Guidance for Industry
  
 
Premarketing Risk 

Assessment  

 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
 
Food and Drug Administration 
 
Center for Drug Evaluation and Research (CDER) 
 
Center for Biologics Evaluation and Research (CBER)
 
 
 March 2005
  
Clinical Medical  

 
 
   
   Guidance for Industry
 
Premarketing Risk 

Assessment 

Additional copies are available from:
 
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Food and Drug Administration
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or
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(Tel) Voice Information System at 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
 
Food and Drug Administration
 
Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

March 2005
 
Clinical Medical 
 Contains Nonbinding Recommendations   
 
 
 
TABLE OF CONTENTS 
 
 
 
 
I.   INTRODUCTION............................................................................................................. 2 
 
II.   BACKGROUND ............................................................................................................... 3 
 
A.   PDUFA IIIs Risk Management Guidance Goal ...................................................................3 
 
B.   Overview of the Risk Management Guidances......................................................................3 
 
III.   THE ROLE OF RISK ASSESSMENT IN RISK MANAGEMENT............................ 4 
 
IV.   GENERATING RISK INFORMATION DURING CLINICAL TRIALS.................. 5 
 
A.   Size of the Premarketing Safety Database.............................................................................6 
 
B.   Considerations for Developing a Premarketing Safety Database ..........................................8 
 
1.  Long-Term Controlled Safety Studies.......................................................................................9 
 
2.  A Diverse Safety Database ......................................................................................................9 
 
3.  Exploring Dose Effects Throughout the Clinical Program.......................................................10
  
C.   Detecting Unanticipated Interactions as Part of a Safety Assessment..................................11
  
D.   Developing Comparative Safety Data .................................................................................12
  
V.   SPECIAL CONSIDERATIONS FOR RISK ASSESSMENT .................................... 12 
 
A.   Risk Assessment During Product Development...................................................................13 
 
B.   Assessing and Minimizing the Potential for Medication Errors ..........................................14
  
C.   Addressing Safety Aspects During Product Development ...................................................16
  
VI.   DATA ANALYSIS AND PRESENTATION................................................................ 17 
 
A.   Describing Adverse Events to Identify Safety Signals .........................................................17 
 
1.  Accuracy of Coding ..............................................................................................................17
  
2.  Coding Considerations During Adverse Event Analysis...........................................................19
  
B.   Analyzing Temporal or Other Associations ........................................................................20
  
C.   Analyzing Dose Effect as a Contribution to Risk Assessment..............................................21
  
D.   Role of Data Pooling in Risk Assessment ............................................................................22
  
E.   Using Pooled Data for Risk Assessment ..............................................................................22
  
F.   Rigorous Ascertainment of Reasons for Withdrawals from Studies....................................24
  
G.   Long-term Follow-up..........................................................................................................24
  
H.   Important Aspects of Data Presentation.............................................................................25
  
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  Contains Nonbinding Recommendations   
 
1
 
Guidance for Industry  
Premarketing Risk Assessment  

 
   
 
 
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.  
 
 
                                                 
1  This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER) at the Food and Drug Administration.  
  
2  For ease of reference, this guidance uses the terms product and drug to refer to all products (excluding blood and 
blood components) regulated by CDER or CBER, including vaccines.  Similarly, for ease of reference, this draft 
guidance uses the term approval to refer to both drug approval and biologic licensure.  
 
Paperwork Reduction Act Public Burden Statement: This guidance contains information collection provisions 
that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 
1995 (PRA) (44 U.S.C. 3501-3520).  The collection(s) of information in this guidance were approved under OMB 
Control No. 0910-0001 (until March 31, 2005) and 0910-0338 (until August 31, 2005).   
 
   
  Contains Nonbinding Recommendations 
II.  BACKGROUND 
A.  PDUFA IIIs 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 products 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 products lifecycle, with the results of risk 
assessment informing the sponsors 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) 
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  Contains Nonbinding Recommendations   
 
 
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 FDAs 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 products 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.  
 
                                                 
3  See 45 CFR part 46 and 21 CFR parts 50 and 56. See also the Health Insurance Portability and Accountability Act 
of 1996 (HIPAA) (Public Law 104-191) and the Standards for Privacy of Individually Identifiable Health 
Information  (the Privacy Rule) (45 CFR part 160 and subparts A and E of part 164).  The Privacy Rule specifically 
permits covered entities to report adverse events and other information related to the quality, effectiveness, and 
safety of FDA-regulated products both to manufacturers and directly to FDA (45 CFR 164.512(b)(1)(i) and (iii),  
and 45 CFR 164.512(a)(1)). For additional guidance on patient privacy protection, see 
http://www.hhs.gov/ocr/hipaa.  
 
 
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  Contains Nonbinding Recommendations   
 
 
It is critical to FDAs decision on product approval that a products 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 
products risk assessment and weighed against the products demonstrated benefits. The fewer a 
products 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 
products 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.  
                                                 
4 Section 505(d)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(d)(1)) requires the conduct of "adequate 
tests by all methods reasonably applicable to show whether or not . . . [a] drug is safe for use under the [labeled] 
conditions. . . . See also 21 CFR 314.50(d)(5)(vi). Section 351 of the Public Health Service Act (42 U.S.C. 262) 
requires a demonstration that a biologic is "safe, pure, and potent." See also 21 CFR 601.2.  
 
5 See the guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs 
Intended for Long-Term Treatment of Non-Life-Threatening Conditions, International Conference on Harmonisation 
(ICH).  
  5 
 
 
  Contains Nonbinding Recommendations 
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 products 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 drugs 
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 
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  Contains Nonbinding Recommendations   
 
 
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)  
                                                 
6 See the guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs 
Intended for Long-term Treatment of Non-Life-Threatening Conditions, ICH.  
  7 
 
 
  Contains Nonbinding Recommendations 
 	  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 products 
safety profile. 
The following elements should be considered by sponsors when developing proposals for their 
clinical programs as these programs pertain to risk assessment. 
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  Contains Nonbinding Recommendations   
 
 
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 
                                                 
7 The memorandum from Janet Woodcock, M.D., to Michael Friedman, M.D., dated July 20, 1998, and titled 
FDAMA  Women and Minority Guidance Requirements (with its attached report) discusses the regulations related  
to diversity. The memorandum can be found on the CDER guidance page under Modernization Act guidance 
(http://www.fda.gov/cder/guidance/women.pdf).  
  9 
 
 
  Contains Nonbinding Recommendations   
 
 
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 products 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.  
 
                                                 
8  See FDAs guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and 
Regulatory Applications.  
 
  10 
 
 
  Contains Nonbinding Recommendations 
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. Johns 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. 
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  Contains Nonbinding Recommendations   
 
 
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.  
 
   There is a well-established treatment with an effect on survival or irreversible morbidity.   
 
In such cases, not only are comparative data important scientifically, but the use of the 
comparator would likely be required ethically, as a placebo control could not be used and 
a single-arm trial would generally be uninformative.  
 
   The sponsor hopes to claim superiority for safety or effectiveness.    
 
If a comparative effectiveness claim were sought, it would be expected that the studies 
would also address comparative safety, since a gain in effectiveness could be outweighed 
by or negated by an accompanying safety disadvantage. 
 
In situations where there is a well-established related therapy, a comparative study of the new 
agent against that well-established therapy would be desirable (e.g., a new NSAID-like drug 
could be compared to a market-leading NSAID).  Such a study could show whether the 
toxicity profile for the established therapy is generally similar to that for the novel therapy or 
whether important differences exist.  
 
V.   SPECIAL CONSIDERATIONS FOR RISK ASSESSMENT  
 
Although many of the previous comments and recommendations are intended to apply to new 
product development programs generally, some risk assessment issues would apply only in 
certain circumstances or to certain types of products.  9  
                                                 
 
9 The Pharmacovigilance Guidance discusses additional risk assessment strategies that may be initiated either pre- 
or postapproval. In particular, the Pharmacovigilance Guidance includes a detailed discussion of 
  12 
 
 
  Contains Nonbinding Recommendations   
 
 
 
A.   Risk Assessment During Product Development  
 
The following are examples of how risk assessment strategies could be tailored to suit special 
situations, where appropriate.  
 
 	  If a product is intended to be chronically used (particularly when it has a very long half-
life) and/or has dose-related toxicities, it can be useful to examine whether a lower or less 
frequent maintenance dose would be appropriate.  
 
 	  If a products proposed dosing includes a proposed titration scheme, the scheme could be 
based on specific studies to define how titration is best performed and the effects of 
titration on safety and efficacy.  
 
 	  Certain kinds of adverse effects are not likely to be detected or readily reported by 
patients without special attention. When a drug has the potential for such effects, 
additional testing or specific assessments within existing trials may be appropriate.   
 
For example, for a new drug with recognized CNS effects (especially sedating effects), 
sponsors should conduct an assessment of cognitive function, motor skills, and mood.  
Similarly, since many antidepressants have significant effects on sexual function, new 
antidepressants should be assessed for these effects.  The use of targeted safety 
questionnaires or specific psychometric or other validated instruments is often important 
for such assessments, since routine adverse event monitoring and safety assessments tend 
to underestimate or even entirely miss such effects.  
 
 	  If a product is to be studied in pediatric patients, special safety issues should be 
considered (e.g., effects on growth and neurocognitive development if the drug is to be 
given to very young children/infants; safety of excipients for the very young; universal 
immunization recommendations and school entry requirements for immunization).  
 
 	  A sponsor may consider reserving blood samples (or any other bodily fluids/tissues 
collected during clinical trials) from some or all patients in phase 3 studies for possible 
assessments at a later time, particularly in circumstances when earlier safety data signal 
an unusual or important concern.  Such later assessments could include 
pharmacogenomic markers, assessments for immunogenicity, or measurements of other 
biomarkers that might prove helpful clinically.  Having samples available for 
retrospective analysis of pharmacogenomic markers could help to link the occurrence of 
serious adverse events to particular genetic markers (e.g., haplotypes).  
 
In unusual circumstances, a large, simple, safety study (LSSS) may be appropriate.  An LSSS is 
usually a randomized clinical study designed to assess limited, specific outcomes in a large 
number of patients. These outcomes  generally important safety endpoints or safety concerns 
                                                                                                                                                             
pharmacoepidemiologic safety studies. Although such studies would principally be initiated after marketing, the 
Pharmacovigilance Guidance discusses certain situations when they could be initiated preapproval.  
 
  13  
 
  Contains Nonbinding Recommendations   
 
 
suggested by earlier studies  should be defined a priori with the study specifically designed to 
assess them.  Although the large simple study model arose in the context of effectiveness 
assessment, and thus always involved randomized, controlled trials, an LSSS could in some 
cases be useful even without a control group  for example, to assess the rate of rare events 
(i.e., events so uncommon that usual safety studies would not be expected to provide good 
estimates of risk).  Although an LSSS would most commonly be performed postapproval, either 
as a phase 4 commitment to address a lingering safety issue that does not preclude approval or 
outside of a formal phase 4 commitment in response to a new safety concern that arises after 
marketing, there are instances where an LSSS may be appropriate prior to approval.  This would 
be the case when, for instance, there is a significant safety signal of concern (e.g., hepatotoxicity, 
myotoxicity) arising out of the developing clinical trial database that is not sufficiently resolved 
by the available data or is unlikely to be sufficiently addressed by the remaining ongoing studies.  
In these circumstances, an LSSS may be appropriate if the safety signal cannot otherwise be 
better delineated and the safety signal would have an impact on approvability.10  
 
In addition, a sponsor seeking to develop a product for preventive use in at-risk, but otherwise 
healthy, individuals could conduct a large trial to investigate the products safety.  The use of a 
large trial may increase the chance of showing the product to have an acceptable benefit-risk 
profile in such cases, because the potential for benefit in the exposed population would generally 
be small.  Such large trials, though not always LSSSs in a strict sense, may in some cases 
appropriately employ limited, targeted evaluations of both efficacy and safety endpoints, similar 
to an LSSS.  
 
B.   Assessing and Minimizing the Potential for Medication Errors  
 
Sponsors can help minimize the occurrence of medication errors by assessing, prior to 
marketing, common sources of medication errors.  Such errors may arise because of the 
products inherent properties or because of the inadvertent contribution of the proposed 
proprietary name, the established name, the proposed labeling (e.g., container, carton, 
patient/consumer labeling, or professional package insert), and the proposed packaging.   
 
Some medication errors, especially those involving parenteral products, have been detected in 
clinical trials prior to marketing.  When occurring in clinical trials, events such as improper 
dilution or improper administration techniques, which may result in non-optimal dosing, should 
be carefully examined as warning signs that the product could be subject to dosing errors that 
warrant changes in labeling, packaging, or design.  Even if errors are not observed in trials, 
careful consideration should be given during development to the implications of the design of the 
product, its packaging, and any device used to administer or deliver the product. For example, 
when a concentrated product that requires further dilution prior to intravenous administration is 
being developed, packaging is important. Packaging such a product in a syringe would make it 
possible to inject the product as a bolus without proper dilution, increasing risks to patients. 
Similarly, when developing a product that is administered or delivered by a device, the 
implications of mechanical failure of the device should be examined. Any such occurrences seen 
                                                 
10 As mentioned in the RiskMAP Guidance, an LSSS could also be a method of evaluating the effectiveness of 
RiskMAP tools in actual practice prior to approval.  
  14 
 
 
  Contains Nonbinding Recommendations   
 
 
or considered during product development should be documented, reported, and analyzed for 
potential remedial actions (e.g., redesign of the device or modification of instructions for use).   
 
Medication errors arising from confusion because of the similarity of the drug name, when 
written and spoken, to the name of another drug are less likely to be detected prior to marketing 
due to the controlled environment of clinical trials.  However, the many well-documented cases 
of medication errors associated with similar proprietary names, confusing labels and labeling, 
and product packaging suggest it is important that sponsors carefully consider these issues before 
marketing a product.   
 
Premarketing assessments should focus on:  
 
 	  Identifying all medication errors that occur during product development  
 	  Identifying the reasons or causes for each identified error (e.g., dosage form, packaging, 
labeling, or confusion due to trade names when written or spoken)  
 	  Assessing the resultant risk in the context of how and in whom the product will be used  
 	  Identifying the means to minimize, reduce or eliminate the medication errors by ensuring 
the proper naming, labeling, design, and packaging of the product  
 
Depending on the nature of the product, the indication, how it is administered, who will be 
receiving it, and the context in which it will be used, one or more of the following techniques 
may be helpful in assessing and preventing medication errors:  
 
 	  Conducting a Failure Mode and Effects Analysis11, 12   
 	  Use of expert panels  
 	  Use of computer-assisted analysis  
 	  Use of direct observation during clinical trials  
 	  Directed interviews of consumers and medical and pharmacy personnel to better 

understand comprehension 
 
 	  Use of focus groups  
 	  Use of simulated prescription and over-the-counter (OTC) use studies  
 
Additional information on the application of these assessment techniques will be published in a 
future guidance document.  
 
                                                 
11 Stamatis, D.H., Failure Mode and Effect Analysis: FMEA From Theory to Execution,. Milwaukee: American 
Society for Quality, Quality Press, 2003.  
 
12  Cohen, Michael R. ed., Medication Errors: Causes, Prevention, and Risk Management, Washington D.C.: 
American Pharmaceutical Association, 1999.  
  15 
 
 
  Contains Nonbinding Recommendations 
C.  Addressing Safety Aspects During Product Development 
FDA recommends addressing the potential for the following serious adverse effects as a part of 
the new drug application (NDA) for all new small molecule drugs: 
	  Drug-related QTc prolongation 
	  Drug-related liver toxicity 
	  Drug-related nephrotoxicity 
	  Drug-related bone marrow toxicity 
	  Drug-drug interactions 
	  Polymorphic metabolism 
Prior experience has shown that these effects can often be identified when properly assessed in 
clinical development programs.  Although FDA believes it is important to address these potential 
effects in all NDAs, adequately addressing all of these considerations would not necessarily 
involve the generation of additional data or the conduct of specific trials. (For some issues, such 
as QTc, specifically conducted preclinical and clinical studies are generally recommended.)  For 
example, a drug that is intended to be topically applied may be shown to have no systemic 
bioavailability; therefore, systemic toxicities would be of no practical concern. 
Some of the above-listed potential effects are relevant to biological products; some are not.  In 
addition, for biological products such as cytokines, antibodies, other recombinant proteins, and 
cell-, gene-, and tissue-based therapeutics, it may be appropriate to assess other issues. The 
issues listed here are dependent on the specific nature of the biological product under 
development. 
 	  Potentially important issues for biological products include assessments of 
immunogenicity, both the incidence and consequences of neutralizing antibody formation 
and the potential for adverse events related to binding antibody formation.   
 	  For gene-based biological products, transfection of nontarget cells and transmissibility of 
infection to close contacts, and the genetic stability of products intended for long-
persistence transfections constitute important safety issues.  
 	  For cell-based products, assessments of adverse events related to distribution, migration, 
and growth beyond the initial intended administration are important, as are adverse 
events related to cell survival and demise.  Such events may not appear for a long time 
after product administration.  
A complete discussion of assessment of safety issues unique to biological products is beyond the 
scope of this guidance.  We recommend that sponsors address the unique safety concerns 
pertaining to the development of any particular biological product with the relevant product 
office. 
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  Contains Nonbinding Recommendations 
VI.  DATA ANALYSIS AND PRESENTATION 

Many aspects of data analysis and presentation have been previously addressed in guidance, 
most notably in FDAs Guideline for the Format and Content of the Clinical and Statistical 
Sections of an Application and the ICH guidances E3 Structure and Content of Clinical Study 
Reports and M4 Common Technical Document for the Registration of Pharmaceuticals for 
Human Use.  We do not repeat that guidance here, but offer new guidance on selected issues. 
With regard to the guidance offered in this section of the document, it is important to emphasize 
that the regulatory approach to the evaluation of the safety of a product usually differs 
substantially from the evaluation of effectiveness. Most studies in the later phases of drug or 
biologic development are directed toward establishing effectiveness.  In such studies, critical 
efficacy endpoints are identified in advance, and statistical planning is conducted based on being 
able to make definitive statistical inferences about efficacy.  In contrast, these later phase trials 
are not generally designed to test specified hypotheses about safety or to measure or identify 
adverse events with any prespecified level of sensitivity. Therefore, the premarket safety 
evaluation is often, by its nature, exploratory and is intended to identify common adverse events 
related to the therapy, as well as to help identify signals for serious and/or less common adverse 
events. 
A.  Describing Adverse Events to Identify Safety Signals 
Because individual investigators may use different terms to describe a particular adverse event, 
FDA recommends that sponsors ensure that each investigators verbatim terms are coded to 
standardized, preferred terms specified in a coding convention or dictionary. Proper coding 
allows similar events that were reported using different verbatim language to be appropriately 
grouped. Consistent and accurate coding of adverse events allows large amounts of data 
regarding these events to be analyzed and summarized and maximizes the likelihood that safety 
signals will be detected.  Inaccurate coding, inconsistent coding of similar verbatim terms, and 
inappropriate lumping of unrelated verbatim terms or splitting of related verbatim terms can 
obscure safety signals. 
In general, FDA suggests that sponsors use one coding convention or dictionary (e.g., MedDRA) 
throughout a clinical program with the understanding that, due to the duration of product 
development, the coding convention used may undergo revisions.  Use of more than one coding 
convention or dictionary can result in coding differences that prevent adverse event data from 
being appropriately grouped and analyzed.  To the extent possible, sponsors should use a single 
version of the selected convention or dictionary without revisions. However, if this is not 
possible, it is important to appropriately group and analyze adverse events taking into account 
the revisions in subsequent versions. It is not advisable to analyze adverse event data using one 
version and then base proposed labeling on a different version. 
1.  Accuracy of Coding 
Sponsors should explore the accuracy of the coding process with respect to both investigators 
and the persons who code adverse events. 
17
  Contains Nonbinding Recommendations 
	  Investigators may sometimes choose verbatim terms that do not accurately communicate 
the adverse event that occurred. 
 The severity or magnitude of an event may be inappropriately exaggerated (e.g., if an 
investigator terms a case of isolated elevated transaminases acute liver failure despite the 
absence of evidence of associated hyperbilirubinemia, coagulopathy, or encephalopathy, 
which are components of the standard definition of acute liver failure).  
 Conversely, the significance or existence of an event may be masked (e.g., if an 
investigator uses a term that is nonspecific and possibly unimportant to describe a 
subjects discontinuation from a study when the discontinuation is due to a serious 
adverse event).  
If an adverse event is mischaracterized, sponsors could consider, in consultation with 
FDA, recharacterizing the event to make it consistent with accepted case definitions.  We 
recommend that recharacterization be the exception rather than the rule and, when done, 
be well documented with an audit trail. 
 	  We recommend that in addition to ensuring that investigators have accurately 
characterized adverse events, sponsors confirm that verbatim terms used by investigators 
have been appropriately coded.  
Sponsors should strive to identify obvious coding mistakes as well as any instances when 
a potentially serious verbatim term may have been inappropriately mapped to a more 
benign coding term, thus minimizing the potential severity of an adverse event.  One 
example is coding the verbatim term facial edema (suggesting an allergic reaction) as the 
nonspecific term edema; another is coding the verbatim term suicidal ideation as the 
more benign term emotional lability.  
 	  Prior to analyzing a products safety database, sponsors should ensure that adverse events 
were coded with minimal variability across studies and individual coders.   
Consistency is important because adverse event coding may be performed over time, as 
studies are completed, and by many different individuals.  Both of these factors are 
potential sources of variability in the coding process.  FDA recommends that to examine 
the extent of variability in the coding process, sponsors focus on a subset of preferred 
terms, particularly terms that are vague and commonly coded differently by different 
people.  For example, a sponsor might evaluate the consistency of coding verbatim terms 
such as weakness and asthenia or dizziness and vertigo. NOS (not otherwise specified)
type codes, such as ECG abnormality NOS, are also coding terms to which a variety of 
verbatim terms may often be mapped. These should be examined for consistency as well. 
Sponsors should pay special attention to terms that could represent serious or otherwise 
important adverse reactions. 
In addition to considering an adverse event independently and as it is initially coded, sponsors 
should also consider a coded event in conjunction with other coded events in some 
18
  Contains Nonbinding Recommendations 
circumstances. Certain adverse events or toxicities (particularly those with a constellation of 
symptoms, signs, or laboratory findings) may be defined as an amalgamation of multiple 
preferred coding terms. Sponsors should identify these events (e.g., acute liver failure) based on 
recognized definitions. 
2.  Coding Considerations During Adverse Event Analysis 
When analyzing an adverse event, sponsors should consider the following: 
 	  Combining related coding terms can either amplify weak safety signals or obscure 
important toxicities.   
 
For example, the combination of dyspnea, cough, wheezing, or pleuritis might provide a 
more sensitive, although less specific, appraisal of pulmonary toxicity than any single 
term. Conversely, by combining terms for serious, unusual events with terms for more 
common, less serious events (e.g., constipation might include cases of toxic megacolon), 
the more important events could be obscured.  
 	  Coding methods can divide the same event into many terms.  Dividing adverse event 
terms can decrease the apparent incidence of an adverse event (e.g., including pedal 
edema, generalized edema, and peripheral edema as separate terms could obscure the 
overall finding of fluid retention).  
Although potentially important safety events cannot always be anticipated in a clinical 
development program, sponsors, in consultation with the Agency, should prospectively group 
adverse event terms and develop case definitions or use accepted standardized definitions 
whenever possible. 
 	  A prospective grouping approach is particularly important for syndromes such as 

serotonin syndrome, Parkinsonism, and drug withdrawal, which are not well 

characterized by a single term. 
 
 	  Some groupings can be constructed only after safety data are obtained, at which time 
consultation with FDA might be considered.   
 
 	  Sponsors should explain such groupings explicitly in their applications so that FDA 
reviewers have a clear understanding of what terms were grouped and the rationale for 
the groupings.   
 	  For safety signals that are identified toward the end of a development program, the pre-
NDA meeting would be a reasonable time to confer with FDA regarding such groupings 
or case definitions.  
19
  Contains Nonbinding Recommendations 
B.  Analyzing Temporal or Other Associations 
For individual safety reports, the temporal relationship between product exposure and adverse 
event is a critical consideration in the assessment of potential causality.  However, temporal 
factors, including the duration of the event itself, are often overlooked during the assessment of 
aggregate safety data.  Simple comparisons of adverse event frequencies between (or among) 
treatment groups, which are commonly included in product applications and reproduced in 
tabular format in labeling, generally do not take into account the time dependency of adverse 
events.  Temporal associations can help further understand causality, adaptation, and tolerance, 
but may be obscured when only frequencies of adverse events are compared. 
Temporal analyses may be warranted for important adverse events whether they arise from 
controlled clinical trial data or treatment cohorts. In both cases, analyzing changes over time 
may be important for assessing risk and potential causality.  Analyses of temporal associations 
are particularly worth conducting in situations where prior experience (e.g., experience from 
similar products) has shown that a temporal relationship between product exposure and ensuing 
adverse events is likely to exist.  In addition, in the context of controlled clinical trials, temporal 
analyses may provide insight into the relative importance of differences in adverse event 
frequencies between study groups. 
Descriptions of risk as a function of subjects duration of exposure to a product, or as a function 
of time since initial exposure, can contribute to the understanding of the products safety profile.  
Assessments of risk within discrete time intervals over the observation period (i.e., a hazard rate 
curve) can be used to illustrate changes in risk over time (e.g., flu-like symptoms with interferons 
that tend to occur at the initiation of treatment but diminish in frequency over time).  It may be 
useful for sponsors to consider event rates (events per unit of time) in reconciling apparent 
differences in the frequencies of events between studies when there are disparities in subjects 
time of exposure or time at risk. 
For important events that do not occur at a constant rate with respect to time and for events in 
studies where the size of the population at risk (denominator) changes over time, a life-table or 
Kaplan-Meier approach may be of value for evaluating risks of adverse events.  Clinically 
important events (e.g., those events for which the occurrence of even a few cases in a database 
may be significant) are of particular interest.  Examples of such events include the development 
of restenosis following coronary angioplasty, cardiac toxicity, and seizures. 
Temporal associations identified in previous experience with related products can help focus 
sponsor analyses of potential temporal associations for a product under study, but sponsors 
should balance this approach with an attempt to detect unanticipated events and associations as 
well. Knowledge of a products pharmacokinetic and pharmacodynamic profiles, as well as an 
appreciation of physiologic, metabolic, and host immune responses, may be important in 
understanding the possible timing of treatment-related adverse events. 
It is important to consider study and concomitant treatment regimens (i.e., single treatment; short 
course of treatment; continuous, intermittent, titrated, or symptom-based treatment) in temporal 
analyses.  Other important factors to consider in planning and interpreting temporal analyses are 
20
  Contains Nonbinding Recommendations 
 
(1) the initiation or withdrawal of therapies and (2) changes in the severity or frequency of 
subjects preexisting conditions over time.  
For events that decrease in frequency over time and are found to be associated with the initiation 
of treatment, supplemental analyses may be of value to discriminate the relative contributions of 
adaptation, tolerance, dose reduction, symptomatic treatment, decreases in reporting, depletion of 
susceptibles, and subject dropout. 
C.  Analyzing Dose Effect as a Contribution to Risk Assessment 
Sponsors should analyze event rates by dose for clinically important adverse events that may be 
product related and events that might be expected based on a products pharmacologic class or 
preclinical data. 
For studies involving the evaluation of a range of doses, dose response is most commonly 
assessed by analyzing adverse event frequencies by administered dose. In such studies, it may 
also be useful to consider event frequencies by weight-adjusted or body surface area-adjusted 
dose, especially if most patients are given the same dose regardless of body weight or size.  It 
should be recognized, however, that when doses are adjusted by a subjects weight or body 
surface area, women are commonly overrepresented on the upper end of the range of adjusted 
doses, and men are commonly overrepresented on the lower end of this range.  For products 
administered over prolonged periods, it may be useful to analyze event rates based on cumulative 
dose. In addition, when specific demographic or baseline disease-related subgroups may be at 
particular risk of incurring adverse events, exploration of dose-response relationships by 
subgroup is important. Subgroup analyses have the potential to provide a more reliable and 
relevant estimate of risk for important subgroups of the target population.  Alternatively, 
multiplicity issues could result in an apparent signal that does not represent a real finding (i.e., a 
false positive). 
Although the most reliable information on dose response comes from randomized fixed dose 
studies, potentially useful information may emerge from titration studies and from associations 
between adverse events and plasma drug concentrations. 
For dose titration or flexible dose studies, it would generally be useful to assess the relationship 
between adverse event frequencies and the actual doses subjects received preceding the adverse 
events or the cumulative dose they received at the onset of the events. The choice is a function 
of the mode of action, pharmacokinetics, and pharmacodynamics of the product. 
For products with a stepped dosing algorithm (i.e., incremental dosing based on age or weight), 
the actual cut points of the paradigm are often selected relatively early in product development. 
Although the cut points may be based on the best knowledge available at the time, it is useful in 
such cases to make a specific effort to explore safety (and efficacy) just above and below these 
points.  For example, if the dose of a product is to be 100 mg for patients weighing less than 80 
kg and 150 mg for patients weighing 80 kg or more, an assessment of the comparative safety 
profiles of patients weighing from 75 to 79.9 kg versus patients weighing from 80 to 84.9 kg 
would be valuable. 
21
  Contains Nonbinding Recommendations 
As is typical of most safety evaluations, the likelihood of observing false positive signals 
increases with the number of analyses conducted.  Positive associations between adverse events 
and dose, as well as signals that emerge from subgroup analysis, should be considered with this 
in mind.  Such associations should be examined for consistency across studies, if possible. 
D.  Role of Data Pooling in Risk Assessment 
Data pooling is the integration of patient-level outcome data from several clinical studies to 
assess a safety outcome of interest. Generally, data pooling is performed to achieve larger sample 
sizes and data sets because individual clinical studies are not designed with sufficient sample size 
to estimate the frequency of low incidence events or to compare differences in rates or relative 
rates between the test drug (exposed group) and the control (unexposed group).  Use of pooled 
data does not imply that individual study results should not be examined and considered.  When 
pooling data, sponsors should consider the possibility that various sources of systematic 
differences can interfere with interpretation of a pooled result.  To ensure that pooling is 
appropriate, sponsors should confirm that study designs, as well as ascertainment and 
measurement strategies employed in the studies that are pooled, are reasonably similar. 
Used appropriately, pooled analyses can enhance the power to detect an association between 
product use and an event and provide more reliable estimates of the magnitude of risk over time. 
Pooled analyses can also provide insight into a positive signal observed in a single study by 
allowing a broader comparison.  This can protect against undue weight being given to chance 
findings in individual studies.  However, a finding from a single study should not be 
automatically dismissed because of the results of a pooled analysis, especially if it is detected in 
a study of superior design or in a different population. Any pooled analysis resulting in a 
reduced statistical association between a product and an observed risk or magnitude of risk, as 
compared to the original safety signal obtained from one or more of the contributing studies, 
should be carefully examined. 
Some issues for consideration in deciding whether pooling is appropriate include possible 
differences in the duration of studies, heterogeneity of patient populations, and case 
ascertainment differences across studies (i.e., different methods for detecting the safety outcomes 
of interest, such as differences in the intensities of patient follow-up).  When there is clinical 
heterogeneity among trials with regard to the safety outcome of interest (e.g., major disparity in 
findings for particular safety endpoints), sponsors should present risk information that details the 
range of results observed in the individual studies, rather than producing a summary value from a 
pooled analysis. 
E.  Using Pooled Data for Risk Assessment 
All placebo-controlled studies in a clinical development program should be considered and 
evaluated for appropriateness for inclusion in a pooled analysis.  Decisions to exclude certain 
placebo-controlled studies from, or to add other types of studies (such as active-controlled 
studies or open-label studies) to, a pooled analysis would depend on the objectives of the 
analysis.  Such analyses should be conducted in a manner that is consistent with the following 
guiding principles: 
22
  Contains Nonbinding Recommendations 
   Generally, phase 1 pharmacokinetic and pharmacodynamic studies should be excluded.   
 
These are usually single- or multiple-dose trials of a short duration conducted in healthy 
subjects or in patients with refractory or incurable end-stage disease who have 
confounding symptoms.  Unless a risk were limited to a short period immediately after 
the first dose, inclusion of these studies in a pooled analysis would not increase the 
statistical power or contribute to the precision of the risk estimates.  However, inclusion 
of these studies could (1) diminish the magnitude of apparent risk by including a 
population with little or no possibility of having had the adverse reaction or (2) increase 
the apparent magnitude of risk because of significant baseline symptoms unrelated to the 
drug.  
 	  The risk of the safety outcome of interest should be expressed in reference to total 
person-time (exposure time) or be evaluated using a time-to-event analysis.   
 
When the duration of drug exposure for the individual subjects included in a pooled 
analysis varies, sponsors should not express the risk merely in terms of event frequency  
(that is, using persons as the denominator).  Use of the person-time approach relies on the 
assumption that the risk is constant over the period of the studies.  Whenever there is 
concern regarding a non-constant nature of a risk, a time-to-event log-rank type analysis 
may be helpful, as it is a robust approach even when risk is not constant over time.  
 	  The patient population in the pooled analysis should be relatively homogeneous with 
respect to factors that may affect the safety outcome of interest (e.g., dose received, 
duration of therapy).   
The pooled analysis should be of a size sufficient to allow analyses of demographic 
subgroups (gender, age, race, geographic locations).  
 	  The studies included in a pooled analysis should have used similar methods of adverse 
event ascertainment, including ascertainment of the cause of dropouts.  
Study-specific incidence rate should be calculated and compared for any signs of case 
ascertainment differences. Since study-to-study variation is to be expected, it is a 
challenge to distinguish between possible case ascertainment differences and study-to
study variation.  
There are some situations in which pooling may be relatively straightforward.  For example, a 
pooled analysis of similarly designed phase 3 studies could readily be used to create a table of 
common adverse events. This type of analysis is typically less subject to the problems discussed 
above because (1) the studies are similar in study design and patient population and (2) the intent 
of such an analysis is often more descriptive than quantitative. However, if a specific safety 
concern is raised during the clinical development program, the guiding principles discussed 
above should be closely followed when conducting a prespecified pooled analysis. 
23
  Contains Nonbinding Recommendations 
F.  Rigorous Ascertainment of Reasons for Withdrawals from Studies 
Subjects may drop out or withdraw from clinical trials for many reasons, including perceived 
lack of efficacy, side effects, serious adverse events, or an unwillingness to expend the effort 
necessary to continue. The reasons for dropout are not always clear.  This lack of information 
may be largely irrelevant (e.g., discontinuation due to moving from the area) or indicative of an 
important safety problem (e.g., stroke).  Therefore, regardless of the reason for withdrawal, 
sponsors should attempt to account for all dropouts. 
 	  Sponsors should try to ascertain what precipitated dropout or withdrawal in all cases, 
particularly if a safety issue was a part of the reason for withdrawal.   
It is not helpful to simply record vague explanations such as withdrew consent, failed 
to return, administratively withdrawn, or lost to follow-up.   
 	  Participants who leave a study because of serious or significant safety issues should be 
followed closely until the adverse events are fully and permanently resolved or stabilized 
(if complete resolution is not anticipated), with follow-up data recorded in the case report 
forms.  
 	  Follow-up information should be pursued on patients withdrawn from the study (for 
reasons other than withdrawing consent in the absence of an adverse event).  
 
If this information is not obtainable, FDA recommends that the measures taken to obtain 
follow-up information be reflected on the case report forms and the resultant failure to 
obtain the information should be discussed in the clinical discussion of safety.   
 	  Patients considering withdrawing consent should be encouraged to provide the reason, 
and patients who withdraw should be encouraged to provide information as to whether 
the withdrawal of consent resulted from a serious or significant safety issue.   
 	  Some patients withdraw due to abnormal laboratory values, vital signs, or ECG findings 
that are not characterized as adverse events. Sponsors should include information on 
these types of discontinuations in addition to information on discontinuations due to 
adverse events.  
G.  Long-term Follow-up 
In some cases, it is recommended that all subjects be followed to the end of the study or even 
after the formal end of the study (e.g., where the drug has a very long half-life, is deposited in an 
organ such as bone or brain, or has the potential for causing irreversible effects, such as cancer).  
The concern over adequate follow-up for ascertaining important safety events in such cases is 
particularly critical in long-term treatment and clinical outcome studies.  In such cases, FDA 
recommends the follow-up for late safety events, even for subjects off therapy, include those 
subjects who drop out of the trial or who finish the study early due to meeting a primary outcome 
of interest.  The duration of follow-up, however, would be dependent on the circumstances of the 
24
  Contains Nonbinding Recommendations   
 
 
product development and therefore should be discussed with the appropriate review division 
(e.g., during end-of-phase 2 meetings).  
 
H.   Important Aspects of Data Presentation  
 
We recommend that once a products safety data have been analyzed, comprehensive risk 
assessment information be presented succinctly.  FDA and ICH have provided extensive 
guidance regarding the presentation of safety data,13,14, 15and we offer these additional 
recommendations, which have not been addressed previously.  
 
 	  For selected adverse events, adverse event rates using a range of more restrictive to less 
restrictive definitions (e.g., myocardial infarction versus myocardial ischemia) should be 
summarized.  
 
The events chosen for such a summary might be limited to more serious events and 
events that are recognized to be associated with the relevant class of drugs;  
 
 	  For a drug that is a new member of an established class of drugs, the adverse events that 
are important for the class of drug should be fully characterized in the NDAs integrated 
summary of safety.  
 
That characterization should include an analysis of the incidence of the pertinent adverse 
events, as well as any associated laboratory, vital sign, or ECG data.  For example, the 
characterization of a drug joining a class that is associated with orthostatic hypotension 
would include analyses of orthostatic blood pressure changes as well as the incidence of 
syncope, dizziness, falls, or other events.  We recommend that when sponsors are 
establishing case definitions for particular adverse events, they consider definitions 
previously used for the other drugs in the class or, if available, standard definitions.  
 
 	  The distribution of important variables across the pooled data, such as gender, age, extent 
of exposure, concomitant medical conditions, and concomitant medications (especially 
those that are used commonly to treat the indication being studied), should be included in 
the integrated summary of safety.  
 
 	  The effect of differential discontinuation rates by treatment on adverse event occurrence 
should be characterized (e.g., when placebo-treated patients drop out of a trial earlier than 
patients being treated with an active drug). This differential discontinuation can lead to 
misleading adverse event incidences unless patient exposure is used as the denominator 
for risk calculations.  
 
 	  Case report forms (CRFs) submitted for patients who died or discontinued a study 
prematurely due to an adverse event should include copies of relevant hospital records, 
                                                 
13 See Guideline for the Format and Content of the Clinical and Statistical Section of an Application. 
 
14  See the guidance for industry E3 Structure and Content of Clinical Study Reports, ICH.  

15 See the guidance for industry M4 Common Technical Document for the Registration of Pharmaceuticals for 

Human Use, ICH.  

  25 
 
 
  Contains Nonbinding Recommendations   
 
 
autopsy reports, biopsy reports, and radiological reports, when feasible.  The possibility 
that such information may be reported to FDA should be stated in the informed consent 
document with a notation that the patient would not be identified in such reports.  
 
These source documents should become a formal part of the official CRF and be properly 
referenced.  
 
 	  Narrative summaries (as previously described in guidance16) of important adverse events 
(e.g., deaths, events leading to discontinuation, other serious adverse events) should 
provide the detail necessary to permit an adequate understanding of the nature of the 
adverse event experienced by the study subject. (This level of detail may be unnecessary 
for events expected in the population (e.g., late deaths in a cancer trial).  This issue 
should be discussed with the appropriate review division.)  
 
Narrative summaries should not merely provide, in text format, the data that are already 
presented in the case report tabulation, as this adds little value.  A valuable narrative 
summary would provide a complete synthesis of all available clinical data and an 
informed discussion of the case, allowing a better understanding of what the patient 
experienced. The following is a list of components that would be found in a useful 
narrative summary:  
 
 Patient age and gender  
 Signs and symptoms related to the adverse event being discussed  
 An assessment of the relationship of exposure duration to the development of the 
adverse event  
 Pertinent medical history  
 Concomitant medications with start dates relative to the adverse event  
 Pertinent physical exam findings  
 Pertinent test results (e.g., lab data, ECG data, biopsy data)  
 Discussion of the diagnosis as supported by available clinical data  
 For events without a definitive diagnosis, a list of the differential diagnoses  
 Treatment provided  
 Re-challenge results (if performed)  
 Outcomes and follow-up information  
                                                 
16 See the guidance for industry E3 Structure and Content of Clinical Study Reports, ICH.  
  26