A Leapfrog Need and Opportunity for mAbs

A LEAPFROG NEED AND
OPPORTUNITY
FDA Thai decided to take the lead in implementing science-based regulatory
reforms that streamline new and biosimilar monoclonal antibody development
1/20/2024 AJAZ | INSIGHTS 1

For us, the guests, it
is an opportunity to
learn.
In what ways Thailand's healthcare system is unique, and what is needed for the
country to innovate for self-reliance and sustainability?
Challenges in Thailand's current drug registration process and suggests potential
solutions to improve it.
State-of-the-art technology analytics and bioassay used to expedite the
regulatory process, ensuring accessibility and affordability for Thai people.
Experience with the CMC reviewing process in Thailand and discussion of the
complexity of authorization in the view of an FDA external expert.
Viewed through the lens of a medical doctor who intends to develop biologics for
Thailand, what is urgently needed to improve its drug registration process to
address accessibility and inequality issues for Thai patients.
Experience with registration and challenges with the current process and how it
can be improved with the existing biological production process from a business
point of view.
Ways CRI can support research and as convener for such a workshop by bringing
various stakeholders together.
CRI infrastructure and capabilities and experience in herbal medicinal product
registration experience at the Thai FDA.
Analytical, QC, and CMC capabilities at Chulabhorn Research Institute.
Thank you!

The ecosystem in Thailand is
conducive to leapfrogging
• Based on my conversations with Professor
Sasisekharan, there is high potential to leapfrog
• To do so, it is essential to have a distinct competitive
advantage in technology that sets you apart from the
competition and gives you the edge needed to
succeed. [Describe what this advantage is]
• Effort leaders should foresee and define how they
will nurture focused and continuous technology and
professional development and its diffusion
• Technical prowess is necessary but not sufficient;
continuing human and professional development
and system maturity is essential
How businesses can win at leapfrog | World Economic Forum (weforum.org) Jan 11, 2018
119849-WP-PUBLIC-Africa-Leapfrogging-text-with-dividers-9-20-17-web.pdf (worldbank.org)

Favorable drivers for
a leapfrog strategy
Driver #1: The partnership between the
Thai FDA, the Chulabhorn Research
Institute (CRI), and MIT creates an
ecosystem that fosters specialized
competitive advantages based on
innovative technology and continuing
professional development.
Driver #2: This workshop, deciding [and
preparing] to leapfrog
[Driver #3: Workshop consensus report
for a SMART beginning]
AJAZ | INSIGHTS 1/20/2024 4
Professor Dr. Her Royal Highness Princess Chulabhorn Krom Phra
Srisavangavadhana has placed human resources at the forefront of the
work of the Chulabhorn Research Institute (CRI) since its inception.

SMART
Strategy and commitment to continuing human and
professional development and system maturity

Favorable drivers for FDA Thai:
Saudi FDA another path forward
Intuitively Moving Institutions Towards Global Regulatory Resilience | 2 December 2023
Dean Aws Alshamsan, now the Saudi
Commission for Health Specialties Secretary-
General, is pursuing a new mission there.” A
constant development for a deserving health
practitioner.”

Different paths to
global regulatory
resilience
1/20/2024
• Low, decreasing, to no trust (White
House Releases Zero Trust Strategy for Federal
Government)
• Perpetual chaos demands
preparedness - multiple mAb
products with the expectation that
may need to be combined with other
mAb products (US FDA Guidance: Development
of Monoclonal Antibody Products Targeting SARS-
CoV-2 for Emergency Use Authorization, December
2023)
• I posit, a leapfrog strategy is
necessary, and this workshop is the
opportunity to begin
• How can we contribute?
AJAZ
|
INSIGHTS
7

How can we
contribute?
1/20/2024
• Dr. Gillian Woollett, VP, Head Regulatory
Strategy and Policy at Samsung Bioepis
• Dr. Steven P. Schwendeman, The Ara G. Paul
Professor and Chair of Pharmaceutical
Sciences, Professor of Biomedical Engineering,
and the Biomaterials and Drug Delivery Thrust
Leader of the University of Michigan
• Myself independent advisor and a research
assistant to a geriatrician spouse on a mission
(Nobody Should Die Alone: A Father's Message
to a Physician Daughter - PubMed (nih.gov))
• We all, including Professor Sasisekharan, have
collaborated over the years to improve and
mitigate the risks inherited in our legacy system
AJAZ
|
INSIGHTS
8
How businesses can win at leapfrog | World Economic Forum (weforum.org)
Jan 11, 2018

Dr. Gillian Woollett
VP, Head Regulatory Strategy and
Policy at Samsung Bioepis
A crucial contributor in the debates
in Washington and helping me
prepare for my testimony to the US
Senate HELP Committee and
through the process that led to the
establishment of The Biologics
Price Competition and Innovation
(BPCI) Act (2009)
Future Evolution of Biosimilar
Development by Application of
Current Science and Available
Evidence: The Developer’s Perspective
| BioDrugs (springer.com) (2023)
Legislative and regulatory legacy challenges

Dr. Steven P. Schwendeman
TheAraG.Paul Professorand Chair of
Pharmaceutical Sciences,ProfessorofBiomedical
Engineering,and the Biomaterialsand DrugDelivery
ThrustLeader ofthe UniversityofMichigan
A keen observer who, at NIPTE,
reminded me of the need to bring
[material] science and engineering
together, as the efforts at NIPTE
were leaning more heavily on
engineering [continuous
manufacturing].
Neglect of formulation science was
and remains a concern, and it
could be a pitfall this effort should
avoid.
Pharmaceutical development, manufacturing, and assurance of
quality at risk: NIPTE a stabilizing “third leg of the stool.”

Jumpstart- and
catch-up efforts
PAT to Pharmaceutical CGMPs for
the 21st Century to Critical Path
Initiative … ICH 21st Century
Pharmaceutical Quality….
4 Life Sciences Lessons from the
PAT to QbD Journey
(valgenesis.com) April 12, 2023
28 November 2001 Meeting of the US FDAs
Advisory Committee for Pharmaceutical Science

The US FDA’s 21st
Century Initiative
What can we learn?
◦ Pharmaceutical development,
manufacturing, assurance of
quality at risk
◦ US FDA’s Process Analytical
Technology Initiative to jumpstart
the 3rd industrial revolution to let
the sector catch-up and begin to
participate in the fourth industrial
revolution
How businesses can win at leapfrog | World Economic Forum (weforum.org) Jan 11, 2018

The US FDA PAT Initiative
It could have leapfrogged 20 years, but it was limited to jumpstarting the main system.
PROBLEM DEFINITION
• Endorsement by FDA Science
Board
• Oversight of the Advisory
Committee for Pharmaceutical
Science
• Federal Register Notice:
Participants for Subcommittees
• Framework Guidance + PAT
Review and Inspection Team, co-
trained and certified
COLLABORATIONS
• Academia
• PHARMI (mit.edu)
• CRADA with Pfizer (Imaging
Technology; with Office of
Testing & Research)
• CRADA with Novartis (QbD
example; Technology; with
Office of Testing & Research)
JUMPSTART
• How did it work, perhaps too well
• FDA White Paper Lessons
Learned (2004)
• Jumpstarted Pharmaceutical
CGMPS for the 21st Century, ICH
Pharmaceutical Quality for
Quality for the 21st Century
• Merged, perhaps too soon; it
could have been a leapfrog ~ 20
years
PAT_AJAZ_HUSSAIN.PDF (gmp-compliance.org)
Roadmap to QbD is (should be) a roadmap to adult human
development | PPT (slideshare.net)

You can change
the world
Never doubt that a small group of
thoughtful, committed citizens can change
the world: indeed, it’s the only thing that
ever has. — Margaret Mead
The world is changing,
and you need to ensure
it changes for the good.
FDA's PAT Team: Shall We Dance? | Process Analytical Technology | Pharmaceutical Manufacturing |
Pharma Manufacturing April 2005

MOVING
FORWARD
Workshop deliverables

Options to streamline new and biosimilar
monoclonal antibody development
FDA THAI PREFER LEAPFROGGING
• In the current state of the
Fourth Industrial Revolution
and geopolitical chaos,
catching up is not a prudent
option
• Leapfrog
• Jumpstart
REGIONAL EFFORTS
FOLLOW
• Focus on the needs and
preparedness of Thailand
• Local developers and
manufacturers are vital
stakeholders, and this
effort considers their
development and maturity
• As the strategy unfolds, it
can also serve to jumpstart
regional efforts and
collaborations

Why local? A
business
perspective
If I were still at Sandoz, I would not be
concerned about Approvability in
Thailand.
I would be involved in addressing
the low Acceptability
We [can] agree that clinical trial data
is often not necessary to address
residual uncertainty following
science-based mAb and mAb
product development; it serves as a
“comforting blanket.”
Act4Biosimilars Impact Index

Stepping out of our comfort zone
Is essential to develop professionals,
processes, and products
One can debate the need for additional
clinical data, as in the case of Generic
Biosimilar Enoxaparin [USA] vs Biosimilar
Enoxaparin [EU], to no avail
Such debates are settled years and decades
later, not on rigorous evidence or deeper
understanding, it just makes sense
1/20/2024
AJAZ | INSIGHTS 18

Generic Enoxaparin Questions
and Answers | FDA
• The European Union issued guidelines for biosimilar
LMWH requiring clinical studies. Why is the FDA
allowing generic LMWHs (without clinical studies)?
• Were the heparin contamination issues in 2008
considered for FDA approval of enoxaparin?
• How did the complex chemical structure of
enoxaparin affect generic approval?
• Why does the FDA expect generic manufacturers of
enoxaparin to conduct immunogenicity studies?
Ajaz | Insights 1/20/2024 19
Scientific considerations in the review and approval of generic enoxaparin in
the United States | Nature Biotechnology (2013)

Enoxaparin Equivalence:
“Assessment Comfort Zone”
• Why were/are there different “assessment comfort zones” in the US
FDA and EU/EMA?
• Residual uncertainty in the EU? Lack of a correlation between surrogate
PD parameters (anti-factor Xa or IIa) and clinical outcome.
• How was this residual uncertainty addressed in the context of the RLD?
For instance, post-approval changes.
• One clinical study to demonstrate efficacy in the prevention of VTE in
patients undergoing surgery with high VTE risk (draft-guideline-similar-
biological-medicinal-products-containing-low-molecular-weight-heparins_en.pdf
(Europa. eu)).
• Incidence (probability of occurrence) of VTE and trial design (Safety and
effectiveness of biosimilar enoxaparin (Inhixa) for the prevention of thromboembolism in
medical and surgical inpatients - PubMed (nih.gov))

Alberto Ganan Jimenez & Brigitte Brake, European Medicines Agency – Bfarm
(German Federal Institute for drugs and medical devices). ICH GCG ASEAN Training
Workshop on ICH Q5C, 30-31 May 2011, Kuala Lumpur.

Another reflection is whether
the “pivotal” trial can mitigate
“the risks.”
• Subcutaneous Eprex(®) in patients with CKD was
contraindicated in the European Union between 2002 and 2006
after increased reports of anti-erythropoietin antibody-mediated
pure red cell aplasia (PRCA).
PRCA incidence was 35.8/100 000 patient-years (95% CI 7.4-104.7) Incidence
of erythropoietin antibody-mediated pure red cell aplasia: the Prospective
Immunogenicity Surveillance Registry (PRIMS) - PubMed (nih.gov)
Was a prospective clinical trial conducted in the case of Eprex®? No, but it was
considered (n ~ 60k+) [Note: From memory; I couldn’t get to the source]
• In early 2000, Sandoz actively sought to incorporate ways to
mitigate the risk (assay for detecting serum anti-EPO Abs,
product design) to mitigate risk, address societal concerns related
to antibody-mediated pure red cell aplasia (PRCA), mount
convincing arguments (e.g., at WHO INN Committee) on a path
forward.
Epoetin alfa biosimilar (HX575): A review of 15 years post-approval clinical experience – ScienceDirect (January 2023)

“Rush to clinical” and
“pivotal” clinical.
• Two legacy mindsets that have been normalized
• Logically, that poses a higher risk to patients, which is
difficult, if not impossible, to come to a consensus,
given that we begin our arguments with the initial
condition being our set minds
• For example, the need for clinical studies for
dermatological products was a never-ending debate
• While another clinical division at the US FDA was
struggled to prevent a rush to clinical trial for a topical
microbicide

Principle: Totality
of Evidence
(at every stage, IND, NDA/ANDA/BLA,
post-approval)
In 2000, the case of the US FDA’s “team approach” and decision on the
specific topical microbicide IND was remarkable. FDA said no; despite
this, real-world study initiated in Africa to disastrous outcomes.
The principle of the totality of evidence can be hard to practice,
particularly in a legacy hierarchy where “MD trumps PhD.”
Years later, at Bfarm, in the case of the “Enoxaparin Biosimilar or Generic”
debate, I became aware of the broader societal and policy implications of
the “MD trumps PhD.” legacy. But arguments fell off deaf ears. Why?
US FDA Advisory Committee for Pharmaceutical Science, 17 November 2000 (Research at Duke University)

Overcoming the “M.D. trumps Ph.D.” legacy to
“Team Science.”
Why did the review process take
eight years? Answer “why”
questions are often outside the
system.
• A relatively recent case
(Apotex Generic mometasone
nasal spray) would be of
interest to this discussion
• “Rush to clinical” [clinical
acceptable]
• PK profile not equivalent
• Particle size difference ignored
• Different polymorph
• Particle size distribution made
similar
• PK “equivalent”
• OGD/FDA insist that clinical trials
should be pretend.
• Complaint: OGD/FDA violating a
fundamental principle
• What principle? How
resolved? Why the review
process took eight years?
Totality of Evidence & Therapeutic Equivalence 15 October
2016 | PPT (slideshare.net)
Guidance for Industry on Formal Dispute Resolution Scientific and Technical
Issues Related to Pharmaceutical Current Good Manufacturing Practice (exp
53121)_0.pdf (fda.gov)

Q1: Same components –Q2:
Same components in same
concentration –Q3: Same
arrangement of matter
(microstructure)
[~ primary, secondary, tertiary
structure of proteins]
“FDA Embraces Emerging Technology for Bioequivalence Evaluation
of Locally Acting Nasal Sprays”(CDER SBIA Chronicles)
Laboratory Performance Testing of Aqueous Nasal Inhalation Products for Droplet/Particle Size Distribution: an Assessment from the
International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) | AAPS PharmSciTech (springer.com) (October 2023)
Validation?
Why?

Principle and
practice: Gaps
• To compare two products intended by design to be
equivalent or comparable, [obviously], clinical trials are
“blunt instruments,” and, in this context, the struggle to
demonstrate a difference between a new drug and a
placebo can also be a helpful reminder
• In principle (e.g., 21 CFR 320.24(a)), in the context of
two products intended by design to be equivalent or
comparable, the most accurate, sensitive, and
reproducible tests should be used to assess their
equivalence, comparability, and similarity
• In practice, however, there is a tendency to violate this
principle: why the P&P Gap, what can we learn from it,
and how can it inform this discussion?
Prescription for trouble / How flaw in FDA safety net
may pose a risk to the public with generic drugs
(sfgate.com) Dec 22, 2002
“Pivotal Bio” mindset, the legacy of discounting
formulation science (pharmaceutical
equivalence) * “promotion of generics” continues
to challenge the US FDA.

“Pivotal Bio” mindset divert
us to wrong questions:
Individual Bioequivalence ?
• What is the question we seek to answer:
Therapeutic equivalence of a highly variable
new drug in a delayed release formulation
• How sure do we need to be in the answer we
obtain (Statistical-Approaches-to-Establishing-Bioequivalence.pdf
(fda.gov))
• What assumptions are we willing to accept,
why? ???
Delayed Release Tablet Dissolution Related to Coating Thickness by Terahertz Pulsed Image
Mapping – ScienceDirect (2008)

Hussain, A.S., Gurvich, V.J. & Morris, K. Pharmaceutical “New Prior Knowledge”: Twenty-FirstCentury Assurance
of Therapeutic Equivalence. AAPS PharmSciTech 20, 140 (2019). https://doi.org/10.1208/s12249-019-1347-6

The legacies of pharmaceutical and
biotechnology have different initial conditions
1/20/2024
Ajaz | Insights 30
• Calls into question the usefulness of comparative efficacy studies for regulatory decision-making when approving
biosimilar mAbs and fusion proteins.
• An in-depth analysis of the quality and clinical packages of trastuzumab and rituximab biosimilars revealed that
no clinical trial data were “necessary to resolve residual uncertainties regarding the quality part.”
Do the Outcomes of Clinical Efficacy Trials Matter in Regulatory Decision-Making for
Biosimilars? | BioDrugs (springer.com) (2023)
• Clinical efficacy endpoints in clinical trials for biosimilars are less sensitive biosimilarity measures than
biochemical, biophysical, and biological functional assays. Additional clinical efficacy studies comparing potential
biosimilars and reference products do not add valuable information for regulatory purposes.
• Large clinical studies of biosimilars with immunogenicity endpoints are of limited value, given the quality control
processes for all biologics, including biosimilars.
• The expectation for multiple-switch studies for US interchangeability designation should be reconsidered
immediately, and the category should be eliminated in the future.
• As biosimilars are typically approved globally based on a single set of clinical trials, and all subsequent
manufacturing changes are already carefully monitored by regulatory authorities, comparative pharmacokinetic
testing of EU and US reference products is unnecessary.
Future Evolution of Biosimilar Development by Application of Current Science and
Available Evidence: The Developer’s Perspective | BioDrugs (springer.com) (2023)
P&P Gap

Leapfrogging on
reforming mAbs polices
• It not only makes sense, but it is a principled duty of
care
• Be principled
Totality of Evidence
.21 CFR 320.24(a))
Quality By Desing
Produce the chemical moieties you want, remove
what shouldn’t be injected, and prove it; if you can’t
ask why, get to the root cause, correct your errors,
prevent mistakes, and improve continually.

How To Break The Pharmaceutical 2-3 Sigma Barrier (Like Amgen)
(pharmaceuticalonline.com) (September 2017)
“If I Don’t Look, There is No Problem”
1/20/2024
AJAZ | INSIGHTS 32

Six Blind Men, Regulatory Science, “Bob’s Big Idea” and Gandhi’s “a way out of hell”: Goodbye 2015 | LinkedIn
Culture of Pharmaceutical Quality: Connecting the Dots (biopharma-asia.com) 2015
Culture of Pharmaceutical Quality: Improving Quality Management System (biopharma-asia.com) 2015
Culture of Pharmaceutical Quality: Personnel Development (biopharma-asia.com) 2016

Finally, an few
intriguing
thoughts
• If Amgen can now claim its products and
QMS is “6σ,” and Sandoz biosimilar would
seek an interchangeable biosimilar
designation, wouldn’t Sandoz QMS also
need to be at the low error rate of “6σ”?
• Why I sought to bind Momenta exclusively
for Sandoz biosimilars?
• What might this suggest for the FDA Thai-
CRI-MIT partnership?
Momenta Pharmaceuticals, Inc. And Sandoz, Inc. Sign Exclusive
Collaboration To Develop Complex Generics And Follow-On
Versions Of Biotechnology Drugs; Initial Payment Of $75M |
BioSpace (2006)

Summary
• Thai FDA – CRI- MIT partnership in Thailand is a
distinct competitive advantage in technology and
professional development that sets you apart from
the competition and gives you the edge needed to
succeed.
• You need to foresee and define how you will nurture
focused and continuous technology and professional
development and its diffusion
• You will need to remain humble, in that technical
prowess is necessary but not sufficient; continuing
human and professional development and system
maturity is essential
SMART Technology, SMART Professionals, SMART
Services, SMART Organization

Favorable drivers for
a leapfrog strategy
Driver #1: The partnership between the
Thai FDA, the Chulabhorn Research
Institute (CRI), and MIT creates an
ecosystem that fosters specialized
competitive advantages based on
innovative technology and continuing
professional development.
Driver #2: This workshop, deciding [and
preparing] to leapfrog
[Driver #3: Workshop consensus report
for a SMART beginning]
Professor Dr. Her Royal Highness Princess Chulabhorn Krom Phra
Srisavangavadhana has placed human resources at the forefront of the
work of the Chulabhorn Research Institute (CRI) since its inception.

A Leapfrog Need and Opportunity for mAbs

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