Risk management of biologicals: a regulatory and clinical perspective

Abstract

Biologicals are a relatively new class of drugs and are important treatment options for a variety of chronic and/or serious conditions. Biologicals have different characteristics as compared to the traditional chemically synthesised drugs, which may result in different risk profiles and the need for different approaches in risk management. Post marketing collected safety data offers a valuable and necessary complement to the information obtained during the clinical trials. The objective of this thesis was to evaluate the risk management of biologicals from a regulatory and a clinical perspective. Therefore we studied the regulatory actions and activities undertaken for these drugs. It was found that at the moment of approval little is known on the safety profile of biologicals as compared to the traditional small molecule drugs. This underlines the need for active pharmacovigilance. In addition, different data sources are used for post-marketing pharmacoepidemiological studies of biologicals as compared to the small molecule drugs. Safety-related regulatory actions initiated for biologicals after use in the clinical setting showed that biologicals first to be approved in a therapeutic class where more prone to a regulatory action. Pharmacovigilance should especially be stringent for these biologicals. In addition, we found that safety-related regulatory actions could often be related to the pharmacological activity of the biological (e.g. adverse drug events (ADRs) related to infections and haematological malignancies) or to the protein nature of these agents (immunogenicity), indicating that biologicals have a different ADR profile as compared to the small molecule drugs. An analysis with spontaneously reported ADRs confirmed this finding regarding the nature of the ADRs. The risk management of biologicals was also studied from a clinical perspective in a cohort of rituximab users. We were interested in the identification of risk factors using clinical laboratory data as this can guide the clinician to identify patients susceptible for an ADR at an early stage. Invasive Aspergillosis (IA) and thrombocytopenia were studied. Patients treated with a higher cumulative dose of rituximab and a Candida infection in the 30 days before the diagnosis of IA had a higher risk for IA. These patients should especially be educated about activities to minimise the risk for fungal infections. The incidence of thrombocytopenia was found to be higher as compared to the clinical trials. Healthcare professionals should therefore consider thrombocytopenia as a relevant ADR during treatment with rituximab. Patients with a relatively low platelet count and/or treated with rituximab in the oncology indication as compared to the auto-immune indication where at an increased risk. More frequent monitoring of the thrombocyte count is advised. It was concluded that information on the characteristics of biologicals and their underlying ADR profile is important in regulatory and clinical risk management. Regulators should use knowledge obtained with other biologicals during the assessment of new biological agents. For clinical risk management, information on the safety profile of biologicals and use of risk factors can lead to a safer use of drugs in clinical practice and minimise the risk for the patient.