India’s bio-pharmaceutical companies are divided in their response to the recently issued draft US Food and Drug Administration (FDA) guidelines on 'Immunogenicity Assessment for Therapeutic Protein Products'.
While a section of the industry is upbeat and viewed the guidelines as a set of systematic norms which would in every way keep poor quality companies at bay, the Association of Biotechnology Led Enterprises (ABLE) Biosimilars Committee has called for better clarity and understanding on the interpretation of norms with regard to biosimilars.
The guidelines are intended to assist manufacturers and clinical investigators involved in the development of therapeutic protein products for human use. It recommends adoption of a risk-based approach to evaluate the immune responses to therapeutic proteins that may adversely affect their safety and efficacy, according to US FDA which is seeking comments from the industry before April 30, 2013.
Therapeutic proteins are manufactured using microbial fermentation route.
Indian companies engaged in the development of therapeutic protein products include Biocon, Panacea Biotech, Serum Institute of India, Reliance Life Sciences, Shantha Biotechniques, Indian Immunologicals, Bharat Biotech, Cadila Health Care, Intervet India and Intas Biopharma.
US FDA draft guidelines for immunogenicity of therapeutic proteins are quite comprehensive and by and large consistent with the approach followed by most advanced biotech companies like Biocon. “We are committed to developing high quality, safe and efficacious therapeutic proteins for global markets and comprehensive assessment of immunogenicity is an integral part of that commitment,” said Abhijit Barve, president, R&D, Biocon Ltd.
However, Dr Cyrus Karkaria, president – Biotech Division, Lupin Ltd and member of ABLE's Committee for Biosimilar, Clinical Research and Advocacy stated that the guideline did not mention anything about biosimilars, which will comprise a major portion of the approved biologics on the market in the coming decade. Therefore, biosimilar manufacturers specifically need more clarity on five aspects:
Firstly, the guideline speaks of ‘Risk-based Immunogenicity Assessment’, yet for products historically known to be non-immunogenic like for instance GCSF (Granulocyte colony-stimulating factor) which can well be categorized under low risk. It is not clear what reprieve could a biosimilar manufacturer expect from the regulators, given that a protein is non-immunogenic by its inherent nature.
Secondly, there is no mention on how to link immunogenicity observed in animals to that for humans. If this link is not provided, a manufacturer may not know to what extent of additional immunogenicity study should be under taken on humans if the drug exhibits higher immunogenicity in animals and vice-versa.
Thirdly, for biosimilar manufacturers, there is no clarity whether one should do immunogenicity study on ‘naïve’ patients who are first time users of the drug or after a wash out period. If the latter is acceptable then the regulatory authority needs to specify the immunogenic memory?
Fourthly, for proving ‘Interchangeability’, the patients would be switched from innovator’s drug to a biosimilar and vice-versa. The guideline does not address the duration that patients should be exposed to Biosimilar and Reference drug before and after making a switch and the duration of the washout period, pointed out Dr. Karkaria.
The therapeutic proteins are used for diseases covering from anemia, cancer, cardiology cystic fibrosis, diabetes, haemophilia, Gaucher’s disease and stroke.
Academia researchers point out that production of therapeutic proteins is a time-consuming and complicated process. Considerable efforts are made to identify protein molecules determining its gene sequence. Therefore guidelines are mandated.
Any given approach to assess immunogenicity is determined on a case-by-case basis and should take into consideration the risk assessment, stated US FDA in its guidelines for Therapeutic Protein Products.