Determining the Extent 

of Safety Data 

Collection Needed in 

Late-Stage Premarket 

and Postapproval 

Clinical Investigations 

 
Guidance for Industry 

 
 
 
 
 
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) 
 
 
 
February 2016 

Clinical/Medical 

 
   
Determining the Extent of 

Safety Data Collection 

Needed in Late-Stage 

Premarket and Postapproval 

Clinical Investigations 

 
Guidance for Industry 

 
Additional copies are available from: 

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Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
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Silver Spring, MD 20993-0002 
  
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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
 
and/or 
 
 
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Email: ocod@fda.hhs.gov 
 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm     
 
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) 
 
 
February 2016 

Clinical/Medical 

 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS  
 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   SELECTIVE SAFETY DATA COLLECTION ............................................................ 3 
 
A. 	  Types of Clinical Investigations That May Be Considered for Selective Safety Data 

Collection......................................................................................................................................... 4
  
B. 	  Types of Safety Data That May Be Appropriate for Selective Safety Data Collection ........... 5
  
C. 	  Other Considerations for Safety Data Collection ....................................................................... 6 
 
D. 	  Types of Safety Data That Should Always Be Collected ............................................................ 6
  
IV.   METHODS FOR SELECTIVE SAFETY DATA COLLECTION ............................. 7
  
V.  	 AGREEMENT BETWEEN SPONSORS AND FDA ON A PLAN FOR SELECTIVE 

SAFETY DATA COLLECTION ......................................................................................... 8 
 
i 
 
  Contains Nonbinding Recommendations 
 
Determining the Extent of Safety  Data Collection Needed in Late-

Stage Premarket and Postapproval Clinical Investigations 

 
1 
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.  
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to help sponsors determine the amount and types of safety data to 
collect during late-stage premarket and postapproval clinical investigations, (e.g., phase 3 
clinical trials, studies of new uses, long-term outcomes).  This guidance discusses a selective 
approach to safety data collection during late-stage premarket development or during the 
postapproval stage based on what is already known about a drugs2 safety profile. This guidance 
provides recommendations on when to consider selective safety data collection and how to do so 
to maintain a balance between eliminating the collection of data that will not be useful and 
collecting sufficient data to allow adequate characterization of the safety profile of a drug.  In 
addition, this guidance provides information to sponsors about consulting with the relevant FDA 
review division or divisions to determine whether a selective approach to safety data collection 
would be appropriate (see section V of this guidance).  
 
This guidance is intended to apply to safety data collection during late-stage premarket and 
postapproval clinical investigations in all disease settings except rare diseases (see section III of 
this guidance). There is an existing FDA guidance that applies to the collection of clinical data 
in all phases of oncology clinical trials,3 but that guidance does not discuss selective safety data 
                                                 
1  This guidance has been prepared by the Office of Medical  Policy in the Center for Drug  Evaluation and Research  
in cooperation  with the Center for Biologics Evaluation and Research at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs or  drug products  include both  human drugs and 
biological  drug products regulated by the Center for Drug Evaluation and Research or the Center for Biologics 
Evaluation and Research  unless otherwise specified.   
 
3 See the guidance for industry Cancer Drug  and Biological  Products  Clinical Data  in Marketing  Applications. 
We update  guidances  periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
  1
  Contains Nonbinding Recommendations 
 
collection in the specific instances covered in this guidance.  For this reason, the 
recommendations in this guidance may differ from those in the oncology-focused guidance.  
Where differences occur, the recommendations in this guidance apply. 
 
FDA is also aware that some of the recommendations in this guidance may not align with the 
expectations of safety data collection in other regions or countries, which may lead to difficulty 
in implementing this guidance in some clinical investigations.  However, we believe this 
guidance will give sponsors the flexibility to design and implement protocols with selective 
safety data collection where appropriate.  
 
This guidance is not intended to affect reporting (as opposed to collection) of postmarketing 
adverse events relevant to an approved drug as required under 21 CFR 314.80 and 600.80 or 
affect reporting of investigational new drug application (IND) safety information as required 
under  312.32 (21 CFR 312.32).4  Those reporting requirements remain unchanged, and 
selective safety data collection may only occur in a manner that would permit all regulatory 
reporting requirements to be fulfilled.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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 robust safety database is critically important to accurately assess and adequately characterize 
the risks of a new drug. Sponsors collect extensive safety-related data throughout the course of 
drug development, and knowledge about a drugs safety profile continually evolves as safety 
data accumulate.  Comprehensive safety data, including essentially all adverse events, are 
collected in the early stages of drug development.  In the later stages  of premarket development 
or in postapproval studies or clinical trials, it may be appropriate to use a selective approach to 
safety data collection for common, non-serious adverse events that have already been well-
characterized through data collection in earlier stages.  For example, if safety data already 
collected on hundreds of patients indicate that 17 percent reported a headache when on drug 
treatment compared with 10 percent on placebo, collection of similar data in thousands of 
additional patients in a large phase 3 trial would minimally refine this value and would require 
extensive resource utilization, while providing no important new information.  In this situation, a 
limited collection of safety data may be appropriate. 
                                                 
4 FDAs final rule discusses the rationale for more-selective use of IND safety reports (Investigational New Drug  
Safety Reporting for Human  Drug  and Biological Products  and Safety Reporting Requirements for Bioavailability 
and Bioequivalence Studies in  Humans (75 FR  59935, September 29, 2010)).  
The guidance for industry and investigators  Safety Reporting Requirements for INDs  and BA and BE Studies also  
discusses FDAs thinking on  reporting information that is interpretable and that will meaningfully contribute to a 
drugs safety profile.  (IND means investigational new drug application; BA and BE means 
bioavailability/bioequivalence). 
  2
  Contains Nonbinding Recommendations 
 
Encouraging selective safety data collection in late-stage premarket and postapproval clinical 
investigations is consistent with FDAs overall approach to safety assessment, which focuses on 
information that is useful and adds to existing knowledge.  For example,  312.32 requires 
expedited reporting of serious, unexpected suspected adverse reactions to FDA and all 
investigators during drug development.   
 
In some cases, collection of data that do not contribute to better characterizing the safety profile 
of a drug may have negative consequences.  For example, there is growing interest in larger, 
simpler trials to obtain outcome data, data on long-term effects of drugs, and data on 
comparative effectiveness and safety.  Excessive safety data collection may (1) discourage the 
conduct of these types of trials by increasing the resources needed to perform them and (2) be a 
disincentive to investigator and patient participation in clinical trials.  Thus, selective safety data 
collection may (1) facilitate the conduct of larger trials without compromising the integrity and 
the validity of trial results or losing important information, (2) facilitate investigators and 
patients participation in clinical trials, and (3) help contain costs by making more-efficient use 
of clinical trial resources. For these reasons, selective safety data collection should be 
considered in circumstances where it is appropriate (see section III of this guidance).  
 
 
III.  SELECTIVE SAFETY DATA COLLECTION  
 
If the drugs safety profile has already been well-established, selective safety data collection may 
be appropriate during late-stage premarket and postapproval clinical investigations.  Examples of 
selective safety data collection include, but are not limited to, the following: 
 
 	  No collection of certain safety data  
 
 	  Less-frequent collection of certain safety data  
 
 	  Collection of certain safety data from only a fraction of the total trial enrollment (e.g., 
10 percent of patients in a large trial)    
 
In general, selective safety data collection may be appropriate for certain types of safety data 
when the following conditions are met: 
 
 	  The number of patients and their characteristics, the duration of exposure, and the 
dose range used in previous clinical investigations are sufficient to adequately 
characterize the safety profile of the drug for common, non-serious adverse events.  
 
 	  The occurrence of common, non-serious adverse events has been generally similar 
across multiple clinical investigations. 
 
 	  The drugs safety profile is established to the extent that it is reasonable to conclude 
that the occurrence of common, non-serious adverse events in the population to be 
studied will be similar to rates observed in previously conducted clinical 
investigations. 
  3
  Contains Nonbinding Recommendations 
 
For clinical investigations in which these conditions are met, the amount and types of data 
appropriate for selective safety data collection will vary depending on a range of factors, 
including the disease being studied, the patient population, subgroup or subgroups of interest, 
nonclinical findings, prior experience with the drug and drug class, and study design.  
 
A. 	 Types of Clinical Investigations That May Be Considered for Selective Safety 
Data Collection  
 
Selective safety data collection may be appropriate in the following types of clinical  
investigations. However, these are not the only circumstances where selective safety data 
collection may be appropriate, and this is not intended to be a complete list.  
 
	   Clinical investigations of new indications of approved drugs:  Selective safety 
data collection may be appropriate in clinical investigations for new indications if the 
existing safety database is relevant to such investigations, including, for example, the 
similarity of the population studied in the new investigation to patients previously 
studied and the doses used. 
 
	   Postapproval clinical studies and trials conducted to fulfill postmarketing 
requirements and postmarketing commitments:  When the study population in 
these types of studies or trials is generally the same as or is similar to the population 
from which the premarket safety database was derived, safety data collection can 
often be limited to the primary safety endpoint and other endpoints of interest.  
 
	   Late-stage premarket and postapproval outcome clinical trials:  Outcome clinical  
trials usually involve relatively large populations (often 5,00015,000 patients) 
similar to populations previously studied and are usually of longer duration than 
earlier studies. Typically, a fairly substantial safety database is in existence before 
initiation of an outcome clinical trial, and this database already provides sufficiently 
precise estimates of common, non-serious adverse events (e.g., those that occur in 5 
percent or more of exposures). Even when there is not extensive prior safety data, 
full data could be collected in a subset of patients (e.g., 1,000) with more-selective 
data collection in other patients. 
 
 	  Premarket clinical investigations for some original applications: Unless 
sufficient safety data already exist to adequately characterize the safety profile of a 
drug, comprehensive safety data collection is expected throughout premarket clinical 
development intended to support approval of a new drug application (NDA) or a 
biologics license application (BLA) for a novel agent in order to elucidate occurrence, 
dose-response, and subset (demographic, concomitant illnesses, concomitant therapy)  
variations for the full range of adverse events of the drug.  However, even in a 
development program for a novel agent, if sufficiently comprehensive safety data 
become available before completion of clinical development, selective safety data 
collection in some late-stage investigations may be appropriate.  For example, 
selective safety data collection may be appropriate in phase 3 trials where the existing  
  4
  Contains Nonbinding Recommendations 
 
safety database adequately characterizes a drugs safety for more common, non-
serious adverse events; therefore, data on those events may not need to be collected.   
 
 	  Postapproval clinical investigations in a different patient population or with 
different doses or other conditions of use:  Selective safety data collection 
generally may not be appropriate in clinical investigations of marketed drugs in which 
there are important differences in the patient population, dose, dosage regimen, 
duration of use, or route of administration compared with the conditions of use for the 
marketed indications.  For example, the safety database of a drug approved to treat 
active cancer generally would not be adequate to permit selective safety data 
collection in an investigation of the long-term use of that drug for adjuvant therapy or 
in the prevention of cancer in a healthy population.  Even in this setting, however, it 
may be appropriate, in some cases, to collect common, non-serious adverse events in 
only a subset of the overall study population.  An exception may also apply in cases 
where a lower dose or shorter duration of therapy is being investigated.     
 
B. 	 Types of Safety Data That May Be Appropriate for Selective Safety Data 
Collection  
 
Where selective safety data collection is suitable, it may be appropriate to limit collection of data  
or stop collection of certain types of data, including the following: 
 
 	  Non-serious adverse events not associated with dose modification, drug 
discontinuation, or withdrawal from the trial:  Generally, these events are well-
characterized when a drug is far along in development or has obtained marketing 
approval, and additional data collection would be unlikely to add to the established 
safety profile of a drug. 
 
 	  Routine laboratory monitoring:  In many cases, it may be possible to eliminate 
routine laboratory monitoring or to decrease the frequency of monitoring certain 
laboratory parameters (e.g., less-frequent liver function testing as safety profile data 
diminish concerns about hepatotoxicity). 
 
 	  Information on concomitant medications: If existing data satisfactorily 
characterize all anticipated drug-drug interactions and metabolic pathways, additional 
detailed information on concomitant medications (e.g., dose, dosing schedule, start 
and stop dates) may be of limited use, particularly for drugs used only short term.  
 
 	  Patient history and physical exams:  Less-detailed histories and less-frequent 
physical exams for patients may be appropriate in some circumstances, especially in 
outcome clinical trials.  If an abbreviated history is considered appropriate but certain 
aspects of the history are considered relevant and should be collected (e.g., 
cardiovascular disease, psychiatric history, including history of depression, 
suicidality, or both), these aspects should be described in the protocol.  
 
 
  5
  Contains Nonbinding Recommendations 
 
C.  Other Considerations for Safety Data Collection 
 
For situations that may be appropriate for selective safety data collection, sponsors should 
nonetheless consider where there may be reasons to collect complete data to better characterize 
the safety profile of a drug. This may apply even for adverse events that are not serious, fatal, or 
dose-modifying or that do not cause drug discontinuation or withdrawal from the trial.  For 
example: 
 
 	  Collection of complete safety data in population subsets:  If availability of data in 
a subset of a population is limited, generally all data on use of a drug in these specific 
populations should be collected (including data on non-serious adverse events).  For 
example, information on exposure in pediatric patients, pregnant and nursing women, 
and geriatric populations is often limited, so that selective safety data collection may 
not be appropriate in those populations. 
 
 	  Collection of complete safety data to identify risk factors:  The incidence and 
severity of an adverse event may be related to baseline factors and other aspects of 
treatment.  For this reason, where there is a known or suspected causal relationship 
between a drug and an adverse event, it may be important to continue collecting 
complete safety information throughout drug development to better characterize the 
relationship and the effect of these influences (e.g., baseline risk or demographic 
factors, dose-response, drug concentration, concomitant therapy, concomitant illness) 
on risk. 
 
D.  Types of Safety Data That Should Always Be Collected 
 
Sponsors should be aware that the following types of data are generally not appropriate for 
selective safety data collection and should always be collected: 
 
 	  Data on all serious adverse events.  
 
 	  Data on non-serious adverse events that lead to dose modification, drug 
discontinuation, or withdrawal from the trial. 
 
 	  Data on unscheduled study visits, hospitalizations, and accidental injuries because 
these events may reflect serious adverse events of the drug.  
 
 	  In an oncology setting, data from all Grade 3 and Grade 4 adverse events, as well as 
Grade 2 adverse events that affect vital organs (e.g., heart, liver). 5,6  
                                                 
5 The grading system was used  for adverse events in cancer trials described in the Common Terminology Criteria for 
 
Adverse Events document from  the National Cancer Institute (U.S. Department of Health and  Human Services 

National Cancer Institute at the National Institutes of Health).  The grading system is accessible at 

http://evs.nci.nih.gov/ftp1/CTCAE/About.html (under the heading Files: Booklet).  

A Grade 4 adverse event results in the need  for life-saving  and urgent intervention.  

  6
  Contains Nonbinding Recommendations 
 
 	  In development programs for rare disease indications, complete safety data should be 
collected, because these trials generally have limited patient populations and are 
unlikely to meet the recommendations for selective safety data collection. 
 
For these types of safety data, it is generally important to collect information on all occurrences 
to better understand the following:  
 
   Causality 
   Incidence  
   Severity of adverse events 
   Populations that are at risk 
   Dose-response  
   Other factors that contribute to our understanding of the nature of the event and who 
is at risk  
 
 
IV.  METHODS FOR SELECTIVE SAFETY DATA COLLECTION  
 
Apart from not collecting certain safety data, a plan for selective safety data collection could 
include the following modifications as appropriate:  
 
 	  Limiting safety data collection to a pre-identified subset of study population:  It may 
be appropriate to collect certain safety data (e.g., non-serious adverse events) from a 
sample of the study population.  Methods for selecting the subpopulation should be 
detailed in the protocol. These may include selecting patients randomly, selecting study 
sites randomly, or selecting only the larger population sites.  When selecting patient 
subsets or sites, it may be important to ensure representation from important demographic 
or disease-specific subgroups.  
 
 	  Decreasing the frequency of data collection:  Less-frequent collection of specific safety 
data, such as laboratory data and physical examination data, may be appropriate for long-
term trials of drugs with substantial short-term exposure.  For example, laboratory studies 
and physical-examination data may be collected at relatively long intervals (e.g., every 6 
months). Telephone and online follow-up between study visits may help maintain 
contact with patients.  
 
Specific safety data that will not be collected for the selective collection plan should be listed in 
the protocol. 
                                                                                                                                                             
A Grade 3  adverse event results in  severe or clinically significant, but not immediately life-threatening,  

consequences;  results in  hospitalization or prolonged hospitalization; disables an individual; and results in
  
limitations on  ability to bathe, dress, undress, feed, use the toilet, and take  medications. 

A Grade 2 event results in the need  for moderate, minimal, or local or invasive intervention and  results in limitations  

on age-appropriate ability to prepare meals, shop  for groceries or clothes, use the telephone, and manage  money. 

 
6 The guidance for industry  Gene Therapy Clinical Trials   Observing Subjects for Delayed Adverse Events 

discusses collecting  delayed adverse event data in long-term follow-up for gene therapy trials. 

  7
  Contains Nonbinding Recommendations 
 
 
 
V.  A	 GREEMENT BETWEEN SPONSORS AND FDA ON A PLAN FOR 
SELECTIVE SAFETY DATA COLLECTION  
 
A sponsor considering selective safety data collection should consult with the relevant FDA 
review division or divisions to determine whether such collection would be considered 
appropriate, and if so, develop its plan for implementation.  The sponsor should discuss its 
specified plan with the relevant FDA review division or divisions at the appropriate time (e.g., at 
the end-of-phase 2 meeting for selective safety data collection for a phase 3 trial) to determine 
whether the plan is acceptable and to reach an agreement with the division or divisions on the 
details of the plan. The agreement should be incorporated into the procedures for safety data 
collection in the protocol, the monitoring plan, and other appropriate trial documents.  These 
steps should help ensure consistent implementation across trial sites, help support risk-based 
monitoring efforts, and help alleviate potential inspectional problems related to safety data 
collection.  
  8