Our company develops medicines that help people with serious diseases. Before obtaining regulatory approval, we conduct clinical studies with patients and, if necessary, also with healthy volunteers to investigate the safety and efficacy of these products. These studies generally run for several years. Before they begin, extensive preclinical testing must be performed to demonstrate that the drug poses no unacceptable risks. This typically includes procedures such as animal studies.
Our approach to safe and transparent clinical studies
We conduct high-caliber clinical research that always complies with applicable laws and regulations. When performing clinical studies, we adhere to the highest ethical and scientific standards worldwide.
We only conduct clinical studies to investigate issues that are relevant to patients, healthcare professionals or society, and only when the medicines being tested show significant therapeutic promise and have a positive benefit-risk ratio. In addition, a sound, established scientific methodology must be available to investigate these scientific or medical questions. We only enroll the number of participants required to answer each of the questions.
Protecting the safety, wellbeing, dignity and rights of the patients and healthy volunteers participating in our clinical studies is of utmost importance to us. We do not intentionally expose study subjects to undue risk or irreversible harm. Personal data privacy is also very important to us, and we maintain a strong focus on data protection and confidentiality, in compliancewith statutory regulations.
Clinical studies in low-and middle-income countries
We conduct all our clinical studies in accordance with local laws and regulations and we adhere to all relevant international scientific and ethical standards, irrespective of the region or country. We are intentionally expanding our medicinal product development to more diverse markets in order to address pressing healthcare needs in low-and middle-income countries, and support the development of their healthcare systems.
When performing clinical studies in low-and middle-income countries, where there is usually a lower level of healthcare and limited healthcare infrastructure, furthermore the following applies:
- We only do so in an environment in which the principles of Good Clinical Practice can be upheld.
- We only investigate diseases and innovative medicines that are relevant to the local population.
- We only conduct clinical studies in countries where we expect that the drug being tested will be submitted for marketing authorization and made available to patients after we have proven its efficacy and safety.
- We assure that no subject enrolling in a clinical study is discriminated against on the basis of ethnic origin, gender or socio-economic status.
How we govern clinical studies
Pharmaceutical development and the related governance process are the responsibility of our Head of Global Research and Development, who co-chairs the Development Decision Group (DDG) with the Global Head of Innovative Medicine Franchises. Decision-makers from all relevant functional areas sit on this biopharmaceutical committee, helping to ensure a cross-functional approach to the governance of drug development.
Under the umbrella of the DDG, two further committees oversee our clinical studies. The Integrated Clinical Study Committee (ICSC) is responsible for the studies performed by the company in pharmaceuticals that are under clinical development, while the Global Medical Decision Board (GMDB) is responsible for our own studies with approved medicines, as well as for all studies performed by independent investigators and supported by us (so-called investigator-sponsored studies). Both bodies consist of medical-scientific experts and executives with longstanding experience in clinical research. The ICSC is also supported by our Therapeutic Area Review Boards, which conduct thorough scientific assessments of new study concepts. Our development and study teams present clinical study concepts to the appropriate committee. Each committee meets regularly to conduct a comprehensive review of the proposed concepts and ascertains that our studies are scientifically sound, have a legitimate scientific purpose and are performed according to the latest standards and best practices.
Before administering a new drug to human subjects, there must be sufficient evidence that it offers a potential therapeutic benefit, is sufficiently safe for use in humans and has a positive benefit-risk profile. We only take the critical step of a first-in-human clinical trial after diligently conducting extensive preclinical testing. The decision resides with a separate committee, the Human Exposure Group chaired by our Global Chief Medical Officer.
We continuously analyze potential risks for study participants before and during the course of our clinical studies. Our Medical Safety and Ethics Board (MSEB) oversees the safety of subjects participating in our clinical studies and, as necessary, reviews the benefit-risk profiles of investigational drugs. You can find further information on the MSEB under Patient safety.
Issues may be submitted to the relevant committees by product teams or other committees (as defined in relevant SOPs or committee charters). If individual employees wish to seek advice or report concerns on ethical questions, they can contact the chairperson or a permanent member of a committee directly.
Our commitment: International guidelines and agreements
Our Human Subjects Research and Development Policy provides the framework for conducting clinical studies and helps ensure that we adhere to all applicable legal, ethical and scientific standards. In addition to the relevant national laws and regulations, these standards also include:
- The Good Clinical Practice (GCP) guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
- The Declaration of Helsinki, published by the World Medical Association
- The Belmont Report by the U.S. Office for Human Research Protections
- Good Pharmacovigilance/Laboratory/Manufacturing/Distribution Practices (GVP/GLP/GMP/GDP)
- The International Ethical Guidelines for Health-related Research Involving Humans, published by the Council for International Organizations of Medical Sciences (CIOMS)
- The Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases and the Joint Position on the Publication of Clinical Trial Results in the Scientific Literature, published by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) the European Federation of Pharmaceutical Industries and Associations (EFPIA), the Japan Pharmaceutical Manufacturers Association (JPMA), and the Pharmaceutical Research and Manufacturers of America (PhRMA)
- The Principles for Responsible Clinical Trial Data Sharing, published by EFPIA and PhRMA, and the IFPMA Principles for Responsible Clinical Trial Data Sharing
Regular supervision of clinical studies
Our clinical study procedures are regularly inspected by health authorities to ensure compliance with the applicable laws and guidelines. We also conduct our own quality assurance audits. These are planned by the Research and Development Quality function, based on a quality risk assessment approach to identify areas for internal and external auditing. In both cases, we respond immediately to any issues found by defining and implementing corrective and preventive actions to improve our processes accordingly.
Conducting clinical studies responsibly
Prior to enrolling subjects, every clinical trial must first be assessed and approved by a qualified independent ethics committee. Furthermore, all regulatory authorizations required in the respective country must be obtained. In accordance with Good Clinical Practice guidelines (ICH-GCP), all study participants must give their explicit informed consent before enrolling in a clinical study. Participants are fully informed about all aspects of the clinical trial in a language that they understand. This includes the potential risks and benefits from participating in the study. All participants are given ample time and opportunity to inquire about details before deciding whether to participate. All questions are answered by the clinical investigator or another qualified healthcare professional familiar with the study. As far as possible, non-interventional (observational) studies are also assessed by an ethics committee.
Every study follows precisely defined procedures to ensure that it is conducted to the highest quality standards in line with good working practices for the development and manufacture of drugs (GxP), the ethical principles of the Declaration of Helsinki and other international guidelines and regulations. In 2019, once again, there were no significant issues which had any impact on patient rights, patient safety or data integrity of a study raised by third parties or regulatory agencies.
We continuously collect and communicate safety data for our investigational drugs and promptly provide clinical investigators with important new findings relevant to the safety of the study participants. In this way, we help to ensure the safe use of our pharmaceuticals. Potential adverse effects and risks are taken into consideration in an effort to evaluate the benefit-risk ratio of our products and manage any risk. Product information, including the Investigator’s Brochure and Information for study participants, is updated accordingly. More information is available under Patient safety.
Conducting clinical trials in vulnerable populations
The implementation of clinical studies in vulnerable populations, such as children or people with mental disabilities, requires special attention and care in order to comply with the highest ethical and scientific standards. The well-being of the individual is our highest priority. For this reason, we only conduct studies with participants from vulnerable population groups if scientifically justified and if there is no other way to achieve conclusive results. When performing such studies, especially when informing study participants and obtaining their consent, we comply strictly with all statutory regulations.
Under our leadership and in collaboration with a consortium of partners, the Pediatric Praziquantel Program has conducted clinical trials with vulnerable populations in low- and middle-income countries. The program aims to develop, register and provide access to a pediatric formulation of praziquantel for treating schistosomiasis in children younger than six years of age. Due to the lack of clinical data as well as a suitable pediatric formulation of praziquantel, this age group currently goes untreated. Following the successful completion of Phase I bioavailability studies with healthy adults in South Africa and the swill-and-spit taste study in children aged six to eleven in Tanzania, Phase II was concluded in November 2018 in Ivory Coast. The results confirmed the validity of lozenges (orodispersible formulation) as dosage form to be pursued to registration. The pivotal Phase III trial, which is being conducted in Kenya and in Ivory Coast, started in September 2019.
The clinical program was designed in line with the recommendations of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for pediatric development. It was planned and is being implemented in close cooperation with regulatory authorities and a panel of international experts, including clinicians from endemic countries. Further details can be found under “Health for all”.
Teaming up to get results
To provide a broad, in-depth basis for the development of new medicines, we frequently conduct clinical studies in collaboration with external partners in academia and industry, as well as with medical-scientific advisory boards, service providers and vendors. We expect all our partners to abide by the same set of high standards when conducting clinical research. This especially applies to contract research organizations (CROs) performing studies on our behalf.
In our collaboration with CROs, we follow established processes of selection, approval, contracting and monitoring defined in comprehensive manuals. We expect their services to comply with the highest quality level including roles and responsibilities as specified in detailed quality agreements. Vendors are audited regularly based upon a risk assessment approach. This is to ensure that they comply with all applicable regulations, guidelines and the requirements defined in the aforementioned manuals and agreements. The same applies to study centers (for example, hospitals) involved in our clinical studies. In 2019, these audits again reveal no indications of systematic or significant non-compliance with the standards mentioned above. One individual critical observation was raised with respect to computerized systems. The root cause was identified and addressed with relevant corrective and preventive actions.
We are a member of TransCelerate, a consortium of 20 pharmaceutical companies seeking to drive the efficient, effective and high-quality delivery of new medicines. In this context, we are currently leading an initiative related to decentralized (virtual) clinical trials.
Close dialogue with patients and advocacy groups
We want to ensure the voice and needs of patients and their caregivers are adequately taken into consideration when developing and conducting clinical studies. We, therefore, established the Patient Advisory Boards (PAB) as one of our crucial communication channels. Our PAB Charter describes how to involve patient advocacy groups in our clinical research process. During Advisory Board meetings, patients, caregivers and representatives from patient advocacy groups are invited to share their experience and perspectives related to clinical trials. We use this opportunity to discuss multiple aspects of the drug development process, including but not limited to, protocol design, educational materials, technology and innovative approaches to clinical trials. Our Global Clinical Operations (GCO) unit values and leverages such information in multiple ways, with a clear focus on prioritizing patient centricity in everything we do. In 2019, we made further strides towards delivering this ambition by executing the first PAB in Asia.
Furthermore, we are involved with multiple organizations that focus on this relevant aspect of patient centricity in clinical studies. In the United States, we are an active member of the Clinical Trials Transformation Initiative (CTTI), which focuses on quality and efficiency in clinical trials. In Europe, we are involved in the European Patients’ Academy on Therapeutic Innovation (EUPATI), a public-private partnership within the Innovative Medicines Initiative (IMI). We extended our participation, which initially ran from 2012 to 2017, until the end of 2019. EUPATI is a pan-European project led by the European Patients’ Forum (EPF). It features partners from patient advocacy groups, universities and not-for-profit organizations, along with a number of pharmaceutical companies.
Responsible data sharing
We support professional circles in advancing medical and scientific knowledge, thereby allowing for informed healthcare decisions for the benefit of patients. Upon request, we provide qualified researchers with study protocols, anonymized patient data, study data, and clinical study reports. We share data and information in a manner that is consistent with the joint Principles for Responsible Clinical Trial Data Sharing of the EFPIA and PhRMA:
- Safeguarding the privacy of patients
- Respecting the integrity of national regulatory systems
- Maintaining incentives for investment in biomedical research
In 2019, we did not receive any substantiated complaints from patients, participants or regulatory bodies concerning breaches of privacy in the context of our clinical studies.
Disclosure of clinical studies and publication of results
We are obliged to disclose findings from our clinical studies, which we do publicly in a complete, accurate, balanced, transparent and timely manner, as laid out in our Clinical Trial Disclosure Policy. Our clinical study designs and results are made public in the international ClinicalTrials.gov database run by the U.S. National Institutes of Health (NIH), which can also be accessed via the World Health Organization’s International Clinical Trials Registry Platform (ICTRP). Furthermore, in accordance with EU regulations, we publish results from our clinical studies in the EU Drug Regulating Authorities Clinical Trials (EudraCT) database, which is run by the European Medicines Agency (EMA). If required by local laws and regulations, we publish study results on other publicly accessible platforms. In 2019, we provided participants of 11 studies with Lay Patient Summaries of clinical study results, which explain the results in plain language. Since November 2019, we have been providing clinical study report synopses and Lay Patient Summaries on our clinical trials website.
We publish results from our clinical studies in medical journals in line with applicable laws and industry codes. In this way, we adhere in particular to the current version of the Good Publication Practice (GPP3) and follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). Our Medical Publications Policy ensures compliance with all relevant standards and we use defined standard procedures for scientific publications on our products.
Immuno-oncology: Major clinical research milestones
Immuno-oncology investigates the extent to which the body’s immune system can be activated or boosted to mount an immune response against cancer cells. As part of our strategic alliance with the U.S. pharmaceutical company Pfizer, we are developing Bavencio® (avelumab), an investigational anti-PD-L1 antibody that we initially discovered and developed as a potential treatment for different tumors. Under this collaboration, in 2015 we launched JAVELIN, our comprehensive international clinical study program in which we investigate the potential therapeutic benefit of avelumab in multiple tumor types. By the end of 2019, more than 12,200 patients had participated in this program.
By the end of 2019, avelumab had gained marketing authorization in 50 countries, including the EU member states, Japan and the United States, for the treatment of patients with metastatic Merkel cell carcinoma (mMCC), a rare and aggressive form of skin cancer. Furthermore, avelumab was granted regulatory approval in three countries for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) following platinum-containing chemotherapy. UC is a malignant tumor of the urothelium lining the urinary tract.
In addition, avelumab, in combination with axitinib, gained FDA approval and European Commission authorization in 2019 for treating patients with advanced renal cell carcinoma. Meanwhile, avelumab continues to be evaluated in several ongoing registrational Phase III studies across different tumor types, including lung and head and neck cancers, as well as the first-line therapy of urothelial carcinoma.
In 2019, we entered into a global alliance with the company GlaxoSmithKline to co-develop and co-commercialize Bintrafusp alfa, a bifunctional fusion protein for immunotherapy. Currently in clinical development, including pivotal studies, it could be used to treat multiple difficult-to-treat cancers.
Enabling early access to new medicines
Not all patients have the opportunity to take part in a clinical study and so must wait for a new pharmaceutical product to be approved. Through our Early Access Program, we can, under specific circumstances, enable patients to gain early access to new, potentially life-saving medicines. The offer is aimed at people with serious conditions who have already received all available therapies without success. It allows them to be treated with medicines that have already been clinically tested but have not yet been approved. Furthermore, we offer patients who participated in one of our clinical studies post-study access to the investigational product, provided that certain conditions are met. Here, too, we meet stringent statutory, ethical and scientific standards. By performing a thorough assessment of all available data, we ensure that the potential benefits outweigh the potential risks for patients. We published position papers on Early Access and Post-Study Access on our website.
Supporting independent human subject research
In addition to conducting our own clinical research programs and studies, we also support studies proposed by independent investigators, so-called investigator-sponsored studies (ISS). Our ISS Principles, published on our website in 2018, define an ISS as “an unsolicited request for funding and/or supply of an investigational or marketed product by a third-party investigator/institution that initiates and conducts an independent scientific investigation as the regulatory sponsor”. By granting financial or material support for independent human subject research, we seek to stimulate the advancement of clinical and medical knowledge and patient care in our therapeutic areas of interest, and to support the safe and effective use of our products. We give priority to research that is innovative and has the potential to address specific unmet medical or scientific needs. Our principles, framework and standards for granting support for ISS and for our collaboration with independent investigators are specified in our ISS Principle and our corresponding policy and standard operating procedure.
Coming to terms with the past
In the 1950s and 1960s, pharmaceutical companies in Germany supplied their drugs to various institutions for clinical trials conducted typically by university clinics or general practitioners, but in certain cases, also in children’s care homes. Since 2015, we have been giving researchers access to the files in our historical archives at our global headquarters in Darmstadt (Germany) and supporting them in the comprehensive historical research of this topic. We maintain full transparency. When their work is completed, their findings can be used for the final assessment of this complex topic.