Current Approaches and Guidelines for BE of Topical Drug ... · *Gould, A L and Shih, W. Sample...

Current Approaches and Guidelines

for BE of Topical Drug Products in

the US and Canada

Derek Ganes, RPh, PhDIndependent Consultant

PQRI Workshop on the Evaluation of New and Generic Topical Drug Products - Current Challenges in Bioequivalence, Quality, and Novel Assessment Technologies, March 11-13, 2013, US Pharmacopeia Meeting Center, Rockville, MD 20852

Overview

• BE of Topical Drug Products

– Waiver

– In Vitro Study

– Pharmacokinetic BE Study

– Pharmacodynamic BE Study

– Clinical Endpoint BE Study

• Binary outcome (Tinea Pedis)

• Continuous outcome (Rosacea)

• Conclusion

Summary of FDA BE Recommendations

for Specific Topical Drug Products (2/13)

BE of Topical Drug Products

• Waiver

– Pharmaceutical equivalence, Q1/Q2

– Solution, spray, shampoo, foam, swab

• In Vitro Study

– Comparative in vitro drug release rate

– Acyclovir Ointment 5%


• Clinical BE Study

– Compare exhibit/pilot batches (Test) with a

Reference product (US RLD, Canadian)

• Pharmacokinetic BE Study

– Measure blood/plasma drug concentrations

– Same rate & extent of absorption (Cmax, AUC)

– Healthy subjects/patients


• Pharmacodynamic BE Study

– Same pharmacological effect/surrogate

marker

– Healthy subjects/patients

• Clinical Endpoint BE Study

– Same therapeutic effect/clinical endpoint

– Patients

Ying Sun, PhD, Topical Product Development: Delivery of Active Agents for Dermatologic Diseases and Skin Care Applications,

AAPS Webinar, March 15, 2012.

Pharmacokinetic BE Study

• Product (Solution)

– Topical anti-inflammatory, analgesic

– Site of action subcutaneous tissues

• FDA: Pharmaceutical equivalence if Product Q1/Q2 with RLD

• TPD: BE study required if vehicle contains a penetration enhancer

• ODB: BE study required since product is applied to the skin

Simulated Multiple Dose, Steady-State

BE Study in Healthy Subjects

Pharmacokinetic BE Study

• Steady-state PK metrics:

– Cmax,0-, Cmin,, AUC0-, AUC0-24

• TPD steady-state BE requirements:

– AUC0-, 90% CI GMR (T/R) 80-125%

– Cmax,0-, GMR (T/R) 80-125%

– Cmin,, GMR (T/R) 80%

Pharmacodynamic BE Study

• Product

– Topical corticosteroid

– Site of action epidermis, dermis

• Vasoconstrictor BE study

– FDA Guidance “Topical Dermatological Corticosteroids: In Vivo Bioequivalence (1995)”

– Pilot dose-duration response study

– Pivotal BE study

– TPD requirements same

Vasoconstrictor BE Study

Typical blanching responses on the volar aspect of a human forearm following application of a topical corticosteroid product

(Haigh and Kanfer, 1984). In: Kanfer I (2010) Strategies for the Bioequivalence Assessment of Topical Dermatological Dosage

Forms. J Bioequiv Availab 2: 102-110.


• Pilot dose-duration response study

– Healthy subjects

– Apply Reference product only (10 L/cm2)

– Increasing dose durations

– Measure vasoconstriction (skin-blanching) up

to 24 hours after product removal

Simulated Vasoconstriction Response

by Dose Duration (Minutes)

Simulated Population Pharmacodynamic

(Emax) Modeling of Negative AUEC0-24

ED50 (half-maximum response)

D1=0.5 x ED50

D2=2 x ED50

D1 ED50 D2


• Pivotal BE study

– Healthy subjects enrolled in sequential groups

(e.g. n=30) to achieve required number of

evaluable subjects

– Apply Test and Reference products (10 L/cm2)

– Dose durations D1 (Ref), ED50 (Ref, Test), D2 (Ref)

– Measure vasoconstriction (skin-blanching) up to

24 hours after product removal

– Subjects qualify if ratio of vasoconstriction

AUEC0-24 D2/D1 ≥1.25

Simulated Vasoconstriction Response by D1, D2, Test & Reference


• PD metric AUEC0-24

• Sample size re-estimation* used to

determine when to stop enrollment (avoid

statistical penalty for analyzing data)

• FDA, TPD BE requirements

– AUEC0-24, 90% CI MR (T/R) 80-125%

– Locke’s method (untransformed data)

*Gould, A L and Shih, W. Sample size re-estimation without unblinding for normally distributed outcomes with unknown variance.

Communications in Statistics - Theory and Methods, 21: 10, 2833 -2853, 1992.


• Highly Variable (>50%)

• Difficult to determine correct ED50

• Can have low qualification rates for ratio of

vasoconstriction AUEC0-24 D2/D1 ≥1.25

• Large number of subjects may be enrolled

(e.g. n=200) to achieve required number of

evaluable subjects

Clinical Endpoint BE Study

Tinea Pedis

• Product

– Topical antifungal

– Site of action is stratum corneum


– BE of Test and Reference products in the

treatment of healthy patients with

tinea pedis/interdigital tinea pedis*

– Primary endpoint: Binary outcome (cure vs.

failure)*Terbinafine Hydrochloride Cream 1%

Clinical Endpoint BE StudyTinea Pedis

Mayo Clinic, Athlete’s foot, http://www.mayoclinic.com/health/medical/IM03573


• Subjects are randomly assigned to test, reference and test vehicle (placebo)

• Regimen: FDA guidance/Canadian (labeling may differ, e.g. apply bid vs. qd)

• Visits– Baseline/enrollment (Day 1)

– End of treatment (Day 7-28*)

– End of study (Day 42/Week 6**)

• Tinea pedis lesions on both feet are treated

• Target lesion on one foot is evaluated

Ketoconazole Cream 2% - *Week 6, **Week 8


• Clinical Signs (fissuring/cracking, erythema,

maceration, scaling)

• Symptoms (pruritis, burning/stinging)

• Scale (0, 1, 2, 3; none, mild, moderate, severe)

• Target lesion

– Positive 10% KOH (fungal hyphae)

– Sum of clinical signs and symptoms scores of

≥4/6*, including a score of ≥2 for erythema and

score of ≥2 or for scaling or pruritis

*Terbinafine Hydrochloride Cream 1%


• Only subjects with a positive pretreatment

baseline fungal culture (Trichophyton

rubrum, Trichophyton mentagrophytes, or

Epidermophyton floccosum) from the target

lesion will be included in primary endpoint

analysis (mITT, PP)

• >50% subjects positive T. rubrum


• Primary endpoint: proportion of subjects

with therapeutic cure, defined as both

mycological cure and clinical cure, at end

of study (Day 42, Week 6)

• Mycological cure: negative KOH &

negative fungal culture

• Clinical cure: total severity score ≤2 with

no individual severity score >1


• Study sensitivity: demonstrated if the

therapeutic cure rates of test and reference

products at end of study (Day 42, Week 6) are

statistically superior to placebo (p<0.05),

mITT population

• Equivalence: 90% CI of the difference in

therapeutic cure rates between the test and

reference treatment groups at the end of

study (Day 42, Week 6) must be within ±20%,

PP population


• TPD: 95% CI ±δ%

–δ = ½ effect size

–δ = ½ (reference cure rate –

placebo cure rate)

• TPD: Combination topical corticosteroid &

antifungal products may not require

VC study


• Study Design & Size

– Patients enrolled >mITT since >25% of

patients have negative baseline fungal culture

– PP 80/85% mITT

– Study Success = Equivalence + Superiority

– Clinical trial simulation (resampling) used to

determine design (i.e. 1:1:1, 2:2:1, etc.) and

number of patients for 80-90% probability of

Study Success

Clinical Endpoint BE StudyRosacea

• Product

– Topical antirosacea agent

– Site of action epidermis, dermis


– BE of Test and Reference products in the

treatment of healthy patients with moderate

to severe rosacea*

– Primary endpoint: Continuous outcome

(mean % change from baseline)*Azelaic Acid Gel 15% - moderate rosacea


Mayo Clinic, Rosacea, http://www.mayoclinic.com/health/medical/IM03557


• Subjects are randomly assigned to test,

reference and test vehicle (placebo)

• Regimen: FDA Guidance/Canadian labeling

• Visits

– Baseline/enrollment (Day 1)

– End of treatment/study (Week 9-12)


• Primary endpoint*: Mean % change from

baseline to Week 9-12 in the inflammatory

(papules & pustules) lesion counts • Secondary endpoint: Investigator’s Global Evaluation

(IGE)

– Scale: 0, 1, 2, 3, 4; clear, almost clear, mild, moderate,

severe

– Binary outcome, Success = clear or almost clear at

final visit

*Metronidazole Cream 1% - Co-Primary Endpoint: Mean % change from baseline to Week 10 in erythema score

(Scale: 0, 1, 2, 3; absent, mild, moderate, severe)


• Study sensitivity: test and reference

products should be statistically superior to

placebo (p<0.05) for the primary endpoint,

mITT population

• Equivalence: 90% CI for the ratio of means

(T/R) for the primary endpoint must be

within 80-125%, PP population


• Study Design & Size

– PP 80/85% mITT

– Study Success = Equivalence + Superiority

– Clinical trial simulation (80-90% probability

of Study Success)

– SD of Primary endpoint has major effect on

study size (>50%)

Conclusions

• VC BE studies are highly variable

• Clinical endpoint BE studies are highly

variable, expensive (3-5$M USD),

time consuming (12-18 months) and

insensitive

Conclusions

• BE studies needed using alternate

approaches which are faster, less expensive

and more sensitive to differences in

multisource topical dermatological

products:

–Updated DPK methods;

–Microdialysis;

–Spectroscopy (Near IR, Terahertz)

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