The issue

Extrapolation is a core principle of biosimilarity. Extrapolation is where the biosimilar is not required to repeat clinical studies in all indications for the reference product where this can be scientifically justified during regulatory approval. However, it is recognised that the principle of extrapolation is not always understood as stakeholders are more familiar with safety and efficacy being determined by clinical testing in each indication for a product.

The BBA’s position

The European Medicines Agency (EMA) is responsible for determining if extrapolation is viable for each biosimilar product.  The high similarity between reference and biosimilar product is the basis for the rational reduction of clinical studies; i.e. the higher the molecular similarity, the less clinical data should be required. Extrapolation has been used for years as part of the approval of manufacturing changes to originator biologics.

The EMA does not automatically grant all the originator indications to a biosimilar but will rather determine the appropriate indications for a biosimilar based on the totality of the evidence (analytical, pre-clinical and clinical) that the biosimilar manufacturer provides. The biosimilar indications approved by the EMA are those considered to have a comparable safety and efficacy profile to the reference product in the same indications.

The EMA allows a biosimilar product to extrapolate to other indications⁹ licensed for the reference product without having to duplicate trials if:

• High molecular similarity between the biosimilar and reference product has been demonstrated.
• The biosimilar has been shown to be of equivalent safety and efficacy to the reference product in one indication that is sensitive to demonstrating any potential differences.
• There is a close match between the biosimilar and its reference product in all relevant functionalities.

Appropriate extrapolation under these circumstances prevents unnecessary and hence unethical duplication of clinical studies in humans.
 
As stated by members of the EMA working party on biosimilars “biosimilars have been on the European market for several years and have performed as expected in all licensed indications, including extrapolated indications.”¹

Our recommendations

It is important that the NHS’s education and support materials properly clarify how biosimilar medicines are developed and build understanding and confidence in extrapolation amongst all stakeholders reflecting the product specific judgements made by the EMA on the basis of scientific evidence and experience.

The supporting evidence

It is widely accepted that for biosimilars, “extrapolation of efficacy and safety data from one indication to another may be considered if biosimilarity^,5 to the reference product has been shown by a comprehensive comparability program... including safety, efficacy and immunogenicity in a key indication that is suitable to detect potentially clinically relevant differences”.⁶

Extrapolation is considered possible if the “mechanism of action of the active substance and the target receptor(s) involved in the tested and  in the extrapolated indication (s) are the same. extrapolation is usually not problematic”⁷

Extrapolation is an established scientific and regulatory standard which has been used for many years; for example, in major changes in the manufacturing process of originator biologicals. Extrapolation is being increasingly considered as a model for enabling the more effective use of medicines, for example in children.⁸

In agreement with current regulatory guidelines therefore, biosimilarity in terms of clinical efficacy and safety needs to be confirmed in an indication that can serve as a sensitive model;^2,3 one with equal or higher sensitivity than the other indications for detecting clinically meaningful differences between the products. Whilst development programmes may not look exactly the same, the two key factors that need to be considered when selecting the sensitive model are:

• Immunocompetence: patients in this patient population should be sufficiently immunocompetent to allow detection of potential differences in immunogenicity
• Large effect size: the expected treatment effect should be large to maximise the reliability of detecting potential differences in efficacy.

A known and shared mechanism of action (MoA) makes the judgement of extrapolation easier, but is not always required if there is a close match between the biosimilar and its reference product in all relevant functionalities. Each indication must be scientifically justified and regulators (EMA, FDA and others) assess each indication separately and approve, or reject it based on this assessment.^2,3

In summary, the totality of the evidence derived from the biosimilar comparability exercise plus the demonstrated safety profile and efficacy in the most sensitive indication are the key factors for the extrapolation of indications. For the biosimilars approved to date, the concept of extrapolation has worked well.

As stated by members of the EMA working party on biosimilars "biosimilars have been on the European market for several years and have performed as expected in all licensed indications,including extrapolated indication."

"Generation of redundant or merely 'comforting data' should not be requested. Instead, extrapolation should be based on sound and objective scientific criteria." ^1​

Further information around the key principles for extrapolation of indications can be found here.

^1. Weise M, Kurki P, Wolff-Holz E, et al. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-3196 
^2. EMA Guideline on “Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues.” EMEA/CHMP/BMWP/42832/2005 Rev. 1. Available to download here, accessed Jan 20, 2015
^3. FDA Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. FDA, February 2012. Available to download here, accessed Jan 20, 2015

^4. Guideline on similar biological medicinal products, EMA. Available here.

^5. Weise M, Kurki P, Wolff-Holz E, et al. Biosimilars: The science of extrapolation, Blood Journal, 2014;124(22):3191-3196

^6. ibid

^7. ibid

^8. Reflection paper on extrapolation of efficacy and safety in paediatric medicine development, EMA, available here

⁹ EMA, Guideline on similar biological medicinal products, 23rd October 2014. Available here

The issue

Whilst biosimilar medicines may offer significant cost savings relative to the originator and the opportunity to expand access to treatment, the same percentage price reduction typical of generic medicines cannot be expected because of the additional complexity of the product, its development, manufacture and pharmacovigilance requirements. 

The production and purification of biologics including biosimilars is a complex process and requires a very high level of monitoring and quality testing. Proteins are usually much bigger in molecular size than chemically synthesised medicines and have higher complexity and variability than smaller chemical compounds. Consequently, biosimilar manufacturing is costly compared to small molecule medicines with additional manufacturing expenses such as expensive raw materials, sophisticated state of the art technology and analytical methods to prove comparability and highly controlled manufacturing processes to guarantee safety and efficacy.

The current procurement system in England may not support the development of a biosimilar medicines industry if it does not take account of these costs and complexities and encourages rapid price reductions to unsustainable levels.

A competitive market will ensure savings are delivered to the NHS now and in the long term. To encourage multiple biosimilar manufacturers to enter the market and compete with each other to deliver these savings, sufficinet financial returns are required. Changes to the current procurement system for biosimilar medicines must ensure they address long term market sustainability and support the rapid uptake of biosimilar medicines in a sustainable way.

The BBA’s position

In respect of procurement and tendering in the UK, biosimilar medicines offer significant value to patients, physicians, payers and healthcare systems by providing immediate benefits in the form of savings, earlier and greater patient access to biologics and thus potentially improved outcomes.¹

• A sustainable pricing scheme¹ allows innovation to be rewarded while at the same time increasing patient access to alternative treatments.¹
• In order to realise financial and health outcome benefits to society³ we believe payers must promote a functioning competitive market including implementing competitive pricing and purchasing  providing for the fast uptake of biosimilar medicines. 
• Competition between products should not be based solely on price but should also take into consideration other overall value factors including formulation, quality and service including support to deliver identified savings and benefits as well as reliability of supply.
• For NHS tenders, all medicines should be grouped according to INN which would include biosimilars and the originator biological medicine. Only EMA approved biosimilar medicines that have demonstrated equivalent safety, quality and efficacy and have the same indications as the originator may be included in a grouped tender. Manufacturers must demonstrate their ability continuously to supply the market. All biological medicines, including biosimilars should be prescribed by brand name in order to facilitate pharmacovigilance in line with MHRA guidance.⁴

Our recommendations

• We are supportive of Framework Tenders but not Single Award Tenders. Framework Tenders allow multiple products to compete ensuring best value decisions are made in terms of formulation including devices, quality and service and not price alone. This respects clinician choice and mitigates risks in respect of sole supply. Public procurement should foster this diversity of suppliers by ensuring the final allocation of contract is not limiting doctors and patients to one treatment choice. New biosimilar products should be allowed to compete within each regional framework, with NHS authorities ensuring their policies contain a process for new biosimilar products to access an existing framework. This is crucial to ensure the UK remains an attractive health economy for manufacturers to bring biosimilar medicines to market.
• We would support the creation of an increased number of smaller tender regions. This reflects the reality of competing in a devolved and local NHS and increases the chance of greater alignment between local Trusts and Clinical Commissionin Groups (CCGs). Alignment will ensure that the financial and patient benefits from biosimilar medicines are actually delivered.
• We would like to see a more efficient approach to gain share²  agreements; seen as a critical device to facilitate more rapid uptake of biosimilar medicines and thereby benefiting society more quickly through the delivery of savings and increased patient access to innovative biologics. The current highly localised approach needs supporting in terms of NHS England guidelines for the operation, implementation and delivery of gain shares. In general, gain shares should be designed to incentivise and directly benefit ‘three ways’; the physicians and patients involved at a unit level, the Trust and the Payor.
• We need Trusts to respond and act on clear market metrics for measuring the uptake of biosimilar medicines and to guide NHS regions to target ‘what good looks like.’ Clear market metrics⁵ for patient numbers, % biosimilar share of molecular class, value delivered and patient outcomes will not only incentivise more rapid uptake but reduce variability in uptake, encourage best practice and support the delivery of financial and patient benefits to the NHS.
• Biosimilar manufacturers should be encouraged and supported to deliver value to both the NHS and patients through product and service differentiation. This could include elements such as support for education programmes, improved drug packaging or delivery. In determining value, payers should consider multi-criteria tenders and not just price.

¹  GfK study “Factors supporting a sustainable European Biosimilars Medicines Market”Pg. 5, 36. Available here
²  The NHS Standard Contract; a guide for clinical commissioners. Available here

³ NICE, Biosimilar medicines, Key Therapeutic Topics, Pg. 1 , NICE, February 2016 Updated January 2017 Available here

⁴ Medicines Healthcare Products Regulatory Agency: Drug Safety Update, Biosimilar products, 2008, Available here

⁵ All Wales Medicines Strategy Group, Secondary Care, National Prescribing Indicators 2016-17, February 2016. Available here

The issue

Biosimilar medicines are only approved in the EU when determined by the Regulator to have the same clinical effect in a given clinical setting as the reference medicines. ^{16, 17, 18, 20} This means that biosimilar medicines are approved to be clinically interchangeable¹⁹ with the reference medicine; i.e. that the originator product or a biosimilar may be chosen by clinicians in the knowledge that each will have a comparable clinical effect on the patient. The European Commission define interchanging as meaning -the medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient on the initiative, or with agreement of the prescriber’.² Understanding this is essential in giving confidence to clinicians to prescribe a biosimilar in new patients and to switch existing patients on to a biosimilar medicine.

Clinicians can confidently choose an originator product or a biosimilar of that product in clear anticipation of delivering a comparable clinical outcome. Interchangeability does not refer to automatic switching of patients from one product to another without the guidance of the clinician, or automatic substitution by a pharmacist at the point of dispensing the medicine.

In NHS England’s document ‘What is a Biosimilar Medicine?’ NHS England permits the switching of patients onto biosimilar medicines at the discretion of by prescribers³; which is consistent with the position taken in Finland where their Regulatory Authority, FIMEA guidance states that biosimilars should be considered interchangeable with their reference product under the supervision of a healthcare person.¹¹  French (ANSM)¹²  Dutch (MEB)¹³ and German (PEI)¹⁴ authorities have also developed clearer positions on interchangeability.

The BBA’s position

When a biosimilar medicine is approved in an appropriately regulated market as a clinically comparable version of the reference product, the biosimilar and the reference product should be considered interchangeable, as defined above, for the following reasons:

Biosimilar medicines are approved by the European Commission and can be considered as interchangeable with originators
To be approved, biosimilar medicines have had to show high levels of similarity with originator products. This is demonstrated in stringent comparability studies which are conducted head-to-head with the reference product.^1,8. EU regulators have asserted that biosimilar products approved according to EU regulatory standards should be considered as interchangeable with the reference product, at least from the perspective of being therapeutically equivalent alternatives¹.

10 years of biosimilars clinical experience shows no additional adverse risks

Physicians and patients can expect the same clinical efficacy and safety profile²² established by a stringent regulatory licensing pathway and confirmed by more than 10 years of experience with biosimilar products on the EU market.²³

The development of a biosimilar medicine is based on the demonstration of comparability of the biosimilar and the reference product.¹  Biosimilar medicines contain a comparable equivalent version of the active substance of its reference product. Whenever there is a manufacturing change to any biologic medicine, regulators require that the efficacy and safety of the revised product have not changed and this demonstration of comparability of the old and new versions is also used in biosimilar medicines’ development. The manufacturing processes for biological medicines are often changed several times⁷ but they remain interchangeable.  For further information on manufacturing change, please contact us.  

The Pharmacokinetic profile is comparable with the reference product
Biosimilars meet the current regulatory requirements, including a comparable pharmacokinetic profile as well as comparable safety and efficacy in at least one therapeutic indication.

Regulators require the biosimilars to be no more immunogenic than the reference product
In being approved by regulators, a biosimilar is required to be equally or less immunogenic than the reference product. Products with an inferior immunogenicity profile will not be approved as biosimilars.⁵
A biological product is immunogenic if the immune system of an individual recognises it as a foreign substance. For the body’s own tissues and fluid, there is an immunological tolerance. It is not always possible to avoid immunogenicity of biological medicinal products. Immunogenicity is important as the immune system may react to a structural difference between different biopharmaceutical products. Such a reaction is highly unlikely with licensed biosimilars since the products have been shown to have comparable structure and immunogenicity in pre-licensing clinical trials.⁹

Biosimilars are required to have the same amino acid sequence as their originator. Factors that might contribute to immunogenicity, such as aggregation, misfolding, impurities and certain glycan variants are well understood and tightly controlled throughout the development phase and thereafter.⁶ If the biosimilar contains the same amino acid sequence to the reference product, it should also have the same T-cell epitope. A strong immune response would require a new T-cell epitope. The level of aggregates and immunogenic impurities is also tightly controlled in biosimilar products, thus further controlling immunogenicity.^5,6

Recent studies^{19, 21} show no evidence of switch-related adverse events. Switching patients onto a biosimilar is the practical implementation of the principle of interchangeability
In a recent analysis conducted by Ebbers and colleagues looking at switching data from three different sources - 1) the EudraVigilance database for serious adverse effects of biosimilar medicines; 2) prospective switch studies of two versions of the same product, including biosimilars; 3) retrospective studies that involved sequential use of biological medicines - no evidence of switch related adverse events was found.⁷ As Kurki noted when citing Ebbers this data should be "reassuring for prescribers who consider a switch from the reference product to its biosimilar version.”⁵

The rigorous scientific data generated for the approval of biosimilar products supports their interchangeability . Patients can expect a comparable outcome with originator or biosimilar whichever is prescribed with regards to safety and efficacy, once approved in an appropriately regulated market.^1,4,10 The EU regulatory system provides the basis for clinical decisions to switch patients to different biological medicines of the same molecule that are approved for the same indication. Considerations around switching are given in our ‘switching patients to biosimilar medicines’ section.

As FIMEA, the Finnish health regulator states in its position on biosimilar medicines - “the current position of FIMEA is that biosimilars are interchangeable with their reference products under the supervision of a healthcare person”. ¹¹ The Dutch Medicines Evaluation Board states "the exchange between biological medicines (regardless of whether they are innovator products or biosimilar medicine products) is permitted" ¹⁴and the French National Security Agency for Medicines and Health Products (ANSM) states "It is clear that a position formally excluding any interchageability during treatment no longer appears justified"¹² both require an informed patient, monitoring and traceability of product.

Furthermore, a survey of European Crohn´s and Colitis Organisation (ECCO) members that was presented at the 2016 ECCO annual meeting showed that of physicians surveyed in 2015, 44.4% believed that biosimilars are interchangeable compared with 6% in 2013, and an additional 27.4% of physicians would switch to a biosimilar after informing the patient.¹⁵ 

Our recommendation

The BBA calls for a clear statement confirming that biosimilar medicines approved for use in the same clinical indications are interchangeable with their reference products and evidence supports this. A clear positive and categorical position on this should come from NICE, NHS, MHRA and stakeholders involved in prescribing such as the General Medical Council (GMC), Royal Colleges and Clinical Commissioning Groups (CCGs) on the basis of the current available evidence and this will help bridge the gap between the clear EU regulatory policy and decisions and prescribing and medical practice in the UK.

This assurance from a wide group of stakeholders will give healthcare providers and patients confidence in their medicine to ensure the necessary savings for the NHS and provide the opportunity to expand patient access to biological medicines.

References:

^1. Weise M, et al. Biosimilars: what clinicians should know. Blood 2012;120(26):5111–7
^2. European Commission Consensus Information Paper 2013, What you need to know about Biosimilar Medicinal Products 2013 (cited 2014 Feb 7). Available for download here  

^3. NHS England What is a Biosimilar Medicine?  Available for download here
^4. EMA Guideline on “Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, EMEA/CHMP/BMWP/42832/2005 Rev. 1. Available for download here. 
^5. Kurki, P. Biosimilars for prescribers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):Epub ahead of print.
^6. Brinks V, et al. Immunogenicity of biosimilar monoclonal antibodies. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):188-93
^7. Ebbers HC, et al. The safety of switching between therapeutic proteins. Exp. Opin. Biol. Ther. 2012;12:1473–1485
^8. Schneider CK, et al. Setting the stage for biosimilar monoclonal antibodies. Nat Biotech 2012;30:745–748
^9. Clinical Pharmacist, Rheumatology, Biosimilar medicines in rheumatology,Tina Hawkins, Paul Emery, 11 NOV 2015
^10. FDA Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. FDA, February 2012. Available for download here, accessed 20th January, 2015.

^11. FIMEA Finnish Medicines Agency position on interchangeability. Available here
^12. National Security Agency for Medicines and Health Products (ANSM) (2016) in the French language only. Available here
^13. Germany Paul- Ehrlich Institute (2015) Available here.
^14. Medicines Evaluation Board (MEB) Netherlands, MEB position on prescription of "biosimilar medicinal products" . Available here.

^15.Danese S, et al. P312 Has IBD specialists' awareness of biosimilar monoclonal antibodies changes? Results from a survey among ECCO members. 11th Congress of ECCO Available here

^16. European Medicines Agency (EMA) Guideline on similar biological medicinal product, 23 October 2014 CHMP/437/04 Rev 1 Available here

^17. EMA, Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), Available here

^18. EMA, Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, Available here

^{19 .}Nor-Switch study: Another significant example of positive real world evidence on physician led switching to biosimilar medicine. More details here

^20. MHRA Drug Safety Update, Biosimilar products, February 2008. Available here

^21. Biosimilars and inflammatory bowel disease: a switch programme using CT-P13, The Pharamceutical Journal, September 2016. Available here

²² EMA, Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues

²³ European Commission Consensus Information Paper 2013, What you need to know about Biosimilar Medicinal Products 2013. (accessed 6.4.17) Available for download here  

²⁴ European Commission Consensus Information Paper 2013, What you need to know about Biosimilar Medicinal Products 2013 (accessed 6.4.17) Available for download here  

 

The issue

Switching is a decision taken by the treating physician to exchange one medicine for another medicine with the same therapeutic intent in patients who are undergoing treatment.⁷  Given that biosimilar medicines are approved as interchangeable with and are thus therapeutic alternatives to their reference products, clinicians should feel confident switching existing patients onto biosimilar medicines of the same molecule, as well as starting new patients on biosimilar medicines. A biosimilar medicine should not be automatically substituted for the originator by the pharmacist at the time of dispensing.’ ¹⁹

The BBA’s position

Switching existing patients onto biosimilar medicines is as important as starting new patients on biosimilar medicines in delivering the benefits derived from competition, including more patients being treated within the same budget. The BBA agrees that switching between a reference product and its biosimilar should be managed at the discretion of the individual prescribing clinician in partnership with the patient with appropriate monitoring in place. However, clinicians and other stakeholders should be confident about switching patients because:
 
A biosimilar is systematically developed to be comparable to the original product and to have no clinically meaningful differences.
This is demonstrated in comparative studies which are conducted head-to-head with the reference product.^1,9

Biosimilars are interchangeable.
EU regulators have asserted that biosimilar products approved according to EU regulatory standards should be considered as interchangeable with the reference product, at least from the perspective of being therapeutically equivalent alternatives.¹   

Biosimilars have no more immunogenic potential than the originators⁴
Concerns have been raised that the immunogenic response to the biosimilar will differ from the original reference compound. This is not justified because the EMA regulatory approval process includes immunogenicity assessment. Biosimilars are required to have the same amino acid sequence as their originator which is a determinant of immunogenicity.⁵ Other parameters such as correct folding, post-translation modifications, aggregates or impurities are rigorously controlled throughout development and also post authorisation.² Before marketing authorisation is granted for a biosimilar product, anti-drug B cell response must be evaluated. If the biosimilar contains the same amino acid sequence to the reference product, it should also have the same T-cell epitope. A strong immune response would require a new T-cell epitope.²⁰ The level of aggregates and immunogenic impurities is also tightly controlled in biosimilar products, thus further controlling immunogenicity.²

There is no scientific rationale or evidence from clinical experience to date that switching itself can induce immunogenicity. ⁴ If this was the case, the same would also apply to switches between different originator biologicals of the same therapeutic class.¹ Switching between different biological products has been happening for many years in patients who are not responding to treatment. Examples of switches between two non-similar but related biological products may help to evaluate the risk of switching between two highly similar biological products. In a study evaluating the effectiveness of switching from various recombinants growth hormone products to the biosimilar Omnitrope in routine practice no negative impact was noted. Patients continue to grow without alteration in their growth trajectories.¹⁸

Development programmes submitted to EMA for product registration including switch studies have not indicated an increased frequency or risk of adverse effects.
Development programmes of several biosimilars have included studies in which the reference product has been switched to the biosimilar and, occasionally, back to the reference product. Switches of somatropins, epoetin alfas, and glargin insulins have not indicated a risk for adverse effects.²² Preliminary results of infliximab do not raise concerns about safety profile differences either.⁶ This view is supported by the fact that switches between reference products and biosimilars have been commonly associated with hospital tendering processes in some EU member states. To date, there is no safety signal associated with such switches in the European EudraVigilance database for serious adverse effects.^3,4 Real world patient experience suggests growing acceptance of switching.

In Poland, biosimilar penetration for Human Growth Hormone (HGH) is 99%, Erythropoietin EPO penetration is 62% in Bulgaria, whilst Granulocyte colony-stimulating factor (G-CSF) penetration in Croatia, Czech Republic, Hungary and Romania with nearly 100%.²³ In an analysis by Ebbers and colleagues looking at switching data from three difference sources - 1) the EudraVigilance database for serious adverse effects of biosimilar medicines; 2)prospective switch studies of two versions of the same product including biosimilar medicines; 3) retrospective studies that involved sequential use of biologicals - no evidence of switch related adverse events was found. ^3,4 As Kurki noted when citing Ebbers this 'data should be reassuring for prescribers who consider a switch from the reference product to its biosimilar version.’⁴

Current clinical practice is increasingly accepting of switching.
An increasing number of clinical and patient group stakeholders are becoming convinced that switching patients to biosimilars of their reference medicine should be routine clinical practice.  For example;

• University Hospital Southampton NHS Foundation Trust’s Consultant led IBD service implemented a managed switching programe for all patients having Remicade to one of the infliximab biosimilars. A gain share agreement was developed to fund additional staffing needs to implement and monitor a safe switch programme.⁶
• The British Society of Gastroenterology has the following position on infliximab: “There is sufficient data from observational studies to show that safety and clinical efficacy of CT-P13 are comparable to the originator drug, with similar immunogenicity, and that switching from Remicade to CT-P13 is also safe and effective.”¹⁵
• The National Rheumatoid Arthritis Society (NRAS) state "the quality controls for the biosimilar are much more stringent than were required for originators back in the early days of biologic DMARDs. We also have to adapt to the reality of what is actually going on in the NHS and the need to make savings where this is possible, feasible and the responsible thing to do, provided that quality and safety of care are prioritised, rheumatology benefits from some of the funds saved and longitudinal safety data is collected via the British Society for Rheumatology Biologics Register are collected.” ⁸ Furthermore, a recent small survey conducted by NRAS via its online community page found that 40.4% of patients didn't mind switching to a cheaper but equally good/safe drug to save money for the NHS so long as the treatment works as well as their existing treatment.¹⁷

In summary, from what is available to date, data do not indicate that switching is associated with cross-reactivity or has compromised patient safety.^{3,4,10,11,12,13,14}

In the UK, automatic substitution – the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber¹⁶ –  is not permitted for any medicine. Further, it is recommended that all biological medicines should be prescribed by brand name and batch numbers recorded.²¹

Our recommendation

As clinical practice and experience of switching increases, we ask that NHS England, the MHRA and NICE share this experience widely among all stakeholders, for example as implemented by NICE on ‘Introducing biosimilar version of infliximab, inflectra and Remsima’⁶. 

An information programme should be established informing clinicians of the benefits of switching patients onto biosimilar medicines and the appropriate way to switch between medicines, in particular:

• Promoting a shared  understanding of how to  involve the patient in the switch process decision ensuring they are informed in a transparent way without encumbering Trusts in unnecessary and costly administration.
• Promulgating national guidance on gain share agreements that ensures reinvestment from switching in departments and improved patient care as well as benefits to the wider Trust and CCG. 
• Issuing specific guidance on how to switch infusion vs subcutaneous products especially around homecare support. 

Given the requirement to prove similarity after changes in manufacturing processes of reference products, as well as in biosimilar medicines, it is imperative that strict traceability should be implemented for all biologic medicines. As such prescribing by brand name must be implemented in the prescribing of all biological medicines.

References:

^1. Weise M, et al. Biosimilars: what clinicians should know. Blood 2012;120(26):5111–7.  
^2. BrinksV, et al. Immunogenicity of biosimilar monoclonal antibodies. Generics and Biosimilars initiative Journal(GaBI journal). 2013:2(4):188-93
^3. Ebbers HC, et al. The safety of switching between therapeutic proteins. Exp. Opin. Biol. Ther. 2012;12:1473–1485
^4. Kurki, P. Biosimilars for prescribers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):Epub ahead of print.
^5. The Pharmaceutical Journal, Biosimilar medicines in rheumatology 11 Nob 2015, Tina Hawkins, Paul Emery.
^6. NICE, Introducing biosimilar versions of infliximab: Inflectra and Remsima. Available for download here
^7. European Commission. What you need to know about biosimilar medicinal products. Process on corporate responsibility in the field of pharmaceuticals access to medicines in Europe. A consensus information document [homepage on the Internet]. 2013 Apr 21 [cited 2014 Mar 31]. Available here. 
^8. NRAS Position Paper on Biosimilars Revised March 2016 Available for download here. 
^9. Schneider CK, et al. Setting the stage for biosimilar monoclonal antibodies. Nat Biotech 2012;30:745–748
^10. Flodmark CE, et al. Switching From Originator to Biosimilar Human Growth Hormone Using Dialogue Teamwork: Single-Center Experience From Sweden. Biol Ther. 2013;3:35-43
^11. Wiȩcek A, Ahmed I, Scigalla P, Koytchev R. Switching epoetin alfa and epoetin zeta in patients with Renal Anemia on Dialysis: Posthoc analysis. Adv Ther. 2010;27(12):941–52
^12. Lonnemann G, Wrenger E. Biosimilar epoetin zeta in nephrology - a single-dialysis center experience.Clin Nephrol. 2011;75(1):59–62.
^13. Yoo DH, et al. Poster presentation at ACR 2013 (L1)
^14. Park W, et al. Poster presentation at ACR 2013 (L15)
^15. BSG Guidance on the use of biosimilar infliximab, available here 
^16. European Commission What you need to know about Biosimilar Medicinal Products page 41
^17. Big Poll Question on HealthUnblocked conducted by NRAS and shared at the NHSE Biosimilar Regional meetings March 2016 “ If your biologic was switched to a cheaper but equally good/safe drug to save money for the NHS, what would be the most important for you to know?”
^18. Nazia R, et al. Switching to Omnitrope from other recombinant Human Growth Hormone Therapies: A Retrospective Study in an Integrated healthcare System. Bio Ther (2014) 4:27-39
^19. NHS England What is a Biosimilar Medicine? Available here

²⁰ The Pharmaceutical Journal, Biosimilar medicines in rheumatology, 11 November 2015, Tina Hawkins, Paul Emery

²¹ MHRA Drug Safety Update, Biosimilar Products, 2008 Available here

²² Roundtable on biosimilars with European regulators and medical societies, Brussels, Belgium, GABI Journal, 12 January 2016 Available here

²³ IMS Institute for Healthcare Informatics, Assessing biosimilar uptake and competition in European markets, October 2014 Available here

Increasing patient access and improving patient care

 

The Issue

The high cost of biological medicines is creating treatment access issues for patients across the world and this is particularly apparent in the UK where:

• Patient access to biologics is more restrictive - for example NICE guidelines on rheumatoid arthritis restricts the use of biological medicines versus the criteria recommended by EULAR. In Europe, biologics are available to patients with moderate disease and as a first line of treatment.¹ However, in the UK, the first treatment strategy is restricted to rare, exceptional situations and only patients with severe disease are eligible.²
• Patients eligible for 3rd line therapy for rheumatoid arthritis receive biologics only in 76% of the cases in France, 65% in Germany and 66% in the UK¹⁴

Competition introduced by biosimilar medicines has the potential to significantly reduce treatment costs and provide the catalyst for increased patient access to biological medicines and in turn improved patient care. Savings for example within the Erytropoietin (EPO) market where biosimilar medicines have been available since 2006 have saved health systems in Germany and France between 31% and 61% and more patients now benefit from biological medicines as a result.³

The BBA’s position

To maximise the benefits of biosimilar medicines in the UK for both patients and the NHS, it is important that clear, positive policy positions are adopted that link the financial benefits of biosimilar medicines uptake for the NHS directly to improving patient access to these vital medicines or the UK could face falling further behind the rest of Europe. Specifically biosimilar medicines can benefit UK patients by; 

Providing the catalyst for increased patient access to biological medicines in line with European standards; for example influencing NICE to align Guidelines for Rheumatoid Arthritis with EULAR.¹ Wider access to treatment for patients in the UK remains unfulfilled since NICE did not accept the BSR/NRAS appeal to widen the access to those with moderate to severe disease with poor prognosis markers.⁴ Competition from biosimilar medicines and their uptake offer the potential to improve patient access to biological medicines and to contribute to the financial sustainability of EU healthcare systems .⁶

Biosimilars can make medicines available to patients within the NHS which might otherwise not be approved for use by NICE and provide patient  & prescriber choice. The cost saving due to competition from biosimilar medicines and the resultant reduction in cost per QALY means that biosimilar medicines may be approved by Health Technology Appraisal agencies when the equivalent originator product was found not to be cost-effective. Biosimilars can help increase the choice of biologics available to patients⁵ for example, NICE approval of  biosimilar infliximab in the treatment of Ankylo Spondylosis.²

Biosimlars can expand access to biologics for existing therapies as was the case with G-CSF which increased in prescription numbers after the biosimilars launch.

Biosimilars can improve patient care. The savings made by switching patients to biosimilars can be used to improve patient care. At University Hospital Southampton NHS Foundation Trust’s Consultant led IBD service the implementation of a managed switching programme for all patients having Remicade to one of the infliximab biosimilars through a gain share agreement funded additional staffing needs to implement and monitor a safe switch programme.¹³ This enabled patients who had not been screened and assessed in accordance with NICE technology appraisal guidance to be assessed and a nurse-led biologics service put in place including increased specialist nurse follow up, improved patient database, a new patient management system and participation in the IBD Registry. 

Biosimilars provide an incentive for originator companies to develop new biological medicines which benefit patients. NHS England supports the appropriate use of biosimilars to release cost efficiencies to support the treatment of an increasing number of patients and the uptake of new and innovative medicines.⁵ Biosimilar medicines use will lead to reduced budgets, positively impact savings, increase flexibility for payers to maintain funding of new and necessary innovations and drive better healthcare outcomes. The savings gained from biosimilar use can be used towards facilitating access to more recent products.⁷

Patient engagement is vital if biosimilars are to be incorporated into clinical practice and benefit patient access. Patient friendly easily understandable information, education and tailored support services will give confidence in the opportunity biosimilars present. Patient information is particularly important when patients switch from an originator to a biosimilar.  Appropriate information should be sent out to both clinician and patients, explaining what biosimilars are and the rationale for switching. Centres that have already switched patients to biosimilar infliximab developed patient information leaflets which were sent out to patients in advance of switch. In addition, a nurse specialist at these centres contacted patients by phone to explain the process and answer any questions. Both University Hospital Southampton NHS Foundation Trust and University College London NHS Foundation Trust have been able to develop and improve their services for inflammatory bowel disease patients as a consequence of commissioners sharing the financial rewards generated by the switch.⁸

Patients can understand and support the shared benefits of improved access to be gained by switching to biosimilars. In a recent small survey conducted by the National Rheumatoid Arthritis Society (NRAS), 40.4% of patients stated they “don’t mind switching to a cheaper but equally good/safe drug to save money for the NHS so long as the treatment works as well as my existing treatment” and a further 27.3% wanted “someone who couldn’t otherwise get access to a biologic treatment to benefit.”⁹ Although the NRAS survey was small and therefore may not be fully representative, it does indicate an important signal of patient acceptance but further education from authoritative bodies (NHS, NICE and MHRA) will only help to improve levels of patient confidence in the quality of biosimilars and accelerate improved patient access.

Participation in biologic Registries will give patients and clinicians confidence in biosimilars. The collection of longitudinal safety data is recommended for all biologics including biosimilars through Registries where they exist such as the BSRBR which capture patient outcomes. Participation will demonstrate confidence in the quality of biosimilars, allay safety concerns and evidence a comparable record of safety over time.

Gainshares should directly benefit patient access. They are a critical device to facilitate more rapid uptake of biosimilars and thereby benefit society more quickly through the delivery of savings and increased patient access to innovative biologics. The current highly localised approach needs supporting in terms of NHS England guidelines for the operation, implementation and delivery of gain shares. In general, gainshares should be designed to incentivise and directly benefit ‘three ways’; the physicians and patients involved at a unit level, the Trust and the Payor.
 

Our recommendation

NICE, the Department of Health and the NHS must develop policy and clinical practice to drive savings made through the use of biosimilar medicines back into increasing patient access to biologics by considering the impact of access thresholds, earlier use, the opportunity to access a wider choice of biologic medicines or access to innovator medicines. It is disappointing that NICE has, thus far, been unable to satisfy itself as other countries have on, for example, access to biological medicines on rheumatoid arthritis.

• Biosimilar medicines are improving patient access. Clinicians should routinely prescribe biosimilar medicines for new patients.
• Clinicians should consider switching patients to a more cost effective biosimilar medicine when one is available in the light of clinical and scientific evidence and appropriate clinical protocols. This requires a clear explanation by the NHS of the benefits to be gained for patients and the NHS by switching to a biosimilars and acceptance of interchangeability.
• Appropriate information and guidance is made available to clinicians and patients not only by industry but also by health technology appraisal bodies {(NICE, Scottish Medicines Consortium (SMC), All Wales Medicines Strategy Group (AWMSG)} and other organisations such as NHS England and patient and professional groups based on regulatory assessment and other available peer reviewed information. This information must be objective and transparent so that clinicians, patients and commissioners are confident about their decision making.
• NHS England guidelines for the operation, implementation and delivery of gainshares should be designed directly to benefit ‘three ways’; the physicians and patients involved at a unit level as well as the Trust and the Payor.
• Increasing patient access to biologics and biosimilars is a tangible, transparent metric in medicines optimisation and is implemented quickly and actively monitored by Trusts and the NHS.  This will ensure patients benefit and regional variation is eliminated.^10,11
• There are no unnecessary barriers to the use of biosimilar medicines within the NHS, nor to their development and production in the UK

References

^1. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying anti-rheumatic drugs: 2013 update
^2.  NICE Technology Appraisal, Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor, 26th Janaury 2016. Available here 

^3. Adapted from IMS Institute for Healthcare Informatics Biosimilar Report 2014 ^.Savings in EPO market between 2006 and 2013.  
^4.  NRAS revised position statement on biosimilar medicines, June 2016 Available here
^5.  NHS England What is a biosimilar? Available for download here 
^6.  EU Consensus Information paper 2013. What you need to know about Biosimilar Medicinal products.
^7.  GfK, Factors supporting a sustainable European biosimilars market, September 2014. Available here
^8.  The Pharmaceutical Journal, Biosimilar medicines in rheumatology, 11^th November 2015, Tina Hawkins, Paul Emery. Available here 
^9.  NRAS, Big Poll Question on HealthUnblocked conducted by NRAS via its online community page and shared at the NHSE Biosimilar Regional meetings  - The question was "If your biologic was switched to a cheaper but equally good/safe drug to save money for the NHS, what would be the most important for you to know?”, March 2016

^10. Nor-Switch study: Another significant example of positive real world evidence on physician led switching to biosimilar medicines, Medicines for Europe. Available here.

^11. The Pharmaceutical Journal, Biosimilars and inflammatory bowel disease: a switch programme using CT-P13, September 2016, Caron Underhill, Available here.

¹² NICE, Introducing biosimilar versions of infliximab: Inflectra and Remsima. Available here

¹³ NHS England, Medicines Optimisation Hospital Dashboard. Available here

¹⁴ Datamonitor Healthcare