HIV Drug Development in Neonates - What Now?

Linda L. Lewis, M.D.Medical OfficerDivision of Antiviral Drug Products FDA

Outline

The Written Request (WR) as a mechanism to request pediatric studies

Current DAVDP standards for WR studiesIssues regarding HIV drug development in

neonates

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

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

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)

Issues Regarding HIV Drug Development in Neonates

Size of the population availableCharacteristics of the population to be

studiedEthics of enrolling uninfected neonates in

studiesAbility of parents to understand and give

informed consent during first few weeks of infant’s life

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

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

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

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)

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%?

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)

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

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

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