0% found this document useful (0 votes)
8 views24 pages

GCDMP Safety Data Management Chapter Public Review

This document discusses the complexities of safety data management and reporting in clinical trials, emphasizing the importance of regulatory compliance, accurate data collection, and the use of medical dictionaries for encoding adverse events. It outlines the historical context of safety regulations, learning objectives for understanding safety data processes, and minimum standards set by the International Council for Harmonization (ICH). The chapter also highlights the need for consistent methodologies and training across regions in multi-regional clinical trials to ensure reliable safety data reporting.

Uploaded by

worstman106
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
0% found this document useful (0 votes)
8 views24 pages

GCDMP Safety Data Management Chapter Public Review

This document discusses the complexities of safety data management and reporting in clinical trials, emphasizing the importance of regulatory compliance, accurate data collection, and the use of medical dictionaries for encoding adverse events. It outlines the historical context of safety regulations, learning objectives for understanding safety data processes, and minimum standards set by the International Council for Harmonization (ICH). The chapter also highlights the need for consistent methodologies and training across regions in multi-regional clinical trials to ensure reliable safety data reporting.

Uploaded by

worstman106
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
You are on page 1/ 24

1 Safety Data Management and Reporting

2
3 Manju Benedicta, Kelly Sclavounosb, Chris Battistonc, Susan Howardd
a
4 : IQVIA; b: Pfizer; c: Women’s College Hospital, d: Verismo Therapeutic

5 1) Abstract

6 Collecting and reporting information about the safety of an experimental compound or product constitutes a significant
7 challenge for clinical data management. This chapter reviews the wide range of factors that must be considered by the
8 clinical research team for the successful completion of a project’s safety data management and reporting
9 responsibilities. Industry guidelines and regulations for collecting and reporting reliable, high-quality safety data are
10 discussed. The importance of degrees of precision and descriptions of severity when capturing data about adverse
11 events is emphasized in this chapter. The use of medical dictionaries, especially MedDRA, is reviewed with consideration
12 for the process of encoding safety data to dictionary terms and various approaches to this task. Laboratory data and
13 other forms of data, such as specialized tests, as potential sources of safety data. Special consideration is given to the
14 capture of serious adverse events and their reporting to regulatory agencies. General issues to consider when reporting
15 safety data to the FDA are also discussed.
16

17 2) Introduction

18 Beginning in 1938, the FDA required that drugs have proof of safety before they could be marketed. This was because of
19 a poisonous ingredient found in Elixir Sulfanilamide. In 1962, after the Thalidomide disaster in Western Europe, the
20 Kefauver-Harris amendment was passed, requiring that drugs must be safe and show evidence of effectiveness for the
21 related use. The 1990s introduced post marketing surveillance, and in 1993, MedWatch was launched to make it easier
22 doctors and consumers to report adverse events.1

23

24 3) Learning Objectives

25 After reading this chapter, the reader should understand:


26 • The purpose of and regulatory basis for safety surveillance and the collection and reporting of safety data.
27 • The categories and classification of safety related events that may occur in clinical trials.
28 • The importance of coding and controlled terminology in safety data.
29 • How AEs and SAEs (Adverse Events and Serious Adverse Events) are identified.
30 • Data collected about safety events.
31 • The reporting process for safety events for trials run under an Investigational New Drug (IND) as well as federally
32 funded studies.
33 • How safety data is validated includes reconciliation of externally managed safety data.
34 The safety data in a clinical study are simultaneously a rich source of information and an enormous challenge. The data
35 manager and the statistician, as part of the product team, must work closely with other team members to ensure that
36 safety data are captured in a sensible way to facilitate proper interpretation and meaningful analysis and summary.
37 Ensuring quality requires that the team capture, process, and report the data in a way that facilitates the drawing of
38 reliable conclusions. When determining the balance between business and science, consideration should be made to
39 collect only data that will support conclusions, and to ensure that data is fit for purpose.
40
41 Safety data may be displayed and reported in many ways. To ensure adequate reporting of results that pertain to
42 product effects, judgment and scientific selection are needed to identify the trends and salient features of the data.
43 Producing voluminous pages that are incomprehensible and clinically meaningless can dilute real effects. However, the
44 discernment of these effects is the driving goal of the safety data processing and reporting.

45 4) Scope

46 This chapter discusses practices, procedures, and recommendations for data managers to understand and implement
47 Safety Data collection, management, and reporting during clinical trials. This chapter will cover identification and
48 classification of safety-related events reportable to IRBs (Institutional Review Board), DSMBs (Data Safety Management
49 Board), regulatory authorities and clinical sites using the investigational therapeutic. The chapter focuses on safety data
50 collection, management, validation, and reporting for investigational drugs in clinical trials run under an IND as well as
51 federally funded studies. Safety processes for devices are only briefly discussed with reference to additional resources.
52 Similarly post marketing surveillance is not covered in depth.

53 5) Minimum Standards

54 The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH)
55 Efficacy Guidelines contain passages of significant relevance to the reporting of safety data in trials:
56 Section 4 of the ICH(E1A), Clinical Safety for drugs used in Long-Term Treatment, states that available information
57 suggests that most ADEs (Adverse Drug Event) first occur, and are most frequent, within the first few months of drug
58 treatment. The number of patients treated for six months at dosage levels intended for clinical use, should be adequate
59 to characterize the pattern of ADEs over time.

60 To achieve this objective the cohort of exposed subjects should be large enough to observe whether more frequently
61 occurring events increase or decrease over time as well as to observe delayed events of reasonable frequency (e.g. in
62 the general range of 0.5%-5%). 300—600 patients should be adequate for observation.

63 Section 1.1 of the ICH(E2F), Pharmacovigilance, states that “periodic analysis of safety information is crucial to the
64 ongoing assessment of risk to trial subject” and impresses the need to “inform regulators and other interested parties
65 (e.g., ethics committees) at regular intervals about the results of such analyses and the evolving safety profile of an
66 investigational drug and apprise them of actions proposed or being taken to address safety concerns.”

67 Section 1.2 and 1.3 note that “A (Drug Safety Update Report) should be concise and provide information to assure
68 regulators that sponsors are adequately monitoring and evaluating the evolving safety profile of the investigational
69 drug,” and that “The DSUR should concentrate primarily on the investigational drug, providing information on
70 comparators only where relevant to the safety of trial subjects.”

71 The ICH E2 offers further guidance on data collection related to pharmacovigilance.

72 Section IIIA (ICH E2) states that all ADRs (Adverse Drug Reactions) that are both serious and unexpected are subject to
73 expedited reporting, and that other ADRs should be considered on a case-by-case basis. Most notably, expedited
74 reporting is needed for an "expected", serious ADR, an increase in the rate of occurrence, which is judged to be clinically
75 significant, for a significant hazard to the patient population, such as lack of efficacy with a medicinal product using in
76 treating life-threatening disease, or for a major safety finding from a newly completed animal study (such as
77 carcinogenicity).

78 The role of statistics in clinical trial design and analysis is essential according to ICH guidelines. ICH E9, Statistical
79 Principles for Clinical Trials, is intended to give direction to sponsors in the design, conduct, analysis, and evaluation of
80 clinical trials of an investigational product in the context of its overall clinical development.
81
82 Section 3.6 describes the data capture and processing requirements:
83
84 “Whatever data capture instrument is used, the form and content of the information collected should be in full
85 accordance with the protocol and should be established in advance of the conduct of the clinical trial. It should
86 focus on the data necessary to implement the planned analysis, including the context information (such as
87 timing assessments relative to dosing) necessary to confirm protocol compliance or identify important protocol
88 deviations. ‘Missing values’ should be distinguishable from the ‘value zero’ or ‘characteristic
89 absent’…Specifically, timely and reliable processes for recording data and rectifying errors and omissions are
90 necessary to ensure delivery of a quality database and the achievement of the trial objectives through the
91 implementation of the planned analysis.”
92
93 Section 6.2 indicates several factors considered to evaluate the safety and tolerability of a drug.
94
95 “In any clinical trial the methods and measurements chosen to evaluate the safety and tolerability of a drug will
96 depend on a number of factors, including knowledge of the adverse effects of closely related drugs, information
97 from non-clinical and earlier clinical trials and possible consequences of the pharmacodynamic/pharmacokinetic
98 properties of the particular drug, the mode of administration, the type of subjects to be studied, and the
99 duration of the trial. Tests such as clinical chemistry and haematology, vital signs, and clinical adverse events
100 (diseases, signs and symptoms) usually form the main body of the safety and tolerability data. The occurrence of
101 serious adverse events and treatment discontinuations due to adverse events are particularly important to
102 register (see ICH E2A and ICH E3).”
103
104 Section 6.2 also shares recommendations while summarizing the data from different trials:
105
106 “Furthermore, it is recommended that a consistent methodology be used for the data collection and evaluation
107 throughout a clinical trial program to facilitate the combining of data from different trials. The use of a common
108 adverse event dictionary is particularly important. This dictionary has a structure which gives the possibility to
109 summarize the adverse event data on three different levels; system-organ class, preferred term or included
110 term…The preferred term is the level on which adverse events usually are summarized, and preferred terms
111 belonging to the same system-organ class could then be brought together in the descriptive presentation of data
112 (see ICH M1).”
113
114 Section 6.3 shares information about the specific set of subjects to be evaluated for the overall safety and tolerability
115 assessment: “The set of subjects to be summarized is usually defined as those subjects who received at least one dose of
116 the investigational drug. Safety and tolerability variables should be collected as comprehensively as possible from these
117 subjects, including type of adverse event, severity, onset, and duration.”
118
119 Section 7.2, summarizing the Clinical Database, reiterates the need for consistent data collection and recording, which
120 will facilitate subsequent interpretation of the series of trials.
121
122 “An overall summary and synthesis of the evidence on safety and efficacy from all the reported clinical trials is
123 required for a marketing application. During the design of a clinical programme careful attention should be paid
124 to the uniform definition and collection of measurements which will facilitate subsequent interpretation of the
125 series of trials, particularly if they are likely to be combined across trials. A common dictionary for recording the
126 details of medication, medical history and adverse events should be selected and used.”
127
128 The ICH General Principles for Planning and Design of Multi-Regional Clinical Trials (MRCTs) (E17) has the aim of
129 increasing the acceptability of MRCTs global regulatory submissions. The guideline addresses “strategic programme
130 issues as well as issues that are specific to the planning and design of confirmatory MRCTs, and it should be used
131 together with other ICH guidelines, including E5, E6, E8, E9, E10, and E18.”
132
133 ICH E17 Section 2.1.2:
134
135 “All sites participating in MRCTs should meet applicable quality, ethical and regulatory standards. Specifically,
136 MRCTs should be conducted in compliance with ICH E6 GCP standards in all regions and sites, including making
137 sites available for GCP inspections by regulatory authorities. Monitoring plans and other quality checks should
138 be pre-specified and implemented to address potential risks to subject rights, safety, and well-being, and to the
139 reliability of study results. Centralized and risk-based monitoring may be particularly useful for MRCTs to
140 monitor and mitigate the impact of emerging regional differences in, for example, trial subject retention or
141 adverse event reporting (ICH E6).”
142
143 Section 2.2.4 offers guidance on the selection of clinical endpoints.
144
145 “An ideal clinical trial endpoint is one that is clinically relevant, accepted in medical practice (e.g., by regulatory
146 guidance or professional society guidelines) and sufficiently sensitive and specific to detect the anticipated
147 effect of the treatment. For MRCTs, the primary endpoint, whether efficacy or safety, should satisfy these
148 criteria as well as being acceptable to all concerned regulatory authorities, to ensure that interpretation of the
149 success or failure of the MRCT is consistent across regions and among regulatory authorities…In addition to
150 endpoint selection and definition, regulatory agreement should also be obtained on the timing and methods of
151 the primary endpoint assessment…Although endpoints may not require formal validation, some endpoints may
152 be subject to subtle differences in understanding, when used in different cultural settings. For example, certain
153 types of adverse events may be more sensitively reported (e.g., more or less frequently) in some regions than
154 others, resulting in differences in reporting patterns due to cultural variation, rather than true differences in
155 incidence. Use of these variables as endpoints in MRCTs will require careful planning. Approaches to minimize
156 the impact of this variation in data collection and interpretation of the trial results should be described and
157 justified in the study protocol.”
158
159 Section 2.2.6:
160 “Methods of collecting and handling efficacy and safety information should be standardized across participating
161 regions. It is also important to provide standardized training for investigators and study personnel in each region
162 before initiating the trial in that region to ensure that the trial objectives are met through standardised
163 implementation of the study protocol.”
164 “Safety reporting should be conducted in accordance with ICH E2. When local regulations specify different
165 requirements, such as timelines and criteria for expedited reporting, these should also be adhered to locally. The
166 specific period for safety reporting should be provided in the protocol, and the investigators should receive
167 sufficient training in accordance with ICH E6 and other relevant guidelines. In the case of MRCTs, important
168 safety information should be managed both with adherence to any local regulations and in adherence to ICH
169 E2A. Important safety information should always be provided to the relevant stakeholders (e.g., investigators,
170 ethics committees) in a timely manner.”
171 “In MRCTs of long duration, where special concerns (e.g., serious adverse events) have been identified, and/or
172 where operational regions are quite large (usually Phase III confirmatory studies), the use of a central
173 independent data monitoring committee (with representation from participating regions to adequately assess
174 the context of the trial) should be considered, in order to monitor the accumulating efficacy and/or safety
175 information from the MRCT while maintaining integrity of the ongoing trial. If adjudication of endpoints and/or
176 events is planned, a centralised assessment by a single adjudication committee should be
177 considered…Coordinated site initiation is particularly important in MRCTs to ensure proper conduct, completion,
178 and reporting of results without any delays among regions. To comply with the quality management described in
179 ICH E6, the sponsor should implement a system to manage quality in design, conduct, oversight, recording,
180 evaluation, reporting and archiving of MRCTs. In this aspect, centralised and risk-based monitoring may be
181 particularly useful for MRCTs to identify variability across regions and sites in protocol compliance (e.g.,
182 differences in follow-up, compliance with study medications, adverse event reporting and/or extent of missing
183 data). Mitigation approaches should take regional variations into consideration.”
184
185 ICH E19-Safety Data Collection expands on issues related to collection of safety data for reporting purposes once the
186 medicinal product has received marketing authorization from a regulatory authority for the indication under
187 investigation.
188
189 Section 2.2 addresses the factors that contribute to a determination that selective safety data would be appropriate and
190 includes:
191 • Availability of post-approval safety data and findings.
192 • The dose, dosing regimen, dosage form, route of administration, and treatment duration used in the previously
193 conducted studies are comparable to the planned use of the drug in the proposed study.
194 • The patient population from previously conducted studies is representative of subjects in the planned study
195 regarding demographic characteristics, underlying medical conditions, concomitant drugs, and other key factors.
196 • In previously conducted (or ongoing, if applicable) studies that contribute to the overall safety database, i.e. number
197 exposure to drug, treatment duration.
198 • Consistency of the safety profile across previous studies.
199 • Characteristics of previous studies, e.g. study design, study conduct, adequacy of safety monitoring/safety data
200 collection availability of protocols statistical analysis plan, and/or access to data.
201 • Knowledge of the mechanism of action of the medicinal product under study.
202 • Knowledge of the safety profile of approved drugs in the same pharmacologic class.
203
204 TITLE 21 CFR 312.32 requires IND holders to notify the FDA and all participating investigators of any event suspected
205 to be related to the serious and unexpected treatment. A serious and unexpected adverse event or unexpected
206 suspected adverse reaction is defined as follows:
207 “An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator
208 brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is
209 not required or available, is not consistent with the risk information described in the general investigational plan
210 or elsewhere in the current application, as amended.”
211
212 This guidance also identifies review of safety information by the sponsor and specifies potential sources of safety data as
213 follows:
214
215 “The sponsor must promptly review all information relevant to the safety of the drug obtained or otherwise
216 received by the sponsor from foreign or domestic sources, including information derived from any clinical or
217 epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished
218 scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial
219 marketing experience for drugs that are not marketed in the United States.”
220
221 The criteria for these IND safety reports are follows:
222
223 “The sponsor must submit each IND safety report in a narrative format or on FDA Form 3500A or in an electronic
224 format that FDA can process, review, and archive. The sponsor must also notify FDA of any unexpected fatal or
225 life-threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after
226 the sponsor's initial receipt of the information.”

227

228 With the review of regulatory requirements and guidance in mind, we recommend the following Minimum Standards for
229 Safety Data Reporting:
230
231 Table 1
232
# Minimum Standard Reference Evidence level Sections referred
1 Appropriately collect, review, analyze and 1. ICH E6 I (Regulatory 1. Sections 6.8
report events (including AEs, DSUR, ADR’s, 2. ICH E8 Guidance) 2. Section 6
Suspected Events, etc.) to authorities on a
consistent and timely manner, and according to
3. ICH E9 3. Sections 3.6,
6.2
the requirements for submission (including
technical requirements).
2 All adverse data should be reported regardless 1. FDA I (Regulatory 1. Section 312.32
of causality. The incidence of AE’s should be 21CFR Guidance) 2. Section 7.3.6 b
analyzed with an appropriate method defined in 2. ICH 3. Section 12.2.2
the protocol. E6(R1)
3. ICH E3

3 Clinical data should be collected based on 1. ICH E9 I (Regulatory 1. Sections 6.2


protocol requirements and chosen specifically 2. ICH E19 Guidance) 2. Sections 2.4,
to assess the treatment under 2.5, 2.6
study. Laboratory, vital sign and adverse event
3. ICH E3
data constructs most safety data,
3. Section 12

4 Develop standard operating procedures 1. ICH E6 I (Regulatory 1. 1. Sections 1.6.


(SOPs) for data capture, data validation, 2. ICH E9 Guidance) 1.38, 1.55
statistical analysis, and reporting of data. The 2. 2. Section 5.8
SOPs should include appropriate detail and
3. ICH E19
resources for this team approach

5 Ensure adequate sample size and duration of 1. ICH E9 I (Regulatory 1. Section 3.6
dosing is collected to characterize possible Guidance)
adverse events.
6 Multi-Regional Trials should follow all the ICH E17 I (Regulatory Sections 2.1.2, 2.2.4,
principles of GCP and regulations across Guidance) 2.2.5, 2.2.6 & 2.2.
regions and satisfy the primary end point.
Standard training and Monitoring of MRCT’s
differences across regions should occur to
maintain consistency, as reporting of adverse
events can differ.
233

234 6) Best Practices

235 Best practices are those identified through the literature or by the chapter writing group that do not have a strong
236 requirement based in regulation or recommended approach based in guidance, but which do have supporting evidence
237 either from the literature or consensus of the writing group. As such best practices like all assertions in GCDMP chapters
238 have a literature citation where available and are tagged with a Roman numeral indicating the strength of evidence
239 supporting the recommendation (see Table 1).
240
241 1. Develop CRFs with teams of individuals from the monitoring, data management, statistics, regulatory affairs,
242 and medical departments, thereby ensuring adequate attention to the collection of safety data. When working
243 on a program of studies for a specific product, ensure the collection is consistent enough to support reporting.
244 (CDASH IG Version 2.1, Page 24).
245 2. Define clear reporting instructions (CDASH IG Version 2.1, Page 11).
246 3. Consider the level of precision that can be attained in the study and select the CRF format for collecting AEs
247 appropriate for that level. Also, consider the level of precision in the analysis.
248 4. Define severity, with an understanding of its uses and limitations. (CDASH IG Version 2.1, Page 168).
249 5. Examine laboratory data from the perspectives of categorical shifts, changes in magnitude for the group,
250 individual significant values or changes, and listings. Consider related parameters for compounds with potential
251 toxicity in specific body systems.
252 6. Consider laboratory normalization techniques when combining data across studies or centers where varying
253 normal ranges are used and that robust lab cleaning occurs, especially for studies utilizing local laboratories, as
254 incorrect laboratory ranges can cause incorrect reporting of the above. (Consensus).
255 7. Include the study team when considering computerization, management, reporting, and analysis of safety data.
256 These tasks are highly integrated and require joint considerations of individual team constituents. (Consensus).
257 8. Ensure that scope of adverse events collection is consistent with the protocol requirements. Sponsor should
258 define appropriate data collection requirements (e.g., therapeutic area specific requirements, special
259 populations, data collection period etc.), which may vary based on the requirements for characterizing and
260 reporting product safety and is usually defined in the protocol. (CDASH IG).
261 9. Identify and define common SAE data fields for SAE data collection (CDASH Serious Adverse Event Supplement,
262 Version 2. 2021).
263 10. Apply standards commensurate with the utilization of the results residing in the databases when using
264 databases for safety reporting (e.g., expedited reporting, ongoing review by monitoring boards, or routine
265 reporting). If important decisions are made based on the information in the database, know the data’s
266 appropriateness and level of quality. (Consensus).
267 11. Use MedDRA for coding Adverse events, to facilitate consistent data retrieval, medically meaningful groupings
268 for review, analysis and/or summary of safety data. Always output the data utilizing the most recent version of
269 MedDRA. (MedDRA Best Practices, Maintenance and Support Services Organization’s (MSSO)
270 Recommendations for Implementation and Use of MedDRA 2018.
271
272 Table 2 GCDMP Evidence Grading Criteria
273
Evidence
Criteria
Level
I Large, controlled experiments, meta, or pooled analysis of controlled experiments, regulation, or
regulatory guidance
II Small, controlled experiments with unclear results
III Reviews or synthesis of the empirical literature
IV Observational studies with a comparison group
V Observational studies including demonstration projects and case studies with no control
VI Consensus of the writing group including GCDMP Executive Committee and public comment process
VII Opinion papers
274

275 7) Safety Data Terminologies, Categorization & Definitions

276 Below is a non-exhaustive list of definitions that are used throughout the following sections, and with which anyone
277 working on or overseeing a clinical trial should be familiar. While company-specific terminology is often present, for this
278 chapter's purposes, the terms defined below will be used in this chapter.
279
280 Adverse Event: Any untoward medical occurrence in a patient or clinical investigation subject administered a
281 pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can
282 therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease
283 temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal
284 (investigational) product (ICH E6 R2).
285
286 Adverse Drug Reactions: In the preapproval clinical experience with a new medicinal product or its new usages,
287 particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal
288 product related to any dose should be considered adverse drug reactions. The phrase “responses to a medicinal
289 product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable
290 possibility, i.e., the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which
291 is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of
292 diseases or for modification of physiological function (ICH E6 R2).
293
294 Unexpected Adverse Drug Reaction: An adverse event or suspected adverse reaction is considered “unexpected” if it is
295 not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an
296 investigator brochure is not required or available, is not consistent with the risk information described in the general
297 investigational plan or elsewhere in the current application, as amended. (FDA – Safety Reporting Requirements for INDs
298 and BA/BE studies, 2012).
299
300 Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the drug caused the
301 adverse event. For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to suggest a
302 causal relationship between the drug and the adverse event. A suspected adverse reaction implies less certainty about
303 causality than adverse reaction, which means any adverse event caused by a drug. (FDA 21 CFR 312.32(a).
304
305 Suspected Unexpected Serious Adverse Reaction (SUSAR): A suspected adverse reaction (see definition above) that is
306 considered both serious and unexpected. (FDA 21 CFR 312.32(a).
307
308 Treatment Emergent Adverse Event: An event that emerges during treatment having been absent pre-treatment or
309 worsens relative to the pre-treatment state. (ICH E9).
310
311 A Serious Adverse Event: This (experience or reaction) is any untoward medical occurrence that at any dose results in
312 death, and/or is life-threatening. Note that the term “life-threatening” in the definition of “serious” refers to an event in
313 which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might
314 have caused death if it were more severe. Requires inpatient hospitalization or prolongation of existing hospitalization,
315 results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. (ICH E2A).
316
317 Adverse Events of Special Interest: A noteworthy event for a particular product or class of products that a sponsor may
318 wish to monitor carefully. It could be serious or non-serious (e.g. hair loss, loss of taste, impotence), and could include
319 events that might be potential precursors or prodromes for more serious medical conditions in susceptible individuals.
320 Such events should be described in protocols or protocol amendments, and instructions provided for investigators as to
321 how and when they should be reported to the sponsor. (CIOMS Cumulative Glossary 2023).
322
323 Reporting an Unanticipated Problem Involving Risks to Subjects or Others (UPIRTSO) to IRBs: Any problem or event
324 which, in the opinion of the local investigator, was unanticipated, places subjects or others at a greater risk of harm than
325 was previously known or recognized and was possibly related to the research procedures.2
326
327 Investigator Brochure (IB): A compilation of the clinical and nonclinical data on the investigational product(s) that is
328 relevant to the study of the investigational product(s) in human subjects. (E6R2).
329
330 Development Safety Update Report (DSUR): presents a comprehensive, thoughtful annual review and evaluation of
331 pertinent safety information collected during the reporting period related to a drug under investigation, whether it is
332 marketed (ICH E2F). A DSUR should be concise and provide information to assure regulators that sponsors are
333 adequately monitoring and evaluating the evolving safety profile of the investigational drug. (ICH E2F).
334
335 Independent Data Monitoring Committee (IDMC) (Data and Safety Monitoring Board (DSMB), Safety Review Committee
336 (SRC)): An independent data monitoring committee that may be established by the sponsor to assess at predefined
337 intervals, the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the
338 sponsor whether to continue, modify, or stop a trial. (E6R2).
339
340 Investigational New Drug (IND) Annual Report: A sponsor is required, within 60 days of the anniversary date that
341 the IND went into effect (i.e. the date the FDA permitted the study to begin), to submit a brief report of the progress of
342 the investigation. Some of the topics include: the status of each study and each study completed during the previous
343 year, description of the investigational plan for the upcoming year, any revisions to the IB and significant protocol
344 updates. To promote global harmonization, the FDA will accept the DSUR (see definition above) to meet an IND
345 application annual report requirement. (21 CFR part 11 312.33.).
346

347 8) Safety Data Management

348 The management of all data collected during a clinical trial is important, however in many aspects the safety data may
349 be the most critical given that the data will lead to conclusions about the efficacy, efficiency, and welfare of the patient
350 population. Various tools and standardized dictionaries are available for use during a clinical trial, and it is the
351 responsibility of the Sponsor to select the most appropriate and the role of the data manager to ensure consistent usage
352 throughout the study.
353
354 I. Identification of Adverse Events
355
356 Adverse events can be reported by subjects via physical examinations, electronic patient reported outcomes (ePRO), or
357 paper questionnaires and open-ended discussions with the PI. Adverse events can also be identified through other
358 clinical trial evaluations, such as laboratory results, neurological exams, and ECGs. It is important not to question
359 participants about specific, expected events to avoid collection bias.
360
361 ePRO tools exist to aid in the subject reported collection of adverse events in real time, such as the PRO-CTCAE™.3, 4 A
362 number of ePRO tools are available for mobile devices, such as Android and iOS, and can seamlessly transfer the data for
363 consumption. These tools often have a library of adverse event terms/symptoms to choose from, along with severity,
364 frequency, and other pertinent adverse event specific information.
365
366 When implementing ePRO for the collection of adverse events, ensure the questions are easy and timely for patients to
367 complete, provide education and step-by-step workflows and perform robust testing of the tool and reconciliations as
368 needed, as well as describe the appropriate process and timing of data transfers.
369
370 II. Data Collection
371 a. CRF/Database design requirements
372 The accuracy of safety evaluation depends on the quality of the data reporting. The quality of an SAE case report
373 depends on the accuracy and completeness of specific information obtained about AE. This issue of completeness or
374 accuracy in SAE case reports has been identified as a crucial factor hampering the usefulness of SAE case reports.5
375
376 The process of detecting and reporting of safety data must be established in collaboration with Sponsor and oversight
377 committees.6
378
379 To ensure uniform Good Clinical Practice standards in the collection of safety data, it is important to harmonize the way
380 to gather data and act on important safety information arising. Clean safety data is promoted through the careful design
381 of data collection forms in accordance with the study protocol, regulatory requirements with proper planning from the
382 monitoring, data management, statistics, regulatory affairs, and medical departments, an extensive training for the
383 study team including site staff, followed by user feedback mechanism that could be built into the CRF design and the
384 maintenance process of the reporting tool. (ICH E6R2).
385
386 While the Clinical Data Management operation may be first to be aware of an adverse event, the responsibility of
387 submitting a Suspected Unexpected Serious Adverse Reactions (SUSAR) to competent authorities, ethic committees and
388 investigators typically lies within drug safety.
389
390 The data management safety role starts with the data collection and clinical database preparation before safety
391 reconciliation. Safety data management includes monitoring and tracking of all adverse events, serious adverse events,
392 serious and medically significant adverse drug reactions (ADRs) and other medical-related product information, coding
393 of all reported events. Reporting of such information in accordance with the sponsor and regulatory reporting timelines
394 should either be done electronically by the system or as an aggregated report.
395
396 Clinical Data Management and Safety organizations may run independently and may use separate databases designed to
397 comply with different data standards. Sponsors can utilize separate reporting databases to meet independent reporting
398 requirements although some data are common. The Clinical Data Interchange Consortium (CDISC) has set the standards
399 for clinical trial data, while the International Conference of Harmonization (ICH) dictate drug safety ones.7
400
401 Without question, electronic case report form (eCRF) design and the ultimate completion of the forms by the clinical
402 investigators or clinical research coordinators is one of the most critical steps in a successful clinical trial. The quality of
403 the data collected relies primarily on the quality of the eCRFs designed and implemented. No matter how the time and
404 effort into conducting the trial, if the correct data points were not collected, a meaningful analysis may not be possible.
405 It is reasonable to state that the design, development, and quality assurance of such an instrument must be given the
406 utmost attention. The quality of the information originally reported directly impacts the quality of data output.6
407
408 b. Key data points
409 The list of variables provided in Table 3 is not exhaustive nor will be applicable to all studies; this is to guide the decision-
410 making process for the Sponsor, and to allow the data manager to have a list of variables that can be referred to and aid
411 in ensuring the most relevant data is collected. Code lists may differ, but CDISC Terms should be considered.
412
Table 3 Key Data Points. (CDASH)
DATA COLLECTED ON THE ADVERSE EVENT FORM
Adverse Event – Preferred and reported term
Start Date and End Date
Severity OR Toxicity Grade
Severity – Either AESEV or AETOXGE must appear on
• Mild the CRF. Some studies may mandate the
• Moderate collection of both. Refer to ICH E3
guidelines for CSR Section 12.2.4. CTCAE
• Severe
grade is commonly used in oncology studies
Toxicity Grade – although it can be used elsewhere.
• Grade 1–5
Serious
• Congenital Anomaly or Birth Defect Assess if an adverse event should be
• Persistent or significant disability/incapacity classified as serious based on the “serious”
• Death criteria defined in the protocol.
• Hospitalization or prolongation of existing
hospitalization
• Life threatening
• Other medically important event
Relationship to Study Treatment(s)
• Not Related
• Unlikely Related
• Possibly Related
• Related
Action Taken with Study Treatment
• Dose Increased
• Dose Not Changed
• Dose Reduced
• Drug Interrupted
• Drug Withdrawn
• Not Applicable
• Unknown
Outcome
• Fatal
• Not Recovered/Not Resolved
• Recovered/Resolved
• Recovered/Resolved with Sequelae
• Recovering/Resolving
• Unknown
Timing
• Start/End Dates
• Optional Timing
DATA COLLECTED ON OTHER CRF FORMS
Patient Identifier Demography Details
Study Treatment at the time of AE
Test drug/investigational product dose
Duration of test drug/investigational product treatment
Concomitant treatment during study
Diagnostic/lab testing

413 c. Recommendations and standards


414 Fundamental eCRF design principles should be followed based on Clinical Data Acquisition Standards
415 Harmonization (CDASH) and internal standards. From an eCRF design perspective, the
416 CDASH represent a global, consensus-based standards development process with commons from organizations
417 in all the ICH regions (US, Europe, and Japan). It describes recommended data collection sets for sixteen
418 domains, including demographic, adverse events and other safety domains that are common to all therapeutic
419 areas and types of clinical research. The document also includes recommendations and best practice guidelines,
420 regulatory references, and other information on the CDASH project. The CDASH Core Team recommendations
421 would encourage consistent implementation and the most optimal use of the CDASH standard. Find these useful
422 publications outlined in the
423
424 III. Reporting
425 a. Precision, specificity, & accuracy
426
427 As the regulated biopharmaceutical industry strives for greater harmonization of safety reporting regulations and
428 standards, there is an increasing emphasis on safety surveillance and data quality. In addition to supporting
429 patient/subject safety, increased data quality facilitates communication of complete and accurate information to those
430 involved in clinical research and post-marketing processes (including regulatory bodies, sponsoring companies, study
431 site personnel, and marketing authorization holders). Collection of high-quality data can also result in greater time and
432 cost efficiency during product development and marketing (e.g. less querying of incomplete data, a decrease in site
433 monitoring costs and reduction of the risk of delayed regulatory approval). The quality of adverse event data is central
434 to safety monitoring in clinical trials, to the risk assessment of marketing applications and in the evaluation of safety
435 signals within post marketing data. (Meddra PTC).
436
437 The data quality recorded by investigators directly impacts the quality of MedDRA coding.
438 Inaccurate coding of safety events results in distortion of safety information. Investigators need to improve their
439 verbatim reporting and to understand the high sensitivity and granularity of MedDRA and their impact on the final
440 coding. Toneatti et al. found that difficulties in coding with MedDRA were due to both the lack of precision in the
441 investigator verbatim and the high specificity and sensitivity of MedDRA. For example, investigators should distinguish
442 between true medical diagnosis and biological qualitative results to avoid as much as possible the lack of multi-axial
443 linkages between the “Investigations” System Organ Class (SOC, the highest level of MedDRA) and any other SOC.5, 8
444
445 Clear initial data can be collected through careful design of data collection forms, and training of individuals in data
446 collection and follow-up. To promote consistency, organizations should document term selection methods and quality
447 assurance procedures in coding guidelines consistent with MedDRA Term Selection: Points to Consider document.
448 CRF Completion Guidelines Chapter in GCDMP covers the general instructions and guidance to be shared to the sites.
449
450 Below are examples of specific scenarios for adverse event reporting, to ensure quality data capture that enable
451 accurate coding:
452
453 • Avoid abbreviations: Some abbreviations are universally accepted, but most are subject to interpretation. For
454 example, GU Pain can be interpreted as Genito Urinary Pain or Gastric Ulcer Pain.
455 • Avoid ambiguous/incomplete terms: Report the specific term with location wherever applicable. e.g. Congestion
456 could be Pulmonary congestion or nasal congestion.
457 • Avoid reporting multiple diagnosis/combination terms: e.g., vomiting and diarrhea, require a query to site to
458 split and report each event separately or to report a single confirmed diagnosis.
459 • Avoid reporting extraneous information that does not contribute to the medical diagnosis or concept: e.g.,
460 “patient had headache,” “headache,” “headache at 2 a.m.,” etc. can be reported as headache without
461 extraneous information which enables auto-encoding.
462 • Avoid reporting laboratory values or investigations without qualifiers. AE should include a qualifier or a
463 diagnosis. If referencing significant Lab or investigation values, the AE must indicate if the result is increased,
464 decreased, high, low etc. or a diagnosed condition that would explain such a value. For example, “Hemoglobin
465 6.0” will not be appropriate to capture as AE. Instead, use a term such as “decreased hemoglobin” or “anemia.”
466 If using CTCAE criteria, the grade will be entered and will indicate severity.
467
468 The precision with which AE data are captured relates directly to how the data can be analyzed and reported. There are
469 three basic types of precision in a clinical trial.
470
471 High Precision: Investigation in a Phase One sequestered environment (i.e. a phase one) often incorporates medical
472 monitoring that is continuous and high precision. With a few subjects in a sequestered environment, a nurse or
473 physician is by the bedside continuously. In such an environment, clock time may be recorded so that precise data can
474 be collected for onset and offset of an AE. Hence, duration of the AE and elapsed time since initiation of treatment can
475 be calculated in a meaningful way. Clock time is meaningful in such an environment for some events, although it may be
476 difficult to assess the precise minute that sleepiness begins, or a rash is cleared.
477
478 Moderate Precision: Investigation in a hospital often incorporates medical monitoring that is daily, frequent (but not
479 continuous), and of moderate precision. Hospitalization offers a controlled and sequestered environment such that a
480 nurse or physician can assess the subject daily. In such an environment, clock time may not make sense for all events,
481 but date can be precisely recorded. Onset and offset of an AE can be recorded in terms of days but not hours. Duration
482 (in days) and elapsed days since initiation of treatment of the AE can be calculated.
483
484 Low Precision: Investigation in an outpatient study where subjects return to the facility after days, weeks, or months
485 incorporates low precision. In such an environment, clock-time and date may not be meaningful. Use of subject diaries
486 may assist with the determination of the duration of the AE or elapsed time since treatment. However, subject diaries
487 are frequently inaccurate. In such studies, it is recommended to capture frequency (e.g. single episode, intermittent,
488 continuous), maximal severity, most-harsh relationship, and other such information rather than to attempt to record
489 each event with time of onset and offset. When an investigation is of low precision, but attempts have been made to
490 record data as if it were moderate or high precision, the result is a database with dates (or times) that are rough
491 guesses and that may be far from accurate.
492
493 The precision with which AE data were collected has an important impact on how the data can be analyzed in a
494 meaningful way. In an outpatient study, dates cannot be interpreted with the same reliance as in a sequestered study.
495 When dates are present in the database, it may be tempting for the statistician to employ survival-analysis techniques to
496 analyze time-to-event. However, if these data are inaccurate, the resulting analysis can lead to incorrect or unreliable
497 conclusions.
498
499 When considering the capture of severity of adverse events, it is tempting to make the assessment in terms of its impact
500 on activities. This method of assessment may be meaningful for some events, such as “pain,” but not meaningful for
501 others, such as “alopecia.” Severity is not assessable at all. For example, “mild suicide” is not meaningful. Some events
502 are episodic rather than graduated by severity, such as “hair-line fracture.” For example, an assessment of diarrhea as
503 “severe” is often made because of duration or frequency of episodes (which are different parameters). However,
504 diarrhea is episodic.9
505 The concept of severity is only meaningful within a particular event. When one considers severity of AEs for an organ
506 class (e.g. CNS), ranking among mild, moderate, and severe AEs is not meaningful. If one considers “mild stroke” and
507 “severe flush” (both CNS events), these rankings are not sensible compared to rankings such as “mild headache” and
508 “severe headache” for which a relative ranking does make sense.
509
510 A common data display encouraged by the ICH and the FDA is a breakdown by severity. In this context, it is easy to
511 confuse severity with seriousness or to misinterpret severity altogether. A breakdown that ignores the particular events
512 and counts mild AEs separately from moderate AEs will give a distorted assessment when the same study includes
513 reports of “mild stroke” or “mild MI” and also reports of “severe rash” or “severe sleepiness.” A more meaningful
514 display breaks down severity within a particular event.
515
516 b. Time period, multiple occurrences
517
518 Baseline AEs: A baseline AE is defined as any adverse event that happens prior to the administration of the
519 investigational product but after the patient has been deemed eligible and consented to the trial. If randomization is
520 part of the study methodology, the Study PI and/or Sponsor if the participant will continue if a baseline AE is identified
521 before Randomization. After Randomization but prior to the start of the study protocol, the AE should be documented
522 but the participant would, depending on the AE, need to remain in the study. Examples of baseline AEs include, but are
523 not limited to, surgery (either emergency or planned), exacerbation of a pre-existing condition, or contracting a
524 temporary condition such as influenza. Baseline AEs need to be documented as carefully as intra- or post-protocol AEs as
525 there may be confounding factors that are introduced.
526
527 Persistent/ Recurring AEs: Persistent and recurring AEs are those that start during the course of the trial and are long-
528 term (e.g., hypertension) or repeated (e.g., migraines); regardless, they should be detected fairly early as they may have
529 long-term effects for the health and well-being of the patient, not the least of which may be introduction of concomitant
530 medication(s) or other therapies that may be contraindications to the study intervention.
531 On the AE form it is strongly recommended that “Ongoing” is a binary field that indicates that the AE is continuous (for
532 persistent) or that the event is a potential for repetition (for recurring). Recurring AEs should each be documented
533 separately. Worsening or other changes to the AE (for example, the migraine symptoms now include auditory and visual
534 auras) should be documented and as appropriate communicated to the Sponsor as soon as a pattern is confirmed.
535 Analysis and data quality checks need to take the repetitive nature into account to ensure that any dates do not overlap,
536 or if there is overlapping that it makes sense (for example, if “numbness in the extremities” is the AE, and the
537 subsequent event starts before the previous event ends, verification of dates should include confirmation that the
538 affected body areas are separate and distinct).
539
540 c. Workflow supporting AE/SAE data collection
541
542 Paper-to-paper workflow: Clinical data are recorded on paper case report forms (CRF) and safety data (AEs/SAEs) are
543 reported on paper SAE report form that is usually faxed to the CRO/sponsor. Within the CRF, the Investigator documents
544 all AEs (non-serious AEs and SAEs) on the provided AE pages which are entered into the clinical database. The DM
545 validates this AE/SAE information (e.g. check for completeness, duplicates, events of special interest) and send queries
546 to sites.
547
548 eCRF-to-paper workflow: Clinical data, including safety data (AEs/SAEs) information, are collected electronically in EDC
549 however SAEs must additionally be reported via paper forms and sent to the CRO/sponsor. The DM validate this SAE
550 information (e.g. check for completeness, duplicates, events of special interest etc.) and send queries to site. Non-
551 serious AEs and SAEs are entered into the eCRF and are available to generate aggregate reports at any time as soon as
552 the site enters that data.
553
554 eCRF-to-electronic workflow for SAEs: Clinical data along with safety data are entered into the eCRF. The SAE may then
555 be sent to the Safety database through a graphical user interface, E2B messaging or a data integration HUB. The timing
556 of the transfer process may vary by the method used. There is a back-up process in case the EDC system would be down
557 when an SAE needed to be reported. The benefit of this is that the SAE reconciliation will be minimal. With this method,
558 the responsibility for data cleaning may or may not be split between Data management and Safety. Companies
559 considering this type of process should consult their EDC provider to see what their system may have in place. It would
560 also be beneficial to read the CDISC SAE Supplement version 2 document.
561
562 d. Medical devices
563
564 Medical Device serious adverse event reporting is similar yet different in from reporting for Biologics and Drugs. There
565 are sections in the reporting form FDA 3500A that are filled out by distinct roles users, distributors, manufacturers, or
566 importers. The reporting requirements for medical devices are specified in 21CFR Part 803.50. The types of data that are
567 different includes device manufacturer, the city and state where this occurred, the product name/brand name and code
568 or serial number. Dates of device implantation or explanation should be recorded. The report needs to include whether
569 the device was operated by a medical professional or a lay person. If the device has an expiration date, this needs to be
570 reported. If the device was removed, it should be noted if the device was returned to the manufacturer. Consideration
571 should also be taken into environmental factors that could have influenced the event.
572
573 The reporting period is 10 days from the awareness for the user facility, and 30 days from awareness for the
574 manufacturer and the importer. A five-day reporting period is required if the event could necessitate remedial action to
575 prevent substantial harm to public health or if the FDA had required a five-day reporting period.
576
577 The types of issues that can occur with medical devices include mislabeling, device failure or malfunction, user error, or
578 inadequate/improper design.
579
580 The reporting standard is to report if the device may have caused or contributed to serious injury or death, or that the
581 device may have malfunctioned in a way that in the future it could cause serious injury or death.
582
583 What is similar with biologics and drugs are the other details reported including subject identifier, subject date of birth
584 or age at time of event, gender, weight, date of event, date of report, outcome of the event, past medical history, and
585 description of relevant tests to include date and result. Concomitant medications and procedures are to be included;
586 however, there is no need to report products used to treat the event.
587

588 9) Data Validation

589 I. Edit Checks


590 Edit checks should be created to help ensure any deviations from key safety parameters are noted and managed. Ensure
591 that edit checks are defined for all safety parameters in CRF and all checks are programmed, validated, and documented
592 in accordance with standard operating procedures.
593
594 The most used types of programmed edit checks include missing values and inconsistencies across CRF modules. For
595 complete information on edit checks, see the GCMDP chapter entitled Edit Check Design.
596
597 In addition to ensuring the database is complete, correct, allowable, valid, and consistent, other types of data quality
598 checks may be applied. Once these checks have been identified, appropriate and verified programs are created to help
599 identify discrepancies. Data quality checks and any manual review specifications, and medical review requirements
600 should be defined and described. All derivation and validation procedures may be fully tested and documented in the
601 Data Management Plan or a referenced validation document.
602
603 A comprehensive safety data review will help identify trends and alert investigators immediately of patient safety issues
604 during the study. In addition to SAEs, non-serious adverse events and other pertinent patient information should be
605 reviewed early in the study, ensuring that the Data and Safety Monitoring Board (DSMB) has a current, complete picture
606 of the patient safety profile. Interim efficacy and safety data reviews can also be performed at earlier points in the study
607 in an EDC-based study using the most current, near real-time patient information.
608
609 II. Serious Adverse Event Data Management and Reconciliation
610
611 Because serious adverse event (SAE) data may be stored in a safety database separate from the clinical trial data, a
612 reconciliation of the two datasets must be conducted to ensure consistency. This procedure applies to all projects where
613 both a clinical database and a drug or device safety SAE database are maintained as two separate databases.
614
615 In instances where data is integrated directly into the safety database, reconciliation is often still required. When there
616 is unexpected system downtime or site staff has incorrectly followed the process, there are instances when the safety
617 database may not match the clinical database, even when the databases are integrated. The processes and procedures
618 around integrating the safety and clinical databases should be thoroughly reviewed to ensure reconciliation is
619 completed.
620
621 Serious adverse event (SAE) data reconciliation involves the comparison of key safety data variables between two
622 databases. Reconciliation is performed to ensure consistency between events residing in the SAE database and those
623 residing in the clinical database. It is an iterative process that occurs multiple times during the study. When to reconcile
624 is determined by the frequency of data receipt, scheduling of safety updates, and timing of interim and final reports and
625 should be documented.
626
627 Standardize the capture of SAE data elements in both the clinical database and the safety database.
628 Conduct the reconciliation of SAE event to ensure that data in safety and clinical databases are consistent.
629
630 Establish the time intervals in the project where reconciliation will be performed and the mechanisms to cover interim
631 analyses or safety data reporting. Often, SAEs continue to be reported after a clinical trial has concluded. It is important
632 to establish a cutoff point after which no SAEs will be added to the clinical database, even if the safety data or safety
633 database is updated. Data items commonly reconciled or used in additional data cleaning can be found in Table 4.
634
Table 4 Data items commonly used in Serious Adverse Event (SAE) Data Reconciliation
Items collected on AE form:
• Protocol
• Investigator
• Subject Identification
o Randomization or Enrollment Number
o Date of Birth (full date of birth not collected)
o Gender
o Race
• Event Number
• Diagnosis/Verbatim
• Coded or preferred term
• Onset date
• Resolution date
• Date of death
• Outcome
• Severity
• Causality assessment
• Action taken with study drug
Sometimes items are used from other modules for further reconciliation, clarification, or cleaning.
From the discontinuation module, items may include but not be limited to:
• Subject identification
• Primary reason for discontinuation being an event
• Hospitalization
• Cause of death listed on the death certificate
• Autopsy result
From the concomitant medication modules, items used for data cleaning outside of reconciliation
may include but not limited to:
• Subject Identification
• Medication name
• Start date
• Stop date or ongoing
• Indication
From the dosing modules, items used for data cleaning outside of reconciliation may include but not
be limited to:
• Start/End dates, including interruptions
635
636 Clinical data management, safety leads, and clinical operations should establish a mutually agreeable turnaround time
637 for researching, retrieving, and correcting any discrepancies found during or since the last reconciliation period.
638
639 Listings are obtained from either the safety database or the clinical database, and the two databases are manually or
640 programmatically reconciled through direct comparison of these listings. Either way, the differences will require manual
641 review by trained staff. Ancillary documents can be used for clarification or corroboration, such as hospitalization
642 discharge summaries, death certificates, or autopsy reports. Even programmatic reconciliation of fewer than one
643 hundred events can be cost effective in both time and quality. The company can validate the process once and run as
644 frequently as data and time allow.
645
646 Verify that all SAEs from the clinical database also reside in the drug safety database. Note that SAEs from the safety
647 database may not be in the clinical database until all data entry has been completed. Depending on the reporting
648 requirements, SAEs in the safety database may span to cover more than one SAE in the clinical database. Some Ss may
649 not be reported in the clinical database due to differing reporting requirements. Thus, there may not be a 1:1 match in
650 the number of events. The documentation of what is expected and acceptable should be defined prior to the
651 reconciliation.
652
653 Document all SAEs included in the clinical database but not included in the safety database. These are potentially
654 unreported events. Include copies of the appropriate CRFs to the safety contact person, if applicable if allowed by
655 company SOPs.
656
657 Research and resolve or document all differences between SAEs that are present in both databases. There may be some
658 acceptable differences. Examples of these differences include but are not limited to:
659 a) possible coding differences if different dictionaries are used for coding;
660 b) date of birth differences if systems and regulations require reporting of DOB as partial in one system; and
661 c) outcomes and causalities may be defined differently between systems, etc.
662
663 A list of acceptable differences should be provided to the reconciler. For example, slight variations in AE terminology
664 used in describing events may be of no consequence, though at the preferred term level, the terms should match. There
665 may also be a difference in start dates as the event may have started prior to progressing to a serious event.
666
667 Documentation of the reconciliation should include the entirety of the issue. If multiple rounds of reconciliation occur
668 prior to the issue being resolved, previous comments and responses should remain.
669
670 Depending on the nature of discrepancies, it may be necessary to seek input from the medical monitor or designee
671 before deciding on a course of action.
672
673 Prior to data lock, verify that all queries have been answered correctly and integrated into the database(s). Ensure that
674 all expected SAE information has been received and reconciliation has been performed on all events. Written
675 notification should be made when reconciliation has been successfully completed. This helps avoid confusion should the
676 safety database be held open for updates after the study ends.
677
678 Any final inconsistencies that cannot be resolved should be documented.
679
680 Adverse events of special interest: Based on CIOMS ICH Glossary:
681
682 “An adverse event of special interest (serious or non-serious) is one of scientific and medical concern specific to
683 the sponsor’s product or programme, for which ongoing monitoring and rapid communication by the
684 investigator to the sponsor could be appropriate. Such an event might require further investigation to
685 characterize and understand it. Depending on the nature of the event, rapid communication by the trial sponsor
686 to other parties (e.g., regulators) might also be warranted.”
687
688 Although not required as part of a protocol, if a definition or criteria has been provided for the AESI, then this may
689 warrant collection of additional information across the entire study population to better characterise these events.
690 These events may fall into any number of categories, and care should be taken to standardize these prior to data
691 collection. Examples of events include laboratory results, vital signs, risk factors, concomitant therapies, and/or
692 concomitant illnesses. For example, if gastrointestinal haemorrhage was an adverse event of special interest, one might
693 want to proactively collect concomitant antithrombotic therapy across the entire study population (see E19 –
694 Optimization of Safety Data Collection). (ICH).
695
696 As indicated in ICH Topic E2F Development Safety Update Report regarding adverse event of special interest (AESI): “If
697 important and appropriate, the report should also include adverse reactions of special interest within the line listings
698 and adverse events of special interest in summary tabulations. The basis for selection of such events/reactions should be
699 explained.”
700
701 AESI has been an important part in presenting the safety profile for a compound in clinical trials. With the use of
702 MedDRA system organ class (SOC), preferred term (PT), along with Standardized MedDRA Queries (SMQs) and even
703 Customized MedDRA Queries (CMQs), AESI reporting becomes more specific and detailed.
704
705 Safety monitoring during clinical trials is a crucial component for drug development. Before a drug can receive
706 regulatory approval for marketing, rigorous safety monitoring and reporting from preclinical to all phases of clinical trials
707 are required. With the reference of guidance on safety reporting and availability of Medical Dictionary for Regulatory
708 Activities (MedDRA), collecting and reporting adverse events are now more of a standardized process.
709
710 III. Data Coding and Dictionary Management
711
712 Medical Dictionary of Regulatory Affairs (MedDRA): A clinically validated international medical terminology used by
713 regulatory authorities and the regulated biopharmaceutical industry throughout the entire regulatory process
714 developed by the International Conference on Harmonization (ICH).
715
716 MedDRA was developed by an ICH Expert Working Group to address many of the limitations of older adverse event
717 terminologies. The intent of ICH, in developing MedDRA, was to have a standard, medically rigorous, and well-
718 maintained terminology to facilitate communication. MedDRA's structure allows for aggregation of reported terms in
719 medically meaningful groupings to facilitate analysis of safety data. Specifically, some of the applications for MedDRA
720 are:

721 To aggregate reported terms in medically meaningful groupings for review, analysis and/or summary of safety data
722 (CDAS SAE Supplement version 2.0

723 To facilitate identification of common data sets for evaluation of clinical and safety information, To facilitate consistent
724 retrieval of specific cases or medical conditions from a database,

725 To improve consistency in comparing and understanding safety signals and aggregated clinical data,

726 To facilitate electronic data interchange of clinical safety information.

727

728
729
730 Organisations are encouraged to document their term selection methods and quality assurance procedures in specific
731 coding guidelines which should be consistent with the MedDRA Term Selection: Points to Consider (MTS: PTC). The
732 quality of the original reported information directly impacts the quality of data output. Clarification should be obtained
733 for data that are ambiguous, confusing, or unintelligible. Clear initial data can be promoted through careful design of
734 data collection forms, and training of individuals in data collection and follow-up (e.g. investigators). To promote
735 consistency, organizations should document their term selection methods and quality assurance procedures in coding
736 guidelines consistent with this MTS: PTC document. MedDRA is a standardized terminology with a pre-defined term
737 hierarchy that should not be altered.
738
739 It is recommended that trial data is coded using the most recent version of MedDRA as it is continuously maintained
740 with the latest terminologies, advances and addresses any errors from previous versions. Trials coded with the same
741 version of MedDRA supports consistency of coding and analysis with related trials. Each organization should have a
742 versioning strategy that should be documented and would to have similar versioning strategy for safety and clinical
743 databases.
744
745 Identifying and reporting Adverse Events of Special Interest (AESIs) are important in clinical trial safety data
746 management with the use of MedDRA terminologies, system organ class (SOC), preferred term (PT), along with
747 Standardized MedDRA Queries (SMQs) and even Customized MedDRA Queries (CMQs). A specific SMQ or a selection of
748 SMQs may be used to retrieve relevant cases for subsequent medical review. SMQs may be used to create a “watch list”
749 (e.g. an automated notification system) to alert the user of incoming cases needing urgent review.
750
751 Cumulative Summary Tabulation: Although not directly relevant to a Clinical Data Manager’s role, it is important to
752 understand the potential impacts downstream of data issues. One such area is the Cumulative Summary Tabulation,
753 which is an overview of the adverse events and other critical occurrences during a trial. Having lower quality data means
754 that this potentially important summary will be incomplete or inaccurate, possibly leading to erroneous and/or life-
755 threatening decisions.
756
757 The ICH E2CR2 Section 3.6.2 outlines some characteristics that a Cumulative Summary Tabulation should have; although
758 none of these are flagged as mandatory, they are important to consider when designing the Safety Data CRFs and
759 collecting/managing that data. From the ICH Guideline:
760
761 System Organ Class (SOC) should organize the tabulation(s), for the investigational drug, as well as for the comparator
762 arm(s) (active comparators, placebo) used in the clinical development program. Although it may appear to be an
763 analytical tool, this section should not serve to provide analyses or conclusions based on the SAEs. In general, the
764 tabulation(s) of SAEs from clinical trials should include only those terms that were used in defining the case as serious,
765 which is one of the reasons having clearly defined terms prior to starting the study is key. MedDRA terminologies,
766 Preferred Term (PT) and SOC, should be in the summary tabulations. The tabulations should include blinded and
767 unblinded clinical trial data and caution should be taken to not unblind data for the specific purpose of preparing the
768 tabulations.
769 Certain adverse events in clinical trials can be excluded from the clinical trials summary tabulations, but such exclusions
770 should be explained in the report (for example, those that have been defined in the protocol as “exempt” from special
771 collection and entry into the safety database because they are anticipated in the patient population.)
772
773 The summary tabulations should include all SAEs for the investigational drug, active controls, and placebo.
774
775 IV. Safety Signals
776
777 According to the WHO (World Health Organization). A signal is “information on a new or known side effect that may be
778 caused by a medicine and is typically generated from more than a single report of a suspected side effect. It is important
779 to note that a signal does not indicate a direct causal relationship between a side effect and a medicine, but is essentially
780 only a hypothesis that, together with data and arguments, justifies the need for further assessment.” Signal detection is
781 a critical component of pharmacovigilance. While it is not an area that data management is commonly involved in, it is
782 essential to understand the need to provide data for this effort. “Signal detection is information that arises from one or
783 multiple sources (including observations and experiments) which suggests a new potentially causal association or a new
784 aspect of a known association between an intervention and an event or set of related events, either adverse or
785 beneficial, that is judged to be of sufficient likelihood to justify verificatory action” according to CIOMS Working Group 8
786 (CIOMS 2010). The WHO definition adds that “a possible causal relationship between an adverse event and a drug, the
787 relationship being unknown or incompletely documented previously. Usually more than a single report is required to
788 generate a signal, depending on the seriousness of the event and the quality of the information.”
789
790 These signals may be identified by data visualization tools, by statistical analysis or by both methods. Signal detection is
791 usually done on a periodic basis during clinical trials. Any potential signals identified should be further explored to
792 validate the signal via statistical methods.
793
794 V. Post Market Safety Surveillance
795
796 Pre-marketing clinical trials often have limitations in obtaining adequate safety information, with limited population,
797 short duration and narrow indications studied. Post marketing monitoring offers the benefits of comprehensive safety
798 evaluation with its ability to study high risk populations, low frequency reactions (not identified in clinical trials), long
799 term effects, drug-drug/ food interactions, increased severity and/or reporting frequency of known reactions.10
800
801 When a treatment is being approved by a regulatory agency, the manufacturer may be required to make a post
802 marketing commitment as a condition of approval. If required, the regulatory agency tracks the progress of these studies
803 via regular communications with the company. These studies may target specific populations such as pediatrics or they
804 may be conducted to further explore known risks or to assess potential signals of serious risk.
805
806 The first system to track adverse events post approval was the Yellow Card scheme in the UK in 1964.11 This was
807 followed by WHO starting the VigiBase, which collects adverse event reports now from around the world and is
808 managed by the Uppsala Monitoring Center. The FDA’s Adverse Event Reporting System (FAERS) started in 1969 and the
809 Vaccine Adverse Reporting System (VAERS) in 1990, which is jointly managed by the FDA and the CDC. (Sonawane,
810 2018). Most Regulatory agencies around the world either have their own reporting or work with the VigiBase System
811 managed by the Uppsala Monitoring Center (UMC) and the World Health Organization. These systems rely on
812 manufacturers, health professionals, and consumers to report events to detect unusual or unexpected events to the
813 agencies.12, 13
814

815 Recommended Standard Operating Procedures

816 • Design of Data Collection Instruments


817 • Coding of Adverse Events
818 • Maintenance of Coding Dictionaries
819 • Reconciliation of Serious AEs in SAE Database with Clinical Trial Database
820 • Management of AE Analysis File
821 • Management of Laboratory Data and Normal Ranges
822 • Preparing Integrated Summaries of Safety Data
823

824 10) Regulations Guidance and Standards

825 US Department of Health and Human Services. Food and Drug Administration Center for Drug Evaluation and Research
826 (CDER) Center for Biologics, Evaluation and Research (CBER), E6 (R2) Good Clinical Practice: Integrated Addendum to ICH
827 E6 (R2) Guidance for Industry. https://www.fda.gov/downloads/Drugs/Guidances/UCM464506.pdf. March 2018.
828 Accessed 5/1/2023.
829
830 U.S. Department of Health and Human Services Food and Drug Administration. Use of Electronic Health Record Data in
831 Clinical Investigations: Guidance for Industry.
832 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryinformation/Guidances/UCM501068.pdf. July
833 2018. Accessed 8/8/2018.
834
835 Medicines & Healthcare Products Regulatory Agency (MHRA). ‘GXP’ Data Integrity Guidance and Definitions.
836 https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/687246/MHRA_Gx
837 P_data_integrity_guide._March_edited_Final.pdf. Revision 1: March 2018. Accessed 6/2/2018.
838
839
840 Council for International Organizations of Medical Sciences. Practical aspects of signal detection in pharmacovigilance:
841 Report of CIOMS Working Group VIII. Geneva: CIOMS. https://cioms.ch/publications/product/practical-aspects-of-
842 signal-detection-in-pharmacovigilance- report-of-cioms-working-group-vii. 2010. Accessed 9/5/2021.
843
844 U.S. Department of Health and Human Services Food and Drug Administration. Introduction to Post-marketing Drug
845 Safety Surveillance: Pharmacovigilance in FDA/CDER. https://www.fda.gov/media/96408/download. February 2016.
846 Accessed 8/8/2018.
847
848 Guidance on computerised systems and electronic data in clinical trials.
849 https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-computerised-systems-
850 electronic-data-clinical-trials_en.pdf. March 2023. Accessed 5/1/2023.
851
852 MedDRA Points to Consider ICH -Endorsed Guide for MedDRA Users.
853 https://admin.meddra.org/sites/default/files/guidance/file/00860_termselptc_r4_23_Mar2023.pdf
854 Version 4.23 March 2023. Accessed 5/3/2023.
855
856 MedDRA® BEST PRACTICES Maintenance and Support Services Organization’s (MSSO) Recommendations for
857 Implementation and Use of MedDRA.
858 https:admin.medrda.org/sites/default/files/guidance/file/000571_termselptc_r4_March2021.pdf. March 2021.
859 Accessed 10/03/2022.
860
861 Glossary of ICH terms and Definitions. https://cioms.ch/publications/glossary-of-ich-terms-and-definitions/ July 2023.
862 Accessed 8/1/2023.
863
864 International Organization for Standardization (ISO) ISO/DIS 21090, Health Informatics – Harmonized data types for
865 information interchange 2011. https://webstore.ansi.org/sta21090ndards/din/dineniso21092011.
866
867 U.S. Department of Health and Human Services Food and Drug Administration. Preparing Regulatory Submissions in
868 Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions using the eCTD
869 Specifications Guidance for Industry. https://www.fda.gov/media/135373/download February 2020. Accessed March
870 15, 2022.
871
872 ICH E19. Optimization of Safety Data Collection (E19). June 2019. Accessed July 3, 2023.
873 www.fda.gov/media/167331/download.
874
875 U.S. Department of Health and Human Services Food and Drug Administration. Guidance for Industry: Postmarketing
876 Safety Reporting for Human Drug and Biological Products Including Vaccines. Draft Guidance.
877 https://www.fda.gov/media/73593/download. March 2001. Accessed, March 21, 2022.
878
879 Clinical Data Acquisition Standards Harmonization Implementation Guide. v2.2. 9/28/2022.
880 https://www.cdisc.org/standards/functional/cdash/cdashig-v2-2.
881
882 U.S. Department of Health and Human Services Food and Drug Administration. Guidance for Industry and Investigators,
883 Safety Reporting Requirements for INDs and BA/BE Studies. www.fda.gov/files/drugs/published/safety-reporting-
884 requirements-for-INDs-%28Investigational-New -Drug-Application%29-and-BA-BE-%28-Bioavailability-
885 Bioequivalence%29-Studies.pdf. December 2012. Accessed March 15, 2022.
886
887 Referenced in Text
888
889 1. Junod SW. FDA and Clinical Drug Trials: A Short History, Junod, Suzanne.
890 https://www,fda.gov/media/110437/download. Accessed 4/5/2023.
891 2. Mayo Clinic. Institutional Review Board Definition of Terms. 1998.
892 https://www.mayo.edu/research/institutional-review-board/definition-terms, Accessed 10/3/2022.
893 3. Smith AW, Mitchell SA, K De Aguiar C, Moy C, Rilehoy WT, Wagster MV, M et al. News from the NIH: Person-
894 centered outcomes measurement: NIH-supported measurement systems to evaluate self-assessed health,
895 functional performance, and symptomatic toxicity. Transl Behav Med. 2016:6(3):470–474.
896 4. PRO-CTCAE. https://healthcaredelivery.cancer.gov.pro-ctcae/ Accessed 03/01/2023.
897 5. Crépin S, Villeneuve C, Merle L. Quality of serious adverse events reporting to academic sponsors of clinical
898 trials: far from optimal. Pharmacoepidemiol Drug Saf. 2016:25(6):719-724. doi: 10.1002/pds.3982. Epub 2016
899 Feb 17. PMID: 26887649.
900 6. Lu Z. Technical challenges in designing post-marketing eCRFs to address clinical safety and pharmacovigilance
901 needs. Contemp Clin Trials. 2010:31(1):108-118. doi: 10.1016/j.cct.2009.11.004. Epub 2009 Nov 10. PMID:
902 19900576.
903 7. Burnstead B, Furlan G. Unifying drug safety and clinical databases. Curr Drug Saf. 2013:8(1):56–62. doi:
904 10.2174/1574886311308010008. PMID: 23656448.
905 8. Tonéatti C, Saïdi Y, Meiffrédy V, Tangre P, Harel M, Eliette V et al. Experience using MedDRA for global events
906 coding in HIV clinical trials. Contemp Clin Trials. 2006:27(1):13–22. doi: 10.1016/j.cct.2005.09.009. Epub 2005
907 Nov 8. PMID: 16288902.
908 9. Notes from Daniel Heatherington from Burroughs-Welcome to Imogene Dunn provided in 1991.
909 10. FDA. Best Practices in Drug Safety and Biological Product Post Market Safety Surveillance for FDA Staff,
910 November 2019. https://www.fda.gov/media/130216/download. Accessed 4/4/2023.
911 11. NHS. History of the Yellow Card Scheme. https//gpcpd.heiw.wales/non-clinical/yellow-card-scheme/history-of-
912 the-yellow-card scheme. Accessed 3/23/2023.
913 12. Lindquist M. VigiBase, the WHO Global ICSR Database System: Basic Facts. Drug Inf J. 2008:42(5):409–419.
914 13. Sonawane KB, Cheng N, Hansen R. Serious Adverse Drug Events Reported to the FDA: Analysis of the FDA
915 Adverse Event Reporting System 2006 – 2014. J Manag Care Spec Pharm. 2018:24(7). doi:
916 10.18553/jmcp.2018.24.7.682
917 14. WHO-Uppsala Monitoring Centre. What is a Signal. Feb 2, 2022.
918 https://who-umc.org/signal-work-/what-is-a-signal/. Accessed 5/3/2023.
919 15. Common Serious Adverse Event SAE Fields – Clinical Trials, Transcelerate Pharma 2021.
920 https://transceleratebiopharmainc.com/assets/common-serious-adverse-events-sae-fields.
921
922 For Further Reading:
923 Gliklich RE, Dreyer NA, Leavy MB, editors. Registries for Evaluating Patient Outcomes: A User's Guide [Internet]. 3rd
924 edition. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Apr. 12, Adverse Event Detection,
925 Processing, and Reporting. Available from: https://www.ncbi.nlm.nih.gov/books/NBK208615/.
926 11) Acknowledgements

927 The authors want to thank Colleen Cox, Sarah Scafidi, and Soha Ali for their assistance with the development of the
928 chapter revision.

929 12) Chapter Revision History

Date Revision description


September 2000 Initial publication.
May 2007 Revised for style, grammar, and clarity. Substance of chapter content unchanged.
January 2022 Content updated and organization of material revised. Revised for style, clarity, and format.
Content refreshed updated to latest information. New information about the DSUR, signal
August 2023 detection and AEs of special interest. Removed some text that was covered in other chapters
Added some information about SAE differences with medical device studies.
930

931

932

933

934
935
936
937
938
939
940

You might also like

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy