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
This has been assumed for HIV disease– we do not assume drug approved for treatment is effective for prophylaxis

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. Clinical components 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) –
Jeff Murray (clinical/regulatory) –
Steve Miller (chemistry/manufacturing) –
Kellie Reynolds (clinical pharmacology) –

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 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 mg 3TC
Trizivir mg ZDV mg 3TC mg ABC
Epzicom mg 3TC mg ABC
Truvada – 300 mg TDF mg FTC
None of these FDC products are scored, none are available as smaller size tablets or as liquids