Kathy Vu1,2, Daniela Gallo-Hershberg1,2, Sean Hopkins1
1. Ontario Health (Cancer Care Ontario)
2. Leslie Dan Faculty of Pharmacy, University of Toronto
BIOLOGICS AND BIOSIMILARS
A biologic is a complex protein molecule created inside a living cell. This living cell can be a human or mammalian body, a bacterial cell or a cell line from a mammal. For instance, insulins, filgrastim (Neupogen®, Grastofil®, Nivestym®) and peg-filgrastim (Neulasta®, Lapelga®, Fulphila®, Ziextenzo®) are produced in E. Coli cells. Larger monoclonal antibodies are produced in mammalian cells like Chinese Hamster Ovary or mouse myeloma cells. Examples of this are denosumab (Prolia®, Xgeva®), infliximab (Remicade®, Inflectra®, Renflexis®), adalimumab (Humira®) and trastuzumab (Herceptin®, Ogivri®, Trazimera®, Herzuma®). These living cells can produce the exact same protein – in the exact same amino acid sequence – required to produce the biologic. Changing a single amino acid or a small number of amino acids makes a completely different medication; for example, the only difference between human insulin and insulin aspart is a single proline amino acid being replaced by aspartate in the 51-amino acid structure. Changing 5 out of 165 amino acids in erythropoietin (Eprex®) results in the creation of darbepoetin (Aranesp®). Both of these changes created dramatically different medications.
A biosimilar is a biologic drug that is highly similar to a biologic drug that was already authorized for sale (reference biologic). Biosimilars are also known as “subsequent entry biologics” or “follow up biologics” in some jurisdictions. The biosimilar has the identical amino acid sequence as its reference biologic. A biosimilar may enter the market after the expiry of the patent and data protection of its reference biologic. There are no expected clinically meaningful differences in efficacy and safety between a biosimilar and its reference biologic.
Biologics and biosimilars exhibit an inherent variability in how the living cells complete the manufacturing of the biologic (and biosimilar) molecule. This inherent variability means that there is not a single identical molecule for a biologic (or biosimilar) product, but that there are multiple molecules manufactured and included in the final product. These are called glycoforms – the biologic and biosimilar must maintain the number and ratios of glycoforms in the approved product within a specified range. This results in no two biologic batches being identical to each other but instead are comparable, and the biosimilar manufacturer needs to maintain this comparability to its reference product.
Biosimilars work in the exact same way as their reference biologic. They have been shown to be analytically comparable to their reference biologic, and large clinical trials have demonstrated that there is no difference in the clinical activity of the biosimilar in indications approved for the reference biologic. These same clinical trials have also shown that there is no difference in the immunogenicity between the reference biologic and the biosimilar – patients do not develop a greater amount of antibodies to the biosimilar when compared to the reference biologic.
Biosimilars are not new products. Europe has been using the same biosimilars that are coming to Canada for more than 10 years. In Europe, there has not been a single biosimilar removed from the market due to concerns about efficacy or safety nor has there been any reported issues about biosimilars. Pharmacists should be confident that when their patient is either started on a biosimilar or changed from the routine use of a biologic to the routine use of a biosimilar, that there will not be any difference in the safety or effectiveness. This article will outline some considerations related to clinical operations, patient safety and patient education to help guide your discussions with patients like Marvin.
ARE YOU PREPARED TO COUNSEL THIS PATIENT ON BIOSIMILAR PRODUCTS?
Marvin is a 64-year-old male with advanced, stage 4 colorectal cancer. He is currently receiving chemotherapy with FOLFOX and bevacizumab every two weeks and has received this treatment for the past two months. He is tolerating his treatment well but did experience two episodes of febrile neutropenia despite a dose reduction. His oncology team will be starting him on filgrastim with future treatments. He is responding well to his treatment and is considered to have stable disease with no major impact on his activities of daily living.
Today, Marvin is in the clinic to receive his FOLFOX and bevacizumab cycle #5. His clinic pharmacist stops by to give him his supportive care prescriptions as well as an information sheet on biosimilars. The pharmacist explains that his bevacizumab is being switched to a biosimilar due to a change in funding policy. Additionally, his filgrastim is also considered a biosimilar. Marvin is concerned about the use of biosimilars instead of the brand name product. Are you, as a pharmacist, prepared to counsel Marvin and address his questions and concerns?
CLINICAL OPERATIONS CONSIDERATIONS
The pan-Canadian Pharmaceutical Alliance (pCPA) and Cancer Care Ontario (now part of Ontario Health) collaborated to lead the pan-Canadian Oncology Biosimilars Initiative (pCOBI), which is a cancer-specific strategy that recognizes the unique considerations for the implementation of oncology biosimilars. A national Clinical Operations Working Group (COWG) developed position statements aimed at guiding organizations’ and jurisdictions’ implementation of biosimilars throughout the entire clinical operations process flow. The full Position Statements for the Implementation of Oncology Biosimilars from the pan-Canadian Operations Working Group can be found on the Ontario Health (Cancer Care Ontario) website. The following are highlights that also apply to community pharmacies dispensing biosimilars.
Procurement and Receiving
- Biosimilars are to be considered as look-alike, sound-alike (LA/SA) products for patient safety.
- Pharmacies are to use the unique Drug Identification Number (DIN), or item number to distinguish biosimilars from reference biologic drugs at procurement.
- Biologics and biosimilars are to be entered as separate drug database entries to allow for tracking utilization, financial impact, and other data.
- In cases of drug shortages where Health Canada allows the use of a biosimilar from an international jurisdiction that does not use the same nomenclature, the product is to be entered as a separate drug entry using Canadian nomenclature.
- To prevent confirmation bias, staff should first look at the drug product received and then confirm against the packing slip (and not vice versa).
- Biosimilars are to be considered as LA/SA products for operational safety.
- Auxiliary labels are to be placed on reference biologics and biosimilars. The auxiliary labels used for biosimilars are to follow LA/SA guidance.
- When storing biosimilars, LA/SA shelf-talkers and stop signs can be used to alert pharmacy staff.
- Pharmacies are to physically separate biosimilars from the reference biologic, and/or from similar-looking products (either by physical location, refrigerator, or physical separation within the refrigerator). If the biosimilar is stored in the same refrigerator or physical location as the reference biologic, or similar looking products, then the biosimilar should not be stored in alphabetical order by international non-proprietary name (INN), also known as the generic name. The reference biologic and biosimilar could be kept in alphabetical order by brand name.
- A prescription for a biosimilar should specify a brand for a specific indication. If this is not the case, a collaborative approach should be taken to determine the intended brand to dispense.
- LA/SA products, including reference biologics and biosimilars, should have the DIN or manufacturer, lot and expiry recorded, regardless of whether institutions have an electronic or manual system.
- When using compounding labels, the DIN or manufacturer, lot and expiry should be recorded.
- The label is to include both the INN and brand name.
- To best identify the product, the product is to be labeled first with its INN, followed by its brand name [e.g. filgrastim (Grastofil®)].
PATIENT SAFETY CONSIDERATIONS
The introduction of biosimilars is not expected to pose an increased risk to patient safety and the typical processes that occur within a pharmacy regarding patient safety issues will continue with biosimilars implementation.
To enhance patient safety from the perspective of ensuring the patient receives the intended product, the naming convention should be addressed. According to their Notice to Stakeholders "Health Canada has decided that biologic drugs, including biosimilars, will be identified by their unique brand name and non-proprietary (common) name, without the addition of a product-specific suffix. Both the brand name and non-proprietary name should be used throughout the medication use process so that biologics that share the same nonproprietary name can be distinguished by their unique brand names.” In an ideal state, both the unique brand name and non-proprietary (common) name should be used throughout the medication use process (i.e. prescription, pharmacy computer system, prescription vial label). However, there may be limitations in the current pharmacy software with character limits and label size that makes this recommendation unrealistic at this time. These are barriers that should be noted and enhanced to ensure patient safety in the future as more biosimilars are expected to be marketed in Canada.
PATIENT EDUCATION MATERIALS
As part of the pan-Canadian Oncology Biosimilars Initiative, the national Education Working Group produced various resources for both patients and healthcare providers. As there are likely many resources available on the internet, it is important to ensure that the information provided to patients and caregiver is evidence-informed and consistent amongst all healthcare providers.
Cancer Care Ontario. Position Statements for the Implementation of Oncology Biosimilars from the pan-Canadian Clinical Operations Working Group, August 2019. Available at: https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/60296. Accessed January 19, 2020.
Notice to Stakeholders – Policy Statement on the Naming of Biologic Drugs. Health Canada, 2019. Available at: https://www.canada.ca/en/health-canada/services/drugs-health-products/biologicsradiopharmaceuticals-genetic-therapies/biosimilar-biologic-notice-to-stakeholders-drugsnaming-of-biologics.html. Accessed January 20, 2020.
Biosimilar biologic drugs in Canada: Fact Sheet. Available at: https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/applications-submissions/guidance-documents/fact-sheet-biosimilars.html Accessed Jan 20, 2020
Ontario Health (Cancer Care Ontario) YouTube Playlist - Biologics and Biosimilars - https://www.youtube.com/watch?v=bPY8NkbotGY&list=PLRNynXKCayZWorBE3mgAS7_mwJmDH1pr4 Accessed March 11, 2020