Legal protection for IP rights in the science and technology domain is a topic of long debate around the world, particularly regarding those technologies that generate economic growth, are beneficial to society and improve patient lifestyle. Releasing novel drugs is a challenge in terms of revenue generation, as well as meeting regulatory standards and improving the safety and efficacy profile. In an era of advanced skills and innovation, the term ‘biopharmaceutical’ is used broadly for pharmaceutical medicines produced with the help of biotechnology and has demonstrated shifts in research areas for specialised medicines and emerging markets. Based on surveys by various market researchers, it is predicted that the global biopharmaceuticals market will exceed $20 billion in 2020, with biosimilars emerging as one of the fastest-growing sectors in the market. An increasing number of patents set to expire in upcoming years, along with clearer regulatory processes and increasing demand for cost-effective treatment, is a major driving force, as these products offer approximately between a 10% and 30% reduction in cost compared with their parent products. In the past, biotech was interpreted for its applications for breeding animals and crop improvement and was understood as part of the R&D activities for generating medical and agricultural products (eg, cloning and tissue culture). However, a biologic is a complex preparation in the form of a drug or vaccine developed from living organisms, in contrast to conventional pharmaceuticals that are manufactured by chemical synthesis.
Biopharmaceuticals are produced from biological sources and are considerably complex in their nature. They are generally used for treating various diseases (eg, vaccines, blood components, allergenics, cells and somatic cells), for gene therapy and tissues used in transplants, recombinant therapeutic proteins and living cells. Proteins, antibodies and nucleic acids (eg, DNA, RNA and antisense nucleotides) are used for therapeutic or in vivo diagnostic treatments, which are usually products of a native or non-engineered biological resource. In general, these products are obtained via laborious experiments on life forms – one outcome of which is the production of biosimilars. Biosimilars are biologic products with a medicinal value modelled after another pre-existing product. Accordingly, these are highly similar in structure, biological activity, efficacy, safety and immunogenicity profile to another already approved biopharmaceutical, known as the ‘reference product’. On the one hand, generic medicines traditionally contain the same active pharmaceutical ingredient or ingredients as the originally approved reference product for which the marketing approval was obtained. On the other hand, biosimilars do not contain active ingredients identical to the originally approved biological product, but instead contain similar active ingredients. Therefore, a biosimilar cannot be regarded as a generic version of an already approved biological product, since the natural variability and complex manufacturing process of biologics does not allow for an exact replication of the original product per se.
Challenges to producing biosimilars in India
In India, biopharmaceuticals and generic medicines are considered to be drugs and are covered under the purview of Drugs and Cosmetics Act 1940. The Central Drugs Standard Control Organisation (CDSCO) is the responsible regulatory authority for obtaining approval and maintaining regulations. In general, rules regarding clinical trials are much more stringent for biosimilars than those applied to generics. Biosimilars are also regulated for various processes (eg, clinical trials, import and manufacture) and are governed primarily by:
- the Drugs and Cosmetics Act (1940; and Rules 1945);
- the New Drugs and Clinical Trial Rules (2019);
- the Guidelines on Similar Biologics;
- Regulatory Requirements for Marketing Authorisation in India (2016);
- the Rules for Manufacture, Use, Import, Export and Storage of Hazardous Microorganisms and Genetically Engineered Organisms or Cells (1989);
- the Environment (Protection) Act (1986);
- the Regulations and Guidelines on Biosafety of Recombinant DNA Research and Biocontainment (2017);
- the Guidelines for Generating Pre-clinical and Clinical Data for rDNA Vaccines, Diagnostics and other Biologicals (1999);
- the CDSCO Guidance for the Industry (2008);
- the Guidelines and Handbook for Institutional Biosafety Committee (2011); and
- the Guidance Document for Industry (regarding the submission of stability data and related documents for review and expert opinion for granting post-approval changes in shelf life of recombinant biotherapeutic products and therapeutic monoclonal antibodies published by the National Institute of Biologicals (2016)).
It is necessary to follow the regulations for manufacturing and clinical trials and to obtain marketing approval for biosimilars. Regarding patenting these inventions, biosimilars are not exempt from fulfilling the patentability criteria of being novel, which involves inventive step and industrial application. However, patenting biosimilars sometimes becomes complicated, as the nature of biosimilars requires that they should be as close as possible to products that are already on the market and accordingly examined critically for patenting. In general, biologic medicines and biosimilars are patentable in India subject to certain exceptions governed under Section 3 of the Patents Act (for biosimilar patents Subclauses (b)-(e), (h)-(j) and (p) are of particular relevance). In particular, biologics comprising living organisms that are not naturally occurring and are developed by humans may be patented; however, if comprising a living organism occurring in nature falls under Section 3(c), which precludes patentability of the mere discovery of a scientific principle or formulation of an abstract theory (or discovery of any living thing or non-living substances occurring in nature). In addition, Section 3(d) prohibits patent protection to:
- the mere discovery of a new form of a known substance if it does not result in the enhancement of the known efficacy of that substance; or
- the mere discovery of any new property or use for a known substance.
Although, some parameters for interpreting enhanced efficacy for pharmaceuticals have emerged from court decisions, in terms of biopharmaceuticals (particularly biosimilar inventions) the nuances remain unknown.
India’s first biosimilar, a vaccine for hepatitis B, was marketed and approved in 2000. With the continued growth in legislation and regulation, the biosimilar market has continued to grow. However, manufacturing biosimilars remains challenging for pharmaceutical companies. A survey reveals that approximately 70 biosimilar products have been approved in India and more than 25 have been developed there since 2000. Further, it has also been predicted that India will be the sixth largest market for pharmaceuticals by the end of 2020.
Although Indian companies are known for producing generic pharmaceutical drugs, many companies are now moving into the global biosimilars market. According to the Associated Chambers of Commerce of India’s 2017 Report, biosimilars amount to $2.2 billion of the $32 billion Indian pharmaceutical market – and is expected to achieve a growth rate of approximately 30% compound annual growth. An excellent example of the partnership of global pharmaceutical firms in agreement with an Indian pharmaceutical company can be found when Swiss-based Roche entered into an agreement with Emcure for Herceptin, a biosimilar used for human epidermal growth factor 2 and in cases of positive metastatic breast and gastric cancer. The drug was later marketed by Emcure in India under the brand name ‘Biceltis’. In another example, Mylan, a global giant with a large generics portfolio, entered into partnership with Bangalore-based biopharmaceutical company, Biocon. Trastuzumab, a biosimilar created by the joint efforts of both the companies to reduce febrile neutropenia during chemotherapy, was approved by the US Food and Drug Administration in 2018 and was the first biosimilar produced by an Indian company to be approved in the United States.
Similar to the emerging complexities regarding patenting biologics and biosimilars, the judicial scenario in India is also developing with its own complexities. Roche and Genentech Inc manufactured a breast cancer drug, Trastuzumab (Herceptin), and eventually imported and marketed it in India. After the lapse of the Indian patent, two drugs were simultaneously launched by Biocon and Mylan under the names of CANMAb and Hertraz. Pursuant to this, Roche filed a case against the Drug Controller General of India, which is primarily responsible for issuing marketing authorisation for drugs before the Delhi High Court. Roche argued for seeking to restrain the sales of Biocon’s and Mylan’s biosimilars, claiming that the approval did not meet the standard laid down in the guidelines for similar biologics.
In April 2016 the single bench of the Delhi High Court ruled in favour of Roche and held that marketing approvals were not in line with the guidelines. However, in view of general public interest and easy access to cost-effective medicines, the court allowed the manufacturing, marketing and advertising of the Biocon and Mylan products to continue and instructed the biosimilar tag be removed. Pursuant to this, in March 2017, a Division Bench at Delhi High Court passed an interim order allowing Biocon and Mylan to market their biosimilars for two additional indications: early breast cancer and metastatic gastric cancer. Prior to this, they had permission for only metastatic breast cancer. Subsequently, Roche moved to the Supreme Court of India and filed a special leave petition to restrain from marketing the biosimilars for these additional indications, but later voluntarily withdrew the petition.
In the Roche judgment, the Delhi High Court held that the predecessor to the Biosimilar Guidelines published in 2012 were enforceable in Roche Products (India) Pvt Ltd v Drugs Controller General of India (MIPR 2016 (2) 217). The court further held that the guidelines were in the nature of directions issued by the government and as long as the guidelines were not in contradiction but merely in addition to already existing rules and regulations, the guidelines will have legal validity. Even though Roche was in the context of the previous version of the Biosimilar Guidelines, the same principle might also apply to the current Biosimilar Guidelines.
Despite the successful development and marketing of some biosimilars by Indian companies, research and development in this area will continue to face challenges regarding the development biologics and biosimilars. In contrast to generics – which are similar rather than identical to the branded drug – biosimilars are much more complex and expensive to manufacture. Further, contrary to the generics industry, biosimilars are also subject to stringent clinical timelines clearly defining regulatory procedures for large-scale, comprehensive clinical programmes establishing the safety and efficacy for treatment of indicated disorders. The novelty of the biologic and biosimilar development process makes it difficult for new companies to enter this space. Considering an example of other pharmaceutical companies in India, Dr Reddy’s Laboratories, Cipla, Lupin and Aurobindo are also manufacturing biosimilars, some of which are approved for marketing. It is expected that more Indian pharmaceutical companies will have the capabilities and resources to produce biosimilar products. Accordingly, stable and clear regulatory and legislative guidelines are currently expected by the industry.
In general, pharmaceutical products take a long time to get from inception to commercialisation with rigorous research efforts. There is a shift in the focus of the pharmaceutical industry in India for developing conventional pharmaceuticals to biopharmaceutical products and novel processes for obtaining the same. It has been observed that despite the additional time and effort required for development and infrastructure for research work, as well as the revamping of mergers and expansions, it is increasing to meet the needs of the biologics.
Certain emerging technologies (eg, augmented and virtual reality, intelligent interfaces and experiential marketing) could help to reduce the time required to bring a biopharmaceutical product to market and minimise the process for designing molecules. Biopharmaceutical companies also appear to be changing and monitoring innovation by implementing different systems and adopting technologies such as blockchain and artificial intelligence, so that results regarding product quality can be obtained in real time. With the biopharmaceutical industry experiencing growth in recent years, complex new therapies have also been discovered. Further, advances in areas like recombinant DNA and hybridoma technology, as well as gene and cell therapies, have propelled biopharmaceuticals forwards. An exciting time lies ahead, promising innovation in biopharmaceutical evolution and breakthroughs in life-changing and life-saving drugs like we have never seen before.
Article by Rajeev Kumar and Pankaj Musyuni
This article first appeared in IAM Life Sciences: Key issues for senior life sciences executives 2020, a supplement to IAM, published by Law Business Research – IP Division