Development of Pediatric ARV Drugs – FDA Perspective

Linda L. Lewis, M.D.Medical OfficerDivision of Antiviral Drug ProductsU.S. Food and Drug Administration

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

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

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

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

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

“Bona fide” approved pediatric formulationsZidovudine Oral SyrupDidanosine Powder (reconstitute with

antacid)Lamivudine Oral SolutionStavudine Oral SolutionAbacavir Oral SolutionNevirapine SuspensionEfavirenz 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)

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

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)

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

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

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

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

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

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)

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

Required components for FDC NDA

FDC application should contain – Clinical Rationale for combination– Clinical Pharmacology-

Bioequivalence– CMC

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

Clinical pharmacology components

Bioequivalence study Bioanalytic method validation Summary of food effect

considerations– Studies usually precede pivotal

clinical studies Dissolution testing

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

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

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

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?

Extra slides

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)

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

Introduction of “generic” products in clinical trials or clinical useFDA 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

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

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

Approved formulations – NNRTIs

Delavirdine – 100 and 200 mg tabs

Efavirenz – mult size caps Nevirapine – 200 mg tabs,

suspension 10 mg/mL

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

Approved formulations – fusion or entry inhibitors

Enfuvirtide – 108 mg/vial lyophilized powder for reconstitution and SQ injection

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