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Since the provision of a legal basis for the approval of biosimilar medicinal products in the EU, several guidelines have been adopted to outline the requirements for the demonstration of comparable quality, efficacy and safety
Martina Weise
Federal Institute forDrugs and MedicalDevices (BfArM)Bonn
Vice-Chair EMEA/CHMPWorking Party on Similar Biological (Biosimilar) Medicinal Products European Medicines Agency (EMEA)
Christian K Schneider
Acting Head Division EU-Cooperation/ Microbiology Paul-Ehrlich-Institut Federal Agency for Sera and Vaccines Langen Germany
Chairman
EMEA/CHMPWorking Party on Similar Biological (Biosimilar)
Medicinal Products/ Member of the Committee for Medicinal Products for Human Use (CHMP) European Medicines Agency (EMEA)
Biological medicinal products have a successful record in treating many serious and chronic diseases, and their market is growing faster than that of total pharmaceuticals. However, their high cost represents a burden to healthcare systems and thus might limit patients’ access to these medicines. The recent expiration of patents and/or data protection for the first innovative biotherapeutics is ushering in an era of products “similar” to the originals and relying in part for their licensing on data from these originator products. One might thus easily consider such “biosimilars” as “generics”. However, biological medicinal products consist of large and highly complex molecular entities that are often difficult to characterise, and whose physicochemical properties are largely defined by their manufacturing process. Therefore, the standard generic approach established for small-molecule medicines is not appropriate for the development, regulatory assessment and licensing of such similar biological medicinal products. Although (assumed) copy versions of original biotherapeutics are already available in different parts of the world, a specific regulatory framework for an abbreviated licensing pathway has so far only been established in the EU.[1]
Since the provision of a legal basis for the approval of so-called similar biological (biosimilar) medicinal products in the EU, several general and product classspecific guidelines have been adopted to outline the requirements for the demonstration of comparable quality, efficacy and safety of a biosimilar medicinal product with a chosen reference product, whose data
protection period has expired.[2] Due to the lack of experience with biosimilars at that time, these guidelines had been developed based on theoretical but sound scientific considerations. They are being updated in the light of ongoing experience gained from marketing authorisation applications.
The guidelines have been developed by the Working Party on Similar Biological (Biosimilar) Medicinal Products (BMWP), which is an expert group of the Committee for Medicinal Products for Human Use (CHMP). The CHMP, the main scientific committee for human medicines at the European Medicines Agency (EMEA), is responsible for the scientific assessment of human medicines that follow the “centralised procedure” of marketing authorisation. According to the legislation, all recombinant proteins must undergo this route of licensing.[3] Since most biosimilars are recombinant proteins, they will usually have to follow this centralised route.
Principles
The main/basic principles for the development of a biosimilar medicinal product in the EU include:
- Demonstration of “similarity” in terms of quality, safety and efficacy to a reference product licensed in the EU. Therefore, all main studies should be comparative.
- Use of the same reference product throughout the development programme.
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- Use of a “sensitive” test model, able to detect potential differences between the biosimilar and the reference product. This choice of a sensitive test model is an important principle, since it highlights a hallmark of a biosimilar development: the aim is to establish not patient benefit (this has been established already by the reference product), but rather *Demonstration of equivalent rather than noninferior efficacy, because the latter does not exclude the possibility of superior efficacy, which would contradict the assumption of similarity and would preclude extrapolation to other indications of the reference product, particularly those with different dose requirements. In the case of higher potency, safety concerns could arise when using the dose(s) recommended for the reference product, especially for drugs with a narrow therapeutic index.
- Demonstration of equivalent rather than noninferior efficacy, because the latter does not exclude the possibility of superior efficacy, which would contradict the assumption of similarity and would preclude extrapolation to other indications of the reference product, particularly those with different dose requirements. In the case of higher potency, safety concerns could arise when using the dose(s) recommended for the reference product, especially for drugs with a narrow therapeutic index.
If similarity with the reference product has been convincingly demonstrated in a key indication, extrapolation of efficacy and safety data to other indication(s) of the reference product, not studied during development, may be possible if scientifically justified.
It is clear that, although a reduction in the data package is possible for a biosimilar, the prelicensing data package is still substantial. The dossier for the CMC part (Chemistry, Manufacturing, Controls, or the “quality” dossier in regulatory jargon) has even higher requirements as a “stand-alone” development of a new biological drug. First, a full-quality dossier has to be provided that satisfies regulatory standards to the same extent as a novel biological medicinal product. Second, a comprehensive comparability exercise to the reference product on the drug substance and drug product level is required, which is an additional undertaking. Likewise, human efficacy and safety data are always required, but – and this is at the heart of a biosimilar development – to a lesser extent than for the development of a novel medicinal product. The amount of possible reduction in nonclinical and clinical data requirement depends on how well the molecule can be characterised by state-of-the-art analytical methods, on observed or potential differences between the biosimilar and the reference product, and the clinical experience gained with the reference product and/or the substance class.
Since the establishment of a legal framework, several biosimilars have already been licensed in the EU: biosimilar somatropins, epoetins and filgrastimcontaining medicinal products.[4] On the other hand, the approval of an interferon alfa has been refused by CHMP,[5] and the marketing authorisation applications for three insulins have been withdrawn by the applicant. [6] This underlines that biosimilar developments are sometimes not straightforward, and that a high quality of these medicines must be ensured.
Experience from marketing authorisation applications
The following experience has been gained from the recent marketing authorisation applications:
- In principle, a biosimilar may be produced in different host cells than the reference product, as long as the resulting product sufficiently resembles the original biological. This possibility, however, will likely be limited to well-characterised nonglycosylated biologicals.
- Impurities such as host-cell proteins may enhance the immune response to a therapeutic protein, as has been observed with a biosimilar somatropin.[7] In this case, the increased immunogenicity was only detected in the phase III trial, emphasising the need for human immunogenicity data prelicensing.
- Due to their temporary contraindication of the subcutaneous route of administration in patients with renal anaemia, Eprex/Erypo (epoetin alfa) could not be used as comparator in respective clinical trials at that time. Therefore, the subcutaneous use of some epoetins developed as biosimilars to epoetin alfa could not be studied according to the requirements laid down in the guidance on similar medicinal products containing recombinant erythropoietins.[8]
- The submitted data, however, allowed licensing with reduced indications in all cases.[9,10] These circumstances also made clear that guidelines have to be revised when more experience has been gained.
- Extrapolation to other indications of the reference product has been granted for biosimilar somatropin, epoetin and filgrastim-containing medicinal products, based on the consideration that the mechanism of action and the receptor involved in the extrapolated indications are the same. However, such extrapolation without any additional bridging data may only be possible for indications with the same route of administration because of differences in pharmacokinetic profiles and often in dose requirements. Another prerequisite for extrapolation is that the safety and immunogenicity profile of the biosimilar must have been properly characterised in the indication studied and that no additional safety issues are expected in the extrapolated indication(s). It must be clearly emphasised that this extrapolation – and thus formal lack of a phase III trial in the respective clinical indication – does not mean less reassurance as regards efficacy and safety of the biosimilar. One should keep in mind that the conclusion of biosimilarity is based on a thorough comparability exercise on a quality, nonclinical and clinical level, and that a biosimilar development is only accepted by regulators where the state of the art allows for this with sufficient reassurance.
- A biosimilar can have less but not more clinical indications than the reference product.
- Specific pharmacovigilance measures imposed on the reference product are usually “inherited” by the biosimilar, unless the applicant can convincingly justify that this is not needed.
Concerns over biosimilars
Concerns have been raised regarding the pharmaceutical quality, safety, interchangeability/substitution and traceability of biosimilar medicinal products, and these are discussed below.
Quality
The fear of low-quality or substandard products is not substantiated because the quality standards for a biosimilar and an original/standalone product are the same. The applicant for a biosimilar must show a profound understanding of the manufacturing process using state-of-the-art methods, resulting in the production of a consistent high-quality product. The extensive comparability exercise is an additional requirement to the normal quality dossier.
Safety
The applicant for a biosimilar medicinal product must convincingly demonstrate that their product closely resembles the chosen reference product in all aspects – molecular structure, pharmaceutical quality, efficacy and safety – in order to allow an abbreviated licensing pathway relying, in part, on the extensive knowledge gained with the reference product. Nevertheless, the prelicensing data package needs to be sufficiently large to characterise the safety profile and exclude markedly increased immunogenicity of the biosimilar product (compared with the reference product).
It needs to be clearly stated that a biosimilar does not have a “worse” quality or a safety profile than the reference product. Regulatory standards in the EU are high and ensure that only biosimilars with adequate quality and safety are brought to market. Further, a comprehensive Pharmacovigilance Plan in line with current EU guidelines[11] is expected to be submitted to the authorities at the time of the marketing authorisation application, taking into account identified and potential safety concerns for the biosimilar, the reference product and/or the substance class, and focusing on rare/serious adverse reactions. This is not only a legal prerequisite, but also makes sense from a medical perspective.
The “real-world use” of any medicinal product will add important safety data to the overall knowledge about this medicinal product that cannot readily be gained in an – always inherently artificial – clinical trial situation. Further, for no medicinal product will clinical trials ever be large enough to detect rare adverse events with sufficient acuity. This underlines the importance of a functioning reporting system of adverse events to regulatory agencies and the Marketing Authorisation Holders of biosimilars.
Interchangeability/substitution
The question has been raised whether biosimilars could be considered interchangeable with the respective reference product and, consequently, the concern that automatic substitution might follow. In this respect, EMEA gave the advice that biosimilars should not be considered identical to their biological reference products and that the decision to treat a patient with either should be made by a qualified healthcare professional.[12] This is also the reason why biosimilars are not called “biogenerics”. It must be stated that the EMEA cannot control for this from a legal perspective, since the regulations on substitution and interchanging of medicinal products is in the remits and responsibility of the individual EU Member States. According to the European Generics Association (EGA), 15 countries across Europe have brought in new rules to prevent automatic substitution of biological medicines by biosimilars.[13]
Traceability
If an adverse drug reaction occurs or is suspected, it is important to identify the specific product causing the adverse drug reaction. Thus, adverse drug reaction reports should also include, in addition to the International Nonproprietary Name (INN), other indicators such as proprietary/brand name, manufacturer’s name, lot number and country of origin.[14] Additional identifiers are particularly important for medicinal products carrying the same INN. If this recommendation is followed, traceability should be possible. This highlights the central role of the prescribing physician and the pharmacist in the overall concept of regulatory control of patients’ health, since only with these precautions is a traceback to the root cause possible.
Conclusion
In conclusion, the experience gained with recent marketing authorisation applications suggests that the EU regulatory process for the development, evaluation and licensing of similar biological medicinal products works and that the guidelines are generally implementable. These guidelines are “living documents” that will be updated in light of ongoing experience and evolution of science. In addition, new (product class-specific) guidelines will be developed, if a need is identified. This highlights that regulators are closely following developments in the field. Although, in principle, the concept of a “similar biological medicinal product” is applicable to any biological medicinal product, in practice it is (likely to be) limited to biologicals that can be well characterised.
As analytical methods become more and more sophisticated, discussions have been initiated over whether it is possible to expand the “biosimilar philosophy” to more complex molecules such as monoclonal antibodies.[15] The field of biosimilars and their implementation as medicinal products highlights the necessary – and fruitful – interplay of developers, regulators, physicians and hospital pharmacists. The licensing of biosimilars should be seen as a chance to widen patients’ access – also on a global level – to biotechnological medicines that are important milestones in the modern treatment of severe diseases.
Disclaimer
The views expressed in this article are our personal views, and may not be understood or quoted as being made on behalf of the CHMP or reflecting the position of the CHMP or any other EMEA Committee or Working Party.
References
1. Directive 2001/83/EC Art 10(4) and Part II of the Annex I of Directive 2001/83/EC, as amended.
2. EMEA. Multidisciplinary guidelines. www.emea. europa.eu/htms/human/humanguidelines/multidiscipline.htm
3. Regulation (EC) 726/2004 of the European Parliament and of the Council. Official Journal of the European Union 2004;L136/1-L136/33.
4. EMEA. EPARs for authorised medicinal products for human use. www.emea.europa.eu/htms/human/epar/eparintro.htm
5. EMEA. Refusals:medicinal products for human use. www.emea.europa.eu/htms/human/efusals/list.htm
6. EMEA.Withdrawals of application: medicinal products for human use.www.emea.europa.eu/htms/human/withdra/withdrawapp/list.htm
7. EMEA. Omnitrope.www.emea.europa.eu/humandoc /Humans/EPAR/omnitrope/omnitrope.htm
8. EMEA.Multidisciplinary guidelines. www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm
9. EMEA. Binocrit.www.emea.europa.eu/humandocs/Humans/EPAR/binocrit/binocrit.htm
10. EMEA. Silapo.www.emea.europa.eu/humandocs/Humans/EPAR/silapo/silapo.htm
11.EMEA.Humanmedicines:pharmacovigilanceguidelines.www.emea.europa.eu/htms/human/phv/phvwp.htm
12.EMEA. Questions and Answers on biosimilar medicines (similarbiological medicinal products). www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf
13. APM Health Europe 2008 Feb 21.
14. EMEA. Eudravigilance expert working group. Volume 9A:
Implementation questions & answers, Version 1.2. www.emea.
europa.eu/pdfs/human/phv/11197208en.pdf
15. Schneider CK, Kalinke U. Toward biosimilar monoclonal antibodies.Nat Biotechnol 2008;26(9):985-90.
