Biosimilars – An NHS perspective Maggie Dolan Regional Pharmacy Procurement Specialist South East Coast

Introduction Currently 2012 – Pharmacy Advisor South East Coast medicine procurement /contracting / medicine optimisation work on behalf of provider trusts and commissioners Surrey and Borders Partnership NHS Foundation Trust Career history Chief Pharmacist - Edinburgh Sick Children's Hospital 1993-1999 Chief Pharmacist – West Lothian Integrated Trust 1999- 2005 Pharmacy Advisor National Services Scotland 2005- 2012 National procurement of Medicines Health Emergency Planning Patient Access Scheme © NHS Commercial Solutions 2014

Aim The changing medicines landscape driving patient access to medicines the Biosimilar Medicine Challenges questions to consider © NHS Commercial Solutions 2014

Medicines are changing

Value of generic medicines to the NHS Health Economy £12.2bn saved in 2012-13. That is the extra cost if all community pharmacy scripts had been fulfilled as a brand. Generic usage is 75.20% of all scripts in primary care Secondary care spend on generics £250m /annum Contracting delivered a £30million cost saving to Trusts across England Branded to Generic – point of savings © NHS Commercial Solutions 2014

Generics - Supporting patients access to life changing medicines Generics at transition – 70-90% price reduction Biosimilars - 20-40% ? More competitive pricing / wider availability Cash releasing contracting invest in new medicines / treat more patients

Biologics – Share of sales Biologics – Share of growth Biologics growth continues to outstrip growth rate of total pharma, showing a steep hike from 2013 Such a trend is putting additional financial pressure on healthcare budgets Biologics – Share of sales Global market trends Sales and Growth Biologics – Share of growth Source: IMS Health, MIDAS, MAT Q2 2014, Rx; Brazil and Mexico Non Retail Sales are included; Share of growth in LC$

Europe illustrates importance of biologic therapies Europe Top 10 products 2009-14 2009 2010 2011 2012 2013 2014 1 LIPITOR HUMIRA 2 SERETIDE ENBREL 3 PLAVIX 4 HERCEPTIN 5 MABTHERA REMICADE 6 LOVENOX AVASTIN 7 8 ZYPREXA 9 PANTOZOL LUCENTIS LYRICA 10 SYMBICORT SPIRIVA Small molecule products Biologic products Source: IMS Health, MIDAS, MAT June 2014. Rx bound. Europe doesn’t include Russia and Turkey.

It’s the loss of exclusivity that drives biosimilar interest All these products will lose patent protection in EU by 2020 ( Global Sales (MAT 06/2014), US$ billion EU expiry date US expiry date 2018 2016 2014 2015 2028 (extended) Expired 2019 2017 10.8 Adalimumab (Humira) 9.2 Insulin Glargine (Lantus) 8.3 Etanercept (Enbrel) 7.9 Infliximab (Remicade) 6.4 Rituximab (Mabthera) 6.3 Insulin Aspart (Novomix, Novorapid) 5.9 Bevacizumab (Avastin) 5.5 Interferon Beta-1A (Avonex, Rebif) 5.3 Total ~ US$ 79 billion Trastuzumab (Herceptin) 4.6 Glatiramer Acetate (Copaxone) 4.5 Pegfilgrastim (Neulasta) 4.5 Ranibizumab (Lucentis) Not considered existing biosimilars such as Epoetin Alfa expired in EU, but still patent protected in the US 5 10 15 Source: IMS MIDAS, 06/2014, Rx bound, IMS Patent focus

Expected UK launch dates Infliximab Insulin Glargine Dalteparin Pegfilgrastim 2015 2016 2017 2018 Enoxaparin Etanercept Trastuzumab Rituximab Adalimumab

UK Anti-TNF Spend © NHS Commercial Solutions 2014 IMS HPA June 2014

Anti –TNF spend © NHS Commercial Solutions 2014 IMS HPA June 2014

Uptake of biosimilars across Europe Taken from a BGMA report

Why slow acceptance / uptake Biosimilar but not identical - confusing Clinical trial data vs characterisation of structure and function to judge safety and efficacy Understanding of the scientific concepts of the development and licensing of biosimilars Resolution- a well informed NHS , peer debate and pharmacovigilance

PMSG Biosimilars Group whilst Tasks Assess Pipeline – engage with suppliers Understand barriers to uptake Provide resources for NHS/ patient educational opportunities Support clinical engagement and contracting Collect data on uptake / implementation Pharmaceutical Industry Sector Board - Biosimilars PMSG Biosimilars Group Purpose To devise a strategy to ensure the NHS makes best use of Biosimilar medicines which has patient safety as a priority supporting a robust Biosimilar market Membership – 4 Nations NICE , CMU, Trusts , Commissioners – CCGs , NHSE Specialist Pharmacy Services - Regional Procurement, QA, MI © NHS CoSolutions mmercial 2014

Implementation Challenges NHS Scotland Biosimilar Procurement Strategy Implementation Challenges Supply Chain Forecasting Storage and Distribution Naming of Biosimilars e.g. Remicade®/ Remsima® / Inflectra® Homecare /Outsourced Outpatients Supply Chain; Funding Model; Governance Compounding Dose Banding; Goods vs. Service Contracts Substitution Strategy for Experienced vs. Naive Patients Clinical Acceptance Therapeutic Similarity Across Licensed Indications Market Defence Strategies Benefit Sharing CCGs/NHSE

Assessment of Biosimilars in the UK (evidence based choice) Scottish Medicines Consortium (SMC) NICE All Wales Medicines Strategy Group (AWMSG) NICE provides guidance to the NHS in England on the clinical and cost effectiveness of selected new and established technologies. The Institute undertakes appraisals of health technologies at the request of the Department of Health. Guidance produced by the Institute on health technologies is also applied selectively in Northern Ireland, Scotland and Wales. England, Wales technology appraisals (both single and multiple technology appraisals) Medicines are funded by NHS Wales following advice from two source, AWMSG and NICE. AWMSG will take into account the NICE future work programme when considering whether a medicine will be appraised. AWMSG will not normally consider appraising a product if NICE intends to publish their final appraisal of the same product within 12 months of the date of marketing authorisation. AWMSG advice, is interim to NICE advice should this be subsequently published. In the absence of AWMSG or NICE advice individual prescribers should exercise their clinical judgement unless there is evidence not to do so in the light of particular circumstances of an individual patient Northern Ireland technology appraisals, both multiple and single, are usually disseminated after local review Scotland multiple technology appraisals (with advice on implementing in the context of the health service in Scotland from NHS Quality Improvement Scotland) SMC reviews manufacturer submissions for every new medicine. Similar to NICE’s STA process. But NICE TA programme prioritised based on need. SMC only applies in Scotland; NICE STAs don’t apply in Scotland; MTAs are reviewed by NHS Quality Improvement Scotland and if appropriate are deemed to apply in which case NICE MTA recommendations replace SMC advice

Biosimilars- protein based medicines EMA- a biosimilar is a medicine which is similar to a biological medicine which has already been authorised ,used in general at the same dose to treat the same disease FDA a biosimilar is a biological product which is highly similar to a US licenced product not withstanding differences in clinically inactive components, for which there are no clinically meaningful differences from the originator © NHS Commercial Solutions 2014

Why ‘biosimilar’ not ‘bioidentical’? Microheterogeneity An effect of the inherent variability of the biological system used for manufacture1 Resulting product is a mixture of different forms of the same protein2 Post-translational modifications3 Glycosylation, methylation, oxidation, deamination May occur after a change in cell line or manufacturing process Resulting product is highly similar, but not identical to the originator Make complex molecules, such as mAbs and –cept fusion proteins, particularly difficult to replicate But...originator products are also subject to variability4 1. Weise M, et al. Nat Biotechnol 2011;29:690-3. 2. European Commission. What you need to know about biosimilar medicinal products. A consensus information document. [Accessed September 2014]. http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf 3. Dörner T, et al. Ann Rheum Dis 2013;72:322-8. 4. Schneider CK. Ann Rheum Dis 2013;72:315-8.

Biologics Manufacturing Process Numerous ways to manufacture the same biologic Different process = Different product Remicade made the first journey. The biosimilar sought to repeat the journey - same start and end point, journey very likely to be the same, might stop at different services on the way and the music in the car might not be the same but would still get to the same end point ie within the goal posts

Process changes are the norm The process used to assess the impact of these changes is called a comparability exercise

Originator product variability All currently licenced mAbs and -cept fusion proteins used in rheumatology have had changes in manufacture after their initial approval Figure adapted from reference Schneider CK. Ann Rheum Dis 2013;72:315-8.

Regulatory requirements Generic drugs Quality assessment Pharmacokinetic assessment To provide information on the quality of the medicine To demonstrate that the generic formulation the same levels of active substance in the body EMA. Generic medicines. [Accessed August 2014]. http://www.ema.europa.eu/

Regulatory requirements Biosimilars Quality comparison Non-clinical comparison Clinical comparison To compare molecular structure and functionality of biosimilar and originator. Involves comprehensive analytical characterisation, receptor binding studies and bioassays – ADCC binding Pk toxicity To provide confidence that any differences seen in the quality comparison do not impact safety and efficacy of the biosimilar European Commission. What you need to know about biosimilar medicinal products. A consensus information document. [Accessed September 2014]. http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf

Regulatory requirements Characteristic EMA requirement Primary amino acid sequence Must be identical to the reference product Potency Must match the reference product Route of administration Must match the reference product, but the device used can be different Higher order structures, post-translational modifications and other potential variants Must be as similar as possible to the reference product, with adequate analysis to ensure no effect on efficacy, safety or immunogenicity Adapted from Dörner T, et al. Ann Rheum Dis 2013;72:322-8.

Regulatory requirements Clinical study parameter EMA requirement Pharmacokinetics Single-dose, comparative human studies Pharmacodynamics Combine with PK studies where a clinically relevant PD endpoint is available. Otherwise, non-clinical evaluation required Efficacy Highly-sensitive, dose-comparative PD studies may be sufficient. Otherwise, at least one adequately powered equivalence trial Safety At least one adequately powered equivalence trial Immunogenicity Must be assessed during the safety trial Adapted from Dörner T, et al. Ann Rheum Dis 2013;72:322-8.

Comparability & Analytics of biologics The goal of the comparability exercise (existing biologics) is to ascertain that pre- and post-change drug product is comparable in terms of quality, safety, and efficacy. The product should be evaluated at the process step (s) most appropriate to detect a change in the quality attributes. Not designed to show they are identical, merely highly similar The battery of tests should be carefully selected / optimised to maximise the potential for detecting relevant differences in the quality attributes The nonclinical and clinical studies include PK, PD, clinical efficacy, specific safety, immunogenicity and pharmacovigilance. If assurance of comparability shown via analytical studies alone then nonclinical /clinical studies not warranted. However, where differences observed, may need a combination of quality, nonclinical, and/or clinical studies. These scientific principles are exactly the same for a biosimilar molecule Analytical high similarity is the most robust scientific basis for comparing independently sourced biologics and analytics provide far more sensitive information than clinical studies.

Reference product variability - the Goal Posts Once “goal posts” are established an iterative process is used to fully evaluated by physicochemical and biological characterisation vs originator. Essentially the goal posts have been set by the originator If attributes fall outside established “goal posts,” various process steps are modified to produce product attributes that are within originator variability. Depending on the extent of the biosimilar/originator overlap, preclinical and clinical development can be abbreviated compared to developing a novel biologic. The goal posts are therefore set by the originator.

Outcome of the biosimilars licensing process… European Medicines Agency (EMA):1 “Like the reference medicine, the biosimilar has a degree of natural variability. When approved, its variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness. An authorised biosimilar is generally used at the same dose to treat the same conditions.” An authorised biosimilar can be therefore be considered to be clinically equivalent to the originator product despite trivial differences in molecular structure. These minor molecular differences are comparable with the level of variation found within originator product2 following a manufacturing change. 1. EMA. Questions and answers on biosimilar medicines (similar biological medicinal products) EMA/837805/2011. 2. Schiestl M, et al. Nat Biotechnol 2011;29:310-2.

Extrapolation of indications – the totality of the evidence Extrapolation is possible based on the overall evidence of comparability provided from the comparability exercise and with adequate scientific justification - decided by EMA. This includes at least one clinical study (if same MOA) in the most sensitive population measuring the most sensitive clinical endpoint(s) ie RA Principles apply to biosimilars AND biologics pre and post-change For infliximab extrapolation was based on the comprehensive characterisation / comparison of the physicochemical, binding and functional characteristics of the biosimilar vs innovator Similar effects seen in a wide range of in-vitro / ex-vivo functional assays, including experimental models tailored to IBD Preliminary clinical data also indicated similar response to CT-P13 compared with historical data on Remicade. It is arguably irresponsible to require clinical studies for which no meaningful scientific conclusions can be drawn because the hypothesis of “sameness” cannot be refuted. Extrapolation already been applied to biosimilars of somatropin, epoetin, filgrastim

Indication extrapolation: conclusion As long as the necessary considerations are taken into account, extrapolation of data to other indications of the reference product, and thus formal lack of a clinical trial in the respective clinical indication, does not imply less reassurance as regards efficacy and safety of the biosimilar Weise M, et al. Blood 2012;120:5111-7.

Immunogenicity must be assessed The Clinical trials were designed to evaluate residual uncertainty in relation to safety and/or immunogenicity Analytical or animal data cannot predict immune responses in humans  human immunogenicity data required Immunogenicity influenced by patient/ disease/ product Patient and disease factors are known so focus was on potential product-related factors Clinical end points / trials - far less sensitive than analytics at picking up even moderate differences between products Trials >6/12 needed but long-term data and pharmacovigilance essential ADAs lead to reduction in serum levels, adverse events and formation of neutralising antibodies and loss of clinical efficacy over time

Post-marketing surveillance At the time of marketing authorisation application a comprehensive plan must also be submitted detailing further safety studies in a post-authorisation setting, including the following aspects: Safety in indications licensed for the reference product that are claimed based on extrapolation of efficacy and safety data, including long-term safety data unless otherwise justified Occurrence of rare and particularly serious adverse events described and predicted, based on the pharmacology, for the reference Pharmacovigilance –for each biosimilar to safety in all indications collate any ADR data and further evidence of immunogenecity EMA. Guideline on similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010

The IBS Position statement A point in time in the evolution of biosimilars An infliximab statement rather than biosimilars per se Currently anti- tnfs have widely differentiating characteristics and efficacy eg Etanercept / certolizumab not licenced for IBD in EU EMA have licensed CT-P13 (Remsima / Inflectra ) and for all indications of the originator (Remicade) Asumption these biosimilars will be as effective as the originator across rheumatology ,gastroenterology and dermatology indications– Only pharmacovigilance will tell © NHS Commercial Solutions 2014

Conclusions Clinician engagement vital But a paradigm shift in thinking is required Clinical Trials vs Analytics Remicade is a biosimilar of itself and Inflectra / Remsima are a biosimilars of Remicade A phased entry will be required but with defined milestones This is the first of many so we need to get it right

The contracting challenge Biosimilar- pricing----- comparable discount on originator Remicade pricing – volume price matrix –IMPACT? Clinical intention ? Regional impact ? © NHS Commercial Solutions 2014

Questions Are current biologic molecules biosimilars of themselves ? Will biosimilars be seen as a new treatment options in class rather that “generics” ? Will they be substituted in existing patients ? Will they be accepted as therapeutically interchangeable in terms of clinical data ? Can the NHS / branded pharma afford the NHS not to use biosimilars ? ONLY TIME WILL TELL – Thank you for listening © NHS Commercial Solutions 2014