1. Overview and Regulatory Issues Regarding Anesthetic Agents for Pediatric Patients Anesthetics and Life Support Drugs Advisory Committee Meeting March 29, 2007 Arthur Simone, MD, PhD Division of Anesthesia, Analgesia and Rheumatology Products Anesthetics and Life Support Drugs Advisory Committee Meeting March 29, 2007 Arthur Simone, MD, PhD Division of Anesthesia, Analgesia and Rheumatology Products Center for Drug Evaluation and Research

2. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 2 The Issue Synaptogenesis (brain growth spurt) Highly regulated period of brain development A process that appears conserved among species –Rodents: 2 days before to 2 weeks after birth –Humans: 3 rd trimester to ~ 3 years of age Second spurt observed in humans during late adolescence Adversely affected by environmental conditions Synaptogenesis (brain growth spurt) Highly regulated period of brain development A process that appears conserved among species –Rodents: 2 days before to 2 weeks after birth –Humans: 3 rd trimester to ~ 3 years of age Second spurt observed in humans during late adolescence Adversely affected by environmental conditions

3. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 3 The Issue Glutamate and γ -amino-butyric acid (GABA) –Non-synaptic trophic factors –Promote neuronal arbor elaboration GABA-receptor stimulation and N-methyl D- aspartate (NMDA) receptor blockade –Deleterious effects on neural development –Apoptosis - programmed cell death Single cell Shrunken, preserved plasma membrane Non-inflammatory Glutamate and γ -amino-butyric acid (GABA) –Non-synaptic trophic factors –Promote neuronal arbor elaboration GABA-receptor stimulation and N-methyl D- aspartate (NMDA) receptor blockade –Deleterious effects on neural development –Apoptosis - programmed cell death Single cell Shrunken, preserved plasma membrane Non-inflammatory

4. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 4 Receptor Activity of Commonly Used Anesthetic Agents

5. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 5 Anesthesia and the Vulnerable Patient Exposures –Maternal surgery –In-utero surgery –Labor and delivery/Cesarian section –Surgical procedures from birth to age 3 years Alternative Therapies –Neuraxial/regional/local anesthesia –Opioid anesthesia –No anesthesia –Delay surgery Exposures –Maternal surgery –In-utero surgery –Labor and delivery/Cesarian section –Surgical procedures from birth to age 3 years Alternative Therapies –Neuraxial/regional/local anesthesia –Opioid anesthesia –No anesthesia –Delay surgery

6. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 6 Commonly Used Anesthetic Agents

7. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 7 Commonly Used Anesthetic Agents With Pediatric Specific Labeling

8. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 8 Commonly Used Anesthetic Agents With Any Pediatric Specific Labeling for Ages ≤ 3 years

9. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 9 Classification of Drug Products for Use During Pregnancy 21 CFR §201.57 A - human studies show no risk B - animal studies show risk but human studies do not C - animal studies show risk but no human studies conducted, or no studies at all D - evidence of human fetal risk X - studies have demonstrated animal or human fetal abnormalities and risk outweighs any possible benefit. 21 CFR §201.57 A - human studies show no risk B - animal studies show risk but human studies do not C - animal studies show risk but no human studies conducted, or no studies at all D - evidence of human fetal risk X - studies have demonstrated animal or human fetal abnormalities and risk outweighs any possible benefit.

10. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 10 Commonly Used Anesthetic Agents – With a Pregnancy Classification of A or B Methohexital Propofol Enflurane Desflurane Sevoflurane Lidocaine Lidocaine-Prilocaine Ropivacaine cis-atracurium Methohexital Propofol Enflurane Desflurane Sevoflurane Lidocaine Lidocaine-Prilocaine Ropivacaine cis-atracurium

11. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 11 Milestones for Drug Regulation 1934 - Thiopental (clinical use; never approved for parenteral) 1938 - The Federal Food, Drug, and Cosmetic (FDC) Act 1942 - Meperidine 1958 - Halothane 1960 - Methohexital 1962 - Kefauver-Harris Drug Amendments 1966 - NAS and NRC to assess efficacy of 4,000 drugs approved 1938-1962 1968 - FDA forms Drug Efficacy Study Implementation (DESI) to implement recommendations of the NAS 1968 - Fentanyl 1970 - Ketamine 1971 - National Center for Toxicological Research established 1979 - 1992 – Isoflurane, Etomidate, Midazolam, Propofol, Desflurane 1994 - Regulations promulgated stating that there must be a pediatric use section in the label 1995 - Sevoflurane 1997 - Food and Drug Modernization Act 1998 - Pediatric Rule 2002 - The Best Pharmaceuticals for Children Act 2003 - Pediatric Research Equity Act 1934 - Thiopental (clinical use; never approved for parenteral) 1938 - The Federal Food, Drug, and Cosmetic (FDC) Act 1942 - Meperidine 1958 - Halothane 1960 - Methohexital 1962 - Kefauver-Harris Drug Amendments 1966 - NAS and NRC to assess efficacy of 4,000 drugs approved 1938-1962 1968 - FDA forms Drug Efficacy Study Implementation (DESI) to implement recommendations of the NAS 1968 - Fentanyl 1970 - Ketamine 1971 - National Center for Toxicological Research established 1979 - 1992 – Isoflurane, Etomidate, Midazolam, Propofol, Desflurane 1994 - Regulations promulgated stating that there must be a pediatric use section in the label 1995 - Sevoflurane 1997 - Food and Drug Modernization Act 1998 - Pediatric Rule 2002 - The Best Pharmaceuticals for Children Act 2003 - Pediatric Research Equity Act

12. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 12 Securing Pediatric Indications Drug is initially approved for adult use. Preclinical evaluation in juvenile animals is not always required. –Guidance for Industry: “Nonclinical Safety Evaluation of Pediatric Drug Products” (Feb., 2006) Pediatric clinical trials are primarily designed for determining efficacious dosing requirements. Assessment of safety – findings from adult trials and new findings from pediatric clinical trials Drug is initially approved for adult use. Preclinical evaluation in juvenile animals is not always required. –Guidance for Industry: “Nonclinical Safety Evaluation of Pediatric Drug Products” (Feb., 2006) Pediatric clinical trials are primarily designed for determining efficacious dosing requirements. Assessment of safety – findings from adult trials and new findings from pediatric clinical trials

13. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 13AlternativesAlternatives Local anesthetics Narcotic-only anesthesia No anesthesia/sedation Delay procedure Local anesthetics Narcotic-only anesthesia No anesthesia/sedation Delay procedure

14. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 14 Local Anesthetics Topical, regional, and neuraxial anesthesia may be suitable for some procedures. Toxicities in pediatric patients have not been fully elucidated. Sedation is generally utilized for anxiolysis and amnesia. Topical, regional, and neuraxial anesthesia may be suitable for some procedures. Toxicities in pediatric patients have not been fully elucidated. Sedation is generally utilized for anxiolysis and amnesia.

15. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 15OpioidsOpioids May be suitable for some procedures. Toxicities for pediatric patients have not been fully elucidated. Sedation is generally utilized for anxiolysis and amnesia. May be suitable for some procedures. Toxicities for pediatric patients have not been fully elucidated. Sedation is generally utilized for anxiolysis and amnesia.

16. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 16 No Anesthesia May work for some procedures Research demonstrates –Morphological changes in rodent brains –Premature infants show metabolic stress responses post operatively that can be blocked by intravenous opioids. –The increasing crying and behavioral changes occur for days after circumcision can be blocked with the use of regional anesthesia. –4- to 6-month old infants circumcised without analgesia had higher pain scores than those circumcised with analgesia as measured by observable indicators such as facial expression, length of crying, and body movement –by 6 months of age, children demonstrate anticipatory fear when taken to places where they experienced pain in the past May work for some procedures Research demonstrates –Morphological changes in rodent brains –Premature infants show metabolic stress responses post operatively that can be blocked by intravenous opioids. –The increasing crying and behavioral changes occur for days after circumcision can be blocked with the use of regional anesthesia. –4- to 6-month old infants circumcised without analgesia had higher pain scores than those circumcised with analgesia as measured by observable indicators such as facial expression, length of crying, and body movement –by 6 months of age, children demonstrate anticipatory fear when taken to places where they experienced pain in the past

17. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 17 AERS Database Post-approval safety data collection Limitations –Voluntary –Submitter status –Data captured Timing of adverse event Nature of events Missing data –Numerator/Denominator Post-approval safety data collection Limitations –Voluntary –Submitter status –Data captured Timing of adverse event Nature of events Missing data –Numerator/Denominator

18. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 18 Ketamine and AERS Database Office of Surveillance and Epidemiology Between approval and 1-29-07 153 pediatric (≤ 16 years old) reports SOCs selected: –Musculoskeletal –Nervous –Psychiatric Office of Surveillance and Epidemiology Between approval and 1-29-07 153 pediatric (≤ 16 years old) reports SOCs selected: –Musculoskeletal –Nervous –Psychiatric

19. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 19 Ketamine and AERS Database 58 reports found –1970-79 (n=9) –1980-89 (n=5) –1990-99 (n=22) –2000-06 (n=22) There were 4 fatalities. 25 reports involved at least one other NMDA/GABA acting anesthetic 58 reports found –1970-79 (n=9) –1980-89 (n=5) –1990-99 (n=22) –2000-06 (n=22) There were 4 fatalities. 25 reports involved at least one other NMDA/GABA acting anesthetic

20. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 20 Ketamine and AERS Database convulsions (n=9) hallucination (n=6) drug ineffective (n=8) medication error (n=6) sedation (n=8) abnormal dreams (n=5) pyrexia (n=7) anesthetic complication (n=5) bradycardia (n=6) coma (n=4) convulsions (n=9) hallucination (n=6) drug ineffective (n=8) medication error (n=6) sedation (n=8) abnormal dreams (n=5) pyrexia (n=7) anesthetic complication (n=5) bradycardia (n=6) coma (n=4)

21. Anesthetics and Life Support Drugs Advisory Committee March 29, 2007 21 Where do we stand? A safety signal has been identified in animals for many drugs used to provide sedation and anesthesia. The relevance of the animal findings to pediatric patients is unknown. The need to provide sedation and anesthesia cannot be avoided in many situations. There is no available alternative therapy proven to be safer. A safety signal has been identified in animals for many drugs used to provide sedation and anesthesia. The relevance of the animal findings to pediatric patients is unknown. The need to provide sedation and anesthesia cannot be avoided in many situations. There is no available alternative therapy proven to be safer.