Transcript Development of Pediatric ARV Drugs – FDA Perspective

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
Rationale for FDA pediatric
initiatives
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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
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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
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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
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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
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15 ARV drugs have pediatric formulations
12 “Bona fide” = NDA for new ageappropriate formulation
– Liquids predominate; one oral powder
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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
formulations
Zidovudine
Didanosine
Lamivudine
Stavudine
Abacavir
Nevirapine
Efavirenz
Ritonavir
Nelfinavir mesylate
Amprenavir
Oral Syrup
Powder (reconstitute with antacid)
Oral Solution
Oral Solution
Oral Solution
Suspension
Capsules (50 and 100 mg)
Oral Solution (contains ethanol)
Oral Powder (to be mixed with
foods)
Oral Solution (contains propylene
glycol)
Lopinavir/Ritonavir Oral Solution (contains ethanol)
Extra problems - use of adult
formulations in children
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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
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Best Pharmaceuticals for Children Act
– Extends 6 months patent protection to
companies that perform requested
pediatric studies (voluntary)
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Pediatric Research Equity Act (2003)
– Any drug that may provide benefit to
children must be studied in children
(mandatory)
Pediatric Research Equity Act
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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:
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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
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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
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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
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Monitor tolerability and safety
Assess activity in pediatric age groups
Evaluating pediatric formulations
– “generics”
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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
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Monitor tolerability and safety
Evaluating pediatric formulations
– “generics”
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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
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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 noninnovator drugs for distribution outside
the U.S.
– Intended to support PEPFAR purchase of
ARV drugs
Required components for FDC
NDA
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FDC application should contain
– Clinical Rationale for combination
– Clinical Pharmacology-Bioequivalence
– CMC
Clinical components
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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)
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Rely on FDA’s previous findings of safety and
effectiveness
Clinical pharmacology
components
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Bioequivalence study
Bioanalytic method validation
Summary of food effect considerations
– Studies usually precede pivotal clinical
studies
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Dissolution testing
Chemistry/Manufacturing
components
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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
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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?
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Contacts at FDA:
– Linda Lewis (pediatric ARV issues) –
[email protected]
– Jeff Murray (clinical/regulatory) –
[email protected]
– Steve Miller (chemistry/manufacturing) –
[email protected]
– Kellie Reynolds (clinical pharmacology) –
[email protected]
Questions for you 
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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
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At least 3 drugs are needed to maintain
suppression of HIV
– More may be needed for resistant strains
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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
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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 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
Introduction of “generic” products
in clinical trials or clinical use
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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
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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
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Delavirdine – 100 and 200 mg tabs
Efavirenz – mult size caps
Nevirapine – 200 mg tabs, suspension
10 mg/mL
Approved formulations – PIs
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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
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Enfuvirtide – 108 mg/vial lyophilized
powder for reconstitution and SQ
injection
Approved formulations - FDCs
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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