Advancements in the biotechnology have presented pharmaceutical manufacturing industries biotherapeutics which are promising as potential future therapeutics. Diverse categories of biotherapeutics are coming into the market which range from monoclonal antibodies, growth hormones and cytokines to vaccines. Present topic will cover the future prospects and challenges to the biotherapeutics.
Biotherapeutics or biological products are generally produced using living cells or organisms (recombinant DNA technology, controlled gene expression and antibody technologies). It may be manufactured using biotechnology derived from natural sources or produced synthetically. Recombinant hormones, vaccines, monoclonal antibody based products, growth factors, blood products and advanced technology products (gene and cell therapy biological products) are few of the biotherapeutics.
According to definition of the PHS (Public health service) act of USFDA, biological products are defined as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesised polypeptide), or analogous product which are applicable to the prevention, treatment, or cure of a disease or condition of human beings. Proteins are classified as drugs as well as biologics in USFDA but proteins are regulated as a biological product, except any chemically synthesised polypeptide, under the BPCI act.
The generic version of biologics are known as biosimilars in Europe, Similar biologics in India, follow-on Pharmaceutical in USA and Japan, subsequent entry biologics in Canada, and biocomparables in Mexico. The origin of the terminology lies in the loss of patent protection of first generation innovator biologics in last decades. Biologics are at least 1000 times larger than conventional drugs or generic drugs in size containing hundreds of amino acids joined by peptide bonds to form a polypeptide. It is very difficult to establish reproducibility for biosimilars whereas reproducibility can be easily achieved by generics or small molecules conventional drugs. Biologics, biosimilars and generics are needed to exhibit comparability, biosimilarity, and bioequivalence respectively. The non-medical switching is not allowed in biologics and biosimilars whereas it is allowed in generics. Biopharmaceutical productions methods are more complex than chemical production methods so production cost automatically goes higher than generic counterparts. Although the goals are same — to treat the disease—biotherapeutics and generics differ substantially in ways that might affect innovation, safety, costs, clinical adoption, patient access, and pricing.
The stable Biotherapeutics consist of Primary (amino acid sequence) and Secondary structures (a-helix and ß-sheets) which are folded to form 3D-Tertritary structures that is converted into quaternary structure. The biological activity can be attributed to glycosylation and sialylation.
The characterisation remains the challenge for biotherapeutics due to larger size and structural complexity. A typical biotherapeutics production involves following steps:
The methods of biotherapeutics characterisation are divided into quality, safety and efficacy of product which requires clearance by regulatory body and further comparability exercise. There is a significant improvement in formulation of biotherapeutics and characterisation of the products due to recent guidelines on the International Conference on Harmonisation Q8 on pharmaceutical development and the roll-out of the Quality by Design and Process Analytical Technology, comparability of biotechnological /biological Products subject to changes in their Manufacturing process Q5E and quality of biotechnological products: stability testing of biotechnological / biological products Q5C. There are methods for characterisation of biotherapeutics as mentioned in the table.
Reference product biologics and their biosimilars are very important treatment options for multiple diseases and have the potential to expand the possibilities for our patients. Switching studies evaluate all the parameters change with exposure to interchangeable product with reference one. The main purpose of this study is to demonstrate the risk in terms of safety or diminished biological activity between interchangeable molecules. As per FDA a product is interchangeable with biosimilars, if the manufacturer proves that it is expected to produce same clinical result in same patient only is product considered as safe. Comparability studies are performed between a biosimilars and its reference product, but studies between one biosimilars and another are not done; two separate biosimilars may have been compared to the same reference but not between themselves.
European Medicine Agency (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 is just the tip of the iceberg, 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 programmes 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. evolve), 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. Until then, there is no option other than 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 authorisation /marketing in several countries. Thorough and defined quality characterisation 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 also resolve the differences in nomenclature that may cause multiple revisions of clinical trials and marketing authorisation applications for consistency with guidelines and regulations.
A number of key biologics are going off patent by 2020, thus there is a huge potential for Biosimilar version of these medicines. The cumulative market potential may reach beyond EUR 100 billion in next five years. There are at least 50 distinct biosimilars in pipeline and will be delivered successfully in next five years. Biosimilars can bring improvements to patient outcomes by providing more treatment options to physicians and reducing the need for rationing.
Though adopted and evolved from similar background, a large amount of discrepancies exists between regulatory guidelines being followed in different countries. There is a mandate for harmonising 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 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.