Biotechnological advancements have gifted pharmaceutical industries biological products which are emerging as potential future therapeutics. As an outcome of the human genome project, several genes of therapeutic interest have been identified and transformed into medicines.  This along with the advances in the fermentation technology has made it possible to produce therapeutic proteins, or so called biologics.

Diverse categories of biologics are coming into the market which range from monoclonal antibodies, growth hormones and cytokines to vaccines. However, several innovator biologics have recently reached/are reaching their patent expiration which has incited several pharmaceutical industries to jump into the race of biosimilars manufacturing owing to a large amount of expected return on investment due to their higher market potential. The rising intellectual property concerns and huge market protection of $ 76 billion by 2020 denotes a huge market boom of biosimilar products in near future.

As USFDA in its recent biosimilar draft guidance of May-2014 defined, a biosimilar product is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that there are “no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.” All regulatory bodies require, though differently, that these requirements be fulfilled by the biosimilar product through extensive physicochemical and biological tests in vitro and in vivo.

What makes biological compounds unique is that they are obtained from living cells and hence possess molecular complexity and heterogeneity making manufacturing in a reproducible manner difficult. Small deviations in the manufacturing process may raise quality concerns and even minute changes encountered during batch to batch manufacturing lead to varying quality. This holds true for all biosimilars whether being manufactured at different volumes, equipment, plants or countries. Ultimately, this forces us to consider each biosimilar as a separate biologic proving the notion “biosimilars are similar but not identical to reference biological products” a factual one.

Different regulatory bodies and approval pathways of biosimilars
As explained earlier, ideally each biosimilar product is a separate biological entity. However, to treat them separately is impracticality on account of a large sum of money and time inputs required for the development and approval process. Hence, different countries have their own regulatory framework for manufacturing/marketing biosimilars in requirements for physicochemical analysis, preclinical studies and clinical evaluation. Even the definition and naming of biosimilar products is different in different regulations i.e. Similar Biological Medicinal Product (EU), Biosimilar (USA, Taiwan and Korea), Similar Biologic (India), Similar Biological Product –SBP (Singapore), Non-innovator Biological Product (China) and Follow-on Biologic (Japan) to quote a few.

Depending on the regulations, countries can be divided in regulated, semi-regulated and non-regulated countries. USA and EU countries make the regulated markets. Biosimilars are established for more than eight years in EU countries with about 14 approved biosimilars. There was no separate pathway for biosimilars approval in USA initially which turned out to be no biosimilar product approved in USA. However, recent draft guidance issued by USFDA has now defined the biosimilar approval pathway. India, along with the countries like Singapore, China, Korea, Philippines, Taiwan, Malaysia and even Japan, falls under the category of semi-regulated countries which have a framework adopted from EU, US and/or WHO guidelines. Other countries which do not have their own rigid regulatory framework are nonregulated markets. Differences in the regulatory guidelines of major countries are depicted in Table 1. Several other countries like Philippines, Taiwan, Indonesia, Thailand etc. are evolving their regulatory framework for control of biosimilars.

The regulatory differences between countries account for the need of strategies and means by which biopharmaceutical companies can manufacture biosimilars to meet their criteria. Companies should consider several factors before setting up manufacturing plants and/or marketing units for biosimilars in such countries (See Table 2).

Need for global standards: What are the challenges?
EMEA has first issued guidelines defining biosimilar approval pathway which has been adopted and/modified by several countries. Guidelines issued by WHO are almost similar to EMEA guidelines. However, similarities in the guidelines are just like the tip of the iceberg in water. And there is an intense need for streamlining the standards.

Furthermore, companies are suspending the development of biosimilars at clinical stages, hesitating to conduct single and global development programs due to the changes in the IP rights, evolving guidelines (many countries are changing their guidelines abruptly as the understanding and definitions of biosimilarity, interchangeability, substitution etc. evolving), unknown patient-to-patient variability between the biosimilar and reference biologic in Phase I/II studies, large variability encountered in PK/PD studies, safety, efficacy and immunogenicity profiles due to manufacturing quality, uncertainty in Phase III trials (whether to consider the Phase III trials as non-inferiority trials or bioequivalence trials) etc. Many countries require that the reference biologic be approved /licensed/ marketed in the country.

So, it becomes very difficult for the companies to target other countries using same biosimilar, as it would raise the questions due to large number of quality comparisons to be established, number of different toxicology and clinical studies to be performed. High development costs force companies to focus first on developed nations with large market size which will delay/limit development of biosimilars for countries with smaller markets. All of this mandates that the biosimilar guidelines evolve and be streamlined as soon as possible. Till then, there is no option rather to consider the specified pathways of each country.  

Streamlining will surely take time; but once done, there will be a step-wise approach for biosimilar authorization/marketing in several countries. Thorough and defined quality characterization tests, non-clinical studies, extent of clinical studies and standards for reference biologics will be specified which will help extrapolation of data from one indication to other approved indications of innovator product. It will even resolve the differences in nomenclature that may cause multiple revisions of clinical trials and marketing authorization applications for consistency with guidelines and regulations.

Optimizing development plan: What should be done?
In view of the wide variability in guidelines and hurdles in streamlining the regulations worldwide, it is difficult to optimize the development plans for biosimilars as compared to innovator biologics, as not all countries have issued the final guidelines. As the regulations are continuously evolving, companies need to optimize their biosimilar development plan and by frequent reevaluations as new information becomes available. One should look for information industry resources, quality publications, however, not keeping themselves limited to industry associations, companies should also go for biological products resources like BIO-Biotechnology Industry Organization, Alliance for Safe Biologic Medicine (IFPMA-International Federation of Pharmaceutical Manufacturers and Associations, ISPE-International Society for Pharmaceutical Engineering, ABLE-Association of Biotechnology Led Enterprises, BioSpectrum Asia, DIA-Drug Information Association etc.  Also, experts of the companies need to read available regulatory guidelines from time to time and see for amendments and not relying on other resources assuming their information to be complete and true. All quality, safety and efficacy parameters from all regulations and guidelines need to be reviewed and understanding of country-by-country differences should be used to prepare the development plan. The information on reference product to be used for each country where the biosimilar is to be marketed as the reference product may not be approved in each country for the same indication.

Conclusion
Though adopted and evolved from similar background, a large amount of discrepancies exist between regulatory guidelines being followed in different countries. There is a mandate for harmonizing the guidelines at global level which will ease the biosimilars product manufacturing in several countries enabling the companies to globally market their biosimilar products. There is a potential opportunity for biopharmaceutical companies for low-cost manufacturing in semi-regulated and non-regulated markets. Companies need to review and follow all quality, safety and efficacy parameters of different countries and revising the development plan for biosimilars from time to time addressing the country-by-country differences. India is gearing up with the companies that are adopting guidelines more in line with EU and USA. Soon, more and more Indian companies will get through the rigid approval framework including refined requirements of non-clinical and clinical evaluations; India is going to make its stance as a provider of low-cost biosimilar products.