Urszula Wojtyra November 20 2019 Update on biosimilars Smart & Biggar | Healthcare & Life Sciences - Canada Urszula Wojtyra Healthcare & Life Sciences Biosimilars approved by Health CanadaBiosimilar submissions under reviewHealth Canada newsBiosimilar litigationMarket accessCompetition BureauCommentBelow is an overview of the biosimilars developments – including with regard to approvals, pending submissions, regulatory developments, litigation and market access – that have taken place in Canada since June 2018 (for earlier developments, please see "Mid-year biosimilars update").Biosimilars approved by Health CanadaSo far in 2019, Health Canada has approved five biosimilars of three innovator products. This brings the total Health Canada approvals to 18 biosimilars of 11 innovator products. BiosimilarManufacturer and year of approvalReview time (from filing to the earlier of approval and IP hold, where available)Medicinal ingredientMarketed?1OmnitropeSandoz; 2009748 daysSomatropinYes2, 3Remsima/InflectraCelltrion and Hospira; 2014427 daysInfliximabYes (Inflectra)4BasaglarEli Lilly; 2015356 daysInsulin glargineYes5GrastofilApotex; 20151039 days(1)FilgrastimYes6BrenzysSamsung Bioepis; 2016358 daysEtanerceptYes7ErelziSandoz; 2017353 daysEtanerceptYes8AdmelogSanofi-aventis; 2017351 daysInsulin lisproNo9RenflexisSamsung Bioepis; 2017793 daysInfliximabYes10Hadlima, Hadlima PushtouchSamsung Bioepis; 2018432 daysAdalimumabNo11LapelgaApotex; 2018349 daysPegfilgrastimYes12MvasiAmgen; 2018358 days (IP hold)BevacizumabYes13FulphilaMylan; 2018754 daysPegfilgrastimYes14TruximaCelltrion; April 2019335 (IP hold)RituximabNo15OgivriBGP Pharma; May 2019745 daysTrastuzumabYes16ZirabevPfizer; June 2019336 daysBevacizumabYes17TrazimeraPfizer; August 2019608 daysTrastuzumabNo18HerzumaCelltrion; September 2019679 daysTrastuzumabNoAccording to its annual report, Health Canada approved 11 biosimilar submissions in the 2018/2019 fiscal year, which ran from 1 April 2018 to 31 March 2019, and seven in the previous fiscal year. Six of these are likely to be on IP hold.Biosimilar submissions under reviewSince October 2018 Health Canada has provided a monthly update of new drug submissions under review, identifying the sponsor, filing date and submission class, including whether the drug is a biosimilar. The most recent submissions under review (as of 13 September 2019) identify the following biosimilar submissions under review along with the month in which each submission was accepted for review:Adalimumab – Sandoz, November 2018;Filgrastim – Tanvex Biopharm, March 2019;Infliximab – Amgen, May 2019;Pegfilgrastim – Sandoz, May 2019; andRituximab – Pfizer, March 2019.There are also new drug submissions pending for the following:Bevacizumab (one);Filgrastim (one);Rituximab (one);Teriparatide (one); andTrastuzumab (five).These are likely biosimilars but they are not specifically identified as such as they were filed before October 2018.Health Canada newsOn 27 August 2019 Health Canada published an updated Biosimilar Biological Drugs in Canada: Fact Sheet. The fact sheet provides an overview of the regulatory framework for biosimilar drugs in Canada, including:the approval process at Health Canada;how safety is monitored; andhow interchangeability and switching are governed at the provincial level.Earlier in 2019, Health Canada announced its Policy Statement on the Naming of Biologic Drugs (for further details please see "Health Canada announces decision on naming of biologic drugs"), which states that "biologic drugs, including biosimilars, will be identified by their unique brand name and non-proprietary (common) name, without the addition of a product-specific suffix". Further, both the brand and non-proprietary names should be used throughout the medication use process to allow biologics that share the same non-proprietary name to be distinguished by their unique brand names.In terms of approvals, according to Health Canada's Regulatory Decision Summaries, the following apply:A drug referencing a biologic may be reviewed as a generic pharmaceutical product rather than a biosimilar – for example, Teva has received an approval for Teva-Teriparatide for which the Canadian reference product was Eli Lilly's Forteo. While Forteo is a biologic product, Teva-Teriparatide, produced using solid phase chemical synthesis, was classified as a pharmaceutical drug substance rather than a biologic and was therefore approved using the abbreviated new drug submission (ANDS) pathway.(2) See also the Teva-Liraglutide pending ANDS discussed below.A biosimilar approved in other countries may not be approved in Canada – while Mylan's Semglee (a biosimilar of Lantus, insulin glargine) is approved by the European Medicines Agency, BGP Pharma cancelled its submission prior to Health Canada rendering a final decision. According to the Regulatory Decision Summaries, Health Canada had issued a Notice of Deficiency and found that the clinical data was inadequate to address Health Canada's concerns. In addition, the chemistry and manufacturing data were deficient.Biosimilar litigationMany of the cases reported in 2018 have been discontinued (for further details please see "Mid-year biosimilars update). The following litigation continues.Filgrastim and pegfilgrastimAmgen has sued BGP Pharma dba Mylan for patent infringement in respect of the pegfilgrastim biosimilar Fulphila. Amgen had previously sought an order under the pre-amended Patented Medicines (Notice of Compliance) (PMNOC) Regulations prohibiting the minister of health from issuing a notice of compliance (NOC) to Mylan, but discontinued the application in light of the court's dismissal of Amgen's application against Apotex.Amgen also has ongoing patent infringement actions against Sandoz pursuant to the amended PMNOC Regulations in respect of Sandoz's proposed filgrastim biosimilar Zarxio (1503-18) and pegfilgrastim biosimilar Ziextenzo (T-902-19). The trials for both actions are scheduled to be heard together in April 2020, although Amgen has a motion scheduled to adjourn the latter trial.Finally, the trial of Amgen's action against Pfizer under the amended PMNOC Regulations is scheduled for January 2020. Pfizer had unsuccessfully sought to dismiss the action as an abuse of process and, most recently, the Federal Court of Appeal dismissed Pfizer's appeal (for further details please see "Amgen not precluded from asserting patent under current PMNOC Regulations").(3)InfliximabJanssen was successful in its patent infringement action against Hospira in respect of Hospira's biosimilar Inflectra (for further details please see "New use patent valid and infringed by biosimilar"). The Federal Court of Appeal heard the appeal of this decision, and other related procedural decisions, on 28 and 29 October 2019 and reserved its decision. The trial of the remedy phase of the patent infringement action is scheduled to start in January 2020.There is also litigation relating to Novo Nordisk's biologic Victoza (liraglutide) against Teva. Teva had filed an ANDS for its proposed Teva-Liraglutide product based on a comparison to Victoza. Novo Nordisk asserted that Teva ought to have filed a new drug submission, as is required for a biologic products, but Novo Nordisk was unsuccessful in its court application challenging the minister of health's decision to accept the submission for review as an ANDS (for further details please see "Court strikes Novo Nordisk's judicial review application"). Novo Nordisk has sued Teva for patent infringement pursuant to the amended PMNOC Regulations and the trial is scheduled for October 2020. Separately, Novo Nordisk has commenced another patent infringement action against Teva with respect to a patent not listed on the patent register. This first-of-its-kind action is permitted by Section 8.2 of the amended PMNOC Regulations, which allows a first person or patentee to bring an infringement action regarding a patent not listed on the patent register once served with a notice of allegation.Market accessIn September 2018 the pan-Canadian Pharmaceutical Alliance (pCPA) issued the Biologics Policy Directions & pCPA Negotiations, which outline the pCPA's policy as it applies to negotiations for the reimbursement of biologics, including biosimilars. The policy includes a statement that offers for biologics that restrict or exclude biosimilars will not be considered and that switching of patients from a reference biologic to a biosimilar may be implemented. The pCPA also partnered with Cancer Care Ontario to create a pan-Canadian Oncology Biosimilars Initiative, which aims to ensure appropriate implementation and cost-effective use of therapeutic oncology biosimilars across Canada. The initiative has released a proceedings report of a summit it held in 2018, as well as a pan-Canadian Oncology Biosimilars Initiative Action Plan.The Canadian Agency for Drugs and Technologies in Health (CADTH) released an Environmental Scan on International Policies on the Appropriate Use of Biosimilar Drugs.(4)There has been a move to improve the efficiency of funding consideration of biosimilars. CADTH announced that as of 1 June 2019 it will no longer review biosimilars through the Common Drug Review (CDR) or the pan-Canadian Oncology Drug Review. Subsequent to CADTH's announcement, the pCPA provided an update advising that absence of CADTH review will not affect when pCPA negotiations may be initiated. As such, a biosimilar sponsor may contact the pCPA up to six months before obtaining an NOC from Health Canada to start the negotiation process. The Ontario Ministry of Health issued a policy directive that announced that new approved biosimilars will not require a routine review by the ministry's expert drug advisory committees.At the provincial level, different provinces have instituted different policies for biosimilars to achieve cost savings:British Columbia PharmaCare instituted the Biosimilars Initiative for Patients to switch patients from using certain reference biologics to biosimilars for certain indications.While the Quebec minister of health and social services sought to halt coverage of Remicade, with certain exceptions, the Quebec Court of Appeal found the minister's decision to delist Remicade invalid and Quebec reinstated the listing (for further details please see "Quebec Court of Appeal overturns decision to delist Remicade from Quebec's List of Medications").In Ontario, the Ministry of Health reimburses infliximab biosimilars (Renflexis and Inflectra) and etanercept biosimilars (Brenzys and Erelzi) as limited-use products for many of the indications of the reference biologics. The reference biologics (Remicade and Enbrel, respectively) are reimbursed under the Exceptional Access Programme (with the exception of Enbrel for severe plaque psoriasis, which is funded as a limited-use product). Similarly, the filgrastim biosimilar Grastofil is funded as a general benefit, whereas Neupogen is funded only as a limited-use product. With some exceptions, the ministry will not consider any new requests for the reference biologics for treatment-naive patients or for patients who do not respond to biosimilars. However, the ministry will generally not require the switching of patients who have existing Exceptional Access Programme approval for the reference biologics.The Patented Medicine Prices Review Board released the 5th Edition of CompassRx, the Annual Public Drug Plan Expenditure Report for 2017/18. The report concluded that the total savings offered by biosimilars were limited, with the three biosimilars marketed by that timepoint "making a small but growing difference in overall drug costs". In a closer look at the disease-modifying antirheumatic drugs market, the report found that once Inflectra, a biosimilar of Remicade (infliximab), was introduced, the number of new patients using infliximab dropped from 23% to 12%, with half of those using Inflectra. However, other biologics grew their market share and occupied the share held by infliximab in previous years.Competition BureauIn terms of marketing practices, in February 2019 the Competition Bureau issued a statement providing guidance on some competition issues relevant to biologics and biosimilars. The statement outlined the various factors that may lead to fewer manufacturers developing biosimilar products (eg, increased risk of failure, higher costs of manufacture and prolonged time for development and regulatory approval) and factors that may lead to lesser penetration in markets (eg, lack of consensus about switching and the role of infusion clinics).The bureau advised that it will continue to monitor the biologic and biosimilar markets to ensure that companies refrain from conduct that has or is likely to have the effect of substantially lessening or preventing competition. In particular, the statement pointed to a likelihood of public and private payers implementing switching policies, noting that the bureau will monitor reference biologic manufacturers' conduct in response. Conduct that could be anti-competitive may include the spreading of false or misleading information about the safety and efficacy of biosimilars or entering into agreements with payers that have restrictions on the reimbursement of biosimilars.CommentSince June 2018 a number of developments relating to biosimilars have occurred. It is anticipated that 2020 will be as eventful as 2019.For further information on this topic please contact Urszula Wojtyra at Smart & Biggar by telephone (+1 416 593 5514) or email ([email protected]). The Smart & Biggar website can be accessed at www.smart-biggar.ca.Endnotes(1) Calculated based on the IP hold date (21 May 2015) in Apotex's statement of claim in Court File T-934-16.(2) Health Canada's Regulatory Decision Summary for Teva-Teriparatide is available here.(3) Further updates to Amgen are available here.(4) An overview of the Environmental Scan's analysis, grouped under the categories of interchangeability, switching and substitution, supply side policies (relating to drug pricing, procurement and pharmacy reimbursement and practices) and prescribing incentives, is available here.