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Intuitively Moving Institutions Towards Global Regulatory Resilience

From my experience, how can I describe an intuitive and self-organizing social force around "attractors" patients' value to be assured of therapeutic equivalence?

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TOWARDS GLOBAL
REGULATORY
RESILIENCE
Out of the Crisis to Ensure
Therapeutic Equivalence
12/2/2023
© AJAZ | INSIGHTS 2023 1
Global Regulatory Resilience
 In May 2023, the US FDA issued an "Immediately in Effect Guidance for Industry"
requiring testing for diethylene glycol in high-risk drug components, highlighting
the vulnerability of the global pharmaceutical supply chain. It also reminds us
that there is a significant difference between knowing what to do and doing it.
 The need for proactive, forward-looking, and strategic approaches to resilience is
becoming palpable worldwide. Was such a condition discernible in 1937 when
the Elixir of Sulfanilamide tragedy was a tipping point for enacting the US Food,
Drug, and Cosmetic Act of 1938? Or was it a “never let a crisis go to waste”
mindset leveraging another crisis for a political agenda? What does it mean? I
anticipate an exponential increase in uncertainty and a decline of trust in our
practice environment, and to exercise our duty to care, we will need to find a way
to make common sense via careful meaning and sensemaking.
 Al-Ghazali (c.1056–1111) and René Descartes (1596–1650) argued against the
infallibility of sense perception, and we, too, must acknowledge that "common
sense is not so common," as Voltaire once said. Yet, we must work to make safety
and quality a matter of common sense.
© AJAZ | INSIGHTS 2023 12/2/2023 2
Commonsense
steps to Resilience
essential for
continued
development
Intuitionally ↔
institutionally
 Don’t fear; learn to channel fear and anger to a purpose you care for
 Beware and keep expanding the scope and depth of your awareness
 In a moment and minutes, reflect on past experiences to reframe in new
knowledge
 Do so repeatedly. It presents us with insightful intuitions to be wiser today than
yesterday and a step closer to resilience needed in the chaos that surrounds us
 A commonsense approach to moving towards global regulatory resilience is
your responsibility, as it once was my duty
 A duty to make common sense of the efforts in the “Office of Pharmaceutical
Science,” the predecessor of the “Office of Pharmaceutical Quality,” of the US
FDA, to come out of the generic drug crisis and to ensure therapeutic
equivalence
© AJAZ | INSIGHTS 2023 12/2/2023 3
© AJAZ | INSIGHTS 2023 12/2/2023 4
From my experience, how can I describe an intuitive and self-organizing social force around "attractors" patients'
value to be assured of therapeutic equivalence?
© AJAZ | INSIGHTS 2023 12/2/2023 5
Following Ranbaxy,* in 2014, there was a
significant surge in BAD-I (breaches in the
assurance of data integrity) observations by
the US FDA. A trade magazine sought four
perspectives: Confronting Illusions of Quality
in Indian Generics Manufacturing (24 March
2014).
FDA: Takahashi: Look Out for These Data Integrity
Issues
A GMP consultant: Cahilly: Focus on India Masks the
Real Data Integrity Problems,
A corporate whistleblower: Thakur: Data Integrity
Requires Stronger Local Enforcement
Myself: Hussain: Empowering Workers is the Key to
Data Integrity
*Bottle of Lies: The Inside Story of the Generic Drug
Boom by Katherine Eban | May 2019
FDA ACPS Meeting November 28, 2001
2014/15: Why FDA reverted to the 21st Century Initiative [2.0.] after it “lost” its original “team” approach
The heart of the
matter
 Experience, the third qualifying leg of “good
practices” alongside education and training,
 How, in [professional] routines, I learn (and
fail to understand) from experience, mine
and others, presents a way to help you
consider how you learn from your
experiences.
 Why epistemology matters in science,
particularly how it influenced my efforts at
the Office of Pharmaceutical Science, CDER,
US FDA advancing BCS, PAT, Process
Validation, and ICH Q8, 9, and 10 guidance.
© AJAZ | INSIGHTS 2023 12/2/2023 6

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Intuitively Moving Institutions Towards Global Regulatory Resilience

  • 1. TOWARDS GLOBAL REGULATORY RESILIENCE Out of the Crisis to Ensure Therapeutic Equivalence 12/2/2023 © AJAZ | INSIGHTS 2023 1
  • 2. Global Regulatory Resilience  In May 2023, the US FDA issued an "Immediately in Effect Guidance for Industry" requiring testing for diethylene glycol in high-risk drug components, highlighting the vulnerability of the global pharmaceutical supply chain. It also reminds us that there is a significant difference between knowing what to do and doing it.  The need for proactive, forward-looking, and strategic approaches to resilience is becoming palpable worldwide. Was such a condition discernible in 1937 when the Elixir of Sulfanilamide tragedy was a tipping point for enacting the US Food, Drug, and Cosmetic Act of 1938? Or was it a “never let a crisis go to waste” mindset leveraging another crisis for a political agenda? What does it mean? I anticipate an exponential increase in uncertainty and a decline of trust in our practice environment, and to exercise our duty to care, we will need to find a way to make common sense via careful meaning and sensemaking.  Al-Ghazali (c.1056–1111) and René Descartes (1596–1650) argued against the infallibility of sense perception, and we, too, must acknowledge that "common sense is not so common," as Voltaire once said. Yet, we must work to make safety and quality a matter of common sense. © AJAZ | INSIGHTS 2023 12/2/2023 2
  • 3. Commonsense steps to Resilience essential for continued development Intuitionally ↔ institutionally  Don’t fear; learn to channel fear and anger to a purpose you care for  Beware and keep expanding the scope and depth of your awareness  In a moment and minutes, reflect on past experiences to reframe in new knowledge  Do so repeatedly. It presents us with insightful intuitions to be wiser today than yesterday and a step closer to resilience needed in the chaos that surrounds us  A commonsense approach to moving towards global regulatory resilience is your responsibility, as it once was my duty  A duty to make common sense of the efforts in the “Office of Pharmaceutical Science,” the predecessor of the “Office of Pharmaceutical Quality,” of the US FDA, to come out of the generic drug crisis and to ensure therapeutic equivalence © AJAZ | INSIGHTS 2023 12/2/2023 3
  • 4. © AJAZ | INSIGHTS 2023 12/2/2023 4 From my experience, how can I describe an intuitive and self-organizing social force around "attractors" patients' value to be assured of therapeutic equivalence?
  • 5. © AJAZ | INSIGHTS 2023 12/2/2023 5 Following Ranbaxy,* in 2014, there was a significant surge in BAD-I (breaches in the assurance of data integrity) observations by the US FDA. A trade magazine sought four perspectives: Confronting Illusions of Quality in Indian Generics Manufacturing (24 March 2014). FDA: Takahashi: Look Out for These Data Integrity Issues A GMP consultant: Cahilly: Focus on India Masks the Real Data Integrity Problems, A corporate whistleblower: Thakur: Data Integrity Requires Stronger Local Enforcement Myself: Hussain: Empowering Workers is the Key to Data Integrity *Bottle of Lies: The Inside Story of the Generic Drug Boom by Katherine Eban | May 2019 FDA ACPS Meeting November 28, 2001 2014/15: Why FDA reverted to the 21st Century Initiative [2.0.] after it “lost” its original “team” approach
  • 6. The heart of the matter  Experience, the third qualifying leg of “good practices” alongside education and training,  How, in [professional] routines, I learn (and fail to understand) from experience, mine and others, presents a way to help you consider how you learn from your experiences.  Why epistemology matters in science, particularly how it influenced my efforts at the Office of Pharmaceutical Science, CDER, US FDA advancing BCS, PAT, Process Validation, and ICH Q8, 9, and 10 guidance. © AJAZ | INSIGHTS 2023 12/2/2023 6
  • 7. OUTLINE Background • From my portfolio of contemporaneously noted experience, which experience would be most relevant to share in this conversation? Sequence and Process: How? • To start and continue this conversation, how should I arrange the chosen experiences? Experiments and a Plan • Journey to 2020: To see more clearly now Synthesis • Some consideration for assuring TE in Saudi Arabia Closing • What if I say we need more common sense? 12/2/2023 © AJAZ | INSIGHTS 2023 7
  • 8. BACKGROUND From my portfolio of contemporaneously noted experience, which experience would be most relevant to share in this conversation? 12/2/2023 © AJAZ | INSIGHTS 2023 8
  • 9.  In a 2018 report of a conference sponsored by King Saud University, what was on the minds of participants?  “Quality is not an act; it is a habit.”  Saudi 21st century pharmacovigilance practices  Regulatory transparency in Saudi Arabia  Should there be “reference regulatory systems”?  SFAD should conduct its bioequivalence studies?  Bioequivalence information should be provided …in leaflets.  Lack of national standards regarding therapeutic switching  Intuitions and habits are subconscious and highly efficient, so they better be good (=valid) and, in uncertainty, intuition is our only guide. , and, in uncertainty, intuition © AJAZ | INSIGHTS 2023 12/2/2023 9 Local concerns
  • 10. Saudi 21st century pharmacovigilance practices?  ICH Topic E 2 E Pharmacovigilance Planning (Step 5, June 2005)  Adoption in Saudi Arabia, and associated training,  Option for SFDA to propose for revision, considering Generics are now part of ICH  Some lessons in the USA, the case of a generic transdermal patch? © AJAZ | INSIGHTS 2023 12/2/2023 10
  • 11. Regulatory transparency in Saudi Arabia  “Therapeutic- In-equivalence, detection and correction, and improvement report”?  In the context of generic drugs, why does the US FDA continue to struggle? What lessons may help inform efforts in Saudi Arabia? © AJAZ | INSIGHTS 2023 12/2/2023 11
  • 12. Should there be “reference regulatory systems”?  The systems in the West are in the modes of “Build Back Better,” and, perhaps in anticipation, letting the existing systems decay.  With the progress at SFDA, committing to. Self-authorship is the way to go forward with a commitment to Self- transforming © AJAZ | INSIGHTS 2023 12/2/2023 12
  • 13. Should SFAD conduct its bioequivalence studies?  The immediate answer is No! Why SFDA should not take this on needs to be explained.  SFDA should utilize a team approach to ensure Therapeutic Equivalence via its established functions.  Perhaps, as an additional layer of security, independent, not- for-profit CRO-type institutions associated with an academic unit should be considered. © AJAZ | INSIGHTS 2023 12/2/2023 13
  • 14. Yes, bioequivalence information should be provided …in leaflets [package inserts] 12/2/2023 14 © AJAZ | INSIGHTS 2023
  • 15. Lack of national standards regarding therapeutic switching: A version of the US FDA “Orange Book”?  Faculty at the King Saud University, Riyadh, Saudi Arabia, and other collaborators have pondered Prospects of Establishing a Saudi Version of the United States Food and Drug Administration Orange Book – ScienceDirect  Perhaps some aspects should be emphasized with a focus on real-world considerations, including a user interface that patients can also use with their devices,  Please do not print a book with an orange cover. Donald Hare, my former colleague who led the Orange Book effort at the FDA, once told me that he chose orange because it reminded him of the Halloween season. © AJAZ | INSIGHTS 2023 12/2/2023 15 Pharma Times - Vol. 52 - No. 09 - September 2020
  • 16. Sequence and Process: How? To start and continue this conversation, how should I arrange the chosen experiences? © AJAZ | INSIGHTS 2023 12/2/2023 16
  • 17. Parts and System  Systems thinking is essentially holistic.  We can not build the ‘best’ car by combining the best parts of all the vehicles on the market. (they won’t fit) ~ Russell Ackoff  Moreover, since we are discussing a social system, it is essential to infuse it with an intuitive and self-organizing force with foundational "attractors" such as care and competence, which are highly valued by the community and institutions. © AJAZ | INSIGHTS 2023 12/2/2023 17
  • 18. Intentionality that intuitively generates responsibility to self-organize around value "attractors" of the community and institutions: SMART © AJAZ | INSIGHTS 2023 12/2/2023 18 SMART
  • 19. Resources 12/2/2023 19  Out of the Crisis, W. Edwards Deming, The MIT Press  In Over Our Heads: The Mental Demands of Modern Life, Robert Kegan, Harvard University Press  Thinking, Fast and Slow, Daniel Kahneman, Farrar, Straus and Girou  The Master and His Emissary: The Divided Brain and the Making of the Western World, Iain McGilchris, Yale University Press © AJAZ | INSIGHTS 2023
  • 20. My Memories, Materials, and Methods.  Our memories are a product of our experiences, but their accuracy is far from reliable.  I kept contemporaneous notes (since 2014), material for my memories  For topics and context before 2014, I refer to FDA meeting transcripts, presentations, and writing in the public domain  This is my “method” to assure the “integrity of experience” illustrated in the discussion 12/2/2023 © AJAZ | INSIGHTS 2023 20
  • 21. © AJAZ | INSIGHTS 2023 12/2/2023 21
  • 22. Insights I derive from intuitions in my experiences I note contemporaneously.  To promote the integrity of my subjective experiences, complementing memories and correcting biases when needed  On LinkedIn there are 111 insightful articles, some stand- alone and others editions of my ”SMART” Newsletter.  Self-monitoring assumptions, researching and testing to generate “new prior knowledge”, © AJAZ | INSIGHTS 2023 12/2/2023 22
  • 23. The Intuitive Mind is a Sacred Gift, and the Rational Mind is a Faithful Servant. INTUITION IS THE HIGHEST FORM OF INTELLIGENCE (FORBES.COM)  But the gift is wrapped, and we need to learn how to unwrap it properly to peel away confirmation biases that favor external validation over internal validation  What [thought] comes to mind quickly, often instantaneously as it seems, is the "available" information in the unconscious. It comes via an availability heuristic (a shortcut (our lazy) mind takes around the effort needed to reason). What comes instantaneously to mind varies with the “state of mind” - fearful, angry, anxious, depressed, or rational. Expanding the available and exploring without fear.  Take a moment, listen to the silence in sounds, and pay attention to breathing (slow your exhalation to tip the balance from sympathetic to parasympathetic); practice repeatedly shifting your on-demand mind to a higher “Order of Consciousness,” an empathetic, self-transforming mind.  Having channeled my anger, not that I was angry at that moment, I achieved a purposeful, empathetic state to ask, am I anchoring onto a familiar and comfortable situation? How should I “pull up” my anchoring bias and sail out of my comfort zone? In mere asking, I have taken a developmental stance, ready to begin good (valid) sensemaking.  This is my sensemaking process to learn from experience (feelings); I suggest you probe how you know from your subjective experience and find a way to improve the process – to make this seamless. © AJAZ | INSIGHTS 2023 12/2/2023 23 SMART Sensemaking Civility, Collapse & "Cartesian Anxiety" | LinkedIn A SMART present of deeds wrapped in recollections of past and future visualizations. | LinkedIn
  • 24. Challenges to Pharmaceutical Quality 2014/15: Lacking “One Quality Voice”  White-Paper--FDA-Pharmaceutical-Quality-Oversight.pdf (2015)  Product recall and defects…unacceptably high occurrences of problems attributed to inherent defects in product and process design  Current regulatory review and inspection practices tend to treat all products equally, in some cases without considering specific risks to the consumer or individual product failure modes  Inspection is not well-connected to knowledge gained from product review. Inspections often cannot cover all products and processes  [“21st Century Initiative 2.0.” What happened to 1.0?] © AJAZ | INSIGHTS 2023 12/2/2023 24
  • 25. © AJAZ | INSIGHTS 2023 12/2/2023 25 Did you know that since its inception in 1984, the US Generic Market has remained chaotic?
  • 26. © AJAZ | INSIGHTS 2023 12/2/2023 26 Is observing (1) to (8) in the same picture rational?
  • 27. © AJAZ | INSIGHTS 2023 12/2/2023 27 After leaving the US FDA, I was in the biotech, not the generic, divisions of the company on the left and then the same in the company on the right.
  • 28. 12/6/2020 AJAZ | INSIGHTS 28 Who insisted on the particular dissolution test and acceptance criteria?
  • 30. Oxymoronic intentionally  Current challenges in approval of ANDA’s. [A] For 10% of all FDA-approved NDAs (100%), no ANDA has been submitted despite expired patents and exclusivities  [B] Quoting an FDA-issued Federal Register notice—“The drugs described in more than half of all FDA-approved ANDAs are never marketed, marketed only after a substantial delay after approval, or marketed only intermittently. Such failures to market contribute to drug shortages and hinder consumer access to approved products.”  [C] Percentage of approved and commercialized ANDAs © AJAZ | INSIGHTS 2023 12/2/2023 30
  • 31. [D] ANDA’s that can take eight or more years to approve  A case example that highlights a struggle to ask the right question at the right time and information silos within the organization that hinders an integrative design and system approach to assessing the “totality of evidence.”  A “scientific dispute resolution” process is often needed in such cases to force all parts of the system to be in the same room and then on the “same page,” © AJAZ | INSIGHTS 2023 12/2/2023 31 Totality of Evidence & Theraputic Equivalence 15 October 2016 | PPT (slideshare.net)Therapeutic
  • 32. © AJAZ | INSIGHTS 2023 12/2/2023 32 FDA Guidance: Size--Shape--and-Other-Physical-Attributes-of-Generic- Tablets-and-Capsules (2015).pdf (FDA.GOV) [Why in 2015?] A Survey of Patients’ Perceptions of Pill Appearance and Responses to Changes in Appearance for Four Chronic Disease Medications | 2019 SpringerLink [a change in the appearance of a generic medication matters] 2015 2019
  • 33. Intuitively, I (we) have known quality is an expectation; can we now [institutionally] acknowledge it? Speaking metaphorically, it seemed an FDA Commissioner, who in a previous role had worked with me in the context of the 3 September 2003 Wall Street Journal report about the PAT initiative, had taken “the Blue Pill.” © AJAZ | INSIGHTS 2023 12/2/2023 33 Color a proxy for lack of assurance!
  • 34. The Pharmaceutical Industry has a “little secret.” NEW PRESCRIPTION FOR DRUG MAKERS: UPDATE THE PLANTS - WSJ  As recognized in the FDA’s Orange Book, “Therapeutic Equivalence” is an expectation. Expectation effects are in play in the real world where patients use the medicine. [Relevance to Saudi ecosystem: Prospects of Establishing a Saudi Version of the United States Food and Drug Administration Orange Book – ScienceDirect]  Might we have been assuming that “placebo-controlled” trials do not merely “account for” but also remove such an effect in the real world? Perhaps now, this may be the “little secret”?  Since its release in 1999, The Matrix has endured as a potent representation of the technologically motivated identity crisis of the early 21st century. The red and blue pill represents a choice between the willingness to learn a potentially unsettling or life-changing truth [taking the red pill] or remaining in the contented experience [the blue pill]. It is a helpful metaphor, which in this context is eerily poignant.  Perhaps we are unwilling to learn to learn any potentially unsettling or life-changing truth? © AJAZ | INSIGHTS 2023 12/2/2023 34
  • 35. Initiative 1.0, erased from memory?  How the initiatives got launched and progressed is outlined in the FDA 2004 White Paper, Innovation, and Continuous Improvement in Pharmaceutical Manufacturing: Pharmaceutical CGMPs for the 21st Century. The PAT Team and Manufacturing Science Working Group Report: A Summary of Learning, Contributions and Proposed Next Steps for Moving Towards the “Desired State of Pharmaceutical Manufacturing in the 21st Century. September 2004 (it is hard to find as it no longer exists on the FDA Internet, and one has to use the “Wayback Machine” to find it).  Also available is a short video recording (~2004) of me explaining How the PAT/QbD Journey Began. © AJAZ | INSIGHTS 2023 12/2/2023 35 Pharmaceutical Quality for the 21st Century 1.0?
  • 36.  "We're a very small part of FDA," says Hussain. "The rest of the FDA still needs to come on board.”  ” The challenge in the industry is even greater, says Afnan. However, the FDA's PAT squad has already begun transforming the Agency's, and the industry's, mindset about quality and compliance.”  “FDA'S PAT TEAM, PAT (Process Analytical Technologies) is the rarest of revolutions. It needed brilliant thinkers and some prodding to get off the ground, but it is now a team- driven movement. If it succeeds, it will mean unprecedented changes for industry and regulators.” © AJAZ | INSIGHTS 2023 12/2/2023 36 FDA's PAT Team: Shall We Dance? | Process Analytical Technology | Pharmaceutical Manufacturing | 6 April 2005 PAT Team and Guidance
  • 37. EMA PAT TEAM Mandate-process-analytical- technology-team_en.pdf (Europa.eu) Should I have insisted on a mandate for the FDA PAT Team? I estimated the sector would take a decade or so (2020) to transform. A mandate in the US FDA context would not be appropriate. Also, mandating would make me an imperialist! The challenge is the deep division between the Review and Inspection functions (as reflected in the following: CDER’s Janet Woodcock “Nobody Can Really Tell Me If FDA Inspections Are Effective” (April 23, 2013 pharmaceuticalonline.com) © AJAZ | INSIGHTS 2023 12/2/2023 37
  • 38. © AJAZ | INSIGHTS 2023 12/2/2023 38 State of QbD Implementation: Adoption, Success, and Challenges: Ted Fur, McKinsey & Co (June 2010), FDA ACPS Meeting 27 July 2011 ? ? Underestimated complexity QTPP = Compendial monograph, “subjective” risk-matrix,………. Video: 360 Degree View of Quality by Design, USP International Conference 2017
  • 39. It takes work to make common sense.  Our compartmentalized functions focus on local objectives, cascaded down from a system output aiming at profit and productivity.  R&D and Regulatory Affairs incentivized for “file first”: Generics are about “file first; figure it out later.”  “Huge amount of reviewer inconsistency” © AJAZ | INSIGHTS 2023 12/2/2023 39 State of QbD Implementation: Adoption, Success, and Challenges: Ted Fur, McKinsey & Co (June 2010), FDA ACPS Meeting 27 July 2011 FDA PAT Guidance 2004 ICH Q8 (2006)
  • 40. © AJAZ | INSIGHTS 2023 12/2/2023 40 SMART Triaxial Compaction, Social Form 483, and VAI or OAI to an Avenger (2023) (slideshare.net) Reflecting on a 2010 FDA conference notes in Pharmaceutical Manufacturing Magazine. “Divide and Rule,” not appreciating the systemic foundation
  • 41. EXPERIMENTS AND A PLAN Journey to 2020: To see more clearly now 12/2/2023 41 © AJAZ | INSIGHTS 2023
  • 42. A journey to reflect, Reframe and Respond,  A: For 10% of all FDA-approved NDAs (100%), no ANDA has been submitted despite expired patents and exclusivities  B: Quoting an FDA-issued Federal Register notice—“The drugs described in more than half of all FDA-approved ANDAs are never marketed, marketed only after a substantial delay after approval, or marketed only intermittently. Such failures to market contribute to drug shortages and hinder consumer access to approved products.”  C: Percentage of approved and commercialized ANDA’s © AJAZ | INSIGHTS 2023 12/2/2023 42 Pharmaceutical “New Prior Knowledge”: Twenty-First Century Assurance of Therapeutic Equivalence | AAPS PharmSciTech (2019) Roadblocks-to-Roadmap-2017-with-A-2020-Vision- 12182016-Final-Version.pdf (NIPTE.ORG)
  • 43. © AJAZ | INSIGHTS 2023 12/2/2023 43 Physicochemical failure modes for Narrow Therapeutic Index (NTI) drugs (2 July 2021 europeanpharmaceuticalreview.com)
  • 44. © AJAZ | INSIGHTS 2023 12/2/2023 44 Corporate training with capstone experience and certification
  • 45. © AJAZ | INSIGHTS 2023 12/2/2023 45 Industrial Policy and NIPTE: Goodbye NIPTE | PPT (7 December 2020) Do we need a new curriculum and ways of educating? “Backward Design” to prioritize the intended learning outcomes instead of topics to be covered* (a pilot program @ US FDA) *Kari L. Clase, Loran C. Parker, Kenneth R. Morris, Stephen R. Byrn, Vadim J. Gurvich: Design of a NIPTE certificate curriculum in industrial pharmacy, drug formulations, and drug quality (to be published) Do we need a new curriculum and ways of training CMC Review staff at the US FDA?
  • 46. CHAOS TO CONTINUAL IMPROVEMENT: PATH TO HARMONIZATION  After taking a break in 2018, partly to make sense of why chaos with continual improvement juxtaposes in the highly regulated environment, I am pleased to contribute to the 2019 CPhI Worldwide report.  This report builds on my previous two contributions to CPhI Worldwide reports, 2016-2017. [  The following musing seeks the emergence of a “Butterfly Effect” around two, not so “strange attractors,” real-world satisfaction in pharmaceuticals and professional development in the sector.  These attractors are intuitive; “common sense.” But it can be in a “blind spot”- and in a globalized supply chain, often needing a reminder. © AJAZ | INSIGHTS 2023 12/2/2023 46 CPhI Annual Industry Report 2019
  • 47. NIPTE goes to Capitol Hill: New Prior Knowledge & Centers for Excellence: US CONGRESS PASSES BILL SUPPORTING NEW ERA OF BIOPHARMA ADVANCED CONTINUOUS MANUFACTURING (JANUARY 2022) In and Beyond COVID-19: US Academic Pharmaceutical Science and Engineering Community Must Engage to Meet Critical National Needs - PubMed (May 2020) © AJAZ | INSIGHTS 2023 12/2/2023 47
  • 48. © AJAZ | INSIGHTS 2023 12/2/2023 48
  • 49. SYNTHESIS © AJAZ | INSIGHTS 2023 12/2/2023 49
  • 50. Saudi 21st-century pharmacovigilance practices?  Pharmacovigilance system in Saudi Arabia – (2017) PubMed (nih.gov) was helpful background. You can read it as I did. My comments are based on my experience.  ICH Topic E 2 E Pharmacovigilance Planning (Step 5, June 2005)  Adoption in Saudi Arabia and associated training: Consider including case examples of what worked and didn’t work well following the implementation of ICH guidelines SFDA is adopting. It will provide an opportunity to reflect and reframe the issue in the local context and how responding to similar situations locally can be of value.  The merit of an option for SFDA to propose for revision, considering Generics are now part of ICH? © AJAZ | INSIGHTS 2023 12/2/2023 50 Regulatory Training on ICH Quality Guidelines | Saudi Food and Drug Authority (sfda.gov.sa)
  • 51. What did I learn from experiences over these years: 1995, 2005, 2006, 2014, 2016, and 2023?  Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy, and quality attribute – (2006) ScienceDirect  Current Good Regulators of Pharmaceuticals (cGRP) | LinkedIn (5 April 2016)  Assessing Adhesion With Transdermal and Topical Delivery Systems for ANDAs Draft Guidance for Industry | FDA (April 2023) © AJAZ | INSIGHTS 2023 12/2/2023 51 Good Regulators of Pharmaceuticals (GRP) 22 October 2014 | PPT (slideshare.net) at University of Iowa. Intuition, Investigation, insight, Institutionalization, Industrialization of an Improvement that saves lives. But..
  • 52. Regulatory transparency in Saudi Arabia  “Therapeutic- In-equivalence, detection and correction, and improvement report”?  In the context of generic drugs, why does the US FDA continue to struggle? Case of “cherry picking” BE studies!  What lessons may help inform efforts in Saudi Arabia? The beginning of the US generic sector (1984) was scandalous. The root cause then persists. Which SFDA can avoid. © AJAZ | INSIGHTS 2023 12/2/2023 52 A case of ignoring Pharmaceutical Equivalence (micro-emulsion vs solution in propylene glycol) and Label (RLD with apple juice, whereas generic BE was with chocolate milk). FDA’s conflicting roles, assessment, and promotion, in general, hinder transparency and “generic hesitancy” and continue to erode confidence. The case led to a rule change – failed BE students must be reported.
  • 53. © AJAZ | INSIGHTS 2023 12/2/2023 53 Prescription for trouble / How flaw in FDA safety net may pose [a] risk to [the] public with generic drugs (22 December 2002, sfgate.com) 2004 2013 The US FDA struggles with conflicting roles, assessment, and promotion and is concerned with “generic hesitancy.” It struggles to self-correct and continues to erode confidence. Hussain041122.pdf (nihs.go.jp)
  • 54. © AJAZ | INSIGHTS 2023 12/2/2023 54 Structural or a functional flaw? Common cause or special cause? Or perhaps Structural functionalism? The FDA emphasizes that this is a special case -- a complex drug for highly sensitive patients -- that should not undermine the presumption that generics can be safely exchanged for brand names in most instances. Compromising in the name of “generic hesitancy”……?
  • 55. Should there be “reference regulatory systems”?  The systems in the West are in the modes of “Build Back Better,” and, perhaps in anticipation, letting the existing systems decay.  With the progress at SFDA, committing to. Self-authorship is the way to go forward with a commitment to Self- transforming © AJAZ | INSIGHTS 2023 12/2/2023 55 The Kingdom has unique and advantageous cultural, economic, political, and social aspects that affect leadership and leadership development compared to the US and EU.
  • 56. ICH in the “Fourth Turning”?  Sen. Johnson Introduces Legislation to Protect American Sovereignty Against World Health Organization, May 27, 2022  Path of Political Disintegration? Common ground, common cause, and common sense  “Sometime before the year 2025, America will pass through a great gate in history, commensurate with the American Revolution, Civil War, and twin emergencies of the Great Depression and World War II.” ― William Strauss and Neil Howe, The Fourth Turning: What the Cycles of History Tell Us About America's Next Rendezvous with Destiny (1996) © AJAZ | INSIGHTS 2023 12/2/2023 56
  • 57. The topic of public health response to COVID-19 is now getting mired in controversy, and how it evolves in the chaos it precipitates is still being determined. What is certain is that it will profoundly impact our lives and practices.  In the USA, grave questions have arisen along with allegations.  Amidst the “bipolar politics” and censorship, there are ongoing investigations  I have informed opinions, a clip from a report in the New York Times that quoted me. © AJAZ | INSIGHTS 2023 12/2/2023 57
  • 58. Should SFAD conduct its bioequivalence studies?  The immediate answer is No! Why SFDA should not take this on needs to be explained.  SFDA should utilize a team approach to ensure Therapeutic Equivalence via its established functions.  Perhaps, as an additional layer of security, independent, not- for-profit CRO-type institutions associated with an academic unit should be considered. © AJAZ | INSIGHTS 2023 12/2/2023 58
  • 59. Yes, bioequivalence information should be provided …in leaflets [package inserts] 12/2/2023 59 © AJAZ | INSIGHTS 2023
  • 60. The FDA ensures “bioequivalence,” so what's the argument about?  Within the FDA, we asked the following questions in the Bioprmaceutics Coordinating Committee Committee, where my focus was on BCS-based waiver of in vivo BA/BE studies (see: 2000).  What is the primary question of the study?  What are the tests that can be used to address the question?  What degree of confidence is needed for the test outcome? © AJAZ | INSIGHTS 2023 12/2/2023 60 Bioavailability and Bioequivalence: An FDA Regulatory Overview (2001)| SpringerLink Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014 | University of Heidelberg
  • 61. Reactions to the 13-November 2014 FDA Action on Generic Methylphenidate ER tablets  Social Media Megaphone, the new Voice of the Patients, see my posts:  Voice of the Patient | PPT (slideshare.net)  Voices of/for Patients | PPT (slideshare.net) © AJAZ | INSIGHTS 2023 12/2/2023 61
  • 62. © AJAZ | INSIGHTS 2023 12/2/2023 62 Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014 | University of Heidelberg Janssen Quietly Ends Concerta Authorized-Generic (27 April 2023, adhdrollercoaster.org)
  • 63. © AJAZ | INSIGHTS 2023 12/2/2023 63 FDA asked that within six months, Mallinckrodt and Kudco (now UCB/Kremers Urban) confirm the bioequivalence of their products using the revised bioequivalence standards (see 2009 on slide #28) or voluntarily withdraw their products from the market. What was the right question to have asked in the first place? Patients still in 2021 are saying: “Concerta Generic Is Not Created Equal: ADHD Medication (additudemag.com).” Readers are reporting getting Concerta, sometimes covered by their pharmacy insurance benefit. However, some have had to go through Prior Authorization (sometimes called an Exception Process). They had to try two other methylphenidate generics first, to poor effect. Only then could they access the brand Concerta. Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014 | University of Heidelberg
  • 64. What went wrong? Questions and Answers Regarding Methylphenidate Hydrochloride Extended-Release Tablets (generic Concerta) made by Mallinckrodt and UCB/Kremers Urban (formerly Kudco) | FDA © AJAZ | INSIGHTS 2023 12/2/2023 64 One-size-fits-all approach to BE, recall in 2009, partial AUC approach was in place.
  • 65. © AJAZ | INSIGHTS 2023 12/2/2023 65 Leadership, Butterfly Effect, Levothyroxine Therapeutic Equivalence LIU, Brooklyn, NY 13 February 2019 | PPT Leadership for 21st Century Pharmaceuticals @ IMT Mines, Albi, France, 14 November 2018 I PPT Previous lectures on this case study: Did you know that Therapeutic Equivalence is an expectation? Do you think expectancy effects are now more prominent than 5, 10, or 20 years ago?
  • 66. TE is an expectation.  Therapeutic Equivalents. Approved drug products are considered to be therapeutic equivalents if they are pharmaceutical equivalents for which bioequivalence has been demonstrated, and they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling  What about Label and CGMP considerations? Why not consider it here but separately? © AJAZ | INSIGHTS 2023 12/2/2023 66
  • 67. In the Orange Book: FDA classifies as therapeutically equivalent those drug products that…  (1) they are approved as safe and effective [1];  (2) they are pharmaceutical equivalents in that they (a) contain identical amounts of the identical active drug ingredient in the identical dosage form and route of administration, and (b) meet compendial or other applicable standards of strength, quality, purity, and identity;  (3) they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b)if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard;  (4) they are adequately labeled; and  (5) they are manufactured in compliance with Current Good Manufacturing Practice regulations. © AJAZ | INSIGHTS 2023 12/2/2023 67 [1] Approval (based on safety and efficacy): Effectiveness is an expectation (2) (3) (4) (5) (1) Effectiveness
  • 68. Why, in 2022, is there a new draft guidance on Therapeutic Equivalence?  GUIDANCE_Draft:_Evaluation of Therapeutic Equivalence_Published_July 2022.pdf (fda.gov)  Beyond reminding that Therapeutic Equivalence [TE] evaluations are a “scientific judgment,” the draft begins to acknowledge that generic substitution may involve social and economic policy administered by the states, e.g., reducing the cost of drugs to consumers. These evaluations [by the States, I wonder if instance, as inequivalent] do not indicate that any product violates the FD&C Act or is preferable to any other.  The FDA may revise a therapeutic equivalence evaluation when new information arises. The FDA has a provision to change a product’s TE code from an A-rating to a B-rating if it obtains any information that raises questions about the data or information on which the Agency relied while approving the drug product. This includes issues related to the facility where the drug product was tested.  It is a helpful summary with important Q&A. Between the lines, the nuances hint at disagreement with some States, and reminders interspersed in the familiar text suggest a concern or suspicion of fraud, perhaps accumulated amidst the COVID-19 lockdown that hindered BIOMO inspections. © AJAZ | INSIGHTS 2023 12/2/2023 68 Is it the month of May? Or is it a distress signal, a mayday call?
  • 69. Lack of national standards regarding therapeutic switching: A version of the US FDA “Orange Book”?  Faculty at the King Saud University, Riyadh, Saudi Arabia, and other collaborators have pondered Prospects of Establishing a Saudi Version of the United States Food and Drug Administration Orange Book – ScienceDirect  Perhaps some aspects should be emphasized with a focus on real-world considerations, including a user interface that patients can also use with their devices,  Please do not print a book with an orange cover. Donald Hare, my former colleague who led the Orange Book effort at the FDA, once told me that he chose orange because it reminded him of the Halloween season. © AJAZ | INSIGHTS 2023 12/2/2023 69 Pharma Times - Vol. 52 - No. 09 - September 2020
  • 70. Do not ignore the expectation vs. reality trap  The US FD&C Act of 1938’s history highlights several challenges that often go unnoticed  It took several years to come up with a draft before 1938, but there was no agreement reached  The tragedy of the Elixir of Sulfanilamide in 1937 was a significant factor that pushed the agreement forward.  How do we remember the tragedy today – Sulfanilamide Disaster | FDA. Why?  The law formalized the requirements for "New Drug Application" and "Inactive Ingredients," while the tipping incident was a formulation issue unrelated to drug safety.  The FDA authorizes pharmaceutical products; it keeps a “drug master file.” The term “pharmaceutical” is only used in a small portion of the FDA’s legal vocabulary. © AJAZ | INSIGHTS 2023 12/2/2023 70 Each amendment is born from a tragedy, some well- known like Thalidomide and Heparin, others unknown to the public.
  • 71. Does anybody remember the poor formulator? © AJAZ | INSIGHTS 2023 12/2/2023 71 Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol | FDA (MAY 2023)
  • 72. CLOSING © AJAZ | INSIGHTS 2023 12/2/2023 72
  • 73. What if I say we need more common sense? Would you accept my answer? © AJAZ | INSIGHTS 2023 12/2/2023 73
  • 74. Would you agree that this is a case of common sense not being so common?  An FDA Compliance Officer noted quarantined albuterol (API) batches and inquired why.  That’s for our animal product. We are investigating complaints. We found an impurity.  But isn’t albuterol made for human use in the same process?  Yes, but it qualifies per USP! Was the response of a master’s degree holder. © AJAZ | INSIGHTS 2023 12/2/2023 74 Product Quality & Patient Safety USP Workshop Mumbai 12 June 2015 | PPT (slideshare.net)
  • 75. © AJAZ | INSIGHTS 2023 12/2/2023 75 Ignoring problems by avoiding them is tempting, yet difficult to overcome for individuals and corporations like "Big Pharma.“ What About the “Small Pharma”? How To Break The Pharmaceutical 2-3 Sigma Barrier (Like Amgen) 2017 (pharmaceuticalonline.com)
  • 76. A practical, intrapersonal SMART, self-monitoring anger to reflect and transform guided by Constructive Theory of Adult Development: In Over Our Heads: The Mental Demands of Modern Life, Robert Kegan (1994), Harvard University Press. 12/2/2023 © AJAZ | INSIGHTS 2023 76 With foundational education and training, the journey toward professional development begins with taking a deep breath and exhaling slowly.
  • 77. “Pharmaceutical” Regulatory Ecosystem in Saudi Arabia  The education and training related to regulating pharmaceutical products is comparatively more established than what is often associated with CMC review in the US. Strengthening statistics and quantitative aspects, such as pharmaceutical engineering, is essential.  In the past, the FDA considered "development pharmaceutics" more of an art than a science in the US, which hindered the advancement of ICH Q8 (Pharmaceutical Development Report).  In the context of ICH, it is essential to consider the significant implications and nuances that arise from such ‘disciplinary” divide and perceptions. © AJAZ | INSIGHTS 2023 12/2/2023 77 Visiting My Alma mater, University of Cincinnati 20 April 2017 | PPT (slideshare.net), The Nation Needs a Comprehensive Pharmaceutical Engineering Education and Research System (2005) Statistical Thinking and Pharmaceutical Professional Development, a keynote by Ajaz NCB 2023 20 June 2023 | PPT (slideshare.net)
  • 78. A solid foundation in pharmacy, combined with knowledge of pharmaceutical engineering and a sense of responsibility to self-author, is the first step towards achieving regulatory resilience on both local and global scales. Understanding therapeutic equivalence (TE) is an essential requirement, and the ability to manage expectations and satisfy others shows our professional maturity. Continuing to develop our skills and knowledge is the path to achieving this level of maturity. © AJAZ | INSIGHTS 2023 12/2/2023 78
  • 79. Ajaz Hussain, Ph.D. | LinkedIn Ajaz S. Hussain, PhD - YouTube 12/2/2023 © AJAZ | INSIGHTS 2023 79 Ajaz Hussain,Slideshare.net)