GCDMP Safety Data Management Chapter Public Review
GCDMP Safety Data Management Chapter Public Review
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
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.”
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
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
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
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
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
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,
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
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,
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896 4. PRO-CTCAE. https://healthcaredelivery.cancer.gov.pro-ctcae/ Accessed 03/01/2023.
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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:
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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.
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