The European Medicines Agency (EMA) has finalized a long-awaited guideline containing new recommendations on how to bring "similar biological medicinal products"—also known as biosimilars—to market in the EU.
EMA first released a draft update of the guideline, Similar Biological Medicinal Products, in early May 2013. The guideline was meant to update an October 2005 guideline on biosimilarity which officials said had become outdated.
The new guideline, they said, would clarify regulators' "biosimilar approach" and explain how companies could establish biosimilarity between their follow-on biologic and the original biologic product approved by EMA.
The basic problem facing regulators and industry is that biologics are quite unlike chemical-based pharmaceuticals. Due to the biological processes involved in making a biologic, it is nearly impossible to exactly duplicate one. The challenge for regulators and companies, then, is to ensure that the small differences between the products don't cause safety or efficacy problems in patients.
That, too, presents a challenge for regulators: Just how similar does the subsequent biological product—the biosimilar—have to be relative to the original one for it to be approvable by EMA regulators?
EMA's guideline tries to answer some of these questions by explaining what it means by a "similar" biological medicine. Four qualities must be taken into account, EMA says: Safety, efficacy, quality and biological activity.
The key to EMA's "biosimilar approach" lies in comparability exercises, the regulator wrote. While various elements of this approach are explained in the International Conference on Harmonization's (ICH) Q5E document, EMA says each biosimilar product will have to be evaluated based on its own merits. For example, regulators say they plan to evaluate the analytical methods, clinical comparability models and manufacturing processes used to create and validate the biosimilar product. Products that can be "thoroughly characterized" and shown to be similar to the reference product are more likely to benefit from EMA's biosimilar approach, it said.
The medicine will also need to be administered in the same way (e.g. injected), though regulators said small changes in the product's strength, form, formulation and use of excipients would be acceptable so long as they could be justified using data and did not "compromise safety."
Foreign Bridging Data
The guideline's biggest piece of information, however, lies in which comparators companies will be allowed to use.
Though EMA will require that all reference products should be authorized in the European Economic area—in other words, no approving a biosimilar product based on a biologic only approved in the US—the regulator said it will allow companies to compare a biosimilar "in certain clinical studies and in vivo non-clinical studies" with a non-authorized comparator.
The goal of this approach is to facilitate "the global development of biosimilars and to avoid unnecessary repetition of clinical trials," EMA wrote.
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.
"However, the final determination of the adequacy of the scientific justification and bridge will only be made during the assessment of the application," EMA cautioned.
The guideline also includes a discussion regarding the "principles of establishing biosimilarity." As with other guidelines on the subject, EMA recommends a "stepwise approach" meant to build upon rigorous data at every stage of the evaluation process.
Notably, EMA explains: "If the biosimilar comparability exercise indicates that there are relevant differences between the intended biosimilar and the reference medicinal product making it unlikely that biosimilarity will eventually be established, a stand-alone development to support a full Marketing Authorisation Application (MAA) should be considered instead."
"Clinical data cannot be used to justify substantial differences in quality attributes," the regulator added.
The final guidance was approved by EMA's Committee for Medicinal Products for Human Use (CHMP) on 23 October 2014, and officially comes into effect on 30 April 2015. Applicants may "apply some of all provisions of [the] guideline" immediately, the guideline notes.
EMA Biosimilars Guideline