Subsequent entry biologics in Canada

Subsequent entry biologics in Canada The case for multi-sector collaboration Roundtable Summary Report March 2014

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The Public Policy Forum is an independent, not-for-profit organization dedicated to improving the quality of government in Canada through enhanced dialogue among the public, private and voluntary sectors. The Forum’s members, drawn from business, federal, provincial and territorial governments, the voluntary sector and organized labour, share a belief that an efficient and effective public service is important in ensuring Canada’s competitiveness abroad and quality of life at home.

Established in 1987, the Forum has earned a reputation as a trusted, nonpartisan facilitator, capable of bringing together a wide range of stakeholders in productive dialogue. Its research program provides a neutral base to inform collective decision making. By promoting information sharing and greater links between governments and other sectors, the Forum helps ensure public policy in our country is dynamic, coordinated and responsive to future challenges and opportunities. Š 2014, Public Policy Forum 1405-130 Albert St. Ottawa, ON K1P 5G4 Tel: (613) 238-7160 Fax: (613) 238-7990 www.ppforum.ca ISBN: 978-1-927009-53-6

This project was made possible through an unrestricted grant from Hoffmann-La Roche Ltd.

Table of contents Acknowledgements……………….…………………………….…………………………………………………….……………....1 Acronyms and technical terms ....................................................................................................... 2 Introduction ................................................................................................................................... 3 Factors for policymakers to consider.............................................................................................. 4 Designation of similarity .......................................................................................................... 4 Post-market testing and traceability ....................................................................................... 5 Nomenclature .......................................................................................................................... 6 Education ................................................................................................................................. 7 Manufacturing drift ................................................................................................................. 7 Cost of care .............................................................................................................................. 8 Areas where further collaboration is required ............................................................................... 8 Clearly identify roles and responsibilities................................................................................ 8 Develop transparent and effective standards that regulate SEBs .......................................... 9 Invest in data collection and information-sharing platforms.................................................. 9 Establish consistent nomenclature ....................................................................................... 10 Address issues around costs .................................................................................................. 11 Appendix: List of roundtable participants .................................................................................... 12

Acknowledgements For over three decades, biologics and Subsequent Entry Biologics (SEBs) have provided therapeutic relief to millions suffering worldwide from chronic illnesses such as cancer, multiple sclerosis and rheumatoid arthritis. As we explored these innovative drugs in detail, it became clear that closer collaboration – among government regulators, policymakers, manufacturers, healthcare professionals and patients – is needed to ensure that the rules that govern their manufacture and use are effective and safe.

To help facilitate this multi-stakeholder collaboration, the Public Policy Forum convened health experts representing different stakeholder groups to examine the regulatory and policy gaps around biologics and SEBs, and to identify whether and how decision-makers might respond.

Participants made it clear that greater coordination is required on several specific issues, including: developing roles and responsibilities; updating and strengthening regulation; developing data collection procedures and information-sharing platforms; establishing common nomenclature; and controlling for high drug costs. The findings from the roundtable discussion form the basis of this report.

I would like to thank Drs. Agnes Klein, Leigh Revers and Shail Verma for delivering informative presentations that helped set the context for the discussion, and for providing feedback on this report.

I would also like to acknowledge the contribution of Roche, our project sponsor who provided us with the research grant to conduct an independent analysis on biologic and SEB regulation in Canada.

Finally, a special thanks to the professional team at the Forum who contributed to this work, including James McLean, Ryan Conway, Julia Oliveira, Natasha Gauthier and Mathias Schoemer.

Paul Ledwell Executive Vice President Canada’s Public Policy Forum

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Acronyms and technical terms (Reference) Biologic: According to Health Canada, “Biologics are derived through the metabolic activity of living organisms and tend to be more variable and structurally complex than chemically synthesized drugs. Biologics are typically labile and sensitive to changes in manufacturing processes and conditions. Biological source materials, production cells or their fermentation media could present risks such as the initial presence of pathogens or the growth of adventitious agents such as viruses. Because of this, careful attention is paid to raw material controls, viral/bacterial inactivation or clearance during product purification and product testing. Changes to source materials, manufacturing processes, equipment or facilities may result in significant unexpected changes to the intermediate and/or final product, so the phrase "the process is the product" is often used in reference to biologics, and much effort is focussed on manufacturing control and quality assurance.”1

Immunogenicity: The ability of a substance to stimulate an immune response. Because biologic drugs are primarily protein-based, there is a risk that they may trigger unwanted immune reactions.2 This risk is particularly high in the case of Subsequent Entry Biologics (SEBs) or when a patient switches from using a reference biologic to an SEB, or vice-versa. Slight differences between the two products may encourage the patient’s body to develop anti-drug antibodies, which can limit the effectiveness of a treatment and compromise patient safety.3

Manufacturing drift: Small changes to the source material, equipment, or facilities used to create biologics and SEBs can cause significant differences in the final product. Over time, these differences can become so pronounced that existing versions of the drug do not resemble the original versions that were approved by regulators. This phenomenon, known as “manufacturing drift,”4 might affect the degree of similarity between an SEB and its reference product.

Subsequent entry biologics (SEBs): Also known as “biosimilars” or “follow-on biologics” in Europe and the US, respectively, “SEBs are follow-on versions similar to an original biologic drug, made by different manufacturers after the patent on the innovator [reference biologic] drug has expired.”5 SEBs are similar, but not identical, to the original innovator drug. This is due to the inherent complexities of large molecule drugs and small differences in the manufacturing process.

In addition, according to current Health Canada guidelines, it is preferable for the reference biologic used in the development of an SEB to be a drug that is authorized in Canada. If this is not possible, the sponsor of an SEB must demonstrate that the non-Canadian reference is a “suitable proxy” for a product with the same medicinal ingredient marketed by the same innovator company in Canada.

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Introduction In Canada, biologic medication has been a source of relief from chronic illness for almost 30 years. Unlike conventional drugs, which are manufactured from chemicals and other agents, “biologics” are developed through the metabolic activity of microorganisms, or extracted from tissues, mostly of animal origin. The use of living agents to produce cutting-edge biosynthetic medicines is rapidly expanding in Canada and around the world, providing practitioners with options that have been effective in treating cancer, rheumatoid arthritis, multiple sclerosis, and diabetes.

An important defining characteristic of biologics is their molecular structure. Since biologic molecules are larger and more complex than conventional drugs, scientists have so far been unable to synthetically replicate them in the lab.

In addition, the microorganisms that produce biologics are notoriously vulnerable to environmental and production conditions. Even very minor changes in manufacturing techniques can have dramatic implications on the effectiveness of a drug and its side effects.

Manufacturers must be vigilant in controlling raw materials, product purification, and testing to ensure that biologics are not modified by exposure and contamination to viruses and pathogens.

For nearly three decades, the complex and variable nature of biologics has been limited to a relatively small number of companies that develop these products. However, as patents expire and copies known as subsequent entry biologics, or SEBs, enter the Canadian marketplace, these issues of variability and complexity will pose significant challenges around safety and production standards.

Some stakeholders suggest that there may be a need to update federal and provincial regulatory practices to provide direction on how SEBs are manufactured, prescribed, and tracked over the long-term. Greater clarity on these issues will allow health practitioners and patients to be more confident that these innovative drugs are both safe and effective.

To help explore the need for enhancing SEB regulation in our country, Canada’s Public Policy Forum, with support from Roche, convened a select group of leading health experts in Toronto to explore the regulatory and policy issues around subsequent entry biologics.

While the roundtable focused on the practical and policy implications of SEBs in Ontario, the discussion expanded into a larger examination on how information and regulation should be developed across all Canadian jurisdictions. It became clear that a pan-Canadian response may be required to help drive forward a number of steps that need to take place in all provinces and territories. These steps include:     

Clearly identifying roles and responsibilities; Developing more transparent, effective standards to regulate SEBS; Investing in data collection and data-sharing platforms; Establishing consistent nomenclature; and Addressing cost issues.

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This report summarizes the main discussion points and areas where consensus was reached.

Throughout the discussion, it was underlined that a better understanding of the current SEB regulatory regime is necessary. Participants also agreed that multi-sector collaboration will better position stakeholders to navigate and strengthen the complex landscape of SEB regulation in Canada.

Factors for policy-makers to consider Although Canada represents a very small percentage of the global pharmaceutical market, our country enjoys a strong reputation as a regulator of drugs and health products. Through vigilant legislation, welltrained public servants and coordination among the public, private and health communities, Canada is able to provide medication to patients both quickly and safely.

However, policymakers have struggled to establish a clear, coherent regulatory framework around SEBs that advances knowledge-sharing, standardization and safety. According to participants, this is due in part to the unique characteristics of SEBs and their recent introduction into the Canadian marketplace.

The limited number of post-market studies conducted internationally and the absence of specific nomenclature have also been a source of confusion.

Since this lack of clarity has safety and efficacy implications, it is important to identify where the key challenges lie so that stakeholders can develop the standards and tools required to better regulate and understand SEBs. Participants suggested that the key challenges that require further examination are:      

Designation of similarity Post-market testing and traceability Nomenclature Manufacturing drift Cost of care Education.

Designation of similarity Biologics are so mutable that experts have noted that it is virtually impossible for SEB manufacturers to replicate an existing biologic drug.6 SEBs are therefore not considered to be pharmaceutically equivalent to their innovative counterparts. Instead, they are regarded as similar to reference biologics. In this respect, SEBs differ greatly from generic synthetic drugs, since the latter are considered identical to their reference counterparts.

For greater clarity, stakeholders often divide the concept of similarity (as it applies to SEBs) into two subcategories: interchangeability and substitutability.1 Interchangeability is generally understood as the ability to prescribe one drug in the place of another with the expectation that it will have the same

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effect. Physicians take interchangeability into consideration when deciding whether to prescribe a reference biologic or its SEB based on the needs of an individual patient.

In contrast, substitutability is understood as the capacity of a pharmacist to dispense either a reference biologic or an SEB to a patient, regardless of what trade name has been written on a patient’s prescription.7 In Ontario, pharmacists may perform substitutions according to the guidelines set out in the Comparative Drug Index.

Cumulative changes in the structure of subsequent entry biologics and their reference products, combined with the potential for immunogenicity and adverse reactions, make it difficult to assess whether an SEB is sufficiently interchangeable or substitutable to its reference drug.

The concept of similarity is central to most policy and practical discussions on SEBs. Since SEBs and their reference biologics are similar, but not identical, there is a need to provide clear rules on a number of important questions, including: 

How closely should an SEB mimic its reference biologic?



Can patients who experience a bad outcome with a SEB use the reference biologic in its place?



How might regulators differentiate the SEB from the reference biologic, particularly with regards to adverse reactions and immunogenicity? What happens if the original reference biologic is removed from the market? Can the SEB be a comparator in and of itself?

These questions require closer examination by all stakeholders, and their answers may require strong post-market and clinical data.

Post-market testing and traceability According to participants, the lack of clinical data on SEBs has had a profound impact on stakeholders’ ability to understand the drugs’ outcomes and their long-term effects. Without a large body of clinical quantitative studies to guide their decisions, many doctors find it challenging to prescribe SEBs with a high degree of confidence. Further complicating this challenge is the fact that many policymakers have found it difficult to define through regulation the minimum amount of clinical data necessary to make safety and efficacy determinations.

In addition, in Canada there is no comprehensive system that allows pharmacists, health practitioners, manufacturers and policymakers to track SEBs and their impact on patients; data collected by manufacturers and patient groups are often limited and incomplete.

However, some existing systems, while limited in scope, that could provide a useful foundation for a more centralized database that pools information for post-market analysis and drug traceability. For example, pharmacies keep a detailed record of the medications they issue to patients, which could potentially provide some insight on whether certain SEBs are having adverse effects. Further, steps have also been taken by rheumatology experts to build a database that tracks the effects of SEBs on patients. The Ontario Best Practices Research Initiative (OBRI) keeps detailed records of patients’

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experience with drugs associated with rheumatoid arthritis.2 The purpose of this system is to gather longterm information in order to “define safety, effectiveness and sustainability of available RA therapies; identify clinical practice patterns that improve patient health outcomes, and; use clinical and economic data to inform efficient health care decisions.”8 While this has been helpful for providing information on post-market effects, it is important to note that the OBRI system collects information from patients and manufacturers on a voluntary basis. This suggests that information that is crucial for evaluating the effectiveness and impact of SEBs may still be missing.

Collaboration, especially around data collection, could help fill in these gaps.

“OBRI provides a possible platform for monitoring SEBs so we will want to look at whether this system can be further developed and, potentially, expanded upon.”

-Roundtable participant

In assessing data on SEBs, policymakers should also consider the findings from jurisdictions outside of Canada. Whereas 10 years ago many healthcare experts questioned the reliability of reports coming out of Eastern Europe and Asia, data collection techniques have improved and these studies could be helpful in providing Canadian stakeholders with valuable information on SEBs. Throughout the discussion, it became clear that more needs to be done in Canada to ensure that all stakeholders – patients, practitioners, pharmacists, manufacturers and policymakers – have comprehensive, up-to-date post-market information to make informed decisions about SEBs and their use. Participants noted that stakeholders have made significant advances in post-market evaluation with the development of new tools such as risk management plans and periodic benefit-risk evaluations.

However, more work needs to be done in this area.

Nomenclature Canadian and international regulators have been unable to provide a consistent method across countries for naming SEBs that would lead to better traceability. Most drugs are identified according to an International Nonproprietary Name (INN) that are issued by the World Health Organization (WHO) to new and unique pharmaceutical substances.9 The purpose of providing each SEB with a unique INN is to differentiate them from their reference biologic on matters of safety. Unfortunately, not all countries follow the INN process which makes comparing drugs and sharing information across jurisdictions difficult.

Inconsistency can complicate pharmacovigilance (the monitoring of adverse reactions to a drug), as an INN alone may not allow public health authorities to trace reported adverse reactions to the appropriate manufacturer or drug.

2

OBRI conducts telephone interviews to determine the effectiveness of medications, changes in the quality of patients’ lives and the utilization of healthcare services.

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The use of an identical INN for all SEBs may make it difficult for officials to trace adverse reaction reports. Many stakeholders – including the Ontario Rheumatology Association10 and Roche Canada11 – have argued that each SEB should be identified by a distinct INN. But Health Canada considers that SEBs can be traced using Drug Identification Numbers (DINs) and brand names.

In addition to the need to establish universal naming practices, stakeholders need to use common terms – such as “substitutability” and “interchangeability” – in a consistent way. The tendency to use terms interchangeably has led to confusion among patients, health practitioners, policymakers, and others.

In the absence of consistent naming practices and nomenclature, stakeholders often find it difficult to fully understand the impact of SEBs or monitor their long-term safety and effectiveness.

Education Stakeholders need to establish how they might share information on SEBs. As these drugs permeate the marketplace, many patients and policymakers will begin questioning their use, risks, and costs.

According to one participant, policymakers, health practitioners, patient groups and manufacturers need to directly address this ‘knowledge vacuum’ by mounting a larger education campaign.

A number of organizations, including the rheumatology associations, are having meaningful discussions to help develop the tools and practices required to share information with patients and the general public. However, these organizations cannot possibly shoulder the full education responsibility by themselves. Other stakeholders, including governments and manufacturers, will need to identify how they can help contribute to more informed patients and doctors.

Manufacturing drift Small changes to source material, equipment, or facilities used to create a biologic can cause significant differences in the final product. Over time, these differences can become so pronounced that existing versions of the drug do not resemble the original versions approved by regulators. This phenomenon, known as “manufacturing drift,”12 can affect the degree of similarity between an SEB and its reference product.

Since SEBs could allow doctors to treat thousands of patients at reduced cost to our healthcare system, it has become a pressing policy imperative to provide clear, consistent standards around how they are manufactured.

“SEBs will drift from their reference drug. It’s not a question of if, but when and by how much.”

-Roundtable participant Subsequent entry biologics in Canada | 6

While Health Canada often compares product lots made before and after manufacturing changes for an individual product, there is no similar mechanism in place to measure the impact of manufacturing drift across different products.13 This is why Health Canada has stated that once authorized for the market, an SEB should be treated as any other stand-alone biological product. Such a product will not be required to demonstrate on an ongoing basis its similarity to its reference biological.

However, according to one participant, with several manufacturers creating SEBs, the drift in each will make them exceedingly difficult to track and compare. Policy-makers should consider whether it might be possible to enact and enforce stricter production standards to track drift and to control for the manufacturing adjustments that affect the drug’s safety and effectiveness.

Cost of care Rising rug costs have been a significant concern for patients, insurers, and governments. It has been estimated that the annual costs of biologic treatment for a single patient ranges from US$25,000 to US$100,000,14 and in 2013 the Canadian Generic Pharmaceutical Association estimated that Canada’s provincial healthcare systems spent more than $3 billion dollars each year on biologic drugs.15 One key benefit of the introduction of SEBs into the Canadian marketplace is that they could help reduce this financial burden by providing a lower-cost alternative to patients, governments, and insurers. Studies on the cost-saving potential of SEBs in Europe, for example, have found that SEBs are 10% to 35% less expensive than their reference counterparts.16 Therefore, given the high costs of biologic drugs, these savings may be quite substantial in absolute terms.17

Areas where further collaboration is required 

Clearly identify roles and responsibilities Due to important health and cost considerations, resolving questions around who should be monitoring and reporting on SEBs will be very important. Whose responsibility should it be to collect data? What methods might be used? Who will bear the cost of conducting research and analysis? Therefore, further dialogue is required to determine whether and how it might be possible to share responsibilities and costs. Since additional information is essential for understanding the impact and effects of SEBs, it is important to clearly outline how this information will be acquired.

Participants were divided over who should lead on the “responsibility to educate.” Since governments have many resources and regulatory expertise, the public sector may be a natural leader in educating the public and others on SEBs. Manufacturers, who develop and profit from the drugs, may also be well positioned to take on the responsibility and costs associated with an education campaign or strategy.

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In truth, the task of providing education and better information will likely fall on all stakeholders – patients, health practitioners, manufacturers, governments, associations and health societies – to ensure that SEBs are better understood, manufactured, and prescribed.

Driving any education strategy forward will require focused and sustained leadership. Therefore, it may be desirable for stakeholders to work together to find consensus around what roles and responsibilities each will play in providing education on SEBs.

Develop transparent and effective standards that regulate SEBs Provincial and federal regulators need to provide greater clarity on the relationship between SEBs and reference drugs. Since provincial governments have the power to designate drug similarity, it falls upon provincial policymakers, with input from other stakeholders, to decide whether SEBs should be considered interchangeable or substitutable for their reference products. They will need to consider the regulatory challenges discussed above, including issues around interchangeability and substitutability, and the risks associated with immunogenicity.

It is important to note that challenges with selecting a SEB’s reference drug are likely to be ongoing, requiring continued examination and coordination among all stakeholders.

In December 2013 the Government of Canada announced that it would be introducing new patient safety legislation to “help identify potentially dangerous drugs, and ensure the quick recall of unsafe drugs…”18 The represents a positive step towards better regulating manufacturing drift and protecting patients’ health and safety. Once this Bill C-17 (Amendments to the Food and Drugs Act) is enacted, the federal government should consider consulting with other stakeholders, including patients, to see whether it effectively meets its objectives and how this can be strengthened.

In addition, in instances where drift becomes an issue for a particular manufacturer, clinical studies could be required to demonstrate that the original product and the one that drifted have similar clinical properties and provide comparable therapeutic effects. Policy-makers need to consider what tests could be used to better measure manufacturing drift, and whether the burden of these tests would be shouldered by the province, the manufacturer of an SEB, or the manufacturer of a reference product.

Invest in data collection and information-sharing platforms Participants agreed that all stakeholders have an interest in expanding the current data capacity to allow for enhanced information-sharing and data pooling. A database or other platform that collects information on SEB use would allow doctors to better manage dosage and understand the long-term effects of the medications. It would also provide policymakers with additional evidence that can be used to develop regulation.

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In conducting post-market analysis, research quality and credibility are crucial. Bridging Canadian studies with international ones can help provide clarity and identify the variability of results. This is true for both the reference product and SEBs. One option might be to mandate post-marketing data collection in order to improve overall knowledge. Some participants embraced this approach, suggesting that it would be easier to establish a requirement for post-market data collection before SEBs enter the market and, potentially, become harder to track.

It will be important for stakeholders to develop post-market analysis tools and regulations in a transparent manner. Close collaboration may also be useful in helping to develop a more comprehensive data-sharing framework that “connects the dots” for patients, practitioners, manufacturers, and policymakers.

“There have been numerous papers published that give cautionary advice on the need for more studies.

This rings hollow if no one acts. A very high standard of study is needed.”

-Roundtable participant

Since Health Canada does not consider SEBs to be pharmaceutically or therapeutically equivalent to their reference products, the federal government has cautioned physicians to make well-informed decisions regarding interchange. In order to make these decisions with confidence, physicians require better long-term studies and information that can help determine the safety and efficacy of certain SEB drugs.

Establish consistent nomenclature Standards and guidelines around nomenclature require greater attention. Participants agreed that stakeholders should decide which issues and terms warrant greater clarification, and then ask Health Canada to play a leadership role to help provide answers and standardization.

Policy-makers will also need to consider multiple perspectives when making decisions about the naming of SEBs. One option would be to require that brand name and lot number be used in addition to INN when identifying a biologic drug. This approach has been proposed by the European Medical Association to ensure traceability.19 A second option would be to identify biologics by their Drug Identification Number (DIN). A unique eight-digit DIN is assigned to every pharmaceutical product in Canada. Different DINs are assigned to products within the same INN if they are produced by different manufacturers, or have different dosage strengths or routes of administration.

Ultimately it may be up to the WHO to set standards for naming generic drugs. However, one participant suggested that stakeholders in Canada should seek to guide the WHO in establishing global standards that align with Canadian rules and expectations.

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Address issues around cost SEBs provide a cheaper alternative to their reference drugs in the treatment of illness. However, for Canadians with no drug plan or high deductibles, they can actually be quite expensive. Participants agreed that stakeholders should work together to ensure that patients who need biologics and SEBs the most do not fall through the cracks.                                             Subsequent entry biologics in Canada | 10

Appendix: List of participants  

Subsequent Entry Biologics The Ontario Agenda List of Participants November 6th, 2013 12:00 – 4:30 MaRS Discovery District 101 College St. Toronto, ON

Dr. Vandana Ahluwalia Rheumatologist Past President, Ontario Rheumatology Association

Denis Morrice Executive Director Ontario Rheumatology Association

Flay Charbonneau Manager, Pharmacy, Odette Cancer Centre Sunnybrook Health Sciences Centre

Dr. Jane Purvis Rheumatologist President, Ontario Rheumatology Association

Ryan Conway Project Lead Public Policy Forum

Dr. Leigh Revers Associate Director, MBiotech Program University of Toronto

Sandra Couto Director Partnerships and Stakeholder Relations Ontario Best Practices Research Initiative

Christine Seager Senior Manager, Drug Programs Management Unit Ontario Public Drug Programs Division (OPDP)

Dr. Agnes Klein Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics Health Canada Paul Ledwell Executive Vice President Public Policy Forum Dr. Dorothy Lo Medical Oncologist St. Joseph's Health Centre Lynn Moore Director of Programs and Services Arthritis Society of Canada

Shannon Sullivan Manager of Reviews Pan-Canadian Oncology Drug Review Dr. Shail Verma High Risk Assessment Clinic, Medical Lead, Medical Oncology The Ottawa Hospital Cancer Centre Deborah Weber Director, Research and Clinical Operations, Mt. Sinai; Associate Director, Division of Advanced Therapeutics Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mt. Sinai

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Observers Jenn Chambers Senior Manager, Ontario Government Relations and Health Policy Hoffmann-La Roche Limited James McLean Project Lead Public Policy Forum Dr. Jascha-N. Rybak Product Manager Breast Oncology Hoffmann-La Roche Limited

1

Health Canada. (2013). Fact Sheet: Subsequent Entry Biologics in Canada. Government of Canada.

Retrieved December 17, 2013 at: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/activit/fs-fi/fs-fi_sebpbu_07-2006-eng.php 2 Health Canada. (2010.) Questions and Answers to Accompany the Final Guidance for Sponsors: information and Submission Requirements for Subsequent Entry Biologics (SEBs). Retrieved September 5, 2013 from http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/01-2010-sebpbu-qa-qr-eng.php.

3 Kay, J., et al. (2012.) “Health Canada/BIOTECanada Summit on Regulatory and Clinical Topics Related to Subsequent Entry Biologics (Biosimilars) in Canada, 14 May 2012.” In Biologicals 40.6 (November 2012): 517-27. Retrieved on September 10, 2013.

4 Ibid.

5 BIOTECanada. (2012). Subsequent Entry Biologics. Retrieved on December 4, 2013 from: http://www.biotech.ca/en/policy-matters/health-bio/seb.aspx 6 Dranitsaris, G., Amir, E., and Dorward, K. (2011.) “Biosimilars of Biological Drug Therapies: Regulatory, Clinical, and Commercial Considerations.” In Drugs 71.12 (August 2011): 1527-36. Retrieved September 10, 2013.

7 BIOTECanada. (2012). Demystifying Biosimilars: Science Writers’ Guide. Retrieved September 10, 2013 from http://www.biotech.ca/uploads/biosimilars%20guide%20english%20high%20resolution.pdf.

8 BioteCanada. (2013). Subsequent Entry Biologics. Retrieved November 20, 2013 from http://www.obri.ca/about-obri/ 9 Canadian Generic Pharmaceuticals Association. “Regulatory Landscape.” In Subsequent Entry Biologics (SEB) Handbook. Retrieved September 10, 2013 from http://www.canadiangenerics.ca/seb/en.

10 Ontario Rheumatology Association. (2012. )“Position Paper on Subsequent Entry Biologics in Canada.”

Retrieved on September 15, 2012 from http://ontariorheum.ca/home/ora-subsequent-entry-biologicposition-paper.

11 Roche Canada. (2013.) “Roche Position Paper on Similar Biologic Medicinal Products.” Retrieved September 19, 2011 from www.roche.com/roche_position_biosimilars.pdf.

12 Ibid.

13 Health Canada. (2010.) Questions and Answers to Accompany the Final Guidance for Sponsors: information and Submission Requirements for Subsequent Entry Biologics (SEBs). Retrieved September 5,

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2013 from http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/01-2010-sebpbu-qa-qr-eng.php.

14 Rovira, J., Espín, L.G., and de Labry, A.O. (2011.) The Impact of Biosimilars’ Entry in the EU Market.

Retrieved on September 10, 2013 from http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_market_ 012011_en.pdf.

15 Canadian Generic Pharmaceuticals Association. “Biologic Drugs and the SEB.” In Subsequent Entry Biologics (SEB) Handbook. Retrieved September 10, 2013 from http://www.canadiangenerics.ca/seb/en.

16 Rovira, J., Espín, L.G., and de Labry, A.O. (2011.) The Impact of Biosimilars’ Entry in the EU Market.

Retrieved on September 10, 2013 from http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_market_ 012011_en.pdf.

17 Ibid.

18 Government of Canada. (2013). Seizing Canada’s Moment: Prosperity and opportunity in an uncertain world. Speech from the Throne. Retrieved on November 20, 2013 from http://speech.gc.ca/sites/sft/files/sft-en_2013_c.pdf 19 Rovira, J., Espín, L.G., and de Labry, A.O. (2011.) The Impact of Biosimilars’ Entry in the EU Market.

Retrieved on September 10, 2013 from http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_market_ 012011_en.pdf.

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