Tag Archives: Trastuzumab

Patent Expiry No Longer End of The Road

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Who says that the phenomenal success of blockbuster drugs is mostly eaten away by  ‘look-alikes’ of the same, immediately after respective patent expiry? It doesn’t seem to be so any longer, not anymore! Several examples will vindicate this emerging trend. However, I shall quote just a few of these from the published reports.

In 2016, the patent of AbbVie’s Humira (Adalimumab), indicated in the treatment of autoimmune diseases and moderate to severely active rheumatoid arthritis, expired in the United States (US). It will also expire in Europe by 2018. This event was expected to create significant opportunities for lower priced Adalimumab biosimilars in the US market, increasing the product access to many more patients at affordable prices. Just as it happens with patent expiry of small molecule blockbuster drugs. One of the classic examples of which, is a sharp decline in sales turnover and profit from Pfizer’s Lipitor (Atorvastatin), as its patent expired on November 30, 2011.

However, Humira topped the prescription-drug list of 2016 with an annual growth of 15 percent, accounting for USD 16 billion sales, globally. More interestingly, according to a recent report of EvaluatePharma, AbbVie’s Humira will continue to retain its top most ranking in 2020 with expected sales of USD 13.9 billion. Nevertheless, possible threat from biosimilars has slightly slowed down its growth. Although, there are many other similar examples, I would quote just three more of these to illustrate the point, as follows:

  • Rituxan (Rituximab, MabThera) indicated in the treatment of cancer and co-marketed by Biogen and Roche, went off-patent in 2015. However, in 2016, the product held 4th position in the prescription drug market with a revenue growth of nearly 3 percent. Even five years after its patent expiry, Rituxan is still expected to occupy the 17th rank with an estimated turnover of over USD 5 billion in 2020, according to the EvaluatePharma report.
  • Remicade (Infliximab) indicated for autoimmune diseases and manufactured by J&J and Merck, lost market exclusivity in 2015. But, in 2016 it still held 5th place in the global ranking. Five years after it goes off patent, Remicade is expected to feature in the 6th rank in 2020, with an estimated turnover of over USD 6.5 billion, according to the same report as above.
  • The US product patent for Lantus – a long-acting human insulin analog manufactured by Sanofi, expired in August 2014. However, in 2016, clocking a global turnover of USD 6.05 billion, Lantus still ranked 10 in the global prescription brand league table. Six years after its patent expiry – in 2020, Lantus will continue to feature in the rank 20, as the same EvaluatePharma report estimates.

These examples give a feel that unlike small molecule blockbuster drugs, patent expiry is still not end of the road to retain this status for most large molecule biologics, across the world. In this article, I shall discuss this point taking Humira as the case study.

What about biosimilar competition?

In any way, this does not mean that related biosimilars are not getting regulatory approval in the global markets, post-patent expiry of original biologic drugs, including the United States. Nonetheless, biosimilar makers are facing new challenges in this endeavor, some of which are highly cost intensive, creating tough hurdles to make such drugs available to more patients at an affordable price, soon enough. It happened for the very first biosimilar to Humira, as well. On September 23, 2016, almost immediately after its patent expiry in 2016, the USFDA by a Press Release announced approval for the first biosimilar to Humira (adalimumab). This was Amgen’s Amjevita (adalimumab-atto), indicated for multiple inflammatory diseases.

The second biosimilar to AbbVie’s Humira – Boehringer Ingelheim’s Cyltezo (adalimumab-adbm), was also approved by the USFDA in August 2017. So far, six biosimilars have been introduced in the United states. But, none of these got approved as an ‘interchangeable’ product. Some of these, such as Cyltezo could not even be launched, as yet. I shall discuss this point later in this article. Thus, Humira is expected to retain its top global prescription brand ranking in 2020 – over 4 years after its patent expiry.

In Europe, two marketing authorizations were reportedly granted by the European Commission (EC) in March 2017 for Amgen’s biosimilars to Humira, named Amgevita (adalimumab) and Solymbic (adalimumab). Later this year, in November 2017 Boehringer Ingelheim’s – Cyltezo also received its European marketing approval.

It is worth noting that in December 2014, the Drug Controller General of India (DCGI) reportedly granted marketing approval for Zydus Cadila’s Adalimumab biosimilar (Exemptia) for treating rheumatoid arthritis and other autoimmune disorders in India. The company claims: “This novel non-infringing process for Adalimumab Biosimilar and a novel non-infringing formulation have been researched, developed and produced by scientists at the Zydus Research Centre. The biosimilar is the first to be launched by any company in the world and is a ‘fingerprint match’ with the originator in terms of safety, purity and potency of the product.”

Several important reasons indicate why a full throttle competition is lacking in the  biosimilar market early enough – immediately after patent expiry of original biologic molecules. I shall cite just a couple of these examples to illustrate the point. One is related to aggressive brand protection, creating a labyrinth of patents having different expiry dates. And the other is a regulatory barrier in the form of drug ‘interchangeability’ condition, between the original biologic and related biosimilars:

In the labyrinth of patents:

The most recent example of innovator companies fiercely protecting their original biologic from the biosimilar competition by creating a labyrinth of patents is Boehringer Ingelheim’s Cyltezo. This is biosimilar to AbbVie’s Humira, approved by the USFDA and EC in August 2017 and November 2017, respectively.

According to reports: “BI does not intend to make the drug commercially available in Europe until the respective SPC (supplementary protection certificate) for adalimumab, which extends the duration of certain rights associated with a patent, expires in October 2018. Cyltezo is also not yet available in the US despite its approval there in August, because of ongoing patent litigation with AbbVie. AbbVie reportedly holds more than 100 patents on Humira, and believes that Boehringer could infringe 74 of these with the launch of its biosimilar. Similarly, the firm has also taken Amgen to court to block the launch of its proposed Humira biosimilar.”

Another interesting example is the epoch-making breast cancer targeted therapy Trastuzumab (Herceptin of Roche/Genentech). The patent on Herceptin reportedly expired in 2014 in Europe and will expire in the United States in 2019. The brand registered a turnover of USD 2.5 billion in 2016. However, a November 21, 2017 report says that creating a series of hurdle in the way of Pfizer’s introduction to Herceptin biosimilar, Roche has sued Pfizer for infringement of 40 patents of its blockbuster breast cancer drug. Pfizer hasn’t yet won approval for its Herceptin biosimilar, though, USFDA accepted its application in August 2017 – the report highlights

‘Interchangeability’ condition for biosimilars:

In the largest global pharma market – the United States, USFDA classifies biosimilars into two very distinct categories:

  • Biosimilars that are “expected to produce the same clinical result as the reference product”
  • Biosimilars that are “interchangeable,” or able to be switched with their reference product

According to reports, experts’ argument over ‘interchangeability’ in the US range from “whether pharmacists should be allowed to switch a biologic for its biosimilar without a doctor’s notification, to whether interchangeable biosimilars might be perceived as better or safer than their non-interchangeable counterparts.” This debate has somewhat been resolved by the US Food and Drug Administration’s (FDA) issuance of draft guidance in January 2017, specifying what should be submitted to support an interchangeable application, the report says.

The article also indicates, “the draft makes clear that switching studies to help gain this designation should evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product. Study design, types of data and other considerations are also included in that draft.” Nonetheless, compliance with this regulatory requirement is expected to be highly cost intensive, too.

Quoting a senior USFDA official, a report dated June 26, 2017 mentioned: “interchangeable biosimilars will come to market within the next two years, though possibly sooner. And the first interchangeable biosimilar will likely be reviewed by an FDA advisory committee of outside experts.” Still the bottom line remains no biosimilar has yet been approved by the USFDA as ‘interchangeable’. Hence, the optics related to desirable success for biosimilars continue to remain somewhat apprehensive, I reckon.

Patent related litigations on Trastuzumab (Herceptin) were filed by Roche in India, as well. However, it’s good to note that on December 01, 2017, by a Press Release, USFDA announced the approval of Mylan’s biosimilar variety of Roche’s blockbuster breast cancer drug – Herceptin. Mylan’s Ogivri was co-developed with Biocon in India to treat breast or stomach cancer, and is the first biosimilar approved in the United States for these indications. It is noteworthy that Ogivri also has not been approved as an interchangeable product.

The global and local scenario for biosimilars:

Be that as it may, the July 26, 2017 study of Netscribes – a global market intelligence and content management firm estimates that the global biosimilar market will be worth USD 36 billion by 2022. Some of the major findings of this study are as follows:

  • With a cumulative share of nearly 85%, North America, Europe, and Japan are the major contributors to global biological and biosimilar sales. Asia and Africa account for 13.2% and 1.2%, respectively.
  • Pfizer is the leading player in the biologic market, with sales of nearly USD 45.9 billion in 2016 followed by Novartis (41.6 billion) and Roche (39.6 billion).
  • Biosimilar approvals are estimated to be around of around 16 to 20 biosimilars between 2018 to 2021 in both US and EU.
  • The US is not a favorable market for biosimilars due to a number of reasons, such as poor access to biologic drugs and an unfavorable regulatory environment.
  • South Africa is one of the best-suited markets for biosimilars due to a favorable regulatory environment and prescriber acceptance.

According to the April 2017 analysis of Research And Markets, biosimilars have started winning key government tenders in countries like Mexico and Russia, and being purchased by a growing number of patients in self-pay markets such as India. The aggregate sales of ‘copy biologics’ in the six BRIC-MS (Brazil, Russia, India, China, Mexico, and South Korea) countries would now almost certainly exceed USD 1.5 billion. Yet Another estimate  expects the Indian biosimilar market to increase from USD 186 million in 2016 to USD 1.1 billion in 2020. It is up to individual experts to assess whether or not this growth trend for biosimilars is desirable to adequately benefit a large number of patients, the world over.

Conclusion:

In my view, if what usually happens to sales and profit for small molecule blockbuster drugs post patent expiry, would have happened to the large molecule biologic drugs, the market scenario for biosimilars would have been quite different. In that scenario, one would have witnessed a plethora of biosimilar competition against high priced and money churning biologics, such as Humira, being launched with a significantly lesser price than the original brand.

Prices of biosimilars would have been much lesser primarily because, the litigation cost, now built into the biosimilar prices for successfully coming out of the labyrinth of patents after the basic patent expiry, would have been minimal. Moreover, restrictions on drug ‘interchangeability’ would not have made the target market smaller, especially in the United states.

Alongside, compliance with the regulatory need to meet the ‘interchangeability’ condition in the US, would drive the product cost even higher. More so, when this specific regulatory requirement is not necessary in other developed markets, like Europe. Both these factors would adversely impact affordability and access to sophisticated biologic drugs for patients, even after the fixed period of market exclusivity.

That said, a virtually impregnable patent labyrinth mostly ensures that going off-patent isn’t end of the road for blockbuster biologic drugs to continue generating significant revenue and  profit, any longer – and it would remain so at least, in the short to medium term.

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.

‘Herceptin Biosimilars’ Seriously Questioned

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The news struck as an anticlimax, close on the heels of high decibel product launch of ‘Herceptin Biosimilars’ in India, being hyped as the first in the world, bringing much needed relief to many diagnosed breast cancer patients for their economical pricing.

At the same time, this legal challenge has now come as an acid test for the regulator to prove that ‘Caesar’s wife must be above suspicion’ for any new drug approval and especially if it is a complex biosimilar used for the treatment of patients suffering from dreaded diseases, such as, breast cancer.

It’s not patent this time:

Interestingly, this is not a patent infringement case, as Roche has reportedly given-up its patent on Trastuzumab (Herceptin) in India last year.

Alleged violations: 

The above media report highlights, in Delhi High Court Roche has sued Biocon of India and its US based generic partner – Mylan along with the Drug Controller General of India (DCGI) related to launch of ‘Herceptin Biosimilar’ versions in India.

The allegation against Biocon and Mylan is that their recently launched drugs are being misrepresented as ‘biosimilar Trastuzumab’ or ‘biosimilar version of Herceptin’ without following the due process in accordance with the ‘Guidelines on Similar Biologics‘, necessary for getting approvals of such drugs in India.

‘Caesar’s wife’ under suspicion too:

The DCGI has also been sued by Roche for giving permission for launch of this product allegedly not in conformance with the above biosimilar guidelines, which were put in place effective August 15, 2012.

Roche reportedly argued that the above guidelines on similar biologics laid down a detailed and structured process for comparison of biosimilar with the original product and all the applications for manufacturing and marketing authorization of biosimilars are necessarily required to follow that prescribed pathway before obtaining marketing approval from the DCGI. Roche has also stated that there is no public record available, in the clinical trial registry India (CTRI) or elsewhere to show that these two players actually conducted phase-I or II clinical trials for the drug.

According to report Roche claims that DCGI has approved the “protocol and design study for testing” of Biocon related to the proposed drug just before the above regulatory guidelines were made effective, predominantly for patients’ health and safety reasons.

Interim restrain of the Delhi High Court:

In response to Roche’s appeal, the Delhi High Court has reportedly restrained Mylan and Biocon from “relying upon” or “referring to Herceptin” or any data relating to it for selling or promoting their respective brands Canmab (Biocon) and Hertaz (Mylan) till the next hearing.

The relevance of ‘Guidelines on Similar Biologics’:

The ‘Guidelines on Similar Biologics’ clearly articulated:

“Since there are several biosimilar drugs under development in India, it is of critical importance to publish a clear regulatory pathway outlining the requirements to ensure comparable safety, efficacy and quality of a similar biologic to an authorized reference biologic.”

Thus for patients’ health and safety interest the above regulatory pathway must be followed, the way these have been prescribed without any scope of cutting corners. This is even more important when so important pharmacovigilance system is almost non-functional in India.

Attempts to dilute the above guidelines from some quarters:

It was earlier reported that strong representations were made to the drug regulator in writing by powerful domestic players in this area urging to dilute the above ‘Guidelines’, otherwise it will be difficult for them to compete with the pharma MNCs.

This argument is ridiculous by any standard and smacks of putting commercial considerations above patients’ health interest.

The key issue:

As I see it, four quick questions that float at the top of my mind are as follows:

  • If the ‘Guidelines on Similar Biologics’ have not been followed either by the applicants or by the DCGI, how would one establish beyond an iota of doubt that these drugs are biosimilar to Trastuzumab, if not ‘Biosimilar to Herceptin’?
  • If these drugs are not proven biosimilar to Trastuzumab, as specified in the ‘Guidelines on Similar Biologics’, how can one use Trastuzumab data for their marketing approvals and the DCGI granting the same?
  • If these drugs were not biosimilars to Trastuzumab, would these be as effective, reliable and safe as Herceptin in the treatment of breast cancer?
  • Further, how are references related to Herceptin being used to promote these drugs both pre and post market launch?

Conclusion:

I guess, predominantly commercial considerations prompted Roche to sue Biocon, Mylan and also the DCGI on ‘Trastuzumab biosimilars’, launched recently in India.

Be that as it may, for the interest of so many diagnosed breast cancer patients in the country, there is crying need for the facts to come out in the open, once and for all. Are these drugs truly Trastuzumab biosimilars with comparable safety, efficacy, quality and reliability of Herceptin?

If the answer comes as yes, there would be a huge sigh of relief from all corners inviting millions of kudos to Biocon and Mylan.

However, if by any chance, the allegations are proved right, I do not have an iota of doubt that the honorable Delhi High Court would ferret out the truth, unmask the perpetrators and give them exemplary punishments for playing with patients’ lives.

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.

Pharma Horizon: Cloud, Rainbow And Smear

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Some recent papers contemplated that the patent cliff for blockbuster drugs has already reached the zenith and early signs of recovery should be visible from 2013 onwards. However, from analysis of the currently available data, contrary to the above belief, I reckon, the downtrend in global pharma is far from over, not just yet.

One of the telltale signs of this slump is near-term patent expiry of today’s blockbuster drugs, the impact of which will continue to keep the global pharma sky overcast with clouds for some more time, especially in absence of replaceable equivalents. Interestingly, on the flip side, a beautiful rainbow, as it were, also takes shape in the horizon, ushering-in a hope to a large number of patients for improved access to newer drugs, just as it does to the generic players for accelerating business growth.

That’s the good part of it, though for the generic drug industry. However, the bad part of the emerging scenario gives rise to a lurking fear of gloom and doom, emanating from self-created evitable smears and taints, blended in vessels of despicable mindsets.

Clouds:

While having a glimpse at that following table, the underlying impact of the dark clouds looming large on the global pharma horizon cannot just be wished away:

Total Patent Expiry:

Year Value US$ Billion
2015 66
2014 34
2013 28
2012 55
Total 183 

(Compiled from FiercePharma data)

Thus, the negative impact from sales lost to patent expiry of blockbuster drugs of today, though declined from US$ 55 billion in 2012 to US$ 28 billion in 2013, the same would start climbing-up again to US$ 66 billion in 2015.

If we take a look at the product-wise details, the picture pans out as under:

Top 10 ‘Patent Expiry’ in 2014:

No. Brand Company Disease Sales 2012   US$ Million Expiry
1. Copaxone Teva MultipleSclerosis 3996 May 2014
2. Nexium AstraZeneca Acid peptic 3994 May 2014
3. Micardis/HCT BoehringerIngelheim Hypertension 2217 Jan 2014
4. Sandostatin LAR Novartis Cancer 1512 June 2014
5. Exforge/HCT Novartis Hypertension 1352 Oct 2014
6. Nasonex Merck Resp. Allergy 1268 Jan 2014
7. Trilipix Abbvie Anti-lipid 1098 Jan 2014
8. Evista Eli Lilly Osteoporosis 1010 Mar 2014
9. Renagel Sanofi Chronic Kidney Disease  861 Sep. 2014
10. Restasis Allergan Chronic Dry Eye  792 May 2014

(Compiled from FiercePharma data)

The above figures, therefore, do reinforce the hypothesis that the following factors would continue to make the best brains of global pharma burning the midnight oil in search of sustainable strategic blueprints, at least, for some more time:

-       Mostly, high growth emerging markets of the world are generic drugs driven

-       Increasing cost containment pressure of Governments and/or other payor

-       Challenges from Intellectual Property (IP) and Market Access related  issues

-       Declining R&D productivity

-       Shift in overall focus for new drugs on expensive biologics

-       Markets turning more Volatile, Uncertain, Complex and Ambiguous (VUCA)

Current strategy to deliver shareholder-value not sustainable:

Since last several years, one has witnessed, despite slowing down of sales growth, big pharma players, by and large, have not failed in delivering impressive shareholder returns. This has been possible mainly due to ruthless cost cutting across the board, restructuring of operational framework and taking measures like, increase in dividends and share repurchases.

These strategic measures, though laudable to keep the head above water, are just not sustainable over a period of time sans strong cashflow.

Thus, for a long haul, robust and consistent business growth with commensurate impact on the bottom-line generating smooth cashflow, is imperative for all these companies.

In this difficult ball game of developing sustainable cutting-edge strategies at an equally challenging time, the consolidation process within the industry would gain further momentum, where only the fittest corporations, led by great corporate brains, would manage to survive and thrive.

However, who all would successfully be able to squarely face the moments of truth, triumphantly seizing the opportunities frozen in time, in the fast changing paradigm of a seemingly VUCA world, is not more than a matter of speculation now.

The Rainbow:

As stated above, while this canopy formed with dark clouds keeps looming large at the global pharma horizon, a beautiful rainbow is simultaneously seen taking shape for the domestic Indian drug manufacturers to cash-on with well-orchestrated strategic measures. One of the critical success requirements for this sprint, is touching the tape in the finishing line to become first to introduce generic versions of the patent expired drugs, especially in the US market.

Indian pharma players have already demonstrated in the past that they do have the wherewithal of making such rare opportunities meaningful by offering affordable new drugs of high quality standards to a large number of patients, while simultaneously accelerating growth of their respective business operations.

Proven acumen even in biologics:

India has recently proven its acumen in the area of biologics too, by developing a biosimilar version of the complex biologic drug – Trastuzumab (Herceptin) of Roche, used for the treatment of breast cancer, and that too in a record time.

As is known to many, earlier in 2013 Roche decided not to defend its patents on Herceptin in India, which reportedly recorded local sales of about US$ 21 million in 2012. Many people opined at that time, it would not be easy for any company to develop biosimilar version of Trastuzumab, mainly due to the complexity involved in its clinical development. Hence, some diehards kept arguing, Roche would not be commercially impacted much for taking the above decision, at least in the near to mid term.

Surprising almost everybody, Biocon and its MNC partner Mylan not only developed an affordable biosimilar version of Trastuzumab successfully, but also got its marketing approval from the Drug Controller General of India (DCGI), thereby immensely benefitting a large number of breast cancer patients in India and hopefully even beyond.

Keeping ‘Eye on the ball’?

Details of ANDA status from the USFDA source probably indicate that several Indian players have started gearing up to move in that direction at a brisk pace, keeping their eyes well fixed on the ball.

The following table further indicates that in 2012 India ranked second, after the United States (US) in terms of number of ANDA approvals and in 2013 till October India ranks number one, overtaking the United States (US):

ANDA’s Granted in 2012 and upto October 2013):

Country ANDA 2012 ANDA (October 2013) Total Since 2007
United States 183 119 1191
India 196 138 993
Switzerland 20 12 134
Israel 28 13 133
Canada 27 13 116
Germany 20 6 107
UK 11 15 95
China 7 10 29

Smears:

Unfortunately, just out side the frame of the above kaleidoscope, one can see large spots of self created slimy smears, which can make the ‘Rainbow’ irrelevant, maintaining the horizon as cloudy even for the Indian generic players.

Continuous reports from US-FDA and UK-MHRA on fraudulent regulatory acts, lying and falsification of drug quality data by some otherwise quite capable Indian players, have just not invited disgrace for the country in this area, but also reportedly prompted regulators from other nations trying to assess whether such bans might suggest issues for drugs manufactured for their respective countries, as well.

Such despicable mindsets of the concerned key players, if remain unleashed, could make Indian Pharma gravitating down, stampeding all hopes of harvesting the incoming opportunities. 

We have one such ready example before us and that too is not an old one. The ‘Import Alert’ of the USFDA against Mohali plant of Ranbaxy, has already caused inordinate delay in the introduction of a cheaper generic version of Diovan, the blockbuster antihypertensive drug of Novartis AG, after it went off patent. It is worth noting that Ranbaxy had the exclusive right to sell a generic version of Diovan from September 21, 2012.

Another report of November 2013 states, “The Drug Controller General of India has ordered Sun Pharmaceutical, the country’s largest drug maker by market capitalization to suspend clinical research activities at its Mumbai based bio-analytical laboratory, a move that could slow down the company’s regulatory filings in India and possibly overseas as well.”

The outcome of such malpractices may go beyond the drug regulatory areas, affecting even the valuations of concerned Indian pharma companies. According to a recent report Strides Arcolab will not get US$ 250 million of the US$ 1.75 billion anticipated from the sale of its injectable drugs unit to Mylan Inc unless regulatory concerns at Agila Specialities in Bangalore are resolved.

Thus the smears though for now are confined to a few large manufacturing units of Indian Pharma, including some located overseas, may eventually play the spoil sport, trashing all hopes seen through the rainbow in the bins of shame.

Conclusion:

In the balance of probability, I believe, the clouds of uncertainty would continue to loom large over the global pharma, at least, till 2015.

However, in the midst of it, heralds a ‘never before opportunity’ for Indian pharma to cash on the early fruits of forthcoming patent expiries of today’s blockbuster drugs, not just for them, but for patients at large.

Already demonstrated capabilities of the homegrown players, trigger expectations of making it happen. The encouraging trend of grant of ANDAs in the US further reinforces this belief.

Despite all these, a lurking fear does creep in. This evitable fear finds its root in repeated fraudulent behavior of some Indian drug manufacturers, seriously compromising with cGMP standards of global drug regulators, including lying and falsification of data generated, thus playing a spoil sport by ‘snatching defeat from the jaws of victory’, as it were.

That said, the question to ponder now is: In the ‘Pharma Horizon’ what would ultimately prevail in the short to medium term, especially in the Indian context – Clouds, The Rainbow or Smears?

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.

The Ghost Keeps Haunting: NCD Dogs Cancer in ‘Compulsory License’ Debate of India

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In November 2012, as a part of the ‘Campaign for Affordable Trastuzumab’ for the treatment of breast cancer, a citizens’ collective, reportedly sent an ‘Open Letter’ signed by around 200 cancer survivors, women’s groups, human rights and health rights campaigns and treatment activists from across the world to the Indian Prime Minister, urging him to ensure that the breast-cancer drug Trastuzumab is made affordable for treating cancer patients in the country.

Trastuzumab was named because of the following reasons:

  • Breast-cancer affects around 28-35 per cent of all cancers among women in major cities of India.
  • No other drug against HER+2 cancer can reduce patients’ mortality as Trastuzumab and reduce the spread of malignancy to other parts of the body.
  • Majority of women with HER+2 breast cancer do not have access to a complete course of the drug, which reportedly costs anywhere between Rs 6 to 8 lakhs (US$ 11,000 to US$ 14,500).

Reaping reach harvest: 

According to a media report, three homegrown Indian companies are currently developing biosimilar drugs to this protein molecule to reap a reach harvest arising out of the emerging opportunities.

However, this is expected to be an arduous, expensive and challenging endeavor, as the concerned companies will require pursuing a complicated biotechnological route to create follow-on biologics for Trastuzumab.

The ‘Trigger Factor’: 

It is widely believed that the above ‘Open Letter’ to the Prime Minister had prompted the Ministry of Health to form an ‘Experts Committee’ to evaluate the situation and make recommendations accordingly.

Thereafter, within a short period of time, in January, 2013, in a move that is intended to benefit thousands of cancer patients, Ministry of Health forwarded the report of the above ‘Experts Committee’ to the Department of Industrial Policy and Promotion (DIPP) for its consideration to issue Compulsory Licenses (CL) for three commonly used anti-cancer drugs namely, Trastuzumab (used for breast cancer), Ixabepilone (used for chemotherapy) and Dasatinib (used to treat leukemia). Public Health Foundation of India (PHFI), among other experts, also reportedly had participated as a member of this ‘Experts Committee’,

For a month’s treatment drugs like Ixabepilone and Dasatinib reportedly cost on an average of US$ 3,000 – 4,500 or Rs 1.64 – 2.45 lakh for each patient in India.

 A ‘Technology Transfer’ discouraged: 

Such a rapid development in the CL landscape of India is indeed intriguing, especially after a voluntary announcement by Roche in 2012 that it will produce Trastuzumab and Rituximab in India through transfer of technology to an Indian contract manufacturer.

Consequently for a month’s treatment, the price of Trastuzumab will come down from around US$ 2,000 to US$ 1, 366, i.e. by 31 percent and Rituximab from around US$ 1,456 to US$ 682 i.e. by 53 percent. This was reportedly announced by none other than the Minister of State of Chemicals and Fertilizers of India Mr. Srikant Jena.

Despite this voluntary decision of technology transfer and price reduction of two life saving drugs in India by Roche, reported Government consideration for grant of CL for Trastuzumab, without getting engaged in any form of a win-win dialogue with the Company, could ultimately prove to be counter productive and may discourage further technology transfer of expensive patented drugs to India.

Increasing incidence of cancer in India: 

Cancer is just not a dreaded disease, but also making a devastating impact, financial and otherwise, on the lives and families of thousands of sufferers in India.

According to ‘The Lancet’, published on 28 March 2012, in India 556 400 people died of cancer only in 2010.

The paper also comments that only half of the estimated 9.8 million total deaths per year is captured by the CRS in India, fewer than 4 percent are medically certified, while more than 75 percent of deaths occur at home.

The Lancet study clearly highlights that most cancer patients in India die without medical attention and drugs. Cancer is, therefore, increasingly becoming a public sensitive disease area with high socioeconomic impact in the country. High treatment cost of this near terminal disease is beyond reach of majority of population in the country.

In a written reply to a question in the ‘Upper House’ of the Indian Parliament, the Minister of State for Health and Family Welfare on March 4, 2012 said that according to “Three Year Report on Population Based Cancer Registries 2006 – 08″ of the Indian Council of Medical Research (ICMR), the estimated numbers of cancer patients for 2015 and 2020 are 1.16 million and 1.27 million respectively. There is a gradual rise in the prevalence of cancer in India, though the government has initiated several measures in this area.

High incidence of breast cancer: 

As per a recent report, an estimated 1, 00,000 – 1, 25,000 new patients suffer from breast cancer every year in India and this number is expected to double by 2025.

Government is mulling CL for NCD: 

Currently the DIPP appears to be planning to extend the provision of Compulsory License  (CL) beyond cancer drugs to other Non-Communicable Diseases (NCD) in the country, like diabetes. 

Domestic Pharma Association supports the move: 

A major domestic pharmaceutical industry association, as per media reports, supports this move by clearly articulating, “Over the years, more deaths are taking place on account of Non-Communicable Diseases (NCDs) than communicable ones. It is, therefore, natural that this provision (CL) will be used for NCDs as well.”

UN declaration on NCD provides flexibilities in TRIPS Agreement: 

Experts believe that this new move on CL for drugs related to NCDs is a consequence of India’s signing the United Nation (UN) declaration on the prevention of NCDs in the country by, among others, using flexibilities in the TRIPS Agreement to increase availability of affordable drugs for such diseases.

The Government has already launched a “National Program for Prevention & Control of Cancer, Diabetes, Cardio Vascular Diseases and Stroke (NPCDCS)” as a pilot project covering 150 million people in 100 inaccessible and most backward districts during the financial year 2011-2012 at a cost of US$ 275 million.

Socio-economic impact of NCDs in India: 

Indian Journal of Community Medicine (IJCM) in an article titled, “Social and Economic Implications of Non-Communicable Diseases (NCDs) in India” has highlighted, among others as follows:

  • NCDs account for 62 percent of the total disease burden in India with a significant ascending trend both in terms of overall mortality and morbidity.
  • This burden is likely to increase in the years to come.
  • Due to chronic nature of the disease and technological advancements in care, costs of treatment are high leading to access barriers, or ‘catastrophic expenditures’ for those who undergo treatment.
  • There are evidences of greater financial implications for the poorer households suffering from NCDs.
  • Most estimates suggest that the NCDs in India account for a significant economic burden ranging from 5 to 10 percent of GDP.
  • An urgent multi-sectoral Government action is strongly warranted both on grounds of economic arguments and social justice.
  • Action needs focus on addressing the social determinants of NCDs for prevention and strengthening of health systems to meet the challenge.
  • A framework for monitoring, reporting, and accountability is essential to ensure that the returns on investments in NCDs meet the targets and expectations set in the national plans.

Innovator companies contemplating legal recourse: 

Reacting to all these developments, the global pharmaceutical companies have, once again, expressed strong commitment to protect and continue to defend their Intellectual Property Rights (IPR) within the legal framework of India.

They have also reiterated their belief that a robust IPR regime will encourage innovation in the country making available more and more innovative drugs for the patients in India.

An interesting WHO report on a ‘robust IPR regime’: 

In this regard a World Health Organization (WHO) research report titled “Patents, Price Controls and Access to New Drugs: How Policy Affects Global Market Entry” makes some interesting observations on a ‘robust IPR regime’.

The report highlights the following four important points:

1. Increasing the strength of a patent system to include long-term protection on pharmaceutical products appears to spur market entry mostly in the high-income countries.

For the low- and middle-income countries that are currently being encouraged to move to stronger protection through trade policies, the evidence that extending protection enhances access to new pharmaceuticals is mixed.

2. There is some evidence that high level of protection might encourage more frequent entry of innovative products in the short term. However, in the longer term the same domestic capacity could well be an alternative source of entry of such drugs.

3. Intellectual Property (IP) holders frequently assert that the poor quality of enforcement in developing countries undermines the value of their patent rights. However, it is quite evident now that patent laws in these countries are at least broadly meaningful commensurate to their respective domestic requirements.

4. The standard argument on price regulation that it will dissuade market entry for innovative drugs appears to have more relevance among the high-income countries and not so for the poorer countries.

The authors further indicate:

“There we find that while price regulation makes it less likely that new drugs will be available quickly, it does not appear to prevent new products from being launched eventually.”

Conclusion: 

Following all these recent developments and weighing pros and cons, one could well imagine that pressure on the Government from various stakeholders for CL on drugs for Cancer and NCDs will keep mounting, unless an alternative measure like, ‘Price Negotiation for Patented Drugs’ is put in place by the Department of Pharmaceuticals, sooner than later, in 2013.

The recent judgment of the ‘Intellectual Property Appellate Board (IPAB)’ on CL to Natco may further add fuel to this raging debate.

It is now quite clear from the Finance Minister’s speech on the ‘Union Budget Proposal’ for 2013-14 that eagerly awaited ‘Universal Health Coverage’ or ‘Free Distribution of Essential Medicines to all’ schemes will not be implemented, at least for now.

Thus in all probability, the ghost of CL will keep haunting the innovators in India unabated, unless an effective, scalable and sustainable model for improving access to patented drugs for majority of population in the country is put in place. This will call for demonstrative, innovative and constructive Public-Private-Partnership (PPP) initiatives, sooner. In this effort  all concerned should at first be aligned with the cause, in principle, and try to be a constructive partner to get it translated into reality together, rather than just playing the role of vociferous critics in perpetuity .

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.

Government Ups the Ante for More Compulsory Licenses in India

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On January 12, 2013, one of the leading dailies of India first reported that in a move that is intended to benefit thousands of cancer patients, Indian Government has started the process of issuing Compulsory Licenses (CL) for three commonly used anti-cancer drugs:

-       Trastuzumab (or Herceptin, used for breast cancer),

-       Ixabepilone (used for chemotherapy)

-       Dasatinib (used to treat leukemia).

For a month’s treatment drugs like, Trastuzumab, Ixabepilone and Dasatinib reportedly cost on an average of US$ 3,000 – 4,500 or Rs 1.64 – 2.45 lakh for each patient in India.

CL through a different route:

This time the government can reportedly notify its intent to grant  CL under Section 92 of the Indian Patents Act 2005, only if any of the following three conditions are met:

- National emergency

- Cases of extreme urgency

- Public non-commercial use

After such Government notification in the gazette, any company interested in manufacturing any or all of these three products can directly apply for a CL to the Indian Patent Office (IPO).

This route is also expected to save usual litigation costs for the interested pharmaceutical players.

In such case, this will be the first time in India, when instead of pharmaceutical players applying for CL the Government on its own will trigger the CL process.

A situation like this will undoubtedly signal immense unpredictability in the IPR environment of the country.

Incongruent with the New Drug Policy 2012:

Interestingly, section 4(xv) of the National Pharmaceutical Pricing Policy 2012 (NPPP 2012) under ‘Patented Drugs’ states as follows:

“There is a separate Committee constituted by the Government order dated 1st February, 2007 for finalizing the pricing of Patented Drugs, and decisions on pricing of patented drugs would be taken based on the recommendations of the Committee.”

A media report also highlighted that an inter-ministerial group constituted for regulating prices of patented medicines in India has recommended using a per capita income-linked reference pricing mechanism for such products.

Thus, it is rather intriguing for many to fathom, why is the Government contemplating to grant CL on the above three anti-cancer drugs in January 2013, despite the decision of the Union Cabinet on the same in the new Drug Policy as recent as December, 2012.

Medicines come at the third stage of a medical treatment process:

For all patients, including the cancer victims, medicines will come at the earliest in the third stage of any treatment process, the first two or in some cases first three stages being:

  • A doctor’s intervention
  • Correct diagnosis through diagnostic processes
  • Surgical interventions (in some cases)

In India, there is no regulation to address the ‘cost issues’ of the first two or three stages of treatment, though there is a dire need to facilitate the entire process and not just one. Coming straight to cancer medicines considering these as the only ‘magic wands’ to improve access to treatment, may well be considered as ‘jumping the gun’ by the Government, if not an imprudent decision.

Skewed healthcare distribution in India:

Healthcare distribution in India is rather skewed and cancer treatment is no exception mainly because of the following reasons:

  • Medical personnel are concentrated in urban areas.
  • 74 percent of doctors work in urban settlements, which is just around 1/4th of the population.
  • 61 percent of the medical colleges are in the 6 states of Maharashtra, Karnataka, Kerala, Tamil Nadu, Andhra Pradesh and Pudicherry.
  • Whereas, just 11 percent of these are located in Bihar, Jharkhand, Orissa, West Bengal and the north-eastern states
  • 369,351 government beds are in urban areas and a mere 143,069 beds in the rural areas.
  • Rural “doctors to population” ratio is lower by 6 times as compared to urban areas.

(Source: KPMG Report 2011)

Huge healthcare Infrastructural Deficiencies:

In India, not just compared to the developed nations, even as compared BRIC countries, there is a huge infrastructural deficiencies as follows:

Indicators

Year

India

US

UK

Brazil

China
Hospital Bed Density(Per 10000 population)

2011

12

31

39

24

30
Doctor Density(Per 10000 population)

2011

6

27

21

17

14

(Source: WHO, World Health Statistics 2012)

  • 0.6 doctors per 1000 population as against the global average of 1.23 suggests an evident manpower gap in the very first stage of a treatment process.
  • Number of beds available per 1000 people in India is only 1.2, which is less than half of the global average of 2.6.

Coming to Medical Colleges, the scenario is equally dismal, as follows:

Year

Number of Medical Colleges

Total Admissions

2011-2012

314

29,263

No of dental Colleges

Total Admissions

2011-2012

289

2783

(Source: Medical Council of India & Dental Council of India)

Thus, India needs to open around 600 medical colleges (100 seats per college) and 1500 nursing colleges (60 seats per college) in order to meet the global average of doctors and nurses.

(Source: KPMG Report 2011) 

Shortages in other healthcare professionals:

It has been reported that a deficit of 64 lakh (6.4 million) allied healthcare professionals India with highest gaps in Maharashtra, Uttar Pradesh, West Bengal, Bihar and Andhra Pradesh, is a stumbling block in providing basic and quality healthcare to Indian population, as follows:

Healthcare Professionals

Shortage
Anesthetists and technicians              850,000
Dental staff              2.04 Million
Ophthalmologists and optometrists              127, 000
Rehabilitation specialists              1.8 Million
Medical laboratory technicians              61,000
Radiographers              19,000
Audiology and speech language specialists                7,500
Medical staff              230,000

(Source: Times Of India, December 20, 2012)

Is the Government ‘missing the woods for the trees’?

In a scenario like this, it is rather impractical to envisage that routine grant of compulsory licenses by the Indian Patent Office will be able to resolve the critical issue of improving access to patented medicines on a long term basis.

Not many CL granted between 1995-2012:

Despite having the provisions of CL in the Patents Act of many countries, not many CLs have been granted across the world from 1995 to date for the obvious reasons.

The details are as follows:

Country Medicine CL granted in:
Israel Hepatitis B Vaccine October 1995
Italy Imipenem (antibiotic) June 2005
Italy Sumatriptan Succinate (migraine) February 2006
Canada Oseltamivir (influenza) July 2006
Brazil Efavirenz (HIV/AIDS) May 2007
Thailand Erlotinib, Docetaxel (cancer) January 2008
India Sorafenib Tosylate (cancer) March 2012

Source: DNA, March 9, 2012

An interesting paper:

However, I hasten to add that despite all these, the provision of CL in the Indian Patents Act 2005 has immense relevance, if invoked in the right kind of circumstances.

In the paper titled ‘TRIPS, Pharmaceutical Patents and Access to Essential Medicines: Seattle, Doha and Beyond’, published in ‘Chicago Journal for International Law, Vol. 3(1), Spring 2002’, the author argues, though the reasons for the lack of access to essential medicines are manifold, there are many instances where high prices of drugs deny access to needed treatments for many patients. Prohibitive drug prices, in those cases, were the outcome of monopoly due to strong intellectual property protection.

The author adds, “The attempts of Governments in developing countries to bring down the prices of patented medicines have come under heavy pressure from industrialized countries and the multinational pharmaceutical industry”.

Right pricing of patented drugs is critical: 

While there is no single or only right way to arrive at the price of an IPR protected medicine, how much the pharmaceutical manufacturers will charge for such drugs still remains an important, yet complex and difficult issue to resolve, both locally and globally. Even in the developed nations, where an appropriate healthcare infrastructure is already in place, this issue comes up too often mainly during price negotiation for reimbursed drugs.

A paper titled, “Pharmaceutical Price Controls in OECD Countries”, published by the US Department of Commerce after examining the drug price regulatory systems of 11 OECD countries concluded that all of them enforce some form of price controls to limit spending on pharmaceuticals. The report also indicated that the reimbursement prices in these countries are often treated as de facto market price.

In India, the Government is already mulling to put in place a similar mechanism for patented medicines, as captured in the NPPP 2012.

Further, some OECD governments regularly cut prices of even those drugs, which are already in the market. The values of health outcomes and pharmacoeconomics analysis are gaining increasing importance for drug price negotiations/control by the healthcare regulators even in various developed markets of the world to ensure responsible pricing of IPR protected medicines.

An evolving global trend:

To address such pricing issues, global pharmaceutical majors, like GSK and Merck (MSD) have already started following the differential pricing model, based primarily on the size of GDP and income status of the people of the respective countries. This strategy includes India, as well.

Reference pricing model is yet another such example, where the pricing framework of a pharmaceutical product will be established against the price of a reference drug in reference countries.

An innovative approach to address patented products’ pricing:

To effectively address the challenge of pricing of patented medicines in India, Swiss drug major Roche, has reportedly entered into a ‘never-before’ technology transfer and manufacturing contract for biologics with a local Indian company – Emcure Pharma, for its two widely acclaimed Monoclonal Antibodies’ anti-cancer drugs – Herceptin and MabThera.

The report says that in the past, Emcure had signed licensing deals with US-based bio-pharmaceutical drug maker Gilead Life Sciences for Tenafovir and with Johnson and Johnson for Darunavir. Both are anti-HIV drugs.

In this regard, media reports further indicated that Roche would offer to Indian patients significantly cheaper, local branded versions of these two anti-cancer drugs by early this year. The same news item also quoted the Roche spokesperson from Basel, Switzerland commenting as follows:

“The scope is to enable access for a large majority of patients who currently pay out of pocket as well as to partner with the government to enable increased access to our products for people in need”.

Such ‘out of box’ strategies and initiatives by the global innovator companies could help keeping prices of patented products affordable to the Indian patients, improving their access significantly and making the likes of the current Government initiative on CL irrelevant. 

Conclusion:

It is generally accepted that the provisions for CL in the Indian Patents Act 2005 has utmost relevance in terms of public health interest for all concerned.

However, keeping in view of recent policy announcement in the NPPP 2012, as approved by the Union Cabinet, on price negotiation for patented products, the reported Government move of invoking these provisions for three anti-cancer drugs is rather intriguing.

Moreover, even for the cancer patients, there seems to be a greater urgency to attend to basic healthcare infrastructural and delivery issues, besides providing Universal Health Coverage  (UHC) as recommended by the High Level Experts Group (HLEG) constituted for this purpose by the Government.

Far encompassing critical decisions like grant of CL, I reckon, should be taken only after exhausting all other access improvement measures.

Thus, recent news reports on the possibility of further grant of three more CLs could make the pharmaceutical business environment for the innovator companies in India more uncertain.

Demonstrable predictability for an innovation friendly environment is critical for the economic growth of India, which the Government should not lose sight of. Just upping the ante for more CL of anti-cancer drugs will not necessarily help improving access to cancer treatments in India.

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.