Dr Falk Ehmann MD, PhD
European Medicines Agency (EMA), Scientific Support and Projects, UK
Dr Christian K Schneider
Paul-Ehrlich-Institut (PEI), Langen, Germany, and Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany
Dr Falk H G Ehmann, c/o European Medicines Agency, 7 Westferry Circus, London E14 4HB
Biological medicines have a successful record in treating serious and chronic diseases. The development of a process for authorising copies called biosimilars (similar biological medicinal products) by the European Medicines Agency (EMA) has led to their safe use in the European Union since 2006.
With US Congress adopting legislation to pave the way for biosimilars in the USA in March 2010 and the World Health Organization (WHO), along with countries including Canada and Australia, publishing a guideline for their development, the development of biosimilars and their market penetration has become a global opportunity.
The imminent expiry of data protection and patents for monoclonal antibodies (mAbs) has inspired industry to investigate the development of biosimilar versions of these ‘blockbuster drugs’. This, in turn, has led to the publication of a ‘Draft guideline on similar biological medicinal products containing monoclonal antibodies’ by EU regulators at EMA as these are another class of biosimilar biological products expected to approach the market in the near future.
We briefly describe the envisaged data requirements for approval of biosimilar mAbs in the EU and explain why this ‘abbreviated data package’ might be considered sufficient to convince regulators of that biosimilar mAbs could be used safely and effectively in clinics.
We postulate that the data package should, from a scientific and medical perspective, not be called ‘abbreviated’, but rather ‘scientifically tailored’. Healthcare professionals need a clear understanding of the principles employed in development of a biosimilar mAb because they differ to those used in development of a first-in-class medicinal product, and also to those usually required for ‘conventioanal’ generics.
The European biosimilar experience
The initiation of a science-based regulatory framework to ensure approval of high-quality biosimilars in the EU has been accompanied by the adoption of several community texts1,2 in 2003 and 2004 modifying Directive 2001/83/CE.3 Consequently, the EMA created a multidisciplinary scientific expert group to implement the new legislation, which has been transformed into the Similar Biological (Biosimilar) Medicinal Products Working Party (BMWP), a Working Party of the Committee for Human Medicinal Products (CHMP), the agency’s main committee.
The concept of ‘biosimilarity’ was created using the same logic as generic medicines, that is to allow developers of molecules claimed to be similar to existing medicines to rely on the non-clinical and clinical experience gained with the originator, thereby reducing the data requirements and costs of development.
European regulators drafted guidance for the development of biological medicinal products (biosimilars) claimed to be similar to a reference medicinal product, based on a stepwise comparison at the levels of quality, safety and efficacy, also referred to as the ‘comparability exercise’.4, 5 To date, 18 biosimilars have been evaluated and 14 recommended for authorisation by the EMA and its main committee, the CHMP, using the biosimilar pathway.
EU guidance published, and that in the process of development by the EMA, defines the main principles of biosimilar development, general guidance on non-clinical and clinical aspects for development of biosimilars, and product class-specific guidelines to date for epoetins, filgrastims, insulins, growth hormones, alfa interferons, monoclonal antibodies, beta interferons, follitropins, and low-molecular weight heparins (LMWH). See Figure 1.
The principles of a biosimilar drug development apply in general to development of all biological medicinal products. As scientific, technical and analytical methods evolve, more complex biological product classes become eligible for the biosimilar pathway.
The success story of
Following the success of recombinant proteins, therapeutic monoclonal antibodies (mAbs) represent the second wave of innovation created by the biotechnology industry in the past 20 years.6
Currently, more than 100 monoclonal antibody-based biologic drugs are under development in hundreds of clinical trials. Many of these are in Phase II and III studies and requests for marketing authorisation are expected in the future. Diagnostic and therapeutic possibilities associated with certain unconjugated monoclonal antibodies will be extended to a broader spectrum of highly active and specific immuno-conjugates with acceptable toxicity.
Currently, mAbs are mainly authorised for the treatment of cancer or as immunomodulators in various therapeutic areas. Monoclonal antibodies differ in mechanism of action but most share some properties, such as cytotoxicity and neutralisation of a cytokine. They are structurally complex and may contain several functional domains. Each individual mAb may present a unique profile with respect to the criticality of the antigen-binding region, the Fc (fragment, crystallisable) cytotoxic effector function, and binding to Fc receptors including the neonatal Fc receptor (FcRn).
Decades of experience with mAbs in practical clinical healthcare and in-depth characterisation on a physicochemical and functional level over the past decade have given regulators the confidence to consider approving copy versions (biosimilars) of these ‘blockbuster’ drugs. The EMA provided several scientific advices for the development of biosimilar mAbs and published a draft guideline of non-clinical and clinical requirements for mAb-containing medicinal products claiming to be similar to ones already marketed.7
Main principles of the draft guideline
The main scope of the draft guideline is to describe the non-clinical and clinical requirements of biosimilar mAbs. As with biosimilars in other product classes, in-depth characterisation on a physicochemical and functional level forms an essential part of their development.7
Without a similarity on this molecular and functional level, a copy version would not be considered a ‘true biosimilar’. Such similarity is the starting point of all further clinical considerations. In vitro biological characterisation is essential, including binding and cell-based assays, which together should address all functional aspects as well as a solid understanding of the relevance of in vitro data to the clinical indications.
Such data forms the basis for claims to extrapolate clinical data between indications. The basic idea is that a functional and structural similarity, together with a clinical proof of similarity (see below), proves that a biosimilar works ‘as well’ as the originator mAb.
The primary objective of the pharmacokinetic (PK) studies is to demonstrate PK comparability of the biosimilar and reference product in a homogeneous population. The idea is that PKs (‘what the body does with the drug’) is a sensitive ‘test system’ to establish that two drugs are similar. This is also the underlying principle of bio-equivalence for chemical generics.
Regulators, however, are aware that PKs of mAbs can vary highly, depending on the patient population. To address this, PK data may be obtained as part of a clinical study designed to establish similar clinical efficacy. Only such trials may be sufficiently powered to demonstrate PK equivalence or detect differences in case of higher variability, since a high number of patients can equal out imbalances between study arms.
There is no need to re-establish clinical benefit, as this has already been demonstrated by the originator mAbs. So the basic principles to establish biosimilarity is to choose the most sensitive ‘model’ where differences can be detected. This could be a pharmacodynamic (PD) readout, although this is currently extensively debated. Can PDs (‘what the drug does with the body) be a substitute for clinical data? If this were the case for efficacy, would this also be the case for safety?
One may speculate that it would be difficult to establish biosimilarity based only on PD similarity. Regulators still ask for adequate reassurance as regards comparable safety in any case. If highly sensitive and dose-comparative PD studies fail to convincingly show clinically relevant comparability, similar clinical efficacy should be demonstrated in a randomised, parallel group comparative clinical trial.
To establish similar clinical efficacy, developers need to monitor sensitive clinical endpoints that are little influenced by factors other than the test product, such as disease stage, patient behavior or subsequent lines of treatment.
Since clinical benefit, including in an oncology setting, will already have been established, one could focus on different clinical endpoints that are more sensitive for the objective (that is to establish biosimilarity), if well justified, for example, response rate may be more sensitive and scientifically appropriate to support the comparability exercise than the usual endpoints, such as progression-free or overall survival (PFS or OS).7,8
It is often argued that it is ‘easier’ for biosimilars to be studied and that there is ‘less clinical evidence’ for biosimilars. However, regulatory considerations for defining a framework for biosimilars are not primarily driven by feasibility considerations, but rather by defining sensitive endpoints and with having the objective in mind. These endpoints are scientifically more appropriate and sensitive to detect potential differences following the principles of a biosimilar development.
We, as regulators, are aware of uncertainty among some users of biosimilars (including doctors) as regards the level of evidence requested for a biosimilar development programme. As mentioned above, the central objective for developing and approving a biosimilar is different to that for a first-in-class medicinal product. It may be more correct to term the principles as a ‘scientifically tailored’ development rather than an ‘abbreviated’ development.
Again, the aim of developing a biosimilar is not to demonstrate efficacy, as this has been done during the development of the reference product. The idea of a biosimilar development is to demonstrate similarity between the reference and the biosimilar product via a stepwise comparability exercise initiated by an in-depth quality comparison followed by non-clinical and clinical data, as necessary (see Figure 2).
The biosimilar clinical development programme should not be viewed in isolation, but be assessed as part of a total package demonstrating similarity with respect to physicochemical analysis, biological testing, non-clinical studies, a clinical PK/PD programme and, finally, clinical therapeutic equivalence and comparable safety (see Figure 2).
This in-depth comparability exercise also forms the foundations to support an extrapolation of indication, that is to allow clinical use in a clinical indication not formally studied, provided that a highly sensitive human model exists and that an adequate study condition to detect potential differences in safety and efficacy has been used.
The extrapolation of clinical efficacy and safety data to other indications approved for the reference product not directly studied during the clinical development of the biosimilar medicinal product will be based on the overall evidence provided by the comparability exercise, and must distinguish clearly between the extrapolation of efficacy and safety supported by structural and functional similarity.7
Safety and pharmacovigilance
Clinical studies in children and other ‘special’ populations are not required for biosimilars, as safety and efficacy in these populations has already been demonstrated by the reference product and can, based on the ‘comparability exercise’, be extrapolated to the biosimilar.
Clinical safety will usually be studied as part of the clinical therapeutic equivalence study. As with all innovative products, the biosimilar safety analysis includes a test for potential immunogenicity. A draft guideline on immunogenicity assessment of mAbs intended for in vivo clinical use has been published for public consultation.9
Rare events such as progressive multifocal leukoencephalopathy (PML) are unlikely to be detected in a pre-authorisation setting and therefore the sponsor will need to propose pharmacovigilance and risk-management activities for the post-authorisation phase at the time of the marketing authorisation application.
It should, however, be stressed that the central question is not whether a biosimilar can induce PML – this has already been described in this example by the reference mAb. The question is whether the risk of PML is different. Inherently, this question will likely never be answered, due to the rarity of the event. Nevertheless, based on the exhaustive and targeted data from the comparability exercise, a licensed biosimilar will have demonstrated sufficient reassurance on similarity.
In this respect, regulatory scrutiny after approval is important to ensure safety of use. This is only possible when regulators have all information necessary to assess which product has induced a reported adverse event. Physicians would therefore be well advised to always document exactly which biological is used for an individual patient. This implies that, in cases where an adverse drug reaction (ADR) occurs, not only should the International Nonproprietary Name (INN) be included in the ADR report, but also further information such as brand name, manufacturer’s name, lot number and country of origin to ensure a proper root-cause analysis.
In Europe, information on the documentation submitted in support of a specific biosimilar application and the related scientific discussion and considerations of the CHMP at time of authorisation are publicly available as European public assessment reports and can be retrieved from the EMA homepage.10 This information may assist physicians in making informed and appropriate treatment choices for their patients, since the website details information on the entire comparability exercise that has formed the basis for approval.
Of major importance to the success of similar biological medicinal products (biosimilars) in the EU is that doctors, pharmacists and reimbursement bodies understand the underlying scientific principles. They must also recognise that, for the process of marketing authorisation, these products are of the same quality, safety and efficacy as their reference product. Following Europe’s initiative to establish principles for biosimilar authorisation and marketing, numerous other regions worldwide developed guidance for biosimilar development including the WHO.11
In March 2010, the US Congress adopted legislation setting the scene for the development and authorisation of biosimilars in the world’s largest pharmaceutical market.12 With the ‘globalisation’ of the biosimilar pathway, new scientific and regulatory challenges became apparent, such as the requirements for reference products in different regions of the world, thus potentially hampering a global product development. These challenges deserve international dialogue and scientific discussion to ensure successful marketing of more affordable, safe and efficacious drugs worldwide.
- European Commission, Directive 2003/63/EC, Eudralex – Volume 1 – Pharmaceutical legislation medicinal products for human use. www.ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-1/index_en.htm
- European Commission, Directive 2004/27/EC, Eudralex – Volume 1 – Pharmaceutical legislation medicinal products for human use. www.ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-1/index_en.htm
- European Commission. Directive 2001/83/EC Art. 10(4) and Part II of the Annex I of Directive 2001/83/EC, as amended. EudraLex – Volume 1- Pharmaceutical legislation medicinal products for human use. www.ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-1/index_en.htm
- European Medicines Agency (EMA) Scientific Guidelines. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000043.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800240cb
- EMA Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac058002958c
- Reichert JM et al. Nat Biotechnol 2005; 23(9): 1073-78.
- EMA draft guideline on similar biological medicinal products containing monoclonal antibodies. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac058002958c
- EMA guideline on the evaluation of anticancer medicinal products in man. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000406.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580034cf3
- EMA draft Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac058002958c
- European Public Assessment Report (EPAR) for authorised Medicinal Products. www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landing_page.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124
- Guideline on evaluation of similar biotherapeutic products (SBPs), ECBS 19-23 October 2009. www.who.int/biologicals/publications/en/
- Implementation of the Biologics Price Competition and Innovation Act of 2009. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm
This publication represents solely the views of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency, nor does it necessarily reflect the view of its committees or its working parties.