#DIACMC17 Assigned title for the talk by the organizers:“The need of conducting clinical study for assuring safety and efficacy, as well as a lack of immunogenicity for generic NBCDs” SUMMARY Integrated analytical, product and process development to reduce uncertainty in ‘pharmaceutical equivalence’ is the foundation on which confidence in generic drugs rests Need to leverage the context: RLD “Prescribe-ability” and lot-lot “Switchability” is acceptable The “sameness” mindset (as opposed to an “equivalence” mindset) poses challenges to evidence ‘synthesis” (not “piece meal” check the box ) in ANDA submissions Integrated evidence must a priori account for posed/anticipated “legal challenges” intrinsic to the US system Clinical assessment of Therapeutic Equivalence of generic product intended (i.e., designed) to be equivalent to RLD should only be needed in rare circumstances When there is a need to provide assurance to non-scientists stakeholders Currently the FDA’s GADUFA Research and efforts by many in the sector are predominantly focused on developing a “test of bioequivalence” For most complex products such a test, in and of itself, may be insufficient to ensure therapeutic equivalence over generic product life-cycle

1. Assigned title for the talk by the organizers:
“The need of conducting clinical study for
assuring safety and efficacy, as well as a lack
of immunogenicity for generic NBCDs”
CHALLENGES IN DEVELOPMENT AND APPROVAL OF
GENERIC NON-BIOLOGICAL COMPLEX DRUGS (NBCDS)
DIA CMC WORKSHOP 2017
HILTON WASHINGTON DC/ROCKVILLE HOTEL , 1750 ROCKVILLE PIKE, ROCKVILLE, MD 20852
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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Ajaz Insights ajaz@ajazhussain.com

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4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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3. Clinical Assessment of Therapeutic Equivalence of
Generic Product Intended (i.e., Designed) to be
Equivalent to RLD. Why?
→ Design (or Pharmaceutical Equivalence)
Uncertainty or Residual Uncertainty
“The need of conducting clinical study for assuring safety and
efficacy, as well as a lack of immunogenicity for generic NBCDs”
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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4. Types of GNBCDs
PER FDA’S CURRENT
CLASSIFICATION
• Complex API
• LMWH, peptides, mixtures, natural sourced
• Complex formulations
• Liposomes, iron colloids
• Complex route of administration
• Locally acting drugs (e.g., topical delivery)
• Complex Drug-Device Combinations
• Dry Powder Inhaler (DPI), Nasal Sprays,
Transdermal
WHY CATEGORIZE SOME GENERIC
DRUGS AS “COMPLEX”?
• Inadequacy of current methodologies to assess
equivalence of a proposed generic drug
product to its RLD
• Context: RLD “Prescribe-ability” and lot-lot
“Switchability” acceptable
• Other reasons NOT adequately appreciated
• “Gaps” in the current socio-politico-
organization system for developing generic
drugs
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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5. Recognizing Complexity: Other reasons, NOT
adequately appreciated
• Gaps in GNBCDs [Research &] Development
• Generic “File-first” Development Mindset: Inadequate “Time & Resource” allotment
• Analytical Method Validation; Asking the right (equivalence) questions?
• Small sample size for RLD Vs. Test Comparison; Beyond compendial methods!
• Integrated product & process Design (not in silos); How are CQAs – CPPs- CMAs related
and controlled?
• “Pilot-Bio” and Pivotal “Bio” Mind-set; high potential for erroneous conclusions
• Not adequately addressing “Blocking Citizen Petition”
• Evidence ‘synthesis” (not “piece meal” check the box ) in ANDA submissions recognizing
and accounting for “legal challenges” intrinsic to the US system
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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6. Generic Iron Sucrose: Reducing uncertainty is a
complex process
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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Wu, Y., Petrochenko, P., Chen, L., Wong, S.Y., Absar, M., Choi, S. and Zheng, J., 2016. Core size determination and structural characterization of intravenous iron complexes by
cryogenic transmission electron microscopy. International Journal of Pharmaceutics, 505(1), pp.167-174.
Gaps in GNBCDs [Research &]
Development hinder application of
sound scientific approaches to
reduce uncertainty!!
Unlikely to be path forward for Iron Sucrose.
Similar to enoxaparin (immunogenicity)?
On 20 May 2016: Emphasized Characterization
Cryo-TEM –RT sample artifacts.
24 July 2013 CP by AMAG raised the bar!
The EU/EMA “nano-similar”
approach and arguments.
On-going FDA’s internal
research (Int. J. Pharm. 2016)
Prof. Amy Barton Pai’s research
funded by FDA is on-going.
FDA response to Citizen Petition
blocking Iron Sucrose is now more
complex.
2011 approval of the first generic
sodium ferric gluconate iron
complex

7. Why this approval
was so noteworthy?
• Evidence of Equivalence:
Generic Nasonex®
• Equivalent in vitro
performance
• Equivalent PK studies
• Equivalent local delivery
through pharmacodynamic
(PD) or clinical studies.
4/24/2017
Ajaz S Hussain | Insight, Advice & Solutions LLC
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FDA Embraces Emerging Technology for
Bioequivalence Evaluation of Locally Acting
Nasal Sprays…. in lieu of the clinical endpoint
study, which was deemed unacceptable by FDA.
This is a first in OGD history.

8. LMWH: Enoxaparin
GENERIC: US FDA
• Sandoz-Momenta, 07/23/2010
• Amphastar, 09/19/2011
• TEVA,06/23/2014
• …
BIOSIMILAR: EMA
• Techdow Europe AB, 2016
• Pharmathen S.A., 2016
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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Same Vs. Similar
Recognizing and accounting for “legal challenges” intrinsic to the US system

9. EMA/536977/2016 Committee for Medicinal
Products for Human Use (CHMP) 21 July 2016
• Inhixa, Assessment report
• 2.5. Clinical efficacy: The clinical similarity program was based on a comparative
PK/PD study in healthy volunteers. No efficacy data has been provided, however, the
dossier contained thorough discussion regarding publications on clinical efficacy of
enoxaparin
• 2.6. Clinical safety: Patient exposure; The safety evaluation was based on a
crossover PK/PD study in healthy subjects and on set of bioassays, submitted with
the responses during the procedure.
• Benefit-Risk Balance?
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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10. EMA concluded that the overall benefit-risk
balance of Inhixa is positive
• Beneficial and adverse effects of the reference product have previously been demonstrated and are now
sought to be extrapolated to the biosimilar product, but need not be replicated
• [Recognizing] Uncertainty in the knowledge about the unfavorable effects
• Initially the lack of an immunogenicity testing strategy has not been addressed in the non-clinical and
clinical parts of the dossier.
• The assessment of antibody formation was limited by the sample size of the PD trial (20 subjects) as
well as the low frequency of immune-mediated events (HITT).
• The development of antibodies to LMWH-PF4-complexes appears to be also influenced by the clinical
context of the treatment. Since no data on the comparability of formation of PF4 antibodies was
available on clinical level, comparative data on in vitro level were considered. Also these additional
examinations were not able to indicate differences regarding antigenicity between test and the RMP.
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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11. “Sameness”: Expect
continual challenges
Mourier, Pierre AJ, et al. "Analytical
and statistical comparability of generic
enoxaparin from the US market with
the originator product." Journal of
pharmaceutical and biomedical
analysis 115 (2015): 431-442.
Guerrini, Marco, et al. "Differentiation
of Generic Enoxaparins Marketed in
the United States by Employing NMR
and Multivariate Analysis." Analytical
chemistry 87.16 (2015): 8275-8283.
4/24/2017
Ajaz S Hussain | Insight, Advice & Solutions LLC
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12. RLD “Prescribe-ability”
and lot-lot “Switchability”
acceptable
Gaps in GNBCDs [Research &] Development
Generic “File-first” Development: Inadequate
“Time” allotment & Mindset
Analytical Method Validation; Asking the right
(equivalence) questions?
Small sample size for comparing
multiple lots of RLD & Test product
Product & Process Design in Silos; How are CQAs –
CPPs- CMAs related and controlled?
“Pilot-Bio” and Pivotal “Bio” Mind-set; high
potential for erroneous conclusions
Not adequately addressing “Blocking Citizen
Petition”
4/24/2017
Ajaz S Hussain | Insight, Advice & Solutions LLC
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13. RLD “Prescribe-ability” and
lot-lot “Switchability”
acceptable
Invest in “New Prior
Knowledge”
RLD lot-lot variability &
failure modes in the
context of CQAs-CPP-
CMA relationship
4/24/2017
Ajaz S Hussain | Insight, Advice & Solutions LLC
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Mark McCamish and Gillian Woollett. Clinical pharmacology & Therapeutics |
VOLUME 91 NUMBER 3 | March 2012

14. 4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
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Ensure all
ANDA’s
have the
necessary
&
sufficient
controls.
Science is
legally
defensible
 Technology and knowledge transfer to ensure adequate
control: Life-cycle approach for analytical method and
process validation and continued process verification
 Science-based review integrated with life-cycle
approach to process validation – the new OPQ
paradigm at US FDA: Minimizing regulator
heterogeneity
 Integrated design and development with effective
synthesis of the accumulated evidence: Research +
Development, appreciating the complexity

15. Summary
• Integrated analytical, product and process development to reduce uncertainty in
‘pharmaceutical equivalence’ is the foundation on which confidence in generic drugs rests
• Need to leverage the context: RLD “Prescribe-ability” and lot-lot “Switchability” is acceptable
• The “sameness” mindset (as opposed to an “equivalence” mindset) poses challenges to
evidence ‘synthesis” (not “piece meal” check the box ) in ANDA submissions
• Integrated evidence must a priori account for posed/anticipated “legal challenges” intrinsic to the US
system
• Clinical assessment of Therapeutic Equivalence of generic product intended (i.e., designed) to be
equivalent to RLD should only be needed in rare circumstances
• When there is a need to provide assurance to non-scientists stakeholders
• Currently the FDA’s GADUFA Research and efforts by many in the sector are predominantly
focused on developing a “test of bioequivalence”
• For most complex products such a test, in and of itself, may be insufficient to ensure therapeutic
equivalence over generic product life-cycle
4/24/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
15