Arthritis patients are on the "front line" of subsequent entry biologics (SEBs) policy making. SEBs to treat three types of autoimmune arthritis are the first to enter the Canadian marketplace. The arrival of SEBs for other diseases such as breast cancer are expected in the next five years.

What are SEBs?

Subsequent entry biologics describe a group of biologic medications that are administered by subcutaneous injection or intravenous infusion and are similar, but not the same, as their originator biologics.

SEBs are not generics of their originator biologics

SEBs are similar, but not the same, as their originator biologics

Medications made with small, chemically manufactured molecules (e.g. acetylsalicylic acid, the active ingredient in aspirin) are made through a relatively simple process. After a manufacturer's patent for a particular medication, like aspirin, expires, other companies can easily make exact copies of the active ingredient of the brand name version. These are known as generics.

Biologics, however, are large molecule medicines made from living cells in a complex process manufacturing process that can have a significant impact on the final drug product. It is impossible to make an exact copy of an originator biologic drug because the living cell structures cannot be the same.

After the originator biologic patent expires, Health Canada reviews and may approve other manufacturers to introduce "similar" versions (i.e. SEBs) of the originator. However, SEBs come from different DNA and cell lines – not from their originator biologic cell lines – and have their own manufacturing processes.

Even minor differences from the originator biologic may change the way a SEB acts in the body. The distinction is important to physicians and patients who consider patient safety as the paramount concern over the use of SEBs in Canada. As a result, SEBs must be effectively tracked in the marketplace and that information must be made available for external review, as it is for their originator biologics.

How are SEB's regulated?

Health Canada reviews the manufacturing process, data on the comparability of the SEB to the originator biologic and non-clinical and clinical data supplied by the SEB manufacturer, to establish similarity to the originator. At the end of the review, Health Canada may approve the product for one or more indications of the originator biologic.

Health Canada may approve a SEB to treat a disease without any clinical trial data to support its use in that disease. This is called "indication extrapolation." Approval of a SEB is not a declaration of bioequivalence with the originator biologic. Post-approval, SEBs are regulated like any new biologic medicine.

Health Canada defines SEBs as a "biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug."

  • No declaration of bioequivalence may be made
  • Post-market surveillance/risk is required
  • Once approved, a SEB is regulated like any other new biologic therapeutic
  • Unlike generics, approval of a SEB is not a declaration of pharmaceutical or therapeutic equivalence to the reference biologic (originator) drug
  • Automatic substitution of a SEB for its reference biologic drug is not supported

How are SEBs reimbursed on public and private drug formularies?

Individual provinces and private insurance plans will make decisions about SEB listings on drug formularies. As SEBs are not bioequivalent to the reference product, it is unlikely they will be listed as interchangeable with the original product. Public and private payers, however, may prefer one product to another opening up the possibility that a SEB could replace the originator biologic that a patient had previously been prescribed due to potential cost advantage.

SEB Equivalence

Unlike generics, SEBs are not identical to innovator biologics. Because every biologic is made from living cells and even minor differences can change the way it behaves in the body. Therefore, not all patients will react to a SEB in the same way as they do to the originator biologic.

SEB Immune Reactions

Immune reactions occur when the body tries to defend itself against a drug. Patients taking a SEB may have a different immune reaction compared to the originator biologic and vice versa.

As a result, switching back and forth between an originator biologic and a SEB may increase the risk of an immune reaction.

SEB Interchangeabilty

"Interchangeability" refers to the ability to switch from one bioequivalent medication to another considered to be its generic equivalent. This practice is most common with small- molecule generic drugs (e.g. Lipitor vs. generic atorvastatin), and often happens automatically at the pharmacy (without physician knowledge or involvement) because of cost differences.

Another commonly used term for medication switching is therapeutic substitution, i.e. the switching from one product in the same class to a non-bioequivalent product in the same class, which is thought to be therapeutically equivalent (e.g. Lipitor vs. Crestor). However, SEBs are not identical copies or "generics" of the original biologic drug; small differences between products can cause unexpected outcomes.

Because SEBs and orginator biologics are not identical, interchangeability or therapeutic substitution at the pharmacy could lead to uncontrolled switching (i.e. without physician oversight) between products. This may be worrisome, as patients could develop antibodies that may affect efficacy and safety of the medication. Health Canada does not support interchangeability or automatic substitution of SEBs and recommends that physicians make well-informed choices when considering switching a patient's biologic medicine.

SEB Naming

Arthritis consumer and healthcare professional groups, and other disease organizations, have called for distinct non-proprietary and brand naming for any and all SEBs entering the Canadian marketplace. They did so because of the need to minimize confusion about which medication was being prescribed or taken, and, equally important, to accurately attribute adverse events to the appropriate product (SEB or originator biologic).

Health Canada has decided to follow the non-proprietary naming protocol for biologics (including SEBs) that is ultimately recommended by the World Health Organization (WHO). At the request of a number of regulatory jurisdictions, the WHO is working to address the issue of non-proprietary naming for SEBs.

Patient Perspectives

SEBs may offer patients and physicians a choice in the treatment of autoimmune forms of arthritis at a reduced price from the originator biologic. The additional treatment option a SEB may provide is compromised if public and private payers decide to reimburse them in a preferential manner to the originator biologic.

Patients want to have a full therapy conversation with their rheumatologist (or other specialist) in order to best decide on their choice of medication(s), including originator biologics and their SEBs.

Patient Priorities

Patient safety is the most important aspect of SEB regulation in Canada.
SEBs should have their own distinct generic and brand names to prevent confusion in marketplace.
SEBs must be effectively tracked in the marketplace, like their originator biologics, and reported regularly to the public.
Patients expect SEB patient programs to meet current standards of originator biologics' patient programs.
Patients must be empowered to have an unencumbered therapy conversation with their physician and choose the best therapy for their disease and life circumstances.

How can patients get involved?

In the long term, SEBs will have an increasing role to play in the Canadian health system. What we don't know is how will SEBs perform once in wide use in Canadian patients compared to their originator biologics. Want to be involved?
  • Stay informed and seek out "lay language", research-based information about SEBs
  • Continue to share perspectives and experiences around this important health topic
  • Help educate your friends, family and community – they will be affected by the arrival of SEBs
  • Understand how SEBs are assessed and listed on public and private formularies

JointHealth™ shareables
"Whether it is with an infographic, video, or text, ACE looks for new ways to share healthcare information, research and policy in a way that is interesting and easy to understand. Our new program, JointHealth™ shareables, presents important health issues in one easy-to-navigate page."