A Look at Biosimilars: An Update
Much discussion on the topic of biosimilars and the many different aspects that come into play has taken place.
We will present an update on our 2013 article on guidelines for the development process and marketing authorisation requirements for biosimilars, as well as an overview of the role of clinical trials, immunogenicity, the impact of glycosylation drift and the naming of biosimilars.
To date, 22 biosimilars have been approved by the European Medicines Agency (EMA) for use in countries that are members of the European Union (EU). Of the 22 biosimilars approved by the EMA, two have since been withdrawn: one for filgrastim and one for somatropin.1 Most of the biosimilars approved by the EMA have been for epoetin alfa, insulin and growth hormones. However, in 2013, a monoclonal antibody biosimilar – infliximab – was approved for use in ankylosing spondylitis, Crohn’s disease, psoriatic arthritis, psoriasis, rheumatoid arthritis and ulcerative colitis. All oncology biosimilars are in the clinical trial phase.
In the USA, no biosimilars have yet been approved although submissions have been filed: two for infliximab and one for filgrastim.
One of the reasons why more biosimilars are available in EU countries is likely connected to patent expiries. For example, the patent for rituximab expired in 2013 but does not expire in the USA until 2016. Another example is somatropin for which the patent only expired in the USA in 2013; a biosimilar version of the product was approved by the EMA in 2006. The timing of the patent expirations necessitated the need for the development of an approval pathway for biosimilars earlier in the EU. This pathway was implemented in 2005. In the USA, the Food and Drug Administration (FDA) issued three draft guidance documents concerning the development of biosimilars in 2012 with additional guidance documents issued in 2014. For more information on the FDA guidance, clickhere.
Biosimilar Guideline Development
The number of countries that have guidelines for the development and approval of biosimilars or are in the process of developing them continues to grow. In 2013, 18 countries had either developed guidelines or were doing so. In 2014, that number has grown to 31. Figure 1 shows the countries either with guidelines or those in the process of developing them.
Figure 1. Overview of Worldwide Development of Biosimilar Guidelines
Acceptance and Use of Biosimilars
Reviewing what has gone on outside of oncology to date will hopefully allow us to understand what is necessary to evaluate once monoclonal antibody biosimilars are introduced in the near future in lymphomas. The following is a look at what is presently occurring within biosimilars outside of oncology.
As shown in Table 1, the use of biosimilars outside of oncology by healthcare professionals varies in Europe.
Table 1. Use of Biosimilars in Europe, January to August 20142
Central and Eastern European Union
Human growth hormone biosimilars
Epoietin biosimilars, nephrology
Epoietin biosimilars, oncology
Granulocyte-colony stimulating factor biosimilars
Biosimilar use seems to be higher in central and eastern EU countries which could be a reflection of less restrictive usage requirements compared with other countries. For example, the introduction of a national tender system in Hungary whereby the product winning the tender requires all hospitals to use that product has led to a rise in the use of granulocyte-colony stimulating factor (G-CSF) biosimilars.2
The introduction of G-CSF biosimilars appears to have changed medical practice in the UK as well with physicians being more likely to use them, as directed by treatment guidelines.3 A guideline published by the National Health Service recommends the use of a filgrastim biosimilar (Zarzio) as the daily G-CSF of choice.4 Prior to the introduction of G-CSF biosimilars, physicians restricted their use to a maximum of four days likely because of cost.
The prophylactic use G-CSFs to prevent the development of febrile neutropenia is also a recommendation of the European Organisation for Research and Treatment of Cancer (EORTC) in patients receiving dose-dense or dose-intense chemotherapy.5 The EORTC also states that filgrastim biosimilars are a treatment option.5
Need for Physician Education
In spite of countries having guidelines or with guidelines in development, there are still misunderstandings about biosimilars.
While biosimilars may prove to be less expensive than the reference product, the lack of understanding among physicians is likely the biggest factor affecting their use in Europe. In a survey of 470 European physicians from France, Germany, Italy, Spain and the United Kingdom conducted by the Alliance for Safe Biologic Medicines (ASBM), only 22% indicated they were very familiar with biosimilars and 24% indicated they could not define or had not heard about biosimilars before.6
“Raising the awareness and education level for physicians so they know more about them, what they are and how they are similar and different from generics is key,” said Michael Reilly, Executive Director of the Alliance for Safe Biologic Medicines.
Clinical Trials with Biosimilars
There may be a perception that biosimilars have not gone through a rigorous approval process. In reality, one of the requirements in the development of a biosimilar is the need for an extensive comparability exercise to demonstrate that the reference product and the biosimilar are indeed highly similar. Currently, LC is tracking 13 clinical trials that are studying the use of seven monoclonal antibody biosimilars. Click here for specific information on each trial.
Clinical trials involving a biosimilar always compare the reference product with the biosimilar. These are double-blind randomised studies so neither the patients nor the physicians know who is receiving which study drug but they know they are not receiving placebo. The purpose of these trials is to show that the biosimilar is neither better nor worse than the reference product, i.e., it demonstrates biosimilarity.
When studying biosimilars, a phase I study is undertaken in healthy volunteers to compare the pharmacokinetics and pharmacodynamics of the biosimilar with the reference product to ensure there are no differences. Phase II studies are not required as the dose and route of administration are already known. A phase III study is required to see if there are any changes in overall response rates with the biosimilar compared with the reference product and is undertaken in only one of the indications for which the reference product is approved. The study results are then applied to all indications. Consequently, in some instances, regulatory agencies, such as the EMA, may require the drug manufacturer to undertake additional safety trials following approval.
Immunogenicity and Biosimilars
With all biologics and biosimilars there is the potential for an immunogenic response because it is a foreign protein that is being infused into the body. Immunogenicity is a measure of the immune response to a therapeutic drug. While the efficacy and safety of a biosimilar may be similar to the reference product, immunogenicity may be different and could result in unwanted responses.7 Factors that can affect immunogenicity include the properties of the biologic, such as glycosylation, issues with production and the formulation, route of administration, dose, length of treatment and patient characteristics.8 Consequently, at all stages in the development of a biosimilar, immunogenicity is assessed to ensure it is comparable with the reference product.
It has been suggested that a risk management plan be part of the guidelines to protect those situations where the risk of unwanted responses are likely to occur especially if a patient is switched from one therapy to another, i.e., from the reference product to the biosimilar or vice versa, or is receiving chronic treatment. In 2012, the EMA issued a guideline regarding the assessment of immunogenicity in monoclonal antibodies intended for use in humans. It was recommended that a risk management plan be included that showed how risks would be identified as well characterised, and address how risks would be minimised, monitored and along with detailed mitigation strategies that would be followed once the biosimilar was approved.7,9
The FDA has also issued guidance in which safety and immunogenicity data need to be collected and evaluated. The guidance also notes that this information may need to be supplemented with additional evaluations either before or after approval.10
Impact of Glycosylation Drift
A biologic manufactured 10 years ago will not be exactly the same as the one manufactured today or tomorrow because the biologic is being produced in a living cell. This is called glycosylation drift. There are also changes or drifts in manufacturing processes over time. This necessitates manufacturers to demonstrate to regulators that these drifts are not clinically significant. Similarly with biosimilars, manufacturers have to demonstrate to regulators that the biosimilar is as similar as possible to the reference product without any clinically meaningful differences.
Interchangeability of Biologics with Biosimilars
The concept of interchangeability is that a biosimilar could be interchanged with the reference product as the two products should be highly similar and there should be no significant risk of an adverse health outcome. There are, however, two main concerns with this. Firstly, if the prescription is not specific to the exact product, tracking of adverse events becomes complicated and secondly, the pharmacist could be the one making the decision rather than the physician as has been the case with generics. Findings from the survey undertaken by ASBM showed that 72% of physicians feel very strongly that the treatment decision is one that they, in consultation with their patient, should make.6
In the USA, the FDA has the authority to determine if a biosimilar can be interchanged with the reference product. The law states that for a product to be interchangeable, it must be “biosimilar to the U.S.-licensed reference biological product” and “expected to produce the same clinical result as the reference product in any given patient.”11 While the FDA has the authority to determine whether a biosimilar is interchangeable with a reference product, the final decision will be made at the state level.
In Europe, interchangeability between a biosimilar and a reference product is a country-specific decision rather than a decision made by the EMA.
Naming of Biosimilars
Biosimilars that have been approved to date by the EMA have the same molecular name or International Nonproprietary Name (INN) as the reference product. In other countries that have approved biosimilars, some have used the same INN, while others have used a modified INN.12 The lack of consistency in naming means that the same biological entity can have different identifiers in different parts of the world.
One of the concerns with using the same INN for the biosimilar as the reference product is that if any issues arise, such as adverse events, it will not be clear as to which product is causing them. Another concern with using the same INN is that while some countries may have a well-established pharmacovigilance system that is able to monitor and track the effects of a biosimilar versus a biologic, other countries may not have such well-developed pharmacovigilance systems.
In the survey undertaken by ASBM, only 32% of respondents used both the brand name and the INN to identify the exact treatment they wished their patient to receive. Some respondents (24%) used the INN only. This could result in patients not receiving the medication they expected. When reporting adverse events, only 17% reported the INN. Two different therapies having an identical INN could lead to pooling of adverse events as well as incorrect attribution.6
“Biosimilars should have a distinguishable INN as they are a different medicine and, therefore, tracking and tracing will be very important,” said Michael.
The World Health Organization (WHO) is in the process of drafting guidance on how biosimilars should be named. The naming system proposed by the WHO is voluntary and is intended to provide a unique identification code – Biological Qualifier – that is distinct from the INN. This code would consist of four letters with each code being assigned randomly.12
The FDA has yet to issue guidance on the naming of biosimilars
The growing availability of biosimilars provides benefits and it is important that we all participate in these discussions to stay informed and understand the best option for the patient. Here are some suggestions on ways to get involved:
- Participate in the WHO discussions. Contact the Programme on International Nonproprietary Names, Dr. Raffaella Balocco Mattavelli, Manager, INN Programme;
- Join the Alliance for Safe Biologic Medicines (ASBM) (http://www.safebiologics.org/index.php);
- Participate in local regulatory body discussions.
Author: Leonie Bedford, Medical Writer, Lymphoma Coalition
November 24, 2014
- Biosimilars approved in Europe. Generics and Biosimilars Initiative. Link. Accessed October 22, 2014.
- IMS Health 2014.
- IMS, National Health Service, 2012.
- National Health Service. Guidelines for the use of G-CSF & pegfilgrastim 2014. Link. Accessed November 7, 2014.
- Aapro MS et al. 2010 update for EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2010;47:8-22.
- Alliance for Safe Biologics. April Newsletter. Link. Accessed November 13, 2014.
- Mendes de Abreu M et al. Putting the value into biosimilar decision making: the judgment value criteria. Autoimmun Rev 2014;13:678-84.
- Choy E, Jacobs IA. Biosimilar considerations in clinical practice. Sem Oncol 2014;41:S3-S14.
- Link. Accessed November 18, 2014.
- Food and Drug Administration. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. Link. Accessed November 18, 2014.
- Information for healthcare professionals (biosimilars). US Food and Drug Administration. Link. Accessed October 22, 2014.
- World Health Organization. Biological qualifier – an INN proposal. Link. Accessed November 13, 2014.