Masterstudiengang "Drug Regulatory Affairs"


Safety reporting in clinical trials

Dr. Doris Wolf (Abschlußjahr: 2005)

This master thesis describes what safety reporting in clinical trials mean and why it is required when a clinical trial is performed. Furthermore, the changes implemented with the Clinical Trial Directive 2001/20/EC are discussed with regard to safety related issues and presented as examples for Germany, Austria, Poland and Czech Republic. In addition, the master thesis would like to advice what safety issues to be considered before a clinical trial starts.

Medicinal products are assessed according to their efficacy but also to their quality and safety profile. It is of tremendous importance if a drug is save or causing adverse reactions if administered to human beings. Adverse reactions are not only depending on the administration of a drug. The occurrence of adverse reactions may also depend on the dosage, the way of administration, concomitant diseases and therapy of subjects participating in a clinical trial.

First hints for the safety profile of a drug are gained through toxicological trials with animals. It is difficult to know if the reactions observed during pre-clinical trials may also appear when the drug is given to a human being. However, first administration in man is done usually in healthy volunteers. The dosage is x times the amount that was used in the pre-clinical trial. This is due to different sensitivities between animals and human beings. Especially adverse reactions are observed when the dosage is increased or the application changed.

Investigators who perform clinical trials are obliged to record every single adverse reaction onto study specific record forms. There is basic information already available about a drug that is collected from results of pre-clinical and clinical trials if already performed. This information is usually summarised in the Investigators Brochure (IB). Subjects who participate in a trial have to be informed by the investigator about possible risks that may occur when the drug is administered to them. They are also informed about the purpose of the trial and why the drug is examined through the performance of a trial. Usually, the risk-benefit should be well balanced.

IB or Summary of Product Characteristic (SmPC) have to be updated by the sponsor in case of any reasonable suspicion about risks that are related with the application of a drug that were not known yet and not described in the basic information summary. The sponsor has the responsibility to collect, evaluate and report suspicious adverse reactions to CAs and ECs and to continuously monitor the drugs safety profile during the drug development.

The reporting of serious adverse events as well as unexpected suspicious adverse reactions were always required during the course of clinical trials. However, this was performed in accordance with national laws and regulations. To facilitate and harmonise the reporting procedures and forms for unexpected reactions, Directive 2001/20/EC was introduced that is an approximation of laws, regulations and administrative provisions of the Member States related to the implementation of GCP for the conduct of clinical trials in human beings.

Further to the Directive 2001/20/EC there is a detailed guidance on the collection, verification and presentation of adverse reaction reports that arises from clinical trials in human beings that defines responsibilities of involved parties, how events are assessed and what information is required for the reporting.

With the implementation of the EU Directive for clinical trials, the EU pharmacovigilance database will be extended to a module for clinical trials where SUSARs are centrally collected. Access to the information of clinical trials and the safety database is granted to CAs and the EMEA as well as to MAH but only for information that concerns their own clinical trials and products. All parties will be able to easily exchange information about safety related concerns that may help to accelerate the assessment of the safety profile of a drug before the application is submitted.

Europe has adopted ICH GCP in July 1996. As Directive 2001/20/EC includes the principles of ICH GCP, unified standards are set and are legally applicable to clinical trials (NtA, 2005). What this exactly means is described in this master thesis and recommendations are given that can be considered prior to commencing of clinical trials.

Pages: 41