Regulatory and Scientific Impact of FDAMA


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

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  • Regulatory and Scientific Impact of FDAMA

    1. 1. Regulatory and Scientific Impact of FDAMA Joseph F. Holson, Ph.D. WIL Research Laboratories, Inc.
    2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.