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
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
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
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.
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