TAG overview

The safety of patients who are treated with our medicines is our absolute priority. Our pharmaceutical products need to be effective in treating the respective disease, while also posing as little risk as possible to patients. That is why we consistently monitor risks and any adverse effects that may arise and take the necessary actions to minimize them.

Our approach to ensuring patient safety

Through rigorous benefit-risk management, we help to ensure that the benefits of our drugs always outweigh the risks for patients. Every new medicine passes a series of precisely defined development stages. Before any drug is given to humans, we conduct extensive preclinical testing both and . Through toxicological testing, we determine whether an active pharmaceutical ingredient is toxic to living organisms and, if so, at what dosage. This also helps us determine the dose that humans can safely tolerate. Only when this is complete do we perform clinical studies to investigate the safety and efficacy of the drug when used in humans. During clinical development, we diligently use all collected data to continuously evaluate the drug’s benefit-risk profile. If we consider the drug’s benefit-risk profile to be positive, we then submit an application for marketing authorization to the regulatory authorities.

Continual monitoring

Once a drug is launched, the number of patients being treated with it increases significantly. In certain circumstances, rare adverse and potentially serious effects that go undetected during clinical development may occur, which is why we continuously monitor and manage the positive benefit-risk profiles after market launch. includes the process of monitoring a drug on an ongoing basis to detect and assess signals as part of activities. The aim is to track any adverse effects in an effort to take appropriate action to minimize and communicate the risks in a transparent way. We always provide physicians and patients with the latest information on the safety of all our marketed drugs. The above applies to the entire life cycle of a product, ranging from development, market launch and commercialization to expiration of the marketing authorization.

Capabilities that we have developed and strengthened in this area include:

  • Advanced benefit-risk management
  • analytics (using real-world data)
  • Advanced signal detection technology
  • Pilot processes in patient-centric adverse effects collection

Based on the conditions of regulatory approval, we regularly develop and publish educational materials for patients and healthcare providers to communicate any known and potential risks and ways to minimize them for newly approved products (such as Bavencio® and Mavenclad®). We assess the effectiveness of these materials in close collaboration with our Benefit-Risk Action Team. If required, we adjust the content of the materials and their distribution, and describe the results from the effectiveness analysis in our periodic safety reports and risk management plans, which we submit to relevant health authorities for evaluation.

How we monitor patient safety

Our Global Patient Safety unit is responsible for pharmacovigilance. It continually collects current safety data from a wide variety of sources across the globe, including clinical studies, early-access programs, , and articles published in medical and scientific journals.

Our experts help to make sure all information on the risks and adverse effects of our medicines is properly documented, tracked and reported to the respective health authorities in accordance with regulatory requirements. The Global Patient Safety unit analyzes all data and reassesses the benefit-risk profile based on these data, where required. We, then, inform regulatory authorities, physicians and patients about new risks, additional risk mitigation measures and potential changes in the benefit-risk balance.

Our Global Patient Safety unit became part of our Global Development function at the end of 2018, enabling us to better integrate sound knowledge of patient safety into early decision-making, in particular through the advent of predictive safety. Our expertise, in close collaboration with Chemical & Preclinical Safety, Translational Medicine and other functions, will help ensure the seamless assessment of benefit-risk profiles throughout the product life cycle to deliver therapies that are truly differentiated and provide transformational value to patients. We restructured the Medical Safety function in 2019. It is now therapeutically aligned as a holistic end-to-end function, including a unified Safety Scientist group and a new function known as Medical Operations and Analytics. and marketed drugs were previously managed through two separate functions within Global Patient Safety. Overall, this newly consolidated department will help us to focus on scientific data and medical safety. Acknowledging the importance and magnitude of our journey, we launched a Transformation Office. To establish a robust and streamlined end-to-end process for Individual Case Safety Report (ICSR) management, the Medical Assessment group was integrated into the Safety Operations group. Thus, one team is now accountable for the entire ICSR process.

The Healthcare Quality (HCQ) unit of Merck KGaA, Darmstadt, Germany processes quality complaints relating to our products. When quality defects may have an impact on patient safety or lead to adverse effects, Global Patient Safety gets involved.

Our Medical Safety and Ethics Board

Our Medical Safety and Ethics Board (MSEB) oversees the safety and benefit-risk assessments of our drugs throughout clinical development and commercialization. It endorses appropriate measures to minimize risk, such as package leaflet updates. This board is chaired by our Chief Medical Officer (CMO) and consists of experienced physicians, scientists and experts from our company. Throughout a drug’s entire life cycle, the MSEB reviews and assesses important medical safety risks and benefit-risk issues, and reviews ethical issues, as appropriate.

Within the Global Patient Safety unit, the Benefit Risk Action Team is responsible for , benefit-risk assessment, risk management and all topics regarding product safety and the benefit-risk profile of our medicinal products. Recommendations from the Benefit Risk Action Team are endorsed by the Pharmacovigilance Advisory Board (PVAB), also chaired by Global Patient Safety unit.

Our commitment: Guidelines and statutory requirements

We follow international guidance and standard procedures, such as the International Conference for Harmonization (ICH) guidelines and the Good Pharmacovigilance Practices (GVP ) established by the European Medicines Agency (EMA) and national health authorities. In addition, we adhere to all statutory regulations in those countries where we market our products, and we continuously work to incorporate all required changes in our Group-wide standards and processes. We began harmonizing the processing of personal data according to new European legislation on data privacy (General Data Protection Regulation) in 2018 and continued this effort globally in 2019.

Collecting information and checking processes

In 2017, the EMA implemented a new process to monitor the safety of medicines in EudraVigilance: This provides marketing authorization holders with access to data on suspected adverse effects and requires them to monitor the EudraVigilance data for safety signals and to report these to health authorities. In response to these new requirements and to the new data transmission format stipulated by guideline E2B (R3), we upgraded our Global Safety Database to ensure the technical capabilities needed to support the coordinated exchange of individual case safety reports. In 2019, we started safety reporting in line with the enhanced E2B(R3) standard in China, Europe and Japan.

In 2019, we assessed new country-specific regulatory requirements and implemented necessary changes in order to meet them. Examples include new benefit-risk assessment and safety signal notification requirements in Canada, Denmark, Serbia, and the United States, and requirements for local pharmacovigilance responsible persons in Botswana, Kazakhstan and Kenya. Other examples include: the EU Falsified Medicines Directive (FMD, 2011/62/EU), the MHRA Guidance on the Regulation of Medicines, Medical Devices and Clinical Trials, and regulatory changes in African countries with – among others – respect to clinical trial guidelines. We also compiled comments on drafted guidelines and provided them to health authorities, for example on “ICH – Draft Guidance E8(R1) General Considerations for Clinical Studies” and “ICH – Draft Guidance E19 Optimization of Safety Data Collection.”

Monitoring drug safety

Regulatory authorities conduct periodic inspections to verify that we comply both with statutory requirements and with our own internal standards for drug safety. In Germany, these are handled on behalf of the European Medicines Agency (EMA) by the German Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI), the German Federal Institute for Vaccines and Biomedicines. We follow up on the findings of health authority inspections and take the necessary actions to ensure the proper functioning of our pharmacovigilance system. In 2019, three pharmacovigilance inspections were conducted (France, Germany and Serbia).

Furthermore, we perform audits to ensure that all our units and subsidiaries involved in pharmacovigilance consistently meet all requirements across the globe. In 2019, we conducted a total of 29 pharmacovigilance audits and found no significant deviations in our pharmacovigilance system from these requirements. We also audit vendors and licensing partners involved in pharmacovigilance, which helps us hone our pharmacovigilance processes so that they surpass statutory requirements.

In line with our goal to enhance patient safety, we implemented a patient-friendly interface in the mobile app agReporter. With this app, not only field nurses and our sales representatives, but also non-medically trained users can report any side effects or adverse events arising from the use of our products. This places patient feedback at the core of our efforts to consistently collect data on adverse effects. In 2019, we implemented further changes to the app to improve data quality for the adverse events reported. We also made the app available in a total of 14 languages, with an Arabic version currently in preparation.

Innovative signal detection

Through our tool for signal detection, called Empirica, we analyze and manage large amounts of global data, such as scientific studies and news about adverse effects. This helps us to comply with regulatory timelines for safety signals and other safety-related factors and will ensure that all signal data, documentation and decisions are captured in one place. It also allows easy access to and analysis of our data as well as cross-functional collaboration between the Global Patient Safety unit and other internal and external . We use a key performance indicator (KPI) to track whether all signals, validated and not validated, detected from external or internal sources are managed and completed within the timeline defined by standard operating procedure, which is 60 days from the date of detection. The KPI shows that the implementation of Empirica improved the tracking of all safety. Using diverse statistical tools and leveraging all available safety data from our internal and external databases also helped to improve our signal detection rate.

Up-to-date labeling and product information

Our product information explains to physicians and patients how to properly use the respective drug and allows for an informed decision on the treatment. In accordance with statutory regulations, the package leaflet contains all relevant information such as indication(s) and ingredients, as well as dosage, storage, mode of action, instructions for use, warnings, precautions and possible adverse effects. Should the medicine contain ingredients that could impact the environment, the package leaflet may also contain information on the proper disposal of the product.

We review and update all product information documents such as package leaflets, ensuring that our medicinal products contain the latest information on safety, efficacy and pharmaceutical formulation, as appropriate. In accordance with statutory requirements, all modifications to the leaflets are submitted to the respective regulatory authorities for approval. In 2019, there were no incidents of non- with statutory regulations concerning labeling of drugs or pharmaceutical products.

Internal and external training

All employees involved in the safety and quality of pharmaceutical products take part in training in line with our global training standards. We verify compliance with these requirements by producing training compliance reports and by performing regular audits.

Our training is delivered via a global-learning platform. All of the approximately 24,000 biopharma employees receive basic pharmacovigilance training once a year that covers the procedure for reporting adverse effects from our products. Other training courses keep employees up to date on their professional expertise as well as internal standard operating procedures and other relevant requirements. This helps to ensure adherence to Good Pharmacovigilance Practice (GVP) requirements.

Sharing expertise with other countries

We endeavor to transfer our drug safety expertise around the world, especially into countries where health workers need to build their pharmacovigilance expertise. In 2019, we continued the pharmacovigilance workshops for medical school students in Guatemala, as reporting adverse effects is often not sufficiently covered by the curricula there.

We also assist Latin American health authorities in implementing electronic reporting processes for adverse effects. We support the implementation of electronic reporting in Argentina, El Salvador and Peru. Health authorities in Brazil, Mexico and Tunisia are also moving towards adopting this technology.

Additionally, we conducted pharmacovigilance training and shared pharmacovigilance expertise in the Eurasian Economic Union (EAEU). As members of the pharmacovigilance working group within the Association of International Pharmaceutical Manufacturers (AIPM), we shared our expertise through conferences, provided training and seminars in the industry, presented to university school students and professors and liaised with the health authority in Russia.

The Medical Dictionary for Regulatory Activities (MedDRA) is a clinically validated medical terminology system used by health authorities and the industry worldwide. Following the release of the new MedDRA version 22.0, the MedDRA Maintenance and Support Services Organization (MSSO) presented the Russian version of MedDRA. We also collaborated with health authorities in Brazil and China to contribute to the creation of local language versions of MedDRA.

In Russia, we implemented a new adverse effects database for the health authority in September 2019. Information for marketing authorization holders is currently being developed in collaboration with the national industry association and health authorities.

In 2019, we also formulated a new strategy to increase the contribution made by our Access to Health Initiative (A2H) to pharmacovigilance. Improving access to high-quality health solutions for underserved populations and communities in low- and middle-income countries is the key objective of A2H Initiative. A key aspect of this new strategy is fostering pharmacovigilance initiatives in safety data-sharing with health authorities and building pharmacovigilance capacity with reputable partners in underserved countries in a sustainable way.

To this end, we selected low- and middle-income countries from the UN Human Development Index (HDI) and included these in our project scope. The primary focus in 2019 was on encouraging universities and ministries of education in these countries to establish pharmacovigilance curricula in schools of medicine, pharmacy and nursing, and to support health authorities in adopting pharmacovigilance systems through industry associations or partnerships.

Furthermore, for the selected countries we appointed ambassadors per region to systematically collect and report information on pharmacovigilance initiatives and activities in each region. The analysis of preliminary information already demonstrated that we actively contributed to the preparation of the Brazil health authority’s new pharmacovigilance regulations and the creation of a Brazilian- Portuguese MedDRA. In Russia, we began a joint educational initiative with the Sechenov University, which took place between October and December 2019, targeting students in their fourth year at the School of Pharmacy. The topic of pharmacovigilance was also covered in this training course.

Through the A2H initiative, we also promoted patient centricity in low- and middle-income countries through a pharmacovigilance awareness video that we developed and distributed. For example, this included presentations at a Tunisian pharmacovigilance congress, information on company-sponsored disease awareness websites in India, pharmacovigilance workshops for medical school students in Guatemala and over 2,300 pharmacists in China. We plan to expand this approach to other countries.

Stakeholder dialogues in 2019

Lecture for pharmacy students of Peoples' Friendship University of Russia

Being members of the pharmacovigilance working group of the Association of International Pharmaceutical Manufacturers (AIPM), both, the Eurasian Economic Union (EAEU) Qualified Person for Pharmacovigilance (QPPV) and the Local Patient Safety Officer (LPSO) in Russia took part in projects to increase pharmacovigilance (PV) awareness among local and international industry, healthcare professionals and university students. They presented PV-relevant topics at professional conferences and educational events. In April 2019, representatives of our company held a lecture for pharmacy students at the People’s Friendship University of Russia. In this way, we increased the students’ knowledge on PV and raised awareness of its importance.

Boosting patient-centricity in North Africa

At the Tunisian pharmacovigilance congress in April 2019, we presented a video on educating patients about adverse drug reactions. Reaching more than 200 participants and speakers from Algeria, Europe, Morocco and Tunisia, our #AdverseEventAwareness video built confidence among our partners and stakeholders, and enhanced patient centricity and pharmacovigilance awareness. The initiative was met with approval from Tunisian and Moroccan health authority representatives, who proposed collaborating to assess opportunities for further development.

Towards a digital pharmacovigilance partnership in Tunisia

To ensure the smooth implementation of accurate, electronic reporting on pharmacovigilance in Tunisia by using the ICH E2B system, we liaised with the Tunisian Pharmacovigilance Department. In this way, we helped to ensure the system complemented the Tunisian pharmacovigilance center’s existing connection to the World Health Organization database for safer use of medicines, called Vigibase. The Tunisian Pharmacovigilance Department tested the system and plans to make it mandatory for all pharmaceutical companies involved in electronic reporting.

In vitro
Procedures involving components of an organism that were isolated from their usual biological surroundings (such as test tube experiments).
In vivo
Latin for “within the living”, this term describes processes that take place within a living organism.
The science and activities related to the detection, evaluation, understanding, and prevention of adverse reactions or other drug-related problems.
Signal management
A set of activities performed to determine whether, based on an examination of individual case safety reports, aggregated data from active surveillance systems or studies, scientific literature information, or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed, as well as any related recommendations, decisions, communications, and tracking.
Big Data
Extremely large data sets that may be analyzed computationally to reveal patterns, trends and associations, especially relating to human behavior and interactions.
Spontaneous reports on adverse effects
If a side effect occurs while using a medicine and is reported, this is called a spontaneous report because the adverse reaction is reported spontaneously (for example by doctors or patients) and not in a trial or an observational study.
Patient support programs
Any organized system providing services and direct patient or patient-caregiver interactions that are intended and designed to educate patients about certain diseases, and help patients with access to and/or the management of prescribed medicines and/or disease outcomes and/or offer doctors support for their patients.
Investigational drug
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including approved as well as unapproved products when used or assembled (formulated or packaged) in a way different from the approved form, when used for an unapproved indication, or when used to gain further information about an approved use.
Signal management
A set of activities performed to determine whether, based on an examination of individual case safety reports, aggregated data from active surveillance systems or studies, scientific literature information, or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed, as well as any related recommendations, decisions, communications, and tracking.
The science and activities related to the detection, evaluation, understanding, and prevention of adverse reactions or other drug-related problems.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) aims to promote uniform assessment criteria for product registration in Europe, the United States and Japan. The ICH develops guidelines for the evaluation of the quality, effectiveness and safety of medicinal products.
People or organizations that have a legitimate interest in a company, entitling them to make justified demands. Stakeholders include people such as employees, business partners, neighbors in the vicinity of our sites, and shareholders.
Adherence to laws and regulations as well as to voluntary codices that are internal to a company. Compliance is a component of diligent corporate governance.

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