTIONS SURVEILLANCE (2)

• Specimens collected based on clinical criteria

• Fever: blood culture, malaria smear + archived acute sera, blood clot

• Pneumonia/SARI/ILI/TB suspect: blood culture, NP/OP swab, acute sera, blood clot, sputum

• Diarrhea: stool collected with enteric microbiology, and rotavirus testing and stool archived for future testing

• Jaundice: sera collected

REAL-TIME DATA COLLECTION

Weekly home visit, PDA

data collection

Computerized data system

in field clinic

Microbiology in the field

MORTALITY SURVEILLANCE

MORTALITY TRENDS – ASEMBO, GEM, AND KAREMO (2003 – 2008)

0

20

40

60

80

100

120

140

160

2003 2004 2005 2006 2007 2008

Mo

rtal

ity

Rat

e/R

atio

Year

Crude Death Rate Under Five Mortality RateInfant Mortality Rate Neonatal Mortality RatioPost -Neonatal Mortality Ratio Child Mortality Rate

METHODOLOGY – VERBAL AUTOPSY (VA)

• VA started in September 2002

• Use village reporters and surveillance to capture deaths

• VA done for both children and adults

• INDEPTH questionnaire from 2002 to 2007

• Core-international VA questionnaire 2008 to 2009

• WHO questionnaire July 2009 to date

• Use of computer algorithm, Inter-VA, which uses standard ICD-10 coding list to assign immediate and underlying causes of death

USES OF THESE UNIQUE PLATFORMS (1)

• Evaluate population-based burden, spectrum of disease, risk factors, outcomes and etiologies of various pathogens

• Evaluate better diagnostic testing

• Pre-vaccine introduction surveillance

• Provide sampling frame for epidemiological studies

USES OF THESE UNIQUE PLATFORMS (2)

• Evaluate public health interventions

• Vaccine and treatment trials

• HIV (HPTN 052), rotavirus (Phase 3), malaria (Phase 3), and TB (Phase 2B)

• Vaccine and treatment programmatic introduction

• PCV10 (including catch-up campaign for 1-4 year olds), rotavirus, malaria (RTS,S), HPV, influenza vaccine, HIV testing B+ regimen for PMTCT

• Pharmacovigilance, both active and passive, for monitoring drug and vaccine safety

• Impact evaluations, e.g., combination HIV prevention on HIV incidence/mortality; combination malaria prevention

• Evaluate who is NOT accessing services

MONITORING ADVERSE EVENTS

FOLLOWING IMMUNIZATION (AEFI) AND

SAFETY OF DRUGS USED IN PREGNANCY

MONITORING SAFETY OF PNEUMOCOCCAL

CONJUGATE VACCINE (1)

• GlaxoSmithKline’s (GSK) 10-valent pneumococcal conjugate vaccine (PCV10) introduced in EPI in February 2011

• First developing country to introduce PCV10 in routine schedule

• Delivered in a 2-dose, no preservative vial

• WHO using our safety data to finalize PCV10 recommendations for other developing countries

MONITORING SAFETY OF PNEUMOCOCCAL

CONJUGATE VACCINE (2)

• KEMRI/CDC partnered with MOH, Wellcome Trust, and GSK to conduct PCV10 safety study

• Vaccination status and aliquot number monitored in enumerated surveillance populations in rural western Kenya, Kibera slum, Kilifi

• Adverse events (abscess, TSS, death) within 2-7 days of vaccination monitored actively through regular home visits, passively at referral facilities, laboratory surveillance, and through VA

• Trained surveillance staff using electronic data capture in the field

MEASURING IMPACT OF PCV10 AND OTHER

VACCINES - PHASE IV

• Population-based surveillance sites in western Kenya and Nairobi provide longitudinal incidence rates of

• Invasive pneumococcal disease

• IMCI-defined severe pneumonia

• Mortality (with causes of death identified by VA)

• Serial pneumococcal carriage studies to document

• Indirect effects on vaccine serotype carriage in adults

• Potential serotype replacement

• Impacts in HIV-infected subpopulations

PCV10 VACCINE IMPLEMENTATION

IN KIBERA

Nurse administering vaccine Nurse updating vaccination records

DEVELOPMENT AND VALIDATION OF A

SUSTAINABLE PHARMACOVIGILANCE

SYSTEM FOR MONITORING SAFETY OF

ANTIMALARIAL DRUGS USED DURING

PREGNANCY

CENTERS FOR DISEASE CONTROL AND PREVENTION (USA)

LIVERPOOL SCHOOL OF TROPICAL MEDICINE (UK)

DIVISION OF MALARIA CONTROL, MINISTRY OF HEALTH (KENYA)

PHARMACY AND POISONS BOARD, MINISTRY OF HEALTH (KENYA)

MALARIA IN PREGNANCY CONSORTIUM

BACKGROUND AND RATIONALE

• Drugs are often marketed with limited information on their safety during pregnancy

• Pregnant women need safe and effective malaria treatment

• Artemisinin combination therapies (ACTs) are very effective and well tolerated, but are NOT recommended in 1st trimester

• High risk of inadvertent exposure during 1st trimester

• Post-marketing system needed to monitor the safety of drugs in this vulnerable group

STUDY OVERVIEW

• Aim: set up a PV system to assess antimalarial drug safety in pregnancy and to provide better estimate of risk-benefit profile

• Design: 2-year observational cohort study

• Setting: enhanced morbidity surveillance in HDSS in western Kenya

• Population: women of child bearing age (WOCBAs, n = ~5,000) and pregnant women(n = ~800 pregnancies per year)

• Enrollment: WOCBAs with pregnancy detection in community and ANC

• Exposure: ACT use during gestational weeks 4-9

• Outcomes: miscarriages, stillbirths, and major congenital malformations

Dru

g as

cert

ain

men

t

Women of childbearing age

Consent to participate

At community or ANC level

Visibly pregnant

Pregnancy test

Positive Negative

Ultrasound

Initial ANC visit

Pregnancy outcome follow up

At home

or Lwak Hospital

ANC revisits Confirmation of

suspected congenital

malformations

EXPECTED OUTPUTS

• Contribute data to evaluate risk-benefit profile of antimalarial drugs for pregnant women

• Long-term outcome is aggregation of data from all pregnancy registries to inform policy makers and treatment guidelines

• Create awareness about the potential risk of drug exposure during pregnancy

• Develop new tools for monitoring drug (or vaccine) safety in resource-constrained settings

• Provide estimate of background rate of adverse pregnancy outcome in western Kenya, which will provide valuable information for services planning and resources for referrals

SUMMARY

• Population-based surveillance platforms around the world are available for post-marketing assessments and are useful cost-effective platforms for pharmacovigilance

• Well-characterized populations with additional patient information available through linked data

• Large populations are needed for safety evaluations

• Sites use standardized case definitions and approaches

• Additional standardization possible for specific purposes

• Great capacity in diagnostics

• Ministry of Health systems may provide additional platforms

ACKNOWLEDGEMENTS • Robert Breiman, CDC-Kenya Director

• Danny Feikin, Heather Burke, and M. K. Njenga (lab), IEIP

• Godfrey Bigogo, Lwak Field Coordinator

• Beatrice Olack, Kibera Field Coordinator

• Allan Audi, Kisumu Lead Statistician

• Leonard Cosmas, Kibera Lead Statistician

• Barrack Aura, Kisumu Statistician

• John Williamson, Statistician

• Henry Njuguna and William Mwiti, Medical Officers, Kibera

• Ochieng, Clinical Officer, Lwak

• Mark Katz and Kathleen Morales, Influenza Program

• Frank Odhiambo, Kisumu Field Research Station/HDSS

• Dr. Stergachis, Coordinator PV for MiPC

• Kibera and Lwak field staff

• IEIP lab team

• Data management team

• Global Disease Detection and Emergency Response Division-CGH, CDC, Atlanta

• Influenza Division, CDC-Atlanta

• All study participants