ISPOR Risk Management Special Interest Group - A Plan For Action

By Dennis W. Raisch PhD, ISPOR Risk Management Special Interest Group (SIG) Chair & Associate Director, VA Cooperative Studies Program, Clinical Research Pharmacy, Albuquerque, NM, USA; Larry Liu MD, PhD, Director, Anti-Infectives US Outcomes Research, Pfizer, New York, NY, USA; Anthony Lockett MD, PhD, ICO, Leeds, W. Yorkshire, UK; Suellen Curkendall PhD, Principal Investigator, Cerner Health Insights, Vienna, VA, USA; and Ateequr Rahman PhD, Assistant Professor, College of Pharmacy, Shenandoah University, Winchester, Virginia, USA

Introduction In the wake of revelations of serious adverse reactions associated with specific drug products (e.g. cyclo-oxygenase-2 inhibitors, troglitazone, cerivastatin, fluoxetine) [1-7], there has been heightened interest in risk management of pharmaceuticals and other health care interventions. Even in cases where black box warnings or withdrawals have been implemented in the US, there remains controversy [8-13]. In March 2005, the Food and Drug Administration finalized new guidelines for risk management, which incorporate the balance of risk and benefit, as well as specifics for development of risk minimization action plans. Similar guidelines have followed in Europe with the ‘Heads of Agreement’ document (http://heads.medagencies.org/heads/docs/ HMA_2ndreport_20050511.pdf) that aims to minimize risk. These changes have stimulated the ISPOR Risk Management Special Interest Group (RM SIG) to identify and assess key issues regarding aspects of risk/benefit management. The RM SIG leadership group identified key components of the risk management process as given in Figure 1. The three key processes were identified: 1) assessment of risk and benefit; 2) development and implementation of interventions to mitigate risk and enhance benefit; and 3) follow-up (i.e. review outcomes and establish standards, if necessary). Risk/benefit communication tactics and legal and regulatory issues are important to all 3 processes. Thus far, the RM SIG has formed the following the Working Groups: Risk/Benefit Assessment, Intervention/Implementation and Communications. The RM SIG Follow-up/Best Practices Working Group and the Legal/Regulatory Implications Working Group are in development. For more information about the RM SIG and its Working Groups, see: http://www.ispor.org/sigs/rm.asp.

The purpose of this article is to summarize the current status of the efforts of the RM SIG Working Groups to generate interest and feedback issues regarding risk management processes from ISPOR members. We are currently seeking leadership for the RM SIG Follow-up/Best Practices and the Legal/Regulatory Implications Working Groups.

Risk/Benefit Assessment Working Group: Assessing Risks and Benefits The risk of medical products is defined as a measure of the probability and severity of adverse affects. Risk assessment is the ability to reasonably define the distributions of potential outcomes caused by medical products in a patient population. Benefit is defined as a measure of the positive impact of a medical treatment, including clinical effectiveness; patient reported outcomes (e.g., quality of life) and economic outcomes (e.g., health care costs and worker productivity). We note that pharmaceutical benefits and risks may extend beyond FDA-approved indications. Thus, risk/benefit assessment involves measuring the types, incidence, and severity of potential adverse effects and benefits of a health care intervention throughout the product’s life cycle. This should occur in pre-clinical testing and phase I-III clinical trials, as well as post-marketing. Clearly, all risk/benefit assessment processes and results can change throughout these periods. Further, the perspective (patient, physician, managed care organization, government, caregivers, societal, or employers) as well as the context (unmet medical needs, burden of illness, severity of disease, and prevention vs. cure) directly influences risk/benefit assessment.

Balancing risks and benefits is a process that involves comparing the risk/benefit profile in published/unpublished clinical trials and data from large clinical populations, such as managed care organizations, Medicare, and United Kingdom (UK) National Health Services. It is important to consider the generalizability of this balance in regards to diversity and size of the study sample used to determine this profile.

The Risk/Benefit Assessment group has cataloged the various calculations used in this process. These include absolute risk, relative and attributable risk, odds ratios, standardized rates, risk ratios, pooled estimates of risk and benefits, life years lost or saved, and quality adjusted life years. Often meta-analysis techniques are needed to combine results from a variety of sources. Tools recently incorporated in RM are number needed to treat (NNT, patients treated to see a certain level of beneficial effect), number needed to harm (NNH, patients treated to result in 1 person harmed, for example one serious adverse event or death), and the Global Index Statistic (GIS, a calculation that groups risks as hazards and benefits as negative hazards) [14, 15].

The FDA Guidance (March 2005) on Risk Minimization Action Plans (RiskMAPS) provide basic structures of the components of RM for the pharmaceutical industry. The RiskMAPS guidance at the US government website at: http://www.fda.gov/cder/guidance/6358fnl.htm#_Toc67721187 and is summarized in Table 1.

General recommendations for ISPOR in risk/benefit assessment are: to identify and assess new technologies and methodologies for early detection of risks of health care interventions (such as drug therapy), to promote improved effectiveness of clinical trials and post-marketing surveillance in detecting and defining risk and benefit, to promote balanced attention to risks and benefits, and to develop more effective tools for assessing and balancing risks and benefits.

Intervention/Implementation Working Group: Developing and Implementing Tools to Mitigate Risk and Enhance Benefits
Risk management tools used in other industries to mitigate risk and enhance benefits were examined. These include environmental, insurance, and banking industries. These industries have rich histories and considerable experience in RM and therefore offer many lessons learned.

Among industries affected significantly by environmental concerns, it is critical to separate the functions of data collection, analysis, and interpretation from those who are key stakeholders in the results [16]. This portends to the need for RM activities to have a level of independence from stakeholders such as pharmaceutical companies, regulatory bodies, and public activist groups [17]. The environmental industry focuses on proactive approaches based on the principle that a lack of knowledge is not a reason to fail to perform a risk assessment [18. The risk assessment process in the environmental industry, therefore, takes a series of discrete steps of risk identification, hazard assessment and problem formulation prior to any attempt to manage risk [16]. Risk management in the environmental services industry is firmly grounded in decision theory with options appraisal at its core. It uses a variety of economic methods - such as risk benefit - to identify the impact of interventions that are then ranked before a monitoring process is implemented. Hence environmental risk assessment is very structured and geared to the maximisation of human well being while taking into account economic progress.

In RM within the insurance industry, it is understood that risks are primarily financial and significantly affected by adverse selection. Processes used to handle risk include the Risk Based Capital approach, Enterprise Risk Management, and reinsurance. There are case studies in RM in the insurance industry that may have implications for pharmaceuticals

Clearly, the banking industry has welldefined procedures for RM, since risks may involve huge financial losses and bank failures that have broad repercussions for the public. Thus, banks are regulated in the amount of capital they must have on hand to cover potential losses. The major method for determining the amount is a financial concept, Value at Risk (VaR) [19]. VaR is the maximum expected loss over a given time horizon at a particular level of confidence. For example, if the one-day VaR is $10 million at a 95% confidence level, it means you are 95% confident that the maximum amount a particular financial institution could lose tomorrow is $10 million. In the US, the Office of the Comptroller of the Currency regulates nationally chartered banks and evaluates their risks and their risk measurement practices, using methods, such as VaR. An important feature of risk measurement in the financial industry is that risk and benefits are measured in common units - dollars - and the various stakeholders agree upon the methods of computing risk. In the pharmaceutical industry, a common standard for measuring both risks and benefits would be useful for the dialogue among stakeholders, but it has not yet emerged. Currently, different stakeholders, using different methodologies - epidemiology for risk and economics for benefits, usually compute risks and benefits

In the case of prescription pharmaceuticals in the US, traditional methods used to mitigate risk include incorporating warnings, contraindications, black box warnings in the drug label; changing the label when a new risk is identified; distributing “Dear Doctor/Health Practitioner” letters; restricting distribution to approved sites; and withdrawing a product from the market. Proposed interventions include modifying standards of approval, new label models, Med Guides (based on FDAMA), special advertising, formal risk management plans (e.g. informed consent, restrictions) and mandatory monitoring, including registries such as those for isotretinoin and thalidomide.

Implementation of risk management for health care interventions is a broad discipline, with much to learn from other areas, including economics, finance and psychology. ISPOR is positioned to take the lead in developing strategies that minimize risk, as many of its foundations lie in options appraisal, while maximizing benefit, because of stakeholders involved and experience with modeling techniques.

Risk Management Followup/ Best Practices Working Group: Follow-up and Establishing Best Practices
As with any technique aimed at quality improvement, follow-up is needed to monitor and assess the impact of RM strategies. However, the method of follow up - for example by audit and registry - is linked to the methods used to regulate the industry Furthermore, the ultimate outcome of RM strategy is to establish best practices not only for use of health care interventions, but also for the process of RM. Standards are well defined within the environmental and banking industries, but perhaps due to the diversity in disease management, it is difficult to establish such standards in health care. The last two steps in the FDA’s guidance on RiskMAPs (Table 1) are: to measure performance of the RM process in terms of behavior and knowledge of stakeholders and health outcomes and to reassess requirements and redesign RiskMAPs during the product’s lifecycle. The goal for this Working Group will involve reviewing follow-up strategies currently employed in the health care industry, identifying successes and failures, and making recommendations to improve this process in health care RM. A key consideration is the balance between risk and benefit to assure that appropriate treatment is provided to the right patients and optimal health outcomes are achieved. Volunteers are sought for this effort.

Communications Working Group: Risk/Benefit Communication
Risk/benefit communication in health care is an interactive process of exchange of information involving media, literature, and advertisement of risk and benefit of health care products among stakeholders, patients, medical care providers, and payers. A key factor is that risk benefit communication involves low trust-high concern situations. Therefore in uncertain and high risk situations, building trust and credibility between various stakeholders is a critical aspect of the risk/benefit communication plan [20, 21].

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, solution-oriented, and collaborative. It is important to plan carefully and evaluate communication performance, keeping in mind those different goals, audiences, and media require different communication strategies. Risk communication within comprehensive risk management programs may be inhibited by privacy legislation, such as the Health Insurance Portability and Accountability Act. Direct-to-consumer advertising may significantly influence risk benefit communication to stakeholders. Credible, neutral sources of information can help to improve the ability to communicate effectively. Public assessment of how much information sources can be trusted and believed is based upon four factors: empathy and caring, competence and expertise, honesty and openness, and dedication and commitment.

Trust and credibility are difficult to achieve; if lost, they are even more difficult to regain [22]. Few things damage credibility more than conflicts and disagreements among information sources. Irrelevant or misleading comparisons can harm trust and credibility [23]. One must know what messages are being delivered by the media to the audiences you wish to reach. It can be helpful to participate in formulating risk benefit messages for the media to deliver.

Some specific risk benefit communication tools include educational outreach. These include physician letters, training programs for health providers and patients; medication guides, reminder systems, forms (e.g., patient agreements or acknowledgement forms), and certification programs for health care professionals. Stakeholders judge the credibility of communication largely by how it addresses personal knowledge. It is important to give a full accounting, both favorable and unfavorable aspects. Although the package insert is one of the most common tools used in the pharmaceutical industry, it can become a barrier to effective risk communication, serving more as a legal document rather than a resource of useful information for health care providers. User-friendlier package information, with simplified information and highlights of prescribing information may be more effective. Furthermore, the package insert, combined with effective post-marketing surveillance, and optimal utilization of media may constitute the risk communication plan for drug and biologic products. The FDA’s structured product label (SPL) is designed to improve health care through making medical information, including risks and benefits, more accessible to stakeholders (http:// www.fda.gov/cder/guidance/6719fnl.doc).

Since stakeholders respond differently to specific risk issues in health care including new technologies, products, or regulations, ISPOR should develop strategies to enhance trust and minimize conflict over risk benefit issues or policies responsive to the various stakeholders’ risk concerns. ISPOR should identify methods for providing health care risk communication proactively.

Legal Regulatory Working Group: Legal/Regulatory Implications
The RM process in health care transpires within a highly regulated environment with a multitude of legal concerns. As the RM-SIG working groups evolve and move closer to their end products, there is a need to outline and address this aspect of RM. The goal for this working group includes describing how the legal/regulatory environment augments or impedes the effectiveness of RM.

Summary
As outlined above, the ISPOR Risk Management SIG has developed a plan for action for ISPOR for risk benefit management of health care interventions. If you are interested in participating on a RM SIG Working Group, email: rmsig@ispor.org.

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