Out-Law Analysis | 30 Nov 2021 | 12:11 pm | 5 min. read
Debate is intensifying over the regulatory hurdles that biosimilar manufacturers should have to jump to get their products to market, and the ultimate impact on access to medicines.
A prominent area of discussion and theme raised at the World Biosimilars Congress, part of the Festival of Biologics, in Basel, Switzerland, is whether biosimilar manufacturers should need to carry out comparative efficacy trials.
The question has taken on particular significance recently after the UK’s medicines regulator, the Medicines and Healthcare Regulatory Authority (MHRA), dropped the requirement for biosimilars to pass through comparative efficacy trials in most cases, and as the World Health Organization (WHO) consults on whether regulators should remove the requirements for comparative efficacy testing too.
Proponents of change cite the scientific advancement of other standard testing methods in the 15 years since biosimilars first came onto the market in Europe, which may make comparative efficacy trials outdated, unnecessary and potentially unethical.
The MHRA’s move has served to intensify debate over the need for comparative clinical efficacy studies. Now the WHO is also asking for views on whether this requirement should be removed
Biosimilars are products that are highly similar to medicines containing biologic products such as proteins or antibodies.
Biosimilar manufacturers can obtain a marketing authorisation through a streamlined process if they can demonstrate no clinically meaningful differences between their biosimilar and the originator reference medicine in terms of safety, quality and efficacy, i.e. demonstrate ‘biosimilarity’ to regulators.
Nevertheless, meeting these regulatory requirements is an intensive and expensive process. It involves a combination of non-clinical and clinical studies, from comprehensive physicochemical and biological characterisation of the product to a pivotal pharmacokinetic (PK) study. The former uses analytical techniques to demonstrate a clear link between the structure and function of the biosimilar and reference molecules. The latter tests what effect the biosimilar product has when it is absorbed by the human body and also provides safety data. In many markets around the world, manufacturers then also have to undertake comparative clinical efficacy studies, which test how effective the biosimilar product is in addressing the illness or disease indicated in comparison to the originator reference product.
However, the requirement for a comparative clinical efficacy study has been dropped by the MHRA in most cases, making it – currently, at least – an outlier from other prominent global medicines regulators, most notably the European Medicines Agency (EMA) and the US Food and Drugs Administration (FDA).
The MHRA moved quickly after Brexit to update its guidance in relation to comparative clinical efficacy testing as a means of enhancing the attractiveness of the UK market to biosimilar manufacturers.
Under its guidance, to avoid having to undertake a comparative clinical efficacy study, biosimilar
manufacturers need to show that their product has comparable efficacy and safety – including immunogenicity – to the reference product on the basis of the non-clinical studies and PK trial they have carried out.
The removal of the requirement for comparative clinical efficacy studies should help companies get their product out to patients much earlier, potentially before other markets. This will in turn allow biosimilar manufacturers to recoup their development costs earlier for reinvestment. The earlier entry of biosimilars to the UK market should also spur greater price competition and drive cost savings for the NHS.
Participants at the Congress agreed that change to regulations should be led by the scientific advancements in testing
The MHRA’s move has served to intensify debate over the need for comparative clinical efficacy studies. Now the WHO is also asking for views on whether this requirement should be removed.
An April 2020 BioDrugs paper, which carried out a retrospective evaluation of comparative efficacy trials, suggests they are redundant. The research reviewed the clinical development of all biosimilar products either approved, refused, or withdrawn in both the EU and US between April 2006 and November 2019.
According to the authors, the comparative efficacy studies carried out on each of the 38 biosimilars approved over the period “confirmed efficacy of the biosimilar candidate”. However, the comparative efficacy studies “added no value to the scientific review process to approve a biosimilar” in 95% of the cases. In the remaining 5%, the clinical differences in immunogenicity occurred prior to 2010, and it was concluded that “the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities.”
In accordance with this, the mechanism of action of the biosimilar is the key component of biosimilarity according to the new MHRA approach, i.e. the primary binding of the active substance to known targets which triggers initial biological events. If similarity is demonstrated in the mechanism of action, via the state-of-the art assays required as part of the non-clinical tests, then there is reason to assume the molecules will behave the same way in the clinic. There is also reason to assume they will be safe, since their safety profile is largely predicted from this initial binding and so called on target effects. Importantly, and as was emphasised by numerous speakers at the Biosimilars World Congress, PK testing should remain as this provides the important further safety check by testing the biosimilar in humans.
Participants at the Congress agreed that change to regulations should be led by the scientific advancements in testing. This is reinforced by the BioDrugs paper which concludes “this approach may apply to complex proteins like monoclonal antibodies and will not jeopardise the regulatory standards in either the EU or US”. However, there was debate regarding whether further education of clinicians and patients is required on these matters before regulators make such changes, to ensure confidence in biosimilars remains high and market penetration is achieved.
A more provocative question raised at the Congress was whether, given the advancements in assays and the apparent redundancy of comparative efficacy trials, it is unethical to require patients to take part in trials which may be unnecessary. This was hotly debated.
Speakers at the Congress also voiced how, if there is development of a consistent global regulatory approach on this point, it could increase patient access to medicines in a number of ways.
First, access could open up to orphan medicines, i.e. a drug developed to treat a particularly rare condition, where there are not sufficient numbers of patients to carry out sufficiently powered comparative efficacy trials.
Second, in instances where a comparative efficacy trial would not be economically viable for a biosimilar manufacturer, perhaps because there is a small population or the projected profit is low, biosimilar manufacturers may be able to consider entering the market if they do not have to carry out such trials.
Finally, it was noted that entry of biosimilars to markets increases the overall number of patients who have access; it is not a straight 1:1 swap with the originator biologic. This can be due to the lower cost enabling healthcare providers to open up the drug to new populations with milder forms of a condition, for instance.
Removing the hurdle of comparative efficacy trials may increase the number of potential biosimilar entrants and thereby increase patient access more broadly. This was considered at the Congress to be particularly pertinent in countries with lower healthcare budgets where biosimilars may, in some instances, be the only financially viable option to get treatment to patients.
The WHO opened a fresh consultation earlier this month on prospective new guidelines on the evaluation of biosimilars. The latest draft guidelines address the topic of comparative efficacy testing. The consultation is open until 7 January 2022 and industry is encouraged to submit its views.
Under the WHO’s proposals, manufacturers would be able to demonstrate biosimilarity without having to undertake “an adequately powered comparative efficacy and safety trial … if sufficient evidence of biosimilarity can be drawn from other parts of the comparability exercise”. The draft guidelines go on to list a series of factors that the WHO considers would be relevant to whether there would be a need for a comparative clinical efficacy and safety trial.
The new approach would reflect the fact that there is increasing data about biosimilars becoming available all the time, as more of those products are assessed and approved as patent protection for some of the first tranche of biologic products expires. Allied to improved analytical tools, it is becoming easier for biosimilarity to be demonstrated without comparative efficacy testing.
Many will argue, as they did at the Congress, that it is right that regulation is adapted to reflect changes in the market brought about by the power of data and technology, and to increase patient access to these important medicines.
02 Nov 2021
13 Nov 2020