1. HIV Drug Development in Neonates - What Now? Linda L. Lewis, M.D. Medical Officer Division of Antiviral Drug Products FDA

2. Outline zThe Written Request (WR) as a mechanism to request pediatric studies zCurrent DAVDP standards for WR studies zIssues regarding HIV drug development in neonates

3. Written Requests for Pediatric Studies zThe Best Pharmaceuticals for Children Act of 2002 re-authorizes the exclusivity provision that grants sponsors 6 months of market exclusivity for conducting pediatric studies outlined in a WR zFDA requests studies that will provide public health benefit zAgreement to a WR is voluntary zIncentive to perform WR studies is potential financial benefit

4. Current DAVDP standard zWR issued when enough data available in adults to indicate drug’s potential efficacy and preliminary safety profile (Phase 2 or 3) zDAVDP has issued 20 WR for HIV drugs in development zDrugs granted exclusivity - abacavir, lamivudine, didanosine, stavudine, and nevirapine

5. DAVDP HIV WR template zType of studies requested: yMultiple dose PK, safety, and activity studies of Drug X in combination with other antiretroviral agents in HIV-infected pediatric patients yMultiple dose PK and safety studies of Drug X in HIV- exposed neonates (born to HIV-infected mothers) zAge group in which studies will be performed: yHIV-infected pediatric patients from 1 month to adolescence and HIV-exposed neonates (born to HIV-infected mothers)

6. Issues Regarding HIV Drug Development in Neonates zSize of the population available zCharacteristics of the population to be studied zEthics of enrolling uninfected neonates in studies zAbility of parents to understand and give informed consent during first few weeks of infant’s life

7. Size of the Available Population zEstimated 300-400 infected infants born annually in U.S. yInfants born to women with known HIV receive prophylaxis through 6 weeks yTreatment is recommended for HIV-infected infants yDiagnosis of HIV infection in infant can be made by 4 weeks of age with recommended testing schedule yNumber diagnosed with HIV and presenting for treatment during neonatal period small

8. Size of the Available Population zNumber of infants born to HIV-infected women in U.S. difficult to determine yReporting of HIV infection not required in all states, no linking to pregnancy yRapid testing of women in labor with unknown HIV status being evaluated yRate of perinatal transmission < 2% in pregnant women receiving appropriate HIV treatment

9. Size of the Available Population zEstimated 600,000 HIV-infected infants born annually worldwide zPopulation of infants born to HIV-infected women outside the U.S. much larger yRates of transmission decreasing in some resource poor countries but not in others yTreatment of HIV-infected children much less common

10. Examples of HIV drug studies performed in neonates zPACTG 354 enrolled from 11/97 to 11/00. 7 pregnant women enrolled, cord blood drug levels in 4, PK in 3 neonates. zPACTG 353 enrolled from 12/97 to 11/01. Cohort I enrolled 10 mother/infant pairs. Cohort II enrolled 23 pregnant women, cord blood levels in 16, PK in 10 neonates. (Reported at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle WA, 2002, Abstracts 794-w and 795-w)

11. Characteristics of Population to be Studied zVast majority of infants born to HIV-infected women in U.S. will be uninfected but status may not be confirmed for 2 to 4 weeks zMost neonates available for research will be uninfected zMost HIV-exposed neonates enrolled in drug studies unlikely to benefit from participation yRisk/benefit assessment different when transmission rate is < 2% compared to rate of 20%? 10%?

12. Ethics of Enrolling Uninfected Neonates in Studies zUninfected neonates exposed to risks of drug exposure and study procedures without potential for direct benefit yPK studies require multiple blood samples yMany HIV drugs not amenable to single-dose PK, require multiple day dosing for accurate assessment yMany drugs have significant potential toxicity (bone marrow suppression, hepatitis, hyperlipidemia, mitochondrial toxicity, and hypersensitivity reactions)

13. Ethics of Enrolling Uninfected Neonates in Studies z1999 Pediatric Advisory Subcommittee recommended adopting principles described in Subpart D (45 CFR Subtitle A) yAdditional Protections for Children Involved as Subjects in Research zEthics of enrolling HIV-uninfected infants in clinical trials discussed in past zLocal IRBs are final judge of acceptability of study in their community

14. Ability of Parents to Provide Informed Consent zParents of newborns very protective regarding painful procedures zParents may be anxious over unknown HIV status of infant until diagnosis confirmed zParents may express feelings of guilt regarding possibly infecting infant zMust not underestimate parents’ ability to make difficult decisions

15. Summary zDAVDP has encouraged the study of neonates through the incentive mechanism of the WR zIssues regarding study of neonates in HIV drug development legitimate zRisk/benefit for this age group, especially uninfected neonates, may be different in areas where the rate of perinatal transmission is low