Presentation at ALZA Corporation, Mountain View, CA, 2001, by Joseph F. Holson, PhD, DABFE, President (ret.), WIL Research Laboratories.

1. Regulatory and Scientific Impact of
FDAMA
Joseph F. Holson, Ph.D.
WIL Research Laboratories, Inc.

2. The ‘carrot’ and the ‘stick’
FDAMA of 1997:
• law
• optional
• 6 months’ additional marketing exclusivity
Pediatric Final Rule 1998:
• regulation (with force of law)
• obligatory
• no additional marketing benefit to sponsors

3. Regulations Requiring Manufacturers to Assess
Safety and Effectiveness in Pediatric Patients
12/98: Final Rule
Effective: 4/11/99
Compliance date: 12/1/00
Purpose:
“…necessary to significantly increase the number of drug and biological products that have
adequate pediatric labeling. …..where there is a great need for data on drugs with relatively
small markets or for studies in neonates, infants, or young children, it may be necessary to
require rather than rely on incentives.”
“Limitations of exclusivity provision and voluntary nature will likely leave unstudied: most
antibiotics, biologics, off-patent products, drugs with smaller markets, youngest pediatric age
groups.”

4. Who has to do What: Scope
Requires pediatric safety and effectiveness data for all new active ingredients,
dosage forms, dosing regimens and routes of administration only for the
indications claimed by the manufacturer. (Orphan drugs not included.)
Requires pediatric safety and effectiveness data for marketed drugs and biological
products that:
• are used in a substantial number of pediatric patients for the claimed
indications and where the absence of adequate labeling could pose significant
risks
OR
• would provide meaningful therapeutic benefit over existing treatments for
pediatric patients, and the absence of adequate labeling could pose significant
risks to pediatric patients

5. Who has to do What: Definitions
“substantial number” = 50,000 pediatric patients
“Meaningful therapeutic benefit” ≈ “Priority” drug:
1. A significant improvement in the treatment, diagnosis or prevention of a disease
compared to drugs marketed for that use. Demonstrated by:
• Increased effectiveness
• Reduction of a treatment-limiting drug reaction
• Enhancement of compliance
• Safety and effectiveness in a new sub-population
2. Drug for an indication for which there is need for additional therapeutic options,
even if not a priority drug

6. Pediatric Final Rule: Summary
Broad application:
all NCEs, indications, dosage
formulations, regimens, routes
Here to stay: regulation/ force of law
Waivers not likely
Tracking/ compliance system in place

7. Pediatric Advisory Council (PAC)
Points to Consider
Regulatory
•
The pediatric rule
• Applies to all NCEs unless a waiver is granted
• For a pediatric indication, the pediatric rule will be met
as part of regular development
•
Is a waiver appropriate? Answer must be no to
• Drugs that will be a meaningful therapeutic benefit
• For an indication needing additional therapeutic options
• Use in substantial number (>50,000) of pediatric
patients
•
Determine whether a waiver for all or some age
groups is warranted

8. Proposed Disease-Specific Waivers
•
•
•
•
•
•
•
•
•
Alzheimer’s disease
Age-related macular
degeneration
Prostate cancer
Breast cancer
Non-germ cell ovarian
cancer
Renal cell cancer
Hairy cell leukemia
Uterine cancer
Small cell and non-small
cell lung cancer
•
•
•
•
•
•
•
•
•
•
Squamous cell cancers of the
oropharynx
Pancreatic cancer
Basal cell and squamous cell
cancer
Endometrial cancer
Osteoarthritis
Parkinson’s disease
Amyotrophic lateral sclerosis
Arteriosclerosis
Infertility
Symptoms of menopause

9. Pediatric Advisory Council (PAC)
Points to Consider
Regulatory
•
Expectations from FDA will be driven by disease target.
Class of Drug
Products for life-threatening
diseases lacking adequate therapy
Less urgently needed drugs
“Me-too” drugs
•
Begin Pediatric Studies
after Phase I
after Phase II
Phase IV
* labeling implications
Original IND should include initial pediatric plan
• Waiver, if appropriate
• Include timing of pediatric study initiation
•
Pediatric plans to be addressed with FDA at earliest meeting
• End-of phase I, end -of phase II, or pre-NDA meeting.

10. Pediatric Advisory Council (PAC)
Points to Consider
Clinical development
• Is the disease indication and PK the same in
adults and children?
• If yes, (and FDA agrees), plan for PK/safety studies
• Efficacy studies may be done for other reasons
(publication, promotion)
• If no, efficacy studies will likely be required
• In general, the safety studies are not more complicated
to run and will not impact timelines
• Timing of formulation work, assay development
and non-clinical supporting studies

11. Pediatric Advisory Council (PAC)
Points to Consider
Clinical Safety
•
Safety is a prime consideration for any pediatric study
• Pharmacokinetic differences
• i.e., clearance and altered protein binding
• Potential excipient toxicity
• Idiosyncratic toxicity not observed in adults due to
age
• Developmental toxicity
• impact on physical growth and cognitive
development

12. Pediatric Advisory Council (PAC)
Points to Consider
Clinical Pharmacology
•
Determine age groups to be studied
• Flexibility to determine appropriate age grouping
• As general guide
• neonate: birth to 1 month
• infant: 1 month to 2 yrs
• children: 2 to 12 yrs
• adolescent: 12 to 16 yrs
•
Limitations of sampling due to blood volume (age
dependent) will determine pharmacokinetic approach
•
Understanding of metabolic differences because of age

13. Pediatric Advisory Council (PAC)
Points to Consider
Drug Safety Evaluation
•
Nonclinical safety studies for support pediatric clinical testing
are the same as those needed for adult testing
• genetic toxicology studies
• acute studies
• multiple dose studies in two species (e.g.,1, 3, 6 months)
•
Reproductive toxicology studies should be completed
• Reproductive Study III, teratology (rat and rabbit)
• Reproductive Study II, peri-postnatal study

14. Pediatric Advisory Council (PAC)
Points to Consider
Drug Safety Evaluation
•
•
Juvenile animal studies are not automatically required.
Pediatric plan for the compound will dictate need
• What age group?
• studies likely if indication or use is expected in
neonates
• Critical periods of development
• can impact/safety be assessed clinically?
• If Yes,
• animal studies will not contribute to safety
evaluation
• if No,
• plan for additional animal studies 3-6 months
duration

15. Standard Designs
A
B
C
D
E
F
Premating to
Conception
Conception to
Implantation
Implantation to Closure
of Hard Palate
Hard-Palate Closure to
End of Pregnancy
Birth to Weaning
Weaning to Sexual
Maturity
Fertility Study
10W
4W
2W
Estrous Cyclicity
Mating
Fertility
Implantation Sites
Pre-Implantation Loss Spermatogenesis
ICH 4.1.1
Corpora Lutea
ƒ
Postimplantation Loss
Prenatal Development
CMAX
AUC
ICH 4.1.3 OECD 414
OPPTS 870.3600
870.3700
Postimplantation Loss
Viable Fetuses
Malformations & Variations
Fetal Weight
F0
ƒ
Pre- and Postnatal Development
CMAX
ICH 4.1.2
AUC
F1
Parturition
Gestation Length
F1 Mating and Fertility
????????????????
Litter Size
Pup Viability
Pup Weight
Organ Weights
Landmarks of Sexual Development
Neurobehavioral Assessment
Acoustic Startle Response
Motor Activity
Learning & Memory
Single- and Multigenerational
OECD 415, OECD 416, OPPTS 870.3800, FDA Redbook I, NTP RACB
Estrous Clyclicity
Mating
Fertility
Corpora Lutea
Implantation Sites
Pre-Implantation Loss
Spermatogenesis
Satellite Phase
Postimplantation Loss
Viable Fetuses
Malformations
Variations
Fetal Weight
F1
????????????????
Parturition
F2
????????????????
Gestation Length
Pup Viability
Litter Size
Landmarks of Sexual Development
Pup Weight
Neurobehavioral Assessment
Organ Weights
Acoustic Startle Response
F1 Mating and Fertility
Motor Activity
Hormonal Analyses
Learning & Memory
Ovarian Quantification
Histopathology
Premature Senescence
Denotes Dosing Period

16. Animal : Human Concordance Studies
for Prenatal Toxicity
Authors
Attributes
Holson et al., 1981 (Tox
Forum)
Kimmel et al., 1984 (NCTR
Report)
Interdisciplinary team
Criteria for acceptance of
data/conclusions
Concept of multiple developmental
toxicology endpoints
No measures of internal dose
Nisbet & Karch, 1983
Many chemicals
Relied on authors’ conclusions
Emphasis on fertility
No measures of internal dose

17. Animal : Human Concordance Studies
for Prenatal Toxicity
Authors
Attributes
Hemminki & Vineis,
1985
Interspecies inhalatory doses adjusted
Relied on authors’ conclusions
23 occupational chemicals and mixtures
No measures of internal dose
Newman et al., 1993
Provided detailed information
Only 4 drugs
Emphasis on morphology
Focus on NOAELs
No measures of internal dose
Schardein, 1995
Many chemicals
Relied on authors’ conclusions
No measures of internal dose

18. Ontogeny of Physiologic
Regulation in Selected Mammals
Stagemarks
Implantation
First Heart Beat
Exterioception
Hemoglobin 8% in Blood
Body Weight 1 gm
Thyroid Iodine
Lung Surfactant
Liver Glycogen 0.05%
Birth
Water 85% of Fat-free
Na/K one gm/gm
Anoxia Tolerance 10 min.
Body Fat 5%
Arterial Pr. 50 mm/Hg
Lethal Temp Shift
Resistance to Cooling
Hamster Rat Rabbit Cat Pig Human
4
8 10
20
40
80 100
Days After Conception
After Adolph 1970
200
400

19. Comparative Age Categories Based on Overall CNS
and Reproductive Development
Rat
B
Minipig
Dog
Human
Pre-Term
Neonate
10
B
B
Nonhuman
Primate
<9
2
0.5
B
B
Term
Neonate
3
21
45
4
90
14
6
0.5
26
Weeks
20
6
0.8
Days
28
36
2
Infant/Toddler
48
12
Child
Weeks
Months
16
Years
Adolescent
Ontogeny
B
Birth
Buelke-Sam, 2001

20. Preterm Infants
•
•
•
•
•
•
•
•
•
Rarely able to extrapolate efficacy from adults or older
pediatric experience
Gestational-age specific, i.e., 500 gm vs. 1500 gm
Immaturity of hepatic and renal clearance mechanisms
Protein-binding and displacement issues (bilirubin)
Penetration into CNS (bbb)
Unique disease states (respiratory distress syndrome, patent
DA)
Unique susceptibility (e.g., necrotizing entercolitis, IV
hemorrhage, retinopathy)
Rapid and variable maturation of physiologic &
pharmacologic processes leading to different dosing
regimens
Transdermal absorption of medicinal products & other
chemicals

21. Term Newborn Infants (0 to 27 Days)
• Volume of distribution because of different body
•
•
•
•
•
water/fat content & higher body-surface-area-toweight ratio
bbb not fully mature
Oral absorption less predictable than older pediatric
patients
Hepatic and renal clearance immature & changing
rapidly
Many examples of increased susceptibility to toxic
effects (e.g., chloramphenicol gray baby syndrome)
Less susceptible to aminoglycocide nephrotoxicity

22. Infants and Toddlers
(28 Days to 23 Months)
• Rapid CNS, immune system development and total
•
•
body growth
By 1-2 years of age, clearance of many drugs on a
mg/kg basis many exceed adult values
Considerable inter-individual variability in
maturation

23. Children (2-11 Years)
•
•
•
•
•
•
Most pathways of clearance (hepatic and renal) are mature
Changes in clearance may be dependent on maturation of
specific metabolic pathways
Achievement of several important milestones of psychomotor
development susceptible to CNS-active agents
Entry into school and increased cognitive and motor skills
may affect child’s ability to participate in certain types of
efficacy studies
May need to stratify by PK and/or efficacy endpoint
considerations
Onset of puberty (earlier in females) can occur as early as 9
years and affects metabolic enzymes (required dose of
theophylin decreases dramatically)

24. Adolescents (12 to 16-18 Years)
• Sexual maturation, potential to interfere with sex
•
•
hormones
Rapid growth & continual neurocognitive
development
Medicinal products/diseases which
delay/accelerate onset of puberty can have
profound effect on pubertal growth spurt, and by
changing pattern of growth, may affect final stature

25. Effects on Prenatal and Postnatal
Development Including Maternal Function
ICH 4.1.2 (Segment III)
GD 6
Female
(Rat)
PND 20
Gestation
Lactation
(Macroscopic Pathology)
F1
Denotes Treatment Period
Denotes Possible Transfer Via Milk
Weaning Growth
PN day 21 9 wks
PN day 17
Mating
2 wks
PN day 80
Behavioral/Anatomic Measures
Motor Activity
Auditory Startle
Water Maze
Developmental Landmark
Vaginal Patency
Preputial Separation
Gestation
3 wks
F2

26. Comparison of Prenatal
and Postnatal Modes of Exposure
Prenatal
Embryo/Fetus
Treatment
Placenta
Mother
Prenatal
Drug Transfer to Offspring
Drug Levels in Offspring
Maternal Blood vs.
Offspring Levels
Exposure Route to
Offspring
Commentary
Postnatal
Mammae
Neonate
Postnatal
Nearly all transferred
Apparent selectivity (“barrier”)
Cmax and AUC measured
Not routinely measured
Maternal often a surrogate
Maternal levels probably NOT
a good predictor
Modulated IV exposure, via
placenta
Oral, via immature GI tract
Timing of exposure is critical
Extent of transfer to milk and
neonatal bioavailability is key to
differentiating indirect (maternal)
effects
from neonatal sensitivity

27. ACE Inhibition-Induced
Fetopathy (Human)
ACEinh
Fetal
Hypotension
Renal
Compromise
(Anuria)
Calvarial Hypoplasia
Oligohydramnios
Neonatal Anuria
IUGR
Death
•
•
•
•
Organogenesis (classically defined) is unaffected
Effects are severe
Risk is low
Caused by ACEinh that cross placenta

28. ACE Inhibition in Developing Rats
• RAS (renin-angiotensin system) matures around
GD17
• No ‘apparent’ effect in initial reproductive studies
• Subsequent postnatal studies with direct
administration to pups
→Growth retardation
→Renal alterations (anatomic and functional)
→Death

29. Examples of Perinatal/Juvenile Toxicants
• The following examples are not the result of an
•
•
exhaustive literature search.
In most instances, the cause of postnatal
morbidity/ mortality has not been investigated or
is not known.
The absence of standard blood
biochemistry/hematology assays and target
organ pathology hinders the identification of
sites and modes of action.

30. Examples of Perinatal/Juvenile (?)
Developmental Toxicants
Toxicant
Exposure
Period
Species
Endpoint
Time of
Manifestation
Estrogen
PND1-5
mouse
cervical/vaginal
adult
cancer
DES
prenatal
human
vaginal cancer/
Reference
Dunn &
Green, 1963;
Takasagi &
Bern, 1964
pubescence
Herbst &
Skully,
1970
reprod. tract effects
DES
PND1-5
mouse
vaginal adenosis
adult
Forsberg,
1976
Sex hormone
(DES)
PND1-5
mouse
vaginal adenosis/
adult
Bern et al.,
1976
DES
GD15, 16, 17
cancer
mouse
vaginal adenosis,
transverse ridges
adult
(14 mo.)
Walker, 1980

31. Selective Juvenile Toxicity of Quinilones
Drug
Ofloxacin
(and other
quinilones)
Species &
Treatment
Effects
Remarks
Multiple Species,
postnatal exposure.
20 mg/kg (dog, 3 mo.)
600 mg/kg (rat, 5 wk)
Chondrotoxic
effects. Cartilage
erosion in weightbearing joints.
Human relevance
unknown; drugs
contraindicated in juvenile
patients.
Gait alterations in
juvenile dogs only.
Mechanism: Probable
deficiency of bioavailable
Mg2+ in cartilage
(quinilones chelate
divalent cations).
No effect in routine
segment III studies.
Modified from Stahlmann et al., 1997.

32. Primary Reasons Experimental
Models Appear to be Invalid
• Findings at, or extrapolated to, exaggerated
•
•
•
•
•
doses
Exposure to and internal dose of noxious agent
not measured
Timing of exposure does not coincide with the
appearance of the developmental target
Duration of exposure not scaled to physiologic
time
Incorrect / unvalidated endpoints assessed
Too little knowledge / data concerning mode of
action

33. Conclusions
•
•
•
•
Parallelism exists among species regardless of
lifespan.
Additional measurements and changes to current
guidelines could increase our ability to predict
postnatal toxicity.
Molecular biology and genomics have influenced
pharmaceutical development toward agents with
increasing specificity.
For novel, selective pharmaceutical agents,
nonclinical testing must be preceded by literature
mining and analysis.