This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

I. INTRODUCTION

This document provides guidance to industry on good risk assessment practices during the development of prescription drug products, including biological drug products.[2] This is one of three guidances that were developed to address risk management activities. Specifically, this document discusses the generation, acquisition, analysis, and presentation of premarketing safety data.

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND

A. PDUFA III’s Risk Management Guidance Goal

On June 12, 2002, Congress reauthorized, for the second time, the Prescription Drug User Fee Act (PDUFA III). In the context of PDUFA III, FDA agreed to satisfy certain performance goals. One of those goals was to produce guidance for industry on risk management activities for drug and biological products. As an initial step towards satisfying that goal, FDA sought public comment on risk management. Specifically, FDA issued three concept papers. Each paper focused on one aspect of risk management, including (1) conducting premarketing risk assessment, (2) developing and implementing risk minimization tools, and (3) performing postmarketing pharmacovigilance and pharmacoepidemiologic assessments. In addition to receiving numerous written comments regarding the three concept papers, FDA held a public workshop on April 9-11, 2003, to discuss the concept papers. FDA considered all of the comments received in developing three draft guidance documents on risk management activities.

The draft guidance documents were published on May 5, 2004, and the public was provided with an opportunity to comment on them until July 6, 2004. FDA considered all of the comments received in producing the final guidance documents.

· Premarketing Risk Assessment (Premarketing Guidance)

· Development and Use of Risk Minimization Action Plans (RiskMAP Guidance)

· Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance).

B. Overview of the Risk Management Guidances

Like the concept papers and draft guidances that preceded them, each of the three final guidance documents focuses on one aspect of risk management. The Premarketing Guidance and the Pharmacovigilance Guidance focus on premarketing and postmarketing risk assessment, respectively. The RiskMAP Guidance focuses on risk minimization. Together, risk assessment and risk minimization form what FDA calls risk management. Specifically, risk management is an iterative process of (1) assessing a product’s benefit-risk balance, (2) developing and implementing tools to minimize its risks while preserving its benefits, (3) evaluating tool effectiveness and reassessing the benefit-risk balance, and (4) making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance. This four-part process should be continuous throughout a product’s lifecycle, with the results of risk assessment informing the sponsor’s decisions regarding risk minimization.

When reviewing the recommendations provided in this guidance, sponsors and applicants should keep the following points in mind:

· Many recommendations in this guidance are not intended to be generally applicable to all products.

Industry already performs risk assessment and risk minimization activities for products during development and marketing. The Federal Food, Drug, and Cosmetic Act (FDCA) and FDA implementing regulations establish requirements for routine risk assessment and risk minimization (see e.g., FDA requirements for professional labeling and adverse event monitoring and reporting). As a result, many of the recommendations presented here focus on situations in which a product may pose a clinically important and unusual type or level of risk. To the extent possible, we have specified in the text whether a recommendation is intended for all products or only this subset of products.

· It is of critical importance to protect patients and their privacy during the generation of safety data and the development of risk minimization action plans.

During all risk assessment and risk minimization activities, sponsors must comply with applicable regulatory requirements involving human subjects research and patient privacy.[3]

· To the extent possible, this guidance reflects FDA’s commitment to harmonization of international definitions and standards.

· When planning risk assessment and risk minimization activities, sponsors should consider input from healthcare participants likely to be affected by these activities (e.g., from consumers, pharmacists and pharmacies, physicians, nurses, and third party payers).

· There are points of overlap among the three guidances.

We have tried to note in the text of each guidance when areas of overlap occur and when referencing one of the other guidances might be useful.

III. THE ROLE OF RISK ASSESSMENT IN RISK MANAGEMENT

Risk management is an iterative process designed to optimize the benefit-risk balance for regulated products. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product. Risk assessment occurs throughout a product’s lifecycle, from the early identification of a potential product, through the premarketing development process, and after approval during marketing. Premarketing risk assessment represents the first step in this process, and this guidance focuses on risk assessment prior to marketing.

It is critical to FDA’s decision on product approval that a product’s underlying risks and benefits be adequately assessed during the premarketing period. Sponsors seeking approval must provide from the clinical trials a body of evidence that adequately characterizes the product's safety profile.[4]

This guidance provides general recommendations for assessing risk. The adequacy of the assessment of risk is a matter of both quantity (ensuring that enough patients are studied) and quality (the appropriateness of the assessments performed, the appropriateness and breadth of the patient populations studied, and how results are analyzed). Quantity is, in part, considered in other Agency guidances,[5] but it is discussed further here. This guidance also addresses the qualitative aspects of risk assessment.

Although risk assessment continues through all stages of product development, this guidance focuses on risk assessment during the later stages of clinical development, particularly during phase 3 studies. The guidance is not intended to cover basic aspects of preclinical safety assessments (i.e., animal toxicity testing) or routine clinical pharmacology programs. Good clinical risk assessment in the later stages of drug development should be guided by the results of comprehensive preclinical safety assessments and a rigorous, thoughtful clinical pharmacology program (including elucidation of metabolic pathways, identification of possible drug-drug interactions, and determination of any effects from hepatic and/or renal impairment). These issues are addressed in other FDA guidances and guidances developed under the auspices of the International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

IV. GENERATING RISK INFORMATION DURING CLINICAL TRIALS

Providing detailed guidance on what constitutes an adequate safety database for all products is impossible. The nature and extent of safety data that would provide sufficient information about risk for purposes of approving a product are individualized decisions based on a number of factors (several of which are discussed below). In reaching a final decision on approvability, both existing risk information and any outstanding questions regarding safety are considered in a product’s risk assessment and weighed against the product’s demonstrated benefits. The fewer a product’s demonstrated benefits, the less acceptable may be higher levels of demonstrated risks. Likewise, the fewer the benefits, generally, the less uncertainty may be accepted about a product’s risks.

To maximize the information gained from clinical trials, FDA recommends that from the outset of development, sponsors pay careful attention to the overall design of the safety evaluation. Potential problems that may be suspected because of preclinical data or because of effects of related drugs should be targeted for evaluation. And, because it is impossible to predict every important risk, as experience accrues, sponsors should refine or modify their safety evaluations.

A. Size of the Premarketing Safety Database

Even large clinical development programs cannot reasonably be expected to identify all risks associated with a product. Therefore, it is expected that, even for a product that is rigorously tested preapproval, some risks will become apparent only after approval, when the product is used in tens of thousands or even millions of patients in the general population. Although no preapproval database can possibly be sized to detect all safety issues that might occur with the product once marketed in the full population, the larger and more comprehensive the preapproval database, the more likely it is that serious adverse events will be detected during drug development.

The appropriate size of a safety database supporting a new product will depend on a number of factors specific to that product, including:

· Its novelty (i.e., whether it represents a new treatment or is similar to available treatment)

· The availability of alternative therapies and the relative safety of those alternatives as compared to the new product

· The intended population and condition being treated

· The intended duration of use

Safety databases for products intended to treat life-threatening diseases, especially in circumstances where there are no alternative satisfactory treatments, are usually smaller than for products intended to treat diseases that are neither life-threatening nor associated with major, irreversible morbidity. A larger safety database may be appropriate if a product’s preclinical assessment or human clinical pharmacology studies identify signals of risk that warrant additional clinical data to properly define the risk. The appropriate size of the preapproval safety database may warrant specific discussion with the relevant review division. For instance, 21 CFR 312.82(b) (subpart E) provides that for drugs intended to treat life-threatening and seriously debilitating illnesses, end-of-phase 1 meetings can be used to agree on the design of phase 2 trials “with the goal that such testing will be adequate to provide sufficient data on the drug’s safety and effectiveness to support a decision on its approvability for marketing.”

For products intended for short-term or acute use (e.g., treatments that continue for, or are cumulatively administered for, less than 6 months), FDA believes it is difficult to offer general guidance on the appropriate target size of clinical safety databases. This is because of the wide range of indications and diseases (e.g., acute strokes to mild headaches) that may be targeted by such therapies. Sponsors are therefore encouraged to discuss with the relevant review division the appropriate size of the safety database for such products. Because products intended for life-threatening and severely debilitating diseases are often approved with relatively small safety databases, relatively greater uncertainty remains regarding their adverse effects. Similarly, when products offer a unique, clinically important benefit to a population or patient group, less certainty in characterizing risk prior to approval may be acceptable.

For products intended for long-term treatment of non-life-threatening conditions, (e.g., continuous treatment for 6 months or more or recurrent intermittent treatment where cumulative treatment equals or exceeds 6 months), the ICH and FDA have generally recommended that 1500 subjects be exposed to the investigational product (with 300 to 600 exposed for 6 months, and 100 exposed for 1 year).[6] For those products characterized as chronic use products in the ICH guidance E1A, FDA recommends that the 1500 subjects include only those who have been exposed to the product in multiple dose studies, because many adverse events of concern (e.g., hepatotoxicity, hematologic events) do not appear with single doses or very short-term exposure. Also, the 300 to 600 subjects exposed for 6 months and 100 subjects exposed for 1 year should have been exposed to relevant doses (i.e., doses generally in the therapeutic range)

We note that it is common for well-conducted clinical development programs to explore doses higher than those ultimately proposed for marketing. For example, a dose tested in clinical trials may offer no efficacy advantage and show some dose-related toxicities; therefore, the sponsor does not propose the dose for marketing when the application is submitted. In such cases, data from subjects exposed to doses in excess of those ultimately proposed are highly informative for the safety evaluation and should be counted as contributing to the relevant safety database.

The E1A guidance describes a number of circumstances in which a safety database larger than 1500 patients may be appropriate, including the following:

1. There is concern that the drug would cause late developing adverse events, or cause adverse events that increase in severity or frequency over time. The concern could arise from:

· Data from animal studies

· Clinical information from other agents with related chemical structures or from a related pharmacologic class

· Pharmacokinetic or pharmacodynamic properties known to be associated with such adverse events

2. There is a need to quantitate the occurrence rate of an expected specific low-frequency adverse event. Examples would include situations where a specific serious adverse event has been identified in similar products or where a serious event that could represent an alert event is observed in early clinical trials.

3. A larger database would help make risk-benefit decisions in situations when the benefit from the product:

· Is small (e.g., symptomatic improvement in less serious medical conditions)

· Will be experienced by only a fraction of the treated patients (e.g., certain preventive therapies administered to healthy populations)

· Is of uncertain magnitude (e.g., efficacy determination on a surrogate endpoint)

4. Concern exists that a product may add to an already significant background rate of morbidity or mortality, and clinical trials should be designed with a sufficient number of patients to provide adequate statistical power to detect prespecified increases over the baseline morbidity or mortality.

The determination of whether the above provisions of the ICH E1A guidance are appropriate for a particular product development program and how these considerations would best be addressed by that program calls for evaluation on a case-by-case basis. Therefore, FDA recommends that this issue be discussed with the relevant review division at the end-of-phase 2 meeting, if not earlier.

In addition to the considerations provided in E1A, there are other circumstances in which a larger database may be appropriate.

1. The proposed treatment is for a healthy population (e.g., the product under development is for chemoprevention or is a preventive vaccine).

2. An effective alternative to the investigational product is already available and has been shown to be safe.

FDA is not suggesting that development of a database larger than that described in E1A is required or should be the norm. Rather, the appropriate database size would depend on the circumstances affecting a particular product, including the considerations outlined above. Therefore, FDA recommends that sponsors communicate with the review division responsible for their product early in the development program (e.g., at the pre-IND meeting) on the appropriate size of the safety database. FDA also recommends that sponsors revisit the issue at appropriate regulatory milestones (e.g., end-of-phase 2 and pre-NDA meetings).

B. Considerations for Developing a Premarketing Safety Database

Although the characteristics of an appropriate safety database are product-specific, some general principles can be applied. In general, efforts to ensure the quality and completeness of a safety database should be comparable to those made to support efficacy. Because data from multiple trials are often examined when assessing safety, it is particularly critical to examine terminology, assessment methods, and use of standard terms (e.g., use of the Medical Dictionary for Regulatory Activities (MedDRA)) to be sure that information is not obscured or distorted. Ascertainment and evaluation of the reasons for leaving assigned therapy during study (deaths and dropouts for any reason) are particularly important for a full understanding of a product’s safety profile.

The following elements should be considered by sponsors when developing proposals for their clinical programs as these programs pertain to risk assessment.

1. Long-Term Controlled Safety Studies

It is common in many clinical programs for much of subject exposure data and almost all of long-term exposure data to come from single-arm or uncontrolled studies. Although these data can be informative, it may be preferable in some circumstances to develop controlled, long-term safety data. Such data allow for comparisons of event rates and facilitate accurate attribution of adverse events. Control groups may be given an active comparator or a placebo, depending on the disease being treated (i.e., the ethical and medical feasibility of using a placebo versus an active comparator will depend on the disease being treated).

The usefulness of active comparators in long-term safety studies depends on the adverse events of interest.

· Generally, serious events that rarely occur spontaneously (e.g., severe hepatocellular injury or aplastic anemia) would be considered significant and interpretable whenever (1) they are clearly documented and (2) there is no likely alternative explanation, since the expected rate is essentially zero in populations of any feasible size. As a result, the events can usually be appropriately interpreted and regarded as a signal of concern whether or not there is a control group.

· On the other hand, control groups are needed to detect increases in rates of events that are relatively common in the treated population (e.g., sudden death in patients with ischemic cardiac disease). Control groups are particularly important when an adverse event could be considered part of the disease being treated (e.g., asthma exacerbations occurring with inhalation treatments for asthma).

Therefore, FDA decisions as to when long-term comparative safety studies should be conducted for a product should be based on the intended use of the product, the nature of the labeled patient population (e.g., more useful if there is a high rate of serious adverse events), and earlier clinical and preclinical safety assessments. Although it is clear that long-term controlled studies will not usually be conducted, such studies may be particularly useful when a safety issue is identified during earlier development of the drug. In these cases, safety studies designed to test specific safety hypotheses may be appropriate. This would be especially true in situations where the safety issue of concern is more common with cumulative exposure. (See section IV.D below for further discussion of comparative trials.)

2. A Diverse Safety Database

Premarketing safety databases should include, to the extent possible, a population sufficiently diverse to adequately represent the expected target population, particularly in phase 3 studies. FDA has previously addressed this issue in a memorandum,[7] and the recommendations provided here are intended to supplement that document. To the extent feasible, only patients with obvious contraindications or other clinical considerations that clearly dictate exclusion should be excluded from study entry. Inclusion of a diverse population allows for the development of safety data in a broad population that includes patients sometimes excluded from clinical trials, such as the elderly (particularly the very old), patients with concomitant diseases, and patients taking concomitant medications. Broadening inclusion criteria in phase 3 enhances the generalizability of the safety (and efficacy) findings. Although some phase 3 efficacy studies may target certain demographic or disease characteristics (and have narrower inclusion and exclusion criteria), overall, the phase 3 studies should include a substantial amount of data from less restricted populations.

3. Exploring Dose Effects Throughout the Clinical Program

Currently, it is common for only one dose, or perhaps a few doses, to be studied during drug development beyond phase 2. Yet, a number of characteristics common to many phase 2 studies limit the ability of these trials to provide definitive data on exposure-response or adequate data for definitive phase 3 dose selection. These characteristics of phase 2 studies (in comparison to phase 3 studies) include the following:

· Shorter durations of exposure

· Common use of pharmacodynamic (PD) endpoints, rather than clinical outcomes

· Smaller numbers of patients exposed

· Narrowly restrictive entry criteria

Although phase 3 trials do not necessarily need to examine a range of doses, such an examination is highly desirable, particularly when phase 2 studies cannot reasonably be considered to have established a single most appropriate dose. When a dose is not established in phase 2, more than one dose level should be examined in phase 3 trials of fixed dose products to better characterize the relationship between product exposure and resulting clinical benefit and risk. Dose-response data from phase 3 trials with multiple dose levels will help to better define the relationship of clinical response to dose for both safety and effectiveness. Furthermore, inadequate exploration of a product’s dose-response relationship in clinical trials can raise safety concerns, since recommending doses in labeling that exceed the amount needed for effectiveness may increase risk to patients through dose-related toxicities with no potential for gain. Exposure-response data from phase 3 trials can also provide critical information on whether dose adjustments should be made for special populations. Finally, demonstrating a dose-response relationship in late phase clinical trials with meaningful clinical endpoints may aid the assessment of efficacy, since showing a dose ordering to efficacy can be compelling evidence of effectiveness.[8] When multiple dose levels are examined in phase 3 trials, the appropriate choice of doses to be included in these studies would be based on prior efficacy and safety information, including prior dose-ranging studies. In these circumstances, an end-of-phase 2 meeting with the appropriate review division would be particularly useful.

C. Detecting Unanticipated Interactions as Part of a Safety Assessment

Even a well-conducted and reasonably complete general clinical pharmacology program does not guarantee a full understanding of all possible risks related to product interactions. Therefore, risk assessment programs should examine a number of interactions during controlled safety and effectiveness trials and, where appropriate, in specific, targeted safety trials. This examination for unanticipated interactions should include the potential for the following:

· Drug-drug interactions in addition to those resulting from known metabolic pathways (e.g., the effect of azole antibiotics on a CYP 3A4 dependent drug)

We recommend that these examinations target a limited number of specific drugs, such as likely concomitant medications (e.g., for a new cholesterol lowering treatment, examining the consequences of concomitant use of HMG CoA reductase inhibitors and/or binding resins). The interactions of interest could be based, for example, on known or expected patterns of use, indications sought, or populations that are likely users of the drug.

· Product-demographic relationships — by ensuring sufficient diversity of the population (including gender, age, and race) to permit some assessments of safety concerns in demographic population subsets of the intended population

· Product-disease interactions — by ensuring sufficient variability in disease state and concomitant diseases

· Product-dietary supplement interactions for commonly used supplements that are likely to be co-administered or for which reasonable concerns exist (e.g., examination of the interactions between a new drug for the treatment of depression and St. John’s Wort).

Again, FDA recommends that any such examinations target likely concomitant use based, for example, on indications sought, intended patterns of use, or the population of intended users of the drug and based on a history of drug and dietary supplement use elicited from subjects.

Generally, a sponsor determines its product's intended use and intended population(s) during product development. Decisions as to which interactions to either explore or specifically test in clinical trials could be based on these determinations and/or surveys and epidemiologic analyses.

One important way to detect unexpected relationships is by systematic incorporation of pharmacokinetic (PK) assessments (e.g., universal steady state sampling or population PK analyses) into some or all of the later phase clinical trials, including any specific safety trials. PK assessments can aid in the detection of unexpected PK interactions and, in some cases, could suggest exposure-response relationships for both safety and efficacy. Such data would allow for better assessment of whether pharmacokinetics contribute to any adverse events seen in the clinical trials, particularly rare, serious, and unanticipated events.

When a product has one or more well-established, valid biomarkers pertinent to a known safety concern, the marker should be studied during the PK studies and clinical development (e.g., creatine phosphokinase assessments used in the evaluation of new HMG CoA reductase inhibitors as a marker for rhabdomyolysis, or assessments of QT/QTc effects for new antihistamines).

D. Developing Comparative Safety Data

Depending on the drug and its indication, much of the safety data in an application may be derived from placebo-controlled trials and single-arm safety studies, with little or no comparative safety data. Although comparative safety data from controlled trials comparing the drug to an active control (these could also include placebo group) generally are not necessary, situations in which such data would be desirable include the following:

· The background rate of adverse events is high.

The new drug may seem to have a high rate of adverse events in a single-arm study when, in fact, the rate is typical of that for other drugs. The additional use of a placebo would help to show whether either drug actually caused the adverse events.