Multidimensional aspect of logistic efficiency within clinical development

1. Multidimensional aspect of logistic efficiency within clinical development ELMEDHealth and its Supply Chain: efficiency and safety for the patient Montpellier, June 16 & 17, 2016 Didier Basseras V.P. Global Head of Clinical Supply Chain Operations

2. Agenda Sanofi R&D - Clinical Supply Chain Operations

3. Translational medicine • Translational and Clinical Science — Time for a New Vision • E. Zerhouni – The new England Journal of Medicinehttp://www.nejm.org/doi/full/10.1056/NEJMsb053723 • Definition • Translational medicine is a medicine that brings the laboratory bench to the bed of the patient. Translational medicine is the link between basic research and clinical research, with the objective of making available more rapidly therapeutic innovations: it is, for example to identify a group of patients for whom conventional treatment works differently in order to understand biological reasons or, conversely, to try to treat a biological characteristic demonstrated in a group of patients (see cons below). This is a universal approach that can be applied to all therapeutic areas. Sanofi R&D - Clinical Supply Chain Operations

4. Patient centricity and Translational medicine challenges for clinical trials • Clinical development must evolve to cope with these new challenges • Trials are more and more developed for specific populations • More trials with less patients • Complexity of the design: Adaptive trial design • Clinical development is evolving between phase 2B and 3 • Attrition rate is less important between phases • Biological products are becoming the first choice to reach this target • Monoclonal Antibody • Peptides • Product is not alone, but integrated in a therapeutic solution • Several items are packaged simultaneously Clinical Dev Research Patient Commercial Product Integrated care Sanofi R&D - Clinical Supply Chain Operations

5. Patient centricity and Translational medicine challenges for clinical trials • Available quantity optimization is becoming a key parameter • We are no more working with unlimited quantities • Chemical vs. biologic • Master production plan has to be more accurate • To reinforce the predictivity of the recruitment curve • Optimization of the shipment flow to increase flexibility: from depots to distribution platforms • Right quantity at the right place and time • Evolution of the role of the distribution platform • Differentiate the product at the latest stage • Our compound versus best in class • How to deal with comparators? • Sourcing of comparators, Common issue: No data sharing between pharma • TransCelerate initiative • TransCelerate BioPharma Inc. is a non-profit organization focused on advancing innovation in research and development (R&D), identifying and solving common R&D challenges and further improving patient safety, with the goal of delivering more high quality medicines to patients. • Most pharma companies are member Sanofi R&D - Clinical Supply Chain Operations

6. Patient centricity and Translational medicine challenges for clinical trials Finally two types of trials: • For rare diseases, we have a small population spread over multiple of countries • It means multiplicity of countries involved in the studies with 1 or 2 patients per investigator site • We are in the “haute couture” • At the opposite, for vaccine development like Dengue, we are targeting specific countries with many patients • South America • South-East Asia Dengue Sanofi R&D - Clinical Supply Chain Operations

7. Bioproduct characteristics (1/2) • Long to produce, short to use • To optimize the cycle through LEAN program deleting non adding value steps • Stability and shelf life can change all along the development plan • No bracketing • In which condition are we storing our products? • Oxidation, light, humidity, cold • How to manage shelf life extension? • Change control management all along the development • Storage conditions could evolve •  Many parameters to take into accountbefore starting clinical development • Packaging has to be adapted to these constraints • Packaging to Design • Influence the packaging solution • Limit packaging volume, Logistics Sanofi R&D - Clinical Supply Chain Operations

8. Bioproductcharacteristics(2/2) • Cold chain all along the supply chain • From production to patient delivery • Packaging in cold room • What are the storage conditions at the hospital? • Most of the deviations are concentrated at the hospital • Hospital receives products from the differentpharmaceutical companies • Constraint up to the patient • Last mile: How to deal with that • Shipment direct to patient: an opportunity but need of risk assessment • From manufacturing facilities dedicated to R&D to a model where marketed products and products in development are competing • To align production plan and elevate the level of confidence in clinical needs. Sanofi R&D - Clinical Supply Chain Operations

9. Time Out of Refrigeration (TOR*) Management *Time out of refrigeration (TOR): Time during which the product is outside 2°-8°C. Sanofi R&D - ClinicalSupply Chain Operations

10. Constraints during packaging To train the team • What are the data to take into account? • TOR: Time Out of Refrigeration • Cycle time example: Future packaging campaigns can be exposed to a maximum of 8 hours of cumulative TOR with (3) “cycles” • Cold storage capacity at the hospital has to be part of the feasibility • Stability data • Packaging in cold room • Specific processesand qualification • How to manage TOR and cycle time • Increase of the complexityof operations • Everything has to be traced : « TOR sheet » • Training must be reinforced Time Out of Refrigeration Statement (used for 2°-8°C products / applicable for manufacturing, packaging and storage before shipment from warehouse to depot/site) Sanofi R&D - Clinical Supply Chain Operations

11. Integrated packaging design • Integrated solution requesting different elements in addition to the compound • Compound can be associated to a device • Ancillaries can be mandatory in order to deliver the product • The objective is to deliver an integrated solution • Thought for investigator and patient • Ready to use • Challenge is to provide the right informationfor the investigator and the patient in order to use correctly the solution • Training is a key element Dengue vaccine Design must be thought with patients and investigators Sanofi R&D - Clinical Supply Chain Operations

12. Constraints during the distribution / Use appropriate equipments & devices up to the patient LAST MILE IMP Kits transportation from site to patient’s home • A cool bag with gel packs delivered on investigational site for patients • To ensure the integrity of IMPs during transportation from site to patient’s home EXEMPLE OF THE INSULATED BAGS PROVIDED TO PATIENTS FOR SPECIFIC STUDIES QR Code: Instructions for use Sanofi R&D - Clinical Supply Chain Operations

13. Some innovations: Moni-TOR …Sanofi Wireless Temperature Recording Solution • Objective • To develop wireless low cost temperature recorders • To automate temperature recording • Technology • RFID (Radio Frequency Identification) chip • Temperature Sensor • RFID reader • Technical feasibility done in 2013 1st phase (2014, Montpellier): Autonomous smart label recorders applied during packaging and readable with RFID readers in warehouses 2nd Phase (2015): Autonomous smart labels recorders Uses Cases Implementation. Optimization of the Solution Sanofi R&D - Clinical Supply Chain Operations

14. MoniTOR : Individual IP traceability unit Y RF 868 MHz Bluetooth Mobile Devicewith Moni-TOR application Shipment … Treatments Kits … RFID Reader Temperaturefollow-up isdone kit per kit instead of doing at the palet leveluniquely Sanofi R&D - Clinical Supply Chain Operations

15. An Example Temperaturearound1°C confirmed by Daily LOG leading to No TemperatureDeviationReport T°C (Min Max) Sign DATE Temperaturerecorded by the MoniTORaround 1°C But expectation was 2°C < Tp < 8°C • Questionnaire Answers for this site : • DomesticFridge • Min Max Thermometer • Controlledlessthan once a month • No Cold Chain Support Organization 1°C Sanofi R&D - Clinical Supply Chain Operations

16. Solutions: what are the trends • Development of new technologies to provide a better information to the HCP and patient • QR-Code • Online information • Expiry date (connected to database) • Augmented reality • NFC • Temperature tracker • Link with IRT • Consortium: ISPE and Transcelerate • Working-group on the development of elabeling • Technology, process and regulation • More and better information for the patient http://www.confrerie-clinique.com Sanofi R&D - Clinical Supply Chain Operations

17. Sameregulations in all countries? A dream Assessing The Future Of The Cold Chain Industry,” conducted between Feb. 26 and July 13, 2014 by Sonoco ThermoSafe New Clinical Trials Regulation, Annex VI – April 2014 2) Immediate packaging labelling requirements Provisions of new Regulation: Labelling requirements for the “period of use” do not only apply to the outer (secondary) packaging but will in the future also apply to the immediate (primary) packaging http://www.europarl.europa.eu/sides/getDoc.do?pubRef=-//EP//TEXT+TA+P7-TA-2014-0273+0+DOC+XML+V0//EN#BKMD-44 Sanofi R&D - Clinical Supply Chain Operations

18. New regulations: Implementation within sanofi R&D (1/2) Concrete Impacts = For each shipment The use of qualified boxes and temperature recorders is mandatory for all IMP* shipments (ambient and cold products) from and to European countries. *IMP: Investigational Medicinal Product Sanofi R&D - Clinical Supply Chain Operations

19. New regulations: Implementationwithin sanofi R&D (2/2) • The EU GDP states: • “The required storage conditions for medicinal products should be maintained during transportation” ISSUE • Numerousstorage conditions depending on the products (15°-25°C / 20°-25°C ….) ExtractfromUSP* General Notices and Requirements (section 10): EXAMPLE *USP: U.S. Pharmacopeial Convention http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/USP33-NF28-ReissueGeneralNotices.pdf Sanofi R&D - Clinical Supply Chain Operations

20. Conclusion • Facts • Operations must evolve rapidly to meet with Translational medicine approach and biologics specifications. • In parallel, regulations are in constant evolution but not uniformly in all countries • Challenges • How to follow the pace of evolution? • And how to limit costs increase? • Trends • Anticipate new regulations in participating to working-groups (ISPE, Transcelerate, Efpia) • Supply chain solutions must become more agile • Better understand the product to adapt the solution • Use less product • Be innovative in delivering IP Sanofi R&D - Clinical Supply Chain Operations

21. Thank-You Sanofi R&D - Clinical Supply Chain Operations