The safety of patients treated with our medicines is our absolute priority. Our pharmaceutical products need to be effective in treating the respective disease, while posing as little risk as possible to patients. That is why we consistently monitor risks and adverse effects that may arise and take the necessary actions to minimize them.
Our approach to ensuring patient safety
Through a rigorous benefit-risk management process, we help to ensure that the benefits of our drugs always outweigh the risks for patients. Every new medicine goes through a series of precisely defined development stages. Before any drug is administered to human subjects, we conduct extensive preclinical testing both in vitro and in vivo. 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 relevant regulatory authorities.
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 were not detected during clinical development may occur, which is why we continuously monitor and manage the benefit-risk profiles after market launch. Pharmacovigilance includes the process of monitoring a drug on an ongoing basis to detect and assess signals as part of signal management activities. The aim is to track adverse effects in an effort to take appropriate action to minimize and communicate the risks in a transparent way. We always provide healthcare professionals 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
- Big Data 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 develop and update educational materials for patients and healthcare providers to communicate any known and potential risks and ways to minimize them for newly approved products. We assess the effectiveness of these materials in close collaboration with our Benefit-Risk Action team. If required, we adjust the contents of the materials and their distribution and describe the results from the effectiveness analysis in our periodic safety reports and risk management plans. We then submit these to the 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, spontaneous reports on adverse effects, patient support 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. Our Global Patient Safety unit analyzes all data and reassesses the benefit-risk profile based on these data, where required. We then inform regulatory authorities, healthcare professionals and patients about new risks, additional risk mitigation measures and potential changes in the benefit-risk profile.
In order to implement our R&D Strategy 2023, our Global Patient Safety unit in on a journey of transformation. Our vision is to integrate deep knowledge of safety into early decision-making as we evolve to practice predictive safety. As part of our transformation, in 2020 we refined our approach to benefit-risk assessments. We now apply a scoring system based on safety aspects and are using it to prioritize product management; in addition, we are redesigning our pharmacovigilance processes.
Our Healthcare Quality unit 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 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 human-related ethical issues, as appropriate.
Within the Global Patient Safety unit, the Benefit Risk Action team is responsible for signal management, 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, also chaired by Global Patient Safety unit. Important issues may be submitted to the MSEB for final assessment.
Effects of the divestment of Allergopharma on patient safety
On March 31, 2020, we completed the divestment of our allergy business Allergopharma to Dermapharm Holding SE. We entered into a transitional service agreement with Allergopharma/Dermapharm that defines certain services from us for an interim period after the closing date. One of these transitional services was a Pharmacovigilance Statement of Work (PV SOW), defining the transitional pharmacovigilance services provided by our company until all affected pharmacovigilance activities had been migrated to Allergopharma/Dermapharm on November 30, 2020. This step was achieved one month prior to the scheduled date.
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 pharmacovigilance regulations in those countries where we market our products.
In 2020, our Global Patient Safety unit formed a Pharmacovigilance Intelligence Council that focuses on changes in pharmacovigilance legislation and their impacts on our global and local pharmacovigilance systems. This enables us to make strategic decisions and to govern changes in pharmacovigilance requirements.
Collecting information and checking processes
In response to new requirements to the new data transmission format stipulated by ICH 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 (ICSR). In 2019, we started safety reporting in line with the enhanced E2B(R3) standard in China, Europe and Japan, and further rolled out the reporting to Russia and Taiwan in 2020.
We are following up on changes to the European GVP guidelines and preparing for the introduction of the new clinical trial regulation. In addition, we are implementing the new pharmacovigilance requirements in the United Kingdom associated with Brexit and introducing changes according to the timeline proposed by the Medicines and Healthcare products Regulatory Agency (MHRA).
In 2020, we assessed new country-specific regulatory requirements and implemented necessary changes in order to meet them.
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 2020 we did not receive any requests for pharmacovigilance inspections.
Furthermore, we perform audits to ensure that all our units and subsidiaries involved in pharmacovigilance consistently meet all requirements across the globe. In 2020, we conducted a total of 19 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 improve our pharmacovigilance processes so that they surpass statutory requirements. In light of the Covid-19 situation, we adjusted our audit plan and methods. Several audits were postponed and others were conducted remotely.
Responding to the Covid-19 pandemic
In light of the Covid-19 outbreak in 2020, various health authorities across the world issued guidance clarifying the expectations for manufacturers, importers and marketing authorization holders on the implementation of clinical trials, reporting of adverse events from clinical trials and post-marketing sources, and the management of other safety aspects during a pandemic.
Based on this we changed several of our standard reporting procedures. For example, adverse event reports associated with Covid-19 were identified as a priority and submitted as required to the respective national health authorities.
Furthermore, some national health authorities adapted their requirements regarding the electronic submission of adverse events and additional risk minimization information, and we did so accordingly. Industry representatives and health authorities discussed the need for more regulatory flexibility to account for the potential increased reporting of adverse events related to widespread use of medical products to help treat or prevent Covid-19.
Our Global Patient Safety unit’s Business Continuity Team (BCP) routinely monitored the impact of Covid-19 on pharmacovigilance operations. No disturbances to our own operations at a local or global level were detected, and the impacts on business partners were minimal.
As in many other areas of our business, we made use of a remote working model due to physical distancing requirements. We introduced electronic signature processes for safety data exchange agreements with business partners as well as for internal documents to safeguard business continuity.
Redefining our approach to benefit-risk assessments
We have developed a benefit-risk blueprint strategy in order to help us transform from a reactive and compliance-driven organization into a proactive and benefit-risk-focused organization. By truly understanding the benefit-risk profiles of our products, we can enable early decision-making within the organization. Ultimately, the aim is to be able to provide the right medicine to the right patient at the right time.
As part of this initiative, we have also developed the concepts and principles for conducting benefit-risk assessments at each stage of product development and post-marketing.
We have completed the design phase of this benefit-risk blueprint strategy, created guidance and developed a change management plan. We are now in the implementation phase and are conducting several pilots to better understand the model’s impacts and adjust it accordingly.
Assessing the safety of our products
We employ a product prioritization tool as a means to score the safety of our products in an objective, proven way, based on several critical safety and relevant cross-functional parameters. The output scores provide a categorization of products into high, medium or low priority. These categories have a major impact on the subsequent methodology used for all safety activities, allowing us to define working models for safety surveillance and benefit-risk assessment activities for low- and medium-priority products, allowing us to focus on high-priority assets. The tool is helping us to further develop an integrated, proactive safety approach. Additionally, it provides us with a reference to ensure regulatory compliance.
We are in the process of redesigning all pharmacovigilance processes (ICSR management, signal management, benefit-risk blueprint strategy and aggregate safety reporting) to account for product priority category in the component process steps.
In particular, we are successfully incorporating the product prioritization tool into the development of our risk-based operating model within the Global Patient Safety unit. We published the initial version of the product prioritization tool in January 2020. A planned annual update ensures that the tool accurately reflects the current safety status of all products.
Innovative safety signal detection
Through our tool for safety 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 helps to 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 stakeholders. The implementation of Empirica has improved the tracking and oversight of all safety signals. Using diverse statistical tools and leveraging all available safety data from our internal and external databases makes it possible to identify new signals and their assessment of risk for the patients.
Up-to-date labeling and product information
Our product information explains to health care professionals and patients how to properly use the respective drug and allows for an informed decision on 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 2020, there were no incidents of non-compliance 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 of our Healthcare 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.
Enhancing patient safety and sharing expertise with other countries
Reporting side effects with the agReporter app
In line with our goal to enhance patient safety, we have created and published a patient-friendly app called agReporter. In 2020, we continued with the rollout in several markets and developed it further. With this app, not only field nurses and our sales representatives, but also non-medically trained users can report any suspected 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 2020 we initiated the collaboration with local professional associations in Kenya, Nigeria and potentially other countries to deliver training to healthcare professionals on identifying adverse events and how to report them. We will roll out the agReporter app in these countries with instructions on how to report suspected adverse events associated with our medicinal products. The app is available in a total of 14 languages and additional language versions are in preparation.
Pharmacovigilance in Access to Health
We endeavor to transfer our drug safety expertise around the world, especially to countries where healthcare workers need to build their pharmacovigilance expertise.
We want to increase the contribution of pharmacovigilance in our Access to Health strategy (A2H). Fostering pharmacovigilance initiatives in safety data-sharing with health authorities and building pharmacovigilance capacity with reputable partners in underserved countries in a sustainable way are key aspects of this strategy. This is why we selected low- and middle-income countries from the UN Human Development Index (HDI) and included these in our project scope. For the selected countries we employ ambassadors in each region to systematically collect and report information on pharmacovigilance initiatives and activities, as further detailed below:
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 and we contributed to the review of the Russian translation. We also collaborated with health authorities in Brazil to support the creation of a local language version, which was released in March 2020.
Through the A2H initiative, we also promote patient centricity in low- and middle-income countries through pharmacovigilance awareness communication measures that we develop and distribute. In 2020, we conducted an adverse event campaign in Kenya and Nigeria. The campaign was aimed at sensitizing the public to unexpected symptoms that individuals may experience after taking a medicine and the actions they can take – such as seeking medical advice and reporting the incident to the relevant health authority or market authorization holder. We also plan to roll out a non-promotional video and audio messages through local media agencies, explaining how to identify adverse events as well as recommended steps in both English and Swahili.
The Kenyan health authority, the Pharmacy and Poisons Board, has approved the project for the awareness-raising campaign, the training of healthcare professionals and the use of our agReporter app. The project is scheduled for rollout in the first quarter of 2021. The lessons learned from this campaign will be incorporated within a similar campaign and initiative that is being planned in Nigeria.
We endeavor to drive scientific and medical progress, often doing so in close collaboration with medical professionals.
We receive inquiries about the therapeutic use of our products beyond the marketing authorization (also referred to as off-label use). For example, while each medicine is authorized for use in specific indications, a physician may wish to administer a product to a patient suffering from a disease for which it is not approved.
We market our medicines only within the scope of their specific marketing approval. Any medical-scientific information about the use of our products beyond the existing marketing authorization is provided by qualified medical personnel only in the case of unsolicited inquiries. The information shared must be backed by scientific evidence and factually balanced clearly stating that it applies to unapproved use. Also, employees of our company are not permitted to give any sort of treatment recommendation on individual patient care or treatment.
Our principles for providing information about the unapproved use of our products have recently been updated in a standard document which became effective in 2020.