Overview and Regulatory Issues Regarding Anesthetic Agents for Pediatric Patients

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 Center for Drug Evaluation and Research

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: 3rd trimester to ~ 3 years of age • Second spurt observed in humans during late adolescence • Adversely affected by environmental conditions

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

4. Receptor Activity of Commonly Used Anesthetic Agents

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

6. Commonly Used Anesthetic Agents

7. Commonly Used Anesthetic Agents With Pediatric Specific Labeling

8. Commonly Used Anesthetic Agents With Any Pediatric Specific Labeling for Ages ≤ 3 years

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.

10. Commonly Used Anesthetic Agents – With a Pregnancy Classification of A or B • Methohexital • Propofol • Enflurane • Desflurane • Sevoflurane • Lidocaine • Lidocaine-Prilocaine • Ropivacaine • cis-atracurium

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

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

13. Alternatives • Local anesthetics • Narcotic-only anesthesia • No anesthesia/sedation • Delay procedure

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.

15. Opioids • May be suitable for some procedures. • Toxicities for pediatric patients have not been fully elucidated. • Sedation is generally utilized for anxiolysis and amnesia.

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

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

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

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

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)

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.