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Industry Challenges in Drug Dosing to Pregnant Women

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Industry concerns on drug usage in pregnant women ... Zidovudine found not to accumulate, and pk similar to non-pregnant adults ... – PowerPoint PPT presentation

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Title: Industry Challenges in Drug Dosing to Pregnant Women


1
Industry Challenges in Drug Dosing to Pregnant
Women
  • Richard V. Clark MD, PhD
  • Metabolic Discovery Medicine
  • GlaxoSmithKline Research and Development

2
Overview of Discussion
  • Industry concerns on drug usage in pregnant women
  • Immediate adverse events to mother and/or fetus
  • Induction of developmental defects - teratogen
  • Reproductive safety studies to develop confidence
    in drug
  • Examples of drug usage in pregnancy
  • Bendectin - a lost therapy?
  • Zidovudine - successful application of a drug
    during pregnancy for fetal protection
  • Anti-malarial - Lapdap - an urgent need
  • Pregnancy Registries

3
Studies to Establish Confidence in Reproductive
and Fetal Safety
  • Pre-Clinical Reproductive Toxicology Studies
  • Pregnancy Studies - rodent or rabbit
  • Fertility Studies - rodent or rabbit
  • Specialty Studies - test specific drugs or
    special developmental abnormalities as with
    primate model
  • Clinical Studies
  • Phase I pk studies to compare pk in pregnant
    women vs established values in normals or target
    population
  • Usually single dose studies in healthy women
  • Larger multiple dose studies to demonstrate
    safety and establish efficacy in target
    population

4
Specialized Study Dutasteride
  • Dutasteride - 5 ? reductase inhibitor
  • Potent, dual enzyme inhibitor, markedly
    suppresses DHT to
  • Indication treatment of symptoms of BPH (LUTS)
  • Reproductive concern
  • Fetal exposure could impair masculinization of
    external genitalia (weeks 8-12), DHT dependent
    process
  • Phenotype of 5 AR deficiency ambiguous
    genitalia with impaired testicular development
    and infertility
  • Tested in primate model with IV dosing daily for
    most of pregnancy with no impairment of
    masculinization

5
Bendectin Case Study
  • Combination drug for treatment of nausea and
    vomiting associated with pregnancy
  • Antihistamine (doxylamine) and pyridoxine
  • Effective and widely used in the late 1950s and
    1960s
  • Series of lawsuits filed in 1970s claiming
    teratogenicity
  • Drug withdrawn from market in 1982
  • Gap between perceived teratogenicity and
    evidence-based proof of safety
  • Rate of malformations same in treated and
    untreated populations (drug use as high as 40)
  • No change in rates after drug withdrawn
  • G Koren, NEJM 338 1128-37, 1998

6
Zidovudine - Reduction of Maternal-Infant
Transmission of HIV
  • Problem
  • Infants infected with HIV, 15-40 born to
    infected mothers became infected in utero, during
    labor and delivery, or by breast-feeding
  • Supporting Studies
  • Animal models demonstrated zidovudine reduced
    maternal transmission of HIV
  • No evidence of teratogenicity
  • High doses induced fetal resorption (cover range
    66-226X rats, 12-87X rabbits human steady state
    levels)
  • No effect on fertility

7
Zidovudine (cont)
  • Human Studies
  • Phase I pk study in 8 healthy women in last
    trimester
  • Zidovudine found not to accumulate, and pk
    similar to non-pregnant adults
  • Placental transmission appeared passive with drug
    levels in mother and infant similar during
    delivery
  • Key Clinical Study - Pediatric AIDS Clinical
    Trials Group (Protocol 076)
  • Multicenter, randomized, double-blind, placebo
    controlled trial (US and France)

8
Zidovudine (cont)
  • Protocol 076 details
  • HIV infected women, 14-34 weeks of gestation
  • Mild to moderate disease with CD4 T lymphocyte
    counts 200 (median 560 in treated group)
  • No antiretroviral treatment during the current
    pregnancy
  • Treatment
  • Antepartum - 100mg PO 5 X per day
  • Intrapartum - 2mg/kg IV (over one hour), then
    1mg/kg/hr IV until delivery
  • Newborn - 2mg/kg PO q 6h for 6 weeks
  • Connor, NEJM 331 1173-80, 1994

9
Zidovudine (cont)
  • Enrollment
  • 477 subjects enrolled April 1991 through Dec 20,
    1993
  • 409 women gave birth to 415 live infants, HIV
    status established in 363 (180 on AZT and 183 on
    placebo)
  • Median gestational age 39 weeks (27 - 43 weeks)
  • Trial discontinued at first interim efficacy
    analysis
  • 67 reduction in relative risk of transmission
  • No infant in treated group became HIV , if
    negative to 24 weeks
  • Connor, NEJM 331 1173-80, 1994

10
Figure 1. Kaplan-Meier Plots of the Probability
of HIV Transmission, According to Treatment Group
11
Neglected Diseases of Developing World A
Sense of Urgency
  • Malaria
  • 5 deaths every minute (2.7 million/year)
  • 1 baby every 2½ minutes (200,000/year)
  • Tuberculosis
  • 4 deaths every minute (1.9 million/year)
  • 2,500 new infections every minute (60
    million/year)
  • HIV/AIDS
  • 4 deaths every minute (2.3 million/year)
  • 9½ new infections every minute (5
    million/year)
  • 50 new infections in young people (15-24 yr.)

12
Why is malaria in pregnancy a priority?
13
Placental malaria
14
Low birth weight
15
Gambia Maloprim prophylaxis trial Greenwood et
al, 1992
  • Low Birthweight ()
  • Placebo
    Chemoprophylaxis
  • Primigravidae 22.0 6.0
  • Multigravidae 5.0 3.8

16
Attributable Risk Estimates for Falciparum
Malaria in Pregnant Women
  • Adverse Prevalence Attributable
    Number of
  • Event Range, Risk, Studies
  • Severe anaemia 1 - 20 2 - 15 5
  • Low birthweight 12 - 20 8 - 14 8
  • Prematurity 3 - 8 8 - 36 3
  • Perinatal mortality 11 - 178 0.1
    - 7.2 3
  • per 1000
  • Infant mortality 60 - 160 3 - 8
    3
  • per 1000

17
Malaria in PregnancyOpportunities for
Intervention
  • Drugs
  • Chemoprophylaxis
  • Protective Intermittent Treatment (PIT)
  • Case Management
  • Insecticide Treated Nets (ITNs)
  • Treatment of anemia
  • Iron/folate
  • Nutritional counseling

18
Protective intermittent treatment
  • WHO recommends use of an effective antimalarial
    for protective intermittent treatment (PIT)
    against malaria for pregnant women living in
    highly malarious areas
  • Likely use, two doses of agent, one in second and
    one in third trimester

19
Anti-Malarial Products potential use in
pregnancy?
  • Chloroquine
  • Lapdap (Chlorproguanil and Dapsone)
  • Malarone (Atovaquone and Proguanil)
  • Fansidar (Sulpadoxine and Pyrimethamine)
  • Riamet (Lumefantrine and Artemether)
  • Atremesinins
  • CDA (chlorproguanil, Dapsone, Artesunate)
  • Larium (Mefloquine)

20
Candidate for Intermittent Therapy
  • All anti-malarials have potential for some degree
    of fetal toxicity
  • Lapdap (Lapudrine and Dapsone)
  • GSK candidate molecule
  • Clinical study in development to evaluate safety
    vs efficacy with intermittent single dose
    applications during pregnancy
  • Protocol being developed with External Advisory
    Board

21
Pregnancy Registry Follow-up Study for Drug
with Potential Concern
  • Likelihood of unintentional 1st trimester
    exposure
  • Potentially large exposed population of sexually
    active women Ages 15-44
  • Animal data and relationship to effect on human
    fetus
  • Underlying medical condition
  • Medications mechanism of action
  • FDA pregnancy category rating

22
Pregnancy Registry Follow-up Studies
  • Acyclovir -- June 1984 (now closed)
  • Antiretroviralsa -- 1 Jan 1989
  • Lamotrigine -- 1 Sept 1992
  • Valacyclovir -- Jan 1995 (now closed)
  • Sumatriptan -- 1 Jan 1996
  • NA AED Pregnancy Registrya -- Nov 1996
  • Bupropion -- 1 Sept 1997
  • Naratriptan -- 1 Oct 1997
  • a Multi-company sponsored studies

23
Design Considerations
  • Objective Estimate risk of major birth defects
    following prenatal exposure to drug
  • Exposure registration and follow-up study
  • Prospective enrollment required
  • Birth defect comparator needed (population risk)
  • Outcomes birth defects consistent with CDC
    definitions
  • Other outcomes not within scope (e.g., maternal
    events, spontaneous abortion)

24
Method - Data Collection
  • Initial data collected at enrollment from health
    professional
  • Exposure, timing, estimated date of delivery,
    prenatal testing
  • Potential confounders specific to the study
  • Basic information from single reporter
  • Likely to be motivated
  • Likely to have exposure and outcome information
  • Will not require additional steps

25
Sources of Calls and Referrals
Patients
Clinical Trials
CDC
Health Care Providers
International Sources
Registry
Operating Companies
Other Manufacturers
Company Sales Force
Genetic Counselors
Teratogen Information Services
26
Methods - Follow-Up
  • Follow-Up
  • Form sent to health professional at estimated
    date of delivery
  • Monthly reminders until data obtained
  • Patient identifiers (no names) may be used and
    are deleted at completion of follow-up
  • Thank-you letter with encouragement to register
    other exposures

27
Targeted Follow-Up of Birth Defects
  • Targeted to specific birth defects reported
  • Based on CDC teratology review
  • May include questions from GSK Pharmacovigilance
    physician

28
Methods - Analysis
  • Separate prospective/retrospective reports
  • Estimate birth defect risk (proportion) from
    prospective reports
  • Compare risk against expected risk
  • Evaluate specific birth defects
  • Analyze defects for evidence of patterns or
    uniqueness
  • Review of all data by Advisory Committee

29
Advisory Committee
  • Reviews data
  • Assists in disseminating information
  • Members represented
  • Centers for Disease Control and Prevention
  • Academic medical practitioners/epidemiologists
  • GlaxoSmithKline medical department
  • Could be expanded to include other disciplines,
    groups
  • Expertise in disease area, Obstetrics,
    Teratology, Pediatrics, Epidemiology

30
Example Acyclovir Pregnancy Registry Final
Results
  • Risk of Birth Defects
  • First -Trimester Exposure 19/596
  • 3.2 (95 CI 2.0, 5.0)
  • Any Trimester Exposure 28/1082
  • 2.6 (95 CI 1.8, 3.8)
  • Does not differ from risk in general population

31
Value of the Pregnancy Registries
  • Information useful to patients and physicians
  • Useful to manufacturer in evaluation of safety
  • Information included in product label
  • Contributed to label change from Category C to B
    for Acyclovir and Valtrex
  • CDC Sexually Transmitted Disease Treatment
    Guidelines

32
Pregnancy Registry - Conclusions
  • Pregnancy Registries are a reasonable approach
    for safety monitoring
  • Voluntary enrollment makes recruitment a
    challenge
  • Simplicity of design important for cooperation
  • Complement, not replace, spontaneous reporting
    mechanisms
  • Data provide an estimate of risk associated with
    drug in population, although no comparison group

33
Overall Conclusions Industry Concerns
  • Pre-Clinical Reproductive Toxicology Studies
  • Can provide assurance or indicate problems
  • Important to consider mechanism of action studies
  • Use of animal models for predicting human risk
  • Phase I studies to determine pk in limited set of
    subjects
  • Proceed with large safety and efficacy study in
    target population
  • Careful study design special attention to
    endpoints and inclusion/exclusion criteria
  • Use of independent Safety and Efficacy Advisory
    Board
  • Use of Pregnancy Registries for post launch
    follow-up
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