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In everything we do, our number one priority is our patients' safety. Before an active pharmaceutical ingredient (API) is used in humans, we conduct extensive pre-clinical trials that test for aspects such as efficacy and toxicity. After this, the API is tested in humans within the scope of clinical trials that extensively investigate the API's efficacy and adverse effects. The trial results are then used to assess the drug's risk-benefit ratio, weighing the benefits of the treatment against its risks. In the case of severe or even life-threatening diseases that have no other treatment option, a higher risk of adverse effects can be more acceptable than for less severe conditions.
Information from clinical trials provides the basis for a drug to be approved by the regulatory authorities. Even after receiving marketing approval, however, we continue to conduct further risk-benefit evaluations on the drug since the number of patients using it increases exponentially – to thousands or millions worldwide. We thus gain a deeper understanding of the safety profile of our drugs and continue performing risk-benefit evaluations.
At our prescription medicines division, Global Drug Safety is responsible for continuously, systematically monitoring the safety of our drugs (pharmacovigilance). Global Drug Safety processes safety information from various sources such as clinical trials, adverse reaction reports and scientific literature in order to provide patients with immediate safety information during the entire life cycle of our drugs.
Pharmacovigilance information is compiled from doctors and patients in all countries in which our products are marketed. Medical specialists and pharmacovigilance teams ensure that information on adverse affects is correctly compiled, tracked, and communicated. The data for all of our drugs are evaluated centrally by Global Drug Safety, and risk-benefit evaluations are modified accordingly, as necessary. In line with regulatory requirements, changes to the risk-benefit evaluation and potential safety risks are reported to the responsible authorities, as well as to doctors and patients.
Global Drug Safety and the drug safety units within our legal entities in all countries where our products are used continuously review changes in the pharmacovigilance regulations worldwide – for products in both the development and the marketing phase. New regulations are continuously integrated into our group-wide processes, thus allowing us to ensure that regulatory requirements and statutory regulations are adhered to.
Health authorities regularly conduct inspections to review adherence to regulatory requirements as well as to our own internal drug safety standards.
The Medical Safety and Ethics Board (MSEB), chaired by the Head of Drug Development and Medical as well as by the Chief Medical Officer, bears ultimate responsibility for drug safety at our prescription medicines division; it convenes once a month, or as required. In addition to the chairpersons, the MSEB consists of experienced drug safety and product experts from our prescription medicines division, and its tasks include assessing risk-benefit evaluations during drug development and marketing, reviewing risk management, and dealing with safety-related communication. Furthermore, it reviews proposals for first-in-man (FIM) dosages as well as for updates to the safety warnings on package inserts.
In collaboration with other companies as well as organizations from the public sector, Merck KGaA, Darmstadt, Germany is engaged in the global research project PROTECT of the Innovative Medicines Initiative (IMI), which was launched during the 2011-2012 period.This project aims to further develop and optimize instruments and methods for the risk-benefit evaluation of drugs.
Our Quality Training Management standard applies to all employees whose work impacts the quality and safety of a drug or clinical trial data. This standard describes how to conduct training workshops and seminars at both the Group level as well as locally within the legal entities. Compliance with these requirements is regularly reviewed during the audits of the safety quality system.
GMP production
In producing pharmaceuticals, quality assurance is a key topic because deviations can impact patients' health. In order to ensure that pharmaceuticals meet the standards set for identity, purity, potency and safety, they must be manufactured according to cGMP (current Good Manufacturing Practice ). Consequently, as a manufacturer we must have appropriately trained employees as well as suitable facilities, processes and procedures. Compliance with cGMP guidelines is required and monitored by the health authorities.
On December 15, 2011, Merck KGaA, Darmstadt, Germany received a warning letter from the U.S. Food and Drug Administration related to inspections of production facilities in Tiburtina in Italy, and Aubonne and Vevey in Switzerland. Rebif® and other products for distribution in the United States are manufactured at these sites. The letter primarily addressed several processes related to the manufacture of Rebif, which the FDA concluded were not in full compliance with good manufacturing practice standards. Merck KGaA, Darmstadt, Germany is working closely with the FDA to address its observations. The agency has completed its initial evaluation of our responses. In its own response, the FDA agreed that the proposed corrective actions, if properly implemented, would adequately address the violations in question. Since this initial evaluation, all actions stipulated by the plan submitted to the FDA have been implemented in a timely fashion. In September 2012, Merck KGaA, Darmstadt, Germany sent a final report to the FDA, and the FDA has already conducted another round of inspections.
Labeling of packaging
All our pharmaceutical packaging comes with the required package insert that informs patients how to correctly use the product. The package inserts furthermore inform patients of the risks and adverse effects associated with taking the drug. They are regularly reviewed and updated to ensure that they are state-of-the-art, particularly in terms of safety-relevant information. The Labeling Oversight Group coordinates this process and regularly reports these updates to the Medical Safety and Ethics Board (MSEB).
