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 In order to reduce the animal studies during the development of biosimilar drugs, the Central Drugs Standard Control Organisation (CDSCO) has proposed steps to determine whether a biosimilar should undergo in vivo animal toxicity studies and criteria under which such animal studies could be waived off.
In the draft revised guidelines on biosimilars with updated requirements for marketing authorisations in the country, the CDSCO says, "A stepwise approach should be applied during nonclinical development to evaluate the similarity of the similar biologic and its selected RBP. At first, in vitro studies should be conducted and then a decision made on whether or not additional in vivo animal studies are required."
After elaborating the methods to conduct in vitro studies, including the general principles applicable for such studies, the drug regulator says that on the basis of the totality of quality and nonclinical in vitro data available and the extent to which there is residual uncertainty about the similarity of a similar biologic and its Reference Biological Product (RBP), it is at the discretion of licensing authority to waive or not to waive a requirement for additional nonclinical in vivo animal studies.
The decision of the licensing authority on whether or not to require animal studies should be arrived at taking into account of certain factors.
"If the quality comparability exercise and the nonclinical in vitro studies have shown high similarity and the level of residual uncertainty is considered acceptable to move to the clinical phase of the similarity exercise then an additional in vivo animal study is not considered necessary," says the draft guideline.
If a need is identified to reduce remaining uncertainties concerning the similarity (including drug safety) of a similar biologic and its RBP before the initiation of clinical evaluations then additional in vivo animal studies may be considered, if a relevant animal model is available.
However, this should only occur when it is expected that such studies would provide relevant additional information and if the needed additional information cannot be obtained using an alternative approach that does not involve in vivo animal studies.
Waiver of animal toxicity studies for a biosimilar product may be considered if certain criteria are met, including that the candidate biosimilar is expressed in an established expression system or the amino acid sequence of the product is identical to that of the RBP. The strength, route of administration, human dose, and indications proposed for similar biologics are the same as the RBP.
If the applicant uses appropriate analytical methodologies to detect and characterise the differences between the biosimilar and the RBP, characterise, identify and quantify product-related impurities between the two, and similar data, the regulator may consider waiver of animal studies. In case, the proposed dosage form and formulation of a similar biologic is different from the Reference biologics, the applicant needs to provide the rationale for this difference.
However, in certain scenarios, the waiver of toxicity study may not be granted for a biosimilar, said the regulator. This include scenarios in which if there are differences that cannot be ruled out as having no safety impact, or when a novel excipient is being used for the first time for biological products specific to the claimed route of administration, or if the applicant plans to do a clinical study using a route of administration that is not tested or approved by regulatory authorities for the RBP.
Similarly, if the planned human dose of the drug is higher than the one approved for the RBP, the toxicity study will not be waived off.
It may be noted that in the existing guideline, published in 2016, the strategy towards animal studies were not specified this elaborate, and meagerly mentioned that, "in vivo evaluation of biological/pharmacodynamic activity may be dispensable if in vitro assays are available, which are known to reliably reflect the clinical relevant pharmacodynamic activity of the Reference Biologic".
In cases where the in-vitro assays do not reflect the pharmacodynamics, in vivo studies should be performed, as applicable, it added.
The newly revised guideline, which has been prepared by a committee comprising technical subject experts, representatives from National Institute of Biologicals (NIB), Department of Biotechnology (DBT), and representatives from industries involved in manufacturing of similar biologics, has been published by the CDSCO inviting comments from the stakeholders within 30 days of publication.
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