The Risk Management Mandate

Last year, FDA released a series of concept papers that summarized the agency's plans for risk management. One described a new mandate for the pharmaceutical industry: to develop a risk management plan (RMP) for each drug, to be submitted to FDA at the time of the new drug application. The concept papers still need to be finalized and converted into a guidance (a document that explains how companies may comply with FDA regulations), but the mandate is likely to go into effect this year.

Risk management is the continuing process of minimizing risks throughout a product's lifecycle to optimize its benefit/risk balance. A risk management program is a strategic safety plan designed to decrease product risk by using one or more interventions or tools. Such tools extend beyond the package insert and routine post-marketing surveillance. An RMP also includes the background, research, rationale, and logic necessary to develop and implement the strategy and tactics for the program.

Developing an RMP requires pharma companies to think through not only how a drug is supposed to be used—the indications, contraindications, precautions, and warnings—but also how it will be used or misused by prescribers, dispensers, and patients throughout its lifecycle. To do so, RMP drafters must seek to influence the behavior of all of the parties responsible for drug safety, particularly patients, physicians, pharmacists, and allied medical staff. This is not an easy task, as evidenced by evaluations of current RMPs such as for Roche's Accutane (isotretinoin). Therefore, a reasonable RMP must demonstrate that the company understands the limits of various tools intended to manage risks, that it will use adequate interventions to control risks, and that it will evaluate the impact of its RMP with sufficient specificity to improve outcomes if it does not reach reasonable effectiveness targets.

Communication Tools

Although FDA's risk management concept paper provides pharma companies with a clear set of directions on the format for RMP submissions, to compile the plan, pharma drafters must apply an appropriate analytical framework, along with insights from original research. This article outlines how pharma companies can approach RMP development.

Level of Risk

Although FDA states that pharma companies need to consider an RMP for all drugs, for many drugs, professional labeling, routine post-marketing surveillance, and perhaps some form of patient labeling will be sufficient. For some drugs, however, pharmaceutical companies must plan for a more aggressive RMP. For drugs for serious or life-threatening illnesses, such as cancer and AIDS, there is a great deal more tolerance for personal risk than for drugs used for cosmetic purposes, such as acne or head lice. Yet even for life-saving drugs, when the risk posed has the potential to be prevented, companies must seriously consider an RMP.

The starting point for any RMP is to obtain as complete a knowledge as possible of the product's safety hazards. Some hazards may be suspected and subjected to continuing post-marketing surveillance. There is always debate about which signals denote real risks and which denote false positives. Following the precautionary principle, even suspected risks will likely require some risk intervention, even if it means only notifying prescribers of the possibility. The proposed package insert will serve as the best source of information about the product's known or suspected risks and the be the best basis for risk management planning.

Drugs that have serious or life-threatening contraindications, warnings, precautions, or adverse effects are the most likely candidates for risk management interventions. Patient behaviors that can mitigate risks, such as pregnancy prevention, blood tests, overdose/misuse avoidance, and awareness and action related to specific safety signals (hypersensitivity reaction, depression, and suicide), will also need to be addressed in an RMP. When people other than the patient may be at risk—by using the product inadvertently—an RMP may also be required.

FDA has specified four levels of risk management:

• Level 1: package insert only

• Level 2: level 1 plus education and outreach to health professionals and patients/consumers

• Level 3: level 2 plus systems that guide the prescribing, dispensing, or receipt of a product

• Level 4: level 3 plus patient adherence to program elements.

It is likely FDA will not require any formal specification of risk management levels in its final guidance. In the past, the industry objected to the concept of specifying levels out of concern that a competitor company could mischaracterize a drug's level as a signal of risk. However, the agency will probably presume that the proper application of risk management requires the progressive application (or "layering") of risk management tools. These tools must be targeted at solving the problems associated with particular pharmaceutical risks and applied with sufficient specificity to mitigate the attendant risks.

Step by Step

The concept paper outlines a three-step process for developing an RMP.

Goals. First, the paper says that each plan must specify the overall goals of the product's risk management program—the desired endpoints for safe product use. For example, if a drug causes birth defects, a reasonable goal would be that no women who are pregnant be given the drug. A second goal might be that no women should become pregnant while taking the drug. It should be noted that goals may never be fully met. However, making progress toward meeting the goal, rather than actually achieving it, may be an acceptable outcome.

Double Test

Objectives. Next, FDA calls for companies to identify a series of objectives for each goal. The objectives must be specific and measurable. They must outline the behaviors and processes necessary for the stated goals to be achieved. For example, if the goal is to prevent pregnancy while taking the product, the RMP may specify an objective that all women must have a pregnancy test within seven days of initiating therapy. Objectives often identify the particular individual—patient, pharmacist, physician, or allied health professional—responsible for the desired behavior. This aids in developing a communications plan directed at that individual, which will likely be a core element of the RMP.

Tools. Pharma companies must also select a series of tools designed to intervene and mitigate risks. Three general types of tools are available. The first set of tools is used for the dissemination of information to the responsible individual. Companies can use several communication tools to provide a coordinated and augmented message. Each tool is focused on an essential communication objective, and there may be multiple redundancies built into the informational interventions.

There are also tools that provide educational or certification processes. These tools may either provide feedback for educational purposes so that knowledge deficits may be corrected on an individual level or they may test the individual to determine his or her qualifications or competency for administration, dispensing, or use of the medication.

The third group of tools applies systems that influence or control the dispensing of the medication. These systems may limit use to patients who have undergone certain testing that demonstrates their ability to continue to use the product. For example, blood testing may be used to check for the occurrence of adverse reactions, so that the drug may continue to be used in a safe manner.

By Design

The FDA concept paper asks companies to select and justify their choice of tools. To do so, companies need to develop a conceptual model for how their drugs are used and what system failures may lead to product misuse. In addition to relying on a systems analysis, using a behavioral model of product use—how beliefs, motives, and situational constraints influence the way a drug is used—can help determine a coordinated set of tools and specify core messages that must be communicated or systems that must be implemented to define the elements of the RMP.

A good starting point for developing a drug-use model is to identify the various steps necessary to use a medication properly. Failure Mode and Effects Analysis (FMEA) is a systematic analysis of how failures may occur in any system. It identifies steps or elements where mistakes may occur, before the system is implemented.

FMEA is a complement of root-cause analysis, which is aimed at identifying the source of a system's failure once a mistake is identified. An effective FMEA identifies corrective actions required to prevent failures and to assure the highest possible system quality.

To undertake an FMEA, pharma companies must identify potential failure modes. This action may be broken down into subprocesses, with each step in the system being considered a separate element with the potential for failure. Each of the postulated steps where failure might occur should be assigned a severity value, a probability that a given effect might occur, and a likelihood value that a user may detect (and correct) the problem. Recommended actions are then developed to increase detectability, to reduce the probability, and, most important, to decrease the severity of harm. Priority is given to problems with the highest index of probability and severity.

Although it was developed as a method to improve product quality, an FMEA can only be as good as the quality of the system description. Specifying steps too broadly can miss important elements. For example, after consultants performed a system analysis for a medications error problem in which pharmacists were dispensing the incorrect medication to patients, they found that the pharmacists were dispensing the drug that physicians had identified.

Although it is usually assumed that medication errors are caused by pharmacists' difficulty reading physicians' handwriting, in this case the problem was that physicians recalled the incorrect drug name from memory when they wrote the prescription. If they had used an FMEA that did not specify the need for the physician to recall the correct drug name from memory, the consultants would have missed an important source of error.

The Human Factor

In addition, to specify the subprocesses, pharma companies and their RMP crafters need to understand the system from the perspective of the individuals who are performing the tasks involved. The relationship between knowledge and behavior is not direct or simple. People often know what they should do but fail to behave in a fashion that is consistent with that knowledge. To develop a predictive model, it is necessary to understand the:

• full set of beliefs underlying behavioral intentions

• motivations that support or stand in the way of exhibiting desired behavior

• environmental conditions that facilitate or place barriers to compliance.

There are a variety of psychological and health behavior models that can be used to organize these influences. Some models may improve the processing of presented information, for example, by improving patients' involvement (personal relevance) or competency (self-efficacy) with the information or advocated behavior.

Some models may help RMP crafters understand the processes underlying the choices among alternative courses of behavior (behavioral decision making). Other models may help structure advocated behaviors into a series of stages, permitting messages that seek to move patients and physicians through necessary stages to attain behavioral compliance (precaution adoption or stage models). Still, other models attempt to motivate compliance through emotion (positive affect or fear appeals) or through highlighting desired outcomes (approach or avoidance goals).

Determining which model to use depends on the particular problem addressed. If the RMP advocates complex behaviors (such as avoiding drug dependency), it may be necessary to move respondents through a series of stages to overcome situational barriers. If the plan calls for simpler behaviors (such as standing upright when taking tablets), offering a strong, even emotional, rationale for compliance and a reminder system might provide the best model to influence behavior. Diagnosing the behavioral problem and selecting (or custom building) the correct behavioral model can produce a clear method for the design of the RMP.

Because companies are dealing with programs that are expected to reach and influence the vast majority of participants, it may be difficult to anticipate the full range of issues influencing the behavior of all patients and healthcare professionals. Research studies that provide insights into the issues are invaluable. Identifying particular at-risk patient segments can also help companies design program interventions targeted at particular failure modes for a specified group of individuals.

Interventions

Implementing an RMP involves the dissemination of information to participants. Multiple interventions or multiple distribution methods are often required, if for no other reason than for the redundancy needed to ensure exposure to the key messages. For patient information, there are several communication vehicles, each with a slightly different purpose. (See "Communication Tools.") The vehicle(s) selected should be based on the purpose of the communication. If patient commitment to a long-term behavior is an issue, a patient agreement or contract may be advised. If situational cues are needed, packaging reminders or telephone calls may the right intervention. Tools should match the need for particular impact.

A broad process model may help companies select the right communication tools. One process model specifies that for communications to influence behavior, participants must:

• be exposed to the information

• pay attention to the communication

• understand what is advocated

• accept the persuasive intent

• remember the message

• incorporate the message in their decision-making process

• display the advocated behavior over the time period as needed.

Designing a set of communications that will fulfill all of these steps is complex and requires some tradeoffs. For example, exposing patients to the message may be accomplished by delivering the information in the medication package. But patients may not pay attention to a long document written in small type on thin paper. Thus, a smaller document that provides key messages may be more likely to be noticed. That, in turn, may be augmented by a longer brochure provided by the physician or pharmacist that explains the rationale for advocated behaviors. Adding a reminder program, such as warning symbols on the package, could also help stimulate the advocated behaviors and provide a more complete communications program.

Information Transfer

Drafting risk management communications requires attention to both the content and the style and format of the communication.

Content. The intended message needs to be clearly specified. Developing a list of communication objectives (COs) can help identify key messages for any document. COs may also be used to assess the effect of the communication and the RMP in general. To develop this list, it is important to rely on the FMEA system, the behavioral model, and the base beliefs of the target audience. Some risk communication experts advocate a mental-models approach to specifying content. In this case, the base beliefs of health experts are compared with those of recipients of the communication.

Areas in which the belief systems vary are highlighted to assure that the risk communication concentrates on areas where information is most needed. To the fullest extent possible, COs should be lean and focused. Too many COs can reduce the likelihood of communicating any single CO. For complex messages, specifying primary and secondary COs will help to organize the information to be communicated.

Style. The design of the communication also needs to match the objective's intent. Primary messages need to be emphasized by "signals" such as placement, graphics, and language. There are a number of document design principles that companies can use to help to make the communications clear and comprehensible. For example, short sentences, vivid and understandable terminology, and avoiding extraneous information can help to reduce the cognitive load of any communication and aid in achieving high levels of comprehension.

The first group of communication tools involves the one-way transfer of information. With well-designed documents and repeated interventions, the probability increases that key messages will be communicated. However, an education program that tests individual respondents' understanding of the messages can go a long way toward improving communication. Another group of tools involves the development of educational or certification systems. Using an interactive voice response (IVR) system, pharmaceutical companies can enroll patients in a system that surveys knowledge, based on the communication objectives. After tests are scored, a feedback message can be delivered to physicians and patients. The feedback message reinforces areas in which key messages were understood and provides tailored feedback and emphasized education in the areas in which the key messages were not understood.

This focus on the patient's knowledge—as opposed to the content and format of the message—improves the likelihood that patients and physicians will comprehend the company's core messages. By testing for beliefs, motivations, decision making ability, and behavioral intent, feedback forms can provide a variety of messages that are intended to influence behavior beyond mere knowledge transfer. Applying the test before prescribing the therapy establishes minimum test scores and assures the company that only competent patients are certified to receive prescriptions for the product.

The third class of intervention tools are used to control the distribution of the medication. Limiting distribution to patients who have provided evidence of compliance with advocated behaviors such as blood testing requires coordinated efforts and enhanced communication among prescribers, dispensers, patients, and sometimes others, such as those conducting laboratory tests.

A distribution control system may require training and commitment by healthcare providers to assure that the communication channels perform as designed. It may also require the development of a new distribution system—such as the use of a sticker on the prescription pad or the issuance of a debit card that must be engaged by the physician before the pharmacist can distribute the medicine. Evaluation programs are typically necessary to assure that these complex programs perform as designed.

Does It Work?

Finally, the FDA concept paper implores pharma companies to test their risk management interventions and to evaluate the RMP. Individual tools should be tested to assure that they meet their intended purposes. For example, it is important that patients be able to comprehend key warnings and be motivated to engage in the advocated behaviors that will prevent harm. By using quantitative testing methods, such as studies that question consumers at shopping malls, pharma companies can assess draft communications to determine if core communication objectives are comprehended. Messages that are not well communicated can be analyzed and re-crafted.

Comprehension testing has become routine in the development of over the counter (OTC) labels. These labels are often drafted several times—changing language, placement, and graphic emphasis—to develop an easily understood label. Comprehension testing not only assesses the communication of core messages, it also allows the measurement of other outcomes, such as belief change and persuasion, the ability to problem solve and influence decisions, and the ability to analyze the impact of the communication on behavioral intentions. Testing communications before implementing them—including those directed at healthcare professionals—may not only improve the tool's utility but also may protect the company from product liability. (See "Double Test.")

Rather than advocate the need to achieve a specified level of performance, each RMP should advocate continuous quality improvement. Before the program is implemented, it may not be possible to understand the degree of noncompliance. It also may not be possible to understand the cause of system failures. Overly burdensome programs may inhibit product use by making prescribers unwilling to try the drug or by making it difficult for patients to obtain the product. These and other unintended consequences may also be assessed through a survey evaluation of the product. By examining the intermediate impacts and modifying the program to shore up the weaknesses, risk management planners can continue to improve the program.

Benefits for All

Companies must propose to FDA reasonable and competent programs for the drug to be accepted for marketing. FDA cannot accept programs that are shown to be ineffective; nor is it reasonable for a program to be fully effective without some trial. Thus, companies must make a commitment to develop and achieve effective RMPs. The alternative, withdrawing the drug from the market, offers little solace to either the pharma company or the patients who need access to the medication.

Risk management provides both a challenge and opportunity for pharma companies. It forces companies to understand not only how a drug treats disease, but how it is used. It also forces companies to develop a coherent set of interventions intended to influence use. Developing such information tools and systems will benefit patients and providers by improving the safe use of medicines. It should also benefit pharma companies, not only by improving drug safety, but by building trust and support and by increasing personal responsibility for safe drug use.