Regulation

Registering biosimilars in the EU

A review of the biosimilars registration process in the European Union

Parminder Kaur

Biosimilar medicines are now a reality in the European Union. The necessary legal framework for biosimilar medicines has been solidly established in the EU and the first biosimilar medicines were approved by the European Commission in April 2006. Guidance on risk management systems has also been developed which assures safe market entry and post-marketing monitoring of these medicines.

The Marketing Authorisation (MAA) dossier of a biosimilar medicinal product claiming to be similar to a reference medicinal product already authorised requires a full quality dossier including comparable clinical efficacy and safety data.

In case the originally authorised medicinal product has more than one indication, the efficacy and safety of the medicinal product claimed to be similar has to be justified or, if necessary, demonstrated separately for each of the claimed indications. In certain cases it may be possible to extrapolate therapeutic similarity shown in one indication to other indications of the reference medicinal product. Justification will depend on for eg., clinical experience, available literature data, whether or not the same mechanisms of action or the same receptor(s) are involved in all indications. Possible safety issues in different subpopulations should also be addressed. In any case, the company should justify the approach taken during the development of the product and might want to contact the EMEA before starting the development for scientific and regulatory advice.

Choice of Reference Product

It is critical that the reference product is sourced from within the EU, as it may otherwise not be possible to demonstrate conformance with the product approved for marketing within the EU. For reference products not approved via the Centralised Procedure, it is even possible for variation between member states, in which case it is advisable to consistently source the reference product from the same EU member state. There are number of aspects which lay the basis for choice of reference product.

These are:

• Active substances must be similar structurally and functionally- a biosimilar approach will only be possible if few or no differences exist;
• Reference product must be approved in the European Community;
• Pharmaceutical form, strength, and route should be the same; differences will have to be justified;
• Remaining period of data exclusivity;
• Generic name and labeling;
• Price of the reference product relative to competitor products;
• Potential for competition from other manufacturers and innovations.

Non-Clinical Data Requirements

Before initiating clinical development, non-clinical comparative studies should be designed to detect differences in response between the similar biological product and the reference medicinal product and not just the response per se.

It is important to note that design of an appropriate non-clinical study program requires a clear understanding of the product characteristics. Results from the physicochemical and biological characterisation studies should be reviewed from the point-of-view of potential impact on efficacy and safety. Case-by-case basis approach should be tailored and fully justified in the non-clinical overview to the specific product.\

Pharmacodynamic studies

In vitro studies: Assays like receptor-binding studies or cell-based assays, many of which may already be available from quality-related bioassays, should normally be undertaken in order to establish comparability in reactivity. If comparability cannot be established, the likely causative factor(s) must be provided.

In vivo studies: Animal studies should be designed to maximise the information obtained and to compare reference and similar biological medicinal products intended to be used in the clinical trials. The erythrogenic effects of the similar biological medicinal product and the reference medicinal product should be quantitatively compared in an appropriate animal assay (for eg. the European Pharmacopoeia polycythaemic and/or normocythaemic mouse assay; data may be already available from quality-related bioassays). Additional information on the erythrogenic activity may be obtained from the described repeat dose toxicity study.

Toxicological studies: The duration of the studies should be sufficiently long to allow detection of relevant differences in toxicity and/or immune responses between similar biological medicinal product and reference medicinal product.

Non-clinical toxicity should be determined in at least one repeat dose toxicity study of at least 28-days in one relevant species (rat). This must include toxicokinetic measurements whereby determination of antibody titres, cross reactivity and neutralizing capacity should be measured.
If there are specific safety concerns, these might be addressed by including relevant observations (i.e. local tolerance) in the same repeat dose toxicity study. Normally other routine toxicological studies such as safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not required for similar biological medicinal products, unless indicated of results of repeat dose studies.

Clinical Data Requirements

Changes in biological structure may impact pharmacokinetics, potency and/or immunogenicity. As there is no certainty that all such changes can be detected, clinical trials will generally be required.

It is acknowledged that the manufacturing process will be optimised during development. It is therefore recommended to generate the required clinical data for the comparability study with the test product as produced with the final manufacturing process thereby representing the quality profile of the batches to become commercialised. Any deviation from this recommendation should be justified and supported by adequate additional data.

The clinical comparability exercise is a stepwise procedure that should begin with pharmacokinetic (PK) and pharmacodynamic (PD) studies followed by clinical efficacy and safety trial(s) or, in certain cases, pharmacokinetic/pharmacodynamic (PK / PD) studies for demonstrating clinical comparability.

Pharmacokinetic Studies

The relative pharmacokinetic properties should be determined in single dose crossover studies using subcutaneous and intravenous administration. The ordinary crossover design is not appropriate for therapeutic proteins with a long half-life, e.g. therapeutic antibodies and pegylated proteins, or for proteins for which formation of anti-drug antibodies is likely.

Healthy volunteers are considered an appropriate study population. The selected dose should be in the sensitive part of the dose-response curve. In fact, differences in elimination characteristics between products e.g. clearance and elimination half-life should be explored. The acceptance range to conclude clinical comparability with respect to any pharmacokinetic parameter should be based on clinical judgement, taking into consideration all available efficacy and safety information on the reference and test products.

Hence, the criteria used in standard clinical comparability studies, initially developed for chemically derived, orally administered products may not be appropriate and the clinical comparability limits should be defined and justified prior to conducting the study.

Pharmacodynamic Studies

Pharmacodynamics should be evaluated as part of the comparative pharmacokinetic studies. The selected dose should be in the linear ascending part of the dose-response curve. The pharmacodynamic (PD) markers should be selected on the basis of their relevance to demonstrate therapeutic efficacy of the product. The pharmacodynamic effect of the test and the reference medicinal products should be compared in a population where the possible differences can best be observed. The design and duration of the studies must be justified. Combined PK / PD studies may provide useful information on the relationship between exposure and effect. The selected dose should be in the steep part of the dose-response curve. Studies at more than one dose level may be useful.

Clinical Efficacy Studies

Comparable clinical efficacy should be demonstrated in at least two adequately powered, randomised, parallel group clinical trials. Confirmatory studies should be double-blind to avoid bias. Equivalence margins for both co-primary endpoints have to be pre-specified and appropriately justified and serve as the basis for powering the studies.

Generally, a post-approval continued benefit-risk assessment (pharmacovigilance plan) is necessary. At least two adequately powered, randomised, parallel group clinical trials are necessary for the evaluation of the adverse effect profile. Safety data collected over at least 12 months from at least 300 patients (cohorts of patients) after repeated dosing is sufficient to provide an adequate pre-marketing safety database.

Since clinical programmes are associated with significant costs and considerable ethical constraints, there is a compelling need to optimise the clinical program so as to limit trial sizes to a minimum. Thus an efficient clinical program needs to be formulated and justified to the regulatory authorities. In preparing such justification, there are a host of factors that will need to be considered. These include physicochemical and biological similarity to the reference medicinal product, relationship between the pharmacodynamic effect, the clinical effect and the administered dose, existence of suitably validated surrogate markers and their relationship to dose and resulting drug tissue levels, statistical burden for proof of efficacy at the 95% confidence level in terms of the acceptability of the equivalence margin, the need for assay sensitivity, the variability in terms of the common standard deviation, and the required power of the study and potential for immunogenicity and the potential impact of neutralising antibodies.

Confirmatory Efficacy And Safety Studies

Comparative clinical trials demonstrating equivalent efficacy required although a comparative PK/PD study may be adequate if an acceptable surrogate marker exists.

Use of surrogate markers is clearly one way of reducing the number of patients and shortening the duration of the trial, but surrogate markers need to be validated and their use as a primary end-point should be discussed in advance with the regulatory authorities (Scientific Advice). In addition to showing equivalence regarding efficacy, there is need to demonstrate non-inferiority in terms of dosage, particularly for Epoetin where a clear inter-dependence between dose and efficacy exists.

By and large, the equivalence margin should be defined in terms of a clinically meaningful endpoint and will need to be sufficiently narrow as to ensure that any potential differences will not be of clinical significance. The number of patients required to demonstrate equivalence will depend on the variability of the endpoint (common standard deviation). In order to estimate the requisite number of patients, the statistician will need have an estimate of the common standard deviation. This is often difficult to obtain from the literature and may require a pilot study. Finally power of the study should be decided; this is usually set between 80 and 90%. The trial size will also be influenced by the allocation of patients between the two groups.

Immunogenecity issues

The prime safety concerns for all biopharmaceuticals relates to their immunogenic potential. Many factors can influence the immunogenic potential of a biosimilar medicinal product for eg., variations in amino-acid sequence and glycosylation patterns in case of a protein. The route of administration may also affect immunogenicity with the SC route being associated with the greatest immunogenicity.

The predictive value of non-clinical studies for evaluation of immunogenicity of a biological medicinal product in humans is low due to inevitable immunogenicity of human proteins in animals. While non-clinical studies aimed at predicting immunogenicity in humans are normally not required, animal models may for example be of value in evaluating the consequences of an immune response.

In the clinical setting, the issue of immunogenicity can only be settled through clinical trials of sufficient duration, i.e. at least 12 months using subcutaneous administration. The comparative phase of this study should be at least six months, to be completed pre-approval. Data at the end of 12 months could be presented as part of post-marketing commitment. Of key importance is the need to distinguish between neutralising and non-neutralising antibodies. Neutralising antibodies are of particular concern as the appearance of neutralising antibodies (NAbs) has been reported in several studies to be associated with reduced clinical efficacy or auto-antigenicity.

The plans for these trials should take into account justification of study population including history of previous exposure,
definitions of pre-specified analyses of the immunogenicity data with respect to effects on clinical findings and immunogenicity issues should be further addressed in the Risk Management Plan.

Injection site reactions

If any concern is raised through non-clinical and short-term clinical studies outlined above, additional evaluation of local tolerability may be needed pre-marketing. Otherwise, such reactions should be monitored and recorded within immunogenicity trials.

Pharmacovigilance Plan

As ever, a rigorous pharmacovigilance plan is required. For every new medicine, including biosimilar medicines, a Risk Management Plan (RMP) must be submitted and agreed by the EMEA. The RMP describes what is known about the safety of the medicine and outlines how the manufacturer will further monitor and fill any gaps in knowledge as well as any measures needed to minimize any risk from the medicine. Attention should be paid to immunogenicity and potential rare serious adverse events, especially in patients undergoing chronic administration. Lack of efficacy should also be monitored. This plan is published in the European Assessment Report (EPAR) and needs to be updated throughout the lifetime of the medicine.

CONCLUSION

It is clear that biosimilars are going ahead, with the potential advantage of reducing healthcare costs. However, care must be taken when weighing the immediate advantages of cost savings versus the well-being of the patient. The development of biosimilars is far more complicated than for synthetic small-molecule generic drugs and, consequently, it is not possible to make an exact copy of the originator protein. Much work needs to be undertaken to ensure that biosimilars are as safe and effective as their originator products.

REFERENCES

a) Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance - quality issues (EMEA/CHMP/4924/05)
b) Guideline on similar biological products (CHMP/437/04), the so-called 'overarching guideline'
c) ICH topic S6 - Note for guidance on Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (CPMP/ICH/302/95) q
d) ICH topic E9 statistical principles for clinical trials - Note for guidance on statistical principles for clinical trials (CPMP/ICH/363/96)
e) ICH topic E10 - Note for guidance on choice of control group in clinical trials (CPMP/ICH/364/96)
f) Guideline on clinical investigation of the pharmacokinetics of therapeutic proteins (EMEA/CHMP/89249/04/in preparation)
g) Guideline on risk management systems for medicinal products for human use (EMEA/CHMP 96286/2005)
h) Note for Guidance on Good Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95)
i) ICH Note for Guidance on Planning Pharmacovigilance Activities (CPMP/ICH/5716/03

(The author is a regulatory affairs consultant, based in the Netherlands and can be contacted at parminder.kaur@consultant.com)