The European Medicines Agency (EMA) has announced the release of a new biosimilars guideline that again looks to clarify the process by which biosimilars come to market, this time refining an earlier guideline in several areas.
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 to determine just how similar a subsequent biological product has 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.
EU regulators are considerably further along in the development of a biosimilars framework than are their US counterparts, who are only just beginning to put into place the regulatory structures by which they plan to regulate biosimilars.
Guidelines: General Biosimilar Products
EMA's most recent guideline, On similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, follows a similar one released in May 2013 on similar biological medicinal products in general.
The prior guideline was noteworthy for its treatment of biosimilars data, and explicitly permitted the use of international comparator studies to support approval so long as the reference product is already approved within the European Economic Area.
As to the question of similarity, EMA decided that it will have to take a step-by-step approach due to the varied nature of biotechnology products. 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.
EMA's new guidance is similar to this other guidance in many regards, calling for a step-wise approach focused on evaluating the similarity of a follow-on product relative to the reference product.
"It is important to note that design of an appropriate non-clinical study program requires a clear understanding of the reference product characteristics," EMA wrote. "Results from the physico-chemical and biological characterization studies (i.e. comparability of the biosimilar to the reference product) should be reviewed from the point-of-view of potential impact on efficacy and safety."
The "steps" in the step-wise process should graduate from in vitro studies to in vivo studies (if needed), and then clinical studies. EMA recommends that once the clinical stage commences that the sponsor use a test product derived from a finalized manufacturing process, as the process can influence the product's safety and efficacy profiles. Any deviations from this process must be "justified and supported by adequate additional bridging data," EMA wrote.
From here, the step-wise process continues, encompassing pharmacokinetic studies, pharmacodynamics studies, safety studies and efficacy studies.
EMA said the revised version of the guidance includes five primary changes to:
- the risk-based approach for the design of non-clinical studies
- the use of pharmacodynamic markers for the demonstration of clinical comparability
- study design
- the design of immunogenicity studies
- extrapolation of efficacy and safety from one therapeutic indication to another
For example, a reference medicinal product that is found to be similar for one indication will not automatically be found to be similar in all other indications for a product due to the various receptors involved in treating different indications. Though EMA says this "is not an argument for additional studies," sponsors will have to provide additional data if there is evidence of different receptors being targeted for different indications.
Elsewhere, EMA devotes a section to discussing the immunogenicity of biosimilar products, noting that sponsors will need to justify and discuss at length the possible safety concerns associated with the use of the product.
"The potential for immunogenicity of a biosimilar should always be investigated in a comparable manner to the reference product … unless it can be justified that there is a need for deviation from this approach," EMA wrote. "The amount of immunogenicity data will depend on the reference product and/or the product class."
Regulators also noted that equivalence designs should, in general, be used unless a sponsor has a strong scientific rationale to use a non-inferiority study. Sponsors wishing to utilize this approach should discuss its practicality with EMA before beginning the trial, regulators added.
Draft guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues