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

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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

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Current DAVDP standard

• WR issued when enough data available in adults to
  indicate drugs 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

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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)

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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
  infants life

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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

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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 lt 2 in pregnant
  women receiving appropriate HIV treatment

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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

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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)

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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 lt 2 compared to rate of
  20? 10?

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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)

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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

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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

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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