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Published on 17 August 2010

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Biosimilars – regulatory frameworks


As clinical knowledge of biopharmaceuticals develops and experience with the reference products increases we can utilise new analytical methods to draw comparisons and ensure safe products for patients

Roger Tredree
BPharm MRPharmS
Visiting Professor
Kingston University

Biosimilars differ significantly from generic low molecular weight drugs with regard to the size and complexity of the drug substance, the manufacturing process and heterogeneity of the product. The safety and efficacy of biopharmaceuticals both depend heavily on the nature of starting materials (cell banks, tissues and other biological substances) and on manufacturing methods.
Existing analytical techniques for biopharmaceuticals do not always detect product changes that could affect efficacy and safety. Biopharmaceuticals are potentially immunogenic. Minor differences in products can significantly affect safety, efficacy and immunogenicity.
This means that the established legal and regulatory principles of ‘essential similarity’ (EU) or ‘bioequivalence’ (USA) cannot be applied to biosimilars. The EU regulatory situation is more advanced than in the USA. The first legal basis in Europe for evaluating biosimilar medicinal products was defined in a revision of Directive 2001/83/EC (approved on 31 March 2004 and published in the Official Journal of the European Union on 30 April 2004 as Directive 2004/27/EC). These EU directives have thorough definitions for biosimilars. Thus, there is a clearly defined regulatory framework for biosimilars in the EU. EU legislation on biosimilars came into force in 2005. The legislation requires that when a biosimilar is submitted for marketing authorisation, the information provided shall not be limited to pharmaceutical, chemical and biological data: bioequivalence and bioavailability data are mandatory as well.
The type and amount of additional data required, ie, toxicological and other non-clinical and (pre-)clinical data, will be determined on a case-by-case basis in accordance with relevant scientific guidelines. If the originally authorised 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. Justification will depend, for example, on clinical experience, available literature data for the reference product, and whether or not the same receptor(s) are involved in all indications.
The Committee for Human Medicinal Products (CHMP) of the EMEA will decide what kind of tests and data will be needed to assess the safety and efficacy of biosimilars. This has driven the need for CHMP scientific advice and the development of EMEA/CHMP.
These guidelines apply to all biopharmaceuticals (comparability after product change) and biosimilars derived from r-DNA and hybridoma techniques (produced from recombinant cell-culture expression systems).
The EMEA guidelines acknowledge the major influence of the manufacturing process on the safety and efficacy of biopharmaceuticals
An essential point is that a comparison based on testing and characterising the active substance and finished product is not sufficient to establish the required quality, non-clinical and clinical aspects of a biosimilar.
The guidelines place considerable emphasis on safety. Before market approval can be given, a manufacturer must present a pharmacovigilance plan in accordance with current EU legislation and pharmacovigilance guidelines. Safety needs to be closely monitored in the post-marketing phase.
The human immune system is more sensitive to alterations in products than physical tests or bioassays currently available. In view of this, immunogenic safety can only be assessed through thorough clinical data gathering, including post-licensing data. This is especially important as some immune-mediated reactions are rare, and may only become evident in robust post-licensing risk management programmes.
Today, the legislation is in place to assess and grant marketing approval to a biosimilar and this legislation is different from the approval process of generic drugs. However, the guidelines only provide a road map, leaving challenging questions still to be answered, including whether the appropriate analytical tools are available, whether bioassays are precise enough to measure all activities and how effects on efficacy and safety can be measured through clinical trials or post-marketing surveillance.
Furthermore, it is likely that it will take 2–3 years after market approval to validate the risk/benefit profile of a biosimilar adequately and compare this with the originator product.

The Regulatory processes for pharmaceuticals
It is a fundamental requirement that decisions about the authorisation of medicines are based on an objective, scientific assessment of their quality, safety and efficacy.
Conducting these assessments is the primary role of the European Medicines Agency. Through its scientific committees, the Agency assesses every medicine for which a marketing-authorisation application has been submitted (in accordance with the centralised procedure), and prepares a recommendation (called an ‘opinion’) that is then relayed to the European Commission, which has the ultimate responsibility for taking decisions on granting, refusing, revoking or suspending marketing authorisations. The evidence is published in the European Public Assessment Report, EPAR, that can be found on the EMA website.

Types of procedure
There are several alternative procedures to choose from depending on which countries the product is going to be marketed in and the type of medicine. Although the centralised procedure is the only allowable route for biopharmaceuticals the others are included for comparison.

Centralised procedure
In the European Union (EU), a company may submit a single application to the European Medicines Agency (EMA) for a marketing authorisation (licence) that is valid simultaneously in all EU Member States, plus Iceland, Liechtenstein and Norway. This is called the centralised (or community) authorisation procedure, and is mandatory for certain types of medicines and optional for others. Other authorisation procedures are used for medicines that do not fall within the mandatory scope of the centralised procedure, these are:

National procedure
Each EU Member State has its own procedures for the authorisation of medicines that fall outside the scope of the centralised procedure. Applicants must submit an application to the competent authority of the Member State. In the UK, this is the MHRA.

Decentralised procedure
Using the decentralised procedure, companies may apply for simultaneous authorisation in more than one EU country of products that have not yet been authorised in any EU country and that do not fall within the mandatory scope of the centralised procedure.

Mutual recognition procedure
In the mutual recognition procedure, a medicine is first authorised in one EU Member State, in accordance with the national procedures of that country. Following this, further marketing authorisations can be sought from other EU countries in a procedure whereby the countries concerned agree to recognise the validity of the original, national marketing authorisation.
The approval to market a medicinal product is based on the evaluation of scientific data provided by the company to support its quality, safety and efficacy. However, most of the ‘new’ products which come on to the market contain drugs which have been previously well tested and approved in other forms or for other companies. In these circumstances the European Directives (in particular Directive 2001/83EC) allow for what are known as ‘abridged’ applications so that companies do not have to repeat the tests and trials on animals and humans unnecessarily.


Types of application
There are a number of different types of application, depending on the nature of the active ingredient of the product. These vary from applications for products containing new active substances, those whose active ingredients have previously been evaluated before, known as abridged applications, to those biological and biotechnology products manufactured by recombinant DNA technology, products where genetic manipulation of cells is required, or monoclonal antibodies.
Applications for new active substances are described as ‘full applications’. Applications for medicines containing existing active substances are described as ‘abbreviated’ or ‘abridged applications’.
The legal basis for all types of application is set out in Directive 2001/83/EC and in Regulation (EC) No726/2004.
Full applications (under Article 8(3)) must be accompanied by a dossier of information covering:

  • Pharmaceutical (physico-chemical, biological or microbiological) tests.
  • Preclinical (toxicological and pharmacological) tests.
  • Clinical trials.

Any relevant published literature should also be included.

Abridged applications
Abridged applications do not require full preclinical or clinical dossiers. Applications for generic medicines are required to identify a ‘reference medicinal product’ from which the RA can determine the preclinical and clinical data. The RA Information Centre can provide lists of products containing a particular active ingredient from which a suitable reference product can be identified.


Generic products
If the new product meets requirements for a generic product defined in Article 10 (2)b of the Directive (2001/83 (as amended)), then it can be authorised without its own clinical and pre-clinical testing data.
The data requirements and the assessment process aim to ensure that patients could be switched between the brand leader product and a generic version without causing any therapeutic problems.

What is a biotechnology product?
A biotechnology product is one manufactured by recombinant DNA technology, one where genetic manipulation of cells is required, or a monoclonal antibody. Applications for these products are required to be submitted through the European centralised procedure (European Medicines Agency website). They comprise List A (the mandatory part) of the procedure.
The UK bids for rapporteurships for these products and is a leader in the field.

What is a biological product?
Biological products are defined as so because they are more difficult to characterise or control than standard chemically synthesised pharmaceuticals.
They include those where the starting material may be human or animal tissue or of microbiological origin. Also included are those where a complex bioassay system is required to monitor potency.
The two largest groups of biologicals are blood products and vaccines. Other products include hormones, larger peptides and a miscellaneous group of tissue derived products.
The Biologicals Unit in the UK is part of the Licensing Division of the MHRA, and is responsible for the assessment of the full range of applications for biological and biotechnology products.
The Unit consists of pharmacists and biochemists who assess the ‘quality’, that is manufacture and formulation of the product, a toxicologist for the pre-clinical data and physicians to assess the clinical data.
The Unit also provides the professional secretariat for the Biologicals Subcommittee of the Commission on Human Medicines.

Existing drugs with new forms, routes and indications
Sometimes, although the drug is the same, the new product has a different strength or pharmaceutical form or is used by a different route or for different clinical uses. In these cases the company can submit more pre-clinical and clinical data to supplement its abridged application. (The ‘Notice to Applicants’ refers to these as ‘other abridged’ applications. The relevant legal basis is Article 10(3) of Directive 2001/83/EC).

The very nature of biopharmaceuticals means that at present the products made in one facility with a specific cell line will not be identical to that made by another cell line no matter how closely the process is copied. How significant this is in clinical care is an important question. However, if we can measure the clinical response and if it is satisfactory, there may be potential to interchange from one brand to another, under clinical supervision. Indeed, this has been the case for insulins for which we have several decades of experience. This is not the same as generic substitution for chemically synthesised pharmaceuticals where the molecules can be clearly defined as identical, (even if the formulations differ!).
The EU guidelines have set standards for biosimilars within the EU and have given purchasing pharmacists greater confidence. There are still issues that need to be considered and the potential for immunogenicity still remains a concern because of the potential for life threatening outcomes.

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