What does the future hold for Subsequent Entry Biologics (SEBs)?

As the debate around biosimilars heats up, a representative from the Ontario Rheumatology Association Executive presents his perspective on the unfolding situation in Canada.

“In the end, we are all separate: our stories, no matter how similar, come to a fork and diverge. We are drawn to each other because of our similarities, but it is our differences we must learn to respect.”

Subsequent entry biologics, follow-on biologics, biosimilars or similar biotherapeutic products. What’s in a name? They all refer to products which are subsequent to and similar to an innovator or reference-based drug and are derived from living organisms. In Canada, these products are known as subsequent entry biologics (SEB). For convenience and constancy I will use SEB and biosimilar interchangeably.

Health Canada defines a subsequent entry biologic as a new biologic entry to the market after patent expiration. Health Canada has issued guidelines on approval of subsequent entry biologics, but federal guidelines do not necessarily affect health care decisions at the provincial level, e.g. drug coverage or designations of similarity.

The European Medicines Agency (EMA) has approved 16 SEBs since 2006. However, eight SEBs have been withdrawn or rejected. High incidence of relapse or adverse events; lack of efficacy, non-validated immunogenicity assays; impurities or simply commercial reasons are some of the explanations for withdrawal from the European market.

“The European Medicines Agency (EMA) has approved 16 SEBs since 2006”

The European market took a big step forward when regulators on the continent approved Remsima (Celltrion) and Inflectra (Hospira) which is an SEB to Infliximab (Remicade) (JNJ). Biosimilar infliximab was approved January 17, 2014 by Health Canada for the indications of Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis and Psoriasis. Europe has moved ahead with clear regulatory pathways that led to approval of subsequent entry biologics allowing a discounted biologic to go head to head with the innovator or original product.

Novartis, Amgen, Sanofi, Pfizer, and Biogen have their own SEB programs. However, subsequent entry biologics are not generics. Subsequent entry biologics are large complex molecules manufactured in living systems. They are challenging to fully characterize and impossible to duplicate exactly. The active ingredient is highly similar to the reference product, but not identical. Approval may come only on the basis of extensive in vitro comparability testing with minimal clinical comparability testing, such as pharmacokinetics, safety and efficacy.

Because of the complexity of biologics and its manufacturing development, any change in the manufacturing process, such as production, formulation, purification, handling and storage could potentially impact the biologic activity and, therefore, safety and efficacy of the product.

Health Canada has stated that SEB authorization is not a declaration of pharmaceutical or therapeutic equivalence to the innovator biologic. Each SEB should be considered a stand-alone product.

Practical concerns and considerations for policymakers approving SEBs include patient safety, approval using a reduced data package, interchangeability, substitutability, extrapolation to other indications, immunogenicity, manufacturing drift, traceability, nomenclature and pharmacovigilance, and finally cost to patient and payers.

“Interchangeability” generally refers to the requirement to “interchange” a lower cost generic version of a brand name drug. E.g.: Plaquenil® being interchanged with hydroxychloroquine.

“Substitutability” or “therapeutic substitution” generally refers to substituting an altogether different drug as functionally equivalent to a prescribed drug for treating the same condition. E.g.: Pantoloc® substituted by Prevacid®.

Data extrapolation refers to the evaluation by Health Canada of a proposal to grant additional indications held by the reference biologic drug to the SEB, in the absence of such clinical data for the specific SEB. Health Canada indicates that extrapolation may be justified based on: mechanism of action; pathophysiological mechanism(s) of the disease(s) or conditions involved; safety profile in the respective conditions and/or populations; and clinical experience with the reference biologic drug. Health Canada is open to the idea of extrapolation of indications; however, this will be decided on a case-by-case basis. Thus, an SEB studied only in rheumatoid arthritis and ankylosing spondylitis, may also be approved for inflammatory bowel disease, psoriasis and psoriatic arthritis if the reference drug has these indications.

“Patients with rheumatic diseases should have access to safe, effective and affordable drugs, but that cost must not override safety and efficacy”

Relevant immunogenicity refers to an immune reaction to a biologic molecule. This can have a number of outcomes to a patient if it induces a native immune response. Immune reactions can: neutralize effects of the biologic drug and compromise further therapy, alter the pharmacokinetics of the drug, cross-react with native proteins and induce adverse reactions or have no effect. A single biologic drug does not necessarily have the same immunogenicity rates in different patient populations.

Traceability and nomenclature is key given the fact that SEB products are not identical to innovator products and could have significantly different clinical outcomes. Regulated nomenclature and unique DIN will allow measurement of uptake, safety and efficacy for all stakeholders including patients, physicians, pharmacists, private payers, and government.

The view of the Ontario Rheumatology Association (ORA) is that long-term monitoring of biologics and post-marketing registries are very important for the chronic management of rheumatic diseases. Patients with rheumatic diseases should have access to safe, effective and affordable drugs, but that cost must not override safety and efficacy. The decision to use SEBs is a planned and shared decision between the patient and his or her physician taking into account many factors.

SEBs are not to be considered for automatic interchangeability or substitution. Each biologic product must have a distinct product name to track real world effectiveness. The ORA supports the development of a province-wide post-marketing registry which should be supported by all stakeholders and run by a third party. Strict post-marketing surveillance must be followed.

Voluntary post-marketing registries in existence in some provinces with a large observational cohorts (E.g.: OBRI=Ontario Best Practices Research Initiative) can provide quality data that would be reflective of the realities (safety and efficacy) of patients in Ontario. We feel that the ORA and the OBRI platform is centrally positioned to cooperate with other important SEB stakeholders including the Exceptional Access Program in Ontario, private payers, Ministry of Health, and the patient.

The ORA stresses that patients renewing their biologic prescriptions should never be considered for substitution with SEBs. Those patients who are biologic-naive may be considered for substitution, if the SEB is mandated by government and private payers. Regulatory framework, data extrapolation to other indications, post-marketing surveillance, and manufacturing decisions are ultimately a regulatory responsibility.

We believe that innovator drug companies are likely to lower their price point to match SEBs, which has already occurred in Europe.

“We believe that innovator drug companies are likely to lower their price point to match SEBs”

In Canada, it is our expectation that SEB companies will develop patient support programs to help with treatment initiation, provide an infusion network if required, monitor ongoing treatment, communicate with the physician and patient, and provide disease support. Alternatively, this responsibility will fall on the ‘system’ of public and private payers, potentially negating cost savings.

Issues such as cost reduction, reduced clinical data package, immunogenicity, extrapolation, interchangeability, substitutability, nomenclature, manufacturing drift, and pharmacovigilance may all have an effect on the patient experience in Ontario.

The Ontario Rheumatology Association is committed to vigorous participation in the SEB discussion with all stakeholders in order to provide safe, effective and timely therapies for patients with rheumatic conditions.

The Ontario Rheumatology Association has published a position paper on SEBs in Canada. The key statements were released in 2012 and are available at http://ontariorheum.ca.


About the author:

Dr. Karasik obtained his Doctorate of Medicine from the University of Toronto in 1977. After a further 5 years of training in Rheumatology and Internal Medicine, he received his fellowship degrees in both Rheumatology and Internal Medicine in 1982. Dr. Karasik was a consultant rheumatologist at the Queensway General Hospital in Toronto from 1983 to 1999 and St. Josephs Health Centre in Toronto from 2000 to 2010. His current position is courtesy staff at St. Josephs Health Centre in Toronto and Trillium Health Partners in Mississauga.

Dr. Karasik is an active member of his professional association. He is the Vice President of the Ontario Rheumatology Association and sits on multiple committees for the association including Ontario Best Practices Research Initiative (OBRI), Models of Care(MOC), Electronic Medical Records(EMR), and the Exceptional Access Program(EAP). He participates in clinical trials of inflammatory arthropathies through the Canadian Rheumatology Research Consortium. (CRRC) In addition to his community clinical practice, Dr. Karasik enjoys consulting for the pharmaceutical industry as well as teaching medical students as an adjunct lecturer at the University of Toronto Medical School – Mississauga Campus.

He can be contacted at drkarasik@bellnet.ca

Closing thought: How will subsequent entry biologics change the Canadian pharma market?