Development of Pediatric ARV Drugs – FDA Perspective

1. Development of Pediatric ARV Drugs – FDA Perspective Linda L. Lewis, M.D. Medical Officer Division of Antiviral Drug Products U.S. Food and Drug Administration

2. Rationale for FDA pediatric initiatives • Lack of pediatric use information poses significant risks for children • Lack of appropriate formulations may deny access and expose children to “homemade” formulations • Prevent adverse events or overdose • Prevent under treatment

3. General requirements for FDA approval of ARV drugs • Information regarding mechanism of action, ADME and PK profile, path to resistance • Chemistry/manufacturing/controls info • Adequate and well-controlled clinical trials of 24 to 48 weeks • Demonstrated beneficial effect on HIV RNA, CD4 counts, clinical course

4. Pediatric drug development • Must include all aspects of general drug development (usually referenced) • Plus must evaluate: • Differences in absorption, distribution, metabolism, elimination - PK profile for age • Differences in side effect profile • Differences in therapeutic effect - not different in HIV disease

5. Key issues in developing pediatric formulations • Stability of formulation (temperature, reliable drug release) • Acceptable palatability • Able to achieve target PK parameter associated with efficacy in adults • Convenience

6. Approaches to pediatric formulations • 15 ARV drugs have pediatric formulations • 12 “Bona fide” = NDA for new age-appropriate formulation • Liquids predominate; one oral powder • Must be open to other approaches and extemporaneous formulations • Delavirdine - disperse tablet in water; example where bona fide formulation not achieved after sufficient developmental effort

7. “Bona fide” approved pediatric formulations Zidovudine Oral Syrup Didanosine Powder (reconstitute with antacid) Lamivudine Oral Solution Stavudine Oral Solution Abacavir Oral Solution Nevirapine Suspension Efavirenz Capsules (50 and 100 mg) Ritonavir Oral Solution (contains ethanol) Nelfinavir mesylate Oral Powder (to be mixed with foods) Amprenavir Oral Solution (contains propylene glycol) Lopinavir/Ritonavir Oral Solution (contains ethanol)

8. Extra problems - use of adult formulations in children • If splitting tablets ensure that procedure can be performed reliably by target population • If crushing tablets or opening capsules may need PK data to support that route • If using adult FDC must ensure each component provided in recommended dose for age range being treated

9. U.S. legislation affecting pediatric drug development • Best Pharmaceuticals for Children Act • Extends 6 months patent protection to companies that perform requested pediatric studies (voluntary) • Pediatric Research Equity Act (2003) • Any drug that may provide benefit to children must be studied in children (mandatory)

10. Pediatric Research Equity Act • Pediatric assessment required for any new ingredient, new indication, new dosage form, new dosing regimen, or new route of administration • Pediatric assessment must contain: • Data adequate to assess the safety and effectiveness of the drug or biological product • Data to support dosing and administration for each relevant pediatric subpopulation

11. Pediatric Research Equity Act If similar course of disease or drug activity anticipated: • Effectiveness in children can be extrapolated from adequate and well-controlled studies in adults when supplemented with other information (safety, PK-PD in children) • Extrapolation from one age group to another age group where appropriate

12. Application of PREA to ARV development • All ARV drugs routinely recommended for evaluation in pediatric patients • May grant Deferral of pediatric studies if drug otherwise ready for approval and sponsor has submitted a pediatric development plan • May grant Partial Waiver for certain age groups because of safety concerns based on known safety profile in adults

13. Evaluating pediatric formulations – new drugs • Pharmacokinetic evaluation • Determine how to achieve target exposure found to be safe and effective • Should include all age groups (enough patients sampled to identify variability) • For initial dose estimate should take into consideration developmental changes in absorption, metabolism, excretion • Monitor tolerability and safety • Assess activity in pediatric age groups

14. Evaluating pediatric formulations – “generics” • Demonstrate bioequivalence • Single product - compare generic to reference drug (innovator) • For FDC product - compare generic FDC to individual reference drugs taken together • Preferred study design is randomized, single-dose, 2-way cross-over • Monitor tolerability and safety

15. Evaluating pediatric formulations – “generics” • Caveats • Bioequivalence studies need not be done in children • If comparing 2 oral solutions no BE study required, if comparing formulations other than solutions BE study required • Evaluating solid or suspension formulations – dissolution testing required (assurance of reproducible drug release)

16. Other recent regulatory activity • Draft Guidance for Industry: Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV • Provides guidelines for rapid approval of innovator or tentative approval of non-innovator drugs for distribution outside the U.S. • Intended to support PEPFAR purchase of ARV drugs

17. Required components for FDC NDA • FDC application should contain • Clinical Rationale for combination • Clinical Pharmacology-Bioequivalence • CMC

18. Clinicalcomponents • Summary or rationale for clinical use • Reference own previous IND/NDA • Right of reference to other sponsor’s IND/NDA • Literature References • Clinical studies: 48-wk effect on HIV-RNA • Other data: resistance studies, safety data • Treatment guidelines (WHO, DHHS, IAS) • Rely on FDA’s previous findings of safety and effectiveness

19. Clinical pharmacology components • Bioequivalence study • Bioanalytic method validation • Summary of food effect considerations • Studies usually precede pivotal clinical studies • Dissolution testing

20. Chemistry/Manufacturing components • Quality standards for each active ingredient and dosage form • Stress studies: lack of interaction between ingredients • Drug release information (dissolution) • Stability data: long term and short term under high temperature and/or humidity • References/data supporting excipients • Manufacturing processes for active ingredients and dosage form

21. Application of pediatric initiatives to FDC development • Fixed dose combination products • Want to encourage development of FDCs appropriate for pediatric patients • Some FDCs may not be appropriate for all ages (dose, proportion of component drugs) • Need to consider on a case-by-case basis

22. Questions? • Contacts at FDA: • Linda Lewis (pediatric ARV issues) – lewisl@cder.fda.gov • Jeff Murray (clinical/regulatory) – murrayj@cder.fda.gov • Steve Miller (chemistry/manufacturing) – millers@cder.fda.gov • Kellie Reynolds (clinical pharmacology) – reynoldsk@cder.fda.gov

23. Questions for you - • What innovative approaches to formulations should we suggest? • How can FDA encourage sponsors to develop pediatric formulations? • How can we help you?

24. Extra slides

25. Concepts Supporting FDC • At least 3 drugs are needed to maintain suppression of HIV • More may be needed for resistant strains • Combination therapy provides a mutational barrier to resistance • Standard of Care • 2 NRTIs + 1 NNRTI • 2 NRTIs + PI (often boosted) • 3 NRTIs (one regimen identified)

26. Optimal FDC Characteristics • Full (3 drug) or partial (2 drug) regimens • Preferred or alternate regimens in treatment naïve patients • Clinical trials of proposed combination completed • Evaluating changes in viral load and CD4 over 48 weeks • Favorable risk-benefit profile • Easy administration and compatible dosing schedules and food requirements

27. Introduction of “generic” products in clinical trials or clinical use FDA recommendations • Chemistry/manufacturing/controls data for product (description of drug substance and method of preparation, components used to manufacture final drug product, stability testing, description of packaging, limits and analytical methods used to assure quality) • Proof of bioequivalence or evidence that therapeutic exposure likely to occur

28. Introduction of “generic” products in clinical trials or clinical use • Monitor long-term safety and efficacy • Optimal to compare to reference product in first use • In clinical trials - probably difficult to use different products in different sites in same trial

29. Approved formulations - NRTIs • Abacavir – 300 mg tab, oral soln 20mg/mL • Didanosine – mult size tabs and EC caps, powder for suspension 10 mg/mL • Emtricitabine – 200 mg tab • Lamivudine – 150 or 300 tabs, oral soln 10 mg/mL • Stavudine – mult size tabs, oral soln 1 mg/mL • Tenofovir – 300 mg tabs • Zalcitabine – 0.75 and 0.375 mg tabs • Zidovudine – 100 and 300 mg tabs, oral syrup 10 mg/mL

30. Approved formulations – NNRTIs • Delavirdine – 100 and 200 mg tabs • Efavirenz – mult size caps • Nevirapine – 200 mg tabs, suspension 10 mg/mL

31. Approved formulations – PIs • Amprenavir – 50 and 150 mg caps, oral soln 15 mg/mL • Atazanavir – 100, 150, and 200 mg caps • Fosamprenavir – 700 mg tab • Indinavir – 200, 333, and 400 mg caps • Lopinavir/r – 133/33 mg gel caps, oral soln 80/20 mg/mL • Nelfinavir – 250 and 625 mg tabs, oral powder 50 mg/g (scoop) • Ritonavir – 100 mg gel caps, oral soln 80 mg/mL • Saquinavir – Fortovase 200 mg soft gel caps, Invirase 200 mg caps

32. Approved formulations – fusion or entry inhibitors • Enfuvirtide – 108 mg/vial lyophilized powder for reconstitution and SQ injection

33. Approved formulations - FDCs • Combivir – 300 mg ZDV + 150 mg 3TC • Trizivir - 300 mg ZDV + 150 mg 3TC + 300 mg ABC • Epzicom - 150 mg 3TC + 300 mg ABC • Truvada – 300 mg TDF + 200 mg FTC None of these FDC products are scored, none are available as smaller size tablets or as liquids