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 subjects to test the safety and efficacy of these products. These studies generally run for multiple 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 testing.
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 as a whole, and only when the medicines being tested show great 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 extremely important to us, and the confidentiality of all data and information collected is ensured in compliance with statutory regulations.
Clinical studies in developing 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 the healthcare needs in various regions and countries and to support the development of their healthcare systems.
In performing clinical studies in developing countries where there is usually a lower level of healthcare and the healthcare infrastructure is less developed, we adhere to all relevant scientific and ethical standards at all times. When we perform studies in developing countries, we also:
- Only do so in an environment in which the principles of Good Clinical Practice can be upheld.
- Only investigate diseases and innovative medicines that are relevant to the local population.
- 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.
- 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. The DDG replaces the former Development Operations Committee (DOC). Decision makers from all relevant functional areas sit on this biopharma committee, thus ensuring 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 studies in pharmaceuticals that are under clinical development, while the Global Medical Affairs Decision Board (GMADB) is responsible for studies involving approved medicines. Both bodies consist of medical scientific experts and executives with long-standing experience in clinical research. The ICSC is also supported by our therapeutic area review boards, which conduct thorough scientific assessments of new drug/pharmaceutical 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 has to verify 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. This important step of exposing humans to an investigational drug is governed by the Human Exposure Group chaired by our Global Chief Medical Officer.
Potential risks for subjects are carefully and continuously analyzed 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.
Our commitment: International guidelines and agreements
We have renamed our Clinical Research Policy and extended its scope. The now so-called Human Subjects Research and Development Policy provides the framework for conducting clinical studies and ensures 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 from the Office for Human Research Protections, USA
- 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
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 internal quality assurance audits. These are planned by the Biopharma Research & 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 subjects must give their explicit informed consent before enrolling in a clinical study. Subjects 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. The subjects are further provided with detailed information.
Every study follows precisely defined procedures to ensure that studies are 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. This approach ensures in particular that studies are designed, conducted, recorded, and reported in line with all applicable requirements. In 2018, once again, no significant issues regarding these clinical study procedures were 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 subjects. In this way, we 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 Subject Information, is updated accordingly. You can find more information 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. As the well-being of the individual is our absolute priority, we involve vulnerable populations only when there is a scientific justification 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.
The Pediatric Praziquantel program led by our company within a consortium of partners has been implementing clinical trials in developing countries and involving vulnerable populations. The program aims at developing, registering and providing access to a pediatric formulation of praziquantel for treating schistosomiasis in children younger than six years of age. Due to a lack of clinical data and no suitable pediatric formulation of praziquantel, this age group currently goes untreated. Following the successful completion of the 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 with children aged younger than six years. The current results confirm the formulation and the dose that will be pursued by the consortium until registration. Phase III is due to start in 2019 with children in the target age group in Kenya and Ivory Coast.
The clinical program was designed in line with the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommendations for pediatric development. It was planned and is being implemented with the support of 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 applies especially to contract research organizations (CROs) performing studies on our behalf.
We have established processes defining the requirements for selection, approval, contracting and oversight-monitoring of CROs. In addition to comprehensive collaboration manuals with a contracted vendor, expectations on the highest quality level of the provided services including roles and responsibilities are specified in detailed quality agreements. Based on a risk assessment approach, vendors are audited regularly against applicable regulations, guidelines and the above-mentioned manuals and agreements. This also applies to study centers (for example hospitals) involved in our clinical studies. In 2018, once again, these audits did not reveal significant non-compliance with the above-mentioned standards.
Close dialogue with patients and advocacy groups
We want to ensure the voice and needs of patients are adequately taken into consideration when developing and executing clinical studies. To this end, we have established Patient Advisory Boards (PABs). Our Patient Advisory Boards Charter describes the process on how to involve the Patient Advocacy Groups in our clinical research. During Advisory Board meetings, caregivers and representatives from patient advocacy groups are invited to share their experience and particular perspective related to our clinical trials, plus multiple aspects including but not limited to protocol design, educational materials, and others. This advice and wealth of valuable insight applies to both the design of the clinical trial and its operational implementation. We use this information to render clinical development and clinical studies more patient-centric by sharing the outcomes of the PABs internally. Our Global Clinical Operations organization uses such information in multiple manners with a clear focus on patient centricity in everything we do.
Furthermore, we are involved in the European Patients’ Academy on Therapeutic Innovation (EUPATI), a public-private partnership within the Innovative Medicines Initiative (IMI). It initially ran from 2012 to 2017 but we have extended our participation until 2020. 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. This partnership has created a suite of resources that is available to better inform patients on the development process and the importance of their involvement while also offering them a way to incorporate their needs into the development of clinical studies. EUPATI also aims to improve the availability of objective and reliable information for the public.
Responsible data sharing
We support professional circles in advancing medical and scientific knowledge, thereby allowing for informed healthcare decisions for the benefit of patients. To this end, 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 following 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
Disclosure of clinical studies and publication of results
We are obliged to disclose information 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 United States 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 European Union 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 2018, we provided participants of ten studies with Lay Patient Summaries, which explain clinical study results in plain language.
We make sure that results from our clinical studies are published in medical journals in line with applicable laws and industry codes. In doing so, 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 have 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 strengthened to mount an immune response against cancer. As part of a strategic alliance with the U.S. pharmaceutical company Pfizer, we are developing avelumab (Bavencio®). This is an investigational anti-PD-L1 (programmed cell death ligand 1) 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 are investigating the potential therapeutic benefit of avelumab in multiple tumor types. As of the end of 2018, more than 9,000 patients have been evaluated within this program.
In 2018, avelumab has continued to gain marketing authorization in several countries including Argentina, Australia, Brazil, Chile, Israel, Lebanon, Mexico, Saudi Arabia, and Taiwan for treatment in patients with metastatic Merkel cell carcinoma (mMCC), a rare and aggressive form of skin cancer. Previously, we successfully started to market the medicine in the EU, Japan and the USA. Subsequently, avelumab has also been granted regulatory approval in Canada and Israel for the treatment of patients with locally advanced or metastatic urothelial carcinoma (a malignant tumor of the urothelium that lines the urinary tract) that had progressed following platinum-containing chemotherapy. Meanwhile, avelumab continues to be evaluated in several ongoing registrational Phase III studies across multiple different tumor types, including lung, gastric, ovarian, renal cell, and head and neck cancers. Positive top-line results were shown in 2018 in renal cell carcinoma.
Enabling early access to new medicines
Not all patients can take part in a clinical study and so must wait for a new pharmaceutical product to be approved. Through our Early Access Program, we are, under specific circumstances, enabling patients to gain early access to new, potentially life-saving medicines. The offer is aimed at people with serious conditions who have already used all the available therapies without success. It allows them to obtain medicines that have already been clinically tested but not yet obtained marketing approval. 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 have published a position paper on the Early Access Program on our website.
Support of 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 areas of therapeutic 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, drugs from various manufacturers were tested on children living in institutions in Germany, often in collaboration with (university) hospitals and general practitioners. In 2015, we made files in our historical archives at our global headquarters in Darmstadt (Germany) available to researchers, in order to help understand and come to terms with this episode in the history of science. When their work is completed, their findings can be used to make a final assessment of this complex issue. We guarantee full transparency and will do everything necessary to help the affected institutions come to terms with the past.