Bioethics vis-à-vis Biosimilars

NamritaKochhar NityaSharma

With India moving from strength to strength in establishment of biosimilars as the current and next step of affordable healthcare, the need of the hour is to understand the regulatory guidelines and their implementation as per current requirements...

- Namrita Kochhar & Nitya Sharma

The term “bioethics” was first coined in 1971 to signify the combination of biological sciences with humanistic knowledge. However, now it can be annotated as the application of ethics to the field of medicine and healthcare. The area of bioethics entails a vast span of concerns ranging from difficult private decisions in respect to clinical settings to the much talked about controversies surrounding stem cell research to implications of reproductive technologies and further broader concerns which include international human subject research, public policy in healthcare and allocation of scarce resources. Bioethics is thus the resultant controversy that results from the advancement of medicine or technology thus rendering the term to hold a fluid connotation. Bioethics brings to the fore fundamental issues and values arising from basic human rights such as the right to life and health, bodily integrity etc.

Usually bioethics as a notion entails discussion amongst experts from a wide range of disciplines – legal, philosophical, theological, nursing, medicine etc. However, the whole world woke up to discussions on bioethics in medicine in 1997 as the sheep Dolly took her first breath. The ethical issues with reproductive cloning included genetic modification and damage, health risks to the mother and the foetus, putting at risk the life contained within the embryo and the commodification of human life countered with the benefits and advancement of medical technology resulting from ‘Somatic Cell Nuclear Transfer’ thus resulting in a veritable plethora of debates.

The increasing need for medicinal drugs vis-à-vis the right of manufacturers i.e., to see a return of profit from their heavy investment in research and development, is a recurrent topic for discussion. It is usually seen that invention in healthcare is driven by the economy rather than the beneficent goal of public healthcare. This continuous endeavor for cost-effective medication to meet public requirement graduated from the era of generics to the epoch of biosimilars.

As defined by the European Medicines Agency “A similar biological medicinal product, also known as a biosimilar, is a product that is similar to a biological medicine that has already been authorized, the so-called ‘reference medicinal product’.”1 Simply put, a biosimilar is essentially a generic version of a biologic drug. Biologics broadly refer to substances produced within/extracted from/synthesized from the cells of living organisms, whether plant, animal or microorganism. Thus, a biopharmaceutical is markedly different from a chemically synthesized pharmaceutical. Biologics are different in their origin from chemically synthesized drugs in such a manner that affects their manufacture, their cost, their administration, their efficacy and safety. As they are derived from proteins, biologics are significantly larger in size, consisting of a chain of amino acids bonded together to form a polypeptide thus resulting in a heavier and more complex structure. Therefore, biologics are more sensitive to the process of manufacture as the method of manufacture of a biopharmaceutical is intricate. A brief overview of the manufacturing process is shown below:

Gene of Interest is extracted and isolated from its natural source

The said gene is incorporated into a vector/ expression vector.
Expression vector containing the gene

Genetically Modified Organism containing the protein of interest which is then purified before storage

Bioethics brings to the fore fundamental issues and values arising from basic human rights such as the right to life and health, bodily integrity etc.

In view of the above, it is clear that biosimilars are near reproductions of the reference product, but unlike generics are not identical to the innovator product. Biosimilars exhibit greater variability in the end-product and challenges remain to identify these differences so as to assess whether the end-biosimilar-product meets the requirements of safety and efficacy. It is common knowledge that biological substances are susceptible to natural degradation, whether as a result of the process of manufacture or even storage thus resulting in increased impurities and even increased immunogenicity. It has been repeatedly seen that despite extensive characterization and product development studies as well as extensive pharmacovigilance programs, biosimilar drugs either failed to exhibit adequate potency at the clinical trial stage or when launched, exhibited dire side-effects. Given the expected differences, regulatory authorities have outlined robust data requirements to demonstrate similarity.

The key issue of Bioethics comes into play when despite the above, Biosimilars, across most jurisdictions, may obtain marketing approval on the basis of a ‘reduced’ pre-clinical and clinical trial package as they claim to be similar to a reference product. In order to establish the appropriate regulatory requirements for the same and to ensure the safety and quality of the drug, India went a step ahead from generics and adopted the all-encompassing CDSCO Guidelines on Similar Biologics, Regulatory Requirements for Marketing Authorization in India, 2012, wherein the requirements of product characterization, in laboratory testing, pre-clinical and clinical studies of a biosimilar have been detailed.2 The same have now been replaced with the 2016 guidelines effective from August 15, 2016.It is a testament to India’s desire to continuously adapt and ensure the availability of drugs to the public at a reasonable price as well as to ensure the safety of patients that the 2016 Guidelines provide more strict regulatory and quality compliance. Amongst others, the Guidelines have made the following changes:

  • A comparison of the molecular structure of active substance in the Similar Biologic and the Reference Biologic which would be regulated on the basis of Critical Quality Attributes i.e., (clinical safety and efficacy) and Key Quality Attributes i.e., process and the product consistency;
  • Defined the number of patients to be treated in Phases III and IV to be a minimum of 300 if pre-approval studies have been conducted for more than 100 years;
  • Additional safety data may be collected through a pre-defined single arm study of around 200 evaluable patients and compared to the data of the Reference product as part of the Post Marketing Study.

At this stage, it is pertinent to highlight that India’s guidelines for similar biologics are on par with International Guidelines3 and have demonstrated their effectiveness on numerous occasions as India has approximately 66 biosimilars in the market. Although the efficacy of certain biosimilars is currently being challenged before the Hon’ble Delhi High Court4, the adequacy or the implementation of the biosimilar guidelines is not in question. It is seen that India is making headway, in leaps and bounds, towards the establishment of biosimilars as the current and the next step of affordable healthcare.

The growing market for biosimilars offers huge potential for companies involved in manufacture, research and development. The need of the hour is to understand the regulatory guidelines and their implementation as per the current requirements. With time, the regulatory guidelines will continue to evolve as the companies gain more experience and new biosimilars keep entering the market. Biotechnological medicines are well on their way to becoming an important part of the healthcare scenario in India and awareness about the deviations between biosimilars and reference products will act as guidance for correct prescription and safety of patients.

1. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000125.jsp.
2. The guidelines provide for detailed studies on the quality and safety of the biosimilar product. The guidelines further specify the need and requirement of sequential comparative testing of the biosimilar, comparative quality studies between the similar biologic and the reference biologic as well as head-to-head characterization studies. The guidelines also provide for pharmacovigilance plans and post marketing studies to ensure the safety and potency of the biosimilar drug.
3. WHO Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs) 2009, Guidelines on Similar Biological Medicinal Products, 2014, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Guidance for Industry, 2015, Quality Considerations in Demonstrating Biosimilarity of a therapeutic Protein Product to a Referece Product, Guidance for Industry, 2015.
4. CS(OS) 355/2014 F. Hoffman La. Roche &Ors. v. The Drugs Controller General of India &Ors, and CS(OS) 3284/2015 M/s Genentech Inc. &Ors v. The Drugs Controller General of India &Ors.

Disclaimer – The views expressed in this article are the personal views of the author and are purely informative in nature.

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