Biosimilars are highly similar, affordable versions of original biologic medicines, offering access for over two decades. They represent a significant leap in medical treatment, offering therapies for several diseases.
While the initial biosimilar regulatory guidelines were reflective of the scientific and technical development existent at that time, the recent advancements in scientific developments, have made the existing regulatory framework for biosimilars redundant.
To keep pace with rapid scientific progress, India’s biosimilar regulatory framework must adapt, ensuring guidelines prioritise both safety and affordability, while maintaining efficacy and accessibility.
Generic vs biosimilar
Both generics and biosimilars drugs provide availability of affordable therapeutics.
However, when a first generic version of a small molecule enters the market, it is priced 90-95% cheaper than the originator’s price. This cost reduction is largely due to the regulatory framework governing the generic marketing approval process.
A generic does not need to repeat the safety and efficacy trials. They only need to show that the version is equivalent to the already approved product. Unlike generics, a biosimilar manufacturer must conduct comparative efficacy trials to demonstrate the biosimilar’s safety and efficacy.
These studies make biosimilar development a cost and time intensive process, with animal studies and comparative clinical trials accounting for more than 50% of the development cost. Consequently, biosimilars cannot achieve the 90-95% of the price erosion always as seen in case of generics.
Questionable science
The regulatory assumption for biosimilar development is underpinned on the premise that any deviation from the reference product will have implications on the safety and efficacy of the product.
Hence the biosimilar developer must prove the safety and efficacy through animal studies and comparative clinical efficacy studies. While biosimilar development involves rigorous batch comparisons, studies have shown that the reference product also shows batch to batch variations. Sometimes these variations exceed those that would be allowed between the originator products and biosimilar candidates , but none of these differences affects clinical safety and efficacy.
Similarly, animal studies are now considered redundant for obtaining toxicological and pharmacological data on biosimilars. Based on the evidence, regulators like the US FDA, UK MHRA and EMA among others have moved away from animal toxicology studies in favour of alternative testing methods.
The perception of comparative efficacy studies as a gold standard among clinicians and regulators was shaped largely by early uncertainties surrounding biosimilar development. However, these theoretical concerns have now been outweighed by scientific considerations.
A review of the approved biosimilars in the EU and USA revealed that these studies provide no new meaningful information in the approval process. From a statistical point of view also, clinical efficacy studies need to be of a sufficient size and duration to detect meaningful differences if any exist. Thus, for example while evaluating a biosimilar cancer drug a large patient cohort (nearly 25000) is required to reveal any meaningful difference. More fundamentally, it has been well established that clinical efficacy endpoints are less sensitive measures of biosimilarity as compared to biophysical, biochemical and functional assays.
The lack of sensitivity of clinical trials and the growing recognition of PK/PD clinical studies as being more valuable is being increasingly recognised by regulatory agencies. The UK MHRA Guidelines acknowledges that “each biosimilar development needs to be evaluated on a case-by-case basis” but explicitly proposes that “in most cases a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach”.
This clearly shows that comparative efficacy trials are an exception rather than a rule. Similarly WHO guidelines on biosimilars too concur with the UK guideline and state: “A comparative efficacy trial may not be necessary if sufficient evidence of biosimilarity can be inferred from other parts of the comparability exercise”. The underlying scientific rational behind both these guidelines is that they take into account the evolution of both analytical technology and production methods. Current US FDA guidance outlines how biosimilars may be approved based on PK and PD biomarker data without clinical testing requirements. Similarly, EMA opened a position paper last year eliciting comments on revisiting the need for clinical efficacy trials for biosimilar development.
As manufacturing technologies have matured, and production methods have become highly comparable, it is an opportune time to replace these insensitive and unethical studies by more sensitive tests and smaller PK/PD studies, which would contribute to a more scientific approach in biosimilar development.
Misconceptions
India along with other Asian countries were pioneers in biosimilar development. The first biosimilar in India was approved in 2000, much ahead of the European Medicine Agency and USFDA approvals. The EMA approved the first biosimilar in 2006, while USFDA approved it only in March 2015.
Another misconception is regarding the side effects of a biosimilar. It is important not to misconstrue that biosimilars are inherently more prone to adverse side effects. Occurrence of side effects or adverse reactions in case of biosimilar is not limited to biosimilars alone but has been generally observed in originator products as well. For example, effects like intraocular inflammation and reticular vasculitis are an inherent class-specific risk associated with anti-VEGF drug.
When a biosimilar matches the reference product in terms of potency, glycosylation profile and impurity level – it is reasonable to conclude that safety and efficacy profile are similar to the originator’s product. The development of biosimilars involves rigorous comparisons with the reference products to assess consistency over batches. Robust comparative analytical studies ensure that the biosimilars remain within the acceptable range of variability and exhibit no meaningful differences in efficacy and safety relative to the reference biologics. Both the developer and regulator must ensure that the biosimilar must match all the critical quality attributes, rigorous batch to batch consistency and robust comparative analytical studies to remove and residual uncertainty between the biosimilar and the reference product.
Several biosimilars have been used over a decade and post marketing studies have shown that the safety profiles of biosimilars is comparable to that of reference products.
More than two decades of more than 100 biosimilar approvals and real-world use spanning close to 15 million treatment days, accumulated data suggests that thorough physicochemical and in-vitro comparisons against the reference product reliably establishes the safety and efficacy of biosimilar product.
Way forward
The introduction of biosimilars in the market has always been met with resistance from entities that want to keep the price of the drugs high.
Originators employ various tactics including litigations, product hopping, regulatory or product misinformation to deter biosimilars from entering the market. For example, in India Roche has filed several cases against biosimilars, raising artificial concerns on safety and efficacy as compared to the originator product.
Reforming the biosimilar marketing approval guidelines to do away with animal toxicology studies and make the clinical efficacy studies as an exception rather than a rule in line with UK and WHO biosimilar guidelines could result in the considerable reduction of costs and time for the biosimilar development without compromising the safety and efficacy. This savings in the cost of development is expected to reduce the prices of biosimilars substantially, a near replication of generic price reduction in India.
Chetali Rao and KM Gopakumar work as senior researchers and legal advisors with the Third World Network (TWN). Chetali Rao can be reached at chetali.rao@gmail.com. KM Gopakumar can be reached at kumargopakm@gmail.com
Published – March 31, 2025 07:08 pm IST
