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Info Service on Health Issues (Jan23/01) Delhi, 4 January (Chetali Rao and K M Gopakumar) – In a major development US President Joe Biden has signed the FDA Modernization Act 2.0, which allows the country’s Food and Drug Administration to do away with animal testing for the purposes of drug and biological product applications. This is a clear endorsement on the growing scientific traction against animal testing for biosimilars and has the potential to reduce biosimilar development costs. Summarizing it “authorizes the use of certain alternatives to animal testing, including cell-based assays and computer models, to obtain an exemption from the Food and Drug Administration to investigate the safety and effectivness of a drug. It also removes a requirement to use animal studies as a part of the process to obtain a license for a biological product that is biosimilar or interchangeable with another biological product.” Biosimilar and Requirement of Animal Studies Biotherapeutics are large, complex molecules that are manufactured through biotechnology in living cells. Unlike the generic version of the small molecules, which are exact copies of the originator’s molecule, biosimilars are not identical to the originator’s biotherapeutic. A biosimilar is “highly similar” to a branded biotherapeutic, which is often referred to as the “reference product.” Since the biological products are manufactured from living organisms, they inherently contain many slight variations between various batches manufactured over time. These inherent variations may occur naturally during the manufacturing process in the reference product (mostly the originator product), biosimilars and interchangeable biosimilar products. Hence for regulatory approval, a biosimilar manufacturer needs to show that the product is highly similar compared to the reference product to support a demonstration of biosimilarity. In most countries, biosimilar regulatory approval requires a comparative clinical efficacy trial to prove the safety and efficacy of the biosimilar drug. In addition, many countries require the assessment of non-clinical animal studies prior to the start of clinical studies. These regulatory requirements make the marketing approval of biosimilar a resource and time intensive activity. In the latest WHO Guidelines issued in April 2022, the World Health Organization waived the comparative clinical efficacy trial requirement, but they were ineffectual on their stand on the elimination of animal studies as part of biosimilar marketing approval. The Guidelines state: that: “Based on the totality of quality and nonclinical in vitro data available and the extent to which there is residual uncertainty about the similarity of a biosimilar and its reference product, it is at the discretion of the involved NRA (national regulatory authority) to waive or not to waive a requirement for additional nonclinical in vivo animal studies”. This change in the US legislation a few months after the revised WHO Guidelines is thus a stand against the ambivalence of WHO. Aligning itself with the growing demands from the scientific community to do away with animal studies and comparative clinical efficacy trials, the United Kingdom’s Medical and Healthcare products Regulatory Agency (MHRA) shifted its regulatory perspective and came out with clear recommendations on removing the need for both animal studies and comparative clinical efficacy trials for biosimilar approval. According to the MHRA Guidelines, “No in vivo studies from animals are requested as these are not relevant for showing comparability between a biosimilar candidate and its RP: this includes pharmacodynamic studies, kinetic studies and toxicity studies.” Similarly Health Canada states that in vivo toxicology studies (animal studies) are generally not needed. Since the introduction of the biosimilar guidelines in 2006, the European Medicines Agency (EMA) has also slowly moved away from conducting animal testing and replacing them with in vitro assays for biosimilar approval. It should not be surprising that EMA too will come out with a definitive statement now, with the US FDA’s stand on removing animal toxicity studies for biosimilar approval. The need for removing animal studies for biosimilar approval is based on scientific underpinnings on the soundness of animal models to predict toxicity in humans. One of the most important issues regarding animal testing for biosimilars is that many animal studies use animal species which lack many binding receptors that humans have for drugs to target. In the absence of clear guidelines based on scientific evidence, biosimilar manufacturers had to spruce up toxicology studies with minimal meaningful relevance, conducting irrelevant testing in animal species which lacked the relevant receptors. Where humanized or genetically modified animal species are used, these are generally considered to be less sensitive in demonstrating differences in the tested products. Furthermore, the method by which animal toxicology studies are carried out makes them less relevant. Generally, animal testing protocols require administering a higher dose to induce a toxic response; however, within this dose range, the responses are not expected to be linear, making it impossible to differentiate between a biosimilar and its reference product. With the recent patent expiries on monoclonal antibodies (mABs), the new biosimilar approvals are mainly focused on the field of mABs related to oncology and inflammatory disorders. A working group that was formed to gather data on the drivers for conducting animal studies concluded that the conduct of in vivo studies was driven mostly by the concerns of the regulatory and the ethical committees, rather than being driven by scientific insights. Apart from the ethical concerns on unnecessary animal testing, these studies add time and cost while adding little benefit in providing information on the safety and efficacy of biosimilars. A detailed review of over 100 approved biosimilar products in the US and the European Union, found that the pre-clinical animal studies did not provide any pivotal data for the approval process. In vivo animal studies of biosimilars have added little evidence to provide clinically relevant information for biosimilar development. On the contrary, it has been suggested that in vitro studies are more likely to detect meaningful differences between the biosimilar and the reference product. It has also been suggested that use of in vitro testing in silico tests, organoids, organ-on-chip technologies and computer modelling, can help to weed out drugs with a potential of causing adverse events in humans, which in turn will enable more predictive scientific methods. WHO’s Reluctance WHO’s current stand on leaving the requirement for animal testing to the discretion of the National Regulatory Authorities (NRAs) may cause significant confusion and inordinate delays in the approval of biosimilars, especially in developing countries including Egypt, India, Malaysia which require extensive animal toxicology studies for approvals. The WHO Biosimilar Guidelines provide a guiding principle for approval and licensing of biosimilar products globally and hence its advice will be incoherent with the growing advances in biologics regulatory science on the removal of animal testing for biosimilars. After allowing a waiver of comparative clinical efficacy trials, it is time for WHO to embrace the change on obviating animal toxicology studies. This will help to reduce the time and cost for biosimilar manufacture, and enable efficiency gains in making biosimilars affordable. Reducing such time- and cost-intensive testing will not only be scientifically driven but would also help in increasing biosimilars affordability and accessibility, especially in developing countries. The crucial question is whether WHO will shake off its stand on animal studies to promote the right to science and health or adhere to its current ambivalent stand on animal studies.
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