Biosimilar Drugs: First Indian Foot Print In An Uncharted Frontier

A homegrown Indian biologic manufacturer is now about to leave behind its first foot-print, with a ‘made in India’ biosimilar drug, in one of the largest pharma market of the world. This was indeed an uncharted frontier, and a dream to realize for any Indian bio-pharma player.                                                      

On March 28, 2016, by a Press Release, Bengaluru based Biocon Ltd., one of the premier biopharmaceutical companies in India, announced that the Ministry of Health, Labour and Welfare (MHLW) of Japan has approved its biosimilar Insulin Glargine in a prefilled disposable pen. The product is a biosimilar version of Sanofi’s blockbuster insulin brand – ‘Lantus’.

The Company claims that Glargine is a high quality, yet an affordable priced product, as it will reportedly cost around 25 percent less than the original biologic brand – Lantus. This ‘made in India’ biosimilar product is expected to be launched in Japan in the Q1 of 2017. Incidentally, Japan is the second largest Glargine market in the world with a value of US$ 144 Million. Biocon will co-market this product with its partner Fujifilm.

Would it be a free run? 

Although it is a very significant and well-deserved achievement of Biocon, but its entry with this biosimilar drug in Japan’s Lantus market, nevertheless, does not seem to be free from tough competition. This is because, in 2015, both Lilly and Boehringer Ingelheim also obtained Japanese regulatory approval for their respective biosimilar versions of Lantus. In the same year, both these companies also gained regulatory approval from the US-FDA, and the European Medicine Agency (EMA) for their respective products.

Moreover, Sanofi’s longer acting version of Lantus – Lantus XR, or Toujeo, to treat both Type 1 and Type 2 diabetes, has already been approved in Japan, which needs to be injected less, expectedly making it more convenient to patients.

Key barriers to a biosimilar drug's success: 

Such barriers, as I shall briefly outline below, help sustaining monopoly of the original biologic even after patent expiry, discourage investments in innovation in search of biosimilars, and adversely impacts access to effective and much less expensive follow-on-biologics to save patients’ precious lives. 

These barriers can be broadly divided in two categories: 

A. Regulatory barriers:

1. Varying non-proprietary names:

A large number of biosimilar drug manufacturers, including insurers and large pharmacy chains believe, just as various global studies have also indicated that varying non-proprietary names for biosimilars, quite different from the original biologic, as required by the drug regulators in the world’s most regulated pharma markets, such as, the United States, Europe, Japan, and Australia, restrict competition in the market for the original biologic brands. 

However, the innovator companies for biologic drugs hold quite different views. For example, Roche (Genentech), a developer of original biologic, reportedly explained that “distinguishable non-proprietary names are in the best interest of patient safety, because they facilitate Pharmacovigilance, and mitigate inadvertent product substitution.”

Even, many other global companies that develop both original biologic and also biosimilar products such as, Amgen, Pfizer and others, also reportedly support the use of ‘distinguishable nonproprietary names’.

That said, the Biosimilars Council of the Generic Pharmaceutical Association argues that consistent non-proprietary naming will ensure robust market formation that ultimately supports patient access, affordability, Pharmacovigilance systems currently in place and allow for unambiguous prescribing, 

2. Substitution or interchangeable with original biologics:

Besides different ‘non-proprietary names’, but arising primarily out of this issue, automatic substitution or interchangeability is not permitted for biosimilar drugs by the drug regulators in the major pharma markets of the world, such as, the United States, Europe and Japan.

The key argument in favor of interchangeability barrier for biosimilar drugs is the fact that the biological drugs, being large protein molecules, can never be exactly replicated. Hence, automatic substitution of original biologic with biosimilar drugs does not arise. This is mainly due to the safety concern that interchangeability between the biosimilars and the original biologic may increase immunogenicity, giving rise to adverse drug reactions. Hence, it would be risky to allow interchangeability of biosimilar drugs, without generating relevant clinical trial data.

On the other hand, the Generic Pharmaceutical Association (GPhA) and the Biosimilars Council, vehemently argue that a biosimilar drug has a lot many other unique identifying characteristics “including a brand name, company name, a lot number and a National Drug Code (NDC) number that would readily distinguish it from other products that share the same nonproprietary name.”

Further, the interchangeable status for biosimilar drugs would also help its manufacturers to tide over the initial apprehensions on safety and quality of biosimilar drugs, as compared to the original ones.

3. 12-year Data Exclusivity period for biologics in the United states:

Currently, the new law for biologic products in the United States provides 12 years of data exclusivity for a new biologic. This is five years more than what is granted to small molecule drugs. 

Many experts believe that this system would further delay the entry of cost-effective biosimilar drugs, restrict the biosimilar drug manufacturers from relying on the test data submitted to drug regulator by the manufacturers of the original biologic drugs while seeking marketing approval.

A rapidly evolving scenario in the United States:

The regulatory space for approval of biosimilar drugs is still evolving in the Unites States. This is vindicated by the fact that in March 2016, giving a somewhat positive signal to the biosimilar drug manufacturers, the US-FDA released another set of a 15-page draft guidelines on how biosimilar products should be labeled for the US market. Interestingly, it has come just around a year of the first biosimilar drug approval in the United States – Zarxio (filgrastim-sndz) of Novartis.

The US-FDA announcement says that all ‘comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.’ Besides labeling issues, this draft guidance document, though indicates that the ‘interchangeability’ criteria will be addressed in the future, does not still throw enough light on how exactly to determine ‘interchangeability’ for biosimilar drugs.

That said, these key regulatory barriers are likely to continue, at least in the foreseeable future, for many reasons. The biosimilar drug manufacturers, therefore, would necessarily have to work within the set regulations, as applicable to different markets of the world.

I deliberated a related point in my article of August 25, 2014, titled “Scandalizing Biosimilar Drugs With Safety Concerns 

B. Prescribers’ skepticism:  

Initial skepticism of the medical profession for biosimilar drugs are, reportedly, due to the high voltage advocacy of the original biologic manufacturers on the ‘documented variability between original biologic and biosimilars. Which is why, any substitution of an original biologic with a related biosimilar drug could lead to increase in avoidable adverse reactions.

‘The medical platform and community QuantiaMD’, released a study just around September 2015, when by a Press Release, Novartis announced the launch of the first biosimilar approved by the US-FDA – Zarxio(TM) (filgrastim-sndz). However, in 2006, Novartis after suing the US-FDA, got the approval for its human growth hormone – Omnitrope, which is a biosimilar of the original biologic of Genentech and Pfizer. At that time a clear regulatory guideline for biosimilar drugs in the United States, was not in place.

The QuantiaMD report at that time said, “Only 12% of prescribing specialists are ‘very confident’ that biosimilars are as safe as the original biologic version of the drug. In addition, a mere 17% said they were ‘very likely’ to prescribe a biosimilar, while 70% admitted they were not sure if they would.” 

Since then, this scenario for biosimilar drugs is changing though gradually, but encouragingly. I shall dwell on that below.

The major growth drivers:

The major growth drivers for biosimilars, especially, in the world’s top pharmaceutical markets are expected to be:

  • Growing pressure to curtail healthcare expenditure
  • Growing demand for biosimilar drugs due to their cost-effectiveness
  • Rising incidences of various life-threatening diseases
  • Increasing number of off-patent biologics
  • Positive outcome in the ongoing clinical trials
  • Rising demand for biosimilars in different therapeutic applications, such as, rheumatoid arthritis and blood disorders. 

This in turn would probably usher in an unprecedented opportunity for the manufacturers of high quality biosimilar drugs, including in India.

Unfolding a huge emerging opportunity with biosimilars: 

This unprecedented opportunity is expected to come mainly from the world’s three largest pharma market, namely the United States, Europe and Japan, due to very high prices of original biologic drugs, and simultaneously to contain rapidly escalating healthcare expenditure by the respective Governments. 

Unlike in the past, when the doctors were apprehensive, and a bit skeptic too, on the use of new biosimilars, some new studies of 2016 indicate a rapid change in that trend. After the launch of the first biosimilar drug in the US, coupled with rapidly increasing incidences of various complex, life-threatening diseases, better knowledge of biosimilar drugs and their cost-effectiveness, doctors are now expressing much lesser concern, and exhibiting greater confidence in the use of biosimilars in their clinical practice.

Yet another, March 2016 study indicates, now only 19.5 percent of respondents feel little or no confidence in the use of biosimilar monoclonal antibodies compared to 61percent of respondents to a previous version of the survey undertaken in 2013 by the same market research group. The survey also shows that 44.4 percent of respondents consider that the original biologic and its biosimilar versions are interchangeable, as compared with only 6 percent in the 2013 survey.

As a result of this emerging trend, some global analysts of high credibility estimate that innovative biologic brands will lose around US$110 billion in sales to their biosimilar versions by 2025.

Another March, 2016 report of IMS Institute for Healthcare Informatics states that lower-cost biosimilar versions of complex biologic, could save the US and Europe’s five top markets as much as US$112 billion by 2020,

These encouraging developments in the global biosimilar arena are expected to encourage the capable Indian biosimilar drug players to invest in this high-tech format of drug development, and reap a rich harvest as the high priced blockbuster biologic brands go off-patent.

Conclusion:

Putting all these developments together, and considering the rapidly emerging scenario in this space, it now appears that challenges ahead for rapid acceptance of biosimilar drugs though are still many, but not insurmountable, at all.

The situation necessitates application of fresh and innovative marketing strategies to gain doctors’ confidence on biosimilar medicines, in total conformance with the regulatory requirements for the same, as they are, in the most important regulated markets of the world.

It goes without saying that success in the generation of enough prescriptions for biosimilar drugs is the fundamental requirement to benefit the patients, which, in turn, would lead to significant savings in health care cost, as estimated above, creating a win-win situation for all, in every way.

As more innovator companies start joining the biosimilar bandwagon, the physicians’ perception on these new varieties of medicines, hopefully, would also change, sooner.

Biocon’s grand announcement of its entry with a ‘made in India’ biosimilar drug in one of the word’s top three pharma markets, would probably be a great encouragement for all other Indian biosimilar drug manufacturers. It clearly showcases the capabilities of an Indian drug manufacturer to chart in an uncharted and a highly complex frontier of medicine.

By: Tapan J. Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.

Pfizer and Biocon deal – heralds dawn of a new era for the Biopharmaceuticals Industry of India

On October 19, 2010, home grown Biotech Company Biocon, based in the IT heartland – Bangalore created a stir in Industry by inking an interesting international corporate business deal with the largest global pharmaceutical company – Pfizer. The deal will bring to Biocon a total sum of US $350 million and enable Pfizer to globally commercialize Biocon’s biosimilar (generic versions of biotechnology medicines) human recombinant insulin and three insulin analogues.

Before this deal, Sanofi-Pasteur, the vaccine business unit of the global major Sanofi-aventis had acquired Shantha Biotech, located at Hyderabad for a sum of Rs 3,750 Crore, in July 2009.

Just a year before the above acquisition in india, on December 11, 2008, Reuters reported, just two days after Merck announced a major push into biosimilar medicines; Eli Lilly signaled similar aspirations. This report, at that time, raised many eyebrows in the global pharmaceutical industry, as it was in the midst of a raging scientific debate on the appropriate regulatory pathways for biosimilar drugs. Be that as it may, many felt that this announcement ushered in the beginning of a new era. An era of intense future competition with biosimilar drugs in the global market, with immense commercial interest. On October 19, 2010 the biosimilar deal between Biocon and Pfizer vindicated this point.

Increasing global interest on biosimilar drugs:

Globally, the scenario for biosimilars started heating up when Merck announced that the company expects to have at least 5 biosimilars in the late stage development by 2012. The announcement of both Merck and Eli Lilly surprised many, as the largest pharmaceutical market of the world – the U.S.A, at that time, was yet to approve the regulatory pathway for biosimilar medicines. However, along with the recent healthcare reform by the Obama administration, the regulatory pathway for biosimilar drugs has now been clearly charted by the US FDA. In the developed world, European Union (EU) had taken a lead towards this direction by putting a robust system in place, way back in 2003.

What then prompts the research based global pharmaceutical companies like Pfizer, Sanofi-aventis, Merck and Eli Lilly to step into the arena of Biosimilar medicines? Is it gradual drying up research pipeline together with skyrocketing cost of global R&D initiatives?

The future global business potential of Biosimilar medicines:

Currently, over 150 different biologic medicines are available in the global pharmaceutical market. However, the low cost biosimilar drugs are available in just around 11 countries of the world, India being one of them. Supporters of biosimilar medicines are indeed swelling as time passes by. At present, the key global players are Sandoz (Novartis), Teva, BioPartners, BioGenerix (Ratiopharm) and Bioceuticals (Stada). With the entry of pharmaceutical majors like, Pfizer, Sanofi-aventis, Merck and Eli Lilly, the global biosimilar market is expected to develop at a much faster pace than ever before. Removal of regulatory hurdles for the marketing approval of such drugs in the US – the largest pharmaceutical market of the world, will be the key growth driver.

Recently, the EU has approved Sandoz’s (Novartis) Filgrastim (Neupogen brand of Amgen), which is prescribed for the treatment of Neutropenia. With Filgrastim, Sandoz will now have 3 Biosimilar products in its portfolio.

Global Market Potential of Biosimilar Drugs:

The biosimilar drug market in the world is estimated to be around U.S. $ 16 billion by 2011. Currently, off-patent biologic blockbusters including Erythropoietin offer an excellent commercial opportunity in this category. By 2013, about 10 branded biologics with a total turnover of around U.S. $ 15 billion will go off-patent, throwing open greater opportunity for the growth of biosimilar drugs internationally.

Biosimilar Drugs in India:

Sales of biosimilar drugs in India are estimated to be around U.S. $ 4 billion by 2011 with scorching pace of growth driven by both local and global demands.

Recombinant vaccines, erythropoietin, recombinant insulin, monoclonal antibody, interferon alpha, granulocyte cell stimulating factor like products are now manufactured by a number of domestic biotech companies like Biocon, Panacea Biotech, Wockhardt, Emcure, Shantha Biotech, Bharat Biotech, Serum Institute of India, Dr. Reddy’s, Ranbaxy, etc. The ultimate objective of all these Indian companies will be to get regulatory approval of these products in the US and the EU either on their own or through collaborative initiatives.

It is worth mentioning here that to give a fillip to the Biotech Industry in India; the National Biotechnology Board was set up by the Government of India under the Ministry of Science and Technology way back in 1982. The Department of Biotechnology (DBT) came into existence in 1986. The DBT now spends around US$ 200 million annually to develop biotech resources in the country and have been making reasonably good progress. The DBT is reported to have undertaken an initiative for quite some time to prepare regulatory guidelines for Biosimilar Drugs, which is expected to conform to international quality and patients’ safety standards.

Steps taken by the Indian pharmaceutical companies:

Biosimilar version of Rituxan (Rituximab) of Roche used in the treatment of Non-Hodgkin’s lymphoma has already been developed by DRL in India. Last year Rituxan clocked a turnover of over US$ 2 billion. DRL also has developed filgastrim of Amgen, which enhances production of white blood-cell by the body, and markets the product as Grafeel in India. Similarly Ranbaxy has collaborated with Zenotech Laboratories to manufacture G-CSF.

On the other hand Glenmark is planning to come out with its first biotech product by 2011 from its biological research establishment located in Switzerland.

The focus is on Oncology:

Many domestic Indian pharmaceutical companies are targeting Oncology disease area for developing biosimilar drugs, which is estimated to be the largest segment with a value turnover of over US$ 55 billion by the end of 2010 growing over 17%. As per recent reports about 8 million deaths take place all over the world per year due to cancer. May be for this reason the research pipeline of NMEs is dominated by oncology with global pharmaceutical majors’ sharp R&D focus and research spend on this particular therapy area. About 50 NMEs for the treatment of cancer are expected to be launched globally by 2015.

Current size of the Indian oncology market is around US$ 18.6 million, which is expected to be over US$ 50 million by the end of 2010; the main reason being all these are and will be quite expensive products.

A trigger point for more collaborative initiatives:

It is expected that the recent Pfizer – Biocon deal will trigger many other collaborative initiatives between the global and the local pharmaceutical companies.

Among India biotech companies, Reliance Life Sciences has already marketed Recombinant Erythropoietin, Recombinant Granulocyte Colony Stimulating Factor, Recombinant Interferon Alpha and Recombinant tissue plasminogen activator. This company has been reported to have the richest pipeline of biosimilar drugs in India. Companies like Wockhardt, Lupin, DRL and Intas Biopharmaceuticals are also in the process of developing an interesting portfolio of biosimilar drugs in India to fully encash the fast growing global opportunities.

Biosimilar global business model will fast gain ground:

Many large research-based global pharmaceutical companies, after having encountered the ‘patent cliff’, are now looking at the generic and biosimilar businesses, in a mega scale, in the emerging markets of the world, like India. Our country has witnessed major acquisitions like, Ranabaxy, Shantha Biotech and Piramal Healthcare by Daiichi Sankyo of Japan, Sanofi-aventis of France and Abbott of USA, respectively. We have also seen collaborative initiatives of large global companies like, GSK, AstraZeneca, and Pfizer with Indian companies like DRL, Aurobindo, Claris, Torrent, Zydus Cadilla, Strides Arcolab and now Biocon to reach out to the fast growing global generic and biosimilar drugs markets.

This trend further gained momentum when immediately after Biocon deal early this week, on October 21, 2010, Pfizer strengthened its footprints in the global generics market with yet another acquisition of 40% stake in Laboratorio Teuto Brasilieiro of Brazil with US $240 million to develop and globally commercialize their generic portfolio.

Conclusion:

All said and done, the recent international deal of Pfizer and Biocon to globally commercialize four biosimilar insulin and analogues, developed by the later in India, does signal a new global status for the Indian biosimilar drugs to the pharma MNCs, who were vocal critics of such drugs developed in India, until recently.

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.