E19 A SELECTIVE APPROACH TO 
SAFETY DATA COLLECTION IN 
SPECIFIC LATE-STAGE PRE-
APPROVAL OR POST-APPROVAL 
CLINICAL TRIALS 
 
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)  
 
 
 
 
December 2022 
ICH 
 
    
E19 A SELECTIVE APPROACH TO 
SAFETY DATA COLLECTION IN 
SPECIFIC LATE-STAGE PRE-
APPROVAL OR POST-APPROVAL 
CLINICAL TRIALS  
 
Guidance for Industry 
 
Additional copies are available from: 
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and/or  
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Email: ocod@fda.hhs.gov  
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances      
 
 
 
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)  
 
December 2022 
ICH 
  FOREWORD 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.  
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines. The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry.  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS  
 
 
I.   INTRODUCTION (1) .................................................................................................. 1  
A.   Objective of  the Guidance (1.1)  .............................................................................................. 1  
B.   Background (1.2) ...................................................................................................................... 2  
C.   Scope of the Guidance (1.3) ..................................................................................................... 2  
II.   GENERAL PRINCIPLES (2) ..................................................................................... 3  
A.   Ensuring Safety of  Trial Participants (2.1) ............................................................................ 3  
B.   Factors That Contribute to a Conclusion That  the  Safety Profile of a Drug Is 
Sufficiently Characterized To Justify Selective Safety Data Collection (2.2) ..................... 3  
C.   Baseline Data (2.3)  ................................................................................................................... 5  
D.   Data That Should Generally Be Collected (2.4) .................................................................... 5  
E.   Data That May Be Appropriate for Selective Collection (2.5) ............................................. 6  
F.   Benefit-Risk Considerations for Selective Safety Data Collection (2.6) .............................. 6  
G.   Early Consultation With Regulatory Authorities  (2.7) ........................................................ 6  
H.   Situations Where Selective Safety  Data  Collection May Be Considered (2.8) .................... 7  
III.   IMPLEMENTATION OF SELECTIVE SAFETY DATA COLLECTION (3) .... 8  
A.   Selective Safety  Data Collection  for All Patients  in a Clinical Trial (3.1) ........................... 8  
B.   Comprehensive Safety  Data  Collection for a Specific Subset(s) of  the Population, With 
Selective Safety Data Collection for Other Patients (3.2)..................................................... 9  
C.   Comprehensive Safety Data Collection for the Initial Period of the Clinical Trial, With 
Selective Data  Collection Thereafter (3.3)  ............................................................................. 9  
D.   Comprehensive Safety Data Collection in a Representative Subset of the Population, 
With Selective Safety Data Collection for Other Subsets (3.4) ..........................................  10  
IV.   PRACTICAL CONSIDERATIONS FOR SELECTIVE SAFETY DATA 
COLLECTION (4)..................................................................................................... 10  
V.   RELATIONSHIP WITH OTHER GUIDANCES/REGULATIONS (5) .............. 11  
A.   Other ICH Guidances Relevant to the Conduct of Clinical Trials and Clinical Safety 
Data Management  (5.1)  .........................................................................................................11  
B.   Other non-ICH Scientific Guidance Documents of Interest (5.2) ......................................  11  
VI.   GLOSSARY................................................................................................................ 12  
VII.   REFERENCES (7) .................................................................................................... 13  
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  Contains Nonbinding Recommendations 
 
E19 A SELECTIVE APPROACH TO SAFETY DATA 
COLLECTION IN SPECIFIC LATE-STAGE PRE-APPROVAL 
OR POST-APPROVAL CLINICAL TRIALS  
Guidance for Industry1  
 
 
 
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 (1)2  
 
A.  Objective of the Guidance (1.1)  
This guidance is intended to provide internationally harmonized guidance on the use of  
selective safety data collection that may be applied in specific pre-approval or post-approval 
late-stage clinical trials. Selective safety data collection refers to the reduced collection of 
certain types of data  in a clinical trial after thorough consideration of factors that would 
justify such an approach. By tailoring the method and streamlining the approach to safety 
data collection, it may be possible to carry out clinical trials with greater efficiency. This may 
facilitate the conduct of large-scale efficacy and safety clinical trials with large numbers of 
participants and long-term follow-up. In all circumstances in which the use of selective safety 
data collection is considered, it is important that the welfare of every trial participant is  
safeguarded.   
 
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.   
 
 
1 This  guidance  was developed within the  Expert  Working Group (Efficacy) of the  International Council for 
Harmonisation  of Technical Requirements  for Registration of Pharmaceuticals for Human Use (ICH) and has 
been  subject to consultation by the  regulatory parties, in accordance with the ICH process.  This document has 
been endorsed by the ICH Assembly  at  Step 4  of the ICH process, September 2022.  At Step 4 of  the process,  
the final  draft  is  recommended for adoption to the regulatory bodies of the  ICH regions. 
2 The  numbers in parentheses reflect  the organizational breakdown of the document  endorsed by the  ICH  
Assembly at Step 4 of the ICH process,  September 2022.  
1 
  Contains Nonbinding Recommendations 
 
B.   Background (1.2) 
A robust safety database is the basis upon which the safety profile of a drug3 is characterized. 
Knowledge about a medicinal products safety  profile continually evolves as safety data 
accumulates over time. Throughout the course of medicinal product development sponsors 
collect extensive safety-related  data that  may include vital signs and other physical 
examination data, laboratory data, and all adverse events. In specific phase 3 or post-approval 
clinical  trials, if the safety profile of a drug is well-understood and documented, collection of 
comprehensive safety data may provide only limited additional knowledge of clinical 
importance. In such circumstances, a more selective approach to safety data collection  may 
be adequate.   
 
Regulators, sponsors, and investigators have a shared interest in facilitating the conduct of 
clinical trials that could yield important new medical knowledge and advance public health. 
With the growing complexity and size of clinical trials, it is recognized that a uniform 
approach no longer applies to all clinical trials. In some instances, a selective, i.e., risk 
proportionate, approach to safety data collection may be acceptable.  
 
This document describes circumstances in which it may be appropriate to reduce the  
collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-
term outcome trials, when appropriate and with agreement from regulatory authorities (see 
section II.G.  (2.7)).  
 
Sponsors and investigators should ensure that routine patient care is not compromised by use 
of a selective safety data collection approach (see section II.A. (2.1)). 
C.   Scope of the Guidance (1.3) 
This guidance is intended to apply mainly to collection of safety data from interventional  
clinical  trials primarily in the post-approval setting. In some circumstances, it may be 
considered for use in the pre-approval setting.  
Pre-approval Setting  
In the pre-approval setting, comprehensive safety data collection is  generally expected to 
elucidate the frequency, severity, seriousness, and dose-response of adverse events, including 
potential differences across subsets, e.g., demographic; medical history; and/or concomitant 
therapy. In rare cases, when sufficient safety data are available from completed clinical trials, 
selective safety data collection may be justifiable in phase 3 trials.  
Post-approval Setting  
Once a drug has been approved, comprehensive collection of  all safety data may provide only 
limited additional knowledge of clinical importance. In such circumstances, a more selective 
approach to safety data collection may be adequate as long as the trial objectives and the 
welfare of trial participants are not compromised.   
 
This guidance is not applicable to gene therapy or rare/orphan disease clinical trials. With  
limited numbers of prospective participants for such trials, the collection of comprehensive 
safety data, from every participant, is warranted.  
 
3 For the purpose  of this guidance, the term investigational product should be considered synonymous with  
drug and medicinal  product, and includes both human drugs and  biological  products. 
2 
  Contains Nonbinding Recommendations 
 
Selective collection of safety data  following the principles of this guidance does not alter 
local/regional safety reporting requirements.  
II.  GENERAL PRINCIPLES (2) 
A.  Ensuring Safety of Trial Participants (2.1)  
Safety monitoring in a clinical trial serves two purposes: (1) to protect the safety and 
wellbeing of individual trial participants; and (2) to obtain safety information to be used in 
the assessment of the risk profile of the investigational medicinal product.  
The selective safety data collection approach described in this guidance refers to the 
recording of certain data (see section II.E (2.5)) by investigators in case report forms,  as well 
as to their reporting to sponsors for subsequent evaluation and submission to regulatory 
authorities. Importantly, this approach does not affect the responsibilities of investigators, as 
health care professionals, to monitor trial participants and ensure they are treated according to 
prevailing standards of  care. Specifically, selective safety data collection does not affect the 
monitoring and clinical care of  individual trial participants or  documentation of their adverse 
events in medical records. Moreover,  selective safety data collection does not obviate other 
reporting obligations of  health care professionals, such as safety reporting in accordance with 
local/regional requirements.  
 
For example, consider a  drug where the safety data are well characterized, where 
hypoglycaemia is a known adverse drug reaction and routine blood glucose monitoring is 
recommended in labelling. In a clinical trial utilising selective safety data collection, blood 
glucose should be monitored in the same way it would be monitored in clinical practice; 
however, the data do not need to be  recorded in the case report form or reported to the 
sponsor as long as they are not stipulated in the protocol and not associated with a serious 
adverse event. Blood glucose levels and hypoglycaemia would be recorded in the case report 
form, however, if  they are stipulated in the protocol, e.g., as an adverse  event of special 
interest, deemed to be clinically relevant, or associated with serious adverse events.   
B.   Factors That Contribute to  a Conclusion That the Safety Profile of a Drug Is 
Sufficiently Characterized To Justify Selective Safety Data Collection (2.2)  
The factors listed below can contribute to the conclusion that  the safety profile of a drug is 
sufficiently characterized to justify selective safety data collection in a proposed clinical trial. 
The presence or absence of any of these factors alone is not determinative; however, the 
greater the number of applicable factors, the stronger the support for selective safety data 
collection. 
Regulatory Status 
1.   The regulatory status of the product, i.e., whether the drug has received marketing 
authorization from a regulatory authority.  
Mechanistic Factors  
2.   Understanding of the drugs mechanism of action; characterization of off-target  
effects (untoward effects mediated through targets other than the target of  interest, 
e.g., mineralocorticoids and gynecomastia; minoxidil and hirsutism).  
 
3.   Knowledge of the safety profile of drugs in the same pharmacologic class, e.g., 
support for selective safety data collection would be stronger for a member of a well-
3 
  Contains Nonbinding Recommendations 
 
established pharmacologic class of drugs than for a drug that is the only member of its 
class. 
 
Clinical Safety Database  
4.   The number  of drug-exposed trial participants who contributed to the 
characterization of the drugs safety. In general, the larger the number, the greater the 
confidence in the prior characterization of safety.4   
 
5.   The consistency of the safety profile across clinical trials where comprehensive 
safety data  collection was used.  
 
6.   The intensity of safety monitoring in the previous clinical trials used to characterize 
the drugs safety. For example, the number and type of safety parameters monitored 
(e.g., laboratory measures, vital signs), thoroughness of assessment, and frequency 
and duration of monitoring can be important.  
 
Similarity of the Planned Clinical Trial to Previous Trials  
7.   The planned dose and dosing frequency in the proposed clinical trial. In general,  the 
planned dose or dosing  frequency of the drug should not exceed what was studied in 
previous clinical trials used to characterize the  drugs safety.  
 
8.   The duration of exposure. The duration of exposure in previous clinical trials should 
be adequate to support the duration in the proposed trial.   
 
9.   Comparability of the drug product (e.g., pharmaceutical form, drug substance, 
excipients) and route of  administration. The drug product and route of 
administration for the proposed clinical trial should be comparable to those used in 
previous trials to characterize safety.  
 
10.   Similarity of the population in previous clinical trials to the population in the planned 
trial with respect to  important demographic characteristics, concurrent  and  previous 
illnesses, concomitant therapies, and other factors, e.g., cytochrome P450 (CYP) 
phenotype. Selective safety data collection would not be feasible if the population to 
be studied is more susceptible to adverse drug effects than the population included in 
the clinical trials used  to characterize  safety, e.g., older or younger trial participants, 
or trial participants who have  renal or  hepatic impairment or  factors associated with 
greater cardiovascular risk. 
 
Clinical Pharmacology 
11.   Drug-drug interactions  have been well characterized. 
 
12.   Drug metabolism and excretion are well described and understood.  
 
Non-clinical Data 
13.   Nonclinical toxicology data have been well characterized.  
 
4  In principle, the number  of patients exposed to investigational product should sufficiently exceed those 
outlined in ICH E1.  
4 
  Contains Nonbinding Recommendations 
 
Post-authorization Data 
14.   Quantity and quality of post-approval safety data. Sufficiency of data  is related to 
several factors, e.g., duration of marketing, number of participants exposed, method  
of data collection. 
 
C.  Baseline Data (2.3)  
Use of a selective safety data collection approach does not change considerations for baseline 
data collection determined by the clinical trial objectives. Baseline data are essential to ensure 
that  prospective trial participants are eligible for trial enrolment. Furthermore, baseline data 
are needed for assessment of efficacy and safety in subgroups based on, for example, 
demographics, baseline disease characteristics, concurrent  and previous illnesses, and 
concomitant therapies.  
D.   Data That Should Generally Be Collected (2.4) 
In accordance with the ICH guidances for industry E2A Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting (March 1995) and E6 Good Clinical 
Practice (March 2018),5 an adverse event can be  any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether considered related to the medicinal product or not.  
The following list includes the data elements that should generally be collected, but is not 
meant to be comprehensive:  
 
1.   Serious adverse events (see ICH E2A; ICH E6) 
 
2.   Important medical events (see  ICH E2A)  
 
3.   Medication error/overdose (intentional or unintentional) 
 
4.   Adverse event that led to  study drug discontinuation  
 
5.   Pregnancy and lactation exposure and outcomes 
 
6.   Adverse events of special interest, including laboratory abnormalities, identified in the 
protocol as critical to safety evaluations (see (see ICH E6; ICH guidance for industry 
E2F Development Safety Update Report (August 2011); The Council for International 
Organizations of Medical Sciences (CIOMS VI))    
 
When allowed/permitted by regional  or local regulations and supported by adequate 
justification in the protocol, a selective collection of some of the data listed above could be 
considered in these regions. 
 
Serious adverse events considered  efficacy or safety endpoints, which would not be subject to 
unblinding and expedited reporting (see ICH E2A), should be prospectively agreed upon with 
the regulatory authority(ies) and described in the clinical trial protocol. They should be  
collected and monitored on a regular basis through an independent data monitoring  
committee established by the sponsor (see ICH E6).   
 
5 We update  guidances periodically.  For the  most recent version of a guidance, check the  FDA guidance  web 
page at  https://www.fda.gov/regulatory-information/search-fda-guidance-documents.    
5 
  Contains Nonbinding Recommendations 
 
E.   Data That May Be Appropriate for Selective Collection (2.5)  
When selective safety data  collection is justified, it may be acceptable to limit collection of 
certain data (while ensuring the safety of trial participants  in  line with section II.A. (2.1)):  
 
1.   Nonserious adverse events may not need to be collected, or collection may be reduced  
in frequency. 
 
2.   Various types of laboratory monitoring (e.g., serum chemistries, haematology) 
electrocardiograms, and imaging trials may not be necessary, or monitoring may be 
performed at a reduced frequency.  
 
3.   Physical examinations and vital sign data may not need to be collected or  may be 
collected at reduced frequency.  
 
4.   Once concomitant medication use is documented at baseline, changes in concomitant  
therapies (e.g., changes in dose, added therapies, discontinuation of therapies) may 
not need to be collected.  
 
However, should any of the events listed in section II.D (2.4).  be identified for collection as 
per the study protocol, sponsors may also need to collect relevant information (e.g., medical 
records, laboratory data) to characterize such event(s) should they occur, including any 
follow-up information.   
F.   Benefit-Risk Considerations for Selective Safety Data Collection (2.6) 
It should be  recognised that the contribution of  non-serious adverse events to the benefit-risk 
profile of  a drug may differ depending on the indication of use and patient characteristics 
(e.g., age, cardiovascular risk factors). These factors should be considered when accepting the 
comparability of patient populations and the applicability of selective safety data collection. 
Specifically, when the safety of a drug is sufficiently characterized in a patient population 
with severe disease (e.g.,  late-stage cancer, heart failure), comprehensive safety data 
collection may still be warranted in a patient population with less severe disease (e.g., 
migraine, hypertension) to ensure that the benefits outweigh the risks  in the latter patient  
population.  
G. Early Consultation With Regulatory Authorities (2.7)  
Clinical trials must be conducted in accordance with local and regional laws and regulatory 
requirements. Sponsors considering selective safety data collection should  gain prospective 
agreement with regulatory authorities. Considerations include: (1) whether the safety profile 
of a drug is sufficiently characterized to justify selective safety data  collection; and (2) the 
specifics of the planned methods of  implementation (see section III  (3)).  
 
It is possible to conduct a multi-regional clinical trial using a single protocol with selective 
safety data collection if the safety profile of the product is considered to be sufficiently 
characterized, and all regulatory authorities agree with the proposed approach. A well-
designed multi-regional clinical trial that takes this guidance into account will help the 
sponsor reach agreement with regulatory authorities in multiple regions (see ICH guidance 
for industry E17 General Principles for Planning and Design of Multi-Regional Clinical  
Trials) (July  2018). 
6 
  Contains Nonbinding Recommendations 
 
If a sponsor or applicant plans to use clinical trial results for regulatory purposes in multiple 
regions, obtaining scientific advice in those regions before trial initiation is strongly 
recommended. 
H.   Situations Where Selective Safety Data Collection May Be Considered (2.8)  
After careful consideration of the factors listed in section II.B (2.2). and a determination that  
the safety profile of a drug is sufficiently characterized, selective safety data collection may 
be appropriate for the situations listed below. The list is not meant to be comprehensive; 
selective safety data collection may be appropriate in other circumstances as well. Additional  
examples and situations  for applying selective safety data collection may be found in section 
III (3).  
 
1.   Clinical trials to support a new indication of an approved drug where the two 
populations are similar (e.g., with respect to  demographic characteristics,  
comorbidities, concomitant therapies), or when the patient population in the new 
indication was well represented in the trials that supported the approved indication. 
For example:   
 
a.   A clinical trial of an anti-thrombotic drug previously approved for reduction of 
cardiovascular events in patients with coronary artery disease, to support a 
new indication to reduce cardiovascular events in patients with peripheral  
artery disease.  
 
b.   A clinical trial of a drug previously approved for the treatment of diabetes, to 
support a new indication for the treatment of heart failure, where many of the 
patients in the diabetes trials had co-existing heart failure.  
 
2.   Clinical trials intended to expand the label information of an approved drug with 
additional endpoints in the same patient population. For example: 
 
a.   A drug is developed for heart failure with a large (e.g., thousands of patients) 
outcome trial. If the safety profile is well characterized, selective safety data 
collection may be appropriate for a trial in a similar heart failure population to 
demonstrate a symptomatic benefit, e.g., improvement in physical function  
based on a 6-minute walk  test; improvement in  a patient-reported outcome. 
 
b.   A drug was previously approved to improve symptoms or  a validated 
surrogate endpoint, e.g., blood pressure, haemoglobin A1c, creatinine 
clearance.  If the safety profile has been well characterized, selective safety  
data collection may be appropriate for a clinical trial designed to demonstrate 
improvement in an outcome, e.g., need for hospitalisation, need for dialysis in 
the same patient population. 
 
3.   Safety trials designed to further investigate potential safety concerns focusing on 
specific parameters, e.g., visual impairment, pulmonary toxicity, cognitive 
dysfunction, major adverse cardiovascular events. Selective safety data collection 
may be appropriate if the safety profile has been well characterized. 
 
4.   Clinical trials designed  to provide additional evidence of efficacy, where the safety 
profile of the drug has been well characterized. For example,  consider  a situation 
7 
  Contains Nonbinding Recommendations 
 
where a  drug is submitted to a regulatory authority for authorisation. After  
comprehensive review, the regulatory authority(ies) determines that  the safety profile  
of the drug  has been well characterized; however, an additional clinical  trial is 
required before authorisation to provide additional evidence of efficacy. Selective  
safety data collection may be appropriate for this clinical trial.  
 
III.  IMPLEMENTATION  OF SELECTIVE SAFETY DATA COLLECTION (3) 
Having considered the general principles outlined in section II (2) with respect to when it  
may be appropriate to reduce collection of certain  types of safety data, a number of 
approaches for selective safety data collection may be considered. These implementation 
methods are meant to be  flexible with respect to the particular types of data for which 
collection can be reduced, as well as the monitoring intervals for these data. Regardless of the 
method chosen, it is essential to ensure patient safety and adherence to local and regional 
laws and regulations.  
 
The selective safety data collection approach should be carefully planned and clearly 
described within the relevant clinical trial documents (e.g., protocol; monitoring plan; 
statistical analysis plan), with reference to this guidance  (see section IV. (4)). Given that  
investigators may not be familiar with selective  safety data collection, case report forms  
should be well-designed, and investigators should receive appropriate training.  
 
When safety findings are presented, the approaches should be described in the appropriate 
document(s), e.g., ICH E2F; ICH guidances for industry E3 Structure and Content of Clinical  
Study Reports (July 1996) and M4 Common Technical Document (October 2017).  
 
The following examples of methods of implementation are not meant to be all-inclusive.  
A.   Selective Safety Data Collection for All Patients in a Clinical Trial  (3.1) 
For all participants in a clinical trial, the parameters listed in section II.D (2.4). would be 
collected throughout the trial; however, collection of some or all of the data types listed in 
section II.E. (2.5) would be limited. For example: 
 
1.   Consider an approved drug with a well characterized safety profile. The drug is 
known to increase transaminases through its mechanism of  action.  A clinical trial is 
conducted where one of the key objectives is to determine the optimal monitoring 
paradigm for serum transaminases to  avoid liver toxicity. The parameters listed in 
section II.D. would be collected throughout the clinical trial, and serum transaminases  
would be evaluated at regular intervals; however, the data described in section II.E. 
(2.5) would not be collected. 
 
2.   Consider a cardiovascular outcomes clinical trial for an approved drug with a well 
characterized safety profile with a  primary composite endpoint that includes deaths, 
non-fatal myocardial infarctions, and non-fatal strokes. These are serious adverse 
events that would always be collected as described in section II.D.(2.4), and they 
could be adjudicated; however, the data described in section II.E (2.5). would not be  
collected.  
8 
  Contains Nonbinding Recommendations 
 
B.   Comprehensive Safety Data Collection for a Specific Subset(s) of the 
Population, With Selective Safety Data Collection  for Other Patients (3.2)  
Comprehensive safety data would be collected for specific subset(s) of the patient population 
where additional information is deemed important; however,  safety data collection would be  
reduced for other patients. For example: 
 
1.   If the patient population in previous clinical trials included few patients over the age 
of 65, it could be of value to collect additional safety data on this population  in a new 
trial in  the same or a related indication. Thus, comprehensive safety data would be 
collected for patients aged 65 and over, whereas data collection would be reduced for 
patients under age 65.  
 
2.   Specific patient subsets could undergo comprehensive safety monitoring based on 
other factors (e.g., race, ethnicity, sex,  baseline disease status, renal/hepatic 
impairment, CYP metabolizer status, genetics, geographic location), with selective 
safety data collection for other patients.  
C.  Comprehensive Safety Data Collection for  the Initial Period of the Clinical  
Trial, With Selective Data Collection Thereafter (3.3) 
In certain settings, comprehensive safety data could be collected from the beginning of the 
clinical trial through some pre-determined period, with selective safety data collection 
thereafter.  
 
In longer clinical trials, safety monitoring is  typically performed quite frequently at the  
beginning of the trial, but the frequency is decreased as the trial proceeds. The planned  
reduction in monitoring frequency is a variation of  selective safety data collection, based on 
the premise that data collected during the early part of the clinical trial will adequately  
characterize non-serious adverse events, as well as important changes in vital signs and 
laboratory abnormalities. This concept may be expandedspecifically, collection  of  some 
types of safety data could be reduced or discontinued for patients once a specific duration of 
follow-up is achieved, e.g., interval physical  examinations and laboratory investigations 
could be discontinued once patients have been followed through 12 months. For example:  
 
1.   Consider a clinical trial of a preventive vaccine in  which solicited signs and 
symptoms are recorded  daily for a pre-specified period post-vaccination (e.g., 7 days), 
all unsolicited adverse events are collected for approximately 4 weeks post-
vaccination, and serious adverse  events and pre-specified adverse events of special 
interest  s are collected  for at  least 6 months post-vaccination. 
 
2.   Consider a cardiovascular outcomes trial that is initiated pre-marketing and ongoing 
at the time of drug approval. At the time of approval, the safety of the drug will have 
been sufficiently characterized in the indicated patient population. From  that point 
forward, adoption of a selective safety data approach could be appropriate for the 
ongoing trial. 
 
3.   Consider a clinical trial of the efficacy of a drug designed to prevent or delay an 
important outcome such as dementia or end-stage kidney disease. Assuming it would  
take many years to collect sufficient endpoint events to  achieve adequate statistical 
power, it may be appropriate to use selective safety data collection once  
9 
  Contains Nonbinding Recommendations 
 
comprehensive safety data have been collected for all patients for a reasonable 
duration, e.g., 1 year.  
D.   Comprehensive Safety Data Collection in a Representative Subset of the 
Population, With Selective Safety Data Collection  for Other Subsets (3.4)  
Some efficacy clinical trials and specific safety clinical trials require enrollment  of many  
thousands of participants to achieve adequate statistical power. In these settings, such as a 
large  clinical outcomes trials, the number of participants planned for enrolment may greatly 
exceed the number needed to assess non-serious  adverse events, changes in vital signs, and 
laboratory abnormalities. In this setting, comprehensive safety data could be collected for 
only a representative subset of participants, with selective safety data collection in other 
participants (see section II.E.(2.5)). For example:  
 
1.   Comprehensive data could be collected at randomly selected sites, perhaps half  of the 
sites in every country or geographic area, with reduced safety data collection at other 
sites. 
 
2.   Comprehensive data could be collected for randomly selected patients across all sites, 
with reduced safety data collection for other patients.  
  
When using these methods, it is  important that patients who receive comprehensive safety 
monitoring are representative of the entire population. Thus, selection bias should be avoided, 
adequate diversity of the patient population with comprehensive data collection needs to be 
ensured, and the method for randomly selecting sites or patients should be described in the 
protocol and other relevant trial documents.  
IV.  PRACTICAL CONSIDERATIONS FOR SELECTIVE SAFETY DATA 
COLLECTION (4)  
A sponsor considering selective safety data collection should  consider impacts to patients,  
trial conduct, data analysis, and interpretation. The feasibility of such approaches and plans 
for implementation should be discussed with regulatory authorities in advance, and 
agreement should be reached. Although these approaches can improve efficiency, there are 
disadvantages. Some questions that may arise retrospectively cannot be explored if the data 
were never collected, e.g., issues with respect to concomitant  medications, laboratory 
parameters, blood pressure.  
 
Concerns may emerge during the conduct of clinical trials using selective safety data 
collection that will necessitate intensification of safety monitoring or reversion to 
comprehensive safety data collection. Such changes may create logistical challenges with 
respect to trial sites, protocols, and data collection forms.  
 
The use of selective safety data collection may present complexities for data analysis,  
presentation, and summarization. If selective safety data collection is used uniformly in a 
clinical trial (i.e., for all patients in a trial; throughout the trial), analyses are straightforward; 
however, frequency summaries would need to describe  the specifics of the approach for 
safety data  collection to  enable interpretation of  the results. In contrast, if  the methods of 
safety data  collection are not consistent for all patients in a clinical  trial or  are not consistent  
throughout the duration of a trial, data obtained under a comprehensive safety data approach 
and data collected under a selective safety data approach cannot be pooled. Methods for 
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aggregating the data should be delineated within the protocol and associated analysis plans. 
Analysis and summarization should be appropriate for the collection approach(es) and results 
should clearly identify data summaries where interpretation is impacted by the collection 
approach. 
V.   RELATIONSHIP WITH OTHER GUIDANCES/REGULATIONS (5) 
A.  Other ICH Guidances Relevant to the Conduct of Clinical Trials and Clinical  
Safety Data Management (5.1)  
This guidance should be considered in conjunction with other ICH guidances relevant to the 
conduct of clinical trials and clinical safety data management, e.g., ICH E2A; ICH E2F; ICH 
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 (March 1995); 
ICH E3; ICH E6; ICH guidance for industry E8(R1) General Considerations for Clinical 
Studies (April 2022); and/or ICH E17. Evaluation of the information generated through post-
approval pharmacovigilance activities is also important for all products to ensure their safe 
use, e.g., ICH guidances for industry  E2E Pharmacovigilance Planning (April 2005), E2D 
PostApproval Safety Data Management: Definitions and Standards for Expedited Reporting 
(September 2003),  and  E2C(R2) Periodic Benefit-Risk Evaluation Report (July 2016).  
B.  Other non-ICH Scientific Guidance Documents of Interest (5.2) 
Given the need for scientific justification of selective safety data collection, pre-existing  
guidances on the same topic and regulatory requirements for safety data collection, the 
following regional and national scientific guidance documents are referenced in addition to  
the list of ICH guidances that supports the selective data collection approach (non-exhaustive 
list):  
1.   FDA, United States. Guidance for Clinical Trial Sponsors, Establishment and 
Operation of Clinical Trial Data Monitoring Committees (March 2006).  
 
2.   EC, Europe. Guideline on Data Monitoring Committees (July 2005). 
EMEA/CHMP/EWP/5872/03. 
 
3.   FDA, United States. Guidance  for Industry, Determining the Extent of Safety Data 
Collection Needed in Late-stage Premarket and Post-approval Clinical Investigations  
(February 2016). And further relevant guidelines from the various ICH contributor 
countries/regions.  
 
4.   EC, Europe. Risk Proportionate Approaches in Clinical Trials; Recommendations of  
the Expert Group on Clinical Trials for the Implementation of Regulation (April 
2017). (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use.  
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VI. GLOSSARY 
Adverse Event: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this  
treatment. An adverse event can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether related to the medicinal 
(investigational) product (see ICH E2A and ICH E6). 
 
Adverse Event of Special Interest:  
An event (serious or non-serious) of  scientific and medical concern specific to  the sponsors  
product or programme,  for which ongoing monitoring and rapid communication by the 
investigator  to the sponsor can be appropriate. Such an event might warrant further 
investigation to characterize and understand it. Depending on the nature of the event, rapid  
communication by the trial sponsor to other parties (e.g., regulators) might also be warranted 
(based on CIOMS VI; see ICH E2F). 
 
Important Medical Event:  
Medical events that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the patient or may require intervention to prevent serious 
outcomes; these events require medical and scientific judgement and fall under the expedited 
reporting rules (see ICH E2A). 
 
Serious Adverse Event:  
Any untoward medical occurrence that at any dose: 
- results in death, 
- is life-threatening,  
- requires inpatient hospitalization or  prolongation of existing hospitalization, 
- results in persistent or significant disability/incapacity,  
or 
- is a congenital anomaly/birth defect 
(See ICH E2A and ICH E6). 
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VII.   REFERENCES (7) 
 
1.   WHO Expert Committee on Biological Standardization. Sixty-seventh report. Geneva. 
World Health Organization; 2017 (WHO technical report series; no.1004); annex 9 - 
Guidelines on clinical evaluation of vaccines: regulatory expectations; p. 503-573.  
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