CADTH Health Technology Review

Formulary Management of Targeted Immune Modulators in Ulcerative Colitis

Environmental Scan

Authors: Sirjana Pant, Kim Le, Chris Vannabouathong, Peter Dyrda

Key Messages

• Health Canada has approved 7 targeted immune modulators for the treatment of adults with moderate to severe ulcerative colitis, which include 5 biologics (adalimumab, infliximab, golimumab, ustekinumab, and vedolizumab) and 2 small molecules (tofacitinib and ozanimod). Biosimilars for adalimumab and infliximab and generics for tofacitinib are currently available in the Canadian market; however, although their patent protection has expired, there are no biosimilars for golimumab and ustekinumab.

• All targeted immune modulators have undergone pan-Canadian Pharmaceutical Alliance negotiations and concluded with a Letter of Intent except for ustekinumab, which is the only targeted immune modulator not included on any public formularies for ulcerative colitis. Coverage is consistent across all drug plans except for golimumab and tofacitinib, which is not covered by all jurisdictions for ulcerative colitis.

• Most public drug plans have implemented or have announced a biosimilar policy to promote the use of biosimilars over originator biologics. The listing status for targeted immune modulators in ulcerative colitis is similar across public drug plans; however, there is heterogeneity in criteria requirements for prior treatments and diagnosis definitions.

• Considering these factors and the emergence of new data, it would be important to reassess these drugs and evaluate their place in therapy. Further research, such as horizon scanning, utilization analyses, and long-term effectiveness and safety studies, is warranted for targeted immune modulators to ensure the appropriate use of these drugs in the treatment of moderate to severe ulcerative colitis.

Summary

Objective

• This Environmental Scan was conducted to gain a better understanding of the current landscape of targeted immune modulators (TIMs) used for treating moderate to severe ulcerative colitis (UC) in Canada. The scan focuses on the regulatory, exclusivity, and reimbursement statuses of these drugs across Canadian public formularies.

Regulatory Status

• The landscape of UC treatment is rapidly expanding with the development of novel therapies, and biosimilar and generic entrants. Health Canada has approved 7 TIMs for the treatment of adults with moderate to severe UC, which include 5 biologics and 2 small molecules:

  • Biologics (5): Tumour necrosis factor antagonists (adalimumab, infliximab and golimumab), an anti-interleukin 12/23 drug (ustekinumab), and an anti-integrin drug (vedolizumab).

  • Small molecules (2): A Janus kinase inhibitor (tofacitinib) and a sphingosine-1-phosphate receptor modulator (ozanimod).

• Adalimumab and infliximab have a total of 8 and 3 biosimilars available in the Canadian market, respectively. Nine of these biosimilars have been in the market since 2020. Tofacitinib has 3 generic versions that became available in the Canadian market in November 2022.

Exclusivity Status

• Of the 7 approved drugs, patent protection for infliximab, golimumab, and ustekinumab has expired.

  • Despite the expiration of both patent and data protection for ustekinumab and golimumab, with data protection having ended over 5 years ago and patents expiring in 2021, there are presently no biosimilar versions available in Canada. A lack of a biosimilar entrant in Canada could be attributed to various factors, including clinical trial development based on exclusivity timelines in the US, where data protection is 4 years longer than it is in Canada. Seven biosimilar versions of ustekinumab have recently completed phase III trials or have an estimated study completion date in 2023.

• Adalimumab still has active patents and predates data protection, and its biosimilar versions were marketed for UC approximately 3 years after the initial Notice of Compliance (NOC) was issued. This delay can be attributed to various factors, including litigation and global agreements between manufacturers.

• Tofacitinib’s data protection expired in 2022 and generic versions are currently available, whereas vedolizumab’s data protection is approaching expiry in 2023.

CADTH Review Status

• All TIMs, including biosimilars, used in UC have had comparable recommendations from CDEC, which were informed by placebo-controlled trials.

Reimbursement Status

• All TIMs, including biosimilars, have undergone pan-Canadian Pharmaceutical Alliance negotiations for UC except for 3 biosimilar versions of infliximab (Remsima, Renflexis, and Inflixi). All negotiations concluded with a Letter of Intent (LOI) except for ustekinumab, which is the only targeted immune modulator not included on any public formularies for UC.

• Coverage is consistent across all drug plans except for golimumab, which is not covered by British Columbia and Prince Edward Island, and tofacitinib, which is not covered by Yukon and Correctional Services Canada (CSC).

• Biosimilar policies in British Columbia, Alberta, New Brunswick, and Newfoundland and Labrador mandate that all patients be administered biosimilar versions of adalimumab or infliximab if they are treatment-naive or switch to these biosimilars even if they are taking the originator biologic. Similar biosimilar initiatives were recently announced by Nova Scotia (effective February 2023), Saskatchewan (effective April 2023), and Ontario (effective December 2023). Currently, Ontario, Saskatchewan, Manitoba, New Brunswick, Newfoundland and Labrador, Prince Edward Island, Yukon, Non-Insured Health Benefits (NIHB), CSC, and Canadian Armed Forces (CAF) drug plans mandate the use of biosimilars for treatment-naive patients only for adalimumab or infliximab.

• Two public drug plans (Manitoba and CSC) currently employ 2-tiered formularies, which require a trial of a tier 1 drug before reimbursement of a tier 2 drug. The second-tier drugs generally include the originator biologics for which a biosimilar version is available and funded.

• The initial coverage criteria for TIMs in UC include an objective diagnosis based on the Mayo Score with a rectal bleeding subscore or an endoscopic subscore, which varies across jurisdictions. Except for Yukon and Ontario, which require a Mayo Score of at least 6 and endoscopic subscore of at least 2, all other jurisdictions require a Mayo Score of at least 4 with or without a rectal bleeding subscore of at least 2. Criteria for adalimumab differs from that of infliximab, golimumab, and vedolizumab in New Brunswick, which does not require a Mayo Score for coverage of adalimumab, and in Yukon, which accepts a lower Mayo Score for coverage of adalimumab.

Conclusion

• In summary, the results of this Environmental Scan have revealed that access criteria for TIMs for UC are broadly similar in terms of being restricted for use in patients with moderate to severe UC after failure of a conventional therapy; however, there is considerable heterogeneity in other criteria related to TIM coverage, including requirements for prior treatments and diagnosis definitions. A tiered approach to ensure optimal sequencing of these drugs, supported by an appropriate drug class review, can seek payers greater value from TIMs that have demonstrated superiority as well as from equally effective drugs that have cheaper generic or biosimilar versions. There may also be opportunities to harmonize requirements for prior therapy as well as coverage criteria between public payers, based on recent evidence on best treatment practices and objective diagnosis.

• Considering these factors and the emergence of new data, it would be important to reassess these drugs and evaluate their place in therapy. Further research, such as horizon scanning, utilization analyses, and long-term effectiveness and safety studies, is warranted for TIMs to ensure the appropriate use of these drugs in the treatment of moderate to severe UC.

Disease and Treatments

UC is an inflammatory bowel disease (IBD) that causes inflammation and ulcers in the digestive tract, affecting the mucosa of the large intestine (colon) and rectum.^1,2 Although the etiology of UC is not completely understood, there is growing evidence to suggest that genetic and environmental factors may contribute to the irregular immune response that aberrantly recruits activated immune cells to the colon,³ which results in chronic inflammation that damages the colon and causes UC symptoms. UC generally develops in young adulthood^4-6 and persists throughout life, marked by periods of spontaneous remission and relapse.⁷ The most common initial manifestation of UC is bloody diarrhea with or without mucus. In addition to frequent evacuations with blood and mucus, other symptoms include urgency or tenesmus of evacuations, fever, abdominal pain, and weight loss.^3,8

UC has a worldwide incidence rate of 1.2 cases per 100,000 to 20.3 cases per 100,000 and a prevalence of 7.6 cases per 100,000 to 246.0 cases per 100,000.³ In 2017, the highest age-standardized prevalence rate of IBD occurred in high-income countries in North America,⁹ with Canada having 1 of the highest rates of in the world.⁴ The incidence rate for UC in Canada ranges from a low of 8.4 per 100,000 people in Alberta to a high of 21.4 per 100,000 people in Nova Scotia.^4-6 There are an additional 15,000 individuals living with IBD in Canada who are not clearly classified as Crohn disease or UC (termed indeterminate colitis).¹⁰ Since 1990, the incidence of UC has remained stable in Manitoba (UC incidence: 10.8 per 100,000 people) while it has decreased in Alberta, Nova Scotia, and Quebec (UC incidence: 10.7 per 100,000 people) and increasing in Ontario (UC incidence: 11.1 per 100,000 people).^4-6

The majority of individuals living with UC have a mild to moderate disease course, generally most active at diagnosis and then in varying periods of remission or mild activity.¹¹ However, aggressive disease course is experienced in 10% to 15% of patients, with a cumulative risk of relapse between 70% to 80% at 10 years postdiagnosis.¹¹ Regardless of severity, UC is associated with high morbidity, with high rates of fatigue, inferior health-related quality of life, and high disability, with approximately half of all patients hospitalized for UC at some point during the disease course. Moreover, approximately 1.5% of patients with UC are diagnosed with colorectal cancer, typically after prolonged active inflammation. Although UC is not associated with increased risk of all-cause mortality in the first year after diagnosis,¹² gastrointestinal-specific mortality may be increased.^11,12 Indeed, data from Manitoba suggest that, compared to the general population, individuals with UC are more likely to die from colorectal cancer or respiratory disease with the greatest risk of death being in the first 30 days following gastrointestinal surgery.¹² In Ontario, the leading cause of death in seniors with UC is solid malignancies;¹³ in Quebec, mortality from digestive, respiratory, and infectious conditions, as well as all-cause mortality, is increased for individuals with UC.¹⁴

In Canada, approximately $1.2 billion is spent on health care utilization costs in patients with IBD, and an estimated indirect cost of $1.5 billion is borne due to loss of work and productivity, disability coverage, and premature retirement or death.^15,16 In fact, the annual cost due to medical absenteeism is approximately $88 million,¹⁷ while the estimated lifetime lost wages due to premature retirement due to UC is $994,760 per person.¹⁷ Furthermore, 56% to 74% of people living with IBD in Canada have reported paying out of pocket for complementary and alternative medicines;^18-20 with no difference between patients with Crohn disease versus those with UC.¹⁸ A US national survey estimated that the annual per-person out-of-pocket cost of using complementary and alternative medicine was US$1,236 for patients with UC.²¹

Treatment strategies have traditionally followed a step-up approach. Mild UC is typically managed using orally or rectally administered sulfasalazine and 5- aminosalicylic acids (5-ASAs). Conventional pharmacotherapy for moderate to severe UC entails an initial induction of remission with a corticosteroid; however, due to the side effects associated with corticosteroid, they should be reserved for induction therapy and not considered for long-term maintenance therapy. For patients who do not have an adequate response on a 5-ASA or corticosteroid, conventional immunosuppressants, such as azathioprine, mercaptopurine, and methotrexate, are treatment options. Should either drug class fail to provide durable effects, TIMs, such as biologics and small molecule drugs, can be used. Biologics for UC include tumour necrosis factor antagonists (infliximab, adalimumab, and golimumab), an anti-integrin antibody (vedolizumab), and an anti-interleukin (IL)-12/23 inhibitor (ustekinumab). The small molecules include a Janus kinase inhibitor (tofacitinib) and a sphingosine-1-phosphate receptor modulator (ozanimod). Biologics may lose effectiveness over time. One cause is the development of antidrug antibodies. In this situation, another biologic of the same class may be given. If loss of response persists or is not attributable to antidrug antibodies, patients may be switched to a different class.²³ Because UC is a lifelong disease, management can become complex and can require multiple drugs in sequence or colectomy. The costs of these drugs can be substantial over time.

Objectives

Given the significant expenditures in Canada on biologic drugs, as well as the changing dynamics regarding loss of exclusivity, market entry of new drugs, biosimilars and generics, and availability of new evidence, an Environmental Scan (ES) was warranted for this treatment class. This ES assessed the regulatory, exclusivity, CADTH review, and reimbursement status of TIMs used to treat adults with moderate to severe UC relevant to Canadian federal, provincial, and territorial public drug plans.

The objectives of this ES were to provide a summary of the following for TIMs in the treatment of moderate to severe UC:

1. Regulatory status: including date of NOC, first marketed date, and indication with regards to UC

2. Exclusivity status: data protection and patent expiry dates, including potential biosimilar or generic entrants

3. CADTH review status: studies assessed and reasons for recommendation

4. Reimbursement status: listing status and coverage criteria across federal, provincial, and territorial public drug plans.

Methods

This ES provides information on the regulatory and reimbursement status and CADTH reviews on TIMs used in patients with moderate to severe UC. The components of the information presented in this scan are presented in Table 1. In this report, the term “drug” is used to refer to biologics and their biosimilar version (if available) and small molecule originators used in the treatment of UC, as listed in Table 1.

Table 1: Components for Literature Screening and Information Gathering

CDR = CADTH Common Drug Review; JAK = Janus kinase; UC = ulcerative colitis.

^aOmvyence (infliximab, Janssen Inc.) was approved on December 29, 2020, by Health Canada. This product is not a biosimilar. The NOC submission was made for an Additional Product Name for Remicade. The product is approved by Health Canada but not yet marketed in Canada.^32,33

^bInflixi is approved, not yet marketed. “Approved” refers to an active Drug Identification number (DIN) for a product that has been reviewed and authorized for sale in Canada but has not yet been marketed in Canada. ‘Marketed’ refers to an active DIN for a product that is currently being sold in Canada. “Dormant” refers to an active DIN for a product that was previously marketed in Canada but for which there have been no sales for period of at least 12 consecutive months.³⁴

^cNunavut and the Northwest Territories follow the coverage category and criteria of the Non-Insured Health Benefits program.^30,31

Literature Search

A grey literature search was conducted on key resources, including the websites of Health Canada’s drug product database, patent register, and data protection register; CADTH website (CADTH Common Drug Review [CDR] records); Canadian public drug plan formulary databases; and clinicaltrials.gov database. No bibliographic literature searches were performed. The public drug plan databases were searched between April 10, 2022, and June 10, 2022. Other databases were searched between April 10, 2022, and December 21, 2022.

Some information presented in this report was not available in the public domain and was obtained through personal communication with members of the CADTH Formulary Working Group Health Technology Assessment (FWG-HTA) committee.²⁹ In these cases, permission was obtained to publish this information in this report, and all details obtained through personal communication were referenced accordingly. Information from 4 federal public drug plans was included: NIHB, CSC, VAC, and CAF. Publicly reimbursed medications for residents of Nunavut and the Northwest Territories follow the coverage category and reimbursement criteria of the NIHB program.^30,31

Exclusions

Private payers and Quebec’s public drug program, the Régie de l’assurance maladie du Québec (RAMQ), were excluded. The drugs included in this report are also indicated for medical conditions other than UC; however, relevant information related only to the UC indication are presented in this report. In addition to coverage criteria for the specific drugs, other relevant formulary policies are presented in this report, such as policies on the use of biosimilar drugs and biosimilar switching. Although the clinical basis and economic basis for a CADTH recommendation for the drugs (biologics and their biosimilar versions and small molecule TIMs) for UC are presented, this ES did not assess the comparative clinical effectiveness or the relative cost-effectiveness of the drugs used in the treatment of patients with UC. Thus, any conclusions or recommendations about the value of these medications or their place in therapy were outside of the scope of the ES.

Findings

A summary of findings related to the regulatory, exclusivity, CADTH review, and reimbursement status of TIMs used in the treatment of patients with UC is presented in the sections that follow.

Regulatory Status

Health Canada has approved 7 TIMs for the treatment of moderate to severe UC. These include 5 biologics and 2 small molecules. Of the 5 biologics for UC, 2 have biosimilar versions (adalimumab and infliximab) available in the Canadian market. Health Canada has approved 8 and 5 biosimilar versions of adalimumab and infliximab, respectively. All 8 biosimilars of adalimumab are marketed in Canada. Among the 5 infliximab biosimilars, 3 are marketed in Canada. Three generic versions of tofacitinib have recently been marketed in Canada. Although all 7 TIMs are indicated for the adult population, only 2 are indicated for pediatrics (adalimumab and infliximab).^33,35-39

Currently, all biologic and biosimilar drugs for UC are available as IV and/or subcutaneous (SC) formulations. Adalimumab is available in SC formulation only.^{45,46,49 to 53,60,64.} Infliximab is available in IV formulation only. One of the biosimilar versions of infliximab (Remsima IV) is indicated in UC, but the product is no longer marketed in Canada. There is an SC formulation of the product (Remsima SC) marketed in Canada; however, it is not considered a biosimilar to the SC formulation of Remicade (originator biologic for infliximab) and is not approved for use in UC.^47,54,56-59 Golimumab, vedolizumab, and ustekinumab are available in both SC and IV formulations; however, the IV formulation of golimumab is not approved for use in UC.^48,61,62 Both the small molecule drugs, tofacitinib and ozanimod, are available in oral formulations.^63,65

The approval timeline in Figure 1 indicates the date of NOC for each drug for the UC indication. Some drugs received NOC for the UC indication after receiving their first NOC (for indications other than UC). Among the originator biologics, adalimumab (Humira), infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio SC only), and ustekinumab (Stelara) received their NOC for UC in 2013 (versus 2004 for first NOC), 2006 (versus 2001 for first NOC), 2013 (versus 2009 for first NOC), 2020 (versus 2015 for first NOC), and 2020 (versus 2008 for first NOC), respectively.^40-49 Both infliximab biosimilars, Inflectra and Remsima, received their NOC for UC in 2016 (versus 2014 for first NOC).^42,43,50,51 Among the small molecules, tofacitinib (Xeljanz) and ozanimod (Zeposia) received their NOC for UC in 2018 (versus 2014 for first NOC) and 2022 (versus 2020 for first NOC), respectively.^52-55 Figure 2 in Appendix 1 presents the approval timeline for the date of first NOC regardless of the indication, and Table 7 in Appendix 1 presents the regulatory information, including manufacturer, date of NOC, first marketed date, and indication with regards to UC for each drug.

Exclusivity Status

Exclusivity status is a function of patent and data protection. Patent protection is a 20-year period offered to innovative drugs from the date of filing that can be applied in various manners (e.g., chemical, change in use). Data protection regulations in Canada are governed by regulations under the Food and Drug Regulations published in 2006.^95,96 These regulations provide data protection for an 8-year term with a possibility of adding 6 more months for submissions that include pediatric studies. During this time, only the owner or generator of preclinical and clinical trial data can use these data to obtain marketing authorization for drugs, effectively preventing a second-entry manufacturer from filing a submission for a copy of that innovative drug. Data protection begins from the time of issuance of NOC by Health Canada and when the drug is added to the Health Canada’s Register of Innovative Drugs.^95,96 Data protection for biologics in the US is 12 years from approval.⁹⁷

Patent protection is still valid for most TIMs except for 4; patent protection for infliximab expired in August 2017, both golimumab and ustekinumab expired in August 2021, and tofacitinib expired in 2022. The other 3 TIMs (adalimumab, vedolizumab, and ozanimod) have existing registered patents in Canada. Of these, the earliest patent to expire will be adalimumab in 2023 and the last patent to expire will be for vedolizumab in 2032.⁹⁸

Figure 1: Health Canada Approval Timeline for Targeted Immune Modulators by NOC Date for UC Indication

NOC = Notice of Compliance; UC = ulcerative colitis.

^a Originator biologics: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Entyvio (vedolizumab), and Stelara (ustekinumab).

^b Small molecules: Xeljanz (tofacitinib) and Zeposia (ozanimod).

^c Biosimilars: Adalimumab biosimilars (Amgevita, Hadlima, Hulio, Hyrimoz, Idacio, Abrilada, Simlandi, Yuflyma) and infliximab biosimilars (Inflectra, Remsima, Renflexis, Avsola, Ixifi). Generics: Tofacitinib (Auro-Tofacitinib, PMS-Tofacitinib, and Taro-Tofacitinib.

^d Remsima IV is indicated in adult and pediatric UC; however, the product is “dormant,” and not marketed in Canada. Remsima SC is marketed in Canada but is not indicated in adult or pediatric UC. “Approved” refers to an active Drug Identification number (DIN) for a product that has been reviewed and authorized for sale in Canada but has not yet been marketed in Canada. “Marketed” refers to an active DIN for a product that is currently being sold in Canada. Dormant refers to an active DIN for a product that was previously marketed in Canada but for which there have been no sales for period of at least 12 consecutive months.³⁴

^e Only approved but not yet marketed.

Sources: Information was collected from Health Canada’s Drug Product Database and Notice of Compliance Database.^{32,33,37-46,48-54,56-94}

Of the 7 TIMs approved for UC, all biologics except for vedolizumab have had their data protection status expire or have predated the enactment of the data protection regulations of 2006. Vedolizumab’s data protection will expire in July 2023. Data protection for tofacitinib expired in 2022 and ozanimod will expire in October 2026.⁹⁴ Table 2 presents the status of data protection and patent expiry for the TIMs.

Biosimilars are approved for adalimumab despite registered patents for the originator biologic because the approval of adalimumab predated data protection regulations, thus data protection does not apply. However, it has been more than 8 years since the NOC date for the UC indication for adalimumab and more than 15 years since the NOC date for the UC indication for infliximab (Table 7). There was almost a 3-year delay between the NOC approval and marketed date for the first adalimumab biosimilar, Hadlima The delay is likely the result of litigation and/or agreements between the originator and biosimilar manufacturers.^99,100 Despite the expiry of data and patent protection for both ustekinumab and golimumab, no biosimilar versions are currently available in Canada. Because the US market presents the largest opportunity for biosimilar developers,¹⁰¹ global development timelines for biosimilars may be based around US exclusivity timelines. The fact that the US applies a longer period of data exclusivity for biologics compared with Canada⁹⁷ may explain some of the previous delays and the future delays that may occur for biosimilar launches in Canada.

A search on the clinical studies database, clinicaltrials.gov, for clinical trials on biosimilar versions of golimumab, ustekinumab, and vedolizumab found 7 biosimilar versions of ustekinumab in phase III (Appendix 2, Table 8). All these clinical studies were on plaque psoriasis. Of the 7 biosimilars, 4 were completed in 2022 and the remaining 3 have an estimated completion date for 2023. No clinical trials on biosimilar versions of golimumab or vedolizumab were identified on clinicaltrials.gov, indicating that biosimilar versions for these biologics are not yet in development.¹⁰² A 2021 CADTH report noted that a generic version of tofacitinib is undergoing a regulatory review for approval in rheumatoid arthritis, psoriatic arthritis, and UC in Canada.¹⁰³ In November 2022, 3 generic versions of tofacitinib entered the Canadian market.^37-39

Table 2: Status of Data Protection and Patent Expiry for Targeted Immune Modulators

NA = not available.

^aNotices of Compliance for adalimumab, and infliximab were issued before the enactment of the data protection regulations in 2006.^79,84,96

^bThe longest patent that was filed for the originator infliximab was found to be infringed by the biosimilar launch. The only other patent filed for infliximab expired March 18, 2012.¹⁰⁴

^cThe patent expiry date for Xeljanz XR is March 12, 2034. However, Xeljanz XR is not indicated for UC.

Sources: Dates for data protection expiry and patent end date are from Health Canada databases.^{72,94,98,105,106}

CADTH Review Status

For the indication of moderate to severe UC, CADTH has reviewed 5 originator biologics (adalimumab, infliximab, golimumab, ustekinumab, and vedolizumab), and 2 small molecules (tofacitinib and ozanimod).⁹⁴ Of the 5 originator biologics, only 2 infliximab biosimilars (Inflectra and Renflexis) were reviewed. Biosimilars approved in Canada after 2019 were not reviewed due to a policy change by CADTH to no longer review files completed after June 1 of that year.⁹²

Infliximab biosimilars, Inflectra and Renflexis, and vedolizumab, ustekinumab, and tofacitinib were recommended to be listed with criteria and conditions.^107-112 Remicade (infliximab originator biologic) was recommended to be not listed, and Humira (adalimumab originator biologic) and golimumab were recommended to not be listed at the submitted price.^113-115

Table 3 provides an overview of the CADTH review status and CDEC recommendations of the TIMs for UC; a summary of the evidence and clinical and/or economic rationale for the recommendations by CDEC are presented in Appendix 3, Table 9.

Table 3: CADTH Review Status and CDEC Recommendations for UC

CDEC = CADTH Canadian Drug Expert Committee; NA = not applicable; SC = subcutaneous; UC = ulcerative colitis.

^aAs of June 1, 2019, CADTH stopped any work on any biosimilar reviews that would have been completed after June 1, 2019.¹¹⁶

Sources: Data were extracted from published CADTH reports.^107-117

Reimbursement Status

Negotiated Agreements

The pan-Canadian Pharmaceutical Alliance (pCPA) was formed in 2010 for public drug plans to work together when entering negotiations with manufacturers for pharmaceuticals, from which, if successful, an LOI was created. The LOI lists the terms and conditions for funding a drug and are used to create a Product Listing Agreement (PLA) between each participating member jurisdiction and the manufacturer.¹¹⁸

The following TIMs have undergone pCPA negotiations for UC that resulted in an LOI: adalimumab (Humira), including 8 of its biosimilars; infliximab (Remicade), including 2 of its biosimilars; golimumab (Simponi); vedolizumab (Entyvio IV and SC); and tofacitinib (Xeljanz). The negotiation for ustekinumab (Stelara) concluded without an agreement. Negotiations have not been held for 2 infliximab biosimilars (Remsima and Renflexis) for UC. Further, negotiation has not been held for ozanimod (Zeposia) for UC because the drug had just received a reimbursement recommendation from CADTH at the time of publication of this report.¹¹⁹ Information on the pCPA negotiation status of TIMs for UC are presented in Appendix 4, Table 10.

Formulary Listing Status

The current process for formulary listings begins with an LOI, which leads to PLAs with individual drug plans. However, not all drugs achieve the LOI stage; when they do, not all LOIs lead to successful PLAs with jurisdictions. Some jurisdictions can choose to not participate in a negotiation, or formulary listings may take longer if the drug is not a priority.⁹⁷

Most jurisdictional drug plans currently provide coverage for almost all the drugs included in this report, except for ustekinumab which concluded without an agreement. Golimumab is not publicly reimbursed by British Columbia and Prince Edward Island. All jurisdictions except Yukon and CSC provide coverage for tofacitinib.

Biosimilar Policies

Most public drug plans have implemented a biosimilar policy to promote the use of biosimilars over originator biologics. Some jurisdictions no longer provide coverage for originator biologics, and only provide coverage for biosimilars of adalimumab (Alberta, British Columbia, New Brunswick) and infliximab (Alberta, British Columbia, New Brunswick, Newfoundland and Labrador). Patients on originator biologics had to switch to the biosimilars versions to maintain coverage under the public drug plan. However, British Columbia (infliximab only) may allow access to originator biologics under exceptional circumstances on a case-by-case basis, and only for those currently treated with originator biologics.^120-141

Most jurisdictions apply their biosimilar policy for treatment-naive patients only for adalimumab (Ontario, Saskatchewan, Manitoba, Nova Scotia, Newfoundland and Labrador, Prince Edward Island, Yukon, NIHB, CSC) and infliximab (Ontario, Saskatchewan, Manitoba, New Brunswick, Nova Scotia, Yukon, NIHB, CSC, CAF). These public drug plans allow patients currently undergoing treatment with originator biologic to continue their treatment with the originator biologic, with an option to switch to biosimilar versions.^142,143 However, Nova Scotia, Saskatchewan, and Ontario have announced that effective February 2023, April 2023, and December 2023, respectively, these drug plans will no longer provide coverage for originator biologics, and only provide coverage for biosimilars of adalimumab and infliximab.^141-143

Manitoba and CSC apply their biosimilar policy for the reimbursement of biologics for UC as a part of their 2-tiered biologics reimbursement policy. As opposed to other drug plans, Manitoba and CSC have an explicit policy to allow access to originator biologics if a patient fails on biosimilars. The policy requires patients to trial and fail the first tier of biologics to be eligible for coverage of the second tier. Manitoba’s policy applies to new patients (biologic naive) and existing patients who have previously trialled and been deemed unresponsive to biologic therapy. Patients must fail to respond to more than 2 tier 1 drugs to be eligible for coverage for tier 2 drugs. Tier 1 drugs include biosimilar versions of adalimumab (Abrilada, Amgevita, Hadlima, Hulio, Hyrimoz, Idacio, Simlandi, and Yuflyma) and infliximab (Avsola, Inflectra, Renflexis), and originator products Entyvio (vedolizumab), Simponi (golimumab), and Xeljanz (tofacitinib). Tier 2 drugs include originator biologics, Humira (adalimumab), and Remicade (infliximab).^120,121,144 CSC also requires existing patients deemed unresponsive to biologic therapy to switch to a tier 1 biologic. Once all options on tier 1 are exhausted, options on tier 2 can be made available for coverage. Tier 1 drugs include biosimilar versions of adalimumab (Abrilada, Amgevita, Hadlima, Hulio, Hyrimoz, Idacio, Simlandi, and Yuflyma) and infliximab (Inflectra, Renflexis) and originator biologic Entyvio (vedolizumab). Tier 2 drugs include originator biologic, Humira (adalimumab).¹²² Additional details on these biosimilar policies are presented in Appendix 4, Table 11.

Type of Listing Status

Public drug plans list prescription medicines according to specific coverage categories that can be broadly classified as a restricted or unrestricted benefit. “Unrestricted benefit” refers to drugs with usage that is not limited by clinical criteria requiring authorization before drug plan coverage. Depending on the public drug plan, this type of formulary benefit status (coverage category) is referred to as open benefit, full benefit, or regular benefit. “Restricted benefit” refers to drugs with usage limited by specific clinical criteria or to a defined patient subgroup. Depending on the public drug plan, this type of formulary benefit status is categorized under Special Authorization, Exceptional Access Program (EAP), Exceptional Drug Status or Exception Status drug, Limited Use, Limited Coverage Drug, or Prior Authorization.¹⁴⁵ The “restricted benefit” categories can be further classified by the following reimbursement processes:

• Restricted Benefit–Active: Applicable to the following coverage categories for biologics for UC: Special Authorization or Limited Coverage Drug (British Columbia), Special Authorization (Alberta, New Brunswick, Newfoundland and Labrador, Prince Edward Island, VAC, CAF), Exceptional Drug Status or Exception Status drug (Saskatchewan, Manitoba, Nova Scotia, Yukon), EAP (Ontario), or Limited Use (NIHB). Application for public reimbursement with the required clinical details must be made by the authorized prescriber using established processes (e.g., use of specific authorization forms). Each request is subject to a medication review by staff responsible for claims adjudication for the public drug plan.^123-136

• Restricted Benefit–Passive: Applicable to the following coverage categories for biologics for UC: Limited Use (Ontario) and benefit with criteria medications (CSC). In comparison with Restricted Benefit–Active, the use of specific authorization forms and a medication review is not a requirement. Rather, a Limited Use code (Ontario) or a Reason for Use code (CSC) must be specified in the prescription.^122,136,137

Table 4 provides an overview of the listing status of TIMs for UC across public drug plans. Appendix 4, Table 11 and Table 12, provides additional details of the coverage criteria. Given that ozanimod (Zeposia) just received a reimbursement recommendation from CADTH, it is not yet covered by any public drug plan and not included in this table. Given that tofacitinib generics have just entered the Canadian market, it is not yet covered by any public drug plan and not included in this table.

Clinical Criteria

All TIMs for UC are categorized as a restricted benefit, in which patients are required to meet specific clinical criteria to be eligible for reimbursement. These clinical criteria could vary between drug plans and between TIMs within a given drug plan. In general, initial coverage criteria for TIMs in UC currently includes some form of the following: objective diagnosis of UC (Mayo Score with a rectal bleeding or endoscopic subscore) and failure to respond to, contraindication to, or intolerance to conventional therapy (5-ASA, mesalamine, corticosteroids, AZA, 6-mercaptopurine [6-MP]). Most of the public drug plans explicitly state that the TIM must be prescribed by a “gastroenterologist” or a “physician with a specialty in gastroenterology.”^120-140 Details on the requirements for diagnosis and prior therapy for each TIM are presented in Appendix 4, Table 11.

Diagnosis Requirements

TIMs are generally eligible for coverage for patients with moderate to severe UC, though some variation was noted between jurisdictions in the diagnosis definitions that are used. British Columbia, Yukon and Ontario require a diagnosis with a full Mayo Score; British Columbia requires a Mayo Score greater than 4, whereas Ontario and Yukon require a score greater than 6 (except for adalimumab, for which Yukon requires a Mayo Score of 4 or greater). In addition, all 3 of these plans require a rectal bleeding subscore (British Columbia) or an endoscopic subscore (Ontario and Yukon) of 2 or greater. To be eligible for initial coverage of a TIM, Alberta, New Brunswick, Nova Scotia, Newfoundland and Labrador, Prince Edward Island, NIHB, CSC, CAF require a diagnosis with a partial Mayo Score of 4 or greater, except for adalimumab in New Brunswick which does not require a score at all. Of the plans that require a partial Mayo Score, New Brunswick, Nova Scotia, Newfoundland and Labrador, Prince Edward Island, and CAF require a rectal bleeding subscore greater than 2.

Prior Therapy Requirements

TIMs for UC are currently only reimbursed if patients are deemed refractory, intolerant, or to have failed to respond to conventional therapy (5-ASA, mesalamine, AZA, or 6-MP). “Refractory” is defined as a lack of effect at the recommended doses and for a specified duration of treatment. “Intolerant” is defined as demonstrating serious adverse effects or contraindications to treatments, as defined in the product monographs. Previous therapy that included corticosteroids alone or in combination with other conventional therapy was applicable to all public drug plans and for all drugs unless contraindicated or not tolerated. Clinical criteria varied between drug plans, with regards to the number of conventional therapy combination regimens that needed to be trialled before requesting reimbursement for the TIM. The minimum dose and duration of treatment with prior conventional therapies may also vary by jurisdiction.

Table 5: Details on Diagnosis of UC

AB = Alberta; BC = British Columbia; CAF = Canadian Armed Forces; CSC = Correctional Services Canada; MB = Manitoba; NIHB = Non-Insured Health Benefits; NL = Newfoundland and Labrador; NS = Nova Scotia; ON = Ontario; PE = Prince Edward Island; SK = Saskatchewan; VAC = Veterans Affairs Canada; UC = ulcerative colitis; YT = Yukon.

Note: Requirement for an objective diagnosis for UC was not identified in SK, MB, and VAC.

Sources: Canadian public drug plan formularies.^120-140

For biologics, Saskatchewan requires failure of a corticosteroid only. Thirteen of 14 drug plans (Alberta, British Columbia, Manitoba, Ontario, Manitoba, New Brunswick, Nova Scotia, Newfoundland and Labrador, Prince Edward Island, Yukon, NIHB, VAC, CSC, CAF) require failure of a corticosteroid in combination with at least 1 other conventional therapy option before being eligible for biologic coverage. Among these plans, British Columbia, Alberta, Manitoba, NIHB, CSC, New Brunswick, Nova Scotia, Newfoundland and Labrador, Prince Edward Island, and CAF specify failure of a corticosteroid and a 5-ASA product for all biologics listed except for adalimumab, for which CSC specifies failure of a corticosteroid and a thiopurine (AZA or 6-MP) and New Brunswick does not specify prior conventional therapy failure. Ontario and Yukon specify failure of a corticosteroid and a thiopurine (AZA or 6-MP) for all biologics listed except for adalimumab, for which Yukon specifies failure of a corticosteroid and a 5-ASA product. Prior therapy requirements for tofacitinib are similar to biologics within each jurisdiction, except for Ontario which requires failure of a corticosteroid only (as opposed to requiring failure of 2 conventional therapies for biologics). VAC requires failure of a corticosteroid and another conventional therapy (unspecified) before being eligible for coverage for any of the TIMs listed. Additionally, patients who are deemed corticosteroid dependent are also eligible for TIM coverage in Nova Scotia, Newfoundland and Labrador, Prince Edward Island, CAF, Yukon, and New Brunswick (excluding adalimumab, where the conventional therapy is unspecified) regardless of the number of previously trialled conventional therapies.

Table 6: Requirement for Failure to Prior Line of Therapy

6-MP = 6-mercaptopurine; 5-ASA = 5-aminosalicylic acid; AB = Alberta; AZA = azathioprine; BC = British Columbia; CAF = Canadian Armed Forces; CSC = Correctional Services Canada; MB = Manitoba; NB = New Brunswick; NIHB = Non-Insured Health Benefits; NL = Newfoundland and Labrador; NS = Nova Scotia; ON = Ontario; PE = Prince Edward Island; SK = Saskatchewan; UC = ulcerative colitis; VAC = Veterans Affairs Canada; YT = Yukon.

^aFor AB, corticosteroid dependence refers to failure to taper off corticosteroids without recurrence of disease or disease requiring a second dose of corticosteroids within 12 months of previous dose. For BC, NB, NS, NL, and CAF corticosteroid dependence refers to unable to withdraw oral corticosteroid within 3 months of initiation without a recurrence of symptoms, a symptomatic relapse within 3 months of stopping, or the need for 2 or more courses of corticosteroids within 1 year). In ON and YT, corticosteroid dependence refers to stabilized with 2 weeks of oral prednisone at daily doses greater than or equal to 40 mg (or 1 week of IV equivalent) but the corticosteroid dose cannot be tapered despite 3 months of AZA or 6-MP or disease-modifying antirheumatic drugs (DMARDS).

^bPrior therapy could vary for patients with severe UC. NB, NL, and PE specify severe UC with a partial Mayo Score of > 6. ON and CSC specify severe UC with a Mayo Score of > 10. For patients with severe UC; ON, NB, NS, NL, PE, and CSC only require failure of corticosteroid.

Sources: Canadian public drug plan formularies.^120-140

Conclusion

The treatment landscape for UC continues to expand with the development of novel therapies with diverse mechanisms of action. Additionally, with the expiration of data protection for some existing treatments, the market is expected to further expand with the emergence of biosimilars and generics. Considering these factors and the emergence of new data, it would be important to reassess these drugs and evaluate their place in therapy. Further research, such as horizon scanning, utilization analyses, and long-term effectiveness and safety studies, is warranted for TIMs to ensure the appropriate use of these drugs in the treatment of moderate to severe UC.

References

1.Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. a randomized study. N Engl J Med. 1987;317(26):1625-1629. PubMed

2.Stenson WF. Inflammatory bowel diseaes. In: Cecil RL, Goldman I, Bennett JC, eds. Cecil Textbook of Medicine, 21st ed. Philadephia (PA): W.B. Saunders; 2000.

3.Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365(18):1713-1725. PubMed

4.Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769-2778. PubMed

5.Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46-54.e42; quiz e30. PubMed

6.Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis. 2011;17(1):423-439. PubMed

7.Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1785-1794. PubMed

8.Travis SP, Stange EF, Lémann M, et al. European evidence-based consensus on the management of ulcerative colitis: current management. J Crohns Colitis. 2008;2(1):24-62. PubMed

9.Alatab S, Sepanlou SG, Ikuta K, et al. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17-30. PubMed

10.Coward S, Clement F, I BE, al e. The rising prevalence of inflammatory bowel disease in Canada: Analyzing the past to predict the future [abstract] In: Abstracts presented to 2018 Canadian Diseases Week. J Can Assoc Gastroenterol. 2018;1(Suppl 2).

11.Fumery M, Singh S, Dulai PS, Gower-Rousseau C, Peyrin-Biroulet L, Sandborn WJ. Natural history of adult ulcerative colitis in population-based cohorts: a systematic review. Clin Gastroenterol Hepatol. 2018;16(3):343-356.e343. PubMed

12.Bernstein CN, Nugent Z, Targownik LE, Singh H, Lix LM. Predictors and risks for death in a population-based study of persons with IBD in Manitoba. Gut. 2015;64(9):1403-1411. PubMed

13.Nguyen GC, Bernstein CN, Benchimol EI. Risk of surgery and mortality in elderly-onset inflammatory bowel disease: a population-based cohort study. Inflamm Bowel Dis. 2017;23(2):218-223. PubMed

14.Bitton A, Vutcovici M, Sewitch M, Suissa S, Brassard P. Mortality trends in Crohn's disease and ulcerative colitis: a population-based study in Québec, Canada. Inflamm Bowel Dis. 2016;22(2):416-423. PubMed

15.Kawalec P, Malinowski KP. Indirect health costs in ulcerative colitis and Crohn's disease: a systematic review and meta-analysis. Expert Rev Pharmacoecon Outcomes Res. 2015;15(2):253-266. PubMed

16.Longobardi T, Jacobs P, Wu L, Bernstein CN. Work losses related to inflammatory bowel disease in Canada: results from a National Population Health Survey. Am J Gastroenterol. 2003;98(4):844-849. PubMed

17.Kuenzig ME, Lee L, El-Matary W, et al. The impact of inflammatory bowel disease in Canada 2018: indirect costs of IBD care. J Can Assoc Gastroenterol. 2019;2(Suppl 1):S34-S41. PubMed

18.Rawsthorne P, Clara I, Graff LA, et al. The Manitoba Inflammatory Bowel Disease Cohort Study: a prospective longitudinal evaluation of the use of complementary and alternative medicine services and products. Gut. 2012;61(4):521-527. PubMed

19.Nguyen GC, Croitoru K, Silverberg MS, Steinhart AH, Weizman AV. Use of complementary and alternative medicine for inflammatory bowel disease is associated with worse adherence to conventional therapy: the COMPLIANT study. Inflamm Bowel Dis. 2016;22(6):1412-1417. PubMed

20.Weizman AV, Ahn E, Thanabalan R, et al. Characterisation of complementary and alternative medicine use and its impact on medication adherence in inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35(3):342-349. PubMed

21.Gunnarsson C, Chen J, Rizzo JA, Ladapo JA, Lofland JH. Direct health care insurer and out-of-pocket expenditures of inflammatory bowel disease: evidence from a US national survey. Dig Dis Sci. 2012;57(12):3080-3091. PubMed

22.IBD treatments. Vienna (AT): European Crohn’s and Colitis Organization; 2013: https://www.ecco-ibd.eu/images/1_About_ECCO/1_8_ECCO/IBDTreatments.pdf. Accessed 2022 Jul 19.

23.Cohen RD, Stein AC. Management of moderate to severe ulcerative colitis in adults. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2022: https://www.uptodate.com. Accessed 2022 Dec 20.

24.Schroeder KW. Mayo Score / Disease Activity Index (DAI) for ulcerative colitis. New York (NY): MD+ Calc; n.d.: https://www.mdcalc.com/calc/3675/mayo-score-disease-activity-index-dai-ulcerative-colitis#pearls-pitfalls. Accessed 2022 Jun 9.

25.Sands BE, Peyrin-Biroulet L, Loftus EV, Jr., et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226. PubMed

26.Ollendorf DA, Bloudek L, Carlson JJ, et al. Targeted immune modulators for ulcerative colitis: effectiveness and value: evidence report. Boston (MA): Institute for Clinical and Economic Review (ICER); 2020: https://icer.org/wp-content/uploads/2020/08/ICER_UC_Evidence_Report_091120-002.pdf. Accessed 2022 Dec 20.

27.FDA approves boxed warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). Silver Spring (MD): US Food and Drug Administration; 2019. Accessed 2022 Jul 19.

28.Summary Safety Review - Xeljanz/Xeljanz XR (tofacitinib) - assessing the potential risks of serious heart-related problems and cancer. Ottawa (ON): Health Canada; 2022: https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00278. Accessed 2022 Jul 19.

29.Pharmaceutical Advisory Committee Formulary Working Group for Health Technology Assessments. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/collaboration-and-outreach/advisory-bodies/dpac-fwg-hta. Accessed 2022 Apr 15.

30.Extended health benefits for specified disease conditions program. Yellowknife (NT): Government of the Northwest Territories (GNWT); 2019: https://www.hss.gov.nt.ca/en/services/supplementary-health-benefits/extended-health-benefits-specified-disease-conditions. Accessed 2022 Apr 15.

31.EHB full coverage plan. Iqaluit (NU): Government of Nunavut; 2022: https://www.gov.nu.ca/health/information/ehb-full-coverage-plan. Accessed 27 April 2022.

32.Notice of Compliance information - OMVYENCE. Ottawa (ON): Health Canada; 2021: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2021 Apr 11.

33.Product information - RINVOQ. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98509. Accessed 2022 Jun 9.

34.Drug Product Database (DPD): terminology. Ottawa (ON): Health Canada; 2022: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/terminology.html. Accessed 2022 Apr 16.

35.Reimbursement review: upadacitinib (Rinvoq). Ottawa (ON): CADTH; 2022: https://www.cadth.ca/upadacitinib-2. Accessed 2022 Dec 19.

36.About EORLA. Ottawa (ON): Eastern Ontario Regional Laboratory Association (EORLA); 2021: https://www.eorla.ca/about-us/. Accessed 2022 Jul 18.

37.Product information - TARO-TOFACITINIB. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=100052. Accessed 2022 Dec 20.

38.Product information - PMS-TOFACITINIB. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=101191. Accessed 2022 Dec 20.

39.Product information - AURO-TOFACITINIB. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=101923. Accessed 2022 Dec 20.

40.Notice of Compliance information - HUMIRA. Ottawa (ON): Health Canada; 2004: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

41.Notice of Compliance information - HUMIRA (UC). Ottawa (ON): Health Canada; 2013: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

42.Notice of Compliance information - INFLECTRA. Ottawa (ON): Health Canada; 2014: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

43.Notice of Compliance information - INFLECTRA (UC). Ottawa (ON): Health Canada; 2016: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

44.Notice of Compliance information - REMICADE. Ottawa (ON): Health Canada; 2001: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

45.Notice of Compliance information - REMICADE (UC). Ottawa (ON): Health Canada; 2006: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

46.Notice of Compliance information - SIMPONI. Ottawa (ON): Health Canada; 2009: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

47.Notice of Compliance information - SIMPONI (UC). Ottawa (ON): Health Canada; 2013: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

48.Notice of Compliance information - STELARA. Ottawa (ON): Health Canada; 2008: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

49.Notice of Compliance information - STELARA (UC). Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

50.Notice of Compliance information - REMSIMA. Ottawa (ON): Health Canada; 2014: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

51.Notice of Compliance information - REMSIMA (UC). Ottawa (ON): Health Canada; 2016: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

52.Notice of Compliance information - XELJANZ. Ottawa (ON): Health Canada; 2014: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

53.Notice of Compliance information - XELJANZ (UC). Ottawa (ON): Health Canada; 2018: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

54.Notice of Compliance information - ZEPOSIA. Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Jun 9.

55.Notice of Compliance information - ZEPOSIA (UC). Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Jun 9.

56.Notice of Compliance information - ADALIMUMAB INJECTION. Ottawa (ON): Health Canada; 2021: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

57.Notice of Compliance information - AMGEVITA. Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

58.Notice of Compliance information - AVSOLA. Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

59.Notice of Compliance information - ENTYVIO. Ottawa (ON): Health Canada; 2015: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

60.Notice of Compliance information - ENTYVIO (UC - sc). Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

61.Notice of Compliance information - HADLIMA. Ottawa (ON): Health Canada; 2018: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

62.Notice of Compliance information - HULIO. Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

63.Notice of Compliance information - HYRIMOZ. Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

64.Notice of Compliance information - IDACIO. Ottawa (ON): Health Canada; 2020: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

65.Notice of Compliance information - IXIFI. Ottawa (ON): Health Canada; 2021: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

66.Notice of Compliance information - RENFLEXIS. Ottawa (ON): Health Canada; 2017: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

67.Notice of Compliance information - SIMLANDI. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

68.Notice of Compliance information - YUFLYMA. Ottawa (ON): Health Canada; 2021: https://health-products.canada.ca/noc-ac/?lang=eng. Accessed 2022 Apr 27.

69.Health Canada approves new indications for Xeljanz in ulcerative colitis (UC) & psoriatic arthritis (PsA) [press release]. Kirkland (ZC): Pfizer; 2018: https://www.newswire.ca/news-releases/health-canada-approves-new-indications-for-xeljanz-in-ulcerative-colitis-uc--psoriatic-arthritis-psa-696193771.html. Accessed 2022 Apr 28.

70.Health Canada approves new indication for STELARA®* (ustekinumab) for the treatment of adults with moderately to severely active ulcerative colitis [press release]. Toronto (ON): Janssen Pharmaceuticals; 2020: https://www.bloomberg.com/press-releases/2020-01-27/health-canada-approves-new-indication-for-stelara-ustekinumab-for-the-treatment-of-adults-with-moderately-to-severely-acti. Accessed 2022 Apr 28.

71.Notice of Compliance search. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/noc-ac/index-eng.jsp. Accessed 2022 Jun 22.

72.Drug Product Database online query. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp. Accessed 2021 Apr 22.

73.Product Information - ABRILADA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=100029. Accessed 2022 Apr 12.

74.Product information - AMGEVITA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=94649. Accessed 2022 Apr 12.

75.Product information - AVSOLA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98681. Accessed 2022 Apr 12.

76.Product information - ENTYVIO. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=92117. Accessed 2022 Apr 27.

77.Product information - HADLIMA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=96243. Accessed 2022 Apr 12.

78.Product information - HULIO. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99197. Accessed 2022 Apr 12.

79.Product information - HUMIRA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=74379. Accessed 2022 Apr 12.

80.Product information - HYRIMOZ. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99460. Accessed 2022 Apr 12.

81.Product information - IDACIO. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99222. Accessed 2022 Apr 12.

82.Product information - INFLECTRA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=90410. Accessed 2022 Apr 12.

83.Product information - IXIFI. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=101230. Accessed 2022 Apr 27.

84.Drug and Health Product Submissions Under Review (SUR): supplemental submissions under review. Ottawa (ON): Health Canada; 2022: https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/submissions-under-review/supplemental-submissions-under-review.html. Accessed 2022 Dec 19.

85.Product information - REMSIMA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=90411. Accessed 2022 Apr 12.

86.Product information - REMSIMA SC. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=100076. Accessed 2022 Apr 12.

87.Product information - RENFLEXIS. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=95936. Accessed 2022 Apr 12.

88.Product information - SIMLANDI. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=101300. Accessed 2022 Apr 27.

89.Product information - SIMPONI. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=81020. Accessed 2022 Apr 27.

90.Product information - STELARA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=80608. Accessed 2022 Apr 12.

91.Product information - XELJANZ. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=90863. Accessed 2022 Apr 27.

92.Product information - YUFLYMA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=101284. Accessed 2022 Apr 27.

93.Product Information - ZEPOSIA. Ottawa (ON): Health Canada; 2022: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99535. Accessed 2022 Jun 9.

94.Register of innovative drugs. Ottawa (ON): Health Canada; 2022: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/register-innovative-drugs.html. Accessed 2022 Apr 10.

95.Guidance document: data protection under C.08.004.1 of the Food and Drug Regulations. Ottawa (ON): Health Canada; 2011: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/guidance-document-data-protection-under-08-004-1-food-drug-regulations.html. Accessed 2022 Apr 20.

96.Kendall M, D. H. A decade of data protection for innovative drugs in Canada: issues, limitations, and time for a reassessment. Biotechnol Law Rep. 2016;35(6). https://www.liebertpub.com/doi/full/10.1089/blr.2016.29030.mk. Accessed 2021 Jun 22. PubMed

97.Reducing data protection for biologics would slow medical procgress and chill R&D investment in the U.S. Washington (DC): Pharmaceutical Research and Manufacturers of America (PhRMA); 2015: http://phrma-docs.phrma.org/sites/default/files/pdf/data-exclusivity-for-biologics-fact-sheet.pdf. Accessed 2022 Apr 12.

98.Patent register. Ottawa (ON): Health Canada; 2021: https://pr-rdb.hc-sc.gc.ca/pr-rdb/index-eng.jsp. Accessed 2022 Apr 14.

99.Courage N, Shivakumar S. The biosimilar landscape in Canada. London (UK): Lexology; 2018: https://www.lexology.com/library/detail.aspx?g=bc06ea65-d2bc-4ffe-bf04-9b497b10fce0. Accessed 2022 Jun 10.

100.Mathias T. AbbVie, Samsung Bioepis in deal; Humira biosimilar U.S. release in 2023 [press release]. Canary Wharf (UK): Reuters 2018: https://www.reuters.com/article/us-abbvie-biogen-idUSKCN1HC1SP. Accessed 2022 Jun 10.

101.Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013;6(8):469-478. PubMed

102.ClinicalTrials.gov. 2022; https://www.clinicaltrials.gov/ct2/home, Accessed 2022 Jun 10.

103.Tadrous M, Shakeri A, Hayes KN, et al. Canadian trends and projections in prescription drug purchases: 2001–2023. Can J Health Technol. 2021;1(11). https://canjhealthtechnol.ca/index.php/cjht/article/view/mt0001/mt0001. Accessed 2022 Jun 10.

104.Lee K, Wojtyra U. New Use Patent for Janssen’s REMICADE valid and infringed by Hospira’s biosimilar INFLECTRA. Ottawa (ON): Smart & Biggar; 2018: https://www.smartbiggar.ca/insights/publication/new-use-patent-for-janssen-s-remicade-valid-and-infringed-by-hospira-s-biosimilar-inflectra. Accessed 2022 Apr 18.

105.Search for expired patents. Ottawa (ON): Health Canada; 2021: https://pr-rdb.hc-sc.gc.ca/pr-rdb/search_expiration-recherche_expires.do. Accessed 2022 Apr 14.

106.Lexchin J. Increase in drug spending in Canada due to extension of data protection for biologics: a descriptive study. Healthc Policy. 2019;14(3):10-18. PubMed

107.CADTH Canadian Drug Expert Committee final recommendation: vedolizumab (Entyvio). Ottawa (ON): CADTH; 2015: https://www.cadth.ca/sites/default/files/cdr/complete/SR0421_cdr_complete_Entyvio_Nov-2-15_e.pdf. Accessed 2022 Apr 18.

108.CADTH. CADTH Canadian Drug Expert Committee final recommendation: infliximab (Inflectra). Common Drug Review2016: https://www.cadth.ca/sites/default/files/cdr/complete/SE0483_IBD_Inflectra-Oct-28-16.pdf. Accessed 2022 Apr 10.

109.CADTH Canadian Drug Expert Committee recommendation: infliximab (Renflexis). Common Drug Review. Ottawa (ON): CADTH; 2018: https://www.cadth.ca/sites/default/files/cdr/complete/SE0532%20Renflexis%20-%20CDEC%20Final%20Recommendation%20February%2020%2C%202018%28redacted%29_for%20posting.pdf. Accessed 2022 Apr 10.

110.CADTH Canadian Drug Expert Committee recommendation: tofacitinib (Xeljanz). Common Drug Review. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/sites/default/files/cdr/complete/SR0572-Xeljanz_UC-Mar-1-19.pdf. Accessed 2022 Apr 18.

111.CADTH Canadian Drug Expert Committee recommendation: ustekinumab (Stelara). Common Drug Review. Ottawa (ON): CADTH; 2020: https://www.cadth.ca/sites/default/files/cdr/complete/SR0627%20Stelara%20-%20CDEC%20Final%20Recommendation%20July%2020%2C%202020_for%20posting.pdf. Accessed 2022 Apr 18.

112.CADTH Canadian Drug Expert Committee recommendation: vedolizumab (Entyvio). Common Drug Review. Ottawa (ON): CADTH; 2020: https://www.cadth.ca/sites/default/files/cdr/complete/SR0635%20Entyvio%20-%20CDEC%20Final%20Recommendation%20%E2%80%93%20May%2021%2C%202020_for%20posting.pdf. Accessed 2022 Apr 18.

113.CEDAC final recommendation and reasons for recommendation: infliximab (Remicade) for ulcerative colitis. Common Drug Review. Ottawa (ON): CADTH; 2009: https://www.cadth.ca/sites/default/files/cdr/complete/cdr_complete_Remicade_Final_April_24_2009.pdf. Accessed 2022 Apr 18.

114.CDEC final recommendation: golimumab (Simponi) for ulcerative colitis. Common Drug Review. Ottawa (ON): CADTH; 2014: https://www.cadth.ca/sites/default/files/cdr/complete/SR0341_complete_Simponi_Mar-28-14.pdf. Accessed 2022 April 18.

115.CADTH Canadian Drug Expert Review Committee final recommendation: adalimumab (Humira) for ulcerative colitis. Common Drug Review. Ottawa (ON): CADTH; 2016: https://www.cadth.ca/sites/default/files/cdr/complete/SR0450_complete_Humira-Apr-19-16_e.pdf. Accessed 2022 Apr 10.

116.CADTH pharmaceutical reviews update — Issue 8. Reimbursement review. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/cadth-pharmaceutical-reviews-update-issue-8. Accessed 2022 Apr 20.

117.Reimbursement review: ozanimod (Zeposia). Ottawa (ON): CADTH; 2022: https://www.cadth.ca/ozanimod-0. Accessed 2022 Jun 9.

118.FAQs. Accessed 2022 Apr 27.

119.pCPA. Brand name drug negotiations status. Toronto (ON): pan-Canadian Pharmaceutical Alliance; 2022: https://www.pcpacanada.ca/negotiations. Accessed 2022 Apr 27.

120.Tiered biologics reimbursement policy by specialty. Winnipeg (MB): Manitoba Health; 2022: https://www.gov.mb.ca/health/pharmacare/profdocs/tiered_biologics_specialty.pdf. Accessed 2022 Apr 27.

121.Tiered biologics reimbursement policy overview. Winnipeg (MB): Manitoba Health; 2022: https://www.gov.mb.ca/health/pharmacare/profdocs/tiered_biologics_overview.pdf. Accessed 2022 Apr 27.

122.CSC National Formulary. Ottawa (ON): Correctional Services Canada; 2022.

123.Interactive Drug Benefit List (iDBL). Edmonton (AB): Government of Alberta; 2021: https://www.ab.bluecross.ca/dbl/publications.php. Accessed 2022 Apr 15.

124.Drug benefit list. Non-Insured Health Benefits. Toronto (ON): Express Scripts Canada; 2020: https://nihb.express-scripts.ca/dbl. Accessed 27 April 2022.

125.Veterans Affairs Canada drug formulary search form. Ottawa (ON): Government of Canada; 2022: https://www.veterans.gc.ca/eng/financial-support/medical-costs/treatment-benefits/poc10/search. Accessed 2022 Apr 22.

126.Canadian Armed Forces drug benefit list. Ottawa (ON): Government of Canada; 2022: http://www.cmp-cpm.forces.gc.ca/hs/en/drug-benefit-list/index.asp. Accessed 2022 Apr 27.

127.Formulary. Halifax (NS): Nova Scotia Department of Health; 2022: https://novascotia.ca/dhw/pharmacare/documents/formulary.pdf. Accessed 2022 Apr 27.

128.Special Authority drug list. Victoria (BC): British Columbia Ministry of Health; 2022: https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/pharmacare/prescribers/special-authority/sa-drug-list. Accessed 2022 Apr 19.

129.Manitoba drug benefits formulary. Winnipeg (MB): Manitoba Health; 2022: https://residents.gov.mb.ca/forms.html?d=details&pub_id=10541&filter_keyword=drug+benefits#page=46. Accessed 2022 Apr 18.

130.PEI pharmacare formulary. Charlottetown (PE): Health PEI; 2022: https://www.princeedwardisland.ca/sites/default/files/publications/pei_pharmacare_formulary.pdf. Accessed 2022 Apr 27.

131.Saskatchewan Online Formulary Database. Regina (SK): Government of Saskatchewan; 2022: https://formulary.drugplan.ehealthsask.ca/SearchFormulary/BG/682840. Accessed 2022 Apr 19.

132.Appendix A: exception drug status program. Regina (SK): Government of Saskatchewan; 2022: https://formulary.drugplan.ehealthsask.ca/PDFs/APPENDIXA.pdf. Accessed 2022 Apr 19.

133.NLPDP drug product database. St. John's (NL): Newfoundland and Labrador Health and Community Services; 2022: https://www.health.gov.nl.ca/health/prescription/newformulary.asp. Accessed 2022 Apr 27.

134.Yukon drug formulary. Whitehorse (YT): Government of Yukon; 2022: https://ihs.gov.yk.ca/drugs/f?p=161:9000 Accessed 2022 Apr 27.

135.New Brunswick drug plans formulary. Fredricton (NB): Government of New Brunswick; 2022: https://www2.gnb.ca/content/dam/gnb/Departments/h-s/pdf/en/NBDrugPlan/NewBrunswickDrugPlansFormulary.pdf. Accessed 2022 Apr 15.

136.Exceptional Access Program reimbursement criteria for frequently requested drugs. Toronto (ON): Ontario Ministry of Health; 2022: https://health.gov.on.ca/en/pro/programs/drugs/docs/frequently_requested_drugs.pdf. Accessed 2022 Apr 19.

137.Ontario drug benefit formulary search. Toronto (ON): Ontario Ministry of Health; 2022: https://www.formulary.health.gov.on.ca/formulary/. Accessed 2022 Apr 19.

138.Adalimumab / infliximab / vedolizumab / tofactinib for ulcerative colitis: renewal coverage. Special authority request. Victoria (BC): British Columbia Ministry of Health; 2022: https://www2.gov.bc.ca/assets/gov/health/forms/5497fil.pdf. Accessed 2022 Apr 19.

139.Adalimumab / infliximab / vedolizumab / tofactinib for ulcerative colitis: initial/switch coverage. Special authority request. Victoria (BC): British Columbia Ministry of Health; 2022: https://www2.gov.bc.ca/assets/gov/health/forms/5388fil.pdf. Accessed 2022 Apr 19.

140.Part 3 Exception Drug Status (EDS). Winnipeg (MB): Manitoba Health; 2022: https://www.gov.mb.ca/health/mdbif/docs/edsnotice.pdf. Accessed 2022 Apr 18.

141.Ontario expanding safe use of biosimilars [press release]. Toronto (ON): Government of Ontario; 2022: https://news.ontario.ca/en/release/1002611/ontario-expanding-safe-use-of-biosimilars. Accessed 2022 Dec 22.

142.Saskatchewan formulary bulletin: Saskatchewan biosimilars initiative announced October 20, 2022. Bulletin #221. Regina (SK): Government of Saskatchewan; 2022: https://formulary.drugplan.ehealthsask.ca/Bulletins/Bulletin-0221-Oct-2022.pdf. Accessed 2022 Dec 19.

143.Nova Scotia Pharmacare: information for prescribers about the Nova Scotia biosimilar initiative. Halifax (NS): Government of Nova Scotia; 2022: https://novascotia.ca/dhw/pharmacare/information-for-prescribers-about-biosimilars.asp#:~:text=The%20Government%20of%20Nova%20Scotia,unless%20an%20exemption%20is%20granted. Accessed 2022 Dec 19.

144.Notice – tiered biologics reimbursement policy. Winnipeg (MB): Manitoba Health; 2018: https://www.gov.mb.ca/health/pharmacare/profdocs/notice_tiered_biologics.pdf. Accessed 2022 Jun 25.

145.Alignment among public formularies in Canada part 1: general overview. Ottawa (ON): Patented Medicine Prices Review Board; 2017: http://www.pmprb-cepmb.gc.ca/view.asp?ccid=1327#a1. Accessed April 2022 Apr 16.

Appendix 1: Regulatory

Note that this appendix has not been copy-edited.

Figure 2: Health Canada Approval Timeline for TIMs by First NOC Date

NOC = Notice of Compliance; UC = ulcerative colitis

^a Originator biologics: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Entyvio (vedolizumab) and Stelara (ustekinumab).

^b Small molecules: Xeljanz (tofacitinib) and Zeposia (ozanimod).

^c Biosimilars: Adalimumab biosimilars (Amgevita, Hadlima, Hulio, Hyrimoz, Idacio, Abrilada, Simlandi, Yuflyma) and infliximab biosimilars (Inflectra, Remsima, Renflexis, Avsola, Ixifi); Generics: Tofacitinib (Auro-Tofacitinib, pms-Tofacitinib, Taro-Tofacitinib).

^d Remsima IV is indicated in adult and pediatric UC, however, the product is ‘dormant,’ and not marketed in Canada. Remsima SC is marketed in Canada but is not indicated in adult or pediatric UC. “Approved” refers to an active Drug Identification number (DIN) for a product that has been reviewed and authorized for sale in Canada but has not yet been marketed in Canada. ‘Marketed’ refers to an active DIN for a product that is currently being sold in Canada. ‘Dormant’ refers to an active DIN for a product that was previously marketed in Canada but for which there have been no sales for period of at least 12 consecutive months.³⁴

^e Only approved but not yet marketed.

Sources: Information was collected from Health Canada’s Drug Product Database and Notice of Compliance Database.^{32,33,37-46,48-54,56-66,68-82,84-87,90,93,94}

Appendix 2: Clinical Trials

Note that this appendix has not been copy-edited.

Table 8: Clinical Trials Registered on Clinical Trials for Ustekinumab (Phase III)

Appendix 4: Reimbursement

Note that this appendix has not been copy-edited.

Table 10: Overview of the pCPA Negotiation Status of TIMs

LOI = Letter of Intent; NA = not applicable; NOC = Notice of Compliance, pCPA = pan-Canadian Pharmaceutical Alliance; SC = subcutaneous; UC = ulcerative colitis.

*Marked [B] if biosimilar

^aFor Humira (citrate-free) and negotiated for multiple indications (details of indications not specified). Negotiation concluded (without an agreement) on March 16, 2020.

^bIxifi had received NOC from Health Canada for UC, but the drug is not yet marketed in Canada.

^cZeposia (Ozanimod) has only recently received CADTH recommendation for UC (December 1, 2022). Given that pCPA negotiations are considered after CADTH review is complete, a pCPA negotiation for Zeposia could be expected to begin in near future.

Source: Data are from LOI timelines published on the pCPA website.^117-119

Table 12: Dose and Duration of Therapy and Supply Limits for TIMs in UC

AB = Alberta; BC = British Columbia; CAF = Canadian Armed Forces; CSC = Correctional Services Canada; MB = Manitoba; NB = New Brunswick; NIHB = Non-Insured Health benefit; NL = Newfoundland and Labrador; NS = Nova Scotia; PE = Prince Edward Island; SK = Saskatchewan; VAC = Veterans Affairs Canada; YT = Yukon.

Note: Information on VAC is based on a personal communication with the jurisdictional representative (Anne Bastarache: personal communication, April 2022).

^aAs an interim measure, an additional 40 mg dose of adalimumab will be provided at week 10 to allow time to determine whether the New Patient meets coverage criteria for maintenance dosing, for a total of 6 doses.

^bFor the first 4 months.

^cFor patients who showed a response to induction therapy then experienced secondary loss of response while on maintenance dosing with 5 mg/kg, the maintenance dose may be adjusted from 5 mg/kg to 10 mg/kg by making an additional special authorization request to Alberta Blue Cross for the increased dose.

^dClaims that exceed the maximum claim amount of $9,999.99 must be divided and submitted as separate transactions as outlined here.

^eAs an interim measure, an additional dose of 50 mg of golimumab will be provided at weeks 6 and 10 to allow time to determine whether the patient meets coverage criteria for maintenance dosing.

^fFor patients who showed a response to induction therapy then experienced secondary loss of response while on maintenance dosing with 50 mg, the maintenance dose may be adjusted from 50 mg to 100 mg by making an additional special authorization request to Alberta Blue Cross for the increased dose.

^gThe maintenance dose of 100mg every 4 weeks can be considered at the discretion of the treating physician.

^hPatients who remain on steroids will be considered on a case-by-case basis.

^IRecommends 5 mg twice daily for maintenance dose. But depending on therapeutic response; 10mg twice daily may also be used for maintenance in some patients. However, the lowest effective dose possible should be used for maintenance therapy to minimize adverse effects.

^jAs an interim measure, coverage will be provided for additional doses of 5 mg twice daily for 4 weeks, to allow time to determine whether the New Patient meets coverage criteria for maintenance dosing.

Source: Listing statuses are from payer formulary websites.^120-140