1. Date of preparation: May 2015 | UK/GLA/00030 An introduction to biosimilar medicines Adverse events should be reported. Reporting forms and further information can be found at: www.mhra.gov.uk/yellowcard. Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on 01256 315 000. Prescribing information can be found at the end of this presentation This presentation includes reference to Boehringer Ingelheim and Lilly Diabetes Alliance products

2. Date of preparation: May 2015 | UK/GLA/00030 An introduction to biosimilars Content What is a biological medicine? What is a biosimilar medicine? What do UK authorities say about biosimilars? Conclusions

3. Date of preparation: May 2015 | UK/GLA/00030 What is a biological medicine?

4. Date of preparation: May 2015 | UK/GLA/00030 Biological medicines versus other medicines Large molecules derived from microorganisms, human or animal cells Made up of proteins, sugars or nucleic acids Large molecules derived from microorganisms, human or animal cells Made up of proteins, sugars or nucleic acids Simpler, smaller structures Chemically synthesised Simpler, smaller structures Chemically synthesised Biological medicines Chemically synthesised medicines Aspirin MW = 180 Da 0 amino acids Monoclonal antibody MW = ~150,000 Da >1000 amino acids Insulin MW = 5,800 Da 51 amino acids

5. Date of preparation: May 2015 | UK/GLA/00030 Biological medicine in clinical practice In contrast to chemical synthesis, production of biologicals usually takes place in batches on different days, not as part of a continuous production line. This means biologicals are subject to: Robust production processes High standards of quality control 1 1. Gough S. Practical Diabetes 2013;30:146–147a. Biological medicines have been around for a long time. The first biological medicine produced by recombinant DNA technology introduced into routine clinical use was recombinant human insulin (Humulin ® Eli Lilly and Company 1982): Humulin S is manufactured using recombinant DNA technology to introduce the human insulin gene into E. coli, which then produces insulin for human use

6. Date of preparation: May 2015 | UK/GLA/00030 What is a biosimilar medicine?

7. Date of preparation: May 2015 | UK/GLA/00030 Defining biosimilar medicines A biosimilar is a medicine developed to be similar to an existing biological medicine Biosimilars have an identical label to the reference medicine As with all biological medicines, biosimilars are produced in or derived from living systems (e.g. using recombinant DNA technology) To gain a licence for use, biosimilars need to demonstrate that they are as safe and as effective as the original reference biological medicine and have the same quality Due to their biotechnological origin and process sensitivity, reference medicines and biosimilars have variations over time, which are monitored and reviewed by the EMA

8. Date of preparation: May 2015 | UK/GLA/00030 Requirements to assure biosimilarity 1 a Efficacy/safety trial needed unless biosimilarity convincingly demonstrated by nonclinical, pharmacology, and immunogenicity studies 1. European Medicines Agency (EMA). Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf (accessed April 2015). Head-to-head clinical trial(s) to detect relevant differences in efficacy or drug-related safety a No clinically meaningful differences in immunogenicity Similarity demonstrated in clinical trials designed to assess PK and PD against standard acceptance limits Similarity demonstrated in preclinical in vitro, in vivo, PD and toxicology studies PD=Pharmacodynamic; PK=Pharmacokinetic

9. Date of preparation: May 2015 | UK/GLA/00030 Biosimilars versus generics Similar versions of biological medicines derived from biotechnological manufacturing processes 1 Amino acid sequence should be identical to the reference product 2 Differences in biotechnological manufacturing processes between companies mean that biosimilar products cannot be described as identical 1,3 Similar versions of biological medicines derived from biotechnological manufacturing processes 1 Amino acid sequence should be identical to the reference product 2 Differences in biotechnological manufacturing processes between companies mean that biosimilar products cannot be described as identical 1,3 Copies of small molecule medical products derived from chemical manufacturing processes 1 Identical chemical structures to those already marketed products 1 Chemical manufacturing process resulting in identical products 1 Copies of small molecule medical products derived from chemical manufacturing processes 1 Identical chemical structures to those already marketed products 1 Chemical manufacturing process resulting in identical products 1 Biosimilar medicines Generic medicines 1. Sekhon BS, Saluja V.Biosimilars 2011;1:1–11. 2. European Medicines Agency (EMA). Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1) 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/WC500167838.pdf (accessed April 2015). 3. Owens DR et al. Diabetes Technol Ther 2012;14:989–96.

10. Date of preparation: May 2015 | UK/GLA/00030 Biosimilars versus generics - regulation Need to demonstrate equivalence to the reference biological product under the following headings 1 : Physicochemical Biological Pharmacological Safety Clinical efficacy Need to demonstrate equivalence to the reference biological product under the following headings 1 : Physicochemical Biological Pharmacological Safety Clinical efficacy Need to demonstrate: Pharmaceutical equivalence (identical amounts of same active ingredient) Bioequivalence 1 Need to demonstrate: Pharmaceutical equivalence (identical amounts of same active ingredient) Bioequivalence 1 Biosimilar medicines Generic medicines 1. DeVries JH et al. Diabetes, Obesity and Metabolism 2015;17:445–451.

11. Date of preparation: May 2015 | UK/GLA/00030 Biosimilar safety – immunogenicity For most biologics the presence of antibodies has no consequences. 1 However, in some cases, antibodies produced to the drug can alter the efficacy of the drug, neutralise the endogenous protein, or increase the development of adverse events. The following requirements are stipulated by the European Medicines Agency (EMA) to assess immunogenicity 2 : The potential for immunogenicity of a biosimilar should be investigated in a comparative manner to the reference product The applicant for a biosimilar should present a risk management plan (RMP) The RMP of the biosimilar should always take into account identified and potential risks associated with the use of the reference biological medicine In addition, it should be discussed in detail how these safety concerns will be addressed in post-marketing follow-up 1. Schellekens H. Nat Rev Drug Discov 2002;1:457–462. 2. European Medicines Agency (EMA). Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500184161.pdf Last accessed April 2015.

12. Date of preparation: May 2015 | UK/GLA/00030 Accofil ® Abasaglar ® Bemfola ® Inflectra ® Remsima ® Ovaleap ® Gastrofil ® Nivestim ® Zarzio ® Filgrastim Hexal ® Biograstim ® Ratiograstim ® Tevagrastim ® Abseamed ® Binocrit ® Epoetin Alfa Hexal ® Retacrit ® Silapo ® Omnitrope ® Biosimilars authorised by the EMA 2006 2007 2013 2010 2009 2008 2014 Human growth hormone (somatropin) Erythropoietin (epoetin alpha, zeta) Granulocyte colony-stimulating factor (filgrastim) Anti-TNF-α mAB (infliximab) FSH (follitropin alpha) Insulin analogue (insulin glargine) Current as at April 2015 FSH=Follicle-Stimulating Hormone; mAB=Monoclonal Antibody; TNF=Tumor Necrosis Factor 1. European Medicines Agency. European public assessment reports. http://goo.gl/x8LP6Z. Last accessed: April 2015.

13. Date of preparation: May 2015 | UK/GLA/00030 What do UK authorities say about biosimilars?

14. Date of preparation: May 2015 | UK/GLA/00030 What does NICE say? (1 of 2) NICE will consider similar biological medicinal products notified to it by the National Institute for Health Research Horizon Scanning Centre for referral to the Technology Appraisal topic selection process. These products will usually be considered in the context of a Multiple Technology Appraisal in parallel with their reference products in the indication under consideration. In other circumstances, where it is considered a review of the evidence for similar biological medicinal product is necessary, NICE will consider producing an ‘Evidence summary new medicine’. 1.National Institute for Health and Care Excellence. NICE’s biosimilar position statement. Available at: https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-technology-appraisals/biosimilars- statement.pdf (accessed April 2015).

15. Date of preparation: May 2015 | UK/GLA/00030 What does NICE say? (2 of 2) NICE technology appraisals will use the name of the active drug substance, including reference products and brand named similar biological medicinal products in its documentation where appropriate to inform clinical decision making and to reflect the remit received from Ministers. The Department of Health in England has confirmed that a technology appraisal remit referred to NICE enables NICE to decide to apply the same remit, and the resulting guidance, to relevant licensed biosimilar products which subsequently appear on the market. Evidence summaries will use the brand names of the medicines because substitutability and interchangeability cannot be assumed. Evidence summaries do not make recommendations hence the decision regarding the choice of biosimilar or originator biologic for an individual patient rests with the responsible clinician in consultation with the patient. 1.National Institute for Health and Care Excellence. NICE’s biosimilar position statement. Available at: https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-technology-appraisals/biosimilars- statement.pdf (accessed April 2015).

16. Date of preparation: May 2015 | UK/GLA/00030 What does Diabetes UK say? ‘Biosimilar insulins will soon be coming to the UK market and people with diabetes and health care professionals need to be better informed about them so that they can make appropriate clinical choices’ ‘With the wide range of different insulins likely to be available, the NHS needs to increase awareness of biosimilar insulins so that people with diabetes are appropriately informed as to what this means for them’ ‘The decision of which insulin is most appropriate should always be made jointly between the person with diabetes and their healthcare professional’ ‘People who are already established on an insulin and well controlled should continue with that treatment and not be made to change to a biosimilar’ ‘As with all insulins, biosimilar insulins should be prescribed by their trade name rather than the generic insulin name to ensure that the correct insulin is dispensed.’ 1.Diabetes UK Position statement on Biosimilar insulins October 2013. Available at: http://www.diabetes.org.uk/Documents/ Position%20statements/diabetes-uk-position-statement-biosimilar-insulins-1013.pdf (accessed April 2015).

17. Date of preparation: May 2015 | UK/GLA/00030 What does the government drug safety update on biosimilar products say? Prescribing biosimilars 1 All biosimilar products are prescription only medicines (POM). When prescribing biological products, it is good practice to use the brand name. This will ensure that automatic substitution of a biosimilar product does not occur when the medicine is dispensed by the pharmacist. Products (biosimilar and reference) that have the same international non-proprietary name (INN) are not to be presumed identical. 1. https://www.gov.uk/drug-safety-update/biosimilar-products Last accessed April 2015.

18. Date of preparation: May 2015 | UK/GLA/00030 Conclusions

19. Date of preparation: May 2015 | UK/GLA/00030 Biosimilar: Conclusions Biosimilars: o are molecules derived from microorganisms, human or animal cells and made up of proteins, sugars or nucleic acids o they should have an identical amino acid sequence to that of a previously marketed product, with no clinically meaningful difference in safety or efficacy 1 o are not generics; they are similar but not the same 2 o provide valuable options that create choice for prescribers and patients 3 1. European Medicines Agency (EMA). Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1) 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/WC500167838.pdf (accessed April 2015). 2. Declerck PJ. GaBI J 2012;1:13–6. 3. Wilkins AR et al. J Diabetes Sci Technol 2014;8:23–5.

20. Date of preparation: May 2015 | UK/GLA/00030 Biosimilar: Conclusions To comply with regulatory guidelines, in comparison to the reference biological medicine, a biosimilar medicine must demonstrate 1 : o similarity in preclinical in vitro, in vivo, PD and toxicology studies o similarity in clinical trials designed to assess PK and PD against standard acceptance limits o no clinically meaningful differences in immunogenicity o data from head-to-head clinical trial(s) to detect relevant differences in efficacy or drug-related safety a 1. European Medicines Agency (EMA). Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf (accessed April 2015). a Efficacy/safety trial needed unless biosimilarity convincingly demonstrated by nonclinical, pharmacology, and immunogenicity studies

21. Date of preparation: May 2015 | UK/GLA/00030