AN EXAMINATION OF THE REGULATORY AND REIMBURSEMENT PROCESSES FOR BIOBETTERS AND COMPARISON WITH BIOSIMILARS de Silva S.U., Dimova M., Bending M.W. Mapi HEOR & Strategic Market Access, LONDON

INTRODUCTION OBJECTIVE Biosimilars and biobetters are subsequent versions of licensed innovator A qualitative documentary analysis was performed to gain an understanding of biotherapeutics. Biosimilars are designed to be similar to an approved originator the regulatory and reimbursement approaches to the appraisal of biosimilars and biologic product, and are expected to demonstrate comparability to the originator biobetters in six European countries using HTA to inform decision making. The product in terms of quality, safety and efficacy;1 whereas biobetters incorporate filgrastims were examined as there are both biosimilars and biobetters approved intentional modifications to the originator molecular profile with the aim of in this product class. producing an improved product.2 This distinction between biosimilars and biobetters has important implications from a regulatory perspective, with METHODS biosimilars following class-specific guidance whereas biobetters are considered innovator drugs. Filgrastim, which is recombinant granulocyte-colony stimulating Within the product class of filgrastim, seven biosimilars, together with factor, is an example of a biologic drug for which there are biosimilar products.3 pegfilgrastim and lipegfilgrastim, were identified to have been approved in Within this product class are also two products referred to as ‘biobetters’  Europe. For each of these drugs, regulatory information and HTA documentation pegfilgrastim and lipegfilgrastim, which are pegylated forms of filgrastim.4,5 These from six European countries, were identified and reviewed for information on the pegylated forms are long-acting versions that require a lower frequency of processes of appraisal, the recommendations by indication, and the key factors administration compared with originator filgrastim.6 driving the reimbursement decisions. RESULTS Table 1. HTA appraisal recommendations for EMA approved biosimilar filgrastims, pegfilgrastim and lipegfilgrastim

Biosimilar/Biobetter Active substance EU approval HTA agency decisions date

Biograstim Filgrastim 2008 Not appraised Not appraised Not appraised Not appraised Not appraised Not appraised Ratiograstim Filgrastim 2008 Recommended Not appraised Recommended Recommended Recommended Not appraised Tevagrastim Filgrastim 2008 Recommended Not appraised Recommended Recommended Recommended Not appraised Zarzio Filgrastim 2009 Recommended Not appraised Recommended Recommended Recommended Not appraised Filgrastim Hexal Filgrastim 2009 Not appraised Not appraised Not appraised Not appraised Not appraised Not appraised Nivestim Filgrastim 2010 Recommended Not appraised Recommended Recommended Recommended Not appraised Grastofil Filgrastim 2013 Not appraised Not appraised Not appraised Not appraised Not appraised Not appraised Neulasta Pegfilgrastim 2002 Recommended Not appraised Recommended Recommended Recommended Not appraised Lonquex Lipegfilgrastim 2013 Not recommended Recommended Recommended Recommended Recommended Not appraised The regulatory approval of filgrastim biosimilars requires the demonstration of Sweden:11 Biosimilar medicines have the same reimbursement process as similarity to originator filgrastims; the specific non-clinical and clinical new chemical drugs in Sweden. Recommendations were based on clinical requirements are detailed in the guidance provided by the European Medicines comparability and lower drug acquisition costs, for the biosimilars versus the Agency (EMA) for the development of similar biological medicinal products originator, and for lipegfilgrastim versus pegfilgrastim. Use of the pegylated forms containing recombinant G-CSF.7 Biosimilar filgrastims were granted European of filgrastim appear to be restricted to certain situations where their use is marketing authorisation based on demonstration of clinical comparability to the considered appropriate.  originator filgrastim Neupogen in one indication (reduce duration of neutropenia Wales:12 The biosimilars and the pegylated forms of filgrastim were and occurrence of febrile neutropenia in chemotherapy patients showing recommended based on demonstration of clinical comparability to the respective cytotoxicity), and extrapolation of the results to all five approved indications. The comparator. Convenience with the use of the pegylated forms of filgrastim were EMA guidance on biosimilars is not applicable to modified ‘biobetter’ versions of additionally noted, and they were recommended for restricted use. A cost- the drug, such as the pegylated forms of filgrastim. Pegfilgrastim (Neulasta) minimisation analysis was provided for the biosimilars, while a cost-utility analysis demonstrated clinical non-inferiority to originator filgrastim in the same indication and budget impact analysis were considered for pegfilgrastim. as above and was approved solely for this indication. The subsequently 13 developed lipegfilgrastim (Lonquex) was approved for the same indication but England: Filgrastims have not been appraised by the National Institute for used pegfilgrastim as the comparator in clinical trials. Health and Care Excellence (NICE). To date, only one biosimilar product (somatropin; Omnitrope) has undergone HTA appraisal in England, with Decision drivers identified in the HTA appraisals were (Table 1): decisions on the use of biosimilars being made at a local payer level. NICE is France:8 The biosimilars were judged to have equivalent efficacy to the expected to publish guidance on the appraisal of biosimilars shortly. originator filgrastim and were placed in the category of no improvement in medical benefit (ASMR = 5). For the pegylated forms of filgrastim, although DISCUSSION there were no improvements in terms of efficacy or safety with respect to Biobetters are drugs in the same class as existing biological drugs but filgrastim, benefits were noted in terms of convenience of use and quality of life, incorporating improvements. Unlike biosimilars, biobetters are considered as leading to a positive recommendation for pegfilgrastim. However, for completely new drugs and cannot use the abbreviated regulatory approval lipegfilgrastim, an increased risk of mortality in a subgroup of patients was noted, pathways used by biosimilars. However, they provide an advantage to which is being evaluated further in post-marketing studies, resulting in the manufacturers through their lower Research and Development costs compared decision to not recommend in light of the availability of alternative drugs in this with originator biologics, and the granting of market exclusivity.2 product class. Beneficial characteristics of biobetters such as convenience of use, in the 9 Netherlands: Similarity to the originator as judged by the EMA was accepted as absence of demonstrated improvements in therapeutic effect, may not be sufficient evidence for the biosimilars and pegfilgrastim to be placed on the sufficient to justify a premium price to payers. This is seen with pegfilgrastim, a reimbursement list (Annex 1a), without undergoing a formal assessment. biobetter of filgrastim, where cost savings were demonstrated only in certain Lipegfilgrastim was added to this reimbursement list, allowing for circumstances as the price was higher than for biosimilars, and is therefore interchangeabilty of the originator filgrastim, biosimilar filgrastims, and the recommended in multiple countries for restricted use only. Follow-on versions of pegylated forms of filgrastim within this product cluster on the GVS formulary. existing biobetters achieve reimbursement by offering lower drug acquisition Scotland:10 Evidence of clinical non-inferiority to the respective comparator was costs, as seen with lipegfilgrastim that was developed subsequently as a accepted in the appraisal of biosimilars and the pegylated forms of filgrastim. comparable product to pegfilgrastim. Other biobetters have demonstrated Economic evidence considered for the biosimilars consisted of a cost- therapeutic benefits, such as improved efficacy observed with pegylated forms of minimisation analysis and a budget impact analysis; cost effectiveness interferon alfa (peginterferon alfa) versus originator interferon alfa, with cost demonstrated in one indication was extrapolated to the other indications. The effectiveness considered in their reimbursement.14 As with biosimilars, payer pegylated forms of filgrastim were considered beneficial in terms of convenience, concerns exist with respect to the need for long-term safety data on biobetters, with cost savings due to lower drug acquisition costs, and recommended for which may preclude reimbursement on the basis of availability of alternative restricted use where a long-acting G-CSF is considered appropriate in line with products. HTA agencies do not currently have any guidance in place on the current clinical practice. appraisal of biosmilars or biobetters. REFERENCES 1. EMA. Biosimilar Medicines. http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000318.jsp 2014; Accessed October 27, 2014. 2. Generics and Biosimilars Initiative. http://gabionline.net/Biosimilars/Research/Biosimilars-or-biobetters-what-does-the-future-hold 2011; Accessed October 27, 2014. 3. EMA. Filgrastim. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124&source=homeMedSearch&keyword =filgrastim&category=human&isNewQuery=true 2014; Accessed October 27, 2014. 4. Satterwhite, C. Assessing Development Needs for Biobetters and Biosimilars. http://www.biopharminternational.com/biopharm/ArticleStandard/Article/detail/804371 2013; Accessed October 27, 2014 5. Biosimilar News. Teva receives EU nod for Neulasta biosimilar. http://www.biosimilarnews.com/teva-receives-eu-nod-for-neulasta-biosimilar 2013; Accessed October 27, 2014 6. EMA. Lonquex; Summary for the public. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002556/WC500148383.pdf 2013; Accessed October 27, 2014 7. EMA. Guidance on Similar Biological Medicinal Products containing Recombinant Granulocyte-Colony Stimulating Factor http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003955.pdf 2006; Accessed October 27, 2014 8. Haute Autorité de Santé. http://www.has-sante.fr/portail/jcms/fc_1249588/en/accueil 2014; Accessed October 27, 2014. 9. College voor Zorgverzekeringen. http://www.zorginstituutnederland.nl/ 2014; Accessed October 27, 2014. 10. Scottish Medicines Consortium. https://www.scottishmedicines.org.uk/Home 2014; Accessed October 27, 2014. 11. Tandvårds-och läkemedelsförmånsverket. http://www.tlv.se/ 2014; Accessed October 27, 2014. 12. All Wales Medicines Strategy Group. http://www.awmsg.org/awmsgonline/app/appraisalinfo/1297 2014; Accessed October 27, 2014. 13. NICE. http://www.nice.org.uk/ 2014; Accessed October 27, 2014. 14. NICE. NICE technology appraisals [TA200] http://www.nice.org.uk/guidance/ta200/chapter/4-evidence-and-interpretation 2010; Accessed October 27, 2014.

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ISPOR 17th Annual European Congress Dr. Shamika de Silva, [email protected] Amsterdam  November, 2014 www.mapigroup.org