Sharing thoughts on what makes a Good Regulator of Pharmaceuticals with pharmacy students at the Universities of Minnesota and Iowa. A point of emphasis on "we all are regulators" is explained and three areas for learning - (a) Systems and Integrative Thinking, (b) Argumentation and (c) Behavioral Economics described. I hope you, the viewers, will also find some value in reviewing these slides. If you are a student and have some questions please feel free to drop me a email (a2zpharmsci@msn.com).

1. Good Regulators of Pharmaceuticals (GRP) (Version 2.0.)
Ajaz S. Hussain, Ph.D., Executive Director
The National Institute for Pharmaceutical Technology & Education
Duquesne University
Illinois Institute of Technology
Purdue University
Rutgers University
Universidad de Puerto Rico
University of Connecticut
University of Iowa
University of Kansas
University of Kentucky
University of Maryland
University of Michigan
University of Minnesota
University of Wisconsin
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2. Objectives

“….A significant number of our graduates have gone to FDA and I see the trend continuing at least in the near future. Any guidance and pointers from an FDA veteran would be of value.”

Raj Suryanarayanan (Sury), PhD, Professor and William and Mildred Peters Endowed Chair, College of Pharmacy, University of Minnesota.

‘Your seminar looks truly stimulating and I believe it would be very beneficial for both faculty and students.”

Lee E. Kirsch, Ph.D. Professor; Division of Pharmaceutics, College of Pharmacy, The University of Iowa
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Steve Jobs -A lot of people in our industry haven't had very diverse experiences. So they don't have enough dots to connect, and they end up with very linear solutions without a broad perspective on the problem. The broader one's understanding of the human experience, the better design we will have.

4. A career at FDA canprovide an amazing opportunity to learn about drug regulations, development & manufacturing while making important contributions to the society.
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5. Why? But remember to .. “Chase your passion, not your pension.” ~Denis Waitley
Focal point receiving information and data seeking approval for state- 0f-art drug development programs and projects
Recognized leader among global regulatory agencies
Opportunities to learn different strategies for developing medicines and making decisions on their approval, the legal dimension of these decisions
Multi-disciplinary review and established procedures to respect and recognize contributions of each discipline and individual
Dynamic scientific environment -science based policies and additional research needed to develop new policies
Opportunity to grow professionally and personally in a secure system designed to ensure staff will speak-up (no fear) 10/22/2014 Ajaz@NIPTE.ORG 5

6. Effective communication to reach consensus efficiently: Share information to change belief and behavior
If I were to start over again in 1995….I would devote more attention, in the early phase of FDA career, to
•Understanding the regulatory & legal context –adequacy of scientific evidence in the context of the US law
•Acceptable assumptions and process of decision-making in other disciplines; identify and understand why certain ‘integrated’ decisions are more optimal than others from patient viewpoint
•‘Human factors’; human behavior –rational vs. irrational –and how these should to be accounted
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7. From academia to FDA –added emphasis needed on human behavior
Why do we regulate?
Pharmaceuticals exhibit market failures that can have devastating consequences
What do we regulate?
Human behavior
How do we regulate?
Laws, regulations, policies, review, inspections, criminal prosecutions,…
Who are the regulators?
All of us, not just the FDA
What is the foundation for modern regulations?
Scientific evidence and compliance with regulations and ‘Good Practices’
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FDA reports 149 deaths with allergic or hypersensitivity symptoms during that period
•Contaminated heparin from China
QC Testing
•Initial testing failed to detect the contaminant
Pharmacovigilence
•Signals in the pharmacovigilence systems responded slowly and
Eventually, the severity of reactions associated made it likely that the contamination would be detected
•too late for those who died or were injured
What is the likelihood, in the US, of detecting a less toxic contaminant?
•(a) Don’t know,
•(b) Higher than what it was for Heparin in 2007, or
•(c) Lower than what it was for Heparin in 2007
Why do you think testing did not detect the contaminant?
•(a) USP test for Heparin were not designed to test this particular contaminant
•(b) The QC labs involved did not know how to test the samples
•(c) QC lab was manipulating the data
The US Heparin Tragedy 2007 and 2008
THE HEPARIN DISASTER: CHINESE COUNTERFEITS AND AMERICAN FAILURES
SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS OF THE COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES. ONE HUNDRED TENTH CONGRESS SECOND SESSION. APRIL 29, 2008. Serial No. 110-109

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Mr. Shimkus: When the drug safety system fails, people get sick.
Some die.
•Some of these people are already very vulnerable, and proving the cause of harm from impurities, adulteration, and counterfeits can be elusive.
It is hard to detect harm
•Certainly the companies are obligated to ensure a culture of quality and maintain vigilance as well. This reflects a systems approach to safety.
FDA inspectors look for a culture of qualityat manufacturing facilities.
•FDA policies led to the failure to inspect the Chinese plant.
This system approach wasn't at play here.
•While it doesn't deny the counterfeit source, tries to say that counterfeits didn't cause the reaction, as if the adulteration itself was no big deal. Is this an acceptable mindset? ……….
This brings me to China and its quality culture or lack thereof. THE HEPARIN DISASTER: CHINESE COUNTERFEITS AND AMERICAN FAILURES
SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS OF THE COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES. ONE HUNDRED TENTH CONGRESS SECOND SESSION. APRIL 29, 2008. Serial No. 110-109

10. 92% of Warning Letters in 2014 (until 7/14/14) related to lapses in data integrity

Not recording activities contemporaneously

Backdating

Fabricating data

Copying existing data as new data

Re-running samples

Discarding data 10/22/2014 Ajaz@NIPTE.ORG 10
Alicia M. Mozzachio, RPh, MPH, July 15, 2014; FDLI,
Washington, DC.
WL in 2013
•+ 31%
WL in 2014 (7/14/14)
•+ 92%

11. Preconditions to malice or disregard
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Attitude towards the behavior
Subjective norm
Perceived behavioral control
Intention
Future
Behavior
usually found to predict behavioral
intentions with a high degree of
accuracy
intentions, in combination with
perceived behavioral control, can
account for a considerable
proportion of variance in behavior.
Past
Behavior
Ajen, I. The theory of planned behavior. ORGANIZATIONAL
BEHAVIOR AND HUMAN DECISION PROCESSES 50, 179-211 (1991)

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attitude toward performing the behavior
Process validation is done so quality is good
test prone to error
“Batch failure means I made a mistake”
subjective norm
documentation not critical
Compendial testing sufficient
Indian regulators collect & test samples –no issue there!
At the individual level, in QC function– how often does this occur?
“Throw-over the wall”
“Testing into compliance”
In general –low empowerment is a significant challenge (low perceived behavioral control); plus reasons to rationalize….

14. Root-cause may be upstream! Satisfy reviewer requirementsThrow-over the wallThen just do it …
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Development
& Application
Commercial
Operations
Pharmacovigilance
Inspections – 483,
WL,…
Marketing,….
Manufacturing
Marketing
Authorization
Pre-Approval
Inspection
Review
Application
Development
Prone to ‘process entropy’ without FDA Inspections!
http://www.nike.com/us/en_us/c/justdoit
“Throw-over the wall”
“Satisfy Reviewer Requirements”

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Chemometrics
Econometrics
Review & Approval
Business Decisions:
Commercial operations,
profitability & availability.
Periodic Regulatory Inspections
Three Econometric Papers on Quality
Decay, Shock, and Renewal: Operational Routines and Process Entropy in the Pharmaceutical Industry. Gopesh Anand, John Gray, and Enno Siemsen. Organization Science. 23:1700-1716 (2012)
Regulator Heterogeneity and Endogenous Efforts to Close the Information Asymmetry Gap: Evidence from FDA regulation. Jeffrey T. Macher, John W. Mayo and Jack A. Nickerson. Journal of Law and Economics. 54: 25 –54 (2011)
Quality Risk in Offshore Manufacturing: Evidence from the Pharmaceutical Industry. John Gray, Aleda Roth, and Michael Leiblein. Journal of Operations Management. 29: 737– 752 (2011)
How do people really make decisions?
Prospect Theory: An Analysis of Decision under Risk. Daniel Kahneman and Amos Tversky
Econometrica. 47: 263-291 (1979)
The Framing of Decisions and the Psychology of Choice. Amos Tversky and Daniel Kahneman
Science. 211, pp. 453-458 (1981)
The End of Rational Economics. Dan Ariely. Harvard Business Review, July 2009.
Chemometric, Pharmacometrics & Econometrics: Three Dimensions of QbD.
Ajaz S. Hussain. Swiss Pharma (2012).

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Culture of Quality
Normal
Rewarding
Easy
QMS
System
Knowledge
Variation
Behavior
Behavior -GXPs
Fear Removed
Mastery
Awareness
Environment Leadership
Emphasis
Message Credibility
Peer Involvement
Employee Empowerment
Connect to CoQ
Connect to GXPs
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
Integrated Framework: Culture of Quality

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Culture of Quality
We do our best to develop medicines and the evidence to meet the needs of patients –we develop these products consciously recognizing quality cannot be tested into our products .
We recognize that nothing is perfect and there will be some errors in our design, systems and procedures, or we may make mistakes in following set procedures.
It is normal, easy and rewarding to work within our quality management system, without fear, to detect, correct and to learn from our mistakes.
In doing so we act consciously in the interest of patients –specially when no one is looking, and continually improve our quality by design and aim for right first time.

18. Reminder –we all are regulators 10/22/2014 Ajaz@NIPTE.ORG 18
A Flood of Opioids, a Rising Tide of Deaths. Susan Okie. N Engl J Med (2010)

19. Case example

Regulating Fentanyl Transdermal Patches (a effective drug when used in the intended population and used properly)

Design and develop robust products –recognizing and addressing likely failure modes

Effective review and approval –asking the right questions

Prescription only for the intended patient population

Verify before dispensing and provide instructions to ensure understand how to use and dispose properly

Effective pharmacovigilence, corrections, learning and improvements
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20. High incidence of deliberate abuse or suicide
Fatal Fentanyl Patch Misuse in a Hospitalized Patient with a Postmortem Increase in Fentanyl Blood Concentration.
•J Forensic Sci. 2014 Jul 17.
Notes from the field: increase in fentanyl-related overdose deaths -Rhode Island, November 2013-March 2014.
•MMWR Morb Mortal Wkly Rep. 2014 Jun 20;63(24):531
Opioid overdose mortality in Kansas, 2001-2011: toxicologic evaluation of intent.
•J Anal Toxicol. 2013 Nov-Dec;37(9):629-35.
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21. Uninformed, improper use
Life-threatening coma and full-thickness sunburn in a patient treated with transdermal fentanyl patches: a case report.
J Med Case Rep. 2012 Jul 26;6:220.
Opioid overdose in a patient using a fentanyl patch during treatment with a warming blanket.
Anesth Analg. 2001 Sep;93(3):647-8
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22. High residual drug; disposed improperlyPoor adhesive performance; accidental patch transfer
Fentanyl Patch Can Be Deadly to Children
FDA has issued two public health advisories—in 2005 and 2007— about the safe use of fentanyl patches and today it is continuing its outreach to patients, caregivers and health care professionals about the dangers of accidental exposure.
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http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm300803.htm

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Why adhesive performance is a
critical quality attribute for all
TDS?
Why was/is this not adequately
recognized?

24. Recalling an investigation of a case that strongly suggested adhesive failure can lead to patient frustration and can pose risk of repeated patch replacements (reservoir effect?); report presented to CDER Drug Safety Oversight Board (July 2005)
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25. July 15, 2005 FDA Public Health Advisory: Safety Warnings Regarding Use of Fentanyl Transdermal (Skin) Patches

Alert for Healthcare Professionals

FDA recently conducted a review of fatalities reported to the voluntary adverse event reporting system that were possibly due to unintentional overdose from the fentanyl transdermal patch

In many cases, establishing whether the overdose was unintentional was difficult

Factors identified as possibly related to unintentional overdose included:

Use of high doses of the fentanyl patch and/or multiple patches (sometimes in combination with other drugs),

Possible medication errors, accidental exposure (e.g., coming in contact with a discarded patch),

Application of a heat source to the patch possibly resulting in increased fentanyl absorption,

Suspected transdermal patch malfunction (e.g., leaking patches).

In addition, several patients reported poor adhesion of the patches to the skin.
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26. What is the current state?

Adhesive properties: a critical issue in transdermal patch development. Expert Opinion on Drug Delivery. January 2012, Vol. 9, No. 1 , Pages 33-45

“numerous reports ofin vivo‘adhesion lacking’ are still addressed to regulatory agencies”

“Expert opinion:The Pharmacopoeias should consider the opportunity of introducing compendial testing to assay the quality of adhesive patch properties, and regulatory agencies should issue proper guidelines to evaluate these features during development.”
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Work to create a culture of quality (CoQ)
Environment that facilitates individuals to guide their
behavior to work consciously in the interest of patients
and to continually improve this ability.

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•Scientific methodology
•Engineering Design
•Plan-Do-Check-Act
Consciously
•Habits (work to get rid of bad ones)
•Habits (work to cultivate good one)
•Keystone habits (Safety @ Alcoa; A.L.C.O.A. of data integrity)
Subconsciously
The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg (2012)
Consciously ask the right questions in the interest of the patients,
describe the accepted assumptions and set the level of precision
needed for the answers to the questions posed. Be a good scientist –
in the interest of the patients.

29. A useful tool
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http://www-2.rotman.utoronto.ca/integrativethinking/definition.htm

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Different functions connected directly or
indirectly to the two products (medicine
and evidence) – their outputs impacts
quality of these products
• Each function within its environment should be
working to ensure the two products are consistently
linked [directly or via the chain of evidence to the
clinical trial product that established the pivotal
evidence of benefit and risk that allows the product
to be sold]
•Multitude of individuals from various disciplines of
science, engineering, management .. Each expected
to be disciplined within their disciplinary
methodologies; a proportion of staff may not have
formal training in any disciplinary methodology
The phrase by design in
Quality by Design – is
therefore, a foundation of
CoQ.
• In this course CoQ –QMS-GXP
and QbD – are viewed and
discussed in the most basic
elements – intention and behavior
• “Features of Quality by Design:
Doing things consciously”
CoQ Manifests in the Organization's Environment by Design

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Culture of Quality
Normal
Rewarding
Easy
QMS
System
Knowledge
Variation
Behavior
Behavior -GXPs
Fear Removed
Mastery
Awareness
Environment Leadership
Emphasis
Message Credibility
Peer Involvement
Employee Empowerment
Connect to CoQ
Connect to GXPs
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
Integrated Framework: Culture of Quality

32. Consider these topics to supplement your technical skills
•Kaplan, G., G. Bo-Linn, P. Carayon, P. Pronovost, W. Rouse, P. Reid, and R. Saunders. 2013. Bringing a systems approach to health. Discussion Paper, Institute of Medicine and National Academy of Engineering, Washington, DC. http://www.iom.edu/systemsapproaches
Systems approach for work-flow, learning and accountability
•the ability to constructively face the tensions of opposing models, and instead of choosing one at the expense of the other, generating a creative resolution of the tension in the form of a new model that contains elements of the both models, but is superior to each. http://www- 2.rotman.utoronto.ca/integrativethinking/definition.htm
Practicing ‘Integrative Thinking’
•Example -The Toulmin's Model of Argumentation
•Williams, Joseph, and Gregory Colomb.The Craft of Argument. New York, NY: Longman Press, 2006.
•Daniel Kahneman. Thinking, Fast and Slow. Penguin Books Limited, 2011
•Behavioral Economics and Health: NIH Adherence Network Seminar Series. June 19, 2013. http://www.nih.gov/news/videos/2013/06192013- BehavioralEconomicsHealth.htm
Argumentation and Behavioral economics
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