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Home , Pharmacovigilance, Risk factor

Unlocking the power of * An adaptive approach to an evolving safety environment

PricewaterhouseCoopers’ Research Institute

Contents

Executive summary 01 Background 02 The challenge to the 02 Increased media scrutiny 02 Greater regulatory and legislative scrutiny 04 Investment in pharmacovigilance 05 The reactive nature of pharmacovigilance 06 Unlocking the power of pharmacovigilance 07 Organizational alignment 07 Operations management 07 Data management 08 management 10 The three strategies of effective pharmacovigilance 11 Strategy 1: Align and clarify roles, responsibilities, and communications 12 Strategy 2: Standardize pharmacovigilance processes and data management 14 Strategy 3: Implement proactive risk minimization 20 Conclusion 23 Endnotes 24 Glossary 25

Executive summary

The idea that controlled clinical incapable of addressing shifts in 2. Standardize pharmacovigilance trials can establish product safety public expectations and regulatory processes and data management and effectiveness is a core principle and media scrutiny. This reality has • Align operational activities across of the pharmaceutical industry. revealed issues in the four areas departments and across sites Neither the clinical trials process involved in operations: • Implement process-driven standard nor the approval procedures of the organizational alignment, operations operating procedures, work U.S. Food and Drug Administration management, data management, and instructions, and training materials (FDA), however, can provide a perfect . • Integrate safety data through guarantee of safety for all potential data and system interoperability consumers under all circumstances. When appropriately aligned and standards Despite this fact, there are viable supported, these areas can work • Implement workflow management solutions that pharmaceutical together to enable a flexible, technology to ensure appropriate companies can implement to support adaptable, and proactive system transparency and accessibility of pharmacovigilance—the systematic for addressing patient safety safety information detection, assessment, understanding issues. Companies can unlock the • Select a vendor that best matches and prevention of adverse drug power of their pharmacovigilance the pharmacovigilance operating reactions. When built into existing activities by creating an operational model, business process and research and development practices, framework that supports the key vendor/system selection criteria pharmacovigilance activities can patient safety infrastructures. The enhance patient safety while reducing following are recommendations for 3. Implement proactive risk or even preventing costly safety- companies developing an adaptive minimization related withdrawals. pharmacovigilance framework: • Develop risk management action plans based on pre-established risk Currently, however, pharmaceutical 1. Align and clarify roles, scoring mitigation processes executives face a number of challenges responsibilities, and communications • Implement data mining techniques in the area of pharmacovigilance. In • Develop an objective, data-driven, to bolster safety analytics, reporting, the four decades from the team-based approach to risk and investigation tragedy to the recent concerns monitoring and evaluation • Incorporate continuous improvement about Vioxx, companies have used • Implement well-defined decision- activities and standardized risk pharmacovigilance methods designed making models, escalation communication plans to identify rare, easily identified safety processes, and communication • Create a dashboard that summarizes problems At the same time, we have channels and promotes timely awareness seen the growth of a fragmented • Determine the pharmacovigilance of safety across the portfolio healthcare system that has lacked workload and sufficiently resource and timely execution of safety risk a unifying infrastructure. As a result, the required effort minimization activities this system operates primarily in • Designate a pharmacovigilance reaction to rather than in anticipation operating model and business of major pharmaceutical safety events. process owner As drug consumption has increased • Ensure that appropriate process and and the public has grown to expect organizational checks and balances greater drug safety, the traditional are in place to limit and manage reactive approach has proven largely regulatory risk

PricewaterhouseCoopers’ Health Research Institute |  Background

The challenge to the Exhibit 1: Frequency analysis of ethical issues pharmaceutical industry Ethical issue Number of references Drug safety 114 A chief problem that pharmaceutical Drug prices 54 companies face in the area of Cinical study design & sponsorship 30 pharmacovigilance is the possibility Data disclosure—clinical and manufacturing 26 that a may be taken in Marketing sales and incentives 14 a manner for which it was neither Reimportation/importation 13 New drug/treatment research 13 intended nor clinically tested. Developing countries 12 This can happen for a number of Issues related to vaccines 12 reasons: the number of participants NIH ethics rule 9 in the average is dwarfed Righ tot life/contraception 9 by the thousands or even millions of DTC advertising 8 biologically unique patients who may Generic 3 Medicare/Medicaid 3 take a marketed treatment; Other 25 can be taken in combination with other with which they have not Source: “Front Page Pharma,” by Stephen J. Porth and George P. Sillup, Pharmaceutical Executive, been clinically tested; and medicines February 1, 2006. may be prescribed for an indication different from the one for which they were approved. All of these factors, Exhibit 2: report growth, U.S., since 1995 including preexisting conditions, may increase the odds that serious adverse 23% events absent in clinical trials might easily occur postmarket. 16% 15% 13% 13% 14% Neither these odds nor the risks 12% 11% average 7% they represent are well understood annual by consumers, the result being that growth rate a spate of safety-related product withdrawals has hastened the recent -4% steep decline of public confidence in the ability of pharmaceutical 1996 1997 1998 1999 2000 2001 2002 2003 2004 companies and regulators to ensure Source: “CDER 2004 Report to the Nation: Improving Through Human Drugs,” Center safety. for Drug Evaluation and Research. August 22, 2005.

Increased media scrutiny Growing public concern over drug safety also has spurred the media to focus on this issue. Drug safety was the top issue in Pharmaceutical Executive’s Annual Media Audit 2005, with drug safety and development issues dominating more than half of the print media coverage (Exhibit 1). Heightened media and public

 | Unlocking the power of pharmacovigilance awareness has combined with Exhibit 3: The downward safety spiral greater scrutiny by regulators and elected officials to create a rapidly evolving—and potentially dangerous—environment for pharmaceutical companies.

One reason for such media scrutiny Upstream risks is the release of reports from the FDA and the World Health Organization’s Vigibase (a global database) of significant increases in the number of adverse events reported in recent years. The FDA, for example, shows an average growth rate of 12% annually in adverse event reports to the agency from 1995 through 2004 (Exhibit 2). The causes and implications of the increase are the subjects of much debate. Despite increases in adverse Business/financial Safety risks event reports, safety-based drug impacts withdrawals in the U.S. have remained essentially flat, at about 3 per 100 New Chemical Entity approvals for the past 35 years.1

The public may view the increase in reported adverse events negatively, but the growing number of reports may result, in part, from increased awareness in the medical community and the sheer increase in drug consumption. The industry could benefit greatly if the public better understood these factors and their impact on pharmacovigilance.

The impacts of safety issues are not limited to perception alone. Safety issues can lead to regulatory fines, litigation costs, reduced market share, diminished brand equity, and decreased shareholder value. Such impacts may affect a company’s ability to finance safety initiatives and thereby induce a downward spiral of further safety-related strategic and operational issues (see Exhibit 3).

PricewaterhouseCoopers’ Health Research Institute |  Consumers do not hold industry solely “The public perception that every Partly in response to the GAO’s responsible for safety issues but blame problem can be solved by a pill has report, the FDA created the position government as well. A 2005 consumer to change,” said Raymond L. Woosley, of associate center director for safety survey conducted by the Henry J. M.D., Ph.D., president of the Critical policy and communication within Kaiser Family Foundation reported Path Institute. “Drugs are foreign the Center for Drug Evaluation and that 77% of respondents were “very” chemicals, and while they have Research to oversee drug safety or “somewhat” confident in the ability beneficial effects, they also have side issues and policies.5 of the FDA to ensure that prescription effects. The public must understand drugs are safe. Even so, 22% were that because of the biologic The FDA also recently changed—for “not at all” or “not too” confident in differences between individuals, all the first time in more than 25 years— the FDA’s oversight ability.2 cannot be discovered prior the requirements for pharmaceutical to marketing. Therefore, it is to be package inserts and warning labels, “Unfortunately, the public has been expected that drugs will be taken released 11 new patient safety led to believe that FDA’s approval of off the market from time to time.” guidance documents, and announced a drug means that FDA’s promise of plans to release guidance on eight ‘safe and effective’ is an absolute,” Nearly all medical treatments and other safety-relevant topics during said Judith M. Sills, Pharm.D., head of products may carry some degree the remainder of 2006.6 global safety intelligence at Novartis of risk to patient health. The public’s Pharmaceuticals. “Neither the FDA ignorance of the risk profiles of The March 2006 GAO report also nor the industry has done a good prescription drug products can has inspired Congress to work toward job in educating consumers that significantly affect its expectations enhancing the oversight authority these terms are relative and not an about and reactions to safety events. of regulatory agencies around absolute guarantee.” postmarket drug safety. Although a Greater regulatory measure that would have granted the And the public’s level of confidence FDA authority to compel drugmakers is slipping. A more recent Wall Street and legislative scrutiny to conduct postmarket clinical trials Journal Online/Harris Interactive Poll Scrutiny of the pharmaceutical failed, similar legislation is in progress, paints an even bleaker picture: 58% industry also extends to the regulatory and the Senate Finance Committee of respondents said they think the and legislative arenas. Regulators has adopted FDA oversight—and FDA does only a “fair” or “poor” job and legislators are subject to public specifically, patient safety—as part of ensuring the safety and opinion, and this has driven expanded of its agenda. of new prescription drugs—up activity in the area of drug safety. significantly from the 37% who said The recent steps in the U.S. parallel so just two years ago.3 To some Despite the FDA’s establishment of the a heightened focus on patient safety degree, these opinions are driven Drug Safety Oversight Board in 2005 in Europe, both within the European by consumers’ misunderstanding of and the consequent drafting of a policy Union and within individual states. This the relative nature of the “safe” and on major postmarket decision making, new emphasis on pharmacovigilance, “effective” descriptions as they apply a March 2006 U.S. Government while welcome, does pose challenges to pharmaceutical products. Accountability Office (GAO) report to U.S. pharmaceutical companies criticized the FDA for lacking “clear doing business in Europe. and effective processes for making decisions about, and providing “Historically, the European authorities management oversight of, post-market adopted a more philosophical view safety issues.”4 In particular, the report of pharmacovigilance, but now noted the FDA’s inability to ensure we’re seeing them move toward that long-term, postmarket follow-up the compliance, surveillance, and studies get conducted, noting that qualifying data that the U.S. has only 24% of agreed-upon studies were typically stressed,” said Barry Arnold, actually conducted from 1991 to 2003. former vice president of global patient safety at AstraZeneca. “And the Americans are moving more toward evaluating the quality of systems and not just the number of reports.”

 | Unlocking the power of pharmacovigilance Until the International Conference on Exhibit 4: The decline in prescription drug spending growth, 1999-2004 Harmonization (ICH) has standardized � Year over year growth rate, perscription drug spending regulations across the globe, companies will grapple with differing and evolving cross-border rules and 18.5% safety reporting requirements. “It’s become clear that even if a country’s regulatory authority signs onto ICH, 15.5% they’ll put their own spin on the 14.5% regulations. This will continue to be a 13.9% challenge,” said Sills.

Investment in pharmacovigilance 10.0% Any discussion of drug safety must acknowledge the fact that 8.2% there is relative underinvestment in pharmacovigilance. A 2003 study by 1999 2000 2001 2002 2003 2004 Duke University and the University of North Carolina at Chapel Hill pegged Source: National Health Expenditures, Centers for Medicare & Medicaid Services. spending on patient safety monitoring following FDA approval at just 0.3% of sales revenue across the top 20 pharmaceutical manufacturers, even though research and development spending—largely in advance of product approval—consumes 15.6% of revenue at these same manufacturers.7

There is no that dictates that a certain percentage of revenue should be allocated to pharmacovigilance, but—in the face of the potentially huge cost of safety-related withdrawals within the context of heightened stakeholder expectations around drug safety—companies should endeavor to strike a better balance between R&D spending and pharmacovigilance spending. The cost of withdrawals—when viewed against a backdrop of annual drug spending growth, that declined from 18% in 1999 to 8% in 2004 (see Exhibit 4)—demonstrates that companies face a rapidly diminishing margin for safety-related error. And government actuaries recently predicted that drug consumption could continue to decline in the future, making it that much harder to recoup losses due to safety- based withdrawals.8

PricewaterhouseCoopers’ Health Research Institute |  The clear implication is that companies The reactive nature should invest more now to implement of pharmacovigilance pharmacovigilance measures. The question, then, for firms willing The interviews found that to make this expanded commitment is: pharmacovigilance programs at How best to deploy that additional time different companies are at various and money? PricewaterhouseCoopers stages of maturity. Regardless of their interviewed 34 industry experts on degree of pharmacovigilance maturity, patient safety and pharmacovigilance however, nearly all of the companies and consulted thought leaders who interviewed are working to improve have successfully addressed similar their pharmacovigilance efforts. challenges in other disciplines both within and beyond the pharmaceutical “The fact that pharmacovigilance is industry. Their insights provided in the spotlight is a mixed blessing,” the basis for the recommendations said Jean-Louis Saillot, M.D., outlined here. vice president and head of global pharmacovigilance, Schering-Plough. “The increased scrutiny makes the challenges harder to surmount, but that same scrutiny forces us to meet those challenges head-on.”

Companies face this challenge because the pharmacovigilance methods developed in the four decades since the thalidomide tragedy have been designed to identify rare, easily identifiable safety problems at the same time as we have seen the growth of a fragmented health-care system that has lacked a unifying infrastructure. As a result, this system operates primarily in reaction to rather than in anticipation of major pharmaceutical safety events.

 | Unlocking the power of pharmacovigilance Unlocking the power of pharmacovigilance

As drug consumption has increased Organizational alignment Operations management and the public has grown to expect higher levels of drug safety, the Traditional department boundaries Many of today’s postmarket safety traditional reactive approach has impede interaction on safety initiatives were either created in an proved largely incapable of addressing issues, inhibit the sharing of best earlier era or built organically over time. shifts in public expectations and practices, and limit integration This ad hoc evolution has not resulted regulatory and media scrutiny. among departments (such as sales in a unified, structured, and adaptable This reality has revealed issues in and marketing, manufacturing, and vision to guide the management of the four areas, or infrastructures, customer service) that have incentive safety-related processes. For example, involved in patient safety operations: structures different from those the generation and dissemination organizational alignment, operations of the safety organization. Many of reports may continue even after management, data management, organizations lack a single individual they have been rendered obsolete by and risk management. with responsibility for the overall quality changes in regulation, technology, and integrity of safety processes and or business processes. This issue is systems. Instead, authority—and common and can be addressed by accountability—are more diffuse building a continuous improvement than is necessary. Developing a framework into the organizations’ team-based and product-focused operating model. staffing model made up of staff from the key functions—such as trial Drug safety operations also frequently registration, regulatory, testing, and lack standardized and aligned investigation—with a dotted-line back activities across product lines and to their functional areas will break across geographic locations, and down departmental barriers and foster thereby fail to leverage opportunities collaboration. for standardization or economies of scale made possible by similarities in the overarching process. For example, when adverse event data arrives, it must be investigated and evaluated regardless of country, product, or source of the report. Lack of a unified operations structure can result in process redundancies or, worse, gaps—all of which create unnecessary risk.

PricewaterhouseCoopers’ Health Research Institute |  Data management Postmarketing, spontaneous reports do not work Today’s data systems often fail to “ capture, standardize, and integrate in certain situations. For example, in the case of a safety information efficiently. common condition like heart , it is impossible Furthermore, current adverse event to tell whether a case is related to a drug or whether reporting processes and systems typically lack a clear standard for it would have happened anyway. When the adverse quality of content. Companies event you’re looking at is the same as or very often find that the safety data available similar to the manifestation or natural history of the to them in spontaneous reports is incomplete and lacks the very disease you are trying to treat, assessment of information necessary to inform individual adverse events is not very helpful.” adequate analyses.

“Physicians working on a hospital Joanna Haas, M.D. staff use hospital-defined parameters Vice president of pharmacovigilance for what constitutes an adverse at Genzyme Corporation event. Reactions the drug sponsor or agency might be interested in could be considered nonissues at specific facilities,” said Beverly Kirchner, president and CEO of Genesee Associates and member of the board of directors of the Association of “With spontaneous reporting, you know you’re seeing Perioperative Registered Nurses. only the tip of the iceberg. And from this tip you cannot event-gauge the full size of the iceberg.” One estimate commonly cited by interview participants is that only about 10% of serious adverse events Jean-Louis Saillot, M.D. are reported. This underreporting Vice president and head is due to several factors: lack of clarity around what events should be of global pharmacovigilance reported, lack of available time, and at Schering-Plough poor recognition of adverse events because of differing standards or lack of training. For example, because there are many possible explanations for an adverse event, it is rarely possible to demonstrate a causal relationship between a compound and a specific adverse event.

Furthermore, the reporting fraction —the number of adverse events per drug that enters the pharmacovigilance reporting system—is often unknown or difficult to quantify with certainty. If 50 people on a given drug report chest pains, the number who actually experience chest pains could be much higher. And the company has no way of knowing just how much higher, which makes analysis difficult.

 | Unlocking the power of pharmacovigilance Even when the data gathered are Exhibit 5: Source of adverse event reports, 4Q04 through 3Q05 acceptably complete, analysis may still prove to be a Herculean task Health professional 59% because of the myriad systems and institutions that store and report safety data. For example, more than 85% Consumer 42% of U.S. physicians store their patient medical records on paper, and even Foreign 27% those offices that are wired do not interface easily with pharmaceutical Other 24% manufacturers.9

Company representative 12% Much pre- and postmarket information is collected and analyzed in separate repositories. Data may be collected Study 10% by different - or compound- specific groups, by different means Literature 7% and for different purposes. Clinical trial data, for example, might not be Distributor 1% leveraged for patient safety purposes simply because the trial data were not User facility 0.5% collected or stored with possible future uses in mind. Integrated analyses Source: AERS Latest Quarterly Data Files, FDA. across departmental databases— analyses that could identify safety trends and facilitate more integrated reporting—are practically nonexistent simply due to the manner in which data are collected and stored (Exhibit 5).

“The challenge is how to connect the data that typically sits in different places; how to aggregate it into information on which the company can act,” said Beth Ziemba, director of compliance management at Elan Corporation. “As an example, pharmacovigilance departments often use a different database than clinical departments do; linking these databases would allow a company to conduct improved analyses throughout product development, including postapproval.”

PricewaterhouseCoopers’ Health Research Institute |  The hurdles in data sharing are significant not only within a company, There is a disconnect between R&D, clinical and but they also prevent data sharing “ between the company and the FDA, postmarket surveillance. There should be a single as well as across the broader scientific repository where all data points, both pre- and community. Further complicating the postmarket, merge. This will drive more-efficacious issue is that the safety information gathered within a single company drug safety monitoring and improve our ability to that has locations in different countries proactively discover potential safety issues before may be owned and stored in the they become widespread.” originating locations.

Risk management Noemi Romero-Kondos Global complaint management Risk can take many forms: operational, financial, regulatory, and reputational, lead process manager at Hospira to name a few. To maintain stability within their core businesses, companies must be equipped to identify, evaluate, and manage those risks effectively. Too often, however, a company’s risk management infrastructure is not integrated with its organizational, operational, and data management systems; there is overreliance on legacy policies and procedures, training, and documentation systems; and the company applies risk management in a reactive, inconsistent manner. The result of such inconsistent, nonsystematic, and uncoordinated approaches can be significant financial and reputational harm to the company.

Even those companies that have begun to use proactive risk management techniques in some functional areas have not used them consistently in areas pertinent to drug safety risk. For example, adverse event frequency data have been used for assessment of real-time risk. But these data typically are not integrated with measures of event severity, and so do not inform decisions through a predefined risk prioritization process.

10 | Unlocking the power of pharmacovigilance The three strategies of effective pharmacovigilance

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“For a pharmaceutical company to be successful, drug safety has to be at the core of all discussions across the organization. Pharmacovigilance has to be embedded into the day-to-day operations of the company. Similar to other systems, most of the issues around pharmacovigilance systems are not IT [information technology] issues but mainly process and people and organization issues. Tools, including IT solutions, must be implemented in the context of addressing process improvements and organizational needs.”

Jean-Louis Saillot, M.D. Vice president and head of global pharmacovigilance at Schering-Plough

PricewaterhouseCoopers’ Health Research Institute | 11 Strategy 1: Align and clarify roles, “There is a pendulum movement right now to move responsibilities, beyond the fact that all have side effects and communications and move more towards a focus on the benefits as well as the risks. We cannot assess the safety risks Appropriate organizational alignment is a crucial enabler of the operating without a calculation in benefits.” and data management models that govern the efficiency and effectiveness Ludo Lauwers, M.D. of a company’s pharmacovigilance activities. Senior vice president Global head of benefit risk management, To establish an organization- medicines and nutritionals sector wide pharmacovigilance program, companies should develop Johnson & Johnson clearly defined safety roles and responsibilities that cover a drug from development through postmarket. This includes an unambiguous chain of command and an explicit “There is a very limited pool of experienced people. escalation process for safety-related issues to prevent problems from Safety is moving to the forefront in companies, and dropping off management’s radar. companies are going to have to resource it better.” Decision-making models that are not hampered by poorly defined roles and responsibilities—as well Judith M. Sills, Pharm.D. as specific processes for handling Head of global safety intelligence safety-related issues—will drive clear at Novartis Pharmaceuticals accountability that will greatly mitigate safety risks before they develop into costly problems that could have been avoided.

12 | Unlocking the power of pharmacovigilance Develop an objective, data-driven, Companies should establish an hospital technicians are enlisted for the team-based approach to risk escalation framework that ensures more operationally focused functions monitoring and evaluation that issues are identified, prioritized, such as processing forms, reporting, Ultimate decisions on how to manage tracked, reviewed, and resolved in a and case investigation. drug safety risks should be made timely manner. The framework would by teams of key stakeholders. also empower employees to escalate Companies also should consider One approach would be to appoint issues to management. a mixture of fixed versus flexible stakeholders to a Data Safety resources, in which fixed resources Monitoring Board. For example, the framework would with deep subject-matter expertise define a number of escalation criteria focus on specific products, while Another would be to establish a Drug that—when matched together— flexible resources cover a greater Safety Risk Management Committee, would guide identified issues through breadth of products. This staffing formed early in the development a path from registration through to concept allows for temporary increases process. By including representatives closure, with clear links to testing and in the safety workload for a particular from discovery, drug safety, clinical investigation processes and regulatory product and also facilitates optimal development, legal, compliance, reporting mechanisms. The criteria staffing in an environment in which marketing and manufacturing, such should be updated regularly based drug safety is still viewed as a a group enables more timely and on a continuous improvement phase cost center. complete safety issue identification, of the business process and ought to as well as more efficient and informed be based on regulation and historical Designate a pharmacovigilance safety decisions. experience with the particular product. operating model and business process owner. Member identification, group To operate effectively, both the One key resource is a designated formation, and membership transition decision-making model and the process owner (not to be confused (as the product moves through its escalation framework require with the head of drug safety, although lifecycle) should be standardized. established, formalized communication the drug safety head could be the Groups should feature diversity of channels. These channels enable process owner), who is responsible perspectives based on criteria such employees, including those without for the safety profile of the product as disease area, mechanism of action, direct drug safety responsibilities, to and who acts as an unbiased steward and stage in the product life cycle. obtain necessary information from of the overall operating model and anywhere in the organization, to principles of ensuring drug safety. Implement well-defined decision- make informed safety decisions, and making models, escalation processes, to communicate those decisions as The individual would be accountable and communication channels. appropriate. for the effective execution of the A pharmacovigilance decision- pharmacovigilance operating model making model should specifically Determine the pharmacovigilance and business process, would ensure define employee roles in gathering workload, and sufficiently resource that pharmacovigilance integrity and and analyzing information that the required effort. quality are kept consistently high, and ultimately influences drug safety Companies also should provide would promote an atmosphere decisions. Such a model allows sufficient resources to support of continuous improvement. employees to take greater ownership their pharmacovigilance efforts, of pharmacovigilance issues, foster although individuals who possess In addition, the process owner should more collaborative relationships, and the specialized skills necessary to oversee internal communications contribute to continuous improvement. execute drug safety activities are that provide for connections between For example, the model would allow relatively scarce. To address this issue, the safety function and marketing, employees to work autonomously some companies have embraced sales, and other units whose primary within their roles while following a staffing model that leverages responsibilities do not include safety. a consistent method to determine diversified advanced degrees in The responsibility for creating and appropriate action. In particular, pharmacovigilance functions such as enforcing appropriate safety checks, a decision-making model would signal detection, signal investigation, balances, and controls must rest with clearly establish ownership for and risk management. Rather than the process owner and be backed specific decisions and would relying solely on safety-related by senior managers who communicate reduce ambiguity. experience, nurses, pharmacists, and the importance of safety to the entire company.

PricewaterhouseCoopers’ Health Research Institute | 13 Ensure that appropriate process and level of internal review, investors can event reporting and risk management organizational checks and balances see that an environment such as decision making. Data standardization are in place to limit bias and manage this one, that promotes compliance is also important because much regulatory risk. and transparency, demonstrates information is collected and analyzed Because departments outside drug an increased level of accountability by discrete business units that have safety have different objectives and by senior executives. This can, in different therapy- or compound- incentives, the importance of drug turn, be particularly helpful in the specific working groups, different safety may not necessarily be current environment—one in which means of collection, and different uses understood or acted upon equally corporate ethics, accountability, and in mind. across a company. responsibility all have been called into question. Several pharmaceutical companies “Companies have to be careful to standardize operational and data ensure that independent, medically The working relationship between management activities in other based decision making is adequately pharmacovigilance and corporate areas, but very few have applied protected. Decisions on safety signals compliance should be supported standardization to pharmacovigilance must be medically and science driven. by quality assurance auditing and activities. In any situation, people have to be business unit monitoring processes mindful of conscious and unconscious that enable organizations to assess Align operational activities across bias,” said Saillot. “To ensure quality of pharmacovigilance quality proactively departments and across sites. decision making, we have to welcome and systematically, as well as by A well-structured operations model checks and balances.” the level of systems that provide provides a common and consistent employees with an authoritative source platform upon which different The responsibility for creating and of readily accessible and cross- geographic locations, functional enforcing pharmacovigilance checks, referenced compliance information. groups, and product lines can refine balances, and controls must rest, their own site-specific processes, therefore, on management that compare operational differences, has cross-functional oversight. For Strategy 2: Standardize and share best practices. example, as part of a continuous improvement process, management pharmacovigilance Safety profiles and regulatory would review the checks, balances, processes and data requirements may differ from drug to and controls with the process owner management drug and location to location. However, to ensure the process is working there are activities and decision points optimally. In addition, by actively Standardization around well-defined, that can be standardized and aligned supporting and communicating the integrated operations and data regardless of product or location. importance of pharmacovigilance to management processes is the salient Additional levels of detail can be the entire enterprise, executives can feature of effective pharmacovigilance developed depending on products, ensure organizational alignment around programs. This enables companies to locations, and organizational roles strong pharmacovigilance. ensure more-efficient patient safety, as one moves further into any one consistent regulatory compliance, area (See Exhibit 6). To ensure that these checks and and controlled risk management while balances are properly understood ensuring scalability by consistently Accordingly, the fundamental throughout the enterprise, furthermore, following a set of procedures. By the safety reporting process should be the cross-functional management use of such consistent procedures, common from country to country, team should foster a transparent both trending and analysis can be though it should also be able to collaborative working relationship performed on the same data set, and accommodate local regulatory between pharmacovigilance and safety-related issues can therefore be requirements or cultural imperatives. corporate compliance programs. compared easily. Such standardization can help pharmaceutical firms cope with the In addition to the ensuring that the Standardizing the sources, reports, and regulatory requirements of the multiple safety risks of the drugs in their analytics used in the translation of data jurisdictions within global markets and portfolios receive the appropriate into safety signals allows for consistent can foster sharing of best practices.

14 | Unlocking the power of pharmacovigilance Exhibit 6: Operations model for pharmacovigilance processes

Receive Report Investigate Case Mitigate Risk

Legend: Other Functional Areas Drug Safety Operations Information Systems Process: represents a specific or roll-up activity in the overall process

Conduct Investigation Communication: represents Clinical Medical process communications (e.g., Others phone, intranet, e-mail)

Input/Output: represents the direction of process activities and handoffs Report Findings Clinical Medical Others Document/Report/System Form: Indicates item created/ used in a given process step

PricewaterhouseCoopers’ Health Research Institute | 15 Implement process-driven standard operating procedures, work It is extremely difficult to find pharmacovigilance- instructions, and training materials. “ Standardization of work instructions, qualified M.D. candidates. You really have to build an training materials, and documentation infrastructure that can train and mature them in-house.” drives greater adherence to quality processes and enables companies to cope with the loss of key employees, Jean-Louis Saillot, M.D. which is especially important in the Vice president and head face of a relatively limited drug safety of global pharmacovigilance talent pool. at Schering-Plough Pharmacovigilance model and process fundamentals training—training on the highest level in the pharmacovigilance model and process—should cover the overall processes, organizations, We don’t view drug safety from a postmarket or and systems and should remain the “ same regardless of a person’s role in premarket perspective but, rather, as a continuum the safety organization. This can also from the time the compound is identified and the time be a useful tool in raising awareness of animal studies on through when companies are throughout the organization. hoping to get approval. This is far more involved than More-customized training for each role looking separately at postmarket and premarket.” in the safety organization should drill down from the fundamentals training into specific roles and responsibilities. Alan Goldhammer Trainers, therefore, can efficiently Associate vice president of mix and match training modules as regulatory affairs for the appropriate to create role-specific and product-specific training materials that Pharmaceutical Research and build upon what employees learned Manufacturers of America (PhRMA) during fundamentals training.

16 | Unlocking the power of pharmacovigilance Integrate safety data through data and Despite the fact that different Work flow management systems system interoperability standards. databases have different uses, their ensure that only the appropriate A single database should include data data contains many common safety- employees receive the data across the entire product life cycle— relevant elements. Companies can required to inform the decisions both premarket and postmarket. link these databases (and thereby they are authorized to make within By viewing postmarket safety as a facilitate integrated safety analyses) the pharmacovigilance model. component of a continuum and by by creating standards around the The technology also ensures that performing analysis of safety data database elements as well as data the appropriate decision, sign- across this continuum, organizations formats, terminology and system off, communication, and retention can identify more safety signals. interoperability. requirements are executed and documented—a process known as “Integration of data is important to Many of the same standardization work flow close out. The technology, perform signal detection across a issues posed by data sets housed therefore, allows for more-controlled product’s development life cycle,” said internally are similar to the issues management of tasks, thus Ziemba. “Integration would include posed by external data sets such ensuring that all safety events are the tools to pool data from the variety as automated claims databases, handled appropriately. of data sets across the company— physician records, pharmacy records, including data on product complaints and clinical registries. As within the Select a vendor that best matches the and sales and marketing information— company, a common format, common pharmacovigilance operating model, and from data sets housed externally, data elements, common terminology business process, and vendor/system so as to create an aggregate data set (such as MedDRA), and system selection criteria. that is as close to complete and as interoperability standards can facilitate Companies recognize that software inclusive as possible.” linkages among safety data. While little and technology vendors have can be done to standardize external made significant advances in safety There are, however, several challenges data without the efforts of groups data mining, in analytics, and in to integration across the safety such as the ICH, companies can other tools required for successful continuum—mostly around data and improve their own management of data pharmacovigilance programs. system interoperability standards. In obtained from internal and external Technology solutions must not drive both pre- and postmarket operations, sources by adopting in-house data and companies’ pharmacovigilance multiple databases may contain similar interoperability standards. processes or operating models, information, but these databases however. typically are neither linked nor linkable Implement work flow management to each other. Each database is technology to ensure appropriate Technology should instead bind the designed and populated for different transparency and accessibility of safety operating model with the organizational objectives and therefore contains information. model, supporting risk management nominally different but inherently Work flow management technology activities throughout the safety similar safety data elements. For already has created value in other organization. To identify the tools example, some databases may be areas of the pharmaceutical value and technologies that are most created for preclinical toxicology and chain—such as in help desk functions appropriate to an organization’s unique studies, some may be and electronic capital expense needs, companies should derive created for each clinical trial and some requests—and consequently is gaining system requirements from process- may be created for each postmarket widespread industry acceptance. based business rules and feed those use (e.g., complaint management, Applied to pharmacovigilance, this requirements into a systematic vendor customer service, or medical technology can identify and distribute selection process. communications). information to stakeholders according to a predetermined set of rules—such as product family, type of safety event, and event severity—and thereby facilitate effective and consistent management of safety reporting and data sharing.

PricewaterhouseCoopers’ Health Research Institute | 17 Within the industry, two concerns have arisen about information technology Comprehensive software is just now slowly developing vendors. First, software solutions are “ expensive, and second, off-the-shelf and has not yet matured. However, it is still important solutions are neither customizable nor for companies to query technology companies flexible enough for an organization’s about developing software to link and evaluate all unique requirements. Companies planning to customize technology safety data.” should undergo a thorough search process for the right vendor and Tobias Peschel, M.D., Ph.D. product. Some companies will find that a homegrown technology solution is Vice president of drug safety the best option, while others will find and public health that off-the-shelf solutions work better. at Gilead “Safety is an evolving area, which is why software is such a challenge. If you build a tool for today’s requirements, the system is static. Safety regulations and safety thinking continue to evolve, so a system that will serve that area has to be dynamic and flexible,” said Sills. “Vendors are out there, but I don’t know if there are any dominant vendors. I think that companies, as they get frustrated, resort to building their own systems.”

In the event of technology gaps, process workarounds can ensure that the integrity of the process and technology solution remains intact, whether the product is off-the- shelf, customized, or homegrown.

18 | Unlocking the power of pharmacovigilance Best practices: Technological concepts for enhanced pharmacovigilance

System Capabilities

Systems should accommodate safety information in multiple formats from both direct sources—such as consumers, physicians, pharmacies, and other third parties—and indirect sources, which include regulatory agencies, electronic medical records, and payer automated claims databases. Systems should also share drug safety information across departments and route that information to the right stakeholders at the right time, in the right format and with the right level of privilege. Further capabilities should include the performance of leading-edge safety diagnostics and analytics as well as the generation of periodic and ad hoc reports for both internal and external consumption.

System Requirements

To support these capabilities, systems should employ data standards— such as the CDISC safety data standards—that facilitate the transfer of data and multisystem analysis of distributed safety data, as well as a medical data dictionary such as MedDRA to support the classification, retrieval, presentation, and communication of medical information to internal and external stakeholders.

Technology Features

• Branching that uses initial responses and specific conditions reported during data entry to collect specific diagnosis information

• Prepopulated data fields that facilitate the diagnosis of suspected safety events—such as specific reactions or symptoms of the event—and that lead to data that is more useful during investigations, analytics, and monitoring

• Data filters that adhere to and satisfy specific regulations such as HIPAA privacy rule regulations

• Data analytics that link data sets and facilitate pattern recognition and detection

• Work flow features that facilitate the controlled routing of events and safety data to the appropriate organizational and scientific stakeholders

• Event- and threshold-based triggers, with a prescribed corrective action and approval process

PricewaterhouseCoopers’ Health Research Institute | 19 Strategy 3: Implement Beyond these fundamental compliance Companies similarly may assign scores proactive risk minimization measures, companies must inject to inform the risk tolerance and risk objectivity and standardization into appetite levels for specific types of In the context of pharmacovigilance, risk management by identifying drug safety issues across the product a risk management framework should risk tolerances and priorities and portfolio. Based on these predefined have three fundamental traits: developing comprehensive mitigation levels, the company can develop plans in advance of drug safety events. appropriate risk mitigation plans. • Ability to quickly identify risks based on internal and external information, “For effective risk management, the For example, pharmacovigilance groups through processes that identify and pharmacovigilance risk identification can work to develop an objective, extract compound- and indication- function alone is far from being standardized approach to investigation specific information from across enough,” said Saillot. “It’s just one of safety signals from the point of the organization of the first steps. For risk minimization initial detection. Standardization of the activities to be effective, everyone investigation approach is essential, • Categorization and ranking of the must be aligned and acting on from hypothesis generation through overall organizational impact of identified risks.” hypothesis testing and, ultimately, safety risks based on the company’s to the process of making final risk risk appetite and tolerance Develop risk management action plans mitigation decisions. Companies that based on preestablished risk scoring employ analyses and reports via a • A predefined process that manages and mitigation processes. standardized, predetermined approach risks and that involves internal Established risk scoring and mitigation can make consistent and appropriate stakeholders who both develop processes can ensure objectivity decisions regarding risk communication the risk management plans and and standardization. Risk scoring and action. Such an approach to risk periodically revalidate pertinent should be based on a combination of management will help companies algorithms and decision criteria industry benchmarking, corporate risk reduce reactionary measures and tolerance, and internal assessments potentially costly and ineffective An essential first step is to ensure that via a set of predefined algorithms decisions made under real-time duress. appropriate controls for regulatory that allow for objective evaluation compliance are in place. Companies of specific issues and actions. For Implement data mining techniques to should carefully document and drive example, the risk impact on individual bolster safety analytics, reporting, and compliance with all policies and products may be determined by the investigation. procedures. Maintenance of records measurement of diverse data points As mentioned earlier, effective is important, especially those of past such as number of adverse events per management of safety data across audits and corrective and preventive product family, patient demographics, multiple platforms is critical to effective action plans (CAPAs). Companies and overall portfolio value of the management of safety events. This should enforce policy and procedure product and product family. Issues may same data can be mined to supplement retirement dates and update processes be assessed either for each product existing safety detection methods to ensure that they meet current legal individually or for a class of products and help assess the patterns, time and regulatory requirements. and should be continuously updated as trends, and events associated with the environment necessitates. As part drug interactions. Dynamic and of the assessment, companies should flexible analytic software and the use evaluate both external risk factors— of new tools, such as biomarkers or such as regulatory, reputation, and pharmacodynamic markers, also can product liability risk—and internal risk help companies maximize the benefits factors—such as portfolio, strategic, of medicines while minimizing safety risk. and financial risk—when examining specific risk events.

20 | Unlocking the power of pharmacovigilance The rationale for data mining is clear: Detection of most safety signals is Using the problem-oriented approach as a difficult. While serious and unlabeled adverse event signals are relatively pharmacovigilance business model straightforward, the more difficult signals require analysis across a Several companies have incorporated the spirit number of data sets. This is an extremely time-consuming task if and intent of proactive risk management into their performed without the aid of data development processes. Joanna Haas, M.D., vice mining technology, which allows for president of pharmacovigilance at Genzyme Corporation, the systematic examination of data with statistical or mathematical tools calls Genzyme’s system the “problem-oriented to determine whether a potential safety approach” to drug safety and pharmacovigilance. In signal warrants further investigation.10 essence, the company looks for the potential risks Data mining typically supplements of its compounds from the time of discovery through and supports existing safety signal preclinical development, and thereafter via postmarketing detection methods and is especially surveillance. “If you think drug interactions may be an useful in assessing the patterns, time trends, and events associated with issue, you’d make that something you look for,” Haas drug-drug interactions. It is an effective said. “To designate something as a potential safety exploratory and hypothesis-generating problem presumes you’re trying to find the answer, which tool that can provide insights into the adverse event reporting patterns may be that there is in fact no problem.” Haas went on for a given product relative to other to say that including risk concerns as well as benefits in products in the same therapy class.11 filings and discussions with the FDA makes the approval It also can indicate the existence of issues around the mechanism of process go more smoothly. action—such as receptor specificity and selectivity, signaling pathways, and intracellular protein interactions. It is the integration of the safety signal data combined with an introspective evaluation of known risks based on internal data that provides the greatest value in an analysis of the true impact of drug safety issues.

PricewaterhouseCoopers’ Health Research Institute | 21 Incorporate continuous improvement Sales representatives, for example, One of the most effective practices activities and standardized risk can play a key role in communicating for dealing with this challenge is a communication plans. risks to physicians. “There is a customized safety risk dashboard Continuous improvement activities role for sales reps to objectively that provides a single, real-time, should include new safety risk give information to physicians on authoritative information source for information to inform changes to the the benefits along with the risks of all risks across the company’s portfolio risk profile that might further minimize products,” said Ludo Lauwers, M.D., of products. product risks and maximize benefits senior vice president and global for the targeted patient population. head of the benefit risk management, The dashboard should include overall Continuous improvement activities medicines, and nutritionals sector at safety histories, short- and long-term also should include reevaluation of risk Johnson & Johnson. “If a product has information on use, case-by-case criteria around new internal or external an issue, it is important to educate. reporting, expected reactions versus factors that may influence overall risk I know it sounds like a contradiction actual adverse events, and a product’s appetite and tolerance. as sales reps have an incentive to regulatory reporting history. Based sell, but we have used sales reps on data gathered from the dashboard, Communication of drug safety in the past to go to physicians with specific risk mitigation procedures risk information both internally educational safety messages. It works tailored to a given type and level and externally is perhaps the most very well because it is a strong way of risk may be accessed and critical output of pharmacovigilance to make sure that an important safety followed for guidance in a timely and risk management activities. message is conveyed to physicians.” effective manner. Communication plans should describe the risk escalation and communication Create a dashboard that summarizes Dashboards facilitate proactive processes both within and outside and promotes timely awareness of management of safety risks by the company. To ensure that messages safety risks across the portfolio summarizing safety information across disseminated are accurate, consistent, and timely execution of safety risk the product portfolio in real time and and not subject to misinterpretation, minimization activities. by identifying the types of data that the drug safety officer, the chief A robust signal detection and action should and should not be used in drug medical/scientific officer, and platform, enhanced by data mining safety decision making. Dashboards the public relations, legal, regulatory, techniques and enabled by a cross- are key means of ensuring that risk and compliance executives should functional team-based approach and management and communication be involved in message design the right communication plans, still has plans are executed in a timely and and deployment. a number of limitations. It is difficult for effective manner. the pharmacovigilance process owner All communication plans should to ensure that all the correct actions consider the audience involved, are taken in a given situation. especially when that audience is composed of the patient- or physician- centric communities that have such a high impact on industry reputation.

22 | Unlocking the power of pharmacovigilance Conclusion

The time for companies to reexamine their pharmacovigilance practices and to develop and implement “Timely communication of emerging risks to physicians effective, best-in-class solutions is and patients, as well as regulators, is extremely now. Many organizations have already important. Everyone who is prescribing, dispensing, begun to evaluate and enhance their pharmacovigilance practices or taking a drug needs to be informed of potential for efficacy and efficiency, and risks as early as possible.” through that experience many have encountered significant obstacles. Tobias Peschel, M.D., Ph.D. We believe that the practical approach Vice president of drug safety we have discussed in this paper can and public health provide a fresh perspective, both to those companies that have just begun at Gilead Sciences the journey and to those that have encountered obstacles along the way. We have provided a framework that will enable companies to find success by concentrating on the integration of operations, risk management and the supporting organization. The power of this approach lies in the alignment of strategy with accountability and in the linkage of functional areas within a single integrated operating model that adapts more easily to the changing characterizes of the industry, regulators and the public alike.

By concentrating on integration across the key infrastructures, companies will enable themselves to avoid the challenges companies typically face when building toward the future. They will create a sustainable infrastructure and a highly adaptive culture, both of which can lead to greatly diminished costs and risks, as well as greatly improved outcomes for patients.

PricewaterhouseCoopers’ Health Research Institute | 23 Endnotes 7 “Is More Money the Answer to Improved Patient Safety Monitoring?” Lisa Roner, ed., 1 “CDER 2004 Report to the Nation: Improving March 9, 2006. Public Health through Human Drugs,” Center for Drug Evaluation and Research, August 22, 8 “Health Spending Projections through 2015: 2005. Changes on the Horizon,” by Christine Borger, Sheila Smith, Christopher Truffer, 2 “HealthPoll Report,” Henry J. Kaiser Family Sean Keehan, Andrea Sisko, John Poisal, Foundation, February 2005. and M. Kent Clemens, Health Affairs, Feb. 22, 2006. 3 Americans Growing Less Confident in FDA’s Job on Safety, Poll Shows,” The Wall Street 9 “Electronic Medical Records Get Closer,“ by Journal Online, May 24, 2006. Julie Schmit (citing Eric Brown of Forrester Research), USA Today, June 7, 2005. 4 Drug Safety: Improvement Needed in FDA’s Post-Market Decision-Making and 10 Portions from “Good Pharmacovigilance Oversight Process, Report to Congressional Practices and Pharmacoepidemiology Requesters, GAO, March 2006. Assessment,” FDA Guidance to Industry.

5 “FDA Appoints New Associate 11 Portions from “Good Pharmacovigilance Center Director for Safety Policy and Practices and Pharmacoepidemiology Communication,” FDA News, April 26, 2006. Assessment,” FDA Guidance to Industry.

6 “FDA Announces New Prescription Drug Information Format to Improve Patient Safety,” FDA News, January 18, 2006.

24 | Unlocking the power of pharmacovigilance Glossary

ADR: Adverse Drug Reaction (see Adverse used to establish causal relationships between from the pharmaceutical industry discuss Event). products and adverse events, but rather as an scientific and technical aspects of harmonizing exploratory or hypothesis generating tool that activities across the lifecycle of pharmaceutical AERS: Adverse Event Reporting System – FDA’s may provide insights into the patterns of adverse products. International harmonization efforts database of reported adverse events. events reported for a given product relative to around Medical Terminology (MedDRA), the other products in the same class or to all other Common Technical Document (CTD), and Adverse Event: Any undesirable experience products. (see also Safety Signal) Electronic Standards for Transmission of associated with the use of a medical product in a Regulatory Information (ESTRI) have been patient Data Warehouse: (Sometimes referred to as a coordinated under the sponsorship of the ICH. “data mart”) a repository of integrated (see also MedDRA) [www.ich.org] Background Rate: Refers to the background rate information, extracted from heterogeneous data of occurrence for an adverse event in the general sources, available for efficient querying and Incidence Rate: Rate at which new cases of population or in a subpopulation with reporting that supports data analysis and adverse events occur in the product-exposed characteristics similar to that of the exposed decision making tasks. population. The numerator consists of the population. Often compared against the number of new cases. The denominator consists Incidence Rate. (See also Incidence Rate, EDC: Electronic Data Capture of the number of exposed patients and time of Reporting Rate and Safety Signal). exposure/time at risk. There are inherent EDR: Electronic Data Record difficulties in calculating incidence rate for spontaneous events due to the uncertainty Biomarkers: Physiologic indicators (e.g. blood around the number of adverse events not protein levels) that can be used to measure the EMR: Electronic Medical Record reported. Oftentimes compared against the progress of a disease, outcomes of Background Rate (see also Background Rate, administration, and/or the positive/negative Expected Adverse Event: (see Adverse Event) Reporting Rate, and Safety Signal). effects of a treatment, sometimes long before other indications or symptoms are apparent. Good Pharmacovigilance Practices: FDA (See also Critical Path Initiative). Labeling: (see PI – Prescribing Information / Guidance on current generally accepted good Package Insert) pharmacovigilance practices for post-market CAPA: Corrective and Preventive Action safety vigilance activities [www.fda.gov/cber/ Labeled (Expected) Adverse Event: An adverse gdlns/pharmacovig.htm] event that is one of the known adverse events CDISC: Clinical Data Interchange Standards listed on the product package insert (PI) Consortium – Organization that establishes and HIPAA: Health Insurance Portability and supports worldwide, platform-independent Accountability Act (1996), which required the Large Simple Safety Studies: (see LSSS) industry data standards to support the electronic Department of Health and acquisition, exchange, submission, and archiving (HHS) to adopt national standards for electronic of clinical trials data and metadata that enable healthcare transactions. The HIPAA Privacy Rule LSSS: Large, Simple, Safety Studies – information system interoperability for medical provides federal protection for the privacy of Randomized clinical studies designed to assess and pharmaceutical research and development individually-identifiable health information (also limited, specific safety outcomes in a large and related areas of healthcare. [www.cdisc.org] known as protected health information [PHI]) by number of patients. These outcomes – generally prohibiting the use and disclosure of PHI except important safety endpoints or safety concerns Clinical Registry: (see Registry). to the individual subject and to HHS – unless suggested by earlier studies – are defined a priori specifically permitted. (See also HIPAA). with the study specifically designed to assess them. Data Mart: (see Data Warehouse). HL7: Health Level Seven, an ANSI-accredited MedDRA: Medical Dictionary for Regulatory Data Mining: Systematic examination of data Standards Developing Organization which produces standards, specifications, and/or Activities – International standard of medical using statistical or mathematical tools to terminology, developed under the auspices of determine a potential safety signal warranting protocols for clinical and administrative healthcare data. [www.hl7.org] (see also NCPDP). ICH, used for regulatory activities. MedDRA is further investigation. Typically used to particularly important in the electronic supplement existing safety signal detection transmission of adverse event reporting, both in strategies, data mining is especially useful for ICH: International Conference for Harmonisation the pre- and post-marketing areas, as well as the assessing patterns, time trends, and events – Organization where regulatory authorities of coding of clinical trial data. [www.ich.org] (see associated with drug-drug interactions. It is not Europe, Japan, and and experts also ICH).

PricewaterhouseCoopers’ Health Research Institute | 25 MedWatch: FDA Safety Information and Adverse READ Codes: United Kingdom’s National Health hospitalization, a persistent or significant Event Reporting Program that allows healthcare Service (NHS) Clinical Terms. Combined with disability/incapacity, or a congenital anomaly/ professionals and consumers to report serious SNOMED-RT to create SNOMED-CT (SNOMED birth defect, or requires intervention to prevent problems that they suspect are associated with Clinical Terms). [www.nhsia.nhs.uk/terms/pages/] permanent impairment and/or damage. [www. the drugs and medical devices they prescribe, (See also SNOMED). fda.gov/medwatch/] dispense, or use. Reporting can be done online, by phone, or by submitting the MedWatch 3500 Registry: An organized system for the collection, Signal Detection: Detection of a safety signal form by mail or fax. [www.fda.gov/medwatch/] storage, retrieval, analysis, and dissemination of (see also Safety Signal). information on individual persons exposed to a NCPDP: National Council for Prescription Drug common factor that predisposes them to the SNOMED: Systemized Nomenclature of Programs – ANSI-accredited Standards occurrence of a health-related event. This Medicine – Universal healthcare terminology that Development Organization (SDO) which creates common factor may include exposure to a enables clinicians, researchers, and patients to and promotes standards for the transfer of data specific medical intervention, a particular share healthcare knowledge worldwide across to and from the pharmacy services sector of the disease, condition, or , or substances clinical specialties and sites of care. SNOMED healthcare industry. [www.ncpdp.org] (see also (or circumstances) known or suspected to cause RT and NHS Clinical Terms Version 3 (READ HL7) adverse health effects. Codes) were combined into SNOMED CT (Clinical Terms) – a single, Non-: All adverse events Reporting Rate: (see Incidence Rate). terminology with a comprehensive structure to not classified as a serious adverse event support electronic health records). [www. RiskMAP: Risk Minimization Action Plan – A snomed.org] (see also READ Codes). Pharmacoepidemiology: Study of the utilization strategic safety program designed to meet and effects of drugs in large numbers of people. specific goals and objectives in minimizing Spontaneous Report: Unsolicited communication To accomplish this, pharmacoepidemiology known risks of a product while preserving its by healthcare professionals or consumers to a borrows from both pharmacology (study of the benefits. A RiskMAP targets one or more safety- company, regulatory authority or other effect of drugs) and (study of the related health outcomes or goals and uses one organization (e.g. WHO, Poison Control Center) distribution and determinants of in or more tools to achieve these goals. that describes one or more adverse drug populations). [www.pharmacoepi.org] [http://www.fda.gov/cber/gdlns/riskminim.htm] reactions in a patient (not deriving from a study or organized data collection scheme) who was Pharmacovigilance: Scientific and data gathering Safety Signal: An excess of adverse events given one or more medicinal products. activities relating to the detection, assessment, compared to what would be expected to be understanding and prevention of adverse events associated with a product’s use. Signals Unexpected Adverse Event: (see Adverse Event) – including, to the extent possible, understanding generally indicate the need for further the nature, frequency, and potential risk factors investigation, which may or may not lead to the Unlabeled (Unexpected) Adverse Event: An of the adverse events. conclusion that the product caused the event, adverse event that is not one of the known whether the product represents a potential safety adverse events listed on the product package PHI: Protected Health Information (see also risk, and/or whether other risk mitigation actions insert (PI) HIPAA Privacy Rule). should be taken. (See also Incidence Rate, Reporting Rate and Background Rate). PI: Prescribing Information / Package Insert – Prescription drug product’s FDA approved Serious Adverse Event (SAE): An adverse event labeling which contains a compilation of that results in any of the following outcomes: information about the product, including death, a life-threatening adverse drug information necessary for safe and effective use. experience, inpatient hospitalization or prolonged

26 | Unlocking the power of pharmacovigilance Health Research Institute Alison Detwiler Michael Swanick Research Analyst, Health Research Institute, Partner, Global Pharmaceutical Tax Leader Jim Henry and Manager, Tax Services [email protected] Partner, Health Industries Leader [email protected] +[1] (267) 330-6060 [email protected] +[1] (703) 610-7459 +[1] (678) 419-2328 Attila Karacsony Director, Global Pharmaceutical Industry Marketing David Chin Health Research Institute Advisory Partner, Health Research Institute Leader [email protected] [email protected] Team +[1] (973) 236-5640 +[1] (617) 530-4381 Anthony L. Farino Sandy Johnston Sandy Lutz Partner, U.S. Pharmaceutical and Life Sciences Director, European Pharmaceutical and Life Director, Health Research Institute Advisory Services Leader Sciences—R&D Advisory [email protected] [email protected] [email protected] +[1] (214) 754-5434 +[1] (312) 298-2631 +[44] 20 7213 1952

Hindy Shaman Michael Mentesana Mike Cunning Director, Health Research Institute Director, U.S. Pharmaceutical and Life Sciences Director, Pharmaceutical Data Management [email protected] Advisory R&D Services Leader Group +[1] (703) 453-6161 [email protected] [email protected] +[1] (646) 471-2268 +[1] (973) 236-4493 Benjamin Isgur Assistant Director, Health Research Institute Simon Friend Kate N. Maloney [email protected] Partner, Global Pharmaceutical Industry Leader Manager, U.S. Pharmaceutical and Life +[1] (214) 754-5091 [email protected] Sciences—Clinical Advisory +[44] (20) 7213 4875 [email protected] Bernard J. D’Avella +[1] (267) 330-1450 Research Analyst, Health Research Institute, Mark Simon and Senior Associate, U.S. Pharmaceutical Partner, U.S. Pharmaceutical Industry Leader Anup Kharode and Life Sciences Advisory [email protected] Senior Associate, U.S. Pharmaceutical and Life [email protected] +[1] (973) 236-5410 Sciences Advisory +[1] (973) 236-4510 [email protected] Eddy Schuermans +[1] (267) 330-1357 Rathish K. Moorthy Partner, EMEA Pharmaceutical Advisory Services Research Analyst, Health Research Institute, Leader Frank P. DePaoli and Associate, Health Industries Advisory [email protected] Senior Associate, U.S. Pharmaceutical and Life [email protected] +[32] (0)2 710 4004 Sciences Advisory +[1] (703) 918-1414 [email protected] Steve Arlington +[1] (973) 236-5267 Annie Chu Partner, Global Pharmaceutical and Life Sciences Research Analyst, Health Research Institute, Advisory Services Leader and Associate, Health Industries Advisory [email protected] [email protected] +[44] (0) 20 780 43997 +[1] (703) 918-3391

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