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Challenges in Bioequivalence Evaluation of Special Dosage Forms. Vinod P. Shah, Ph. D. Pharmaceutical Consultant III Symposium Sindusfarma – IPS-FIP - ANVISA

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Challenges in bioequivalence evaluation of special dosage forms

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
Generic Drug Product Forms

  • 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
Generic Drug - Standards Forms

  • 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

Complex drugs special dosage forms
Complex Drugs Forms Special Dosage Forms

Complex drugs
Complex Drugs Forms

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 drugs1
Complex Drugs Forms

  • Generic Approvals

    • 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
Special Dosage Forms 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
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
Highly Variable Drugs in BE Evaluation

  • 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
HVD and Quality in BE Evaluation

  • 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
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, Pharm Res. 25, 237-241, 2008

Nti drugs
NTI Drugs for BE

  • 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 drugs1
NTI Drugs for BE

  • 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 drugs2
NTI Drugs for BE

  • 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
NTI Drug: Warfarin for BE

  • 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
Multiphasic MR Dosage Forms for BE

  • 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-∞

Challenges in bioequivalence evaluation of special dosage forms

Propose to use 4 metrics for BE

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
BE of Topical Drugs - case-by-case for BE

  • PK approach: Topical patch – Lidocaine 5% - Lidocaine concentration in plasma – it is proportional to the concentration at site of action

  • PD approach:Flucocinoloneacetonide 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
Bioequivalence of Local Acting Orally Inhaled Drug Products for BE

  • 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
Bioequivalence of Dry Powder Inhaler for BE

  • 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: SalmeterolXinafoate (FP/SX) inhalation powder aerosol. September 2013

Challenges in bioequivalence evaluation of special dosage forms

The FDA approach for demonstrating BE of DPI’s for BE

---- Weight of Evidence ----

Challenges in bioequivalence evaluation of special dosage forms

Inhalation Products for BE

Stepwise approach in EMA guideline



Lungdeposition similar?


Similar safety?



PD similar?





Phase 3 similar?





Conclusions for BE

  • BE methodology and criteria for evaluation depends on the complexity of the special dosage forms –

    HVD, NTI, Topical, Inhalation