The challenge before pharmacists is to ensure that all the
biopharmaceutical medicines they choose to use are the best available, no matter which regulatory pathway they have followed
Seven biopharmaceuticals have now been approved under the EMEA biosimilar pathway (see Table 1).
This is good for patients, doctors and healthcare payors in Europe and also, the European biotech industry, where manufacturing innovation has been stimulated by the opportunity that biosimilar pathway approval of biopharmaceutical medicines brings. The companies with successful introductions of the biosimilar-approved epoetins are based in Europe, with manufacturing in Europe.
Developed over the last five to ten years, the European Medicines Agency (EMEA) has introduced guidelines for the approval of new versions of existing medicines, which are based on protein structure and thus have a built-in, natural variability.
The EMEA must be congratulated on the careful and detailed approach they have taken to establish a route for introduction of new versions of existing biopharmaceuticals whose patents have expired.
The EMEA leads the world in the development of the law and specific guidelines in this area. In the USA, the Food & Drug Administration (FDA) is still attempting to put controls in place! Figure 1 shows the development from a legal and guideline standpoint in this area.
All the products in Table 1 have received Marketing Authorisation (MA), but, like all MAs, the data available does little for the pharmacist and prescriber who need to differentiate between similar products. It has been suggested that other data held on file by the companies would be helpful. This does not call into question the importance of the MA – it amplifies that information and qualifies any selection process that may take place.
The erythropoiesis stimulating agents are a good
The European Pharmacopoeial limits are ± 20% of the stated amount on the label. For conventional medicines these would be extremely wide limits. When the monographs for biopharmaceuticals were conceived this wide variation limit was proportionate to the manufacturing capability. As time has moved on, processes have improved, so the most recent products should have much closer compliance with the stated amount. This information is important because greater purity implies greater safety and can confer greater stability – for example, Binocrit (Sandoz) has an overall higher stability than Eprex (24 months vs 18 months shelf-life).
The newer products demonstrate a lack of dimers and aggregates, which may imply less immunogenic risk.
New manufacturing techniques are producing greater yields, and this leads to better pricing for the customers. This is augmented by better purification methods that have previously diminished the yield considerably. By learning from experience and by designing products with increased quality, the newer products can often be superior to the original in these respects (eg, less oxidised methionine is a marker for greater stability – if it can be reduced then the product will be improved).
Particulates in any injectable are to be avoided. It can be shown that counts can be reduced by changing techniques either during manufacture or packaging (eg, silicone oil droplets in Binocrit are ten times less than the reference product).
The active component in the biopharmaceutical medicine which has been produced by recombinant technology may have a number of active components called isoforms. Whereas great variations in isoform profile could be demonstrated for non-EU products, information is now available that shows the EMEA
approved “biosimilars” are directly comparable in profile to the reference products.
As time goes by, we shall need to develop an understanding of the important factors that differentiate products, because the same factors will also show how they are similar.
We now need to develop criteria for other products such as growth hormone and G-CSF.
The biosimilar pathway allows pharmaceutical companies to introduce new versions of existing protein-based medicines or biopharmaceuticals.
The challenge for such a pathway is that, by definition, each biopharmaceutical medicine is unique. This holds regardless of the approval process. The nature of proteins is such that it is not possible to create new versions of existing medicines, such as, for example, epoetins, which are identical to the earlier versions of the medicines.
As a result, achieving this is not the goal of the guidelines for biosimilar approval. The guidelines demand that, versus a comparator or reference product, the manufacturer first demonstrates physical, chemical and biological comparability. This requires extensive high technology analysis of the two candidates with multiple techniques, including mass spectrometry and capillary zone electrophoresis. For the pharmacist in practice, the standard gel electrophoresis gives a good indication of the beginning of such analysis. Figure 2
shows the comparable results produced in the development of an epoetin recently approved as a biosimilar. The typical set of bands, forming as a result of glycosylation, are noted to be similar in these impressive results. Relatively simple techniques such as this do not give the whole story of the comparative analysis, however; it is critical to confirm physicochemical and in-vitro biologic comparability of the new and existing versions of the medicine.
It is important to understand the differences, or, for that matter, the similarities, between biopharmaceuticals approved by existing regulatory pathways in Europe and the biosimilar approval pathway. A comparison is shown in Table 2. Broadly, the approval processes are similar. A major difference is the lack
of phase II dose-finding studies: dosing is expected to be the same as existing medicines. The assumption must be tested in phase III studies which provide clinical evidence of outcome after a switch from the comparator to the new version. Postmarketing commitments, such as safety studies, are common to both types of approval pathway, and pharmacovigilance or drug safety monitoring is identical.
The EMEA biosimilar pathway, and the introduction of medicines approved under it, has stimulated great debate in many circles. Largely, however, the debate has not focused on the critical issue.
The critical issue is not whether a medicine approved under the biosimilar pathway is safe or efficacious, because the approval process ensures that. The issue is also not whether one protein is identical to another existing one – it is not, by definition. The issue is not whether pharmaceutical companies introducing biosimilar-approved medicines should carry out pharmacovigilance – they do because the guidance mandates that. The issue is not about interchangeability and substitution, because existing guidance is clear.
The EMEA biosimilar approval pathway determines quality, comparability, clinical safety profile and efficacy for approved medicines. By definition, a medicine approved under the EMEA biosimilar guidelines shows comparable or improved quality and therapeutic equivalence to another existing medicine or reference.
The critical issue is not about biosimilars, but about biopharmaceuticals.
Biosimilar approval raises many new points about biopharmaceuticals overall. Focus on the biosimilarapproved medicines is not the right way to go. As can be seen from the development of the story in Table 3, the debate must now move on to ask the key questions of all biopharmaceuticals.
It is not the EMEA approval process that should be the focus, but it is the best way to approach all biopharmaceuticals, in general. In particular for hospital pharmacists today, the critical issue is how to access standard information demonstrating the quality, clinical efficacy, safety profile of all biopharmaceuticals.
In addition, the debate should focus on how to implement detailed pharmacovigilance for biopharmaceuticals efficiently, so as not to further increase the cost of medicines.
1. Kraemer I,Tredree R, Vulto A. Points to consider in the evaluation of biopharmaceuticals. EJHPP 2008;14(1):73-6.
2. Schellekens H. Biosimilar epoetins: how similar are they. EJHP 2004;3:243-7.