Why comparative efficacy trials for biosimilars must go

Businesses, healthcare systems, and patients alike stand to lose out if the cost of developing some biosimilars is so prohibitive that it serves to dissuade investment in these products.

Biosimilars provide competition to originator biologics, often spurring innovation in the market from biologics and biosimilars manufacturers alike – such as new clinical indications for existing products or improved delivery mechanisms. For example, in the face of increased competition, Roche and Genentech developed subcutaneous versions of their intravenous cancer drugs Herceptin (trastuzumab) and Rituxan (rituximab), respectively. Likewise, Celltrion developed a subcutaneous formulation of its infliximab biosimilar product to enable self-administration at home and compete against Janssen’s Remicade product.

The loss of exclusivity for biologics commonly forces down the price of medicines too, offering significant savings – estimated at €30 billion in Europe alone since 2011, according to health information technology company IQVIA – for healthcare systems that are operating under tight budgets as they seek to serve ageing populations amidst constrained economic growth and high inflation. IQVIA predicts cost savings from biosimilars will reach $215 billion globally by 2026 – a huge incentive for healthcare systems to welcome these products.

For patients, the race to develop new biologics and, thereafter, rival biosimilars, provides them with faster access to new treatments, so far particularly for cancers and autoimmune diseases which were previously lacking in treatment options.

However, a stark statistic shared by Medicines for Europe from IQVIA at the recent Festival of Biologics in Basel, Switzerland, suggests that these benefits are at risk for many biologic product markets – for 55% of originator biologics products where the product patent will expire between now and 2027, there is no record of any rival biosimilar medicines in development.

Comparative efficacy requirements are one issue that regulators can take action on to relieve cost burdens on biosimilar manufacturers and help encourage a new wave of biosimilar medicines to be developed.

Developers of biosimilars must show regulatory authorities that their product has comparable efficacy, quality and safety to the original approved biologic product, known as the 'reference' medicine. Biosimilar manufacturers that are able to do this can benefit from receiving a marketing authorisation through a quicker and more streamlined regulatory process than if they had to apply for the product as an entirely new product.

In most jurisdictions, however, regulators require biosimilar manufacturers to carry out comprehensive scientific comparative efficacy studies to evidence ‘biosimilarity’ between their product and the reference biologic on which they are relying to obtain their marketing authorisation. This entails conducting expensive and time-consuming clinical trials with patients. Such comparative efficacy trials are required by the European Medicines Agency (EMA) in Europe and in most cases by the Food and Drug Administration (FDA) in the US, which cover significant markets for biosimilar products.

In recent years, amidst improvements in scientific understanding of biological drugs and growing experience with these products, there has been increased debate about the need for comparative efficacy trials in the biosimilars regulatory approval process.

In May 2021, the UK’s Medicines and Healthcare Regulatory Authority (MHRA) updated its guidance to state that a comparative efficacy trial may not be necessary in most cases if sound scientific rationale supports this approach. That move is designed to help biosimilar manufacturers satisfy regulatory requirements on the basis of comparative analytical and functional data of the biosimilar product and what is known from clinical experience and quality attributes of the reference product. This is then supported by data from a confirmatory pharmacokinetic (PK) trial usually in healthy volunteers, which already forms part of the regulatory requirements.

In April 2022, the World Health Organization (WHO) took a similar stance – it said a comparative efficacy trial would not be needed if sufficient evidence of biosimilarity can be drawn from other parts of the comparability exercise, such as analytical and functional studies alongside knowledge regarding immunogenicity, which could be understood from the reference product. This guidance from the WHO is a useful indicator to regulators but is not binding.

In the US, the law allows the FDA to waiver studies they consider unnecessary, and it has granted waivers for some less complex biosimilars, such as filgrastim, pegfilgrastim, and insulin, but not to other more complex biosimilars, such as monoclonal antibodies.

Yet, the MHRA remains an outlier among the world’s foremost medicines regulators in the position it has taken. Neither the FDA nor the EMA have adopted similar guidance. This means biosimilar manufacturers have derived little practical benefit from the MHRA’s pragmatism – carrying out comparative efficacy trials remains a core component to satisfy regulatory requirements on both sides of the Atlantic, to gain access to the lucrative US and European markets.

At the Festival of Biologics, however, there was talk among delegates that, following an International Pharmaceutical Regulators Programme (IPRP) Biosimilars Working Group workshop in September 2023, the EMA may be about to shift its position, with new papers addressing biosimilarity requirements reportedly anticipated in the coming months. The EMA confirmed to Out-Law that future regulatory considerations regarding the need for comparative clinical efficacy trials to support biosimilars was the theme of the meeting.

In a statement, the EMA said: “Part of the meeting was public and was followed by a closed session among international regulators. EMA and the other regulatory authorities are now evaluating the outcome of this conference, considering if and to what extent comparative efficacy trials will be needed for every biosimilar development. This is expected to be reflected in future guidance documents.”

The science supports a move away from requiring comparative efficacy trials in most cases. In fact, several studies have now shown that for biosimilars approved by the EMA and FDA which were found to be highly similar to their reference product in analytical and PK studies, the comparative efficacy trials added no new information of actionable value. Earlier this year, a group of regulatory assessors from EU health authorities looked at the similarity data of seven adalimumab and five bevacizumab biosimilars and found that any minor differences in quality observed were justified by quality data and/or clinical PK data and no comparative efficacy trials were needed.

Removing the requirement for comparative efficacy trials would go a long way to cutting the time and cost involved in bringing new biosimilar products to market in Europe, and elsewhere. It could be the difference between new biosimilar products entering markets and their development being unviable commercially.

Beyond the issue of finance, there are also practical considerations. In the context of so-called ‘orphan’ drugs, for example, the patient population is smaller, so finding candidates to participate in clinical trials for prospective new biosimilars can already prove difficult. Ethical questions also arise if regulatory requirements mandate comparative efficacy trials, but manufacturers are in fact able to demonstrate biosimilarity without undertaking them.

Whilst streamlining the regulatory pathway for biosimilar medicines should facilitate more efficient development and reduce the financial burden on healthcare systems, other changes may also be needed to drive a more sustainable biosimilars market.

To establish biosimilars as the most cost efficient first line biologics, there is also a need to align reimbursement criteria with treatment guidelines and educate clinicians and patients on the availability of biosimilars as an alternative to more expensive biologics they may be used to prescribing and consuming. The EMA’s recent statements on the interchangeability of biosimilars with biologics are welcome in this respect.

At the World Biosimilars Congress, a range of conference speakers and delegates reiterated calls for changes to be made to national procurement practices to safeguard future availability of biosimilars, for the benefit of all stakeholders.

Currently, some countries’ health systems operate ‘winner takes all’ tenders that can shut unsuccessful bidders out of the market. Industry is keen to see multi-winner tenders become more common – these would help encourage investment in the development of new biosimilars and in turn offer better choice and access to innovative new treatments. There are also calls for successful bids to be determined in accordance with factors beyond price – to take into account a bidders’ ESG credentials and their ability to provide continuity of supply, for example.

Further, even after reimbursement, many biologic medicines are failing to make it into the hands of patients. Looking at rheumatoid arthritis treatment with biologics, data presented at the conference sourced from the Decision Resources Group, now Clarivate, showed that around only 13% of patients diagnosed with rheumatoid arthritis are receiving treatment with a biologic, despite them being eligible and having a reimbursed product available. In many cases, there is a relatively small window of opportunity for giving effective treatment to patients early in the progression of disease. For instance, patients with rheumatoid arthritis can achieve complete remission if treated early, but that outcome decreases the longer the delay from diagnosis to treatment.

Blockers on accessing new treatments, whether because of time and cost burdens entailed in the regulatory process, or short-termist procurement practices, can have a real impact on patient outcomes – with delayed access more likely to mean patients suffer from debilitating conditions that require more intensive, and costly, care.

With the next wave of biologics facing loss of their product patent in the coming years, this provides opportunities for biosimilars to enter the market and deliver real benefits to patients. But for the 55% of biologics where there is no record of any rival biosimilar medicines in development, changes are needed to make them commercially viable and provide greater patient access to these life-saving and life-changing medicines.

In this context it is good to hear that the EMA and other medicines regulators globally are reviewing their position on the need for comparative efficacy trials. We look to them to make changes, following the MHRA’s lead, and support growth in the biosimilars market.

Pinsent Masons was a sponsor of the Festival of Biologics 2023.