regulatory approaches for generic drugs
TRANSCRIPT
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Regulatory Approaches for Generic
Drugs: BE of Topical Drug Products
Barbara M. Davit, Ph.D., J.D.
Director, Division of Bioequivalence II
Office of Generic Drugs, CDER, FDA
PQRI Workshop
Evaluation of New and Generic Topical Drug Products
March 11-13, 2013
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Agenda
• Bioequivalence issues unique to topical
drug products
• Pharmacokinetic (PK) approach
• Pharmacodynamic (PD) approach
• Clinical approach
• In vitro approach
• Waiver of BE requirement (biowaiver)
• Summary and conclusions 2
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Why do bioequivalence (BE)
studies of topical products
present unique regulatory issues?
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Why are BE studies necessary for
proposed new generic products?
• The US Code and FDA’s regulations require
that a generic drug product be bioequivalent
to its corresponding reference listed drug
(RLD) product for marketing approval
• It is not necessary to demonstrate safety and
efficacy for the new generic
– Relies on RLD safety and efficacy data
• If certain criteria are met, FDA may grant a
biowaiver
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Objective of BE studies in generic drug
approval process
• In an acceptable BE study, the generic and reference product should not show a significant difference in the rate and extent of availability at the site of action
• FDA’s regulations list suitable BE approaches ranked by sensitivity, accuracy, reproducibility
• For each new generic topical drug product, FDA must consider
– The optimal BE approach; or
– Whether a biowaiver is appropriate 5
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BE approaches, ordered by accuracy,
sensitivity, reproducibility
• PK
• PD
• Clinical endpoint
• In vitro
• Any other approach deemed
suitable by FDA
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Considerations in selecting BE approach
for a generic topical drug
Choice of BE study
design depends on
ability to compare
drug delivered by
generic & RLD at site
of action
Site of
action
Mechanism
of action
RLD
formulation
Sensitivity
of
approach
Feasibility
of
approach
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Some definitions applied in comparing
generic and RLD topical formulations
Terminology Abbr. Definition
Qualitatively the
same Q1
Generic and RLD products
contain the same active and
inactive ingredients
Quantitatively the
same Q2
Generic and RLD products
contain the same amounts of
active and inactive ingredients
Physicochemical
attributes of a
topical dosage form
Q3
Generic and RLD products
have the same
physicochemical properties
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Several case studies illustrate how
FDA determines an appropriate BE
approach for a generic topical
product
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Application of PK approach:
lidocaine topical patch 5%
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Application of PK approach:
lidocaine topical patch 5%
Drug substance
• An amide-type local anesthetic agent
Indication
• Relief of pain associated with post-herpetic neuralgia
Mechanism of action
• Lidocaine acts on nerves in dermal tissue
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Application of PK approach:
lidocaine topical patch 5%
Site of action
• Lidocaine penetrates beneath the stratum corneum to reach the site of action in dermal tissue
RLD formulation
• An adhesive material containing 5% lidocaine, to be applied to the skin
Sensitivity, feasibility
• Lidocaine in plasma is proportional to its presence at site of action
• Measuring lidocaine in plasma is feasible
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Application of PD approach:
fluocinolone acetonide 0.01%
topical body oil
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Application of PD approach:
fluocinolone acetonide topical oil
Drug substance
• Low-to-medium range potency corticosteroid
Indication
• Topical treatment of atopic dermatitis
Mechanism of action
• Has anti-inflammatory, antipruritic, & vasoconstrictive properties
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Application of PD approach:
fluocinolone acetonide topical oil
Site of action
• Absorbed percutaneously; not intended to be systemically absorbed
RLD formulation
• A solution of fluocinolone acetonide in a blend of oils
Sensitivity, feasibility
• The PD vasoconstrictor assay can accurately detect rate and extent of availability in skin
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Fluocinolone acetonide topical oil:
additional considerations for BE
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Application of clinical endpoint
approach: 5-flourouracil
(5-FU) cream 5%
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Application of clinical approach:
5-FU cream 5%
Drug substance
• A fluoro-pyrimidinedione which is cytotoxic
Indication
• Topical treatment of actinic keratoses (AK)
• Treatment of superficial basal cell carcinomas (sBCC)
Mechanism of action
• Creates a thymine deficiency, provoking unbalanced growth in rapidly-growing cells, such as carcinomas
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Application of clinical approach:
5-FU cream 5%
Site of action
• Acts on AK and sBCC lesions in the epidermis and dermis
RLD formulation
• Cream contains 5-FU in a vanishing cream base comprised of several inactive ingredients
Sensitivity, feasibility
• AK treatment is considered more sensitive to formulation performance than sBCC treatment
• It is feasible to perform a clinical endpoint BE study in AK patients
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Clinical endpoint BE studies of 5-
FU: additional considerations
• Primary endpoint is proportion of subjects with
treatment success at study week 6
• Success is defined as 100% clearance of all
AK lesions within the treatment area
• A placebo control arm is recommended to
– Demonstrate that the generic and RLD are active;
– As a parameter to show that study is sufficiently
sensitive to detect differences between products
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Application of in vitro approach:
acyclovir ointment 5%
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An in vitro approach can be used for
acyclovir ointment 5% Drug
substance
• A synthetic nucleotide analogue active against herpes viruses
Indication
• Initial outbreaks of genital herpes
• Treat certain types of lesions caused by Herpes simplex virus
Mechanism of action
• Converted to acyclovir triphosphate intracellularly
• Acyclovir triphosphate stops replication of herpes viral DNA
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An in vitro approach can be used for
acyclovir ointment 5%
Site of action
• Acyclovir delivered by the ointment functions in the upper layer of the skin
RLD formulation
• Considerably less complex than a cream
• Consists of one active ingredient suspended in a polyethylene glycol base
Sensitivity, feasibility
• An in vitro BE approach more sensitive than a clinical endpoint BE study
• Due to low potency of ointment, a clinical endpoint BE study may not be feasible or reliable
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BE of acyclovir ointment 5%:
additional considerations
• The generic and RLD products must be Q1/Q2
• To show that generic and RLD are also Q3,
conduct in vitro tests to compare
– Release rates
– Particle size, viscosity, morphic form, PEG
molecular weight distribution
• If not Q1/Q2, conduct clinical endpoint study
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For the diclofenac sodium gel 1%,
FDA recommends a PK endpoint
study and a clinical endpoint
study to demonstrate BE
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For diclofenac sodium gel 1%, FDA
recommends two in vivo BE studies
Drug substance
• Non-steroidal anti-inflammatory
Indication
• Relief of the pain of osteoarthritis
Mechanism of action
• Inhibits cyclooxygenase, resulting in decreased synthesis of molecules associated with inflammatory response
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For diclofenac sodium gel 1%, FDA
recommends two in vivo BE studies Site of action
• The joint or local soft tissue
• Diclofenac penetrates the soft tissue
• Diclofenac is also well-absorbed
• Unclear if effects are due solely to local delivery or if systemic delivery contributes
RLD formulation
• A gel comprised of several different inactive ingredients
Sensitivity, feasibility
• A PK study is most sensitive, accurate, reproducible but may be unsuitable if drug acts mainly by local action
• As there is evidence that drug may be locally-acting, an in vivo study with clinical endpoints should also be conducted
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The FDA will consider granting
biowaivers for topical products
provided certain criteria are met
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Criteria for granting a biowaiver for a
topical solution
• Formulation is a solution for application to skin;
• Generic and RLD contain the same active
ingredient in the same concentration and
dosage form;
• The generic contains no inactive ingredient or
other change in formulation from the RLD that
might significantly affect availability – e.g, FDA may request in vivo and/or in vitro BE studies if
generic and RLD have differences in penetration enhancers
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Biowaivers for products coded “AT”
in FDA’s Orange Book
• Applies to very few topical formulations
approved prior to 1962
• Underwent review by the Drug Efficacy Study
Implementation (DESI) panels of experts
• Generic and RLD must contain same active
ingredient and be of same dosage form
• Examples
– Erythromycin topical gel
– Hydrocortisone topical cream
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Summary and conclusions
• FDA determines the optimal BE approach for
each proposed generic topical formulation on
a case-by-case basis
• Approach may be PK, PD, clinical, in vitro
• In determining the optimal BE approach for
each product, FDA considers
– Drug mechanism of action, site of action
– Complexity of RLD formulation
– Feasibility, sensitivity of an approach 31
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References
• http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
o Voltaren® gel, NDA 22122
• http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
o Electronic Orange Book
• http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/ucm075207.htm
o Bioequivalence Recommendations Guidance for the diclofenac
sodium topical gel, 1% strength
• http://www.regulations.gov
o Acyclovir ointment 5%, Docket No. FDA-2012-P-0779
o Fluocinolone acetonide topical oil 0.01%, Docket No. FDA-2004-P-
0215
o Fluorouracil cream, Docket No. 2004P-0557/CP1
o Lidocaine patch 5%, Docket No. FDA-2006-P-0356
o 21 CFR Section 320.22 (biowaivers) 32
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Acknowledgements
• Josephine Aimiuwu
• Shawn Blue
• April Braddy
• Parthapratim Chandaroy
• Dale Conner
• Kuldeep Dhariwal
• Brenda Gierhart
• Tapash Ghosh
• Yih-Chain Huang
• Loice Kikwai
• Rob Lionberger
• Steve Miller
• Jeff Murray
• Cecelia Parise
• John Peters
• Kimberly Raines
• Andre Raw
• Shirley Seo
• Aaron Sigler
• Ethan Stier
• Scott Vehovic
• Keith Webber 33
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Thank you for your attention!
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