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Good Regulators of Pharmaceuticals (GRP) 22 October 2014


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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 (

Published in: Education

Good Regulators of Pharmaceuticals (GRP) 22 October 2014

  1. 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 10/22/2014 Ajaz@NIPTE.ORG 1
  2. 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 10/22/2014 Ajaz@NIPTE.ORG 2
  3. 3. 10/22/2014 Ajaz@NIPTE.ORG 3 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. 4. A career at FDA canprovide an amazing opportunity to learn about drug regulations, development & manufacturing while making important contributions to the society. 10/22/2014 Ajaz@NIPTE.ORG 4
  5. 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. 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 10/22/2014 Ajaz@NIPTE.ORG 6
  7. 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’ 10/22/2014 Ajaz@NIPTE.ORG 7
  8. 8. 10/22/2014 Ajaz@NIPTE.ORG 8 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
  9. 9. 10/22/2014 Ajaz@NIPTE.ORG 9 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. 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. 11. Preconditions to malice or disregard 10/22/2014 Ajaz@NIPTE.ORG 11
  12. 12. 10/22/2014 Ajaz@NIPTE.ORG 12 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)
  13. 13. 10/22/2014 Ajaz@NIPTE.ORG 13 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. 14. Root-cause may be upstream! Satisfy reviewer requirementsThrow-over the wallThen just do it … 10/22/2014 Ajaz@NIPTE.ORG 14 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! “Throw-over the wall” “Satisfy Reviewer Requirements”
  15. 15. 10/22/2014 Ajaz@NIPTE.ORG 15 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).
  16. 16. 10/22/2014 Ajaz@NIPTE.ORG 16 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 Integrated Framework: Culture of Quality
  17. 17. 10/22/2014 Ajaz@NIPTE.ORG 17 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. 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. 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 10/22/2014 Ajaz@NIPTE.ORG 19
  20. 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. 10/22/2014 Ajaz@NIPTE.ORG 20
  21. 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 10/22/2014 Ajaz@NIPTE.ORG 21
  22. 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. 10/22/2014 Ajaz@NIPTE.ORG 22
  23. 23. 10/22/2014 Ajaz@NIPTE.ORG 23 Why adhesive performance is a critical quality attribute for all TDS? Why was/is this not adequately recognized?
  24. 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) 10/22/2014 Ajaz@NIPTE.ORG 24
  25. 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. 10/22/2014 Ajaz@NIPTE.ORG 25
  26. 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.” 10/22/2014 Ajaz@NIPTE.ORG 26
  27. 27. 10/22/2014 Ajaz@NIPTE.ORG 27 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.
  28. 28. 10/22/2014 Ajaz@NIPTE.ORG 28 •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. 29. A useful tool 10/22/2014 Ajaz@NIPTE.ORG 29
  30. 30. 10/22/2014 Ajaz@NIPTE.ORG 30 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
  31. 31. 10/22/2014 Ajaz@NIPTE.ORG 31 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 Integrated Framework: Culture of Quality
  32. 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. 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- 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. BehavioralEconomicsHealth.htm Argumentation and Behavioral economics 10/22/2014 Ajaz@NIPTE.ORG 32