The Current Landscape For Developing Biosimilars In India

This article was created from the author's presentation at the 2018 Bioprocessing Asia conference, with Cytiva as principal sponsor. The BioProcessing Asia Conference series was created to provide a platform to advance the contribution of bioprocessing sciences towards the development and manufacture of affordable biopharmaceutical products in Asia.

The lucrative patents for many top-selling biologics will expire in the next couple of years, opening up opportunities for the introduction of a wide range of biosimilars. These products are defined as complex biotherapeutic molecules that show similarity to their reference products, in terms of quality, safety, and efficacy. In the emerging market of India, a mature biosimilar manufacturing ecosystem and regulatory environment have led the way to considerable growth in the country’s biosimilar market, where over 25 biosimilars have been approved and marketed.1 As it moves toward a promising future, it is important to gain an overview of the current regulatory and clinical expectations in India for biosimilar products.

Revised Guidelines For Biosimilars In India

The national regulatory body for Indian pharmaceuticals consists of four organizations. They are:

• Institutional Biosafety Committee (IBSC) – Completes initial review of applications to be recommended to RCGM and ensures biosafety onsite; also responsible for training personnel on biosafety and organizing healthy monitoring programs for lab personnel
• Review Committee for Generic Manipulation (RCGM) – Responsible for authorizing the conduct of R&D and approval of preclinical studies
• Genetic Engineering Appraisal Committee (GEAC) – Reviews activities involving large scale use of genetically-modified organisms and their products
• Central Drugs Standard Control Organization (CDSCO) – Monitors product safety and efficacy and is responsible for clinical manufacturing and market approval for drugs

In 2012, India’s Central Drugs Standard Control Organization (CDSCO) released new guidance for biosimilar developers. These guidelines were later revised and updated in 2016 in consultation with stakeholders from various industry associations and scientific organizations.2 Summaries of the changes, which begin with section 6.1, are as follows:

6.1 Selection Of Reference Biologic

The 2012 guideline stated reference biologics (RB) must be “licensed and widely marketed for four years post-approval in the country where the innovator product was approved with a well-established regulatory framework,” However, the updated guideline states if the RB is not marketed in India, it can be imported from any ICH country (i.e. EU, USA, Japan, Canada, and Switzerland) “for developing the similar biologic for quality, preclinical, and clinical comparability.”

6.2 Manufacturing Process

In addition to renaming this section from “Fermented Process Development” to “Manufacturing Process” to align with global terms, the update also included a requirement to include “a complete description of the manufacturing process from development and characterization of cell banks, stability of clone, cell culture/fermentation, harvest, excipients, formulation, purification, primary packaging interactions (if different form the RB), etc. and the consequences on product characteristics.” Previously, the inclusion of the media components used for cell growth was not required, as it was considered confidential information.

For upstream process development (6.2.2), details of upstream process kinetics from “a representative batch” are now required “from consistency batches.” This means companies must report the process kinetics data indicating cell growth, product formation, pH, temperature, dissolved oxygen, major nutrient consumption, and agitation rate from three batches of reproducible fermentation data at pilot scale (batch size adequate to give enough purified product to generate preclinical data). This is to verify protein yield and its consistency apart from demonstrating overall reproducibility and scalability.

6.3 Quality Based Considerations For Similar Biologics

The updated guideline changed the word “calibrated” to “validated” in the following sentence: “The methods used to measure quality attributes for batch release, stability studies and in- process controls should be validated in accordance with ICH guidelines (ICHQ2⁷,Q5C⁸,Q6B⁹), as appropriate.” Typical validation characteristics to be considered (as mentioned in ICH guidelines and USP guidelines) include accuracy; precision; specificity; detection limit; quantitation limit; linearity; and range.

Finally, this sentence about acceptance limits was added to the 2016 guideline: “Acceptance limits should be set based on RB data and data from a sufficient number of batches from preclinical or clinical batches, which must be in line with international norms.” Without it, the guideline left an opportunity for variability in limits among manufacturers.

6.4 Quality Comparability Study

In the 2012 guideline, the following sentence in this section did not mention key quality attributes: “From the perspective of establishing Similarity, quality attributes of a Similar Biologic have been considered in two categories; Critical Quality Attributes (CQA) and Key Quality Attributes (KQA).” There was also no segregation of the attributes in the original guideline, whereas the 2016 version separates the impact of critical quality attributes and key quality attributes.

The quality attributes that have a direct impact on the clinical safety or efficacy are covered under a section for CQAs, where it is noted that they “must be controlled within limits that need to be established based on the RB.” The KQAs are defined as those quality attributes “not known to impact clinical safety and efficacy but are considered relevant from a product and process consistency perspective.” While the KQAs must necessarily be controlled within acceptable limits, it may be acceptable to have slight differences in comparison to the RB. Check boxes for quality comparability exercise of CQAs and KQAs are now well defined under Annexure II of the current guideline in terms of what data is expected to be submitted. This is bound to increase the overall timeline as well as the cost of developing a similar biologic (SB). However, the resulting data would be more acceptable for claiming biosimilarity.

7.3 Immune Responses In Animals

The updated guideline states applicants may now “submit parallel applications to RCGM and the office of DCG (I) seeking approval to conduct clinical trial.” This helps save regulatory review time as previous applicants had to wait for the RCGM to review and approve the toxicity study reports before proceeding with DCGI filing to seek clinical trial approval. In fact, the DCGI office had already started accepting parallel applications beginning in August 2016 (prior to the release of the current guideline), for which they had issued a separate notification.

In regard to what should occur “if the pharmacologically relevant animal species is not available for doing repeat dose toxicity studies and has been appropriately justified,” the 2012 guideline required studies be undertaken in two species: one rodent and one non-rodent. However, more consideration has now been given on the species differences as part of selection criteria, as there could be molecules for specific indications where a non-rodent (e.g. rabbit) would be the pharmacologically relevant animal species rather than a rodent (e.g. rat/mouse). Because of this, the current guideline states that, in such scenarios, one can do the study only in rabbits (the pharmacologically relevant animal species) and justify the same to RCGM while seeking approval.

8 Data Requirements for Clinical Trial Application

The 2012 guideline stated, “The quality data submitted should establish comparability of SB manufactured at clinical stage against RB”. As commented under subsection 6.4, CQAs and KQAs are now defined. Therefore, companies will have to ensure that quality data meets the current requirements before applying for clinical trial approval.

In addition, the 2012 guideline did not provide an indication of the number of patients for a Phase 3 study. Rather, it offered that a sample size should have statistical rationale. The Indian Good Clinical Practice guideline and the draft guideline from CDSCO titled “Approval of CTs and New drugs” released in July 2011 states, “If the drug is already approved/marketed in other countries, Phase 3 data should generally be obtained on at least 100 patients primarily to confirm the efficacy and safety of the drug in Indian patients when used as recommended in the product monograph for the claims made.” With SB being classified as “new drugs” under the D&C Act, companies were exercising the option of designing Phase 3 protocols with the sample size over 100 evaluable patients in the test and reference arms put together. As per the current guideline, the number of evaluable patients on the test arm itself cannot be less than 100.

10.3 Post Marketing Studies (Phase IV Study)

A single arm study of generally, more than 200 evaluable patients, compared to historical data of the RB needs to be conducted with primary endpoint as “safety” and secondary endpoint as “efficacy and immunogenicity.” The Phase IV protocol should be submitted along with the marketing authorization application for approval. If immunogenicity has already been evaluated during clinical studies, then it does not be done as part of Phase IV. The study should be completed preferably within two years of the marketing permission/manufacturing license unless otherwise justified.

Understanding India’s biosimilar market is a critical aspect of successful development in an area where this is continuously evolving international guidelines. Due to the market’s complexities, it may be valuable to work with a consultant or even partner with a company who has experience before entering India’s increasingly competitive biosimilar industry.

1. Generics and Biosimilars Initiative. (2018, February 15th). ‘Similar Biologics’ approved and marketed in India. http://www.gabionline.net/Biosimilars/General/Similar-biologics-approved-and-marketed-in-India  
2. World Health Organization. (2019, April 25th). Similar biotherapeutic products.https://www.who.int/biologicals/biotherapeutics/WHO_TRS_1004_web_Annex_2.pdf?ua=1

Ms. Ankita Bhargava is a Senior Research Fellow at the Department of Chemical Engineering, Indian Institute of Technology in Delhi, India. Her previous roles included technical assistant at Biosafety Safety Support Unit, Regional Centre for Biotechnology, Delhi, India and research fellow in at the Central Board of Secondary Education (CBSE), Delhi, India.  She has written a book chapter titled Development and Commercialization of Biosimilars in India: Current Regulatory & Clinical Experience in “Biosimilars: Regulatory, Clinical and Biopharmaceutical Development” (published by Springer). Other review articles related to biosimilars regulatory guidelines worldwide are scheduled to be  published in the near future. She has a master’s degree in the field of biotechnology from Amity University in Noida, India. Her total experience includes seven years in the areas of project management, R&D, administration, and event management.