“A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company.”
However, Biosimilar is very different from the conventional medicine system involving small molecule drugs. Unlike such small molecule drugs, the Biosimilars are complex glycoprotein molecules produced inside living cells under by special manufacturing process optimized to ensure that the Biosimilars are near identical versions of on original biological molecules (called as a “reference product”).
In spite of the biosimilar technology being in the global market since more than two decades and in spite of the fact that the global biosimilars market is expected to shoot beyond $10 billion by 2021 (as per “Biosimilars Global Forecast”), there still remain several legal challenges that the industry stakeholders and the legal authorities have not been able to resolve.
While the major challenges pertain to the approval process of the Biosimilars, few out of several other issues the industry is experiencing revolve around the manufacturing process, comparability with the reference product, adverse events, patentability of biosimilars, labelling, etc. It may also not be wrong to state that the issues remain unresolved or even far from resolution due to the lack of a concrete legal framework clarifying the approval process, requirements of the manufacturing process, parameters used for ascertaining compatibility and interchangeability, labelling, etc. Dealing with each of these issues may give the reader a better insight as to the current situation where lack of legal framework is deterring the pace of Biosimilar entry into the market in full swing
The clinical performance of Biosimilar very much depends on the manufacturing process by which it is produced and therefore clinical studies are required to demonstrate safety and efficacy of the Biosimilar. However, if a company manufacturing a Biosimilar product is required to undertake complete and exhaustive clinical research then there is no cost and time advantage in bringing the Biosimilar to the market, neither to the company and nor to the public. Bringing Biosimilar to the market will be similar to bringing a new drug to the market which is a big deterrent factor to the companies in the business. It is possible that the companies making Biosimilars may choose to make certain manufacturing changes in order to improve the product stability and yield.
Minor changes in the process may sometimes result in drastic difference in the final Biosimilar product and batch-to-batch variability. However, this solely should not be a criterion to judge the efficacy of a Biosimilar since for a Biosimilar approval all what is needed is comparability, interchangeability and demonstration of equal amount of safety, efficacy and quality as of the reference product.
The current Biosimilar Approval Guidelines notified by The Central Drugs Standard Control Organization (CDSCO), India are lacking in any specific guidance on the requirements the Biosimilar manufacturers should follow at the time of implementing their unique manufacturing processes. It may be helpful if there is clarity on what type and level of variations are permissible in the manufacturing processes and the kind of exemptions that are possible. In other words, there is a need of defined and approved limits of variations permissible in the manufacturing process. While it is understandable that it may be difficult to consolidate and articulate manufacturing conditions for each and every Biosimilar that is developed in the future, it may also not be fair to question the manufacturing process employed by the biologic manufacturers who have not been provided any clear guidance under the law as to what standards are to be followed, specially when the Biosimilar product has been demonstrated to be near identical the original reference product. And even if it was possible to establish “sameness” of biologics without clinical trials, the reviewing authorities will never be in a position or equipped to the rigorous scientific comparative assessment that would be otherwise required to conclude the “level of similarity”, without examining trade secret data concerning the manufacturing processes of the innovator, which is otherwise prohibited by law.
While the apparent criteria of approving a Biosimilar product is demonstration of its comparability with the reference product on safety, efficacy and quality, an interchangeable product needs to meet some additional requirements such as it must yield the same clinical result (with negligible risks) as the reference product in a patient. Also, an interchangeable product may be substituted for the reference product without the involvement of the prescriber. However, due to the lack of legislation and regulation, most countries, specially in Europe, currently prohibit pharmacy-level substitution of biosimilars.In the USA, the Food and Drug Administration published draft guidance on interchangeability in January 2017 but, to date, no biosimilars have been approved as interchangeable.In India, the picture is far from being clear and the current set of guidelines in India only discuss
Comparability and not interchangeability which is otherwise will be more beneficial to the public.
While labelling and nomenclature of Biosimilar products have caused significant amount of debate in the industry, it is surprising that the Indian Biosimilar guidelines do not even discuss this issue. Various other Guidelines around the world on Biosimilars have set forth different preferences and prohibitions on the labelling practices. For instance, the WHO guidelines on Biosimilars stipulate that the Biosimilar packet insert must identify biological products as biosimilar, as well as identify the source of clinical data and details of manufacturing process so that the medical practitioner is able to articulate the possibilities of specific adverse reactions. EP and USA have adopted different naming and labelling protocols including naming using international non-proprietary names (INNs) and brand names. The Indian Guidelines not providing any standards for India have led to the companies framing their own standards and protocols which may not be totally incorrect so to say as they may be a mix of standards taken from different countries.
While there is a lot of confusion on patentability of Biosimilar products, it may prima facie appear that the Biosimilar being a near identical product cannot pass the test of novelty and obviousness. However, the same may hold true only for the Biosimilar product per se or may be not is the Biosimilar product was produced from a much different manufacturing process resulting into unique characteristics or added advantages of the Biosimilar. The efficacy, quality and safety parameters are functional and utility characteristics and are usually not used to judge the patentability of the subject matter.
Two different subject matters can have same function, efficacy and safety level and therefore may qualify for two different patents. It is also possible that the biosimilar products may not fall within the scope of a claim covering the reference product because the biosimilar compound may vary from the molecule or sequence claimed in the reference product patents.
Further, there several other IPRs can be generated over Biosimilars, such as over the formulation, dosages, compositions, processes, etc. These possibilities may give opportunities to both the innovators and generics to develop their patent portfolios around the drug, however, can also result in evergreening practice if misused by the Innovators.
While there are several other pertinent issues around Biosimilar products, the current article has endeavored to provide a glimpse of a few major ones, especially from the Indian context. There had been only one dispute in India around Biosimilars, i.e. on Roche’s product Herceptin and the same is pending before the Delhi High Court as on date. However, with the pace at which the biosimilars are replacing the conventional medicinal system, the time is not far when the disputes around Biosimilars will increase in India we well. The adoption of a robust legal framework is what is needed at this stage so that the disputes as and when they arise can be resolved in the most efficient and judicious manner.
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