When Stanley N. Cohen of Stanford and Herbert W. Boyer obtained a US patent in 1980 for the process for joining and replicating DNA from different species (popularly known as recombinant technology) little they realized that they are ushering the era of Recombinant revolution for the entry of biologics as potential drugs or organic food products. Amidst controversy and tension over the commercialization of academic biology and genetic engineering, recombinant technology opened the floodgates of biologics in the food, agriculture, drug and pharmaceutical market. Recognition of recombinant chymosin as safe enzyme, finds the use of first recombinant product in cheese making in 1990. This in fact replaced the traditional process for obtaining chymosin from rennet derived from the fourth stomach of milk-fed calves. First medical product of gene-splicing technology and the recombinant DNA drug product—human insulin ‘Humulin’ of Eli Lilly & Co entered the drug market thirty five years ago replacing the insulin for human use harvested from slaughterhouse animals, usually porcine or bovine.
Entry of Biologics patents in India
In India, in January 2001, in Dimminaco A.G. vs Controller of Patents, Kolkata High court, ruled that ‘the controller erred himself in law by holding that merely because the end product contains a live virus, the process involved in bringing out the end product is not an invention.’ and sent back this application for reconsideration. The patent was eventually granted. The instant patent application was for a process for preparation of a live vaccine against infectious Bursitis Virus which infects poultry. This judgement in fact cleared the hurdle for obtaining patents in India on microorganism related inventions. By this time many patents relating to biologics were already granted in India. For example patent no. 183925 for penicillin v Acylase,183927 for single chain glycoprotein hormone,183928 for high purity Gamma Interferon,183939 for pure Monospecific polyclonal antibodies of Malarial lactate dehydrogenase used for detection of malaria,184298 for transfer vectors pCBT1 and pCBT4,184437 for producing DEVR protection of mycobacterium tuberculosis and so on.
Era of Biologics monopoly
Capitalizing on this newfound ability of recombinant technology, both industrial and academic institutions went ahead in creation of many more recombinant products during last three decades. Notable recombinant drugs such human growth hormone (HGH, somatotropin), blood clotting factor VIII, hepatitis B vaccine, herceptin and so on established supremacy in drug market. Similarly many transgenic varieties of important agricultural crops such as soy, maize/corn, sorghum, canola, alfalfa and cotton have been developed that incorporated a recombinant gene for herbicide resistance or insect resistance. In India BTcotton commercial success is significant in making India as third largest exporter of cotton. However, strong patent portfolios on these recombinant products kept the biogenic away from denting the biologics market space.
Reasons for slow entry of Biogernics
In last decade even after the expiry of many biologic drug patents biologics copy drug could not make head way in the market. Partially it was due to the fact that making of large molecule biologics required use of living organisms through a complex analytical specialized process. Perhaps, this factor played a significant role in keeping biosimilar market closed for many countries. Since, biologics drugs were not easy to be manufactured the original patent holders faced little competition and the prices of these drugs were set by what market would bear. Another factor which influenced the slow entry of biosimilar was stringent procedure for getting the regulatory approvals. It is not surprising that only two biosimilar drugs Zarixo, [a biosimilar version of Amgen Inc.’s Neupogen,] and Inflectra, [a biosimilar version of Johnson & Johnson/Merck & Co. Inc.’s Remicade] were approved in US. It is noteworthy that the “blocking” patents on these brand biologics had expired, leaving these multibillion dollar free for biosimilar manufactures.
Guidelines for Biological Products in India
The marketing of Biologics/ biosimilar products in India is regulated as per the Drugs and Cosmetics Act, 1940, the Drugs and Cosmetics Rules, 1945 (as amended from time to time) and Rules for the manufacture, use, import, export and storage of hazardous microorganisms/ genetically engineered organisms or cells, 1989 (Rules, 1989) notified under the Environment (Protection) Act, 1986. Various other applicable guidelines were also issue to meet the dug usages standards. These guidelines includes-
- Recombinant DNA Safety Guidelines, 1990.
- Guidelines for generating preclinical and clinical data for rDNA vaccines, diagnotics and other Biologicals, 1999.
- CDSCO guidance for industry, 2008:
- Submission of Clinical Trial Application for Evaluating Safety and Efficacy
- Requirement for permission of New Drug Approval
- Post approval changes in Biological products: Quality, Safety and Efficacy
- Preparation of Quality Information for Drug Submission for New Drug
Approval: Biotechnological/Biological Products
- Guidelines and Handbook for Institutional Biosafety Committees (IBSCs), 2011.
Role of Central Drugs Standard Control Organization (CDSCO)
In India Central Drugs Standard Control Organization (CDSCO) is the national regulatory authority with four zonal offices of the Central Drug Standard Control Organization at Mumbai, Kolkata, Chennai, and Ghaziabad to evaluate safety, efficacy and quality of drugs in the country. These Zonal Offices work in close collaboration with the State Drug Control Administration to ensure securing uniform enforcement of the Drug Act and other connected legislations throughout the country. Department of Biotechnology (DBT) through Review Committee on Genetic Manipulation (RCGM) is responsible for overseeing the development and preclinical evaluation of recombinant DNA derived products. Till 2011, organizations which were actively engaged in manufacturing and marketing Similar Biologics in India were seeking approval from RCGM and CDSCO. And these ‘Similar Biologics’ were approved by RCGM and CDSCO using an abbreviated version of the pathway applicable to new drugs on a case by case basis. During this influx period of biosimilar guidelines between 2000 to 2011 , many Biologics/ Biosimilar drug products were eyeing India as destination. Particularly many biologics from abroad for gaining market penetration capabilities in India and likewise Indian biologic manufactures as investors find biosimilar manufacture as a less risky venture. In 2000, a hepatitis B vaccine was the first ‘similar biologic’ to get the approval for marketing in India thus announcing the India capability in biogenerics. This Launching rather signaled entry of India as biosimilar hub.
Similar ‘biological product’ regulatory guidelines of 2012 & 2016
Since there were several such biological similar products under development in India, both regulatory agencies considered the imperative need to publish a clear regulatory pathway outlining the requirements to ensure comparable safety, efficacy and quality of a Similar Biologic to the reference Biologic. Sensitive to the immense potential of Indian Pharma as the potential producer of biologics/biosimilar the draft guidelines to regulate the manufacture, use, import, export and storage of hazardous microorganisms/ genetically engineered organisms or cells were announced at the BIO industry conference in Boston, USA, on 19 June 2012.These guidelines were finalized as ‘Guidelines on Similar Biologics: Regulatory Requirements for Marketing authorization in India 2012’ and were implemented from 15 September 2012. These guidelines were further amended in 2016 and termed as ‘Guidelines on Similar Biologics: Regulatory Requirements for Marketing authorization in India 2016’ and were implemented from August 2016. According to the latest guidelines ‘A Similar Biologic product is that which is similar in terms of quality, safety and efficacy to an approved Reference Biological product based on comparability.’ It was understood that based on demonstration of similarity in the comparative assessment, a Similar Biologic may require reduced preclinical and clinical data package as part of submission for market authorization. These guidelines were published to enable the applicants of biologically similar products to understand and comply with the regulatory requirements for market authorization of Similar Biologics in India.
Biosimilars market is experiencing a growth at an exponential rate. Six out of the top ten selling drugs are biological drugs. . According to pharma reports more than 700 biologics are making progress in the research pipelines of about 250 biopharma companies. No doubt lucrative biologicals market including biosimilar is driving many Indian players into the bandwagon of biosimilar. With Biosimilar insulins have already started revolutionizing the future drug development in the realm of diabetology in India. Biosimilars of Adalimumab, bevacizumab, Etanercept, Rituximab, Peg-Filgrastim , Trastuzumab are expected to hit the market soon. According to one estimate Biosimilar of Humatrope, biosimilar of Eprex, biosimilar of Neupogen, biosimilar of Remicade have already been enjoying a greater market share in Europe than the reference product itself. In India Biocon/Mylan partnership now has conducted global phase III clinical trials for biosimilar of adalimumab, bevacizumab, pegfilgrastim and trastuzumab and Biocon and Mylan are permitted to sell Trastuzumab under their brand names CANMAb and HERTRAZ. Meanwhile, Indian biologic drug maker Intas Pharmaceuticals has launched its ‘similar biologic’ of etanercept (Intacept) in India which is reported to be the 'first biosimilar' of Amgen’s Enbrel (etanercept).At this writing, over 50 Biologics biosimilar have been approved by Central Drug Standard Control Organization for marketing in India against about sixteen in Europe and two in US. All the biosimilar drug makers claimed that they would to be able to reduce the cost of treatment for patients to about half that of the imported reference biologics.
According to India’s national pharma regulator the Central Drugs Standard Control Organization (CDSCO), there are 10 blockbuster biologics with combined annual sales of $60bn that have patents due to expire over the next four years. According to another pharma estimate the proportion of different Biosimilars that reached market are Low Molecular Weight Heparins 44%, Epoetins 19%, HGH 11%, G-CSFs 7%, Interferons 6%, Insulins 5%, Others 8%.The growing clinical, regulatory, and commercial importance of biologics stem from the value of the global biosimilar market which is estimated to hit $35bn mark by the end of 2020. With biosimilar versions of effective but a bit expensive biologic treatments set to unlock major opportunities around the world, does India’s pharma sector and regulatory system have what it takes to repeat its generics success with much more complex Biosimilars? Although the clear answer to this certainly lays in the future yet the Indian biologics drug makers do have the potential to achieve this milestone in biogenerics like they did in generic era. But in view of the recent Delhi High court Judgement in an appeal case between Biocon Vs Roche wherein the court ordered that ‘till further orders, Biocon and Mylan are permitted to sell Trastuzumab under their brand names CANMAb and HERTRAZ, respectively,’ and they were in the meanwhile, asked to maintain accounts with regard to the said products, the biosimilar maker may feel encouraged. We may wait for the outcome of Appeal in Reliance Life sciences vs Roche for selling of biosimilar of Trastuzumab in another case. Finally, one must realize that biologics and Biosimilars are fiercely competitive and biologics do have dominant position to put hurdles in launching of Biosimilars but Indian companies are also inching ahead to gain and repeat the success of generics. Let’s wait and watch who will win or lose this tactical battle. And till than we must admit that both the biologics and biosimilar are necessary for effective healthcare in India.