E19 O S D C
PTIMISATION OF  AFETY  ATA  OLLECTION 
 
 
 
 
 
 
 
 
 
 
 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 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 staff 
responsible for this guidance as listed on the title page. The draft guidance has been left in the original 
International Council for Harmonisation format.  The final guidance will be reformatted and edited to 
conform with FDAs good guidance practice regulation and style. 
 
 
 
 
For questions regarding this draft document, contact 
(CDER) Ellis Unger, M.D., 301-796-2270. 
  INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL 
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE 
 
 
ICH HARMONISED GUIDELINE 
 
 
Optimisation of Safety Data Collection 
E19  
 
 
Draft version  
Endorsed on 3 April 2019 
Currently under public consultation 
 
 
 
 
 
At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate 
ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory 
authorities of the ICH regions for internal and external consultation, according to national 
or regional procedures.  E19 
Document History 
 
Code  History  Date 
E19  Endorsement by the Members of the ICH  3 April 2019 
Assembly under Step 2 and release for public 
consultation (document dated 28 February 2019). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2  ICH HARMONISED GUIDELINE 
Optimisation of Safety Data Collection 
3 
E19  
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5   
6  TABLE OF CONTENTS 
7  1  INTRODUCTION ............................................................................................................ 4 
8  1.1  Objective of the Guideline ...................................................................................................... 4 
9  1.2  Background ............................................................................................................................. 4 
10  1.3  Scope of the Guideline ............................................................................................................ 4 
11  2  GENERAL PRINCIPLES ............................................................................................... 5 
12  2.1  Types of Data for Which Selective Safety Data Collection May be Appropriate .................. 5 
13  2.1.1  Types of Safety Data Where it May be Appropriate to Limit or Stop Collection ............ 5 
14  2.1.2  Types of Safety Data That Should Generally be Collected under All Circumstances .... 5 
15  2.1.3  Baseline 
16  Data...........................................................................................5 
17  2.2  When May Selective Safety Data Collection Be Considered? ............................................... 6 
18  2.2.1  Benefit-Risk Considerations for Selective Safety Data Collection .................................. 6 
19  2.2.2  Extent  of 
20  Exposure.....................................................................................7 
21  2.3  Examples Where Selective Safety Data Collection May be Considered ................................ 7 
22  2.4  Ensuring Patient Safety within Studies ................................................................................... 7 
23  2.5  Changes in Approach to Safety Data Collection ..................................................................... 8 
24  2.6  Early Consultation with Regulatory Authorities ..................................................................... 8 
25  3  METHODS OF IMPLEMENTATION .......................................................................... 8 
26  3.1  Selective Safety Data Collection for All Patients in the Study ............................................... 9 
27  3.2  Comprehensive Safety Data Collection for a Specific Subset(s) of the Population, with 
28  Selective Safety Data Collection for Other Patients ........................................................................... 9 
29  3.3  Comprehensive Safety Data Collection in a Representative Subset of the Population, with 
30  Selective Safety Data Collection for Other Patients ........................................................................... 9 
31  3.4  Comprehensive Safety Data Collection for the Initial Portion of the Study, with Selective 
32  Data Collection Thereafter .................................................................................................................. 9 
33  4  RELATIONSHIP WITH OTHER GUIDELINES/REGULATIONS ....................... 10 
34      ICH E19 Guideline 
35  1  INTRODUCTION 
36  1.1  Objective of the Guideline  
37  This Guideline is intended to provide internationally harmonised guidance on an optimised 
38  approach to safety data collection in some late-stage pre-approval or post-approval studies 
39  when the safety profile of a drug is sufficiently characterised.  Optimisation of safety data 
40  collection using a selective approach may improve the efficiency of clinical studies while 
41  reducing the burden to study participants.  Adoption of an internationally harmonised approach 
42  to selective safety data collection may facilitate global participation in clinical studies.   
43  1.2  Background 
44  Regulators and industry have a shared interest in reducing the burden to study participants 
45  while facilitating the conduct of studies that could yield important new medical knowledge and 
46  advance public health.  Although safety monitoring of patients during clinical studies remains 
47  critically important, unnecessary and burdensome data collection may serve as a disincentive 
48  to participation in clinical studies, e.g., frequent and time-consuming patient visits; laboratory 
49  tests; and/or physical examinations.   
50  Knowledge about a medicinal products safety profile continually evolves as safety data 
51  accumulates.  Throughout the course of medicinal product development and subsequently 
52  while the drug is marketed, sponsors collect extensive safety-related data, including all vital 
53  signs, laboratory data, and adverse events.  In the later stages of drug development, and if the 
54  safety profile is well-understood and documented, comprehensive collection of all safety data 
55  may provide only limited additional knowledge of clinical importance.  In such circumstances, 
56  a more selective approach to safety data collection may be adequate and optimal, as long as the 
57  study objectives and the welfare of study participants are not compromised. 
58  Importantly,  sponsors  and  investigators  should  ensure  that  routine  patient  care  is  not 
59  compromised by the selective safety data collection approach outlined in this Guideline.  It is 
60  recognised that safety monitoring serves to protect individual study participants and will 
61  continue to be performed as per standard of care. 
62  1.3  Scope of the Guideline 
63  This guidance is intended to apply to collection of safety data during the late-stage development 
64  of medicinal products in interventional and non-interventional studies, in the post-approval 
65  setting and, for specific cases, in the pre-approval setting. 
66  In the pre-approval setting, comprehensive safety data collection is expected in order to 
67  elucidate frequency, severity, seriousness, and dose-response of adverse events, including 
68  potential  differences  across  subsets,  e.g.,  demographic;  concomitant  illnesses;  and/or 
69  concomitant therapy.  However, even before approval of a new medicinal product, if there is 
70  agreement with regulatory authorities that sufficient safety data are available or are being 
71  collected in ongoing late-stage studies, selective safety data collection may be appropriate in 
72  certain studies. 
4  ICH E19 Guideline 
73  Selective safety data collection following the principles of this Guideline does not alter 
74  local/regional safety reporting requirements. 
75  2  GENERAL PRINCIPLES 
76  2.1  Types of Data for Which Selective Safety Data Collection May be Appropriate 
77  2.1.1  Types of Safety Data Where It May be Appropriate to Limit or Stop Collection 
78  1.  Non-serious adverse events  
79  2.  Routine laboratory tests 
80  3.  Information on concomitant medications 
81  4.  Physical examinations (including vital signs) 
82  5.  Electrocardiograms 
83  2.1.2  Types of Safety Data That Should Generally be Collected under All Circumstances 
84  For the following types of events/data, comprehensive details should generally be provided to 
85  allow adequate assessment of the event/data, e.g., history; associated adverse events; relevant 
86  laboratory values; concomitant medications; vital signs; and/or follow-up outcome. 
87  1.  Deaths  
88  2.  Serious adverse events 
89  3.  Significant adverse events that led to an intervention, including withdrawal or dose 
90  reduction of investigational medicinal product or addition of concomitant therapy 
91  4.  Marked laboratory abnormalities (other than those meeting the definition of serious)  
92  5.  Overdose 
93  6.  Pregnancies  
94  7.  Adverse events of special interest (if defined). These adverse events may warrant 
95  collection of additional information across the entire study population to better 
96  characterise these events (e.g., particular laboratory parameters; vital signs; risk 
97  factors;  concomitant  therapies;  and/or  concomitant  illnesses).  For  example,  if 
98  gastrointestinal haemorrhage was an adverse event of special interest, one might 
99  want to proactively collect concomitant antithrombotic therapy across the entire 
100  study population  
101  8.  Laboratory data, vital signs, electrocardiograms of special interest (if defined) 
102  2.1.3  Baseline Data 
103  Use of a selective safety data collection approach does not change considerations for baseline 
104  data collection.  Baseline data are needed to ensure that subjects meet inclusion and exclusion 
105  criteria for study enrolment and are important in the assessment of safety.  For example, 
106  particular serious adverse events may occur more frequently in subgroups defined on the basis 
107  of  demographics,  baseline  disease  characteristics,  coexisting  illnesses,  or  concomitant 
108  therapies; analyses of such information can be important in considering the benefit-risk profile 
109  of the drug.  
5  ICH E19 Guideline 
110  2.2  When May Selective Safety Data Collection Be Considered? 
111  When sponsors choose to implement selective safety data collection for a clinical study, a 
112  scientific justification should be provided.  Factors that contribute to a determination that 
113  selective safety data collection would be appropriate include: 
114  1.  The medicinal product  has received marketing authorisation from a regulatory 
115  authority for the indication under investigation 
116  2.  Availability of post-approval safety data and findings  
117  3.  The dose, dosing regimen, dosage form, route of administration and treatment 
118  duration used in the previously conducted studies are comparable to the planned use 
119  of the drug in the proposed study 
120  4.  The  patient  population  from  previously  conducted  studies  is  representative  of 
121  subjects in the planned study regarding demographic characteristics, underlying 
122  medical  conditions,  concomitant  drugs,  and  other  important  factors  (e.g., 
123  Cytochrome P450 enzymes (CYP) metabolizer status)   
124  5.  Exposure in previously conducted (or ongoing, if applicable) studies that contribute 
125  to the overall safety database, i.e., number exposure to drug, treatment duration 
126  6.  Consistency of the safety profile across previous studies 
127  7.  Characteristics of previous studies, e.g., study design; study conduct; adequacy of 
128  safety monitoring/safety data collection; availability of protocols; statistical analysis 
129  plan; and/or access to data  
130  8.  Knowledge of the mechanism of action of the medicinal product under study 
131  9.  Knowledge of the safety profile of approved drugs in the same pharmacologic class 
132  The above factors should be considered in determining whether the safety of the medicinal 
133  product has been sufficiently characterised to provide justification for selective safety data 
134  collection in the proposed study. 
135  In the pre-approval setting, selective safety data collection may be justifiable if sufficient safety 
136  data are available from completed studies.  Moreover, when sufficient safety data will be 
137  forthcoming from one or more ongoing late-stage study(ies), selective safety data collection 
138  may be appropriate for a concurrently conducted study-initiated pre-approval. 
139  2.2.1  Benefit-Risk Considerations for Selective Safety Data Collection 
140  It should be recognised that the contribution of non-serious adverse events to the benefit-risk 
141  profile of a drug may differ depending on the indication of use and patient characteristics (e.g., 
142  age and/or cardiovascular risk factors).  These factors should be considered when accepting the 
143  comparability of patient populations and the applicability of selective safety data collection.  
144  For example, even when safety of a drug is sufficiently characterised in a patient population 
145  with advanced disease, comprehensive safety data collection in a patient population with less 
146  advanced disease may be appropriate to ensure that the benefits outweigh the risks in the less 
147  severely affected population.  
6  ICH E19 Guideline 
148  2.2.2  Extent of Exposure 
149  Selective safety data collection could be considered for studies using lower doses and/or shorter 
150  durations than in previous studies.  Conversely, selective safety data collection would generally 
151  not be acceptable if higher doses and/or longer treatment durations than previously studied are 
152  planned.  Nonetheless, even when exposure is greater in the planned study, there may be 
153  circumstances where selective safety data collection is still appropriate, e.g., a study designed 
154  to characterise infrequent serious adverse events (e.g., renal toxicity; myocardial infarction; 
155  and/or stroke) associated with longer term use of the medicinal product within the labelled 
156  indication; a planned five-year study when a one-year study has been completed. 
157  2.3  Examples Where Selective Safety Data Collection May be Considered 
158  Selective safety data collection may be appropriate in studies used to evaluate some of the 
159  following  objectives.  These  are  not  the  only  circumstances  where  selective  safety  data 
160  collection may be appropriate. 
161  1.  New indications of approved drugs 
162  2.  To  study  additional  endpoints,  e.g.,  patient-reported  outcome  for  symptomatic 
163  improvement; quality of life; and/or outcome studies (e.g., mortality; morbidity; and/or 
164  specific safety issues) 
165  3.  To study comparative effectiveness/efficacy 
166  4.  Demonstration of superiority when non-inferiority has been demonstrated 
167  5.  Characterisation of adverse events of special interest 
168  6.  Fulfilment of post-approval requirements, post-authorisation safety studies based on 
169  data collection from registries or electronic health records  
170  7.  Late-stage premarketing outcome study in a large population   
171  Additional examples and situations for applying selective safety data collection may be found 
172  in Section 3, Methods of Implementation. 
173  2.4  Ensuring Patient Safety within Studies 
174  Patient safety monitoring serves two purposes: 1) to protect the welfare of individual study 
175  participants; and 2) to accumulate safety information to be used in the assessment of benefit-
176  risk for the proposed indication.  The recommendations in this Guideline do not obviate the 
177  need for monitoring to protect individual patient welfare.  Although certain safety data, e.g., 
178  non-serious adverse events, would not need to be recorded in the case report form (CRF) when 
179  selective safety data collection is determined to be appropriate, the protocol should stipulate 
180  that patients are monitored per standard of care.  For example, for a medicinal product known 
181  to cause hyperglycaemia, where routine blood glucose monitoring is recommended in labeling, 
182  glucose should be monitored in patients participating in a study.  If hyperglycaemia is well-
183  characterised with this medicinal product, the glucose data do not need to be recorded in the 
184  CRF or reported to the sponsor in studies using selective safety data collection.  Glucose levels 
185  would be recorded in the CRF and reported to the sponsor if stipulated in the protocol, e.g., as 
186  an adverse event of special interest, associated with a serious adverse event. 
7  ICH E19 Guideline 
187  2.5  Changes in Approach to Safety Data Collection 
188  When an unexpected safety issue arises during the course of a study, e.g., a postmarketing 
189  safety signal; a finding from a nonclinical study; higher than expected withdrawals; and/or 
190  concern from a data monitoring committee; a change in the selective safety data collection 
191  approach may be warranted, e.g., denoting a new adverse event of special interest; and/or 
192  reverting to comprehensive safety data collection. 
193  2.6  Early Consultation with Regulatory Authorities 
194  Studies must be conducted according to local and regional laws and regulatory requirements.  
195  When sponsors are considering selective safety data collection in interventional studies, they 
196  should discuss their scientific rationale and planned methods with regulatory authorities prior 
197  to initiating the study(ies).  The same applies to non-interventional studies that are being 
198  conducted to address requests from regulatory authorities.    
199  It is possible to conduct a multi-regional clinical study using a single protocol with selective 
200  safety data collection if the safety profile of the product is considered to be sufficiently 
201  characterised, and all regulatory authorities agree with the proposed approach.  A well-
202  designed multi-regional clinical study that takes this Guideline into account will help the 
203  sponsor reach agreement with regulatory authorities in multiple regions (See ICH E17  
204  General Principles for Planning and Design of Multi-Regional Clinical Trials). 
205  3  METHODS OF IMPLEMENTATION 
206  Having considered the principles outlined in Section 2, General Principles, with respect to 
207  when it may be appropriate to limit or stop collection of certain types of safety data, a number 
208  of approaches for selective safety data collection may be considered.   
209  Use of selective safety data collection can introduce important complexities in study conduct 
210  and safety analysis.  The specific approaches should be carefully planned and clearly delineated 
211  within the relevant study documents, e.g., protocol; monitoring plan; and/or statistical analysis 
212  plan, with a reference to this Guideline. 
213  Regardless of the method chosen, it is essential to ensure patient safety and adhere to local and 
214  regional laws and regulations.  When the selective safety data collection approach is used for 
215  a clinical study, the approach should be described in the appropriate document(s) when safety 
216  findings are presented, e.g., the Clinical Study Report (CSR); Development Safety Update 
217  Report (DSUR); Periodic Benefit-Risk Evaluation Report (PBRER); Periodic Safety Update 
218  Report (PSUR); and/or Common Technical Document (CTD).  
219  The following examples of methods of implementation are not meant to be all-inclusive. These 
220  approaches can be applied in both the pre- and post-approval settings and require a scientific 
221  rationale and justification.  The data supporting these approaches are more likely to be available 
222  in the post-approval setting than in the pre-approval setting.    
8  ICH E19 Guideline 
223  3.1  Selective Safety Data Collection for All Patients in the Study 
224  For all patients in the study, parameters listed in Section 2.1.2, General Principles, are collected 
225  throughout the study, e.g., serious adverse events; adverse events of special interest; and/or 
226  deaths.    Conversely,  the  parameters  listed  in  Section  2.1.1,  General  Principles,  are  not 
227  collected,  e.g.,  non-serious  adverse  events;  routine  laboratory  values;  concomitant 
228  medications; physical examination data; vital signs; and/or electrocardiograms.   
229  In the post-approval setting, this approach may be useful to address a specific safety concern, 
230  for example, to meet a post-authorisation commitment, when safety in other regards has been 
231  sufficiently characterised.   
232  In  the  pre-approval  setting,  this  approach  may  be  also  used.  For  example,  consider  a 
233  development programme for a lipid-lowering drug, where a decrease in low-density lipoprotein 
234  (LDL) cholesterol will serve as the basis of approval, but the impact on cardiovascular risk is 
235  being investigated.  In addition to the completed Phase 2 programme, two Phase 3 studies are 
236  ongoing with LDL cholesterol as the primary endpoint, which will provide adequate exposure 
237  to assess safety sufficiently.  The sponsor wishes to initiate a third study with major adverse 
238  cardiovascular events as the primary endpoint.  For the third study, a selective safety data 
239  collection approach could be justified considering the data available in light of the principles 
240  above.  
241  3.2  Comprehensive Safety Data Collection for a Specific Subset(s) of the Population, 
242  with Selective Safety Data Collection for Other Patients 
243  Comprehensive safety data are collected for specific subset(s) of the patient population where 
244  additional information is deemed important, whereas selective safety data are collected for 
245  other patients.  For example, if the patient population in previous studies included few patients 
246  over the age of 65, it could be of value to collect full data on this population in a new study in 
247  the same indication or in a related indication.  Other examples of specific subsets include those 
248  based on geographic location; ethnicity; sex; baseline disease status (renal/hepatic impairment), 
249  CYP status; or genetics.   
250  3.3  Comprehensive  Safety  Data  Collection  in  a  Representative  Subset  of  the 
251  Population, with Selective Safety Data Collection for Other Patients 
252  In some cases, efficacy studies must enrol many thousands of patients in order to achieve 
253  adequate statistical power.  In such settings, such as a large clinical outcomes study, the number 
254  of patients planned for enrolment may greatly exceed the number needed to assess the non-
255  serious adverse events adequately.  In this setting, comprehensive safety data could be collected 
256  for  only  a  representative  subset  of  patients,  for  example,  full  data  collection  could  be 
257  undertaken at randomly selected sites.   
258  3.4  Comprehensive Safety Data Collection for the Initial Portion of the Study, with 
259  Selective Data Collection Thereafter 
260  Comprehensive safety data are collected from baseline through some pre-determined interval 
261  of the study, with selective safety data collection thereafter.  A data monitoring committee 
9  ICH E19 Guideline 
262  could consider the safety data and provide agreement with selective safety data collection for 
263  the subsequent portion of the study.  These approaches can be useful for studies designed to 
264  assess important long-term drug effects, where safety would be adequately characterised in the 
265  early part of the study, e.g., one year, through comprehensive safety data collection.  For 
266  example, consider a study to prevent an important outcome such as dementia, end-stage kidney 
267  disease, and/or hepatic failure.  Assuming it would take three years to collect adequate events 
268  to have adequate statistical power for efficacy, it may be appropriate to utilize a selective 
269  approach to safety data collection once data have been analysed for all patients followed 
270  through  one  year  and  non-serious  adverse  events  have  been  deemed  to  be  adequately 
271  characterised.  The selective approach would discontinue collection of non-serious adverse 
272  events, vital signs, laboratory tests, etc., and utilize less frequent study visit intervals.  The 
273  protocol should include a prospective plan for concurrence of a data monitoring committee 
274  prior to the change to selective safety data collection.   
275  4  RELATIONSHIP WITH OTHER GUIDELINES/REGULATIONS  
276  This guideline should be considered in conjunction with other ICH guidelines relevant to the 
277  conduct of clinical studies and clinical safety data management, e.g., E2A (Clinical Safety Data 
278  Management: Definitions and Standards for Expedited Reporting); E2F (Development Safety 
279  Update Report); E3 (Structure and Content of Clinical Study Reports ); E6(R2) (Good Clinical 
280  Practice: Integrated Addendum to ICH E6(R1)); E8 (General Considerations for Clinical 
281  Trials); and/or E17 (General Principles for Planning and Design of Multi-Regional Clinical 
282  Trials).  Evaluation of the information generated through post-approval pharmacovigilance 
283  activities is also important for all products to ensure their safe use, e.g. E2E (Pharmacovigilance 
284  Planning); E2D (Post-Approval Safety Data Management:  Definitions and Standards for 
285  Expedited Reporting); and E2C(R2) (Periodic Benefit-Risk Evaluation Report).   
10