Biologics are biopharmaceutical drugs obtained from a living system or genetically modified organism. Biologics usually contain wellcharacterized proteins as their active substance, derived through modern biotechnological methods such as recombinant DNA technology and large-scale cultures of living cells. New versions of the originally innovated and patented biologics are called follow-on biologics, similar biologics or biosimilars. In the context of a biosimilar, the biologic to which it is similar to is called a reference biologic. The biosimilar can only be launched in the market after the patent on reference biologic expires.
Compared to traditional chemical drugs, even a minor change in the conditions, formulation or the processes of a similar biologic as compared to its reference product can dramatically affect the safety and efficacy of the therapeutic molecule. According to Hans Sauer of the Biotechnology Industry Organization, “biologics are inherently much more difficult to copy and to replicate than small-molecule products.” Biologics are unstable, having high molecular complexity, and their preferred delivery is intravenous.
The regulatory process for biosimilars in India has been on a case by case basis, using an abbreviated version of the pathway followed for small molecules, involving the Drug Controller General’s office under the Central Drugs Standard Control Organization (CDSCO) and Department of Biotechnology (DBT). The CDSCO evaluated safety, efficacy and quality aspects while the DBT was responsible for overseeing the development and preclinical evaluation of recombinant biologics. India has now launched the Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India, which have been developed by the CDSCO and the DBT and provide a regulatory pathway for a similar biologic claiming to be similar to an already-authorized reference biologic. In addition to the DCGI/CDSCO and DBT, the draft biosimilar guidelines have added the Genetic Engineering Appraisal Committee under the Ministry of Environment and Forests as a statutory body for review and approval of activities involving large scale use of genetically engineered organisms.
The guidelines have been designed to create a pathway for local and international companies to invest in biosimilar development and manufacturing in India, with increasing access to medicine, international investment and reducing government expenditure on drugs in mind.
The term “similar biologic” is defined by the guidelines as a biological product or drug produced by genetic engineering and claimed to be “similar” in terms of safety, efficacy and quality to a reference biologic, which has been granted a marketing authorization in India by the DCGI on the basis of a complete dossier, and with a history of safe use in India.
Similar biologics can only be developed against an authorized reference biologic that has been approved using a complete data package in India, or, in case the reference biologic is not authorized in India, it should have been licensed and marketed for at least four years with significant safety and efficacy data. The biosimilar products for which the reference biologic is not authorized in India is to be considered on a case by case basis if such products have been granted marketing approval in countries with well established regulatory systems and have been in wider use for a minimum of four years.
The guidelines lay down in great details the requirements for quality, preclinical studies and clinical trials for the similar biologics. The demonstration of similarity depends upon detailed and comprehensive product characterization, preclinical and clinical studies carried out in comparison with the reference biologic. A reduction in data requirements may be possible for preclinical and/or clinical components of the development program by demonstration of structural and functional comparability of product, i.e. similarity of the similar biologic to the authorized reference biologic, and the consistency in production process, which may vary depending on the characteristics of the already authorized reference biologic. However, if any significant differences in safety, efficacy and quality studies are identified, a more extensive preclinical and clinical evaluation will be required and the product will not qualify as a similar biologic.
Jonathan DJ Loeb, a partner in Dechert’s Silicon Valley office, suggests that worldwide approval for similar biologics can be hastened if the approval is first sought in India. The same data package, as well as long-term pharmacovigilance data (gathered from sales in India) and required post-marketing studies, can be used as the basis for approval in other jurisdictions as soon as the market exclusivity period expires there. This would not only improve the likelihood of world-wide approval based on the long history of safety in India, but also generate revenue from sales in India, which can be subsequently channelled towards the regulatory package for other jurisdictions. The low cost of development and manufacture of biosimilars, a huge market, lack of market exclusivity and a science driven biosimilar guidelines to ensure that biosimilar drugs approved in India are of good quality and meet global standards, would combine to create a conducive environment for a boom in biosimilar industry in India.
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