Daan J.A. Crommelin - "Introduction" Arnold G. Vulto* - "The hospital pharmacist's tools to make the choice"
Paul Declerck* - "The regulatory rules of engagement in Europe" Paul Cornes* - "Is our present system economically sustainable?"
Compared to "standard" small-molecule drugs, biologicals are considerably larger and more complex molecules. They are more difficult to characterize and are produced by living organisms. Due to this complexity and to the dependency of the protein characteristics on the manufacturing process, the 'classical' generic pathway for regulatory approval cannot be used for biosimilars. This is the reason why regulatory authorities, such as the EMA and FDA have designed specific protocols for the approval of follow-up versions of innovator biologicals and why they were given a special name: 'biosimilars'. As a rule, in these protocols clinical comparability tests are requested to be performed. E.g. the similarity of the follow-on version of infliximab that was recently approved by the EMA was tested in two clinical trials.
Biosimilars are not new innovator drugs for which a complete evaluation dossier is necessary. Interestingly, the technology to produce and purify these biosimilar products has greatly improved since the innovator product was introduced. Thus, biosimilar manufacturers can use state-of-the-art technology. Consequently official documents for the registration of biosimilars made available by the European Medicines Agency indicate that the biosimilars of epoetin alfa and one of the biosimilar filgrastims have fewer impurities and less modified products than their reference products.
An interesting point of discussion is whether over time the 'similarity' may be lost in future batches because of drifting and shifting of the protein structure as the manufacturing process, including up and downstream processing, are changed. This may happen to the innovator product as well as for the follow-on product.
Interchangeability is defined by the FDA as:
"According to the FDA a biosimilar product is a biological product that is approved based on it showing that it is highly similar to an FDA approved biological product, known as a reference product and has no clinically meaningful differences in terms of safety and efficacy from the reference product. An interchangeable biological product is biosimilar to an FDA approved reference product and meets additional standards for interchangeability that include the same expected result in any given patient and no increased risks or decreased efficacy with multiple switches. Such an interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the healthcare provider who prescribed the reference product."
Other organisations are defining interchangeability in a similar way. Biosimilars are approved via the central procedure by the EMA and enter the national clinical markets without information on interchangeability. This is not the jurisdiction of the EMA but depends on national rules. In Europe these rules vary per country.
In this Synergy Seminar various aspects of the system of registration/approval, launch and use of biosimilars will be highlighted and the consequences of the existing different interchangeability policies will be explained. What are the 'tools' for a health care professional to choose for one or the other product? Can we predict if an individual patient is at risk in case of interchanging between two brands, from originator to biosimilars, or vice versa? Are there general rules to be made to quantify the risk of under treatment or toxicity for any drug? And are biologicals the only group of drug products where this issue of similarity instead of equality occurs?
Another aspect of the discussion on biosimilars is the increasing costs of biologicals and the impact the introduction of biosimilars may have on this upward trend. In the last five years the rise in costs for medication has shown to be disproportionate to the increase in daily living costs. About 50 drugs out of more than a total of 1000+ will cost the community almost 80% of the available budget. We reach the financial limits of our healthcare system. Ethical aspects of the treatment of one patient with a drug costing 100,000 Euro per year must be discussed before we use all available funds for these 50 "indispensable" new drugs.
- To describe the problem of interchangeability both regarding the science and daily practice;
- To discuss the need to perform therapeutic equivalence testing of biosimilars before approval and after approval (PMS);
- To discuss the economic and ethical implications of the availability of expensive drugs for a few patients.
- to become familiar with the way of thinking and protocols used in therapeutic equivalence studies of biosimilars;
- to recognise that interchangeability for similar biological products is not an automatism as for small molecule drugs;
- to recognise that there is a need for harmonization of the rules used for interchangeability of biologicals throughout Europe.
* Indicates speaker or SC member has stated a conflict of interest.