Transcript Document

Challenges in Bioequivalence Evaluation
of Special Dosage Forms
Vinod P. Shah, Ph. D.
Pharmaceutical Consultant
III Symposium
Sindusfarma – IPS-FIP - ANVISA
New Frontiers in
Manufacturing Technology, Regulatory
Brasilia, Brazil. August 4-5, 2014
Generic Drug Product
• The drug product safety and efficacy for the
generic product is established by it being
pharmaceutically equivalent and bioequivalent,
and thus therapeutically equivalent.
• The quality of the product is ensured thru product
identity, strength, purity, assay, potency, content
uniformity, dissolution (for solid oral dosage
forms) and being manufactured under FDA’s good
manufacturing practice.
Generic Drug - Standards
• Pharmaceutically Equivalent – all of the following
– the same active ingredient
– identical in strength, dosage form, and route of
administration
– the same use indications (labeling)
• Bioequivalent – by any one method
– Pharmacokinetics
– Pharmacodynamics
– Clinical trial
– In vitro
• Same batch requirements for identity, strength, purity and
quality as the brand name drug product
• Manufactured under the same strict standards of FDA’s cGMP
• PE + BE = TE = TI
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Complex Drugs
Special Dosage Forms
Complex Drugs
What are Complex Drugs?
• Complex active ingredients
– LMWH, peptides, complex mixtures, natural
source products
• Complex formulations
– Liposomes, iron colloids
• Complex route of delivery
– Locally acting drugs
• Complex drug-device combinations
– DPI, MDI, nasal sprays, transdermal system
Complex Drugs
• Generic Approvals
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Enoxaparin (2011)
Sodium Ferric Gluconate (2011)
Doxorubicin HCl – Liposome(2013)
Lidocaine Patch
Acyclovir Ointment (2013)
• Can be Controversial
– Citizen petitions
– Differences in international regulations
– Efforts to define NBCD as new category
• More complex compared to standard generics
– Complex development
Special Dosage Forms
Guidance on Equivalence of
Special Dosage Forms
• Lidocaine Patch
• Acyclovir Topical Ointment
• Cyclosporin Ophthalmic Emulsion
Orally administered non-absorbed drugs
• Mesalamine (multile forms)
• Vancomycine
Special Dosage Forms
Challenges in BE Evaluation
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Highly variable drugs
NTI drug products
Multiphasic MR dosage forms
Topical drug products
– Glucocorticoids
– Other topical products (BE – Clinical studies)
• Inhalation drug products
• Orally administered non-absorbed drugs for GI
activity
• New drug delivery system – new technology
Highly Variable Drugs
• HVD: Drugs for which within-subject variability
in AUC and/or Cmax is >30%
• Characteristics of Highly Variable Drug
Substances
– Poor and variable absorption
– Extensive pre-systemic metabolism
– Food effects
– Low oral BA
– Instability in GI tract
– Poor aqueous solubility
HVD and Quality
• High variability is frequently not due to poor
product quality, but due to variable absorption
process and/or post absorptive first pass
metabolism that reflects drug substance
• FDA/OGD review of BE studies (2003-2005) –
Davit et al. AAPS Journal 2008.
– Over 1000 in vivo BE studies of 180 drugs
– 31% were Highly variable.
60% highly variable due to drug substance PK characteristics.
20% were due to formulation
– 83% with high variability exhibited high first pass
metabolism.
21 % not HVD show first pass metabolism
Highly Variable Drugs
Recommended Approach for BE
• Reference-scaled average BE (ABE) for CV > 30%
– Three period, reference replicated, crossover study
design with sequences of TRR, RTR, RRT. Four period
design is acceptable.
– Minimum number of subjects 24
– PK measures - include Cmax, AUC0-t and A0-∞
– Calculate C.I. using reference scaled ABE
• Ref: SH Haidar et.al., Pharm Res. 25, 237-241, 2008
NTI Drugs
• What are NTI Drugs?
– Where a small difference in dose or blood
concentration may lead to serious therapeutic
failures and/or adverse drug reactions.
• NTI drugs generally have the following
characteristics
– Steep dose-response curves for both safety and
efficacy
– Subject to therapeutic monitoring based on PK or
PD measures
– Small within subject variability
NTI Drugs
• Drug product quality requirements
- identity, purity, assay and other quality attributes
and rigid standards of GMP;
- assay potency limits: 95-105% and USP <905>
content uniformity
• BE Criteria
2 studies – fasting and fed
4-way, fully replicated crossover design in vivo
Bioequivalence based on 90% Confidence Interval
NTI Drugs
• BE Studies: Two treatment, four period replicated
crossover design to quantify the variability of both T and R
products and use reference scaled average BE approach for
determination of BE.
• The BE limits would change as a function of within subject
variability of the reference product. FDA proposes for NTI
drugs that the default BE limits be 90-111% and that
they be scaled using a regulatory constant of sigma0 = 0.1
(which corresponds to a CV of 10.03%).
• Point estimate limits for Cmax and AUC and a requirement
that 90% CI of T/R Cmax and AUC ratios include 100%.
• Ref: Draft Guidance - Warfarin
NTI Drug: Warfarin
• BE Studies:
– Dosage form: 10 mg strength tablets.
– Two studies – Fasting and Fed
– Study design: 4-way, fully replicated crossover
– Subjects: Healthy males and nonpregnant females
• BE based on 90% CI – Statistical analysis using reference-scaled ABE
• Waiver of in vivo testing: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6
mg and 7.5 mg based on:
(i) acceptable BE on 10 mg
(ii) acceptable dissolution of all strengths – paddle method, water,
50 rpm, NLT 80% in 30 minutes
(iii) proportional formulation similarity across all strengths.
• Ref: FDA Draft Guidance on Warfarin Sodium, December 2012
Multiphasic MR Dosage Forms
• BE requirements for multiphasic MR dosage forms
e.g., Zolpidem ER tablet
– Exhibits biphasic absorption characteristics
– Treatment of insomnia, difficulties with sleep onset and/or
maintenance
• Multiphasic MR dosage forms comprised of IR and
DR and/or ER portions, where
– IR portion is needed for rapid onset of activity
– DR or ER portion is needed to sustain the activity
– Additional measure of pAUC in BE studies is required.
(For Zolpidem ER AUC0-1.5)
– Four BE metrics (BE limits of 80-125) are needed:
Cmax, AUC0-T, AUCT-t and AUC0-∞
Propose to use 4 metrics
Cmax, AUC0-T AUCT-t AUC∞
AUC0-T should compare T & R exposure
responsible for early onset of response
AUCT-t should compare T & R exposure
responsible for sustained response
All metrics should meet BE limits (80-125)
FDA: Pharm Sci Advisory Committee meeting: April 2010
BE of Topical Drugs - case-by-case
• PK approach: Topical patch – Lidocaine 5%
- Lidocaine concentration in plasma – it is proportional
to the concentration at site of action
• PD approach: Flucocinolone acetonide topical oil
-Vasoconstriction . If Q1 and Q2 then biowaiver
• Clinical approach: 5-Flourouracil cream 5%
- Clinical endpoint BE study using actinic keratoses lesions
(100% clearance)
• PK & Clinical approach: Diclofenac sodium gel 1%
• In Vitro approach: Acyclovir Ointment 5%
- If generic and RLD are Q1 and Q2  Q3 (IVR)
- If not Q1 and Q2  clinical end point study
Bioequivalence of Local Acting Orally
Inhaled Drug Products
• Challenges – GDUFA Research in FY 2013
• Development of in vivo predictive dissolution
method for orally inhaled drug products
• Systemic evaluation of excipient effects on the
efficacy of MDI products
• Systemic sensitivity of PK in detecting differences
in physicochemical properties of the active in
suspension nasal products for local action
• PK of locally acting orally inhaled drug products
Bioequivalence of Dry Powder Inhaler
• DPI Design - DPI Formulation - Patient Factors
 Regional Airway Deposition 
Local Effect and Systemic Effect
• Weight of evidence:
- In vitro BE (All strengths)
- Pharmacokinetic (PK) BE (All strengths)
- Clinical Endpoint (Lowest strength)
• Ref: Draft BE Guidance for Fluticasone Propionate: Salmeterol
Xinafoate (FP/SX) inhalation powder aerosol. September 2013
The FDA approach for demonstrating BE of DPI’s
---- Weight of Evidence ---Formulation and
Device Design
Comparative
Systemic
Exposure
Studies
Bioequivalence
of Dry Powder
inhalers
Pharmacodynamic or
clinical Endpoint
studies
Comparative In
Vitro Tests
Inhalation Products
Stepwise approach in EMA guideline
In vitro
similar?
No
Yes
Lung
deposition
similar?
Yes
No
Yes
Similar
safety?
PD similar?
Yes
Equivalent
No
Yes
Phase 3
similar?
No
No
Equivalence not proven
Conclusions
• BE methodology and criteria for
evaluation depends on the complexity of
the special dosage forms –
HVD, NTI, Topical, Inhalation
Thank You for
Your Attention