Challenges in Bioequivalence Evaluation of Special Dosage Forms

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 FDAs 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
  FDAs cGMP
• PE BE TE TI

4

5
(No Transcript)
6
Complex DrugsSpecial 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
• 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
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

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 gt30
• 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 (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

13
Highly Variable Drugs
Recommended Approach for BE

• Reference-scaled average BE (ABE) for CV gt 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 A0-8
• Calculate C.I. using reference scaled ABE
• Ref SH Haidar et.al., Pharm Res. 25, 237-241,
  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
  95-105 and USP lt905gt content uniformity
• BE Criteria
• 2 studies fasting and fed
  
  4-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 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

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 80-125) are
  needed
  Cmax, AUC0-T, AUCT-t and AUC0-8

19
Propose to use 4 metrics Cmax, AUC0-T AUCT-t
AUC8 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
DPIs ---- Weight of Evidence ----

24
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