Risk Management Process. Plan for the Workshop. Risk/Benefit Assessment Working Group. Topics of Interest. Objectives

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1 Risk Management Process BALANCING RISKS AND BENEFITS OF HEALTH CARE TREATMENTS IN THE 21 ST CENTURY Communication (Creating balanced perceptions of risk/benefit) Assessment of Potential Risk Intervention and Implementation Legal and Regulatory Issues Members: Dennis Raisch, Anthony Lockett, Larry Liu, Nick Lipskiy, Ateequr Rahman, Paul Stang Follow-up (Establishing standards) 1 2 Plan for the Workshop Leaders of each subgroup will present the overview of their White Paper Focused, participative, i small group discussion of a case scenario Open forum for discussion of case and White Papers Risk/Benefit Assessment Working Group Members: Larry Liu, MD, PhD, Pfizer Inc., Co-chair Nick Lipskiy, MS, MBA, DrPH, CDC, Co-chair Lynda Bryant-Comstock, Fanny Ki, PhD, Leslie Wilson, PhD 3 ISPOR Annual Conference, May 16, Objectives Evaluate methods/tools on identifying and assessing risk & benefits Develop a framework on how to balance benefits/risk Topics of Interest Definition of risk and benefit Risk assessment Benefit assessment Benefits/risk balance Recommendation 5 6 1

2 Definition of Risk Risk is a measure of the probability and severity of adverse affects (Lowrance, 1976). Risk was defined as a situation in which the potential outcomes can be described in reasonably well-defined distributions (Haimes, 1998). Pharmaceutical risk: adverse events and drug interactions Definition of Benefit A measure of positive impact of a treatment Pharmaceutical benefits include clinical effectiveness, patient reported outcomes (e.g., QoL) and economic outcomes (e.g., healthcare costs and worker productivity) Pharmaceutical benefits may extend beyond FDA-approved indications 7 8 Risk Assessment: Consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product Occurs throughout a product s lifecycle Risk Assessment: Pre-Marketing Pre-clinical safety assessment Pharmacokinetic/Pharmacodynamics Clinical i l trials Relative small sample size Short-term exposure FDA Guidance on Premarketing Risk Assessment, March Risk Assessment: Post-Marketing Phase IV studies Pharmacovigilance Spontaneous reporting Epidemiology studies Healthcare database Registry Benefit Assessment Who s perspective? Patient, physician, MCO, government, caregivers, societal, employers What is the context? Unmet medical needs, burden of illness, severity of disease What benefits should be considered?

3 Benefit Assessment: Measures Clinical efficacy Effectiveness in real world Patient reported outcomes Worker productivity Caregiver burden Cost-effectiveness Benefit/Risk Balance: A Process not a number Compare benefit/risk profile in published/unpublished clinical trials & large clinical populations p (HMOs/Medicare) Model effects in larger, longer trials in different groups Interpret benefit/risk balance by weighing all factors Collect additional information and update as new evidence is determined Benefit/Risk Calculations: Current Risk and absolute risk, relative and attributable risk reduction, odds ratio Standardized rates Risk ratio and difference Pooled estimates of risk and benefits Benefit: outcomes, life years saved, QALYs Difference in risk/difference in benefit Meta-analysis techniques Benefit/Risk Calculations: Newer Number needed to treat (NNT): a number treated to see a beneficial effect Number needed to harm (NNH): a number treated in order for 1 person to be harmed (i.e., adverse event) Global Index Statistic: to group both risks and benefits as hazards Balance is multidimensional Risk assessment: mathematical Risk perception: fear or optimism Risk attitude: level of risk aversion or acceptance Risk Minimization Action Plans (RiskMAPS) FDA Guidance March 2005 Feature Determine need Identify benefits Set Goals RiskMAP activities Assess effectiveness Re-evaluation FDA RiskMAP Guidance Document Unusual type or level of risk of adverse event Maximize benefits to improve overall balance of risk/benefit State safety-related goals in absolute terms Interventions: Targeted education, communication, reminder systems, and performance-linked systems Evidence-based performance measures: Health outcomes, safety behaviors. Assessment of provider/patient knowledge and attitudes Requirements may change throughout product lifecycle

4 Major components of RM Risk Assessment Core definitions for the Risk Assessment: Risk Uncertainty Risk Analysis RM Risk Minimization Core definitions for the Risk Minimization (FDA, 2004): Assessing a product s benefit-risk balance Developing and implementing tools to minimize its risks while preserving its benefits Evaluating tool effectiveness and reassessing the benefit-risk balance Making adjustments, as appropriate, to the risk minimization tools to further improve the benefitrisk balance 19 Recommendations Early detection of risk using new technologies Improve clinical trials and post-marketing surveillance Give balanced attention ti to risks and benefits Develop effective tools for assessing and balancing risks and benefits Enhance ISPOR s involvement in risk management 20 References FDA Guidances on Risk Management (3 documents), March 2005 Haimes, Y.Y. Risk modeling, assessment and management. A Wiley-Interscience Publication, Marrison, C. The Fundamentals of Risk Measurement. McGraw-Hill, 2002 Risk Implementation Working Group Members: Tony Lockett, Suellen Curkendall, Wallace Marsh, Jeff J. Guo Contact Information - SIG Members Implementation Working Group Goals Name Institution Phone Tony lockett Information Alockett8@hotmail.com change Suellen Curkendall Cerner Health Insights Suellen.Curkendall@ cerner.com Wallace Marsh Jeff J. Guo, Nova Southeastern University University of Cincinnati Medical Center wmarsh@nova.edu 513) jeff. guo@uc.edu Topics Environmental risk Bankng Insurance Healthcare Recommending new areas of research Persons assigned Tony Suellen Wallace Jeff All

5 Environmental Risk Management Risks identified Range of chemical, environmental Strategies t for handling risk Evidence-based principles Proactive approaches Case studies Environmental Risk Management Applications Separation of analysis from stakeholders Need to consider the separation of roles Proactive approaches Insurance Risk Management Risks identified Financial Adverse selection Risk is handled by RBC (Risk Based Capital) ERM (Enterprise Risk Management) Reinsurance Insurance Risk Management Case Studies lessons learned from 9-11 Applications Banking Risk Management Risks identified Large financial losses Bank failure Strategies for handling risk Regulate the amount of capital banks must keep on hand to cover potential losses Major method for determining this amount is a financial concept, Value at Risk Case Studies VaR Value at Risk VaR = The maximum expected loss over a given time horizon at a particular level of confidence Eample Example: Theoneda one-day VaR is $10 million at a 95% confidence level if you are 95% confident that the maximum amount a particular trading house could lose tomorrow is $10 million. The VaR might be $25 million at a 99% confidence level

6 How the Financial Community computes VaR There are agreed-upon methods of estimating the distribution function of potential losses Build models using historical data Monte Carlo simulations Portfolio theory that rates the risk of assets based on the variance in their prices Banking Regulation The Office of the Comptroller of the Currency examines risks at banks and reviews nationally chartered US banks risk measurement practices, including VaR methods The FDIC insures bank depositors against loss of principal and uses VaR as one method to estimate the losses they may need to pay over a one year time frame The Federal Reserve examines risks at state chartered US banks Bank regulators in the developed countries cooperate to align their Risk regulation strategies through a forum called Basel II Can we learn from finance? Sources of Risk From Rx Products Benefits We have accepted methods and units for computing expected benefits - QALY Risks We have accepted methods for computing incidence of adverse events and risk ratios Would our drug approval process be more efficient if we could compute risks and benefits in the same units, such as expected QALY gained and QALY risked? 33 Source: FDA, Pharmacovigilance Practices and Pharmacoepidemiologic Assessment FDA It is post-marketing risk management process to identify and monitor suspected adverse events that are not identified during development and premarketing review. Safety signal identification Pharmacoepidemiologic assessment and safety signal interpretation, and Pharmacovigilance plan development. Reference: FDA. Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Drug Safety & Surveillance Program FDA Multidisciplinary method to document, monitor and evaluate ADEs, and plan interventions. Applies to the life of a drug (IND, NDA, postmarketing, and removal from MKT). Incorporates epidemiologic methodology to monitor drug use and effects in population using modern tools, such as, Spontaneous Reporting System, automated clinical data

7 Traditional Interventions Labeling changes Warnings, contraindications, boxes. Education Dear Doctor Letter, Dear Health Practitioner (Pharmacists) Letters Restricted Distribution Withdrawal Potential Interventions Modify standards of approval New Label models Patient inserts/medguides (based on FDAMA) Special Advertising Formal risk management plan (e.g. informed consent, restrictions) Mandatory Monitoring Registries (e.g. Accutane, Thalidomide) Methodology of Risk Management in Drug Safety & Surveillance Case reports/case series Case-control study Cohort study Meta-analysis Causal analysis (Randomized Clinical Trials) The EU response ICH E2E Requirements for Pharmacovigilance specifications Pharmacovigilance plans Specification Summary of risks Important potential risks Missing information Preclinical Populations Plan Summary of pharmacoviglance practices Methods of monitoring Signal detection ti Organization and practices Evaluation signal detection and reporting

8 Differences FDA preventative EU reactive - emphasis on audit Previous Lessons Vioxx (Cox2 inhibitor) case story Cisapride case story Troglization case story Other case stories Messages for ISPOR The implementation of risk management is a broad discipline Much can be learned from other areas Economics, psychology, ISPOR positioned to take the lead Stakeholders Modeling Should ISPOR form a policy advisory group References Dowd, K. Beyond Value at Risk. John Wiley & Sons, Paustenbach DJ Human and ecological l risk assessment Wiley 2003 ICH E2 guidelines FDA guidance documents Risk Benefit Communication Group Ateequr Rahman MBA, PhD, Paul Stang MS, PhD, Ole Hauch MD, Peter Malamis MBA, Louis Morris PhD, Harry Smolen MS, Dennis Raisch, PhD Working Group Objectives 1. To identify the different sources of information that is used by individuals and other stakeholders to shape perceptions regarding health benefits and risks. 2. To review the effectiveness of different forms of information in shaping and changing risk and benefit perceptions

9 Working Group Objectives 3. To suggest improvement of risk and benefit communication among various stakeholder groups in order to enhance risk perception and management. Definition of Risk Communication An interactive process of exchange of information involving media, literature, and advertisement of risk and benefit among individuals, groups, and institutions Risk Communication Concerns Risk benefit communication involves low trust-high concern situations. Building trust and credibility between various stakeholders is a critical aspect of the risk benefit communication process. Information Sharing What are the most effective methods of informing health system decision makers about the balance of risk and benefit of therapeutics? Privacy Concerns What is the impact of privacy legislation (Such as HIPAA) on the ability to conduct risk management programs? What is the Influence of direct to consumer advertising on risk benefit communication to stakeholders. Risk Benefit Communication Tools Accept and involve the recipient of information as a Legitimate Partner. The goal of risk benefit communication is not necessarily to diffuse concern or to avoid action. Instead, it is to produce an involved, informed recipient of information that is interested, thoughtful, solutionoriented, and collaborative

10 Risk Benefit Communication Tools Plan Carefully and Evaluate Communication Performance. Different goals, audiences, and media require different communication strategies. 55 Risk Benefit Communication Tools Coordinate and Collaborate with other Credible Sources. Credible, neutral sources of information can help communicate effectively. Few things hurt credibility more than conflicts and disagreements among information sources. 56 Risk Benefit Communication Tools Plan for Media Influence. It is important to know what messages are being delivered by the media to the audiences you wish to reach as well as to participate in formulating messages for delivery through the media on topics of interest to your audiences. Risk Benefit Communication Tools Targeted education and outreach (e.g., physician letters Training gprograms for physicians or patients; medication guides) Reminder system Processes or forms (e.g., patient agreements or acknowledgement forms) Certification programs for health care professionals Package Insert Package insert has become a barrier to effective risk communication, serving more as a legal document rather than a resource of useful information for practicing physicians. User friendly package information with simplified, information and Highlights of Prescribing Information would be helpful. Risk Benefit Communication Strategy The package insert, combined with effective post-marketing surveillance, and optimal utilization of media should constitute the risk communication plan for the vast majority of drug and biologic products

11 Message for ISPOR Understand the likely responses of various audiences to specific risk issues in health care, including new technologies, products, or regulations. Craft organizational policies responsive to various stakeholders risk concerns. Develop strategies to enhance trust and minimize conflict over risk issues. Understand ways to deal with healthcare risk communication proactively. 61 References html alth_risk_communication.html ment/superfund_communication.htm 62 Focused, Participative, Small Group Discussion of a Case Scenario 63 A new lifestyle drug is approved, "Paris-Tab". Clinical trials have shown that the drug speeds metabolism (so patients lose weight), and gives a warm healthy glow to the skin. It also has a slight euphoric effect. The drug is approved based upon clinical trials demonstrating effectiveness in weight loss. A total of 3,000 individuals had received the drug for a median of 3 months. Through an excellent direct-to-consumer advertising campaign, Paris-tab quickly becomes es a block-buster buste drug. After 3 months on the market, reports surface that Paris-Tab can cause cognitive impairment, resulting in an increased likelihood of poor decision-making. Estimated prevalence is 0.1%. The side effect is reversible upon discontinuance. One year later, two case reports of a fatal blood dyscrasia from Paris- Tab have been published in the literature. No patients experienced this the side effect in clinical trials. Find 3 to 5 people with the same color handout and discuss the questions on the handout. 64 Risk/Benefit Assessment Does Paris-Tab represent a worthwhile risk/benefit situation for the public? Why or why not? Discuss different risk/benefit assessment techniques. What assessment method would be best in the case of Paris-Tab? Why? What are the implications of this case regarding public policy and regulations associated with risk/benefit assessment? 65 Interventions In Risk Management In the case of Paris-Tab, whose responsibility is it to collect and report adverse event data (doctors, patients, regulators or the pharmaceutical industry)? Why? Discuss different risk mitigation interventions. What interventions would be best in the case of Paris-Tab? Why? What are the implications of this case regarding public policy and regulations associated with risk mitigation? 66 11

12 Communication of Risks and Benefits Discuss the different sources of information about Paris-Tab that might be important for stakeholders in shaping risk/benefit perceptions. Which sources might be more effective in shaping and changing risk/benefit perceptions regarding Paris-Tab? How might risk and benefit communication among various stakeholder groups be improved to enhance clarity of risk perception in the case of Paris-Tab? Open Forum