Biosimilars

Biosimilar treatments

by: Natasha Mistry, former manager of Public Policy and Stakeholder Relations

In inflammatory bowel disease (IBD), biologics are drugs produced in living cells that target and block molecules involved in inflammation. Biologics are used to treat moderate to severe disease and are normally prescribed after first line (traditional) therapies and treatments fail to improve the person’s health and well-being.

As patent protections expire for biologics, manufacturers are  developing biosimilar products, also known as subsequent entry biologics (SEBs), drugs that are similar to the innovator biologic drug. In Canada, the patent for infliximab (Remicade) expired in 2012 and adalimumab (Humira) is set to expire in 2017. In September 2013, the European Medicines Agency (EMA) approved the first biosimilar, infliximab (Inflectra) for indications including Crohn’s disease and ulcerative colitis.

About biologics and  biosimilars

Biologics are generally administered by injection or intravenously (a drip) to allow the drug to enter through the muscle tissue or blood stream and be filtered by the kidneys. Synthetic drugs, such as aspirin, on the other hand, are produced by chemical reactions. Synthetic drugs are generally available in a tablet or capsule and are taken orally to digest and pass through the stools.

Biologic drugs differ from synthetics because they are created from or by living cells acquired from human, animal or microorganisms (for example, algae, fungi and bacteria). Furthermore, biologics are often large, complex molecular structures. Vaccines, insulin and monoclonal antibodies are examples of biologics. Due to the complexity in manufacturing biologics from living cells, they tend to be higher in cost and are relatively difficult to replicate precisely in comparison to conventional (“small molecule”) drugs, which are composed of simple chemical structures.

The term “generic” is used to identify drugs that contain the same active ingredients as the “innovator” small molecule drug. Generics become available once the patent for the original drug manufacturer has expired. According to Health Canada – the government body that regulates and grants approval and entry of new drugs in Canada - a generic “must be the pharmaceutical equivalent and bioequivalent of the innovator drug, have the same route of administration and its use must fall within the conditions of marketing approval for the innovator drug. ”[1] The side effects and efficacy with generics are typically the same as the innovator drugs; however, sometimes slight variations have been reported. Generics are cost effective alternatives to originator products and help lower the market price of drugs, thus improving accessibility.

“Similar” but not “identical”

In Canada, biosimilar drugs are not considered ‘generic biologics’. They may be similar to the innovator biologic drug, but they are not exact duplications. Like innovator biologics, biosimilars are generated from living cells. Because their molecular structures are large and complex, any slight change or alteration in formula can result in structural changes to the product with potential for different clinical effects. Manufacturers of the innovator drugs are not required to share their original formulas. For this reason, it is challenging to create an exact replica of the innovator drug.

Potential benefits and challenges of biosimilars

One potential benefit is that biosimilars may offer an affordable alternative to the innovator products. Biosimilar drugs may help to curb the trend of rising costs of healthcare and increase access to costly medications. Similar to what generics have done to bring down the prices of innovator synthetic drugs, the introduction of biosimilars may also bring down the costs of innovator biologics.

Biosimilars developed for Crohn’s disease and ulcerative colitis will increase treatment options, may prevent surgeries and could decrease episodes of active disease (flare-ups). Currently, the alternative to failed biologic treatments is often surgery. Biosimilars will provide more options for patients.

One potential challenge of biosimilars involves implementing and developing appropriate regulations. Health Canada views biosimilars as standalone products and their approval for use in Canada would not be considered a declaration of pharmaceutical or therapeutic equivalence. In addition, Health Canada does not support the substitution or interchangeability of a biosimilar from the biologic innovator drug. To date, Alberta is the only province/territory to state that it will not sanction interchangeability. Despite these guidelines, there is risk in interpreting the biosimilar as a ‘generic biologic’ by other groups, including medical practitioners, pharmacists and insurance plan sponsors.

Patients should seek information and ask questions about drug prescriptions with their gastroenterologist, general practitioners and/or pharmacists. Individuals doing well on a biologic innovator drug should be aware of the risks and benefits of substitution. In some cases, substitution may lead to the formation of anti-drug bodies that will cause both the biosimilar and the innovator drug to stop working. Medical practitioners, pharmacists and insurance plan sponsors will need proper information and guidance on how and when to prescribe the appropriate biosimilar or innovator biologic.

According the Health Canada guidelines, manufacturers of biosimilars are not required to provide the same level of clinical and non-clinical results as their innovator biologic counterparts, since information submitted for the drug review process will rely on information of the biologic innovator. Health Canada states that “the biosimilar manufacturer must rigorously demonstrate that their active ingredient is sufficiently similar to the innovator’s active ingredient, in order to justify less clinical data. ”[2] Though the formula may be similar, there is still no understanding on how slight alterations in these molecules resulting from differences in manufacturing processes may affect patients. However, unlike generics, biosimilars are required to undergo controlled efficacy (“Phase III”) trials in patients to be approved. Nevertheless, the relatively small sparse clinical data available to researchers and medical practitioners may limit understanding the efficacy and safety of a particular biosimilar.

Another potential challenge will be regulating the drug approval process for multiple indications, a practice that is commonly used for innovator biologics. For example, some drugs, like infliximab (Remicade), are used to treat multiple conditions, e. g. Crohn’s disease, ulcerative colitis, rheumatoid arthritis and other inflammatory diseases. There is a separate drug review process to approve each new indication for a biologic which requires unique trials in each disease. Extrapolation of efficacy results across diseases is not allowed. Further clarification is required whether extrapolation will be allowed for biosimilars. Health Canada states that extrapolation will be reviewed on a case by case basis and will depend on scientific data provided. The review process must ensure that patient safety and drug effectiveness should be ensured for each new approved indication.

To add to the list of challenges, Health Canada has not mandated unique International Non-proprietary Names (INN), also known as molecular names, for biosimilars. INNs are needed to distinguish differences between drugs. Without an INN, medical practitioners cannot easily distinguish between biosimilars and the biologic innovator drugs.

To help clarify some of the challenges, in 2010 Health Canada developed guidelines to regulate the biosimilar market. Health Canada compares the drug processes before and after to ensure that patient outcomes are not altered. Manufacturers must satisfy regulatory requirements under the national Food and Drugs Act and Regulations. Drugs that clearly use different approaches in manufacturing may not be considered for approval.

The international landscape

In 2010, the United States enacted the Biologics Price Competition and Innovation Act that sets out guidelines for follow-on biologics or follow-on proteins. It has yet to finalize the guidelines and approve any biosimilars under this new framework.

The European Medicines Agency (EMA) was one of the first regulatory bodies to develop formal regulations for what they refer to as biosimilars, biogenerics or biobetters. Since the framework was established in 2004, the EU has approved six biosimilars, rejected one and has withdrawn five (two of which were previously approved). Earlier this month, the EMA approved Inflectra, a SEB for infliximab. It approved the use of Inflectra for multiple indications including Crohn’s disease (adult and paediatric), ulcerative colitis (adult and paediatric), ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis and psoriasis.

In 2009 the World Health Organization (WHO) established guidelines with a view to ensure better access to safe and effective biosimilars worldwide through global harmonization of the regulatory framework for drug approvals. The framework is used as a model for newly developed guidelines for countries around the world.

The decision about whether or not to use a biosimilar is a personal one, taken in consideration with your gastroenterologist, medical practitioner and/or pharmacist. Access to a biosimilar is comparable to any other drug in Canada, since it requires approval initially by Health Canada. Next, the provinces and territories review the drug’s potential listing on and coverage by, provincial/territorial drug coverage plans. Private insurance will also make decisions about coverage through their various insurance plans.

Biosimilars have potential benefits and challenges that have yet to be explored. Crohn’s and Colitis Canada will continue to follow the public discussions on biosimilars and disseminate new information to assist the one in every 150 Canadians living with inflammatory bowel disease.

For questions and comments about this article on subsequent entry biologics, also known as biosimilars, please visit our Facebook page to share your thoughts 

This article has been made possible through an unrestricted educational grant by Janssen.

For additional information on Crohn’s and Colitis Canada’s 2016 “No Forced Switch” initiative, please visit: (new page)

Written for Talk About Guts, circa 2014 – minor edits made in 2016.

References:

  • Attara, G. (2013). Subsequent Entry Biologics, Inside Tract Canada’s Gastrointestinal Disease and Disorder Newsletter, Issue 185, 12.
  • Biologics and Genetic Therapies Directorate, Health Canada. (2009, November 9). Fact Sheet: Subsequent Entry Biologics in Canada. Hc-sc.gc.ca. Retrieved 13 September 2013, from http://www.hc-sc.gc.ca/dhp-mps/brgtherap/activit/fs-fi/fs-fi_seb-pbu_07-2006-eng.php.
  • BIOTECanada. (2012). Subsequent Entry Biologics (SEBs). Biotech.ca. Retrieved 19 September 2013, from http://www.biotech.ca/en/policy-matters/health-bio/seb.aspx.
    European Medicines Agency. (2013). Inflectra.Ema.europa.eu. Retrieved 19 September 2013, from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002778/smops/Positive/human_smop_000531.jsp&mid=WC0b01ac058001d127.
  • Ghosh, Dr. S. (2013, July). SEB, 2013 Overview. Lecture conducted at Bioadvance Tour, Richmond Hill.
    Health Products and Food Branch, Health Canada. (2010). Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). Hc-sc.gc.ca . Retrieved 6 September 2013, fromhttp://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/seb-pbu_2010-eng.php.
  • Ontario Association of Gastroenterology. (2012, October). Revised Consensus on the use of Biologics for Inflammatory Bowel Disease.
  • Ontario Rheumatology Association. (2012, November). Position Paper on Subsequent Entry Biologics in Canada.
  • The Arthritis Society. (2012, May). Subsequent Entry Biologics and Current Issues Affecting Canadians Living with Arthritis.
  • [1] Biologics and Genetic Therapies Directorate, Health Canada. (2009, November 9). Fact Sheet: Subsequent Entry Biologics in Canada. Hc-sc. gc. ca. Retrieved 13 September 2013, from http://www. hc-sc. gc. ca/dhp-mps/brgtherap/activit/fs-fi/fs-fi_seb-pbu_07-2006-eng. php.
  • [2] Biologics and Genetic Therapies Directorate, Health Canada. (2009, November 9). Fact Sheet: Subsequent Entry Biologics in Canada. Hc-sc. gc. ca. Retrieved 13 September 2013, from http://www. hc-sc. gc. ca/dhp-mps/brgtherap/activit/fs-fi/fs-fi_seb-pbu_07-2006-eng. php.

  • Canada has among the highest incidence rates of Crohn's and colitis in the world.
  • 1 in 150 Canadians lives with Crohn’s or colitis.
  • Families new to Canada are developing these diseases for the first time.
  • Incidence of Crohn’s in Canadian kids under 10 has doubled since 1995.
  • People are most commonly diagnosed before age 30.

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