1. Opiate Analgesic Use in Pediatric Patients Bob Rappaport, M.D. Deputy Division Director Division of Anesthetic, Critical Care and Addiction Drug Products, FDA

2. Hypothetical Vignettes in Pediatric Drug Development

3. DRUG 1 Novel long-acting sustained release opiate Multiple-dose PK study in children > 7 years Efficacy not a primary endpoint -can we extrapolate from adults? -reliability of endpoints in children Pediatric waiver requested for  7 years -“substantial use” -recruitment -lowest dose dangerously high

4. Discussion points: Efficacy endpoints in pediatric age groups Pediatric recruitment for long term analgesic trials Appropriateness of formulations -tablets/capsules, etc -age groups Use of long-acting opiates in children

5. Discussion points: Pediatric Rule: study pediatric-appropriate formulations Sponsor arguments: New formulation would not retain sustained-release features No meaningful therapeutic benefit over existing No plans to market Value of requiring new formulation studies?

6. DRUG 2 New delivery system for chronic malignant pain >24 hrs: reservoir adherent to skin continuous SQ (25G needle) previously approved intermediate-duration opioid (adult only) PCA boluses Pediatric waiver requested for  12 years Unsafe (dislodgment of needle) PCA inappropriate PCA boluses too large

7. Discussion Points: Appropriate age groups for: Continuous infusion devices Patient-controlled dosing Needle delivery devices Devices applied externally over a period of time Value of mandating studies of a pediatric- appropriate formulation (e.g. oral, IV) without the subcutaneous injection device

8. DRUG 3 New fixed-dose opioid-acetaminophen combination Pediatric waiver requested Are fixed dose combinations inappropriate in this setting? IRB: Analgesic trials unethical in children (especially placebo-controlled)

9. Discussion Points: Fixed-dose opioid combination drugs: appropriateness, dosing considerations Ethical concerns in pediatric analgesic trials Types of trials (e.g. placebo-controlled) Age groups

10. Currently Available Formulations (Majority without pediatric indications) Powder Injectable Oral –concentrate, solution, suspension, suspension XR, syrup, elixir, tablet, tablet XR, capsule, capsule XR, lozenge Transdermal Film Nasal Rectal Suppository Intrathecal Epidural

11. The FDA is aware that there are still significant unmet needs in pediatric pain management. In the context of the Agency's new mandate to require studies of drugs in children, discuss these unmet pharmacotherapeutic needs in current pediatric pain management and how they might be met with regard to opioid drug products. Include discussion of the significance of barriers to opioid analgesic trials in children (ethical, safety, scientific, practical, etc), and what strategies might be used to overcome those barriers?

12. Many different opioid formulations, delivery methods, and drug ‑ device combinations are currently on the market or may be available in the future. Discuss the age appropriateness and limitations of these various methods of administration, as well as any others that may be particularly useful or particularly hazardous in the treatment of pediatric pain patients.

13. It has been historically accepted that the mechanisms of action of opioid analgesics are sufficiently similar between adults and children that large controlled studies to demonstrate efficacy have not been required for a pediatric indication. Instead, pediatric trials have been largely focused on investigating safety, pharmacokinetics and appropriate dosing regimens. Discuss the shortfalls, if any, to this approach. Include discussion of approaches to dose finding and the evaluation of pain in the very young.

14. As new opiate analgesic products become available for home use in younger patients, there may be a risk of accidental ingestion by family members, or deliberate abuse and diversion of these medications. Discuss the strategies for risk communication and risk management that should be considered at the time of pediatric opioid drug approval.