HIV Drug Development in Neonates - What Now?

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

2. Outline • The Written Request (WR) as a mechanism to request pediatric studies • Current DAVDP standards for WR studies • Issues regarding HIV drug development in neonates

3. Written Requests for Pediatric Studies • The 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 • FDA requests studies that will provide public health benefit • Agreement to a WR is voluntary • Incentive to perform WR studies is potential financial benefit

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

5. DAVDP HIV WR template • Type of studies requested: • Multiple dose PK, safety, and activity studies of Drug X in combination with other antiretroviral agents in HIV-infected pediatric patients • Multiple dose PK and safety studies of Drug X in HIV-exposed neonates (born to HIV-infected mothers) • Age group in which studies will be performed: • HIV-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 • Size of the population available • Characteristics of the population to be studied • Ethics of enrolling uninfected neonates in studies • Ability of parents to understand and give informed consent during first few weeks of infant’s life

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

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

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

10. Examples of HIV drug studies performed in neonates • PACTG 354 enrolled from 11/97 to 11/00. 7 pregnant women enrolled, cord blood drug levels in 4, PK in 3 neonates. • PACTG 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 • Vast 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 • Most neonates available for research will be uninfected • Most HIV-exposed neonates enrolled in drug studies unlikely to benefit from participation • Risk/benefit assessment different when transmission rate is < 2% compared to rate of 20%? 10%?

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

13. Ethics of Enrolling Uninfected Neonates in Studies • 1999 Pediatric Advisory Subcommittee recommended adopting principles described in Subpart D (45 CFR Subtitle A) • Additional Protections for Children Involved as Subjects in Research • Ethics of enrolling HIV-uninfected infants in clinical trials discussed in past • Local IRBs are final judge of acceptability of study in their community

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

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