Safety Data & Required Reporting

clinical_trials_artSafety data are reported and examined at various stages of an investigation and by different assessors. IND regulations specify expedited reporting for serious and/or unexpected adverse events.  Data managers and statisticians need to ensure that the reports provided are supported by the quality appropriate for the purpose of the report. The FDA requires sponsors to meet their obligations to Congress and to the public as outlined in their guide for safety reporting requirements for INDs and BA and BE studies. Also available in the Small Compliance Guide version. Compliance with IND and NDA regulations is aided by an understanding of the mission and motivation of these regulations. Before marketing, IND regulations apply. One key purpose of the IND regulations is to facilitate the FDA’s monitoring of the investigation, including protection of the safety and rights of individuals enrolled into trials, and the scientific quality of the investigation in terms of its ability to adequately demonstrate the efficacy of a compound. The FDA requires annual reports, which are brief updates concerning the progress of the investigation, including any newly identified safety trends or risks that may impact the investigation. FDA also requires expedited reports of “any adverse experience associated with the use of the drug that is both serious and unexpected” (21 CFR 312.32). Written notification of such events is required within 15 calendar days. For events that are fatal or life threatening, a telephone or facsimile transmission is required within seven calendar days. Additional details of IND safety reports, annual reports, and IND specifications are provided in 21 CFR 312. The FDA has also provided the guidance for industry and FDA to use when designing, conducting, and analyzing pharmacoepidemiologic safety studies.

Expedited reports are required by regulatory agencies for certain serious adverse eventsFDA Guidance for Industry Good Pharmacovigilance practices and Pharmacoepidemiologic Assessment.

MedWatch is the FDA’s reporting system for adverse Events (AEs), founded in 1993, and is intended to detect safety hazard signals for medical products. If a signal is detected, the FDA can issue medical product safety alerts or order product recalls, withdrawals, or labeling changes to protect the public health. Important safety information is disseminated to the medical community and the general public via the MedWatch web site. AEs can be reported on a single, one-page reporting form (Form FDA 3500 or 3500A). Reporting can be conducted online by phone (1-800-FDA-1088) or by submitting the MedWatch Form 3500 or 3500A by mail or fax (1-800-FDA- 0178). Or via online link for electronic submission of AEs for commercial agents via the MedWatch Form 3500 or 3500A. For international studies SAEs may be required to be reported via the Council for International Organizations of Medical Sciences (CIMOS) 3500 form.

For those studies with funding through the National Cancer Institute (NCI) and conducting a National Institutes of Health (NIH) sponsored IND, SAEs are to be reported utilizing the NCI Adverse Event Expedited Reporting System (AdEERS) for expedited AE reporting (ie for Cooperative Group trials). Please also refer to the NIH SAE Recording and Reporting Guidelines.

The also has available the Guide to adding a toll free number for reporting AEs and Guide to notifying regarding Drug storage issues.

For additional thoughts and concerns on the area of drug safety and reporting see CIOMS Report on Current Challenges in Pharmacovigilance.

Safety data often present the most challenging aspects of the management and reporting of clinical trial data. Consideration for return-on-investment frequently curtails the query process for cleaning safety data and limits reporting methods. When information that has a soft basis is stored and cleaned as if it has a high degree of precision and reliability, reports can reflect an over-reliance on questionable data and lead to inferential errors. Soft information can still be quite useful, but to avoid misrepresentation, a clear identification of the nature of the data is necessary. The quality of data is really determined in the field. Instead, data managers should ensure that the database accurately conveys the limitations of the data’s quality to users. Statisticians have an imperative to ensure that analyses and data displays acknowledge their limitations. The processes of data capture, management, and reporting are highly integrated.

Clinical AEs frequently house the most important safety information in a clinical study. The precision with which AE data are captured relates directly to how the data can be analyzed and reported. There are three basic types of precision in a clinical trial; The precision with which AE data were collected has an important impact on how the data can be analyzed in a meaningful way. Investigation in a Phase One environment with continuous monitoring utilizes high precision; Investigation in a inpatient hospital with daily monitoring utilizes moderate precision; Investigation in an outpatient facility with monitoring over weeks, or months utilizes low precision. When considering the capture of severity of adverse events, it is tempting to make the assessment in terms of its impact on activities.  A common data display that is encouraged by the ICH and the FDA is a breakdown by severity.

The FDA draft document Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review (November 1996) provides specific guidance to industry that reflects thinking within the FDA about safety data. In the above-referenced document, the FDA described the concept of clinical domains for a review of the following systems: Cardiovascular, Gastrointestinal, Hemic and Lymphatic, Metabolic and endocrine, Musculoskeletal, Nervous, Respiratory, Dermatological, Special Senses, Genitourinary, Miscellaneous.

In the guidance document, the FDA specifies that an NDA should be reviewed against each clinical domain with two key questions as goals: Are the safety data adequate to assess the influence of the product on the clinical domain? What do the data indicate about the influence of the product on the clinical domain? In a multi-center study, center effects are typical and are a nuisance. There are three sources of contributions to center effects: The investigator as an individual; The environment, The subject population Serious adverse event (SAE) data reconciliation involves the comparison of key safety data variables between two databases. Reconciliation is performed to ensure consistency between events residing in any SAE database and those residing in the clinical database. It is an iterative process that occurs several times during the study. When to reconcile is determined by the frequency of data receipt, scheduling of safety updates, and timing of interim and final reports.

Some companies maintain two databases: a safety database and a clinical database. Conversely, some companies collect all information in a single database. When two databases are used, obtain the SAE information to be reconciled from both the safety and the clinical databases.

The SAE database often includes safety data from various sources.  The data within these SAE databases may be dirty, incomplete, duplicate, fragmentary, or have other issues. In contrast, the reports of SAEs from clinical trials that are reported on the AE page of the CRF are subjected to rigorous data management procedures,  including scrubbing, querying, and verification to ensure accuracy. These two types of databases generally have important differences in their sources (including electronic source data), their quality levels, their uses, and their customers. Reconciliation of SAE data and the clinical trial database that houses the relevant SAE reports is not always straightforward.

The business-balance perspective encourages users of these databases to recognize that clinical trial databases may be queried or updated while SAE databases are not and that, consequently, some discrepancies may exist  because preliminary medical judgments were later changed in light of updated information. See FDA guide to risk based monitoring and FDA Guide to reporting AEs when resources are limited.

Listings are produced from either the safety database or the data management database for direct comparison by trained staff for manually reconciliation. Documentation of all SAEs included in the clinical database but not included in the safety database. These are potentially unreported events. Include copies of the appropriate CRFs to be forwarded to the safety contact person. Research all SAEs in the safety database that are not found in the clinical database. Research and resolve all differences between SAEs that are present in both databases.

Site-authorized updates to CRFs received by clinical data management are copied to drug safety for assessment and, if appropriate, for inclusion in the safety database. Clinical data management generates queries to clarify discrepancies, and forwards them to the sites for resolution. Resolved queries from the site are returned through data management, to be used to update either or both databases by their respective staff. Communication of these updates can be facilitated by use of a standard template, such as the Sample SAE Data Reconciliation Form provided in Appendix A of this chapter.

Prior to data lock, verify that all queries have been correctly returned and integrated into the database. A quality control process should be in place to ensure this is done accurately and consistently. Ensure that all expected SAE information has been received and reconciliation has been performed on all events. Any final inconsistencies that cannot be resolved should be documented in a CDM Data Handling Report or the equivalent.

Ancillary documents can also be used for clarification or corroboration, such as hospitalization discharge summaries, death certificates, or autopsy reports. Note that some SAEs from the safety database may not be in the clinical database until all CRFs are collected and entered. If the visit has been monitored, collected, and entered by CDM, the site should be queried to request the original missing event page. Do not add SAEs to the clinical database without the data for that visit having been monitored against source documents according to the study’s clinical monitoring guidelines. Only those updates signed and dated by site staff after the CRF page has been monitored and retrieved are acceptable for updating the clinical database. Depending on the nature of discrepancies, it may be necessary to seek input from the medical monitor first as some discrepancies may be acceptable.

Capture, Management, and Reporting of Laboratory Data

When data across studies are combined, it becomes particularly challenging and important to ensure proper linkage with the units.

This linkage can protect against unreliable conclusions being drawn from the reported laboratory data. One of the most challenging aspects of managing laboratory data is linking the data to the appropriate normal range.  The ICH and FDA have given specific guidance for how to report laboratory data.

  1. Treatment-emergent Abnormal Values (TEAVs): For hematology, clinical chemistry, urinalysis, or other laboratory panel or group, comparative data summaries and supportive listings that provide a onepage summary by treatment group (for parallel studies) for analytes included in the study are strongly encouraged. Such a summary provides a valuable overview of movement from the normal state pre-dose to an abnormal state at any time post-treatment, in either direction, and for any analyte.
  2. Clinically Significant Values or Changes: Comparative data summaries and supportive listings are recommended. These documents provide summaries and details by treatment group of analytes with significant changes or values, such as an analyte for which the baseline value is doubled or tripled, an analyte for which the value is observed to be twice the upper limit of the normal range, or an analyte for which the change in value exceeds the width of the normal range.
  3. Groups Means and Changes: Displays of means and mean changes from baseline levels are useful within a group—to indicate a trend in an analyte—or among groups—to examine treatment group differences or trends that may be dose-related.
  4. Shift Tables: Shift tables frequently are 3×3 tables that show the status before treatment compared to the status after treatment (e.g., below normal, normal, above normal, in both cases). These displays ignore magnitude of change.
  5. Individual Data Displays: Listings of individual data are needed for adequate reporting of most clinical trials.
  6. Related Groups of Analytes: Summaries by related groups of analytes are useful for some studies or integrated summaries.

Other Data

Safety data can have forms other than AEs and laboratory values. Capture of data from specialty tests (e.g., electrocardiograms, electroencephalographs) requires an understanding of the common data derived from the test and of the format, precision, and special attributes of the data. Physical examinations are customary in clinical trials. In a broad sense, the physical exam is a screening method; if an unexpected, significant abnormality is detected during a physical exam, a specialty test is generally used to confirm the event. In this case, the data from the specialty test has greater reliability.

In considerations of data capture, free-text commentary boxes are generally discouraged. If they are used for medical monitoring purposes, they can be shaded so that the reviewing medical monitor can have the prose handy, but the text does not need to be computerized. Making effective use of the investigator’s comment log can ensure that essential text (which is generally minimal) is computerized, if warranted.

The management of “other data” depends on the form of that information. For physical examinations or specialty tests for which free-text commentary is permitted, methods exist for managing the commentary without compromising the qualit y standards of the database.

Free-text commentary can be computerized using word-processing rather than a data entry system. Subsequently, the commentary can be proofread rather than double-keyed. Through this method, the free-text commentary can be computerized and linked to the database without being a part of the database itself. As a result, quality standards can be maintained for the database proper, but reasonable standards may apply to free-text prose.

One method used by some sponsors that avoids computerization of verbose commentary is codification, in which a medically qualified individual reads the information and judges it to be relevant, not relevant, or perhaps critical. A code can be applied and keyed, where “0=no comment,” “1=comment, not relevant,” “3=comment, relevant,” and “4=comment, critical.”

Available Guidelines

One definition of “quality data” is “a collection of data from which reliable conclusions can be drawn.” The goal of reporting safety data is to convey information that would facilitate the drawing of reliable conclusions. Generally, one of the key objectives in investigative clinical research trials, is to characterize, investigate, establish, or confirm the safety profile of an investigational product. The management and reporting of the safety data from the trial should support that objective. The ICH has issued several guidelines to provide guidance to the industry for how to manage and report clinical trial safety data.

  • E1A describes expectations for extent of population exposure for drugs intended for long-term treatment of non-life-threatening conditions. The guideline acknowledges that safety evaluation during clinical drug development is not expected to characterize rare adverse events (AEs), such as AEs that occur in less than 1 in 1000 subjects. Total short-term exposure is expected to be about 1500 subjects. Exposure for six months by 300 to 600 subjects should be adequate. Exposure for a minimum of one year by 100 subjects should be adequate. Exceptions are noted.
  • E2AE2B, and E2C are clinical safety data management guidelines. They provide guidance for definitions and standards for expedited reporting, for the data elements for transmission of individual case safety reports, and for periodic safety update reports for marketed drugs. Also see the European Commission’s guide to Safety Reporting.
  • E3 is the guideline on “Structure and Content of Clinical Study Reports.” This guideline provides detailed recommendations and specific suggestions for data displays of safety data. It is noted that the guideline shows “demography” as a subsection of “efficacy evaluation” and “extent of exposure” as a subsection of “safety evaluation.” For studies for which doing so makes sense, and for integrated summaries, FDA regulations require that efficacy and safety data be analyzed with particular consideration in regard to age, sex, and race. ICH guidance encourages that the analysis of both efficacy and safety data consider extent of exposure, including compliance. It is imperative to understand that demography and dose exposure relate to efficacy and safety. Therefore, the analysis and reporting of safety data should consider the  characteristics of the presenting population and the extent of exposure to the investigational compound.
  • E5, Ethnic Factors in the Acceptability of Foreign Clinical Data advises that there are concerns “. . .that ethnic differences may affect the medication’s safety, efficacy, dosage, and dose regimen.” This guideline also delineates between extrinsic ethnic factors—those factors associated with environment and culture (e.g., diet, use of tobacco, use of alcohol)— and intrinsic ethnic factors—those factors that help define and identify a subpopulation (e.g., age, sex, weight, organ dysfunction). Please also see FDA Guidance on Acceptance of Foreign Clinical Studies.
  • E6 is the consolidated good clinical practice (GCP) guideline. This guideline contains principles of GCP that underscore the scientific basis of the clinical trial and specify qualifications for the personnel and systems involved in all aspects of the clinical trial. The guideline also asserts that adherence to good scientific principles is required and that the documentation of the adherence is needed. Also note the European Commission guide to GCPGuide to Quality documentationRules governing Medicinal products in the EU, and Inspection Guidelines.
  • E9 is a guideline geared toward the statistician, which includes substantial advice for the analysis of safety data.
  • Other guidance documents that give advice for capturing, managing, and reporting safety data are available from the ICH and from regulatory agencies. Sponsors should refer to IND regulations (21 CFR 312) and NDA regulations (21 CFR 314) to ensure compliance with FDA regulations for investigational and marketed products.And the European Commission’s Report to the Collection, Verification and Presentation of Adverse Event Reaction.