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  • 1. Practical Signal ManagementRodney L. LemeryVice President of Safety and PharmacovigilanceBioPharm Systems, Inc.Sixth Annual Pacific Drug Safety SummitSeptember 20-21, 2012San Francisco, CA USA
  • 2. Disclaimer • The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to BioSoteria, Inc. or Pacific Drug Safety Summit (“PDSS”). • These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. BioSoteria, Pacific Drug Safety Summit and PDSS logo are registered trademarks or trademarks of BioSoteria, Inc. All other trademarks are the property of their respective owners.Practical Signal Management 2
  • 3. Contents • Part I: Overview of Signal Management – Common Language – Current Regulatory Environment – Proposed Signal Management Methodology • Prioritization • Evaluation – Overview of Decision Support Systems • Part II: Small Group Break-out – Description of activity – Overview of Prozac – Prioritize signals, evaluate signals, evaluate risksPractical Signal Management 3
  • 4. Part I: Overview of Signal Management Signal Prioritization and Evaluation ProcessPractical Signal Management
  • 5. Detailed Signal Management Process Signal Detection Signal PrioritizationSignal 5Evaluation
  • 6. Simplified Safety Signal Lifecycle Signal Signal Detection Prioritization Signal Evaluation CIOMS (2010, p. 9)Practical Signal Management 6
  • 7. Common Language • Prevalence – The total number of cases of a disease in a given population at a specific time • Incidence – The number of newly diagnosed cases during a specific time period • EMA – European Medicines Agency • ADR – Adverse Drug Reaction • APR – Adverse Product Reaction • ICH – International Conference on Harmonization • CIOMS – Council for International Organizations of Medical SciencesPractical Signal Management 7
  • 8. Common Language… • Two pervasive definitions (Abenhaim, Moore, & Begaud, 1999) 1. The collection and scientific evaluation of adverse drug reactions (ADR), under normal conditions of use for regulatory purpose. −Restricts the concept to regulatory Pharmacovigilance compliance only and only medicinal products. 2. Watchfulness in guarding against danger from products or providing for safety of the product −Expansive beyond just regulations and frames the construct for use in academia and the sciencesPractical Signal Management 8
  • 9. Common Language… •The application of epidemiologic techniques used to study the effects of Pharmacoepidemiology drugs in populations −First mentioned in the early 1980’s (Abenhaim, Moore, & Begaud, 1999)Practical Signal Management 9
  • 10. Exercise 1 Define the following 1. Please segregate into your terms: small group as assigned by the index card in your chair 2. Using collaborative discussion, please reach consensus for the Signal definition of the following terms: Signal Detection  “Signal”  “Signal Detection” Signal Prioritization  “Signal Prioritization”  “Signal Evaluation” Signal Evaluation 3. Nominate a single spokesperson from the group to share the definition with the larger audience.Practical Signal Management 10
  • 11. Common Language… •Much debate on the definition (we will use the following): •Information that arises from one or multiple sources, which suggests a new potentially causal association, or a new Signal aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory actions. (CIOMS, 2010 p.14)Practical Signal Management 11
  • 12. Common Language… •Much debate on the definition (we will use Signal the following): •The act of looking for and/or identifying Detection signals using event data from any source . (CIOMS, 2010 p.116)Practical Signal Management 12
  • 13. Common Language… Waller (2010, p.50) defines this as an important and controversial method of ensuring only those signals worthy of internal resources are passed into the formal evaluation process —The WHO uses a method similar to Emergency Room triage processes in hospital Signal settings to quickly evaluate the aspects of a Prioritization case that make it critical for research while placing other cases on hold until a later investigation period —The MHRA uses an analytic methodology comprised of two mathematical scores contributing to a final score that will prioritize the case —Other articles exist in the literature suggesting valid decision support methodsPractical Signal Management 13
  • 14. Common Language •The formal process of reviewing scientific data sources to refute or confirm the existence of a signal in a company product safety profile; this confirmation will elevate the signal to a potential or identified risk Signal •CIOMS VIII (2010, p. 90) indicates that Evaluation this process should be multi-faceted: 1. Collect evidence to evaluate causal link between the product and the event 2. Determine if the signal represents an identified or potential risk 3. Communicate the identified risk and to propose its further evaluation and mitigationPractical Signal Management 14
  • 15. Current Regulatory Environment… • As of July 2, 2012, the EMA has required among other things… – “All validation, prioritisation, assessment, timelines, decisions, actions, plans, reporting as well as all other key steps should be recorded and tracked systematically. Tracking systems should be used for documentation and should also include signals, for which the validation process conducted was not suggestive of a new potentially causal association, or a new aspect of a known association. All records need to be archived” (EMA, 2012).Practical Signal Management 15
  • 16. Current Regulatory Environment • In June of 2002, the US Congress reauthorized (for a second time) the Prescription Drug User Fee Act (PDUFA III) – “Specifically, FDA issued three concept papers. Each paper focused on one aspect of risk management, including • (1) conducting premarketing risk assessment • (2) developing and implementing risk minimization tools • (3) performing post marketing pharmacovigilance and pharmacoepidemiologic assessments.” (FDA, 2005)Practical Signal Management 16
  • 17. Exercise 2 1. Please segregate into your What does your small group as assigned by the index card in your chair company do to 2. Using collaborative discussion, adhere to these please discuss your response to requirements? the question to the left of this slide 3. Nominate a single spokesperson from the group to share your team’s perspective with the larger audience.Practical Signal Management 17
  • 18. Proposed Signal Management Methodology• A workflow to document the stage of the signal is important especially when dealing in large volumes of potential signalsPractical Signal Management 18
  • 19. Signal Prioritization Methodology • For our purposes we use the following method to prioritize our signals for further investigation: – Is the signal and expected event (without a change in intensity)? – Is confounding by indication likely? – Final prioritization • High – Signal should be placed into formal evaluation • Medium – Signal should be placed into formal evaluation though evaluation work can be minimized compared to High signals • Low – Signal is currently confounded by indication, expected (known) • Monitor - Requires additional information to fully appraisePractical Signal Management 19
  • 20. Proposed Signal Evaluation Methodology… • Once prioritized, formal signal evaluation must occur – CIOMS VII focuses their discussion of this effort on the importance of confirming the signal strength and using a comprehensive safety management team approach (CIOMS, 2010 p. 91) – Final evaluation categories • Verified – Signal has been confirmed using scientific sources and thus should move into a risk assessment category. • Refuted – Signal has been refuted using current epidemiologic, biologic or other scientific criteria • Monitor - Requires additional information to fully evaluatePractical Signal Management the signal 20
  • 21. Proposed Signal Evaluation Methodology… • Signal strength (S) – Degree to which we believe the ADR represents a causal relationship between the drug and the event – How common is the term? • Very Common 1:10 affected persons • Common 1:10 to 1:100 affected persons • Uncommon 1:100 to 1:1000 affected persons • Rare 1:1000 to 1:10,000 affected persons • Very Rare less than 1:10,000 affected persons – Rechallange proof? – Positive dose response? – Supporting Quality Data? – Is there a consistent trend in epidemiologic studies/literature? – Is there evidence of a class effect?Practical Signal Management 21
  • 22. Proposed Signal Evaluation Methodology… • Novelty (N) – Degree to which a signal has not been observed before or the degree to which the reporting frequency of a known ADR has changed – Is this a newly identified signal? – Is this an existing signal/term that is now increasing in frequency or intensity over time?Practical Signal Management 22
  • 23. Proposed Signal Evaluation Methodology… • Importance [clinically speaking] (I) – Degree to which such a causal relationship impacts patients’ lives or how the potential relationship is viewed by regulatory bodies/scientific/legal community – Is this signal being monitored at the behest of a regulatory agency? – Is this signal part of internal targeted surveillance efforts? – Is this signal part of an ongoing legal issue? – Is there a significant public interest or concern about the signal?Practical Signal Management 23
  • 24. Proposed Signal Evaluation Methodology… • Prevention potential (P) – Degree to which an clinical/epidemiological prevention program could be established to prevent the signal – Are there existing treatments or preventions in place for this signal? – If such a prevention is required, is it practical/likely or not?Practical Signal Management 24
  • 25. Part II: Small Group Project Signal Prioritization and Evaluation of ProzacPractical Signal Management
  • 26. Overview • Purpose: To gain experience and exposure in the practical signal prioritization and evaluation process and to practice the use of a decision support system in this analysis • Product of interest: Fluoxetine (Prozac) • Population: For any signals, assume all reporters/patients are >21 and that this is a category of ADULT sufferers of depression • Source: Routine signal detection methods of querying the FDA AERS database using a data mining queryPractical Signal Management 26
  • 27. Prozac Overview • Fluoxetine (Prozac) – This selective serotonin ( 5- hydroxytryptamine [5-HT]) reuptake inhibitor (SSRI) is used in the treatment of depression, anxiety and personality disorders (Stahl, 1998) – Inhibits the reuptake of the neurotransmitter serotonin into the presynaptic cell resulting in an increase of serotonin in the synaptic gap – It often takes several weeks for the body to adapt the brain to deal with the increased serotonin and its effect on the downstream synaptic processes • This can result in anxiety being reported in patients within the first several weeks of treatmentPractical Signal Management 27
  • 28. Mechanism of SSRI ActionPractical Signal Management 28
  • 29. Detected Signals (MedDRA PT) • Retrieved from Adversevents.com on August 28, 2012Practical Signal Management 29
  • 30. Prozac Package InsertPractical Signal Management 30
  • 31. Exercise 3 1. Please segregate into your small group as assigned by the index card in your chair 2. Please use the information on the previous several slides to Prioritize your formally prioritize the signals according to our methods signals described above and complete the following slide 3. Nominate a single spokesperson from the group to share your team’s perspective with the larger audience.Practical Signal Management 31
  • 32. Confirmed Signals • Regardless of your small group, we will assume for the next part of the exercise, that the only confirmed signal from the data above was – Completed Suicide – Suicide Ideation • Remember too that we are focusing on MDD use of Prozac so it will be important to understand the etiology and epidemiology of depression.Practical Signal Management 32
  • 33. Exercise 4 1. Please segregate into your small group as assigned by the index card in your chair 2. Please use the information on the next several slides to Evaluate your formally evaluate the signals according to our methods signals described above and complete the following slide 3. Nominate a single spokesperson from the group to share your team’s perspective with the larger audience.Practical Signal Management 33
  • 34. Small Group Project • Retrieved using Oracle Empirica Signal on August 28, 2012Practical Signal Management 34
  • 35. Small Group Project Reports of Prozac Use 45, 3% and Suicidal Issues 59, 4% • NOTE: These suspect reports 178, 10% of Fluoxetine, Fluoxetine And Olanzapine use and reports one of the following PT: • Completed suicide, Suicidal behavior, Elderly Suicidal ideation, Suicide Adult attempt Adolescent Child 1419, 83% • Retrieved using Oracle Empirica Signal on August 28, 2012Practical Signal Management 35
  • 36. Small Group Project Reports of Prozac Use and Suicidal Issues 181, 11% • NOTE: These suspect reports of Fluoxetine, Fluoxetine And Olanzapine use and reports one of the following PT: • Completed suicide, Female Suicidal behavior, 585, Suicidal ideation, Suicide 34% Male attempt 935, Unknown 55% • Retrieved using Oracle Empirica Signal on August 28, 2012Practical Signal Management 36
  • 37. Depression Co-Morbidities • Retrieved from Epoctrates.com on August 28, 2012Practical Signal Management 37
  • 38. Risk Factors for Depression • Retrieved from Epoctrates.com on August 28, 2012Practical Signal Management 38
  • 39. Epidemiology of Depression • Retrieved from Epoctrates.com on August 28, 2012Practical Signal Management 39
  • 40. Epidemiology of Depression • Retrieved from http://www.nimh.nih.gov/health/publications/the-numbers- count-mental-disorders-in- america/index.shtml#MajorDepressive on September 5, 2012Practical Signal Management 40
  • 41. Epidemiology of Suicide • Retrieved on September 5, 2012 from http://www.nimh.nih.gov/health/publications/suicide-in-the- us-statistics-and-prevention/index.shtml 41Practical Signal Management
  • 42. Epidemiology of Suicide • Retrieved on September 5, 2012 from http://www.nimh.nih.gov/health/publications/suicide-in-the-us- statistics-and-prevention/index.shtml 42Practical Signal Management
  • 43. Epidemiology of Suicide • Retrieved on September 5, 2012 from http://www.afsp.org/index.cfm?fuseaction=home.vi ewPage&page_id=04EA1254-BD31-1FA3- C549D77E6CA6AA37Practical Signal Management 43
  • 44. “Completed Suicide” Reports in other SSRI • Retrieved from Adversevents.com on August 28, 2012 44Practical Signal Management
  • 45. Class Effect of SSRI • Retrieved using Oracle Empirica Signal on August 28, 2012Practical Signal Management 45
  • 46. Class Effect of SSRI (cont.) • Retrieved using Oracle Empirica Signal on August 28, 2012Practical Signal Management 46
  • 47. Epidemiologic Study Data • (Pariente, A., Daveluy, A., Laribie`re-Be´nard,Practical Signal Management 47 A., Miremont-Salame,G., Begaud, B., and Moore, N. 2009)
  • 48. Epidemiologic Study Data• (Barbui, Esposito, and Cipriani, 2009) 48Practical Signal Management
  • 49. Epidemiologic Study Data• (Barbui, Esposito, and Cipriani, 2009) 49Practical Signal Management
  • 50. Decision Support Systems… • Given the altered regulatory environment (specifically in the EMA; for now), it is important that we focus our attention to a related field and see what might be applied from like experiences – In the world of traditional health care, billing reimbursements, legal disputes and other practice specific matters often require clinicians to justify their particular advocation for patient treatment • Tan (2010, p. 125) indicates that more and more clinicians are turning to clinical decision support systems to document the “…rationalization of the clinical decision-making process and/or justifying final choices…” (Tan)Practical Signal Management 50
  • 51. Decision Support Systems • Given the shifting regulatory environment, perhaps DSS could assist us in compliance and protect our organizations from litigation • I propose the use of such systems (or their equivalent) are mandatory given the specifics of the EMA regulations • One such system is Oracle Empirica Topics; this system empowers organizations to document and track all decisions surrounding the signal management processPractical Signal Management 51
  • 52. Exercise 5 Does your company 1. Please segregate into your use a DSS to small group as assigned by the document signal index card in your chair 2. Nominate a single management? spokesperson from the group to Enter your decisions enter your team’s signal prioritization and evaluation into into the DSS the system provided by the instructor.Practical Signal Management 52
  • 53. Conclusions • The current regulatory environment suggests the need for a comprehensive decision support system surrounding signal management • Signal management should include at least prioritization and evaluation of the signal • Prioritization is designed to minimize the resource utilization in formal signal evaluation and to quickly identify major threats to public health • Evaluation is designed to formally gather scientific evidence to confirm or refute the prioritized signal – This may be in the form of existing data or new pharmaco-epidemiologic investigations • Decision support systems can be used to Protect the organization from litigation or regulatory non-compliancePractical Signal Management 53
  • 54. References • Barbui, C., Esposito, E., Cipriani, A. (2009). Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies. Canadian Medical Association 180(3) • Bennett Levitan, B., Yee, C. L., Russo,L., Bayney, R., Thomas, A. P. and Klincewicz, S. L.. (2008). A Model for Decision Support in Signal Triage. Drug Safety. 31 (9), pp. 727-735 • Council for International Organizations of Medical Sciences (CIOMS). (2010). Practical Aspects of Signal Detection in Pharmacovigilance. Report of CIOMS Working Group VIII, Geneva . • EMA. (2012). Guideline on good pharmacovigilance practices. Retrieved from http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2 012/06/WC500129138.pdf on September 10, 2012 • FDA. (2005). Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. Retrieved from http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf on September 10, 2012 • Heeley E, Waller P, and Moseley J. (2005). Testing and implementing signal impact analysis in a regulatory setting: results of a pilot study. Drug Safety 28 (10), pp. 901-6Practical Signal Management 54
  • 55. References • Pariente,A., Daveluy, A., Laribie`re-Be´nard, A., Miremont-Salame,G., Begaud, B., and Moore, N. (2009). Effect of Date of Drug Marketing on Disproportionality Measures in Pharmacovigilance; The Example of Suicide with SSRIs Using Data From theUKMHRA. Drug Safety 32 (5): 441-447 • Power, D. J and Sharda, R. (2009). Springer Handbook of Automation. Springer Berlin Heidelberg. pp. 1539-1548 • Strengthening Pharmaceutical Systems [SPS], (2009). Supporting Pharmacovigilance in Developing Countries: The Systems Perspective. Submitted to the U.S. Agency for International Development by the SPS Program. Arlington, VA: Management Sciences for Health. Retrieved from http://www.msh.org/projects/sps/SPS-Documents/upload/SPS_PV_Paper.pdf on August 20, 2012 • Tan, J. (2010). Adaptive Health Management Information Systems. Jones and Bartlett Publishers, Sudbury MA, USA • Waller P, Heeley E, and Moseley J. (2005). Impact analysis of signals detected from spontaneous adverse drug reaction reporting. Drug Safety 28 (1), pp. 843-50 • Waller P, Lee E. (1999). Responding to drug safety issues. Pharmacoepidemiology and Drug Safety 8 (7), pp. 535-52 • Waller, P. (2010). An Introduction to Pharmacovigilance. Wiley-Blackwell. Oxford, UKPractical Signal Management 55
  • 56. Contact Rodney has over 15 years experience in clinical research including laboratory experimentation, clinical data management, clinical trial design, dictionary coding and safety management/pharmacovigilance. Rodney has worked for BioPharm Systems for eleven years now serving in a variety of roles all related to the technical and/or clinical implementations of software systems used in the clinical trial process. Prior to coming to BioPharm Systems Rodney worked at pharmaceutical and technology companies in the Dictionary Coding, Statistical Programming and Data Management areas. In addition to his current work at BioPharm Systems, Rodney holds an Associate faculty position at Walden University teaching Public Health Informatics and disease surveillance courses. Rodney holds a Bachelor of Science in Genetic Engineering, a Masters of Public Health in International Epidemiology and a Ph.D. in Epidemiology focusing on Social EpidemiologyPractical Signal Management 56