Clinical Trials: Ensuring Quality and Standardization

Fig. 2.1
Example of case report form template

2.5 Adverse Event Reporting

While the CRF records all events in a trial related to each subject, a subset of the record must include adverse events that occur during and after the course of a clinical trial. Adverse events (AE) are defined as any unfavorable or unintended medical occurrence, including any abnormal sign (physical exam or laboratory finding), symptom, or disease temporarily associated with the use of a medical treatment whether or not it is considered related to the medical treatment (causality) [10, 12]. The purpose of AE reporting is to monitor the safety of the study, inform the investigators, regulators, and subjects of risks potentially associated with the intervention and allow for timely intervention if it appears that the risks of the clinical trial have changed. In general the majority of AE reporting has centered around events associated with drugs and devices, and less standardization has occurred with reporting of adverse events in purely surgical clinical trials. In the United States, adverse event reporting has recently been restructured to address causality more specifically [12]. With the globalization and massive growth of clinical trials over the past 10 years [17], the FDA has been flooded with volumes of adverse event reports and other regulatory documentation. Many of these adverse event reports have been uninterpretable or irrelevant as reporting individuals were often blinded and unable to relate events to the investigational drugs or devices [18]. The Clinical Trials Transformation Initiative has since worked to improve the quality and efficiency of reporting by requiring the investigational sponsor to assign attribution or causality to each adverse event and provide both the FDA and the study investigators with an aggregate report of adverse events that are attributable to the investigational drug or device.

The process surrounding the ascertainment, recording, and reporting of adverse events remains moderately challenging especially to the surgeon scientist who may not be involved in drug- or device-related surgical research. It is however important to understand the basic definitions of AE reporting in order to ensure that the proper information is included in a clinical trial protocol, so AE determination does not become challenging because adequate definitions were not provided a priori. Expected adverse events are those that have been identified in nature, severity, or frequency in the current clinical trial protocol, investigator brochure (if available for a drug or device), and current consent form. For example, a 5 % incidence of surgical site infection is anticipated or expected in a clinical trial that tests the efficacy of laparoscopic versus open distal pancreatectomy for resection of benign pancreatic tumors. The research team is informed of this in the clinical trial protocol, and subjects are made aware of this risk during the consent process. Therefore an occurrence of surgical site infection in a subject would be an expected event but would still be recorded on the AE forms to determine the extent of this event across the entire patient accrual. Anticipated or expected events can be internally documented, monitored, and analyzed in aggregate.

An unexpected adverse event is any event, the severity or specificity of which is not consistent with the risk information described in the clinical protocol or investigator brochure, and is more likely than not related to the research, and it suggests that the research places subjects or others at greater risk than previously known [19]. “Relatedness” of the AE to the clinical study is defined differently for each regulatory body:


ICH definition requires evidence suggesting a causal association.



FDA definition requires a reasonable possibility that the AE is associated with the research drug or device.



NCI has a more complex reporting structure for AEs which is best described below in the description of CTCAE but moves through five categories from not related to definitely related to the intervention.


It is worth noting that not all unanticipated problems involve an unexpected adverse event. For example, the absence of laparoscopic equipment for a patient randomized to the laparoscopic approach in the aforementioned distal pancreatectomy trial would be an unanticipated problem but not an unexpected adverse event as would the administration of an incorrect dose of a study medication if drawn up incorrectly by the pharmacy. The distinction between unanticipated and unexpected outcomes in the ascertainment of adverse events is important because they each prompt different documentation and management processes. Unanticipated adverse events such as incorrect study drug dosing are reported to the IRB, the patient, and potentially the sponsor but are recognized to not be causal in adverse events. Unexpected adverse events must be reported to the IRB of the study site and subsequently sent to the Office for Human Research Protection in accordance with US Health and Human Services regulations 45 CFR 46.103(a) and (b)(5) [11, 19].

Prior to management of an unexpected adverse event, some analysis is required to understand the process that led to the event and how to address it. First a basic classification of the adverse event is needed. The Medical Dictionary for Regulatory Activities [20] is a standardized system of medical terminology that is used internationally to classify adverse event information associated with the use of biopharmaceuticals and other medical products. MedDRA is maintained by the International Conference on Harmonization and is the required terminology in reports to many regulatory agencies. The National Cancer Institutes’ Common Terminology Criteria for Adverse Events (CTCAE) [21] is also an instrument used to classify adverse events. It uses clinical and laboratory evaluation criteria and is required in studies that are funded by the NCI. Grading of adverse event severity is a key component of the classification process. The CTCAE has a grading scale of 0–5. Zero is no adverse event, 1 is mild, 2 is moderate, 3 is severe, 4 is life-threatening, and 5 is death [21]. Life-threatening adverse events and death must be reported to the IRB and the FDA within 7 calendar days, in accordance with 21 CFR 312.32(a) [12]. Of note, the CTCAE grading scale describes severity of an event but not “seriousness.” SAEs or serious adverse events are any adverse drug event (experience) occurring at any dose that results in ANY of the following outcomes: “death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization (for >24 h), a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect. Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition” [12]. The process of reporting SAEs is variable for clinical trials and can be anywhere from within 24 h to up to 10 days depending on the sponsor of the trial and associated regulatory agencies. For example, a phase I trial evaluating the safety of a novel drug may require the submission of an SAE within 24 h to assure that additional patients are not placed on the study until the SAE has been fully investigated.

The standard operating procedures of a clinical trial should also delineate the methods for ascertaining adverse events. Adverse events can be ascertained by elicited or volunteered report from subjects or by direct observation. Direct observation is the most reliable method to ascertain adverse events, but it is not always feasible. Studies have demonstrated that adverse event reporting increases when subjects are asked open-ended questions to elicit reports of adverse events [2224]. Subject-elicited adverse events or patient-reported outcomes (PRO) are increasingly studied, particularly with the inception of patient-centered outcomes research [25, 26]. Research focused on the development of standardized and generalizable patient-reported outcome instruments remains ongoing. The majority of clinical trials currently rely on volunteered reporting of adverse events or direct observation of them during study visit examinations.

The ICH has developed the Harmonized Tripartite Guidelines [10] that detail the key components of an adverse event report, summarized here:


Subject identifier



Demographic data: age, race, sex, weight, and height



Location of case report forms and source documents (for reference)



The adverse event



Duration of the adverse event



Severity (mild, moderate, severe)



Seriousness (life-threatening, death)



Action taken (none, dose reduced, treatment stopped, specific treatment instituted, etc.)






Causality assessment (unrelated, unlikely, possible, probable, definite causality)



Date of onset or date of clinic visit at which the event was discovered



Timing and onset of the adverse event in relation to last dose of test drug/investigational product



Study treatment at time of event or most recent study treatment taken



Test drug/investigational product dose at time of event


Sep 26, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Clinical Trials: Ensuring Quality and Standardization

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