Biologics and Biosimilars: Information for Healthcare Providers

Biologics and Biosimilars: Information for Healthcare Providers


Biologics & Biosimilars An Introduction from the Pan-Canadian Oncology Biosimilars Initiative This presentation has been prepared by Cancer Care Ontario and is part of the pan-Canadian Oncology Biosimilars Initiative, funded by the pan-Canadian Pharmaceutical Alliance. The aim of this presentation is to educate clinicians (oncologists, nurses, pharmacists etc.) on the topic of biologic and biosimilar medications. The learning objectives for this presentation are to: Define biologic medications (Biologics) Define biosimilar medications (Biosimilars) Describe: How biologics and biosimilars are produced Why there is inherent variability within and between them, and How they are comparable to each other Explain the regulatory approval process with respect to: Efficacy, and Safety (Immunogenicity) State the regulations around extrapolation in Canada Describe the implications to your clinical practice in terms of: Extrapolation, switching, clinical operations, and pharmacovigilance What are biologics? A biologic is a complex protein molecule created inside a living cell or system. This living cell (or system) can be a human/mammalian body, a bacterial cell or a cell line from a mammal. Examples of this are transgenic rabbits, E. Coli bacteria or Chinese Hamster Ovary cell lines. These living cells (or systems) can produce the exact same protein (in other words, the exact amino acid sequence) and higher level structures. Biologics help to treat diseases and medical conditions, including: cancers, arthritis, psoriasis, inflammatory digestive disorders, growth disorders and diabetes. The next slide is a visual representation of the differences between small molecules, simple biologics and very complex biologics Small molecules (e.g. aspirin) are chemically synthesized and have a very small molecular weight Biologics are more complicated in structure and require a living system for replication Simple proteins like insulin can be created inside E. Coli cells. Natural insulin has 51 amino acids, and synthetic insulins have 50-53 amino acids Larger proteins, like erythropoetins, need to be produced by mammalian cells. Erythropoetins have approximately 165 amino acids and 40-50% of their molecular weight is made up of sugars Complex large molecules, like monoclonal antibodies, are also produced by mammalian cells. They can have more than 1600 amino acids and do have sugar residues as well What are biosimilars? A biosimilar is a biologic medication that is demonstrated to be highly similar to a biologic medication that is currently marketed (a.k.a. reference biologic). They can be sold in Canada once the patent of the innovator company has expired. Biosimilars are not necessarily identical to its reference biologic, but based on Health Canada’s guidelines and approval standards for the pharmacokinetics, pharmacodynamics, safety and clinical efficacy of biologics, the two are highly similar. A biosimilar approved by Health Canada has no clinically meaningful differences in safety and efficacy with its reference biologic Biosimilars are not new. Biosimilars have been approved internationally since 2005. At that time, Australia approved a biosimilar for human growth hormone. Europe has 10+ years of experience with biosimilars. Over 54 biosimilars approved as of March 2019 Nearly 700 million patient days US and Canada are catching up with the use of biosimilars. Health Canada approved the first therapeutic oncology biosimilar in 2018. How are Biologics and Biosimilars Produced? A simplified description of the process is: Master cell lines are cultured from cell banks in bioreactors to expand the number of cells These cells are then induced to produce the biologics The resulting product is then purified and formulated for clinical use Biologics and Biosimilars have inherent variability. Why does their production lead to this? For all biologics (biosimilars included), the exact same molecule cannot be produced every time, specifically when using mammalian cells; there is some natural variability between the molecules produced. This is because of the post-translational modifications, primarily the glycosylation of the proteins. However, variability must remain within a regulated threshold from batch to batch. The approval of the process of making a biologic gives boundaries as to how much variability is allowed to exist in a biologic in order for it to be considered comparable or highly similar to the approved biologic medication. When changes are made to a manufacturing process, the biologic products made after the change in process are not identical to the products made before the change, however they are highly similar. Thus, manufacturers must demonstrate to regulators that these changes do not have an adverse impact on the safety or efficacy of their product. How is this variability demonstrated? Variability is demonstrated by characterizing the key attributes of the biologic/biosimilar. The number of key attributes varies from biologic to biologic and there are many. The key attributes for biologics (including biosimilars) include: Amino acid sequence of the protein (which must be identical) Primary structure Glycosylation patterns Other modifications For monoclonal antibodies specifically, there are two key attributes: Binding to their target (antigen) Ability to activate the immune system (if that is part of their mechanism of action). Examples are antigen-dependent cellular cytotoxicity and complement dependent cytotoxicity This is a table that summarizes the key attributes of some important oncology biologics that face biosimilar competition in the near future. They are important to understand their relationships to the natural variability of biologics and biosimilars. This is important as each biologic has very different characteristics that require clarification. The antigens are obviously all different but impact the mechanism of action of the medication. Bevacizumab really only targets VEGF, not any target on a cancer cell. Trastuzumab will bind to the HER/2 transmembrane tyrosine kinase receptor. Rituximab binds to the CD20 antigen on all mature B-cells or other CD20 positive hematologic cells. Signal transduction is one mechanism of action that is important in cancer cells. Bevacizumab does not directly impact signal transduction as it sequesters the ligand that stimulates the VEGF-receptor. This does not target cancer cells, only the vasculature that will supply the entire tumour with oxygen and nutrients. Trastuzumab has a direct effect on the anti-apoptotic HER/2 pathway – by blocking the ligand binding site it allows the cell that has the HER/2 receptor to undergo apoptosis if is signaled to do so by another pathway. This may include chemotherapy signaling cell death that is protected by the HER/2 pathway. Rituximab binds to the CD20 antigen on the cell surface – CD20 is thought to be a calcium channel but rituximab does not affect this function. ADCC is an important mechanism of action for trastuzumab and rituximab. Both of these medications rely on ADCC in order to enhance their effects on the cells that hosts their target. What is the Significance of Changes to the Production Process after Licensing of a biologic? When biologics were first developed, it was assumed that the approved process for manufacturing the biologic would not change. However as scientific data grew and matured, companies have made changes for non-medical reasons. Regulators, like Health Canada, take a risk-based approach when evaluating the potential impact of the change Low risk changes may require very little evidence to demonstrate comparability High risk changes may require extensive evidence for comparability and may even require a clinical trial Relevant to oncology biologics that are used in Canada, the biologics produced in the EU have had several changes in their production process. For example: Rituximab has had 23 changes, one that was considered high risk Trastuzumab has had 26 changes, 2 that were considered high risk Bevacizumab has had 12 changes, none of which were considered high risk The changes in process and the natural variability lead to variable quality characteristics. Here we see the effects on the antigen binding ability of EU, US and biosimilar bevacizumab This scatter plot demonstrates the characterization of the VEGF-binding of the three biologics, one of which is referencing the other two as a biosimilar. Since this is its primary MOA the activity of binding VEGF must be highly conserved. The range of activity of the EU batches was from ~75% to 100% The range of activity of the US batches was from ~80% to 105% The proposed biosimilar MVASI had activity that ranged from ~85-100%. This was part of the non-clinical data that allowed the FDA to declare MVASI comparable to Avastin and licensed as a biosimilar This scatter plot demonstrates how the ADCC activity is much more variable in the EU and US batches of Herceptin. The relative ADCC activity ranges from 65-140% – this demonstrates that this key attribute has significant natural variability As per the Health Canada Summary Basis of decision document, the biosimilar must show that its range of variability is highly similar to the innovator biologic Now that we have examined the natural variability of biologics and biosimilars, it explains why biologics and biosimilars can only be comparable, not identical. The general principle about comparability is that it does not necessarily mean that the quality attributes of the pre-change and post-change [from manufacturing] are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product. An example of this from the literature is when the manufacturing process for trastuzumab Active Pharmaceutical Ingredient (API) was successfully transferred from… USA [site] to… Germany site… As a result of the process validation, the USA and the Germany processes were found to be comparable. In particular, the analytical comparability of the USA and Germany API could be demonstrated This demonstrates that a biologic product, that originates from within the originator company, when produced at a different manufacturing facility, is only deemed to be comparable to the product from the other manufacturing sites that it is also manufactured at. As a conclusion to the discussion about biologics, biosimilars and what “highly similar” and “comparable” actually mean, it is worthwhile pointing out how organizations that have been critical of biosimilars use the terms incorrectly and deceptively. The Biosimilars Working Group produced the tweet that is shown in this slide. They claim that biologics and biosimilars are as different as apples and oranges. This claim is misleading and they use the term “similar” in an inappropriate way. This misinformation is primarily targeted at patients to reduce their confidence in biosimilars. The concept of apples and oranges is an inappropriate comparison. Apples and oranges are very different, not even remotely similar. As an analogy, it is more like comparing Red Delicious Apples from Orchard A to Red Delicious Apples from Orchard B. Despite being “manufactured” at two different sites by two different processes, you would not be able to tell the difference between the apples without being told where they came from! There is inherent variability in the manufacturing of Red Delicious Apples which results in a difference in size, weight etcetera. It is important to understand the appropriate and inappropriate uses of the terms surrounding biosimilars, especially when they are used to create confusion and reduce confidence in biosimilars. Now looking at the regulatory approval process – what information is needed by regulators for approval? Both reference biologic and biosimilar need clinical data, pharmacokinetic and pharmacodynamic data, non-clinical as well as analytic data. These pyramids represent the evidence or data that is generated in order for a product to become approved. While they are visually the same size in order to be readable, the amount of data that a manufacturer of a biosimilar submits for approval is overall less than what is needed for the reference biologic. This is primarily due to the reduction in clinical data. This reduction in clinical data is why biosimilars can be less expensive – there are fewer resources needed for approval. Clinical data includes the various clinical trials that are needed to demonstrate activity. For originator products this includes Phase I, II and III trials in all of the indications that they are seeking to determine the effectiveness in. For biosimilars, there is no requirement for any Phase II trials as the proposed biosimilar only needs a Phase I trial for pharmacokinetic and pharmacodynamic data, followed by a Phase III trial in a sensitive population. Non-clinical data includes the pharmacology of the molecule, such as in-vitro activity. This varies from biologic to biologic. In-vitro activity can include the binding to the antigen/target, the effects on the target, the recruitment of the immune system as well as other product specific activity that the manufacturer and regulator deem appropriate to demonstrate comparability. Pharmacokinetic and pharmacodynamic (PK/PD) data are non-clinical as well but occur in humans or suitable surrogates (for example mice, rats). Analytical data refers to the analysis or characterization of the biologic and biosimilar. Prior to any other activity in demonstrating comparability to the reference biologic, the process that creates the proposed biosimilar must demonstrate analytic comparability to its reference. Based on the previous slide we know that no two batches of a biologic are identical to each other, and there is International guidance to keep biologic batches comparable/highly similar to ensure the safety and efficacy of the batches. The biosimilar manufacturers must characterize the key quality attributes of its reference biologic and demonstrate comparability. It is impossible to determine the source of a biologic or biosimilar based on its quality characteristics. Once approved the biosimilar needs to maintain this comparability to the reference biologic. Health Canada, the EMA and the FDA all use the same international standards in determining comparability/high similarity. As to the clinical regulatory requirements, clinical trials are almost always needed for approval of indications. For example, a clinical trial was not conducted for bevacizumab in metastatic colorectal cancer as data from NSCLC trials was extrapolated and used for its approval. Now the type of clinical trial depends on the type of biologic. Indications with highly sensitive endpoints may require less evidence for approval. For example the first biosimilar filgrastim brands in the EU required Phase III equivalence trials for approval. More recent approvals only require non-comparative safety studies. This is due to a highly sensitive endpoint, duration of severe neutropenia (DSN), that could be measured. The following slide summarizes the trials used in approving biosimilar filgrastims In this summary of the phase III trials, Nivestim and Tevagrastim used randomized equivalence studies, while Grastofil and Zarzio used safety studies compared to historical clinical trials of filgrastim. Notice the similarity in the highly sensitive endpoint, duration of severe neutropenia, with a range of 1.1 to 1.8 days When we examine the regulatory requirements for therapeutic oncology biosimilars we see that they need more robust clinical data for approval due to a lack of sensitive endpoints. Clinical trials must be conducted in a suitable indication that has a: Highly sensitive population – for example, active disease, the medication has a large effect on the disease, and the patient population is immunocompetent (not suppressed). It must be a homogeneous population – single disease, with balanced patient characteristics Equivalence trials are preferred by regulators but non-inferiority trials may be permitted with an appropriate rationale. Non-inferiority trials have been used for oncology biologics in conjunction with equivalence trials in non-oncology indications. Clinical trial design is detailed in the next slide, followed by three slides that are summaries of the top-line clinical results of biosimilars and their reference products. They are not a comprehensive review of the published data (and some data is not yet published). It does however summarize some of the key talking points that many clinicians are either uncertain of or are interested in. These include: Type or hypothesis of clinical trial (Equivalence vs Non-Inferior) Which population the trial studied The size of the clinical trial (some clinicians perceive that the trials are too small as they are comparing the trials to the superiority trials that they are accustomed to reviewing) The primary and secondary endpoints of the trials – what they are and what the results are from the trial Clinicians are typically exposed to superiority trials. Biosimilars use equivalence and non-inferiority trials. The delta that is used for a trial is agreed by the sponsor and the regulator. For non-inferiority trials, the confidence interval is greater than the non-inferiority margin but does not cross “0”; meeting this criteria allows for a claim non-inferiority of the new treatment In equivalence trials, the confidence interval is greater than the non-inferiority margin and less than the non-superiority margin; meeting this criteria allows for a claim equivalence of new treatment. The next three slides summarize the key characteristics of biosimilar clinical trials. In the rituximab clinical trials, Truxima demonstrated non-inferiority in a clinical trial with 121 lymphoma patients. Rixathon demonstrated equivalence in a trial with 624 lymphoma patients. Despite several brand names, there are only two approved rituximab molecules. In the rituximab clinical trials, Truxima demonstrated non-inferiority in a clinical trial with 121 lymphoma patients. Rixathon demonstrated equivalence in a trial with 624 lymphoma patients. Despite several brand names, there are only two approved rituximab molecules. For the trastuzumab phase III clinical trials, biosimilar trastuzumab has been studied in both early and metastatic breast cancer. All of the studies have been equivalence studies, except for one non-inferiority study for Trazimera that was conducted for a non-medical reason (a change in process) that was requested by the FDA. All of the studies are deemed to have met the statistical endpoint of equivalence or non-inferiority. Note the pathologic complete response rate of 40-50% across all trials in early breast cancer, and the overall response rate in the mid to high 60’s in metastatic breast cancer, all demonstrating comparability Finally, the clinical summary of the phase III bevacizumab studies. There are currently two approved bevacizumab biosimilar molecules. MVASI was studied in an equivalence trial in NSCLC; its data has been published. Zirabev has not had data published outside of an abstract, but the data is available in its submission to the EMA. Note the overall response rate of 39-45% in the trials. Another part of the regulatory approval process is the immunogenic safety of the biologic. Immunogenicity consists of the development of Anti-drug antibody (ADA) which is where the human immune system has recognized the biologic medication as foreign and it develops immunity to the biologic medication. The immune system now has antibodies circulating that can bind to the biologic medication. If this progresses to the development of Neutralizing ADA (NADA), this is when the circulating antibodies neutralize the activity of the biologic medication. This may reduce efficacy or it may impact pharmacokinetics. Immunogenicity in oncology is relatively low overall and highly similar among studies for reference biologics and biosimilars. This contrasts to immunogenicity in inflammatory conditions like Crohn’s Disease and Rheumatoid Arthritis, where ADA’s may be as high as 50-60% . The following slides are summaries of the immunogenic findings of the biologics and biosimilars in oncology. Looking at the immunogenic safety of a rituximab biosimilar in their phase III clinical trials, you see a very low range of ADA’s – 0.7% to 4.3% and very similar between the biologic and a biosimilar. With respect to the immunogenic safety of a trastuzumab biosimilar, the phase III clinical trials show a very low, and similar rate of ADA development (in the range of 0-4.4%). Finally the immunogenic safety of a bevacizumab biosimilar is summarized. Both biosimilars and the reference biologic have a low immunogenic rate from 0% to 2.5%. Turning now to extrapolation, Health Canada has guidance on extrapolation. HC approves which indications can be listed on the official product monograph. These are indications that the innovator has performed clinical studies for and has applied for the indication with HC. Off-label use occurs as well where the innovator did not apply for the indication to be added to the product monograph. Extrapolation has been used with reference biologics. Extrapolation occurs for a reference biologic when it makes significant changes to its production and all indications are applied to the new comparable product. Subcutaneous formulations of trastuzumab applied for approval by Health Canada by submitting data for treatment of early breast cancer but indications for metastatic disease were extrapolated in the approval. HC can authorize the extrapolation of indications from a reference biologic to a biosimilar based on: Comparative structural, functional, non-clinical and clinical studies Approval of indications may be granted even if clinical studies are not conducted in each indication. A biosimilar manufacturer cannot apply for an indication where there is a valid patent on the indication. Some patents on indications that were applied for by the innovator company may expire at different times. An example of how extrapolation of indications is handled is rituximab. In the three listed indications (Lymphoma, Rheumatoid arthritis and chronic lymphocytic leukemia), Truxima was demonstrated to be: Non-inferior in lymphoma Equivalent in RA But was not studied in CLL However, all are approved indications in Canada in the EU. A similar strategy of having one type of trial in oncology and another type in RA was used by the other biosimilar that is approved in the EU. With respect to clinical operations and education, National Working Groups have been convened to address two major work streams, clinical operations and education. Stakeholders are: Evaluating the clinical process flow (drug procurement to administration) to ensure ease of implementation of biosimilars. They are developing a position statement noting best practices (e.g. ISMP risk-mitigation strategies) to guide biosimilar implementation across Canada as well as Developing resources to raise awareness and educate clinicians and patients on biosimilars. The implications for Clinicians are Modified prescribing practices and Accessible resources for clinicians and patients for informed clinician-patient conversation What happens post notice of compliance? As with all approved medications, biosimilar manufacturers must track the safety of their product (post-NOC* surveillance). This includes class-specific safety information Pharmacovigilance with biosimilars will occur in the same manner as with all reference biologics. Immunogenicity will only be included in the post-NOC surveillance if there are concerns raised prior to approval or if there is insufficient information available Biosimilar manufacturers may also apply for more indications post-NOC. How did Health Canada decide to identify biologic and biosimilar drugs? 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 non-proprietary name can be distinguished by their unique brand names. There will continue to be unique DIN’s for biologics and biosimilars. The impacts of the naming policy is part of the mandate of the pan-Canadian Oncology Biosimilars Initiative’s Clinical Operations Working Group. They will seek pan-Canadian consensus and best practices and will release a position statement on the impacts of biosimilars to clinical operations. How will decisions on switching, extrapolating and funding be made? Decisions regarding switching and extrapolation of indications will be made by Canadian jurisdictions. Expert committees are being engaged to help inform these decisions. Public funding decisions for on-label and off-label indications will also be made by jurisdictions. Nearly all Canadian jurisdictions fund off-label indications for reference biologics. For example, bevacizumab is funded in cervical cancer but has not been Health Canada-approved for that indication. Finally, here are the key takeaways from this presentation. Biologic medications are complex molecules with natural variability that are made inside living cells. Biosimilars are biologic medications that are highly similar to a reference biologic. Biologics and biosimilars are manufactured under the same international guidance for maintaining the comparability of the product. Biosimilars approved by Health Canada are safe and effective with no clinically meaningful differences from the reference biologic. Extrapolation of indications occurs with both reference biologics and biosimilars. The impact of biosimilars on oncology clinical practice is being evaluated across Canada by the pan-Canadian Oncology Biosimilars Initiative. For further information on this, use the link below or search for biosimilars at www.cancercareontario.ca

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