Challenge: As a system or cohort, we can do more to adequately appreciate that “systems” proficiency is a stage in adult development that most struggle to achieve.

1. Ajaz | Insights 1
4/15/2021

2. Objective, What: Why, how and what the
AAPS “Bioequivalence Community” can do more
to mature and help others mature.
Ajaz | Insights 2
4/15/2021

3. Methodological maturity: Bioequivalence
Assessment (21 CFR 320.24(b))
75/75 Rule → Average,
Population and
Individual
Bioequivalence January 2001
BA/BE of solutions “self-
evident” to BCS-based
biowaivers 2000, 2013, ICH
M9 Nov 2019
IVIVC to IVIVE, for example
- Bio predictive IVPT)and an in
vitro in vivo extrapolation (IVIVE)
model for an intranasal drug
product → Virtual BE?
Pivotal BE → Weight of
Evidence for “complex
generics” and Totality of
Evidence for “biosimilars”
From a Procrustean
“one size fits all” to a
systems approach!
Theory & practice of systems approach and maturity of systems and professionals.
Ajaz | Insights 3
4/15/2021

4. How methodological
maturity facilitates
maturity of professionals
and systems?
Compliance in the Age of Lockdowns &
Disruptions: Reconciling Different Perspectives
Ajaz | Insights 4
4/15/2021

5. Professional
Development
(Maturity)
“Adequate and well-controlled”
investigations are further defined in
21 CFR 314.126
“evidence consisting of adequate and well-
controlled investigations, including clinical
investigations, by experts qualified by scientific
training and experience to evaluate the
effectiveness of the drug involved, on the
basis of which it could fairly and responsibly
be concluded by such experts that the drug
will have the effect it purports or is
represented to have under the conditions of use
prescribed, recommended, or suggested in the
labeling or proposed labeling thereof.”
The FD&C Act
Ajaz | Insights 5
4/15/2021

6. Why, Assurance. Why Woodcock notes
[in a broader context] a “Sea of Useless
Studies,” need “very serious soul searching”
Nov. 2018
FDA's Woodcock: 'The clinical trial system is broken'
Sept. 2020
“Right now the situation for clinical trials with this
disease is like starvation in the midst of plenty.”
April 2021
Warp Speed Lessons to Cut Clinical Trial Paperwork
Ajaz | Insights 6
4/15/2021

7. Within our context, What steps will
help to better ensure a systems
approach to Therapeutic Equivalence
and beyond to minimize delays, CRLs,
unnecessary clinical BE trials, etc.?
Pharmaceutical
equivalence
Label
Bioequivalence
CGMP
Ajaz | Insights 7
4/15/2021

8. Ajaz | Insights 8
4/15/2021

9. Challenge: As a system or cohort, we can
do more to adequately appreciate that
“systems” proficiency is a stage in adult
development that most struggle to achieve.
Ajaz | Insights 9
4/15/2021

10. Better than placebo, pre-
approval and post-approval!
Ajaz | Insights 10
4/15/2021

11. Equivalence
is for “automatic
substitution”
Ajaz | Insights 11
4/15/2021

12. Ajaz | Insights 12
4/15/2021

13. Ajaz | Insights 13
4/15/2021

14. Ajaz | Insights 14
4/15/2021

15. What questions need to be
answered?
How sure/confident one needs
to be?
What assumptions are
accepted?
Ajaz | Insights
15
4/15/2021

16. Remember
the “Nocebo”
Nature Reviews Rheumatology (2018)
Ajaz | Insights 16
4/15/2021

17. Ajaz | Insights 17
4/15/2021

18. Systems Understanding is a Stage in
Adult Development
Ajaz | Insights 18
4/15/2021

19. Ajaz | Insights 19
4/15/2021

20. Multiple Review Cycles, Delays, Recalls,
CGMP Enforcement Actions
Ajaz | Insights 20
Why do these
challenges occur?
How impact “Therapeutic
Equivalence”?
What to do to minimize
challenges?
Legacy challenges: Mind set on “Pivotal Trial”
Consensus on Weighting for “Weight of Evidence”?
Suboptimal Development Plans
“Time to Clinical/Bio” drives project managers
US FDA working to build “integrated review”
Lacking expertise in certain disciplines
Slow maturing of integrated, design and systems thinking
4/15/2021

21. How public perceives & values
pharmaceutical quality?
Ajaz | Insights 21
Why do these challenges
occur?
How impact “Therapeutic
Equivalence”?
What to do to minimize
challenges?
MRCs distract attention away from what gives Assurance
Recalls and CGMP Enforcement Actions erode Assurance
Assurance critical to real world therapeutic outcomes
We are in “Personalized Experience Economy”
Real-world evidence, Bigdata, AI & Social Media
Outcome-based reimbursement * Value-based pricing
First, self-assurance to deliver Assurance
4/15/2021

22. Therapeutic Equivalence is an
Expectancy!
Ajaz | Insights 22
Why do these challenges
occur?
How impact “Therapeutic
Equivalence”?
What to do to minimize
challenges?
A system of four parts: PE, [BE], Label, CGMP
Pivotal mindset led to rigorous Clinical/BE methodology
Pivotal mindset needed for all four parts!
Recognize gaps in expertise; maturity needed for integration
Project management plans and “gates” to ensure integration
CTD P2 Section written to facilitate integration
Quality Overall Summary (QOS) a key document
4/15/2021

23. Ajaz | Insights 23
4/15/2021

24. Maturating my
thinking
2004 Biopharmaceutics and Drug Product Quality:
Performance Tests, A Look Into the Future
2013 Biopharmaceutics Classification System (BCS) &
Waiver of Bioequivalence
2014 Voices of/for Patients
2014 Bioequivalence – Still a Quality Achilles’ Heel?
2015 Complex Generics Developing Defensible Statistical
Analyses and Acceptance Criteria
……..See posting on SlideShare
2018 Therapeutic Equivalence in Inequality and Our
Quality Scorecard
2020 Repurposing in the Chaos of 2020 and Validity of
Scientific Evidence
2020: Architecture of Pharmaceutical Evidence
for Real-world Generic, Follow-on and Biosimilar
Products
Ajaz | Insights 24
4/15/2021

25. Why ask?
What role does, can, and should the AAPS Bioequivalence
Community play in the assessment and in facilitating maturity
of pharmaceutical quality management systems (pQMS)?
How can and should?
What steps?
Ajaz | Insights 25
4/15/2021

26. Systems &
Professions
Interact, interrelate and
Integrate: As within so without
Ajaz | Insights 26
4/15/2021