Pharmacovigilance: Regulators’ Perspective     on Proactive Risk Management,    Challenges & Collaborative Efforts        ...
Disclaimer• The views and opinions expressed in the following PowerPoint slides  are those of the individual presenter and...
Basics…                  Efficacy Safety                            QualityAll need to be evidenced by the regulations!
Safety Assessment During Development,   Clinical Trials & Post-Market Trials Known and Knowable
Chance to Observe SAEs through RCTsreaction Rate   Sample Size   Pr (at least 1)   Pr (at least 2)1%              500     ...
Sales and growth of US Rx market only                        Aitken M et al. (2009). Health Affairs, 28, w151-160w
Blockbusters           Aitken M et al. (2009). Health Affairs, 28, w151-160w
Statins Rx             Aitken M et al. (2009). Health Affairs, 28, w151-160w
Price patterns of regulated vs.   non-regulated countries                  Stremersch et al. (2009). Marketing Science, 28...
Sponsors                       Regulatorslaunch the   Time Constraint    safety & product                        efficacy ...
Erice declaration 1997 on PV transparency• Drug safety information must serve the health of the public• Education in the a...
Erice manifesto of 2007 on continuing    development ond usefulness of science in PV•   The Erice Manifesto specifies the ...
A high impact article•Waller PC, Evans SJ. A model for the future conductof pharmacovigilance.   • Pharmacoepidemiol Drug ...
Number of reports received (solid bars) andentered (checkered bars) into AERS of US FDA
Waller & Evans Model1. Known problems    i. Known problem but unknown rate &        possibly risk factors are unknown    i...
Vioxx lessons
Regulators’ Perspective: India• The Central Drugs Standard Control Organization (CDSCO): National  Pharmacovigilance Progr...
India: Current Safety Reporting Standards   • Clinical Trial        SUSARS within 14 calendar days        In practice ca...
Regulators’ Perspective: EU• EMEA: European Risk Management Strategy…2007   – Systematic implementation of risk management...
Regulators’ Perspective: EU      Improve PV                     Strengthen safety       operations           EU       moni...
Regulators’ Perspective: US FDA•The FDA Amendment Act, 2007 (FDAAA)   • now authorizes FDA to significantly increase the u...
Regulators’ Perspective: US FDA One reason drugs may be used for years before risks become evident is that we have no acti...
Risk management plans• RMPs are to “decrease product risk  by using one or more interventions or  tools …”.• consider how ...
Elements of Risk management plans  •   FDA Guideline  •   RMP Elements  •   Learning about and interpreting a products    ...
Risk identifying & management strategies1. Review the project wrt risk and issue management2. Establish the approach to ef...
Risk identifying strategies: specific• Factors Suggestive of a Possible Adverse Drug Reaction:   – Unlikeliness of event i...
Risk analysis1.   Define the criteria that will be used to classify each risk     and issue.2.   Identify the product, pro...
Data-mining and signal detection protocol        Collection of ICSRs from CADRMP                                  or any c...
Casestudy example: Propranolol-bradycardia• PRR = 2.51                                                            Not     ...
Industry-industry & industry-FDA           collaboration, e.g.,•   Collaboration among Eli Lilly and Company, Pfizer Inc.,...
IT: Industry-agency PV networks
Conditional approvals• For drugs treating seriously debilitating or life-  threatening diseases, conditional approvals (fo...
RMP – in a nutshell• What risks are involved? – Identification• What impacts do the risks have? – Evaluation• How do we ma...
Thank You Very Much
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Pharmacovigilance: Regulators’ Perspective on Proactive Risk Management, Challenges & Collaborative Efforts with Pharma Companies

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The prescription drug sales have been growing globally at a rate of 12-20%, which is lucrative by any standards, especially when top companies’ total sales are approaching 25-40 billion USD a year. Such market forces create tremendous pressure on one side on the drug sponsors to launch their product as early as possible, and on the other hand on the significantly regulators to decide on the product safety for approval with a tremendous time constraint. In such a scenario, drug regulatory authorities in US, Europe and elsewhere have renewed their mandate to fortify the “safety” regulations so that the drugs released to the market are highly safe and effective. The FDA Amendment Act, 2007 (FDAAA) have now authorized FDA to significantly increase the user fees for safety initiatives and evaluations. The FDA initiatives include its authority to ask from a drug sponsor a Risk and Evaluation Mitigation Strategy (REMS) with a detailed risk minimization action plan. FDA can now require the sponsor to develop a comprehensive safety surveillance system as well. For each new drug, FDA will now also establish an internal committee for a safe use of this drug in pediatric population. Similar approaches and authorities have also been given to European drug regulatory agencies.

This presentation will take you through the current proactive risk management approaches used or proposed by the prominent regulatory agencies for both pre- and post- market safety surveillance of new drug and new drug products. It will also discuss the challenges and collaborative efforts of both regulators and industry to work with a multidisciplinary safety management system to identify and assess the risk signals as early as possible in drug development process. Further it will discuss the reporting and evaluation of this data such that it helps pre-market approval of the safest possible product and a transparent post-market surveillance plan.

Published in: Health & Medicine

Pharmacovigilance: Regulators’ Perspective on Proactive Risk Management, Challenges & Collaborative Efforts with Pharma Companies

  1. 1. Pharmacovigilance: Regulators’ Perspective on Proactive Risk Management, Challenges & Collaborative Efforts with Pharma Companies • Dr. Bhaswat S. Chakraborty • Senior Vice President, R&D • Cadila Pharmaceuticals Ltd.
  2. 2. Disclaimer• The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.• Specifically, the opinions presented in talk are not an official position of any Regulatory Agency.• These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.
  3. 3. Basics… Efficacy Safety QualityAll need to be evidenced by the regulations!
  4. 4. Safety Assessment During Development, Clinical Trials & Post-Market Trials Known and Knowable
  5. 5. Chance to Observe SAEs through RCTsreaction Rate Sample Size Pr (at least 1) Pr (at least 2)1% 500 0.993 0.9600.5% 500 0.918 0.713 1000 0.993 0.9600.1% 1500 0.777 0.442 3000 0.950 0.8010.01% 6000 0.451 0.122 10000 0.632 0.264 20000 0.865 0.594
  6. 6. Sales and growth of US Rx market only Aitken M et al. (2009). Health Affairs, 28, w151-160w
  7. 7. Blockbusters Aitken M et al. (2009). Health Affairs, 28, w151-160w
  8. 8. Statins Rx Aitken M et al. (2009). Health Affairs, 28, w151-160w
  9. 9. Price patterns of regulated vs. non-regulated countries Stremersch et al. (2009). Marketing Science, 28, 690–708
  10. 10. Sponsors Regulatorslaunch the Time Constraint safety & product efficacy approval
  11. 11. Erice declaration 1997 on PV transparency• Drug safety information must serve the health of the public• Education in the appropriate use of drugs, including interpretation of safety information, is essential for the public at large, as well as for health care providers• All the evidence needed to assess and understand risks and benefits must be openly available• Every country needs a system with independent expertise to ensure that safety information on all available drugs is adequately collected, impartially evaluated and made accessible to all• Innovation in drug safety monitoring needs to ensure that emerging problems are promptly recognised and efficiently dealt with, and that information and solutions are effectively communicated
  12. 12. Erice manifesto of 2007 on continuing development ond usefulness of science in PV• The Erice Manifesto specifies the challenges which must be addressed to ensure the continuing development and usefulness of the science. In particular:• The active involvement of patients and the public in the core debate about the risks and benefits of medicines, and in decisions about their own treatment and health• The development of new ways of collecting, analysing and communicating information about the safety and effectiveness of medicines; open discussion about it and the decisions which arise from it• The pursuit of learning from other disciplines about how phamacovigilance methods can be improved, alongside wide-ranging professional, official and public collaboration• The creation of purposeful, coordinated, worldwide support amongst politicians, officials, scientists, clinicians, patients and the general public, based on the demonstrable benefits of pharmacovigilance to public health and patient safety
  13. 13. A high impact article•Waller PC, Evans SJ. A model for the future conductof pharmacovigilance. • Pharmacoepidemiol Drug Saf. 2003;12:17-29.•Pharmacovigilance should be less focussedon finding harm and more on extendingknowledge of safety
  14. 14. Number of reports received (solid bars) andentered (checkered bars) into AERS of US FDA
  15. 15. Waller & Evans Model1. Known problems i. Known problem but unknown rate & possibly risk factors are unknown ii. Potential but not actually known to occur Risk Management2. Unknown –any possible AE i. “Data mining” in medical record/clinical databases ii. Spontaneous reporting Data mining for Signal Detection
  16. 16. Vioxx lessons
  17. 17. Regulators’ Perspective: India• The Central Drugs Standard Control Organization (CDSCO): National Pharmacovigilance Program (NPP), 2005• A nationwide network with 25 peripheral centers, 5 regional centers, and 2 zonal centers with responsibilities as follows: • monitor the adverse drug reactions of medicines to identify unexpected adverse drug reactions • review Periodic Safety Update Reports (PSURs) submitted by pharmaceutical companies for all new chemicals drugs for 4 years • maintain contacts with international regulatory bodies • assess the regulatory information relating to safety • provide information to end-users through adverse drug reaction news bulletins, drug alerts and seminars CDSCO official website http://cdsco.nic.in
  18. 18. India: Current Safety Reporting Standards • Clinical Trial  SUSARS within 14 calendar days  In practice can propose reporting (aligned with EMEA or FDA) • Postmarketing  No reporting for generics  PSURs 30 days after data lockBut with the implementation of patent laws and possibility of new drugdiscovery, India needs a comprehensive risk management andpostmarketing PV now!
  19. 19. Regulators’ Perspective: EU• EMEA: European Risk Management Strategy…2007 – Systematic implementation of risk management plans – Strengthening the spontaneous reporting scheme through improvements of the EudraVigilance database – Launching the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) project to strengthen the monitoring of medicinal products – The conduct of multi-centre post authorisation safety studies – Strengthening the organisation and the operation of the EU Pharmacovigilance system
  20. 20. Regulators’ Perspective: EU Improve PV Strengthen safety operations EU monitoring science• EC Enterprise & Indurty DG: Strategy to better …PV 2007 – fast and robust decision-making on safety issues – clarification of roles and responsibilities for industry and regulators – strengthening of the role of risk-management planning – improvement of the quality if of non-interventional safety studies – Simplification of ADR reporting Harmak et al. (2008). Eur J Clin Pharmacol, 64, 743-752
  21. 21. Regulators’ Perspective: US FDA•The FDA Amendment Act, 2007 (FDAAA) • now authorizes FDA to significantly increase the user fees for safety initiatives and evaluations. • other initiatives include its authority to ask from a drug sponsor a Risk and Evaluation Mitigation Strategy (REMS) with a detailed risk minimization action plan • FDA can now require the sponsor to develop a comprehensive safety surveillance system as well • for each new drug, FDA will now also establish an internal committee for a safe use of this drug in pediatric population.
  22. 22. Regulators’ Perspective: US FDA One reason drugs may be used for years before risks become evident is that we have no active drug-surveillance system Dr. Mark McClellan, Former USFDA Commissioner• Risk Management Programs (RMP) • RMP identifies the possible risks (and benefits) associated with a product or with the process used to develop, manufacture, and distribute the product. The following questions should be asked at each stage of the product’s life cycle:  What are the safety risks?  Who is at the highest risk?  What populations are at risk?  Are the risks predictable?  Are the risks preventable?
  23. 23. Risk management plans• RMPs are to “decrease product risk by using one or more interventions or tools …”.• consider how to minimize risks from the product’s use• encompasses all efforts by a sponsor to minimize the risk from its product’s use and may include product labeling, risk• assessment, pharmacovigilance, and special studies or interventions.• product labeling (i.e. the package insert or PI) alone is not always sufficient to minimize a product’s risk, therefore, FDA proposes that sponsors submit a risk management program (RMP)
  24. 24. Elements of Risk management plans • FDA Guideline • RMP Elements • Learning about and interpreting a products benefits and risks • Risk and Issue Management Strategy • Risk Identification Technique • Risk Evaluation Technique • Designing and Implementing Interventions • Risk Response Planning • Risk and Issue Management Plan • Evaluating and Revising Interventions • Risk and Issue Management Plan Fujitsu consulting
  25. 25. Risk identifying & management strategies1. Review the project wrt risk and issue management2. Establish the approach to effectively manage the risks and issues (what, who, when, how).3. Define the approaches including the documentation structure that will be used for the initial identification of the risks and issues.4. Determine the notification process and the way to document the risks and issues.5. Establish the escalation process that will be used to obtain decisions on major risk or issue situations.6. Identify the management areas under which risks and issues can be raised (e.g., relationship with the end user, third party contract organizations, product pre / post market surveillance, internal Corrective and Preventive Actions (CAPA), etc.).7. Identify the personnel and experts for each management area. Fujitsu consulting
  26. 26. Risk identifying strategies: specific• Factors Suggestive of a Possible Adverse Drug Reaction: – Unlikeliness of event in a given patient or disease state – Absence of prodromal signs or symptoms of the adverse event before drug exposure – Consistency with drug pharmacology and typical onset pattern of injury (e.g., allergic reactions within days after therapy, cancer after years of therapy) – Recurrence of event with reintroduction of drug (rechallenge) – Abatement with discontinuation of drug (dechallenge) – Known relationship to underlying mechanism of drug action – Similarity to adverse reactions seen with related drug products – Related toxicity seen in vitro or in studies in animals Trontell A. (2004). NJEM, 351, 1385-1387
  27. 27. Risk analysis1. Define the criteria that will be used to classify each risk and issue.2. Identify the product, process, or program areas that might be impacted by a risk or a problem.3. Define the criteria that will be used to evaluate the impact of arisk or a problem. These criteria are defined for each project area that can be impacted by a risk or a problem and for each level of impact (low to high).4. Create the Risk and Problem Impact Evaluation Table that will be used to determine the potential impact of a risk or a problem.5. Define the Risk Severity Matrix that will be used to determine how much a risk can threaten the product, process, or program. Review the Risk and Issue Management Plan and obtain approval from the stakeholders.6. Make any necessary corrections to the plan, according to comments received. Fujitsu consulting7. Communicate the projects Risk and Issue Management Plan to all interested parties.
  28. 28. Data-mining and signal detection protocol Collection of ICSRs from CADRMP or any comprehensive database Conversion of free text to structured information Data cleaning and duplicate detection Applying quantitative or statistical methods Computing an accurate measure for SD Gavali, Kulkarni, Kumar and Chakraborty (2009), Ind J Pharmacol, 41, 162-166
  29. 29. Casestudy example: Propranolol-bradycardia• PRR = 2.51 Not Bradycardia Bradycardia• ROR = 2.58 Casestudy Example: Propranolol-82 Propranolol HCL 4• χ2 = 3.26 Bradycardia 52 Not Propranolol 2749 HCL• Therefore, bradycardia is not a significant disproportional signal (Serious Adverse Event) associated with Propranolol Gavali, Kulkarni, Kumar and Chakraborty (2009), Ind J Pharmacol, 41, 162-166
  30. 30. Industry-industry & industry-FDA collaboration, e.g.,• Collaboration among Eli Lilly and Company, Pfizer Inc., Johnson & Johnson Health Care Systems, Inc. and two community–based initiatives with rich data sources – Supported and coordinated by eHealth Initiative Foundation (multi- stakeholder non-profit organization with focus at both the national and community levels) – Overall Purpose: To test and evaluate the feasibility of using clinical information at the community level for a set of safety activities• Data management consortia, e.g., CDISC• FDA
  31. 31. IT: Industry-agency PV networks
  32. 32. Conditional approvals• For drugs treating seriously debilitating or life- threatening diseases, conditional approvals (for 1 year) are possible when – A positive risk–benefit balance of the product – Likeliness that the applicant will be in a position to provide the comprehensive clinical data – Unmet medical needs being fulfilled – The benefit of the immediate availability of the medicinal product to public health outweighing the risk inherent in the absence of additional data Harmak et al. (2008). Eur J Clin Pharmacol, 64, 743-752
  33. 33. RMP – in a nutshell• What risks are involved? – Identification• What impacts do the risks have? – Evaluation• How do we manage the risks to keep them within acceptable levels? – MitigationAll regulatory agencies now are seriously interested in aproactive risk evaluation and mitigation (REMP) plan
  34. 34. Thank You Very Much

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