A PHARMACEUTICAL triumph in India has been caught up in an unexpected legal tangle over regulatory concerns, with the innovator company stymieing the launch of the world’s first biosimilar version of a top-selling biological drug to treat breast cancer three weeks ago. It signals the start of a new battle between generic drug manufacturers and originator companies which is expected to be tougher and dirtier than the high-profile patent battles witnessed in the past decade.
On February 5, the Delhi High Court granted the plea of drug multinational Roche to stop the biosimilar version of its blockbuster anti-cancer drug, trastuzumab, developed by Bengaluru-based Biocon Ltd in collaboration with generics giant Mylan of the US. It said it was not sure if the clinical trials were adequate and were in accordance with the Indian government’s pathway for biosimilars laid out in 2012.
Roche’s trastuzumab—it is sold primarily as Herceptin in India along with lesser known brands such as Herclon—acts on a particularly virulent form of breast cancer known as HER2-positive cancer. The biosimilar developed by Biocon was all set for launch in mid-February when the Swiss pharmaceutical giant managed to block its release in India and a large swathe of the developed world through its lawsuit in Delhi. This is a significant case because it makes the Drug Controller General of India (DGCI) the first respondent in the case and challenges the regulator’s approval given to the jointly developed biosimilar.
The Biocon-Mylan drug would have been the world’s first biosimilar for trastuzumab—and somewhat cheaper. According to Biocon, its CANMAb—marketed as Hertrez by Mylan—would have knocked 25 per cent off the cost of Herceptin which now sells at Rs 72,000-Rs 75,000 per dose, down from the initial Rs 1,10, 000 in India. Biocon has priced its vial of 440 mg at Rs 57,500 and a smaller doze of 150 mg at Rs 19,500.
Although Roche had allowed its patents to lapse in 2013, it was unlikely that it would allow more affordable versions of its blockbuster drug, according to industry analysts. Global sales of trastuzumab touched $6.75 billion in 2013 and although sales in India are limited, it earned a tidy $21 million from patients here.
According to the World Health Organization (WHO), 1.7 million women were diagnosed with breast cancer in 2012, swelling the list of 6.3 million women who had been living with the disease in the previous five years. Since the 2008 estimates, breast cancer incidence has increased by more than 20 per cent, while mortality has risen by 14 per cent. Breast cancer is also the most common cause of cancer death among women (522,000 deaths in 2012) and the most frequently diagnosed cancer among women in 140 of 184 countries worldwide. It now accounts for one in four of all cancers in women.
Trastuzumab is a type of biologic medicine called a monoclonal antibody. These are much more complex to develop than small molecule drugs and as difficult to manufacture consistently (see ‘Medicines of the future’). As such, there is a big difference between generics and biosimilars. Unlike generic medicines, biosimilar are not exact copies of the innovator product and, therefore, not identical in function or safety. Roche also points out that not all patients respond positively to the therapy. Trastuzumab is approved for the treatment of patients with a specific type of breast cancer (HER2-positive) that is seen in about 25 per cent of breast cancer patients.
Domestic reactions
The Roche action may have caught domestic industry offguard, but it is not exactly surprised by the development. “Roche’s move was disappointing considering they had decided not to pursue Indian patents for their breast cancer drug. However, Roche’s actions were not unexpected, given past examples of innovator companies taking all measures to protect their monopoly over their products,” says Biocon chairperson and managing director Kiran Mazumdar-Shaw. She believes that Roche’s current action attempts to restrict communication about this more affordable trastuzumab. “This restriction goes against the interests of breast cancer patients in India. The first order was passed ex parte and we are confident that once the matter is finally heard the court will appreciate our case.”
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| Comments made by originators mimic those that were expressed during the advent of generics decades ago in order to protect their monopoly positions |
— KIRAN MAZUMDAR-SHAW,
CHAIRPERSON AND MANAGING DIRECTOR, BIOCON |
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Justice Manmohan Singh issued an ex parte injunction, which means that he did so without hearing the defendant-companies and, more significantly, the DGCI.
“This is an unusual lawsuit on several fronts,” says Shamnad Basheer, who till recently taught law at West Bengal National University of Juridical Sciences in Kolkata. Firstly, it is not a patent case, since Roche gave up its patent on trastuzumab, but involves an issue of regulatory compliance and effectively challenges the decision of the DGCI in giving an approval.” Therefore, the proper format, he argues, should have been a writ petition against the Government of India directing it to cancel the permission to market and not the civil suit that has been filed.
The case hinges on the data submitted by Biocon on the biosimilar and the extent of its clinical trials. Biosimilars have to show a clinical and efficacy profile that is comparable with the profile of the parent biological in clinical trials. For Biocon, the stakes are high since the court order has barred it from using or even referring to Roche’s data on trastuzumab to sell the jointly developed biosimilar drug.
Roche’s argument
“We have taken action because as the holder of the Herceptin trademark we have a duty to ensure that if a company claims its product is a biosimilar of, or similar to our innovator product trastuzumab, that this really is the case,” explains a Roche spokesperson.
Claudia Schmitt, head of communications for Roche Applied Science, told Down To Earth (DTE): “Biocon and Mylan Inc have claimed in both the media and on their websites that their products are a biosimilar of Herceptin, and more recently Biocon has claimed to provide a ‘world class product’. Yet, based on the limited information in the public domain and results from the unpublished 132 patient study, it is unclear how Biocon and Mylan’s products would fulfil the requirements for biosimilars. Furthermore, by not publishing the results of its studies, the company has denied the medical community the opportunity to judge their claims. We believe patients and physicians have a right to make informed treatment decisions, and that to do this they must have full access to information about products.”
Roche’s complaint appears to centre on the limited number of patients in the Biocon-Mylan trials, whereas trastuzumab “demonstrated its efficacy and safety profile in numerous international trials involving thousands of patients with HER2-positive breast and gastric cancer”.
Biocon, however, rejects any implication of having cut corners. Mazumdar-Shaw says: “Biocon has conducted extensive process development and performed meticulous product characterisation based on state-of-the-art technology and a rigorous scientific approach, in conformance with applicable guidelines. Additionally, a multi-centric clinical trial in India has also been conducted.”
Replying to questions from DTE, she points out that Biocon has been working on trastuzumab since 2006 and has worked in partnership with Mylan since 2009. “It took us approximately seven years to develop this product.” Besides, Biocon, along with other domestic and international pharma companies, including Mylan, was engaged extensively with the Department of Biotechnology and DGCI in formulating the Indian regulatory guidelines for biosimilars. “That said, the development of Biocon’s trastuzumab is aligned with all relevant guidelines,” says Mazumdar-Shaw.
While this may be the case, Roche insists that “thorough clinical trials” are fundamental to patient safety and must be the first priority for all products. Roche’s contention is that since biosimilar monoclonal antibodies are not exact copies of the innovator product, they may not be identical in function or safety. “We believe assurance in patient safety can only be achieved when products have been subject to thorough clinical trial programmes and there are well-regulated processes in place to ensure manufacturing standards are appropriate and market pharmacokinetic data can be accurately captured,” says Schmitt. The implication could be that India’s Guidelines on Similar Biologics laid out in 2012 are not adequate.
The patient safety argument is only to be expected, according to the industry which says casting doubts on the safety and efficacy of biosimilars is a familiar tactic used by innovator companies. As Mazumdar-Shaw points out, “Comments made by originators mimic those that were expressed during the advent of generics decades ago in order to protect their monopoly positions.
There are other aspects to the case that have ruffled feathers in India. Intellectual property analysts, in particular, are looking askance at the ex parte injunction. “It’s absolutely ridiculous that an ex parte injunction was granted by the Delhi High Court without hearing the defendants,” says Basheer. India, according to him, is the only country to grant ex parte injunctions in pharma cases. Pharma patents are highly technical matters and most patent offices, even those in the developed countries, don’t always get it right. Close to 40 per cent of the patent challengers win their cases and that is why courts do not award ex parte injunctions without hearing both parties. He argues that although this is not a patent case, it is still a highly complex and technical matter and an order ought not to have been issued without hearing the defendants.
While Biocon braces itself for the next hearing of the lawsuit on February 28, the case highlights the tough road ahead for biosimilars. For one, the DGCI will have to demonstrate that our pathways are fully compliant with international standards—at least of those prescribed by WHO.
Drug innovator companies are clearly shifting the battleground from patent challenges to regulatory issues because they know the patent applicability threshold is high in India. “As long as Section 3d (of the Indian patents Act) exists and patents can be opposed before the patent office and courts, you can be rest assured the drug companies will find it extremely difficult to get secondary patents in India. So strategically, it makes more sense for them to go after generic drugs on the regulatory front,” predicts Basheer.
So will it be good for patients, specially those suffering cancers and other life-threatening diseases? It will be both good and bad. On the one hand, tighter regulations and scrutiny will ensure that consumers get safer and more effective drugs. However, on the other hand, with the increasing cost of compliance for Indian companies, the prices of domestic drugs will rise as well. “As everyone knows, regulations have been pretty lax and both innovator companies and our Indian companies have benefitted from this. On balance, it’s great that regulations are being tightened,” finds Basheer. So watch out for skirmishes of a new kind in the pharma arena.
| Medicines of the future
Biologics are used to describe medicines derived from living sources. While traditional medicines are chemically synthesised, these are developed from a biological process and are typically composed of large molecules (5,000 to 20,000 atoms), produced from living cells. Chemical drugs, on the other hand, are made up of small molecules.
Manufacturing biologics is extremely complex and pharma experts say even minor differences in manufacturing processes, such as different host cells, cell culture and purification methods, can have a significant impact on such a drug’s safety and effectiveness.
As such, it is not enough to define the product by just its molecular composition. It is also defined by the process through which it is made. However, given the complexity of biologicals and their process of manufacture in which living cells are used to produce the core molecule, the innovator product, too, has inherent variability in each lot.
Biological medicines are the drugs of the future and in the next two years, these will comprise an estimated 48 per cent of the top 100 best-selling drugs, according to US-based nonprofit Washington Policy Center. Biosimilar drugs are structurally similar versions of biological drugs in the market that have to be highly similar, both structurally and clinically, to an original innovator drug.
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