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U.S. Department of Health and Human Services

Animal & Veterinary

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A Contemporary Approach to Risk Analysis in GFI #152

by H. Gregg Claycamp, Ph.D.
FDA Veterinarian Newsletter January/February 2003 Volume XVIII, No 1

In the FDA's mission "to promote and protect the public health . . . and [monitor] products for continued safety after they are in use," the Agency relies regularly on the principles and practice of risk analysis. CVM is likewise using risk analysis for approving new animal drug applications, in surveillance and compliance activities, and for its business planning. This essay describes the risk assessment model recently adapted by CVM for antimicrobial resistance risk assessment.

Risk analysis encompasses four major elements: hazard identification, risk assessment, risk management, and risk communication. These elements include the processes by which public health agencies recognize public health hazards, prioritize resources to prevent or mitigate health risks, monitor the successes and failures of public health initiatives, and communicate hazards and risks to the public and industry stakeholders. Two of the four activities, hazard identification and risk assessment, rely primarily on objective scientific and statistical methods-the facts of hazards and risks. The remaining two activities, risk management and risk communication, involve consideration of legal and economic constraints, cost-benefit analysis, and public tolerance for risk-the societal values pertaining to hazards and risks. For many public health risks, the natural tendency for tension between objective and subjective processes or between societal values and economic limits to resources for risk management often embroil risk analyses in lively and prolonged debates.

Risk assessment is a process in risk analysis in which information about the potential exposures to identified hazards is analyzed in order to inform a risk decision to be made by risk managers. Risk, broadly defined as exposure to a chance of loss, can arise in almost any activity in life. Most individual decisions to engage in risky activity or exposure are made intuitively- i.e., accomplished immediately and without conscious use of reasoning- and without the need to analyze the probability of harm, the quantity of exposure, and the subsequent probability of loss. For example, it is known by anyone past a very young age that crossing a busy street involves exposure to the hazards of moving vehicles and the risk of injury or death. It is unlikely that anyone would commission a quantitative study to inform the personal decision to cross the street: this decision is made intuitively. Yet, the incredible breadth of risk analysis in human endeavors is evident in the fact that a team of municipal risk managers might approach essentially the same risk decision (to define a crossing point on the same busy street) by commissioning a formal risk assessment to inform their decisions about how to manage the risk. Both the mind's intuitive process and the formal process capture qualitatively the same kinds of information for the decision about crossing: the nature of the hazard (i.e., trucks, cars, or bicycles), the magnitude of potential exposure (traffic density), and the likelihood of successful crossing. The difference between the two decisions is largely in the degree of sophistication of the analyses and the formality of the decisionmaking steps.

The past few decades have witnessed an exponential increase in our understanding of health risks and of how to use risk assessment to inform risk management decisions to allocate scarce resources for the management or prevention of public health risks. Numerous risk analysts and theorists have participated in this growth by contributing to the development of risk analysis paradigms that can capture the logical reasoning and technical know-how in their respective scientific fields. Very recently, CVM contributed to these developments by proposing a qualitative risk assessment process for pre-market approvals of antimicrobial new animal drugs.1 Although CVM's qualitative model adapts a contemporary approach to risk assessment, it is based on the fundamental scientific principles shared by all risk assessment paradigms.

Similar to most contemporary health risk assessment models, the CVM model in Guidance for Industry (GFI) #152 evolved from The National Research Council report to the National Academy of Sciences (NAS), Risk Assessment in the Federal Government: Managing the Process.2 This report, also known as the "Red Book" for its red cover, is often cited as providing the definitive paradigm for risk assessment. Although developing a paradigm was not one of the committee's charges, the risk assessment model evolved naturally from the committee's consideration of "the current practice of risk assessment and its relation to the process of regulations of hazards to human health." Viewed with the clarity of hindsight, the committee's outline of the common processes used in health risk assessment helped to focus a discussion among risk assessors toward defining risk assessment paradigms that have broad applicability in public health.

According to the Red Book, risk assessment is "the characterization of the potential adverse health consequences of human exposures to environmental hazards" (p.18). Although the definition is often modified to fit specific types of hazards, it is generic enough to suffice as a basic definition for this discussion. The risk assessment process was divided into four processes ("steps") of hazard identification, dose-response assessment, exposure assessment, and risk characterization. The first three processes are combined in the risk characterization process to produce the risk assessment that informs risk management decisions.

Hazard identification, the first step in the Red Book model, answers the question, "Can the biological, physical, or chemical agent cause an adverse health effect in humans, given an exposure?" In some if not most health risk assessments, hazard identification is retrospective, derived from observations in epidemiological studies of associations between exposures to specific hazards and the occurrence of adverse health effects.

In the second step of the four-step paradigm, the focus is on how much of the hazardous agent is necessary to be ingested, inhaled, or absorbed to elicit an adverse health effect in the exposed individuals. This information is needed not only to understand the severity of the risk, but also to project future risk given a projected exposure.

The third step of the four-step paradigm, exposure assessment, deals with the question of how much of the hazardous agent is presented to the individual or "receptor" in various environmental (including dietary) pathways. A complete exposure assessment estimates the duration, intensity, and likelihood of exposures of a given intensity and duration occurring in a given population or individual.

Finally, risk characterization is the step in which the results of the other three steps of risk assessment are analyzed and risk is estimated. Risk characterization considers the quality of the data, the likelihood that plausible cause and effect (biological) models have been proposed, and the statistical uncertainty in the overall estimate of risk. While still part of the overall "objective" process of risk assessment, risk characterization usually reviews multiple risk scenarios (derived from multiple exposure scenarios) and relies on professional judgment for identification of the most appropriate scenario(s) for risk estimation.

Public Understanding

During the past two decades, there has been much growth in the public's understanding of risk and risk analysis. Additionally, numerous risk scholars and practitioners discussed the merits of various risk analysis paradigms for diverse kinds of hazards and adverse health outcomes. Out of this discussion has developed an understanding of the recursive nature of risk analysis: health hazards are identified and prioritized for attention, risks from exposures to the hazards are assessed, risk management decisions are made, and-given new information about the risks-the process repeats itself in a new prioritization of the health hazards. A second realization about risk analysis is that some health hazards are identified but a formal risk assessment is not initiated due to scarce risk assessment resources. Finally, public interest in health risks, coupled with increasing demands for transparency in governmental decision making, have led to growth in risk communication as a distinct and important process within risk analysis. These features have combined to justify the contemporary approaches to risk analysis.

CVM's Risk Assessment Model in GFI #152

The evolution of risk analysis continues as CVM adapts contemporary risk analysis for approvals of antimicrobial new animal drugs for food animal uses. The proposed model in GFI #152 is an adaptation of the paradigm proposed by the Office International des Epizooties (OIE) (Figure 1).3 CVM believes that this contemporary model offers a convenient compartmentalization of the information needed for specialized risk assessments in NADAs as they apply to issues in human food safety. For example, the human food exposure pathway for either residues of animal drugs or resistance determinants from the use of animal antimicrobial drugs is a complex exposure beginning on the farm and ending in the human intestine. CVM believes that it is convenient to compartmentalize the animal-based components of the risk assessment paradigm in the release assessment and the human-dominant factors in the remaining portion of exposure assessment.

The departures of the CVM paradigm from the classical, four-step paradigm are first, the exposure assessment phase is divided into two parts, release assessment and exposure assessment and, second, consequence assessment is used in place of the more narrowly defined concept of dose-response assessment from the Red Book's four-step paradigm. Otherwise, the organization of the steps or elements of risk analysis are similar to those widely used in the practice of health risk assessment.

A final note on contemporary risk assessment paradigms: risk analysis paradigms are logical processes and frameworks for the organization of information to inform a risk management decision. It should be apparent that the goal is to bring organized and high-quality risk information to a risk management decision. Thus, flexibility in how this is accomplished is mentioned in the preamble to GFI #152: "An alternate approach may be used as long as it satisfies the requirements of applicable statutes and regulations." In fact, contemporary risk analysis is a process that encourages deliberation and analysis under a goal of reducing uncertainties in risk management decisions. CVM recently invited comments on the proposed Guidance and will continue to encourage new ideas and methods for using risk assessment to inform risk management decisions.

[Table follows]


The release assessment describes the probability that factors related to the antimicrobial new animal drug and its use in animals will result in the emergence of resistant bacteria or resistance determinants in the animal.

The exposure assessment describes the likelihood of human exposure to the hazardous agent through particular exposure pathways. The exposure assessment should provide a qualitative estimate of the probability of this exposure occurring.


The consequence assessment describes the relationship between specified exposures to a biological agent (the hazardous agent) and the consequences of those exposures.


The risk estimation integrates the results from the release assessment, exposure assessment, and consequence assessment to produce an overall estimate of the risk. All three elements of the risk assessment process are important contributing factors and should be integrated and considered as a whole when assessing the risk.

Dr. Claycamp is Director of CVM's Scientific Support & Generic Animal Drug Staff.

  1. Guidance for Industry #152, "Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern."
  2. National Research Council, Risk Assessment in the Federal Government: Managing the Process Washington, DC: National Academy Press, (1983). See http://www.nap.edu/.
  3. OIE Ad hoc Group on Antimicrobial resistance, Office International des Epizooties, Organisation Mondiale de la Santé Animale (World Organization for Animal Health), Guideline No. 1, Risk Methodology for the Potential Impact on Public Health of Antimicrobial Resistant Bacteria of Animal Origin.