Case report forms , adverse event reporting

The following points are worthy of note in terms of the placement of data. In the case of studies with multiple objectives, reports should be placed in the section corresponding to their primary purpose. Reports of laboratory studies conducted with human materials to investigate pharmacokinetic effects should be placed in Section 5.3.2 of the clinical module, as opposed to the non-clinical module. A US submission requires that the individual case report forms of all trial subjects that died or were dropped from a study due to adverse events are included in Section 5.3.7. 

The final meddra data set in this program contains the lower-level term code (llt code) that can then be merged with the adverse events or medical conditions database. By merging the MedDRA dictionary data with the disease data, you can match the verbatim event text captured on the case report form with the preferred term and associated body system. Then you can summarize these data by body system and preferred term you will see an example of this in Chapter 5. 

In any case, injection site responses (erythemia, edema, pain, and tenderness) and systemic responses are both evaluated in subjects (Mathieu, 1997). USFDA also has specific guidance on the tracking and reporting of adverse clinical responses to vaccines. Any adverse events or product problems with vaccines should not be sent to MedWatch but to the Vaccine Adverse Event Reporting System (VAERA), operated jointly by FDA and the national Centers for Disease Control and Prevention. For a copy of the VAERS form, call 1-800-822-7967, or download the form (in PDF format) from www.fda.gov/cber/vaers/vaersl.pdf on FDA s Website. 

Clinical research coordinators (CRCs) are the research personnel who assist with pahent visits, and perform study-related procedures that do not require a physician (phlebotomy, vital signs, adverse event, and concomitant medicahon discussions, etc.). CRCs provide the PI or physician with data required for interpretation, medical decisions (inclusion/exclusion, dosage adjustment, patient withdrawal, adverse event causality, etc.), and trial oversight. In addition, CRCs are usually responsible for transcribing source documentation (medical records, clinic notes, laboratory reports, etc.) into case report forms (CRF) supplied by the study sponsor. 

An important aspect of the trial is the meticulous monitoring required. This is a process to interact with the subjects monitoring their well-being, the effects of drug and placebo, adverse events, and so on. Information is recorded on the Case Report Forms. All the processes are recorded in accordance with Standard Operating Procedures, which describe how the trial is to be conducted, and GCP. 

Adverse events should be tabulated for easy inspection but the case report form should be available and all laboratory data such as blood coimts, renal function and liver function tests should be inspected closely The absence of obvious adverse events does not mean that all is well, and careful scrutiny of data by an experienced physician can often spot problems before they become troublesome. Not infrequently one or more volunteers become imwell during the course of a study, usually due to intercurrent viral infections, and decisions about postponement of study days and subject withdrawal follow-up can be made during these meetings. Data that are missing because of non-attendance of volunteers, for whatever reason, may lead to a delay in the study, with postponement of dose escalation imtil they have caught up. 

Case report forms and narratives should be provided for all patients who died, discontinued from a study due to an adverse event, or experience a serious adverse event. Case report forms for all patients involved in pivotal well-controlled studies should be available upon request. 

Case report forms. The application is required to contain copies of individual case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event, whether believed to be drug related or not, including patients receiving reference drugs or placebo. This requirement may be waived by the FDA for specific studies if the case report forms are unnecessary for a proper review of the study. 

The regulations request that the NDA contain copies of the complete case report forms for any patient who died during a clinical study or who withdrew due to an adverse event. The FDA may not require the case report forms if they are considered unnecessary for a review of the NDA. On the other hand, the FDA may request copies of case report forms for other patients, such as all those who did not complete the studies, regardless of cause. This should be discussed with the reviewing division before the NDA is prepared. 

As implied by its title, the safety update report is not submitted with the original BLA, but is submitted in the form of updates at specific points in the application review process. Applicants must submit safety update reports 4 months after the BLA submission, after receipt of a complete response letter, and other times requested by CBER. In these reports, the sponsor must update the pending BLA with new safety information learned about the product that may reasonably affect the labeling statements in the contraindications, warnings, precautions, and adverse reactions sections. The updates must include the same types of information from clinical studies, animal studies, and other sources, and must be submitted in the same format as the BLA s integrated safety summary. They must also include case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event. 

There should also be an explanation and justification of the method by which the clinician s words, such as lethargy, severe pain, stupor, etc., are transformed into numbers that can be manipulated in statistical calculations. The coding of case report forms entering adverse event and concomitant medication information, whether done manually or electronically, is obviously necessary. This is easily done with the use of standard references, such as the COSTART and the WHO dictionaries. 

After the case report forms are retrieved from the investigational centers, they are typically reviewed by inhouse auditors. Medical review by a physician for safety and efficacy and review of adverse events may be conducted. The data are then entered into a computer database. 

Case report forms, drug complaints, and adverse events are also documents that should be managed. These can be kept in such a system for all of... 

A new feature, recognizable from the Annuals, but not incorporated into previous editions, is the inclusion of case reports of adverse effects. This feature reflects the fact that about 30% of all the literature that is reported and discussed in the Annuals derives from such reports (see Table 1). In some cases the only information about an adverse effect is contained in an anecdotal report in other cases the report illustrates a variant form of the reaction. A case report also gives more immediacy to an adverse reaction, allowing the reader to appreciate more precisely the exact nature of the reported event. 

The scientific literature is an important source of adverse event information, particularly in the form of case reports. Pharmacovigilence departments routinely scan the published literature for references to their products in order to identify adverse experiences. Case reports and case series can give clues to emerging safety issues. Because of the importance of these experiences, clinicians should publish case reports as soon as possible rather than waiting to assemble a case series. 

Whilst the conditions under which large simple trials can provide efficacy data are fairly well worked out, it is important to consider whether (or which) tolerability issues can be precisely addressed in this way. If a tolerability factor (adverse event) relates to the efficacy variable of interest (e.g. a fatal adverse event in a patient survival study), then a simple case report form may provide relevant information. However, if the adverse event type is rare or unanticipated (e.g. the test drug causes unanticipated, significant anemia in 0.1% of patients, and the protocol and case report form do not collect hemoglobin values before and after treatment), then it is very likely that the adverse event will be missed. Large simple studies can thus create undue confidence in product tolerability ( thousands of patients were exposed to the agent during clinical trials ). 

Technology, television, transcontinental travel and international scientific and medical conferences continue to narrow the subjective variations. Differences in diagnosis, data measurement and interpretation will diminish with such exchanges. It is possible that methodology, study design and case report forms can be constructed that correct for culture, diet, and at least some subjective factors, which will allow comparability of efficacy and adverse events on dose/mg/ kg body weight measured between European, US and Japanese data. 

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