The European Medicines Agency (EMA) has just published a new biosimilars draft guideline for consultation that outlines the general principles that industry must take into account when developing an application to the agency.
Generic products have long been an integral part of the pharmaceutical ecosystem. Starting in the 1980s, frameworks were set up around the world to allow for generic pharmaceutical companies to make chemical copies of existing drugs after a period of market exclusivity ended for the innovative product.
But biological products pose unique challenges to that model, even as policymakers have sought to build a similar framework for generic biopharmaceuticals. The primary challenge is that unlike chemical drugs, it is nearly impossible to make an exact copy of a biological product because of the huge number of variables inherent to the manufacturing process.
That leaves regulators in a predicament: Just how similar does the subsequent biological product have to be relative to the original one for it to have the same qualities of safety and efficacy?
That question has confounded regulators around the globe, including in the EU, where the subsequent biological products have been referred to as "similar biological medicinal products" and marketed for a short number of years.
A New Draft Guideline
Now EU regulators are looking to clarify the process a bit more, releasing a draft guideline on 2 May 2013 that aims to clarify how sponsors are to apply what EMA calls the "biosimilar approach" and the "principles of establishing biosimilarity."
At the core of the guideline is a basic precept explained by EMA: "Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the similar biological medicinal product and the chosen reference medicinal product authorized in the EEA."
While regulators said that biosimilar medicines could in theory be made for any biological medicine, they conceded that in practice, some of these medicines would fail to reach the market unless they can appropriately demonstrate sufficient levels of similarity relative to the original product.
What constitutes similarity? Four basic things, according to EMA: safety, efficacy, quality and biological activity.
"This includes physicochemical and biological characterization and requires knowledge on how to interpret any differences between a biosimilar and its reference medicinal product," EMA added. For practical purposes, that means that the standard approach used to determine the similarity of chemical drugs-bioequivalence and bioavailability testing-"is in principle not appropriate to biological/biotechnology-derived products due to their complexity," EMA wrote.
Sponsors should look to the International Conference on Harmonization's (ICH) Q5E guideline for further principles of biosimilar comparability.
Regulators also explained that comparability of the two products was paramount. Accordingly, those products that can be highly purified, allowing for in-depth characterization, are more likely to obtain approval.
As with generic pharmaceuticals, the posology and route of administration will need to be the same as that used by the reference product. Changes meant to improve efficacy will disqualify a product from the biosimilar pathway, and any deviations from the reference product (such as a new excipient or formulation) will require either justification or new studies to placate regulators, EMA said.
Use of International Comparator Studies
Reference products must also be authorized in the European Economic Area (EEA), and only a single reference medicinal product should be used as the comparator during the course of quality, safety and efficacy testing.
But there's a major caveat to this approach, EMA said: "With the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible for an Applicant to compare the biosimilar in certain clinical studies and in vivo non-clinical studies (where needed) with a non-EEA authorised comparator (i.e. a non-EEA authorised version of the reference medicinal product) which will need to be authorised by a regulatory authority with similar scientific and regulatory standards as EMA (i.e. ICH countries)."
Companies will need to be able to show that the product approved outside the EEA is "representative of the reference product authorized in the EEA." The relevance of that data will need to be justified, but that justification should in theory be far easier than re-conducting clinical trials just for the EEA. This "bridging data," as EMA calls it, will need to include data from analytical studies that compare the biosimilar, the EEA-approved product and the non-EEA-approved product, and may also include pharmacokinetic and pharmacologic bridging data as well.
How do you Define Similarity?
But that still leaves one question unanswered: What will EMA's standard for "similarity" actually be? What is a "significant difference?"
As with other regulators, EMA says that will depend on each product individually. Small differences, including added benefits, might not disqualify a biosimilar product, but they will need to be justified. But the guideline doesn't address the possibility of a similarity threshold or automatically disqualifying characteristics, saying only that studies need to be sensitive enough to find the differences.
"In general … approaches should always be discussed with Regulatory Authorities before commencement of such development," EMA concluded.
A consultation on the draft guideline is open until 31 October 2013.
EMA: Draft guideline on similar biological medicinal products