Research and innovation 3 for progress Research and innovation for progress Our policies

Research is fundamental for Bracco: the company’s Code of Ethics competitiveness is strictly correlated with its capacity Quality Policy to improve the quality of life of patients and customers. The Group devotes significant resources and investments to quality research and continuous innovation for the benefit of the general public.

Our numbers in 2019

56% 34 quality inspections of the people working in the R&D successfully passed (100%) function of the Imaging Global Business Unit are women 14 clinical trials performed 30 involving more than 3,500 people new priority and international patent applications filed +14,000 accesses to training and educational events organised online in the area of diagnostic imaging

2019 Sustainability Report 46 Europe - italy Our vocation Konstanz - Germany Paris - France to research Medical & Regulatory

The Bracco Group’s research activities are performed at centres in Geneva and Lausanne (), Colleretto Giacosa (Italy), Oxford (UK), Monroe, New Jersey (US), Freemont, Silicon Valley (US) and Maple Grove and Eden Prairie, Minnesota (US). The various centres have consolidated local and international partnerships of excellence with universities, hospitals and research institutions. In 2020, the new research centre in Munich, Germany, will begin operating.

Canada Italy Japan Montréal Ivrea Tokyo Medical & R&S Centre Medical & 56% Regulatory (Bracco Imaging S.p.A.) Regulatory United States 100 people work in the R&D Minneapolis function of the Imaging R&S Centre (ACIST) Global Business Unit, of Princeton Switzerland China which 56% are women. R&S Centre Geneva Beijing Medical Regulatory R&S Centre Medical & Regulatory (Bracco Research USA) (Bracco Suisse SA) Silicon Valley Lausanne R&S Centre R&S Centre

2019 Sustainability Report 47 The broad product portfolio developed with R&D activities over the years today makes Bracco a significant player in a range of sectors. In diagnostic imaging, Bracco Imaging has achieved a significant role thanks to the diagnostic and treatment solutions developed through the R&D function of the Imaging Global Business Unit (IGBU). The R&D centres of the IGBU are in Colleretto Giacosa, Geneva, Monroe Ernst Felder Award and, as of 2020, Munich, Germany. The effectiveness and success of Bracco research In 2019, the Bracco Foundation launched an award for research devoted to the memory of scientist Ernst projects arise from the active participation and Felder, whom we owe for great discoveries in the field of diagnostic imaging. The project was developed engagement of the various company functions. The in collaboration with Bracco Imaging, the Polytechnic University of Milan and the Polytechnic University of research centres and the R&D department of the Milan Foundation. IGBU share daily updates; the CEO and the managers of the functions concerned (GM&RA, IP, Business The reward is intended for young Italian academics who are carrying out educational or post-doctoral Development, Technical Operation) are constantly research activities abroad in the sector of flow chemistry and in particular in the transformation of chemical informed on project results and progress. synthesis processes from discontinuous to continuous mode. The reward aims to favour the birth in Italy of a centre of excellence which will become a hub to attract young experts in a cutting-edge field such as that For Bracco, research is strategic not only for business of green chemistry. development, but also to contribute to scientific progress. Over the years, Bracco Imaging laboratory “Within the Bracco Foundation’s progettoDiventerò project, we decided to set aside a total of 1 million research has led to the publication of articles in euros for this project”, affirmed Diana Bracco, Chairperson of the Bracco Foundation and the Bracco Group, international scientific journals, 40% of which obtained “to us, this seemed to be the best way to celebrate Ernst Felder, a great chemist whom we recently lost, an Impact Factor exceeding 4 points. Bracco’s who as head of our research unit in the 1970s discovered Iopamidol, a non-ionic contrast media which contribution to research also encompasses publications revolutionised diagnostic imaging at global level. It was a great turning point for , for people’s and scientific posters presented at national and well-being, for prevention, monitoring and the treatment of a great number of illnesses”. The winner of international conferences. the award on green chemistry was Gianvito Vilè, originally from Brindisi, who graduated with honours in Chemical Engineering from the Polytechnic University of Milan and received his doctorate in Zurich. Bracco Innovation Hub

Bracco Innovation Hub was founded in 2019 as the expression of the joint expertise of the Bracco Group and the Italian Diagnostic Centre. It has three main areas of research: precision medicine, big data and advanced industrial technologies, with a particular focus on the circular economy. Its duty is to favour innovation processes across all business units with a holistic view of technology, optimise internal “key skills” and potential external opportunities, and enact an innovative approach open to interaction with external research institutions.

2019 Sustainability Report 48 Safe activities and products

The activities of the Bracco research centres REACH are governed by specific Standard Operating For years now, the Bracco Research Centres have Procedures (SOP) that provide instructions applied REACH, the European regulation that requires on the management of worker safety, businesses that manufacture and import chemicals training, the maintenance of instruments to evaluate the risks associated with their use. The and the validation of experimental results. activities carried out also require attention in taking the The application of the SOPs plays an even necessary measures to manage any risks identified, more critical role as the project development through the adoption of an integrated system for phase becomes more advanced. In particular, registering, evaluating, authorising and restricting for all pharmacotoxicology activities, trials chemical substances. From this perspective, the take place according to the Good Laboratory oversight and monitoring of HSE topics at the research Practices (GLP) developed by the OECD 5 and sites is continuous and scrupulous. applied at international level. In addition, the Geneva R&D centre includes a pilot plant that operates according to the Good Manufacturing Practice (GMP) standards and is authorised to manufacture pharmaceutical product lots for clinical trials.

5 OECD, Organisation for Economic Co-operation and Development

2019 Sustainability Report 49 Research attentive to the Environment

The production processes of new Magnetic resonance diagnostic entities refined at the R&D A new molecule for magnetic resonance with the same laboratories are developed beginning diagnostic performance levels and a safety profile that from the more exploratory phases using exceeds current market standards is in the clinical X-Rays eco-sustainable solvents and reagents, development phase. During activities to create this placing an increasingly specific focus on the new diagnostic entity, from the laboratory to the pilot A new project under way is focused environment. Indeed, “green” approaches scale and subsequently at industrial scale, the research on studying a new production process are applied across all new product group has defined an as“green” as possible production that makes it possible to reduce and/ production phases. process. Significant attention has been paid to reducing or eliminate solvents and reagents that the use of solvents that harm the environment and the are toxic and harmful to the environment policy of recycling regenerable raw materials. and allows for the virtuous recycling of raw materials and an increase in energy efficiency. In parallel, as regards Low environmental the processes currently in use at the production sites, studies are carried out impact product packaging for continuous process improvement To minimise the environmental footprint of its products, with a positive impact on the quantity of innovative low environmental impact or biodegradable wastewater, product waste materials and materials have been identified for primary and the recovery of several key raw materials secondary packaging. The objective is to reduce that are used in excess (such as iodine); unnecessary materials or replace them, when possible, furthermore, more environmentally with 100% recyclable material. friendly alternatives are evaluated, with the reduction or replacement of certain solvents.

2019 Sustainability Report 50 The patent portfolio

Intellectual property (IP) is one of the fundamental There are roughly 1,900 patents granted at assets for the development of research and innovation. global level present in the Bracco portfolio To adequately protect the company’s patents, within and 350 patent applications under review Global Innovation & Technical Operations (GITO), at the main Patent Offices. In the course Bracco Imaging has created the IP function consisting of 2019, 30 new patent applications and of professionals who work directly or with the support of local representatives at the main Patent Offices all international patent applications were filed. over the world. Continuous interaction between this structure and the R&D function makes it possible to monitor project evolution right from the initial phase, identify possible innovations in a range of areas and evaluate the most suitable instruments for protecting them, for example with patenting.

220

In 2019, Bracco was granted 20 patents in Europe and 20 in the USA. It now holds a total of 220 new patents worldwide.

2019 Sustainability Report 51 Quality

The quality system adopted meets the requirements Quality Policy of national and international standards and regulations Formalised and shared at Group level, it pursues the and guarantees safe and reliable products and services. highest quality standards at international level and In all of its business areas, the Group complies with the promotes a culture of quality within the Group. The most advanced and innovative regulations: Policy is the basis for the Quality Management System, which measures and constantly improves processes • Good Manufacturing Practices (GMP), Good and activities for ensuring ethics and integrity in all Distribution Practices (GDPs) and Good Quality Transformation activities. Pharmacovigilance Practices (GVPs) for all medicinal products; Journey Corporate Quality Management (CQM) • Good Clinical Practices (GCPs) and Good Laboratory Practices (GLPs) for all products The medium/long-term quality It is responsible for adapting the quality systems and • EU Medical Device Regulations; transformation plan, launched in 2013 adopting the tools required for their implementation by the Corporate Quality Team, includes and monitoring for the entire Group. It works directly • ISO 13485:2016; five phases: organisation; governance in 19 countries from the three offices in Milan (Italy), • 21 CFR part 800 (US Code of Federal Regulations); and processes redesigned - quality model Cadempino (Switzerland) and Shanghai (China), through improvement; spread of the culture • ISO 9001 Quality Management; its own governance which ensures independence and of quality; employees engagement effectiveness. • ICH Guidelines (European Medicines Agency). programme; and quality programme “looking to the future”. Continuous improvement initiatives Its objectives are to promote a culture • Continuous processes verification; of shared quality and to make people • Optimisation of Quality function infrastructure; accountable. It also makes quality data • Digitalisation of various quality processes; visible and accessible and favours the reporting of potential quality incidents from • Programmes involving employees engaging, such as below. The plan is currently part of the the reporting of potential quality incidents; Heracles 2.0 programme. • Improvement in the decision-making process supported by the deployment of the risk management methodologies and tools.

2019 Sustainability Report 52 Controls on product and service reliability At all production sites, medical device (MD) units and commercial affiliates dedicated Quality Management Reviews (QMR) are performed and reported monthly and annually to the Corporate Quality Management and to the Senior Management. Likewise, for Medical Devices and pharmaceutical Operations, Periodic Global Quality Councils are held, chaired by the CEO, and attended by various executive managers.

The Bracco manufacturing sites received 19 inspections. 5 were carried out by major Health Authorities like the US FDA, AIFA (Italian Drug Agency), the Chinese FDA, the PMDA and Swiss Medic, and had very positive results; for instance, the Torviscosa and Ceriano Laghetto production sites had their ISO 9001:2015 certification renewed.

The 15 inspections carried out by Health Authorities and Notified Bodies at branches and commercial affiliates all received positive outcomes; they also led to the achievement of a range of certifications, including ISO 13485 and MDSAP 6 audit issued for instance to the Bracco Injeneering plant and ISO 13485 issued to the Bracco Suisse Geneva plant by the BSI (British Standard Institution). 34

In 2019, the Group hosted 34 inspections by third-party entities (Health Authorities and Notified Bodies), all of which were passed successfully.

6 Medical Device Single Audit Program

2019 Sustainability Report 53 Digital innovation 6,500 In 2019, the Solutions in Bracco adopts digital solutions which enhance and Contrast Imaging platform improve the quality of the services and products offered counts 33 active online and process transparency. This makes it possible to publications for a total of over anticipate new trends and be competitive in the market. 6,500 visitors.

Online platforms. To improve marketing and BraccoMDCT.com is the company’s web-based • http://www.mrisafety.com/ 7 promotional activities while taking a paperless platform that supports the use of contrast media • www.mdct.net approach, Bracco is increasingly adopting online (Iopamidol and Iomeron) with the most recent CAT platforms in the various geographical areas, to technologies and offers a personalised approach to • https://ceus-liver-course.com replace paper materials. For example, the Solutions radiological exams based on patient characteristics. • http://cardiocontrast.com in Contrast Imaging digital platform collects • http://icus-society.org/ publications, clinical cases and videos relating to the The use of technology is also fundamental for the dissemination of educational content. Bracco supports three methods for using contrast imaging solutions: As part of the new European Medical Device Regulation the development and implementation of specific x-ray, MRI and CEUS. (MDR), Bracco is developing new web repositories that websites that convey educational content on various gather together the data of certain devices such as Sharepoint Bracco Imaging gathers the most recent topics such as that of radiology on Imaging Education 8, Vuebox, already activated in 2019 for CEUS, and certain promotional materials in their various forms (scientific which registered 7,050 participants and on Applied accessories for gastrointestinal imaging and products articles, brochures, monographs, videos and product Radiology 9, which involved 3,818 people. for devices. campaigns). The platform is accessible to all Group branches for the paperless sharing of materials with Through an unrestricted educational grant, Bracco external customers. Bracco uses digital platforms supports the development and implementation of (Auntminnie, Diagnostic Imaging Europe) before, other thematic websites, specifically: during and after international conferences for product, institutional and specific event communications.

7 www.BraccoMDCT.com

8 www.imagingeducation.com

9 https://www.appliedradiology.org/3a/

2019 Sustainability Report 54 In the course of 2019, in collaboration with ESOI (European Society of Oncologic Imaging), Bracco Digital solutions developed periodic training sessions on a range of Vuebox®. This is Bracco’s patented technology for topics relating to diagnostic imaging, which recorded a diagnostic quantification procedures. The total of 3,575 accesses. These include: software quantifies tissue perfusion with the Dynamic Contrast Enhanced Ultrasound (DCE-US) methodology. • Prostate cancer: A multidisciplinary approach to In the course of 2019, it was further updated to imaging (705 participants); improve its functioning and interface. • Immune therapy: Response assessment and toxicity Nexo®. Since 2014, Bracco has developed and (440 participants); marketed NEXO Contrast Management System, the • Small bowel tumours (418 participants); web application for the electronic and automated • Rectal cancer: A multidisciplinary approach to management of information relating to the Imaging (486 participants); administration of contrast media in patients undergoing CAT procedures. Nexo® minimises manual steps and Imaging and response assessment of multiple • the use of paper documentation in the management myeloma (291 participants); of protocols and in data reporting at the end of the • Artificial Intelligence in oncologic Imaging: Current test. The innovations introduced in 2019 will improve status and future direction (319 participants); its effectiveness because, at the time of the exam, they • Clinical relevance of PSMA PET/CT: An overview and will make it possible to transport directly to the injector update (618 participants); the history of the administrations of contrast media of a given patient. Nexo® will manage not only data relating • Assessing response to therapy of brain tumours (298 to CAT procedures with contrast media, but also MR participants). procedures with contrast media.

DI Injectors App for iPad. This provides access to the full range of products in the DI Injectors portfolio (contrast medium injectors), product demos, images, videos and brochures, and supports personalised interactions with the reference healthcare professionals. Available in English, the app is currently used in the UK, Austria, Switzerland and .

2019 Sustainability Report 55 Bioethics and transparency in clinical trials

In the field of clinical research, the Group carries out national and international programmes aiming to rigorously define the risk/benefit ratio deriving from the introduction into clinical practice of new medicinal products not yet approved, as well as to better define the effectiveness profile and safety of use of products already used in patient management. The end goal is again that of providing experimental evidence to meet the clinical needs of patients and medical professionals.

The design and performance of clinical trials must All of Bracco’s clinical trials are fully compliant with the guarantee that research participants’ rights, integrity regulations established by the regulatory authorities, and confidentiality are protected. The monitoring such as EU Directive 2001/20/EC, 2005/28/EC, 2010/ of activities at the trial centres, the management C82/01, EU Regulation No. 536/2014 of the European and analysis of data as well as the final reports on Medicines Agency (EMA), Title 21 of the Code of those clinical trials must ensure that the results of Federal Regulations (CFR) of the Food and Drug such studies are reliable and accurate. To this end, Administration (FDA) in the United States and the the Group has set up a control mechanism (Defined National Medical Products Administration (NMPA) as a Clinical Quality Management System) intended in China. For years now, Bracco has worked in close to ensure that clinical trials are fully compliant with contact with national and local regulatory authorities the various regulatory requirements and meet the to ensure compliance with the highest international international ethics and scientific quality standards standards, such as the Declaration of Helsinki, necessary to design, perform, register and report on the International Conference on Harmonization research activities involving human subjects. of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and Good Clinical Practices (GCPs) standards.

2019 Sustainability Report 56 Clinical research activities must respect data Employee engagement Data transparency and protection transparency and publicity criteria. Thus, the studies The people involved in the development of new drugs Bracco shares the results of clinical trials and data with are recorded in databases and databanks open to the and medical devices commit to ensuring that the a view to helping medical professionals and healthcare public and their results are disclosed irrespective of the approval process is effective, efficient and rapid, and service providers take diagnostic and treatment outcome of the trial. that innovation is made available in compliance with decisions that are as accurate as possible to ensure the laws, regulations, guidelines and codes of ethics relating progress of scientific knowledge for the benefit of the Providing transparent results helps to guarantee that to pharmaceutical research. To remain updated on the general public. It also guarantees the protection and decisions relating to the safety and effectiveness of operating procedures and standards to be respected, confidentiality of the personal data of patients involved drugs and medical devices are supported by the best those working on clinical research activities have access in the study in compliance with the provisions of the available scientific evidence. Indeed, public health to training through a global Learning Management most recent international standards on the matter, such decisions and strategies based on scientific evidence System platform. Thanks to an innovative Key Quality as the General Data Protection Regulation (GDPR) and guarantee the optimal allocation of public resources Indicator (KQI), training courses are continuously the Health Insurance Portability and Accountability Act to foster health and the best results for patients. updated to guarantee compliance with the procedures (HIPAA). Bracco also undertakes to protect copyright, Therefore, Bracco has decided to meet requirements and processes adopted by the Group. following the recommendations of the International for the publication of protocols and clinical trial results Committee of Medical Journal Editors (ICMJE) on the on public websites such as clinicaltrials.gov and protection of copyright and the results of clinical trials. EudraCT.

3,500

In 2019, 14 clinical trials were planned or conducted which involved roughly 3,500 people. For 2020, an increase of 71% (24 trials) is planned.

2019 Sustainability Report 57 Technology for cost reduction and data reliability Over recent years, the agencies involved in the regulation of clinical trials, such as the US FDA and the European Medicines Agency (EMA), have promoted technological modernisation initiatives. For example, in the United States, the FDA adopted the CFR 21 Part 11 regulation with a view to supporting the use of electronic registers, media and digital signatures in clinical trials.

Also in Europe, the EMA has issued policies to support the use of digital signatures in clinical trials. These initiatives lead to cost reduction and accelerate trial approval processes. Bracco has adopted these regulations and implemented an EDC (Electronic Data Capture) system within clinical trials to improve data reliability and transparency. It has also digitalised its trial master files (TMF), used to organise and archive documents, images and other digital content for pharmaceutical clinical trials which may be requested by government regulatory entities.

2019 Sustainability Report 58