1. 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

2. 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.

3. 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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6. Complex Drugs Special Dosage Forms

7. 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

8. Complex Drugs Generic Approvals Can be Controversial
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

9. Guidance on Equivalence of Special Dosage Forms
Lidocaine Patch
Acyclovir Topical Ointment
Cyclosporin Ophthalmic Emulsion
Orally administered non-absorbed drugs
Mesalamine (multile forms)
Vancomycine

10. Special Dosage Forms Challenges in BE Evaluation
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

11. 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

12. 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 ( ) – Davit et al. AAPS Journal 2008.
Over 1000 in vivo BE studies of 180 drugs
31% were Highly variable % highly variable due to drug substance PK characteristics % were due to formulation
83% with high variability exhibited high first pass metabolism % not HVD show first pass metabolism

13. 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, , 2008

14. 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

15. NTI Drugs
Drug product quality requirements identity, purity, assay and other quality attributes and rigid standards of GMP; assay potency limits: % and USP <905> content uniformity
BE Criteria
2 studies – fasting and fed way, fully replicated crossover design in vivo Bioequivalence based on 90% Confidence Interval

16. 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 % 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

17. 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

18. 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 ) are needed: Cmax, AUC0-T, AUCT-t and AUC0-∞

19. FDA: Pharm Sci Advisory Committee meeting: April 2010
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

20. 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

21. 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

22. 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

23. The FDA approach for demonstrating BE of DPI’s
---- Weight of Evidence ----
Bioequivalence of Dry Powder inhalers
Formulation and Device Design
Comparative In Vitro Tests
Pharmacodynamic or clinical Endpoint studies
Comparative Systemic Exposure Studies

24. Lung deposition similar? Equivalence not proven
Inhalation Products
Stepwise approach in EMA guideline
In vitro similar? No
Lung deposition similar?
Yes
Similar safety?
Yes No
PD similar?
Yes
Yes
Equivalent No
Phase 3 similar?
Yes No No
Equivalence not proven

25. Conclusions
BE methodology and criteria for evaluation depends on the complexity of the special dosage forms –
HVD, NTI, Topical, Inhalation

26. Thank You for Your Attention