Regulatory and Scientific Impact of FDAMA

Joseph F. Holson, Ph.D.

WIL Research Laboratories, Inc.

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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

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1122//9988:: FFiinnaall RRuullee 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.”

WWhhoo hhaass ttoo ddoo WWhhaatt:: SSccooppee 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

WWhhoo hhaass ttoo ddoo WWhhaatt:: DDeeffiinniittiioonnss “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

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Broad application: all NCEs, indications, dosageformulations, regimens, routes

Here to stay: regulation/ force of law

Waivers not likely

Tracking/ compliance system in place

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

Pediatric Advisory Council (PAC)Pediatric Advisory Council (PAC) Points to Consider

Proposed Disease-Specific WaiversProposed 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

Regulatory

• Expectations from FDA will be driven by disease target.

• 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.

Class of Drug Begin Pediatric Studies

Products for life-threateningdiseases lacking adequate therapy

after Phase I

Less urgently needed drugs after Phase II

“Me-too” drugsPhase IV* labeling implications

Pediatric Advisory Council (PAC)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

Pediatric Advisory Council (PAC)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

Pediatric Advisory Council (PAC)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

Pediatric Advisory Council (PAC)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

Pediatric Advisory Council (PAC)Pediatric Advisory Council (PAC) Points to Consider

Pediatric Advisory Council (PAC)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

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

Parturition Litter Size Landmarks of Sexual DevelopmentGestation Length Pup Viability Neurobehavioral Assessment F1 Mating and Fertility Pup Weight Acoustic Startle Response

Organ Weights Motor Activity Learning & Memory

ParturitionGestation Length Pup Viability Litter SizeLandmarks of Sexual Development Pup WeightNeurobehavioral Assessment Organ Weights Acoustic Startle Response F1 Mating and Fertility Motor Activity Hormonal Analyses Learning & Memory Ovarian QuantificationHistopathology Premature Senescence

Postimplantation Loss

Postimplantation LossViable FetusesMalformations & VariationsFetal Weight

Postimplantation LossViable FetusesMalformationsVariationsFetal Weight

Estrous Cyclicity Mating Corpora Lutea Fertility Implantation SitesPre-Implantation Loss Spermatogenesis

Estrous ClyclicityMatingFertilityCorpora LuteaImplantation SitesPre-Implantation LossSpermatogenesis

Denotes Dosing Period

Standard DesignsStandard Designs

Single- and Multigenerational

Satellite Phase

OECD 415, OECD 416, OPPTS 870.3800, FDA Redbook I, NTP RACB

F1

F2 ????????????????

????????????????

Pre- and Postnatal Development

F1

ICH 4.1.2F0

????????????????

Prenatal DevelopmentICH 4.1.3 OECD 414

OPPTS 870.3600 870.3700

Fertility StudyICH 4.1.12W4W

CMAX

AUC

CMAX

AUC

10W

Animal : Human Concordance StudiesAnimal : Human Concordance Studiesfor Prenatal Toxicityfor Prenatal Toxicity

Authors

Holson et al., 1981 (Tox Forum)

Kimmel et al., 1984 (NCTR Report)

Attributes

Interdisciplinary team Criteria for acceptance of

data/conclusionsConcept of multiple developmental

toxicology endpoints No measures of internal dose

Many chemicalsRelied on authors’ conclusionsEmphasis on fertilityNo measures of internal dose

Nisbet & Karch, 1983

Animal : Human Concordance StudiesAnimal : Human Concordance Studiesfor Prenatal Toxicityfor Prenatal Toxicity

AuthorsAuthors

Hemminki & Vineis, 1985

Newman et al., 1993

Schardein, 1995

Attributes

Interspecies inhalatory doses adjustedRelied on authors’ conclusions23 occupational chemicals and mixtures No measures of internal dose

Provided detailed informationOnly 4 drugsEmphasis on morphologyFocus on NOAELsNo measures of internal dose

Many chemicalsRelied on authors’ conclusionsNo measures of internal dose

ImplantationFirst Heart BeatExterioceptionHemoglobin 8% in BloodBody Weight 1 gmThyroid IodineLung SurfactantLiver Glycogen 0.05%BirthWater 85% of Fat-freeNa/K one gm/gmAnoxia Tolerance 10 min.Body Fat 5%Arterial Pr. 50 mm/HgLethal Temp ShiftResistance to Cooling

Ontogeny of Physiologic Ontogeny of Physiologic Regulation in Selected MammalsRegulation in Selected Mammals

Stagemarks

4Days After Conception

Hamster Rat Rabbit Cat Pig Human

8 10 20 40 80 100 200 400

After Adolph 1970

Comparative Age Categories Based on Overall CNS Comparative Age Categories Based on Overall CNS and Reproductive Developmentand Reproductive Development

Days

Months

Years

Weeks

Weeks

Pre-Term Neonate

Term Neonate Infant/Toddler Child Adolescent

161220.8B

483660.5B

2820630.5B

261442B

90452110< 9B

B Birth

Ontogeny

Minipig

Rat

Dog

Nonhuman Primate

Human

Buelke-Sam, 2001

Preterm InfantsPreterm 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

Term Newborn Infants (0 to 27 Days)Term Newborn Infants (0 to 27 Days)

Volume of distribution because of different body water/fat content & higher body-surface-area-to-weight 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

Infants and ToddlersInfants and Toddlers (28 Days to 23 Months) (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

Children (2-11 Years)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)

Adolescents (12 to 16-18 Years)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

Effects on Prenatal and Postnatal Effects on Prenatal and Postnatal Development Including Maternal FunctionDevelopment Including Maternal Function

ICH 4.1.2 (Segment III)

Denotes Treatment Period

GD 6 PND 20

Gestation Lactation

Weaning Growth Mating GestationPN day 21 9 wks 2 wks 3 wks

F1

F2

Female (Rat) (Macroscopic Pathology)

PN day 17 PN day 80

Behavioral/Anatomic Measures

Motor ActivityAuditory StartleWater MazeDevelopmental Landmark

Vaginal PatencyPreputial Separation

Denotes Possible Transfer Via Milk

Comparison of PrenatalComparison of Prenataland Postnatal Modes of Exposureand Postnatal Modes of Exposure

Drug Transfer to OffspringDrug Transfer to Offspring

Drug Levels in OffspringDrug Levels in Offspring

Maternal Blood vs.Maternal Blood vs.Offspring LevelsOffspring Levels

Exposure Route toExposure Route toOffspringOffspring

CommentaryCommentary

Drug Transfer to OffspringDrug Transfer to Offspring

Drug Levels in OffspringDrug Levels in Offspring

Maternal Blood vs.Maternal Blood vs.Offspring LevelsOffspring Levels

Exposure Route toExposure Route toOffspringOffspring

CommentaryCommentary

PrenatalPrenatal

Nearly all transferredNearly all transferred

CCmaxmax and AUC measured and AUC measured

Maternal often a surrogateMaternal often a surrogate

Modulated IV exposure, via Modulated IV exposure, via placentaplacenta

Timing of exposure is criticalTiming of exposure is critical

PrenatalPrenatal

Nearly all transferredNearly all transferred

CCmaxmax and AUC measured and AUC measured

Maternal often a surrogateMaternal often a surrogate

Modulated IV exposure, via Modulated IV exposure, via placentaplacenta

Timing of exposure is criticalTiming of exposure is critical

PostnatalPostnatal

Apparent selectivity (“barrier”)Apparent selectivity (“barrier”)

Not routinely measuredNot routinely measured

Maternal levels probably NOT Maternal levels probably NOT a good predictora good predictor

Oral, via immature GI tractOral, via immature GI tract

Extent of transfer to milk and Extent of transfer to milk and neonatal bioavailability is key to neonatal bioavailability is key to differentiating indirect (maternal) differentiating indirect (maternal) effectseffectsfrom neonatal sensitivityfrom neonatal sensitivity

PostnatalPostnatal

Apparent selectivity (“barrier”)Apparent selectivity (“barrier”)

Not routinely measuredNot routinely measured

Maternal levels probably NOT Maternal levels probably NOT a good predictora good predictor

Oral, via immature GI tractOral, via immature GI tract

Extent of transfer to milk and Extent of transfer to milk and neonatal bioavailability is key to neonatal bioavailability is key to differentiating indirect (maternal) differentiating indirect (maternal) effectseffectsfrom neonatal sensitivityfrom neonatal sensitivity

Prenatal Treatment Postnatal

Embryo/FetusEmbryo/FetusEmbryo/FetusEmbryo/Fetus PlacentaPlacenta MotherMotherMotherMother MammaeMammae NeonateNeonate

ACE Inhibition-InducedACE Inhibition-InducedFetopathy (Human)Fetopathy (Human)

Organogenesis (classically defined) is unaffected

Effects are severe

Risk is low

Caused by ACEinh that cross placenta

ACEinhFetal

Hypotension

RenalCompromise

(Anuria)Oligohydramnios

Calvarial Hypoplasia

Neonatal Anuria

IUGR

Death

ACE Inhibition in Developing RatsACE 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 pupsGrowth retardation

Renal alterations (anatomic and functional)

Death

Examples of Perinatal/Juvenile ToxicantsExamples 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.

Examples of Perinatal/Juvenile (?) Examples of Perinatal/Juvenile (?) Developmental Toxicants Developmental Toxicants

Exposure Time ofToxicant Period Species Endpoint Manifestation Reference

Estrogen PND1-5 mouse cervical/vaginal adult Dunn & Green, 1963;

cancer Takasagi & Bern, 1964

DES prenatal human vaginal cancer/ pubescence Herbst & Skully, 1970

reprod. tract effects

DES PND1-5 mouse vaginal adenosis adult Forsberg, 1976

Sex hormone PND1-5 mouse vaginal adenosis/ adult Bern et al., (DES) 1976

cancer

DES GD15, 16, 17 mouse vaginal adenosis, adult Walker, 1980transverse ridges (14 mo.)

Selective Juvenile Toxicity of QuinilonesSelective Juvenile Toxicity of Quinilones

Drug

Ofloxacin (and other quinilones)

Modified from Stahlmann et al., 1997.

Species &Treatment

Multiple Species,postnatal exposure.20 mg/kg (dog, 3 mo.) 600 mg/kg (rat, 5 wk)

Effects

Chondrotoxic effects. Cartilage erosion in weight-bearing joints.

Gait alterations in juvenile dogs only.

Remarks

Human relevance unknown; drugs contraindicated in juvenile patients.

Mechanism: Probable deficiency of bioavailable Mg2+ in cartilage (quinilones chelate divalent cations).

No effect in routine segment III studies.

Primary Reasons ExperimentalPrimary Reasons ExperimentalModels Appear to be InvalidModels 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

ConclusionsConclusions

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.