Biopharmaceuticals account for almost 50% of products under development. It can be expected that there will be many options for healthcare practitioners to consider in the future, which will include both innovative products as well as biosimilar products
University of Cambridge
The European Community and the European Medicines Authority have implemented a legislative and regulatory approach to facilitate the entry of similar biological medicinal products (biosimilars) to market when the patent has expired from the innovator product. This has been implemented with the introduction of seven biosimilars representing three different product classes and five different active pharmaceutical ingredients. The regulatory process has been rigorous and critical, resulting in the rejection of two products and the withdrawal of three products. The approval of the biosimilars has been based on assuring high-quality product and rigorous testing to assure that patients receive safe and efficacious drugs.
The approval of biosimilars has focused on the following important considerations for determining similarity with a reference product:
- Analytical and physicochemical data to compare quality.
- Comparative biological data.
- Clinical data to demonstrate comparative safety, efficacy and immunogenicity.
These considerations have been developed through the use of both general guidelines and product classspecific guidelines that have been published by the EMEA after a public and transparent process involving consultation with stakeholders.
The general guidelines outline the important principles for the quality, preclinical and clinical considerations, while the product class-specific guidelines outline the specific recommendations that are unique to each product class and therapeutic area. The product-specific guidelines are for erythropoetins, granulocyte colony-stimulating factors, insulins, growth hormones and low-molecular-weight heparins. It is expected that additional guidelines will also be developed for other product classes.
Europe has taken the lead in developing a regulatory path for biosimilar products, which allowed both legislation and regulatory activities to be completed prior to the patent expiration of some of the leading biopharmaceuticals. As a result of the success and scientific discussions that occurred commensurate with the European biosimilar activities, other regions are looking at developing approaches for bringing noninnovator off-patent biotherapeutics to market.
Biosimilar approaches in other regions
Most of the major biopharmaceutical products in the US have been approved under a legislative act that would preclude the use of a generic approval process. However, there is a significant discussion currently ongoing in the US with regard to developing a legislative pathway for biosimilar products based on the pending patent expiration of a number of biological products in 2013 as well as for other products that are already off patent (Table 1).
The legislative discussions have not focused on the specific requirements for the approval of a biosimilar medicine in the US; however, the FDA published information on previous types of approvals for protein products that were similar to already marketed products. In all cases the FDA required data that was defined based on the specific product therapeutic area, and in most cases data from clinical studies were necessary for the
evaluation and approval.
Although there is no specific FDA guidance on the topic of biosimilar products, there are some indications that the FDA might have a similar approach as that of the EMEA with regard to approval standards for biosimilar products. This approach and thinking was summarised in a letter in response to questions from the US Congress. The letter indicates that it is not possible to approve biosimilars without the evaluation of clinical data to be able to compare safety and efficacy with the reference or marketed product.
The letter also reiterated concerns related to immunogenicity of biosimilar products and the need for clinical data to evaluate the safety with regard to immunogenicity. It is not clear whether the FDA also develops product class-specific guidance documents in a similar manner as the EMEA, but it can be expected that the requirements will be quite similar.
The FDA has also suggested that it is not clear how to assess the therapeutic substitution of biopharmaceuticals and has indicated that any substitution should be done after consultation with the patient’s doctor. These are similar to the current approach by the EMEA.
Additional considerations in the US will involve how to balance investment for innovation with the availability of off-patent biological products. For comparison purposes, the European framework provides for a period of market exclusivity that could range from eight to 11 years after approval. In addition, any discussions related to market exclusivity will have to assess the impact on innovation associated with second-generation products which result from either genetic engineering or chemical modification such as pegylation.
These can result in significant benefit to patients, and it will be important to ensure that there is appropriate incentive for manufacturers to continue to innovate on currently marketed products. There are similar activities ongoing in the rest of the world with regard to formalising regulatory approaches for biosimilar products. Health Canada has published a guideline on subsequent-entry biological products, Canadian terminology
for biosimilar products. The fundamental principles outlined
in the document are very similar to those in the EMEA’s guidance. Japan has also recently published a guidance document on biosimilar products that reiterates the need for clinical evaluation of the product.
The WHO held an informal consultation on Therapeutic Biological Medicinal Products that discussed the different approaches for evaluating biotherapeutic products and resulted in a recommendation that the WHO develop guidance for similar biotherapeutic products (SBP). The guideline is currently being drafted, but it is anticipated that a draft will be available for consultation in late 2009. It is likely that the WHO guideline will also reflect the current scientific consensus that has derived through the recent discussions on biosimilar medicinal products in Europe and the US.
The general concepts that appear consistent in all of the guidelines are based on ensuring that drugs will maintain a high quality and deliver the appropriate safety and efficacy to patients:
- A generic approach restricted only to chemical data and bioequivalence data would not apply for biopharmaceuticals.
- Comparative data with a reference product would need to be based on detailed quality data with additional comparative nonclinical and clinical data for efficacy and safety.
- The specific nonclinical and clinical data would be defined based on the specific product and product class.
Biosimilar products of greater complexity
The guidelines for biosimilar products generally include a scope that is restricted to well-characterised biotherapeutic proteins. Products that appear to be excluded due to their complexity or for which additional considerations would be necessary include vaccines, plasmaderived blood products, which might include polyclonal immunoglobulins, and recombinant clotting factors, for example.
The market for monoclonal antibodies is significant in areas such as oncology and inflammation and is expected to grow significantly. Monoclonal antibodies are significantly more complex than some of the recently approved biosimilar products. The structural correlates with biological activity and clinical safety and efficacy are also less defined. One of the major issues that will impact the development of such products will be the ability to define a reasonable clinical trial programme for demonstrating similarity. Many of the current monoclonal antibodies are estimated to go off patent starting around 2012 and through 2016. The requirements for assessing a biosimilar monoclonal antibody are already under discussion, and it can be expected that this will be an active area over the next few years as patent expiry becomes closer and there is greater experience with the biosimilar products that have been approved.
There are additional important considerations with regard to biosimilar products that still require further consideration such as naming and substitution. The common name (INN or international nonproprietary name) is quite important with regard to postmarketing surveillance as well as prescribing. In order to ensure specific identification of a biosimilar product, the EMEA has said that all biosimilar products will need to be uniquely identified, and the Japanese guideline currently states that each biosimilar product must have a unique common name. The issue of specific INN names for complex biological products is an issue not just for biosimilars but also pertains to biotherapeutics in general, and this has been the subject of a
consultation at WHO. The introduction of biosimilars has opened up a number of opportunities for biological therapeutics, but it has also highlighted a number of issues for these types of products. Currently, biopharmaceuticals account for almost 50% of products under development. It can be expected that there will be many options for the healthcare practitioner to consider in the future which will include both innovative products as well as biosimilar products. These will raise novel issues for the healthcare practitioner regardless of the approval mechanism, as pointed out in a previous article in this journal.
1. Schneider CK, Kalinke U. Toward biosimilar monoclonal antibodies. Nature Biotechnol 2008;26(9):985-90.
2. European Medicines Agency. Scientific guidelines for human medicinal products. 2008. Retrieved from www.emea.europa.eu/htms/human/humanguidelines/
3. Woodcock J, Griffin J, Behrman R. The FDA’s assessment of follow-on protein products: a historical perspective. Nature Rev Drug Discovery 2007; published online 13 April 2007. http://www.aei.org/docLib/20070608_WoodcockTemple.pdf
4. Letter from Frank M Torti. (n.d.). Retrieved from:http://www.gene.com/gene/about/views/pdf/FDA_Pallone%20Resp%20dtd%209-18-08.pdf
5. Retrieved from Health Canada: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/activit/fs-fi/fs-fi_seb-pbu_07-2006-eng.php
6. WHO informal consultation on regulatory evaluation of therapeutic biological medicinal products. http://www.who.int/biologicals/areas/biological_therapeutics/Final%20Biosimilar%20meeting%20Report%20for%20web%201
7. Lanthier M, Berman R, Nardinelli C. Economic issues with follow-on protein products. Nature Rev Drug Discovery 2008;7:733-7.
8. Tredree R. Progress with biopharmaceuticals in Europe. Hosp Pharm Eur 2008 Nov/Dec;41:17-20.