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 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

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 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-∞

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

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 ---- Bioequivalence of Dry Powder inhalers Formulation and Device Design Comparative In Vitro Tests Pharmacodynamic or clinical Endpoint studies Comparative Systemic Exposure Studies

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

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

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