Paper or electronic form designed to capture data from a clinical trial.

Fig. 8.15. Definitions/Terms -2

Fig. 8.15. Definitions/Terms -2

assessments of efficacy and adverse event); subjects are informed of the study and are providing informed consent as required; the data collected is accurate and is being recorded as required; the drug is being stored, prepared, and accounted for as required; the site is notifying the IRB of the progress of the study as required; and study documents are being maintained appropriately. Monitoring site visits typically are done at several key milestones in the study timeline and consist of the following: prestudy site visit and initiation site visit ensure that the study staff and systems are prepared to follow the protocol and follow GCP; interim monitoring visits ensure all procedures and guidelines are being followed, answer questions from the site, and proactively audit for compliance; and close-out site visit is an audit-type visit to collect all data, inspect necessary records, and meet with investigators and staff.

Adverse events (or experiences) and serious adverse events are defined in the CFRs [9, 10]. An adverse drug experience is any adverse event associated at any dose in any treatment group with the use of a drug in humans, whether or not considered drug related. Blinded studies including placebo groups have these recorded. A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any of the following five outcomes: death, immediately life threatening, a persistent or significant disability/incapacity, requires or prolongs inpatient hospitalization, and a congenital anomaly or birth defect.

As stated in 21 CFR 312.32, the IND safety report must be submitted to all the regulatory authorities by the sponsor of an IND, and the sponsor must notify all investigators when any SAE occurs that is unexpected (i.e., not listed in the investigator brochure) and "associated with the use of the drug," that is, "there is a reasonable possibility that the experience may have been caused by the drug" (Fig. 8.15) [9]. Of note, the sponsor must notify the FDA by telephone or facsimile within 7 calendar days of any unexpected fatal or life-threatening experience. All other IND safety reports must be submitted within 15 calendar days of becoming aware of the event.

Institutional review boards (IRB) and an independent ethics committees (IEC) are groups external to the sponsoring company that serve an important role in the protection of the rights and welfare of human research subjects. They have been formally designated to review and monitor biomedical research involving human subjects. Each university and health care institution involved in a study will have their own IRB, who each will approve a study. For multiinstitution studies, especially with clinics and physician offices without IRBs, commercial IRBs are available to perform all the necessary functions. The regulations are the same no matter what IRB is used. Membership on IRBs is usually several physicians with appropriate experiences, a lay person, and an ethicist. In accordance with the regulations, an IRB has the authority to approve, require modifications, disapprove research, or stop an ongoing study. The PI and sponsor are responsible to report periodically to IRBs on progress in the study, and SAEs are reported as well [11, 12].

Case report form (CRF) is a paper or electronic form designed to capture all the data from a clinical trial. One CRF for a single patient can be 50 to 100 pages for one study. Please be reminded that the data is voluminous and includes, for example, a patient's demographical profile, checklists for inclusion criteria and exclusion criteria, drug administrations throughout the study, clinical assessments for efficacy at each time point (once or up to 12 months per protocol), clinical assessments for adverse event monitoring, AE report forms, and checklists for patient withdrawals from a study no matter what the reason. Technology is being used by some companies wherein data is remotely entered directly into the database via computers or personal data assistants (PDAs) by the investigator's staff. CDM group uses CRFs for data entry at the company.

Clinical data management (CDM) is the functional group within clinical operations that is responsible for the data derived from clinical trials, its storing, preparing, and entrance into databases (Fig. 8.16). Also, they usually create the forms (case report forms) wherein the data, for each patient throughout the study, will be recorded by the investigator and staff at the sites.

Electronic data capture (EDC) is used for collection and entry of patient information into case report forms by the staff at the investigators' sites. The staff uses varied computer/database systems, such as laptop computers or PDAs. The goal is improved efficiency of a very time consuming and labor intensive process, that is, data entry. Otherwise, staff enter data and information into paper CRFs, which in turn is entered into computer databases from the paper CRFs by the CDM staff of the company. The CDM group must still check the data entry for accuracy, consistency, and missing information. Issues limiting application of EDC are costs of implementation and comfort level and capabilities at the sites for this type of data processing by study staff [13, 14].

The biostatistics group will ultimately analyze these data. Biostatistics is the functional group that applies statistical methods to the data derived from a clinical trial. This group will help write protocols, particularly the statistical analysis section dictating how and what statistical methods will be used to analyze the data. Each type of data requires different types of mathematical tests. Also, their expertise is study design as well, and they will critique many other aspects to enhance quality of the data to be collected (e.g., appropriate comparison groups, frequency of testing, the amount of change in a disease parameter that is significant). They write a report summarizing all the study results, as well as present the results in appropriate tables and graphs. A database is secured (that is, "locked") to prevent any further changes from being made. A lock will occur after procedures that are designed to verify the quality of the data have been carried out; for example, computerized edit checks, manual review of the data listings and tabular output, and audit of database output versus case report forms. When the database is locked, the

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