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
2Overview 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
3Studies 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
4Specialized 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
5Bendectin 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teratogenicity - Drug withdrawn from market in 1982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untreated populations (drug use as high as 40) - No change in rates after drug withdrawn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
6Zidovudine - 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
7Zidovudine (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)
8Zidovudine (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
9Zidovudine (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
10Figure 1. Kaplan-Meier Plots of the Probability
of HIV Transmission, According to Treatment Group
11Neglected 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.)
12Why is malaria in pregnancy a priority?
13Placental malaria
14Low birth weight
15Gambia Maloprim prophylaxis trial Greenwood et
al, 1992
- Low Birthweight ()
- Placebo
Chemoprophylaxis - Primigravidae 22.0 6.0
- Multigravidae 5.0 3.8
16Attributable 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
-
17Malaria in PregnancyOpportunities for
Intervention
- Drugs
- Chemoprophylaxis
- Protective Intermittent Treatment (PIT)
- Case Management
- Insecticide Treated Nets (ITNs)
- Treatment of anemia
- Iron/folate
- Nutritional counseling
18Protective 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
19Anti-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)
20Candidate 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
22Pregnancy 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
23Design 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)
24Method - 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
25Sources 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
26Methods - 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
27Targeted Follow-Up of Birth Defects
- Targeted to specific birth defects reported
- Based on CDC teratology review
- May include questions from GSK Pharmacovigilance
physician
28Methods - 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
29Advisory 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
30Example 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
31Value 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
32Pregnancy 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
33Overall 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