Pharmaceutical companies developing ‘biosimilar’ medicines can avoid carrying out expensive “comparative efficacy studies” when seeking approval to sell those products in the US, the Food and Drugs Administration (FDA) has confirmed.
Biosimilars provide competition to originator biologics, which are drugs that contain active substances derived from biological sources. Unlike small molecule generic medicines where the active ingredient is chemically identical to the originator drug, biosimilars, while highly similar to the originator biologics, are never completely identical to those biologics they are developed with reference to. This scientific reality has had a bearing on the regulatory hurdles biosimilar developers need to clear to obtain marketing authorisation.
Businesses behind biosimilar candidates must evidence ‘biosimilarity’ with the originator product to regulators. In practice, regulators – including the FDA – have typically required for comparative efficacy studies, which are perhaps better referred to as clinical comparability studies, to be carried out to meet this requirement. This entails conducting expensive and time-consuming ‘phase three’ clinical trials with patients.
In the US, the law provides the FDA with a degree of discretion over how it enables biosimilar developers to demonstrate biosimilarity. However, guidance it issued in 2015, while not binding, effectively recognised carrying out clinical comparability studies as a necessary part of that process, with the onus on developers to provide scientific evidence to justify a departure from that approach.
Now, however, in draft new guidance it has issued, the FDA has shifted its position (7-page / 241KB PDF), outlining how biosimilar developers can demonstrate biosimilarity without necessarily having to undertake a clinical comparability study.
According to the FDA, if the comparative analytical assessment (CAA) developers carry out “supports a demonstration that the proposed biosimilar is highly similar to its reference product” then demonstrating biosimilarity may be possible by undertaking an “appropriately designed human pharmacokinetic similarity study and an assessment of immunogenicity” – without the need to also complete a clinical comparability study. It will depend, it said, on whether those other assessments provide data “sufficient to evaluate whether there are clinically meaningful differences between the proposed biosimilar and the reference product in terms of safety, purity, and potency”.
Where the “streamlined approach” is justified, the FDA said the adequacy of the data advanced in support of claims of biosimilarity “would be evaluated based on the totality of the evidence submitted in the biologics license application”.
The FDA has updated its guidance after acknowledging changes in scientific practices over the past 10 years and its own “significant experience” gained in “evaluating data from comparative analytical and clinical studies”.
In July, biosimilar developer Formycon announced it had stopped recruiting patients for a phase three clinical trial in relation to a biosimilar it is developing to compete with the blockbuster cancer drug Keytruda, its pembrolizumab biosimilar FYB206, after receiving positive feedback from the FDA on its plans to “demonstrate the therapeutic comparability of [pembrolizumab biosimilar FYB206] with …Keytrudabased on comprehensive analytical data and data from the [pharmacokinetic] study” it had run in Europe.
In September, academic and entrepreneur Sarfaraz Niazi claimed to have “secured the first-ever FDA acceptance to waive clinical efficacy studies (CESs) for monoclonal antibody biosimilars” for his biosimilar application for the branded drug Stelara. Also known as ustekinumab, Stelara is a biologic product used to treat a range of conditions such as Crohn’s disease and psoriasis.
The FDA’s updated position aligns with that of other major medicines regulators in Europe.
In 2021, the Medicines and Healthcare Regulatory Authority (MHRA) in the UK updated its guidance to recognise that conducting comparative efficacy studies will not always be necessary if there are other sound scientific ways of demonstrating biosimilarity. That move allows biosimilar manufacturers to rely more heavily on comparative analytical and functional data, as well as what is known from clinical experience and quality attributes of the originator biologics product, to meet their regulatory requirements.
As Pinsent Masons reported in April this year, the European Medicines Agency (EMA) has also said that biosimilar manufacturers may not always need to undertake clinical comparability studies to obtain marketing authorisation for their products. The EMA has backed “a tailored approach” to demonstrating biosimilarity, stating that clinical comparability studies may not be necessary for “biosimilars that can be thoroughly characterised and have shown high similarity on an analytical and in vitro pharmacology level”. However, the EMA’s comments were set out in a draft ‘reflections’ paper, which does not constitute formal guidance.
“The MHRA has led the way in this field, demonstrating the scientifically rigorous and innovative approaches for which it is known,” said Catherine Drew of Pinsent Masons
“The latest guidance from the FDA indicates that international regulatory alignment is proceeding at pace, which can only be a good thing for originators and biosimilar manufacturers alike. It can help with reducing the regulatory burden when seeking to bring medicinal products to market in multiple geographical markets. The MHRA has its own ‘international recognition procedure’ wherein it is able to take into account the expertise and decision-making of trusted regulatory partners, including the EMA and FDA,” she said.
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