Investigator’s Brochure

The investigator’s brochure is a “compilation of the clinical and nonclinical data on the investigational product(s) that is relevant to the study of the investigational product(s) in human subjects.” (ICH E6). In general, the investigator’s brochure provides more complete background information on the investigational product than is provided in the protocol. The investigator’s brochure assists the investigator in interpreting and implementing the study protocol, and may be of particular importance in helping the investigator determine whether specific adverse events are unanticipated, and accordingly, when and how such events should be reported to the sponsor, IEC/ IRB, and regulators.

Source: ICH E6

What is the ideal approach to pharmacovigilance- Signal Detection

Various methods are used throughout the life cycle of the product (from all phases of clinical trials and post-marketing) to evaluate new information that comes in routinely. This is called signal detection. Signal detection is one of the most important objectives of pharmacovigilance. The whole process of risk/benefit evaluation depends on effective detection of signals. Methods for signal detection include observations by clinicians and patients, case reports in the literature, assessment of individual case reports or clusters of reports that are received from healthcare professionals, patients and consumers etc, data from formal studies, e.g. clinical trials, epidemiological studies like cohort studies and case control studies.

The detection of signals require clinical assessment assisted by epidemiological and statistical analysis. Information technology tools also help in the generation of signals and enhancing its effectiveness. Automated signal generation is used by many MNCs, where reported safety profile of a particular product is compared with other products in the database using simple statistical methods like proportional reporting rates (PRR). Apart from PRR, which is very popular, there are other statistical tools used for signal detection that are used like incidence rates, frequency of adverse events and trend analysis.

Understand the SAE process

When an SAE report arrives in-house from an investigator, health worker, or employee (clinical research associate or customer service representative, for example), it is immediately assigned a number and reviewed to determine whether the event is a reportable SAE. If it is reportable, the company needs to send the SAE to FDA by one of the following methods.
• Form 3500A only (can be filed manually or electronically via the AERS system)
•A narrative report
• VAERS form (vaccines only)
• CIOMS I form (foreign reports only).

A company’s culture and experience dictate the way it meets these reporting requirements. Whatever the method it uses, a company must keep an audit trail, either manual or electronic, that shows
• the initial receipt date of the SAE
• all changes made to the original SAE by any personnel.
• all supporting documentation requested and sent in from the site.
• any internal or external correspondence.
• any internal notes, such as medical review.
• all attempts to get additional information regarding the event.
• whether the event is open or closed.

We need to code the SAEs in such a way that they become categorical in nature, such as assigning a code for the event and a MedDRA term

Company Core Data Sheet(CCDS)

A document prepared by the marketing authorization holder containing, in addition to safety information, material relating to indications, dosing, pharmacology and other information concerning the product.

The CCDS is required to judge whether an adverse event or adverse drug reaction is labeled / listed or unlabelled / unlisted and is therefore always included in a periodic safety update report (PSUR).

In many countries involved in the international conference on harmonization (ICH) as members or observers, this kind of document is similar to the labelling approved as part of the marketing authorisation, although there are often differences because of differences in the scope of the document, principles for inclusion, indications and / or recommended dosage of the drug, experience drawn from pre-registration studies and from the market, local habits for concomitant drugs and local or ethnic sensitivity. The classification ‘labeled’ or ‘unlabelled’ has many more consequences for expedited reporting than for periodic reporting. The CCDS must be dated, including the date of last revision (or all revision dates).
 
CCDS are usually prepared by an applicant for a drug substance (active ingredient) rather than a drug product because post-marketing PSUR’s and IPSR’s would be based on a drug substance.

Source:  EU Guidelines

Differences between PSUR and PADER

Preapproval reports include IND Annual Reports in the U.S. and Annual Safety Reports (ASRs) in Europe. Some of these documents may provide cumulative information, while others contain aggregate information specific to the reporting period. Postapproval cumulative reports of safety include NDA Periodic Adverse Drug Experiences Reports (PADERs) in the U.S. and Periodic Safety Update Reports (PSURs) in many other countries, including in Europe. Their purpose is to update and evaluate the worldwide safety experience with a medicine at defined time points after approval.

These reports provide succinct summary information together with an evaluation of the benefit-risk
profile of approved medicines in the light of new or changing postapproval information.This evaluation is designed to help ascertain whether further investigations need to be carried out and whether changes should be made to the approval and/or to the medicine’s labeling.

In summary, the aim of cumulative reports of safety is to:
• Report all the relevant new information from appropriate sources.
• Relate these data to patient exposure to the medicine.
•  Summarize the medicine’s approval status in different countries and any significant variations  related to safety.
• Create periodically the opportunity for an overall reevaluation of safety.
• Indicate whether changes should be made to an approved medicine’s label in order to optimize the use of the product.

Source: FDA and EU Guidelines