Barriers towards uptake of Biosimilars and how to solve them. Separate facts from fiction.

Transcription

1 Barriers towards uptake of Biosimilars and how to solve them. Separate facts from fiction. Prof. Arnold G. Vulto PharmD PhD FCP Hospital Pharmacist / Pharmacologist Professor of Hospital Pharmacy & Practical Therapeutics

2 Conflict of Interest Statement I declare no personal financial interest in any pharmaceutical bussiness I entertain friendly relationships with all innovative and generic / biosimilar companies (like AbbVie, Amgen, Biogen, EGA, Pfizer/Hospira, Mundipharma, Roche, Sandoz) As a co-founder I have a societal but not financial - interest in the advocacy of cost-effective treatments via the Generics & Biosimilar Initiative (GaBI) My employer Erasmus University Hospital - receives any honoraria (advisory boards, speakers honoraria) if they let me speak at scientific or commercial meetings. 2

3 Who is Arnold Vulto? A practising hospital pharmacist, not a lawyer nor regulator Member of ErasmusMC Medical Ethical Review Board In the pharmacy we see and run all drug trials Qualified Person (QP) for biotechnology medicines Got involved in biosimilars as early as 2004 via Eur J Hosp Pharmacy How to guide hospital pharmacists in this difficult area 2008 Founder of GaBI, with Huub Schellekens and Lasia Tang To provide transparency to cost-effective medicines 2013 Co-founder of the Dutch Biosimilar Initiative Independent platform to promote efficient use of medicines My motto: For each patient the best medicine at the best price 3

4 Agenda 1. How the drug market is exploding 2. Generic medicines affect drug expenditure 3. Uptake of biosimilars in Europe is variable 4. Barriers to market access of biosimilars 5. Do s and don ts in biosimilar use 6. Summary and Take Home Message

5 FDA new drug admissions Mullard, Nat Rev Drug Discovery 15(2016)73

6 Blockbusters forecast > 36 billion dollars extra cost each year Medicines licensed by FDA Mullard, Nat Rev Drug Discovery 15(2016)73

7 Blockbusters forecast billion dollars extra cost each year Medicines licensed by FDA 2014 Mullard, Nat Rev Drug Discovery 14(2015)

8 2015 worldwide sales of biopharmaceuticals (billion US$) Anti-tumor necrosis factor (TNF): $ 35.7 (+4%) (Enbrel, Remicade, Humira, Cimzia, Simponi) Anti-cancer monoclonals: $ 29.2 (+15%) (e.g. MabThera, Herceptin, Avastin, Erbitux, Vectibix, Yervoy, XGeva) Insulin and insulin analogues: $ 21.2 (+12%) (e.g. Humalog, Humulin, Lantus, Levemir, NovoRapid, Actrapid, Novomix-50) Anti-inflammatory antibodies $ 15.5 (+21%) (e.g..tysabri, Xolair, Orencia, Soliris, RoActemra, Stelara) Ophthalmic antibodies $ 7.7 (+11%) (Eylea, Lucentis) Recombinant coagulation factors $ 7.7 (+6%) (e.g. Advate, NovoSeven RT, Kogenate FS) Erythropoetins (alfa- and beta-): $ 6.3 (-5%) (Aranesp, Procrit, Eprex, Epogen) LaMerie Publishing, March 2016

9 2015 Top-10 worldwide sales biologicals (billion US$) Product Sales 2015 (vs 2014) Company Patent expiration 1. Adalimumab 14.3 (+12 %) AbbVie / Eisai Etanercept 9.0 (+2 %) Amgen / Pfizer Infliximab 8.9 (-9 %) J&J / MSD Insulin glargine 7.2 (+6 %) Sanofi Rituximab 7.1 (+4 %) Roche Bevacizumab 6.8 (+6 %) Roche Trastuzumab 6.6 (+6 %) Roche Pegfilgrastim 4.8 (+5 %) Amgen Aflibercept 4.1 (+47 %) Regeneron / Bayer Ranibizumab 3.6 (-13 %) Roche / Novartis? 2022? 2020 EU 9 US LaMerie Publishing, March 2016

10 The exploding drug budget Global sales 2015 Recombinant Therapeutic Proteins & Antibodies 154 billion US$ (+ 9.2 % versus 2014) Budget increase due to blockbusters by : + 65 billion US$ Biosimilars might offer some solace in this budget pressure: potential for ~US$ 55 to ~US$ 110 billion in savings (in US and UK/F/S/D/I) IMS: Delivering on the Potential of Biosimilar Medicines: 10 March 2016

11 Agenda 1. How the drug market is exploding 2. Generic medicines affect drug expenditure 3. Uptake of biosimilars in Europe is variable 4. Barriers to market access of biosimilars 5. Do s and don ts in biosimilar use 6. Summary and Take Home Message

12 Marketeffects of the introduction of generic medicines 3 categories 1. No of users increase, total cost decrease 2. No of users stabilises, total cost decrease 3. No of users decrease, total cost decrease faster Ref: Dylst, Vulto & Simoens (2015) Exp Rev Pharmacoecon Outcomes Res Based on GIP Prescription Database, The Netherlands 12

13 Category 1: Number of users increase, total cost decrease (mind X-axis: Millions of Euros) 13

14 Category 2: Number of users stabilises, total cost decreases (dramatically) 14

15 Category 3: Number of users is decreasing (shift in therapy), but cost is decreasing stronger 15

16 Example of generic saving: temozolomide 2010: generic introduced on the market Red line: No of users (right) Blue dotted line: costs (left) (Dylst, Vulto & Simoens, 2015)

17 What are biosimilars? How I see biosimilars as of April 2016 A biosimilar is a pharmaceutical product, that as such has been licensed by e.g. EMA or FDA via the WHO regulatory pathway (=minimum global standard) EMA definition of a biosimilar It is a version of an already licensed rec-dna drug product, for which similarity has been proven in an extensive comparability exercise, encompassing physical, chemical, biological and pharmacological properties, including efficacy and safety This excludes all kinds of bio-questionables in existence in other regions of the world that have not been endorsed via the WHO pathway as a biosimilar. Reference to such products as if biosimilars may be inferior is thus WRONG.

18 Agenda 1. How the drug market is exploding 2. Generic medicines affect drug expenditure 3. Uptake of biosimilars in Europe is variable 4. Barriers to market access of biosimilars 5. Do s and don ts in biosimilar use 6. Summary and Take Home Message

19 2014: First generation Biosimilar uptake in the EU (as % of accessible market) Source: IMS Health / EU Commission Nov 2015

20 An EU unified licensing system with 100% variation in uptake (GCSF uptake, 2013) 20

21 Granulocyte Colony Stimulating Factor (GCSF - filgrastim) in Australia (source: IMS 2014) Over 5 years: 30% market expansion 13% cost reduction Amgen originator GCSF (Neupogen) Hospira biosimilar (Nivestim) Aspen (Teva) (Tevagrastim) Sandoz (Zarzio)

22 Summary of where are we now The total drug bill will grow exponentially with the many new blockbuster breakthrough drugs The savings-potential of biosimilars is highly underused Why is this so? What can we do about it? 22

23 The hot patato When will a physician prescribe a biosimilar and when will a pharmacist dispense a biosimilar product? If the physician has sufficient trust in the sameness of the biosimilar If the pharmacist is allowed to dispense a biosimilar And if both have sufficient incentive to do so 23

24 We have unified licensing, but not unified access Legislation is only part of the story There exists a formal legal framework Versus a less formal local interpretation with many variations Acceptance of a biosimilar is dependent on how different stakeholders act. Physicians, patients, pharmacists, 3rd party payers, policy makers Essential to buy in ownership from stakeholders like prescribers (e.g. via guidelines) and patients(-organisations) Pharmacists can have here a unique added value The biosimilar does not exist 24

25 Three generations of therapeutic proteins (biologicals) Generation 1: substitution products Hormones like growth factors or insulin Effect visible / measurable in hours or days Generation 2: proteins with a specific pharmacological effect Like TNF-alfa inhibitors Effect only visible after some time, but not in all patients Generation 3: proteins with a less concrete clinical effect Targeted therapies in oncology The effect is a statistical chance some time in the future (survival) 25

26 Biosimilars licensed in the EU (1/1/2016)

27 New arrivals 2016 Etanercept (Benepali ) Market authorisation (16/1/2016) Infliximab (Flixabi ) Positive opinion (2/4/2016) 27

28 12 biosimilars in EMA licensing pipeline (EMA 4/4/2016) Adalimumab (2x) Enoxaparine (2x) Etanercept (1x) Insuline glargine (1x) Peg-filgrastim (3x) Rituximab (1x) Teraparatide (2x)

29 Agenda 1. How the drug market is exploding 2. Generic medicines affect drug expenditure 3. Uptake of biosimilars in Europe is variable 4. Barriers to market access of biosimilars 5. Do s and don ts in biosimilar use 6. Summary and Take Home Message

30 Six Barriers to market entry and success Manufacturing process Challenge of biological unpredictability Consistency after upscaling and over time Regulatory process IP challenge Lack of incentive Impossibility of substitution Reach of innovator Unclear for long time Different between EMA and FDA Extrapolation of indications Patents on composition of matter, production process, formulation and application of end product Patent prolongation strategies For payer For physician For patient Country specific regulation Switching chronic patients versus only new patients Indication specific Brand stickiness Relationship with key physicians Naming debate (INN or Brand) (Jonker-Exler, MBA thesis 2014; adapted from Gal, Sonnenefeld & Blanckley, 2013) 30

31 And how to overcome them Moorkens, Jonker- Exler, Huys, Declerck, Simoens & Vulto 2016 (submitted) 31

32 4. What incentive do prescribers have to prescribe a biosimilar? It takes time to educate the patient about switching & uncertainties Where lies the burden of change and where the benefit? The physician may not be convinced himself about the quality of the product There is this nagging uncertainty about immunogenicity The patient may not like talk about a cheaper alternative The price advantage for 3 rd party payers is not an incentive for prescribers nor patients 32

33 5. Regulators / policy makers are reluctant in interchangeability debate Lobby has been successful against switching and substitution Interchangeability (at a population level) is assessed during the licensing process EMA assumes biosimilarity (equivalence) Has no say over individual substitution or switching, that is a national matter (subsidiarity principle) At a national level a variety of conditions affect prescribing: Legislation (at least 8 EU countries prohibit substitution) National (professional) guidelines 33 INN-prescribing required under brandname / EU directive

34 Screenshot April 2015

35 Dutch Medicines Evaluation Board new position on biosimilars (April 2015) New patients can be treated with a biosimilar right away. Uncontrolled exchange between biologicals (whether originators or biosimilars) must be avoided. In other words, a patient must receive adequate clinical monitoring and clear instructions. If a patient is treated with a biological, detailed product and batch information must be recorded in the patient file to guarantee the traceability of the product in the event of problems.

36 April 2016 Active support for patients and patient organisations

37 Switching practice in first year of treatment (Italy) Ingrasciotta et al. BioDrugs 29(2015)275

38

39 FIMEA position on interchangeability (2015)

40

41 6. Innovative companies have high stakes Have invested for years in a strong prescriber relationship Now innovators have joined the biosimilar bandwagon, they can exploit this advantage double Some companies may send mixed messages The biosimilar industry was reluctant with high quality scientific information; it came too late or it was impossible to find Smaller marketing budgets They have to build a relationship with prescribers Price competition alone will not make the difference (Cf. biosimilar growth hormone and Infliximab in Scandinavia) 41

42 The close relationship between innovator and health care professionals Academic research departments are supported by innovator industry Clinical trials performed with the reference product provide a loyal user base Procurement deals for hospitals can include multiple products with the reference product being one. How to overcome Education and easy access to impartial information. Support investigator initiated trials with biosimilars.

43 Biosimilars create uncertainty with prescribers Innovative medicines Offer a clear advantage whether real or not Marketeers promise a solution for a therapeutic problem And hence, the physician is prepared to take a certain risk Biosimilars Don t offer prescriber and patient a clear therapeutic advantage May offer a modest price advantage for the patient / 3 rd party payer They may carry as with any other new drug some risk Doctors and patients don t like trouble with their medicines 43

44 How to build trust in biosimilars? Reduce the information gap Regulators can communicate their knowledge actively to medical professionals: The past 10 year there has not been a single serious incident with biosimilars The assessment system worked as expected Mistrust was not justified; we learned better in the meantime Avoid trouble around switching Call upon societal responsibility; convince prescribers on the (financial) advantages for the society, without compromising quality of treatment. 44

45

46 Founded in 2008 by Schellekens, Tang & Vulto) (14d13)

47 47

48 Agenda 1. How the drug market is exploding 2. Generic medicines affect drug expenditure 3. Uptake of biosimilars in Europe is variable 4. Barriers to market access of biosimilars 5. Do s and don ts in biosimilar use 6. Summary and Take Home Message

49 Do s and Don ts in designing biosimilar policies Medicines agencies should emit a clear message Scientific Medical Societies Should support patient organisations In general, there is no problem in switching Record carefully product used (as with any biological!) Monitor patients Relief physicians from the burden of change Facilitate electronic record keeping Reimbursement systems should encourage cost-effective options

50 Uptake biosimilar infliximab in 4 Scandinavian countries Norway 75,7% 94% Denmark Finland 40,2% Sweden 6,7% Source: G. Befrits, EGA meeting 2015

51 Conflicting acceptance Why do physicians have a lack of confidence in fully licensed medicines, once they are coined biosimilar? Example 1: Omnitrope in the US is a generic medicine (ANDA-route) that is widely prescribed; in the EU the same product is licensed as a biosmilar with very limited uptake. Example 2: The SC forms of trastuzumab and rituximab with completely overhauled formulations and different route of administration were assessed and licensed with a biosimilar-like abreviated pathway (ICHQ5E) and found rapid acceptance by clinicians 51

52 Key message Lack of a solid knowledge base among prescribers and patients is the single most reason for not using these much more cost-effective treatments with same efficacy and safety.

53 Summary Biosimilars are in all aspects more complicated than generic medicines Saving potential is highly dependent on right conditions Educate prescribers, pharmacists and patients Create proper administrative environment (registries) Relief prescribers from burden of change Use savings for facilitation and creating win-win Find biosimilar ambassadors and champions Objective and independent information for patients and health care professionals (nurses) Support switching initiatives

54 Take home message We need biosimilars to reduce drug costs We need biosimilar-ambassadors for education We have to build trust now for the generation of biosimilars to come (oncology) If we fail now, oncology biosimilars may get lost We need consistent policies to get the full saving potential of biosmilars

55 GaBI is supporting you Thank you for your attention Please support GaBI Contact: 55

56 References MBA-thesis of Mrs. Clara Jonker-Exler, pharmacist ErasmusMC Pharmacy Market entry of biosimilar monoclonal antibodies; current barriers, how they could be removed and what will be the economic and other impacts of their removal Imperial College London, UK, May 2014 Downloadable from: Contact: or Moorkens, Jonker-Exler, Huys, Declerkck, Simoens & Vulto. Overcoming barriers to the market access of biosimilar monoclonal antoibodies in the European Union (2016; submitted) 56

57 Backup-slides

58 Infliximab biosimilar in Norway Steinar Madsen, EGA Biosimilar Meeting

59 Market share biosimilar infliximab in Norway (based on vials sold) Steinar Madsen, EGA Biosimilar Meeting

60 What were the succes factors in Norway An advisory board with most of the (clinical) opinion leaders were involved in deciding on the pre-tender conditions To start with, only new patients will receive the biosimilar After each year: new tender, again for NEW patients (existing patients will not be changed); further cost reduction Savings will be invested in: Treating more patients for less money Trials in support of unresolved areas like extrapolated indications and controlled switching This is a win-win for everybody (Torfinn Aanes, National Procurement Board LISS) 60

61 Managed switching infliximab in IBD Southampton (UK) (courtesy Dr. Fraser Cummings) Zorgvuldige informatie en overeenstemming betrokken artsen Voldoende personeel om project uit te voeren Switch-plan in detail doorgesproken met IBD patiënten-panel Goede randvoorwaarden (registratie, monitoring) Besparingen werden deels geïnvesteerd in betere zorg (win-win) Tijdens uitvoering periodiek overleg met alle betrokkenen Dus: in goed overleg en niet top-down NICE Adoption Programme Biosimilar versions infliximab 31/7/2015

62 Managed switching infliximab in IBD Southampton (UK) (courtesy Dr. Fraser Cummings) Resultaten: Januari 2015: 350 IBD patiënten, waarvan 150 op infliximab April 2015: start Safe Switch Programma Juli 2015: alle 150 patienten overgezet van originator biosimilar infliximab. Slechts 2 patienten vroegen om een herziening Jaarlijkse besparing (naar NL maatstaven): ca. 1 miljoen En een betere kwaliteit van zorg! NICE Adoption Programme Biosimilar versions infliximab 31/7/2015

63 5 reasons why physicians are reluctant to prescribe biosimilars European J Hospital Pharmacy 13(2007) No5,

64 5 criteria that play a role in adoption of a new drug Adoption: a decision to make full use of an innovation as the best course of action available 1. Relative advantage * Is the innovation perceived as better? * What is the added value? Effectiveness, quality, safety, ease of use, economic factors 2. Compatibility * Perception of consistency with past experience and current needs Does it fit expectations? Moors EHM, Eur J Hosp Pharmacy Practice 13(2007)No.5,

65 5 criteria that play a role in adoption of biosimilars 3. Complexity * Perception of degree of difficulty in using the innovation 4. Trial data * Proving and understanding similarity is serious barrier to biosimilar drug development and uptake (when is enough, enough?) * Overall clinical experience before drug is adopted 5. Observations * How reliable, informative and convincing are the proof-of-clinical - equivalence studies? How observable are the results of the innovation? 65

66 Acceptatie van een nieuw geneesmiddel Affiniteit met een bestaand product (innovatieve merk) (= huidige waarde, inclusief gewoonte) Versus Aantrekkelijkhied van het alternatief (biosimilar) (die een verandering met onzekere uitkomst kan inhouden) Voorschrijven van geneesmiddelen is zowel emotioneel als kennisinhoudelijk gestuurd Zonder prikkel om te veranderen, Zal een dokter voorschrijfgedrag niet aanpassen 66