Tag Archives: Biologic

A Game-Changing Non-Covid Drug Approval In the Pandemic Milieu

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Amid high decibel deliberations on Covid-19 pandemic, something similar to groundbreaking happened – involving Biosimilar drugs, in just a couple of months ago. On July 28, 2021, in the Eldorado of the pharma industry, the US-FDA approved  the first ‘interchangeable’ biosimilar drug, for wider access to modern and much affordable treatment of diabetes. This is expected to open new vistas of opportunity for biosimilar drugs, in general, across the world.

The development is even more interesting, as the product named Semglee belongs to India’s largest biopharmaceutical company - Biocon Biologic. It’s an ‘interchangeable’ biosimilar insulin glargine, referencing Sanofi’s, reportedly  the second best-selling product in 2020 - Lantus. Notably, the Biocon product was launched in 2020 without the ‘interchangeability’ designation.

Although, the patent of this long-acting insulin (glargine) – used to treat diabetes type I and II, expired during 2015, in 2020 also Lantus generated some 2.7 billion U.S. dollars worldwide. Many envisage, the approval of this first ‘interchangeable’ biosimilar insulin glargine will foster stronger competition in the insulin market, which is currently dominated by a handful of brands, like Lantus – and characterized by their stubbornly high prices.

In today’s article, I shall focus on what it means to pharma marketers for greater market access to ‘interchangeable’ biosimilar drugs.

What ‘interchangeability’ really means:

As I wrote in my article on July 31,2017, there are two key barriers to improving patient access to biosimilar drugs, and one of which is the issue of their ‘interchangeability’ with original biologic drugs. It means, besides being highly similar, a biosimilar drug would require indisputable clinical evidence – that it gives the same result to patients, just as the original biologic medicine.

Thus, lack of the ‘interchangeability’ designation makes many physicians hesitant to switch, for all those existing patients who are on expensive original biologic drugs, to less expensive available biosimilar alternatives. Only new patients in that case, are prescribed biosimilar drugs, sans ‘interchangeability’ label from the drug regulator, especially in the US.

Overcoming a tough barrier to biosimilar market growth:

This was echoed by another article on ‘Interchangeability’ of biosimilars, published in the Pharmaceutical Journal on July 22, 2020. It wrote, ‘One of the hurdles in the adoption of biosimilars is the lack of interchangeability with reference biologics.’ While interchangeability is an important issue for doctors, ‘different definitions and regulatory frameworks that exist in the United States, Europe and other jurisdictions add to the complexity.’

What the ‘interchangeable’ designation of Semglee will really mean, in terms of affordability to patients, was lucidly explained in an article, published in the AJMC – the center for Biosimilars – on July 29, 2021. It underscored: ‘An interchangeable designation means that Semglee can be substituted for Lantus automatically by pharmacists without physicians’ permission.’ As reported, Semglee will cost nearly 3 times less than the list price of Sanofi’s Lantus, which in 2019 clocked in at $283.56 for a single vial and $425.31 for a box of five pens, in the US.

Are interchangeable biosimilars superior to other biosimilars?

The ‘interchangeable’ designation is not meant to suggest that such biosimilars are superior to ones without this label. However, to obtain the ‘interchangeable’ designation, biosimilar manufacturers are required to perform ‘switching studies.’ These provide evidence that patients who are using originator’s biologic drug, when switch to a comparable biosimilar, do not experience higher rates of adverse events or decreased efficacy. The same has also been clearly explained in the AJMC article of July 29, 2021, as mentioned above.

But, if marketed well, ‘interchangeable’ biosimilars can provide a cutting edge to encourage consumers to switch to the less-expensive ‘interchangeable’ versions of the original higher priced biologic drugs. Consequently, more economical ‘interchangeable’ biosimilars would carve out a larger market share, creating a win-win situation. For patients, it will expand affordable access to biologic drugs- and for the company increased revenue from the expanding biosimilar market, as several studies point out.

Expanding biosimilar market:

According to the IQVIA report of March 04, 2021, the global biosimilars market currently shows double-digit growth and is expected to maintain a similar level of uptake in the coming years. This will be driven by the rising incidence of chronic diseases and the cost-effectiveness of biosimilars, especially as more stringent cost-containment measures are likely – post COVID-19 pandemic.

The paper concluded, biosimilars will continue to register impressive growth in their market share, aided by patent expiries and regulatory improvements which will permit easier and more rapid market access. Many pharmaceutical companies – having witnessed this trend, are now preparing to leverage the biosimilar opportunity. However, marketing large molecule biosimilar drugs will not be quite the same as marketing small molecule generics. 

Estimated savings to patients with biosimilars – in Covid-19 context:

As the IQVIA Institute estimates, over the next five years biosimilars could globally contribute a cumulative $285 billions of savings to patients and payers. To put this in context, it says, over the same period, around $150 billion will be spent on COVID-19 vaccines. According to a senior IQVIA official, as quoted by Reuters Events of July 2, 2021: “The five-year savings from biosimilars could almost double the amount of incremental spending that will be going out to get everybody vaccinated around the world.”

Going by the IQVIA data, biosimilars are between 20% and 50% more affordable. And this is especially at a time when affordability drives a lot of healthcare - sustainability that has emerged as a major issue during the pandemic.

Conclusion:

Currently, in many countries of the world, alongside Covid vaccination drive in top gear, creation of a disruptive pandemic-specific – a robust health infrastructure for the future, is yet to be in place. More importantly, public health facilities, especially in India, are still struggling hard to meet affordable health care needs of patients – sans restrictions or apprehensions of getting infected by Covid-19.

Against this backdrop, the very first approval of an ‘interchangeable’ biosimilar drug, in the Eldorado of pharma business – the US, brings a new hope to many patients, in 2021. An expectation of reducing their healthcare burden, significantly. This will happen, as the prescribers muster enough confidence to advise patients switching from highly expensive original biologic to more affordable ‘interchangeable’ biosimilar drugs, as and when these are launched.

In tandem, with this growing new confidence, others – even ‘non-interchangeable’ biosimilar drugs, will be able to deliver more value being, besides greater affordability – wider access to sustainable-treatments for patients.

This comes, possibly with a caveat. Biosimilar drug marketers will need to chart a new marketing frontier, without holding on to their pre-covid strategies – especially for large molecule biosimilar drugs.

From this perspective, the US-FDA’s regulatory approval of the first ‘interchangeable’ biosimilar insulin to Sanofi’s high-priced Lantus, carries a game-changing potential in the biosimilar drug market, for astute pharma marketers to leverage.

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.

Spirit Behind Drug Patent Grant: Secondary Patents: Impact on Drug Access

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For more effective treatment against existing diseases, besides combating new or a more complicated form of existing ailments with precision, drug innovation is absolutely necessary and on an ongoing basis. This makes innovative drugs so important for the population, globally.

Besides academia, the pharma industry has remained in the forefront of the search for new drugs, for so long. What makes this process so crucial is, cheaper generic drugs flow from the innovative drugs, post market exclusivity period, which together form the bedrock of the pharma industry’s business model. Consequently, a robust patent protection for the new molecular entities, not only enable the drug innovators to make a reasonably good profit, but also encourage them to keep this virtuous circle moving, faster.

Although, the drug patents are granted for 20 years, after obtaining marketing approval from the respective drug regulators, a time period - ranging between 7 and 12 years, is available to the company to realize its maximum commercial benefits. Thereafter, the patent expires, paving the way of market entry of cheaper generic equivalents to make the drug accessible to a larger population. This is the playbook, which deserves to be accepted and respected by all, both in the letter and spirit.

Currently, the narrative has started changing, apparently, repudiating the spirit behind the grant of new drug patents, especially with the entry of a number of expensive, large molecule biopharmaceutical drugs. After obtaining a fixed-term market exclusivity, more intricate legal measures are being taken to extend the fixed-term market monopoly for an unknown period, delaying market entry of cheaper biosimilar equivalents, post patent expiry, as long as possible.

In this milieu, India appears to be the only country in the world, where the country’s ‘Patents Act’ provides enough safeguard to blunt those legal tools, effectively, to protect patients’ health interest. Quite expectedly, this new narrative of the drug innovators is yielding the best return in the Eldorado of the pharma world – the Unites States. It is also no secret that US vehemently opposes several provisions of the Indian Patents Act 2005, under pressure from the most powerful pharma lobby group, as many believe.

Using the spirit behind drug patent protection as the backdrop, I shall dwell in this article, how this so precious spirit is gradually losing its basic purpose, especially for blockbuster biopharma drugs. Is the key intent behind sacrificing the spirit behind drug patent grant to keep their brands money spinners and big – even after expiry of original patent – as long as possible – at the cost of patients’ health interest?

Despite the original patent expiry, biggest biologic drugs remain big:

The fact that original patent expiries have done little to halt sales of some of the industry’s biggest products – mostly biologic drugs, was clearly elucidated in an  Evaluate Pharma article – “Biopharma’s biggest sellers – the oldies that just keep giving,” published on August 14, 2019. This gets vindicated, as we look at the ‘top ten pharma brands with biggest lifetime sales – from launch to 2018’, in the following Table I:

Product Company Launch year USD Billion
1. Lipitor Pfizer 1997 164.43
2 Humira AbbVie 2003 136.55
3. Rituxan Genentech/Biogen 1997 111.50
4. Enbrel Amgen 1998 108.16
5. Epogen Amgen 1988 107.90
6. Advair GSK 1998 104.20
7. Remicade Janssen 1998   98.00
8. Zantac GSK 1981   97.42
9. Plavix Sanofi/BMS 1998   90.63
10. Herceptin Genentech/Roche 1998   87.97

(Adapted from Evaluate Pharma data of August 14, 2019)

The point to take note of:

The point worth noting here, with the exception of Advair, Zantac, Lipitor and Plavix, all others – among the top ten brands, are biologic drugs. Moreover, what is most striking in the Table I, despite the expiry of the original patents, a large number of biologic brands were able to expand their sales, pretty impressively, for well over two decades. As we shall see later, this situation is expected to continue, at least, till 2024.  As the Evaluate Pharma article states, for various reasons, these multibillion dollar brands have been able to avoid the expected post patent expiry ‘onslaught from biosimilars in the key US market’, which is incidentally the most valuable pharma market in the world.

One of the key reasons that helps delaying cheaper biosimilar drug entry expanding patient access, is a crafty strategic measure adopted by these companies through the creation of a Patent Thicket with secondary patents. As I discussed in this Blog on April 22, 2019, this is a crafty way of ‘evergreening’ patent term beyond 20 years, legally. Whether such measures conform to the spirit of granting 20 years product patent, becomes a moral question, or an issue of probity for the concerned companies, at the most. Be that as it may, a concern over this situation has been raised in many countries, including the United States.

Barrier of secondary patents: 

Biosimilar drug developers continue facing multiple non-financial challenges, such as, scientific, regulatory, pricing. I have already discussed some of these barriers in this blog on July 31, 2017. Instead, I shall focus in this article, with greater detail, on the intricate and a well-woven net of secondary patents. However,before delving into this area, it will be worthwhile to have a quick recap on the basic differences between original patents and secondary patents.

According to WIPO, “Patents on active ingredients are referred to as primary patents. In later phases of the drug development, patents are filed on other aspects of active ingredients such as different dosage forms, formulations, production methods etc. These types of patents are referred to as secondary patents.”

Another excellent paper, authored by two distinguished researchers from Columbia University and LSE, makes some important points on this subject. It says, secondary patents have become increasingly important to the pharma industry, especially in the U.S. and Europe over the past three decades. The basic purpose of ‘taking out multiple patents on different aspects of a drug in order to cordon off competitors is now standard practice in the pharmaceutical industry.’ As the authors further said, this is primarily because: ‘Secondary patents can protect market shares by extending periods of exclusivity beyond the dates in which patent protection would otherwise lapse.’

Interestingly. devising patent strategies to extend periods of market exclusivity is generally considered in the industry, as a key component of ‘product life cycle management,’ – not by the marketing whiz kids, but by astute patent attorneys. Nevertheless, as the paper articulates, critics of this practice often use the more pejorative – evergreening, to describe it.

Examples of impact of secondary patents:

Many research papers suggest, besides scientific complexity in biosimilar drug development being a key reason for their delayed market entry, secondary patents are even tougher barriers for the same. This was brought to light a few years ago in a ‘Review Article’ – ‘The Economics of Biosimilars’, published in the September/October 2013 issue of American Health & Drug Benefits.

Some of the key points made on this issue include,AbbVie plan to defend Humira (adalimumab) with more than 200 secondary patents, Merck’s giving up its biosimilar project on Enbrel when Amgen got its expanded patent life. There are many other such instances.

Its effect would last longer: 

Experts believe, the effect of creating a strong secondary patent shield around blockbuster biologic would last much longer. As the above Evaluate Pharma article underscores: ‘This ability to fend off biosimilar competition is one of the reasons Humira is set to snatch Lipitor’s crown next year as the industry’s most successful drug.’

The Table II below that lists ‘top 10 pharma brands from their respective launch date, including estimated forecast till 2024’, vindicates its long-lasting impact:

Product Company Launch year USD Billion
1. Humira AbbVie 2003 240.05
2 Lipitor Pfizer 1997 180.19
3. Enbrel Amgen 1998 139.83
4. Rituxan Genentech/Biogen 1997 136.07
5. Revlimid Celgene 2008 123.64
6. Remicade Janssen 1998 117.20
7. Epogen Amgen 1988 115.87
8. Herceptin Genentech/Roche 1998 114.89
9. Avastin Genentech/Roche 2004 114.27
10. Advair GSK 1998 113.61

(Adapted from Evaluate Pharma data of August 14, 2019)

Although, Zantac and Plavix no longer feature in this table, one drug that leapfrogged much of the competition to become one of the industry’s biggest future bestsellers is Revlimid. The projected sales of the drug over the next six years will actually outstrip its sales to date. However, much of this is dependent on whether generic competition will arrive ahead of Revlimid’s 2022 patent expiry, the paper indicated.

Concern expressed even in the US for the delay in biosimilar market entry:

Many big spending countries on health care, such as the United States expected that timely biosimilar drug entry will help contain health expenditure significantly. However, the article published in the Fierce Pharma on August 29, 2019, raises an alarm, but with a hope for the future. It says: “It’s no secret biosimilars haven’t made a big dent in U.S. drug spending. Some experts have even said it’s time to give up on copycat biologic.”

This hope gets resonated with what, ‘the former US-FDA commissioner Scott Gottlieb argues’. He feels, ‘It’s too soon for that’, while ‘calling on Congress to bolster the budding market.’ However, in my personal view, this will remain a difficult proposition to implement, as biologic drug players will continue using their relatively new, but powerful weapon of filing a number of complex ‘secondary patents.’ These will help extend the market exclusivity period of their respective brands, much beyond the original patent grant period, unless a counter legal measures are taken by the lawmakers of various countries, including the United States. But, India is an exception in this regard.

Indian patent law doesn’t encourage ‘secondary patents’:

The good news is, Indian Patent Act 2005, doesn’t encourage ‘secondary patent.’ This is because, section 3 (d) of the Indian Patent Act 2005 limits grant of ‘secondary pharmaceutical patents.’ An interesting study reported on February 08, 2018, discussed about 1,700 rejections for pharma patents at the IPO spanning over the last decade. But, there is a huge scope for improvement in this area.

Which is why, the not so good news is under-utilization of the same section 3.d by the Indian Patent Office (IPO), as are being voiced in many reports. One such paper of April 25, 2018 highlighted,72 per cent of pharma patent grants are secondary patents. These were granted for marginal improvements over previously known drugs for which primary patents exist. That said, despite such reported lapses, blocking of some crucial secondary patent grant has benefited a large number of patient population of India.

Blocking secondary patent grant has helped India immensely:

While US recognizes secondary patents, blocking secondary patent grant, especially for biologic drugs has helped Indian patients immensely, with expanded access to those medicines. This was also captured in the above study. Besides the classic case of Novartis losing its secondary patent challenge for Glivec in the Supreme Court of India in 2013, several other examples of secondary patent rejection are also available. This includes, among others, Glivec of Novartis and the world’s top selling drug for several years – Humira of AbbVie.Against a month’s therapy cost of ₹1,6o, ooo for Glivec in the US, its Indian biosimilar version costs for the same period ₹11,100. Similarly, while the treatment cost with Humira in the US is ₹85,000, the same with its biosimilar version in India is ₹ 13,500, as the above study finds.

Conclusion:

The core purpose of drug innovation, as widely touted by the R&D-based drug companies, is meeting the unmet needs of patients in the battles against diseases. Thus, drug innovation of this genre must not just be encouraged, but also be adequately protected and rewarded by granting product monopoly for a 20-year period from the date of the original patent grant. Curiously, piggybacking on this basic spirit behind the drug patent grant, pharma lobby groups are now vocal on their demand for giving similar treatment to secondary patents on various molecules. The tone of demand gets shriller when it comes to section 3. d of the Indian Patents Act, which doesn’t allow such ‘evergreening’ through secondary patents.

Thus, the key question that surfaces, while the original patent grant for innovative drugs help meeting unmet needs of some patients, whose unmet needs would a secondary patent grant meet, except making the concerned company richer? Further, for highly expensive biologic drugs, delayed market entry of cheaper biosimilars in that process, would deny their expanded access – failing to meet the unmet needs of scores of others.

Hopefully, India won’t give in to pressure of multinational pharma lobby groups, channeled through various powerful overseas government entities. At the same time, I hope, the government in power at the Eldorado of the pharma industry, will consider giving a fair chance of market entry to cheaper biosimilars, including those from India, to also grow their business globally, but in a win-win way.

The key objective of all stakeholders involved in this process, should be to uphold the basic spirit behind drug patent grant. It may even call for challenging the core intent behind secondary patent applications, the world over, that deny quicker market entry for cheaper biosimilars, sans heavy litigation expenses. This will help expand access to cheaper biologic medicines to all those who can’t afford those, otherwise.

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.

 

 

 

 

Is India A Success Story With Biosimilar Drugs?

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How Indian generic companies are expanding, if not shifting their business focus on biosimilar and complex generic drugs, may be a current trend of general discourse – but the initiative is not a current one. This journey commenced decades ago with an eye on the future. In those days, Indian players were already dominating the global markets of small molecule generic drugs. Interestingly, it started much before the big global players decided to enter into this segment – especially post patent expiry of large molecule blockbuster drugs.

This strategy not just exhibits a sound business rationale, but also benefits patients with affordable access to biosimilar versions of high cost biologic drugs. In this article, I shall dwell on this subject, basically to understand whether India is a success story with large molecule biosimilar drugs, both in terms of drug development, and also in its commercial performance.

India’s journey began with the dawn of the new millennium:

About two decades back from now, some Indian pharma companies decided to step into an uncharted frontier of large molecule biosimilar drugs. According to the ‘Generics and Biosimilars Initiative (GaBI)’, in 2000 – the first biosimilar drug, duly approved by the Drug Controller General of India (DCGI), was launched in the country.  This was hepatitis B vaccine from Wockhardt – Biovac-B.

I hasten to add, in those years, there were no specific regulatory pathways for approval of large molecule biosimilar drugs in India. Thus, the same marketing approval guidelines as applicable to small molecule generic drugs, used to be followed by the DCGI for this purpose. Specific guidelines for biosimilar drugs were implemented on September 15, 2012, which was subsequently updated in August 2016. To date, around 70 large molecule biosimilar drugs, including biopharmaceuticals, have been introduced in India, as the GaBI list indicates.

It is equally important to note that well before any other countries, domestic pharma companies launched in India, AbbVie’s blockbuster Humira (adalimumab) and Roche’s breast cancer treatment Herceptin (trastuzumab). In this context, it is worth mentioning that US-FDA approved the first biosimilar product, Zarxio (filgrastim-sndz), in March 2015.

Will India be a key driver for global biosimilar market growth?

According to the Grand View Research Report of July 2018, increasing focus on biosimilar product development in countries, such as India, China and South Korea, is a major growth driver of the global biosimilar market. As this report indicates, the global biosimilars market size was valued at USD 4.36 billion in 2016, which is expected to record a CAGR of 34.2 percent during 2018-25 period.

Europe has held the largest revenue market share due to a well-defined regulatory framework for biosimilars was in place there for quite some time, and was followed by Asia Pacific (AP), in 2016. Growing demand for less expensive therapeutic products and high prevalence of chronic diseases in the AP region are expected to contribute to the regional market growth – the report highlighted.

Further, the Report on ‘Country-wise biosimilar pipelines number in development worldwide 2017’ of Statista also indicated that as of October 2017, India has a pipeline of 257 biosimilar drugs, against 269 of China, 187 of the United States, 109 of South Korea, 97 of Russia and 57 of Switzerland. However, post 2009 – after biosimilar regulatory pathway was established in the United States, the country has gained significant momentum in this segment, presenting new opportunities and also some challenges to biosimilar players across the world.

Is Indian biosimilar market growth enough now?

An important point to ponder at this stage: Is Indian biosimilar market growth good enough as of now, as compared to its expected potential? Against the backdrop of India’s global success with generic drugs – right from the initial stages, the current biosimilar market growth is certainly not what it ought to be. Let me illustrate this point by drawing an example from theAssociated Chambers of Commerce of India’s October 2016 White Paper.

According to the Paper, biosimilars were worth USD 2.2 billion out of the USD 32 billion of the Indian pharmaceutical market, in 2016, and is expected to reach USD 40 billion by 2030. This represents a CAGR of 30 percent. A range of biologic patent expiry in the next few years could add further fuel to this growth.

A similar scenario prevails in the global market, as well. According to Energias Market Research report of August 2018, ‘the global biosimilar market is expected to grow significantly from USD 3,748 million in 2017 to USD 34,865 million in 2024, at a CAGR of 32.6 percent from 2018 to 2024.’

Many other reports also forecast that the future of biosimilar drugs would be dramatically different. For example, the ‘World Preview 2017, Outlook to 2022 Report’ of Evaluate Pharma estimated that the entry of biosimilars would erode the total sales of biologics by as much as 54 percent through 2022, in the global markets. It further elaborated that biologic sales may stand to lose up to USD 194 billion as several top blockbuster biologic drugs will go off-patent during this period.

Although, current growth rate of the biosimilar market isn’t at par with expectations, there is a reasonable possibility of its zooming north, both in India and the overseas markets, in the near future. However, I would put a few riders for this to happen, some of which are as follows:

Some uncertainties still exist:

I shall not discuss here the basic barriers that restrict entry of too many players in this segment, unlike small molecule generics. Some of which are – requisite scientific and regulatory expertise, alongside wherewithal to create a world class manufacturing facility a complex nature. Keeping those aside, there are some different types of uncertainties, which need to be successfully navigated to succeed with biosimilars. To get an idea of such unpredictability, let me cite a couple of examples, as hereunder:

1. Unforeseen patent challenges, manufacturing and regulatory issues:

  • Wherewithal to effectively navigate through any unexpected labyrinth of intricate patent challenges, which are very expensive and time-consuming. It may crop up even during the final stages of development, till drug marketing, especially in potentially high profit developed markets, like for biosimilars of Humira (AbbVie) in the United States or for Roche’s Herceptin and Avastin in India.
  • It is expensive, time consuming and risk-intensive to correct even a minor modification or unforeseen variation in the highly controlled manufacturing environment to maintain quality across the system, to ensure high product safety. For example, what happened to Biocon and Mylan with Herceptin Biosimilar. As the production volume goes up, the financial risk becomes greater.
  • There are reports that innovator companies may make access to supplies of reference products difficult, which are so vital for ‘comparability testing and clinical trials.’  This could delay the entire process of development of biosimilar drugs, inviting a cost and time-overrun.
  • Current regulatory requirements in various countries may not be exactly the same, involving significant additional expenditure for overseas market access.

2. User-perception of biosimilar drugs:

Studies on perception of biosimilar vis-à-vis originator’s biologic drugs have brought out that many prescribing physicians still believe that there can be differences between originator’s biologic medicine and their biosimilar equivalents. With drug safety being the major concern of patients, who trust their physician’s decision to start on or switch to a biosimilar, this dilemma gets often translated into doctors’ preferring the originator’s product to its biosimilar version. One such study was published in the September 2017 issue of Bio Drugs. Thus, the evolution of the uptake of biosimilars could also depend mainly on similar perception of physicians.

What happens if this perception continues?

Whereas, the W.H.O and drug regulators in different countries are quite clear about comparable safety and efficacy between the originator’s product and its biosimilar variety, some innovator companies’ position on biosimilar drug definition, could help creating a perception that both are not being quite the same, both in efficacy and safety.

To illustrate this point, let me reproduce below how a top ranked global pharma company - Amgen, defines biosimilar drugs, starting with a perspective of biologic medicines:

“Biologic medicines have led to significant advances in the treatment of patients with serious illnesses.These medicines are large, complex molecules that are difficult to manufacture because they are made in living cells grown in a laboratory. It is impossible for a different manufacturer to make an exact replica of a biologic medicine due to several factors, including the inherent complexity of biologics and the proprietary details of the manufacturing process for the original biologic medicine, often referred to as the reference product.It is because of this that copies of biological products are referred to as “biosimilars”; they are highly SIMILAR but not identical to the biologic upon which they are based.”

Could dissemination of the above concept through a mammoth sales and marketing machine to the target audience, lead to creating a better perception that the originators’ biologic drugs are better than their biosimilar genre?

Other realities:

Despite the availability of a wide array of biosimilar drugs, the prescription pattern of these molecules is still very modest, even in India. One of its reasons, as many believe, these are still not affordable to many, due to high out-of-pocket drug expenses in India.

Thus, where other biosimilars of the same category already exist, competitive domestic pricing would play a critical role for faster market penetration, as happens with small molecule generic drugs.

Another strategic approach to address cost aspect of the issue, is to explore possibilities of sharing the high cost and risks associated with biosimilar drug development, through collaborative arrangements with global drug companies. One good Indian example in this area is Biocon’s collaboration with Mylan.

Conclusion:

The question on whether Indian biosimilar market growth is good enough, assumes greater importance, specifically against the backdrop of domestic players’ engagement in this segment, since around last two decades. Apart from the important perception issue with biosimilars , these medicines are still not affordable to many in India, owing to high ‘out of pocket’ drug expenditure. Just focusing on the price difference between original biologic drugs and their biosimilars, it is unlikely to get this issue resolved. There should be enough competition even within biosimilars to drive down the price, as happened earlier with small molecule generics.

That said, with around 100 private biopharmaceutical companies associated with development, manufacturing and marketing of biosimilar drugs in India, the segment certainly offers a good opportunity for future growth. Over 70 such drugs, most of which are biosimilar versions of blockbuster biologic, are already in the market. Today, Indian companies are stepping out of the shores of India, expecting to make their presence felt in the global biosimilar markets, as they did with generic drugs.

The future projections of biosimilar drugs, both in the domestic and global markets are indeed very bullish. But to reap a rich harvest from expected future opportunities, Indian players would still require some more grounds to cover. Overall, in terms of biosimilar drug development since 2000, India indeed stands out as a success story, but a spectacular commercial success with biosimilars is yet to eventuate.

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.

A ‘Toxin’ Delaying Success of Biosimilar Drugs

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The above comment, although sounds a bit harsh, was made recently by none other than Scott Gottlieb - the Food and Drug Administration Commissioner of the United States. He expressed his anguish while explaining the reasons for a delayed launch of several important biosimilar drugs.

We know, this new genre of drugs has a potential to be a quick game changer, significantly improving access to affordable biologic medicines for many patients. Unfortunately, much desired accelerated progress in this direction, got considerably retarded in the face of a strong headwind, craftily created by the innovator companies, as is widely believed. There are various ways of creating the same. However, the two major ones can be ascribed to:

  • Getting caught in the labyrinth of complex patent challenge.
  • General apprehensions of many doctors on the efficacy and safety of biosimilars as compared to reference drugs.

This is happening in major markets, including India, in varying degree, though.  In this article, I shall deliberate on this issue, starting with the largest pharma market of the world and then focusing on India.

‘Toxin’ that delays biosimilar drug launch:

“Americans could have saved $ 4.5 billion in 2017, if all of the FDA-approved biosimilars were actually available in the United States, instead of getting delayed because of litigations or other agreements.” The Food and Drug Administration Commissioner of the United States – Scott Gottlieb, reportedly, made this comment on July 18, 2018.

Gottlieb referred to some of these as a “toxin” that have prevented other drug makers from launching biosimilar medicines. He accused the manufacturers of pricey biologic medicines of using “unacceptable” anti-competitive tactics to keep competitors off the market. These cost Americans billions of dollars – the report highlighted.

These tactics, as the US FDA commissioner said, are being deliberately used by the innovator pharma and biotech companies and can be corroborated with several examples. One such is the fact that despite the expiration ofthe ‘composition of the matter’ patent for Humira (adalimumab) in December 2016, its ‘non-composition of the matter’ patent would expire not earlier than 2022. The company has therefore made settlement agreements with Amgen and Samsung Bioepis, delaying the launch of adalimumab biosimilars until January 2023.

Protecting own patents Big Pharma challenging rivals’ patents:

Both these are happening for original biologic and biosimilar equivalents, often by the same manufacturers. For example, the Reuters report of October 02, 2016, titled  ‘Big Pharma vs Big Pharma in court battles over biosimilar drugs’ highlighted, although Novartis and Amgen are at each other’s throats in court over the Swiss drug maker’s Enbrel copy, but the two are still cooperating on a drug for migraines.

“One of the biggest surprises has been the number of innovator Biopharma companies, like Amgen, now developing biosimilars to compete with the products of other innovator companies,” the article observes. It also reports that Sanofi, Merck, Eli Lilly, Pfizer, Johnson & Johnson and Biogen are also embroiled in lawsuits over biosimilars.

This trend vindicates that the line dividing makers of brand-name drugs and copycat medicines is blurring as companies known for innovative treatments queue up to peddle copies of rivals’ complex biological medicines, Reuters noted. Consequently, they are now doing both – protecting their high-price products from biosimilars drugs,while simultaneously challenging rivals’ patent claims.

There is another interesting side to it. Notwithstanding, biosimilars are a cost-effective alternative to biologic drugs that could improve patients’ access to expensive biological medicines, prescribers’ perception of biosimilar medicines are still not quite positive, just yet.

Doctors’ attitude on biosimilar prescription:

To illustrate this point, let me quote from recent research findings in this area. One such is the May 2017 study on “Medical specialists’ attitudes to prescribing biosimilars.” The key points are as follows:

  • Between 54 and 74 percent of the specialists are confident in the safety, efficacy, manufacturing and Pharmacovigilance of biosimilars.
  • 71 percent of specialists agreed that they would prescribe biosimilars for all or some conditions meeting relevant clinical criteria.
  • Specialists are less confident about indication extrapolation and switching patients from an existing biologic.
  • The most common situations that they would not prescribe a biosimilar was where there was a lack of clinical data supporting efficacy (32 percent), or evidence of adverse effects.

Overall, medical specialists held positive attitudes towards biosimilars, but were less confident in indication extrapolation and switching patients from the original biologic. Several experts believe that constantly highlighting the fear factors against biosimilar drugs, such as possible risks of interchangeability with reference product, or immunogenicity related serious consequences, though very rare, are fueling the fire of apprehensions on the wide use of biosimilar medicines.

However, several reviews, like the one that I am quoting here finds that ‘switching from the reference product to related biosimilar drug is not inherently dangerous.’I discussed this issue, with details in one of my articles, published in this blog on July 31, 2017.

Any therapeutic difference between the original biologic and biosimilars?

As the US-FDA says: “Patients and their physicians can expect that there will be no clinically meaningful differences between taking a reference product and a biosimilar drug when these products are used as intended. All reference products and biosimilar products meet FDA’s rigorous standards for approval for the indications (medical conditions) described in product labeling.”

The key point to take note of is that the US drug regulator categorically reiterates: “Once a biosimilar has been approved by the FDA, patients and health care providers can be assured of the safety and effectiveness of the biosimilar, just as they would for the reference product.”

The invisible barriers to biosimilar drugs in India:

Although, there are no specific data requirements for interchangeability of biosimilar drugs with the reference product, as mentioned in the latest Indian Guidelines on similar biologic, other visible and visible barriers are restricting the rapid growth of drugs belonging to this genre.

An interesting research study finds, like many other drugs, the cost of biosimilars is a major barrier to the rapid growth of the market in India. The Deloitte Report, titled “Winning with biosimilars: Opportunities in global markets” also articulated: “Approximately 70 percent of the country’s population is considered rural and will focus on the cost of therapy – a 20-30 percent discount on originator biologics may not be sufficient.”

Moreover, many patients who are on original biologic drugs, costing higher than related biosimilars and want to switch over to affordable equivalents, are not able to do so. In many cases, doctors’ do not encourage them to do so, for various reasons, including the general assertion that original biologic drugs are more effective. India being considered as the global capital of diabetes, let me cite an example from this disease area, just to drive home the point.

A recent experience on biosimilar drug interchangeability in India:

Just the last week, I received a call from a friend’s wife living in Delhi who wanted to know whether Lantus 100 IU/ml of Sanofi can be replaced with Glaritus 100 IU/ml of Wockhardt, as the latter costs much less. I advised her to consult their doctor and request accordingly. She said, it has already been done and the doctor says Lantus is a better product.

To get a fact-based idea on what she told me, I referred to two circulars of the National Pharmaceutical Pricing Authority (NPPA) – one for Glaritus and the other one for Lantus and found that both are under drug price control and have respective ceiling prices. As both the circulars are of 2009, these may probably be treated as an indicative price difference. NPPA notified price for a 3 ml cartridge of Glaritus reads as Rs.135. 24. Whereas, the same for Lantus was mentioned as Rs.564.84.

Is an original biologic generally superior to Indian biosimilars?

US-FDA has already reiterated, “Once a biosimilar has been approved by the FDA, patients and health care providers can be assured of the safety and effectiveness of the biosimilar, just as they would for the reference product.”

However, to get India-specific, evidence-based information in this area, I checked, whether Lantus has any clinically proven therapeutic superiority over Glaritus. Interestingly, I came across the results of a 12-week study concluding that biosimilar insulin glargine, Glaritus, is comparable to the reference product, Lantus – providing a safe and effective option for patients with T1DM. Nevertheless, the researchers did say that more studies are required in this area.

The core question that needs to be addressed why is the doctor’s perception so different and the reasons for the same?

Conclusion:

In view of all that has been discussed in this article, I find it challenging to fathom that in the absence of any credible and conclusive specific study, how could a doctor possibly infer that higher priced imported original biologic drugs are generally superior to lower priced biosimilar equivalents? More so, when in India, there are no regulatory issues on interchangeability between original biologic and its biosimilar equivalent.

Or for that matter, a branded generic product is superior to all other equivalent generic drugs without a brand name? This can happen, especially when the vested interests actively work on ensuring that such a perception gains ground, boosting the sales revenue and mostly at the cost of patients’ interest.

As one would witness in many other spheres of life that creating a blatantly self-serving, positive target audience perception, by any means, primarily aimed at destroying the same of others, is assuming increasing importance. Are we seeing the reflection of the same, even in the field of evidence based medical science?

I reckon, it raises a flag for all to ponder, particularly after reading the recent candid comments of the US-FDA commissioner, as quoted above.

Could this be one of those ‘Toxins’, which delays success of biosimilar drugs?

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.

 

‘Rigged’ Payment System Limits Biosimilar Access

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As often discussed, market entry of biosimilars, in general, brings a new hope not just for many patients, but also to biosimilar drug manufacturers – planning to get marketing approvals of these drugs in the United States, the El Dorado of global pharma industry.

Stakeholder expectations keep increasing manifold as biosimilars offer cheaper treatment options with biologic drugs in many life-threatening and rare diseases. However, biosimilars still remain an unfulfilled promise.

The January 2018 paper by Trinity Partners on “The State of US Biosimilars Market Access” in the largest drug market of the world makes an important observation in this regard. It says, the promise of biosimilars offering cost-saving competition in the lucrative US biologic market, remains largely unfulfilled.

As on date, adoption of biosimilars has been hindered by lack of market access due to complex contracting dynamics, besides regulatory and legal uncertainty, and a general lack of clinical comfort with biosimilars.

Consequently, current state of biosimilar acceptance and access appear too insignificant. More so, as compared to traditional small molecule generic markets where their use is fueled by automatic substitution and payer formularies, over higher priced branded reference drugs.

It would not have been difficult, especially for the innovative biologic drug makers to brush this important study aside, had the US-FDA Commissioner – Scott Gottlieb would not have voiced what he did in March this year.

With this perspective, I shall discuss in this article, how access to biosimilar drugs are getting limited. In doing so, I shall begin with what the US-FDA Commissioner has recently highlighted in this area.

Yet another barrier:

As reported by Bloomberg on March 07, 2018, the US-FDA Commissioner Scott Gottlieb unambiguously expressed that biologic drug manufacturers enter into exclusive arrangements with Pharmacy Benefit Managers (PBMs) and insurers, who agree to cover only the old brands in return for rebates or discounts. This “rigged” payment scheme might quite literally scare the biosimilar competition out of the market altogether, he articulated, categorically.

US-FDA Commissioner delivered this speech at the National Health Policy Conference for America’s Health Insurance Plans. During this deliberation, Gottlieb criticized some unwanted and avoidable practices that stifle biosimilar development.

He observed, of the 9 approved biosimilars in the US, only 3 could be launched market. In many instances, patent litigation is the reason for such delay in launch, post FDA approval. Connecting the dots, the Commissioner observed, even after being in the market, biosimilars continue facing more uncertainty due to a ‘rigged payment scheme.’

Started with a great promise:

It is worth noting, till 2010 no regulatory pathway for marketing approval of biosimilars was in place in the world’s largest pharma market – the United States. Hence, despite biosimilar drugs being a treatment option in many countries over the last two decades, the first biosimilar was launched in the US, following this pathway, only in 2015. It was Zarxio ((Filgrastim-sndz) of Novartis – indicated for the treatment of patients with acute myeloid leukemia (AML).

Since then, US-FDA has approved nine biosimilars. Ironically biosimilar market size still remains small and much below the general expectations. Most biosimilar manufacturers are navigating through multiple tough hurdles for market launch of this relatively new genre of complex drugs.

Navigating through tough hurdles:

There are tough hurdles to navigate through, while launching biosimilars, especially in the US. Some of which are as follows:

Protracted litigations: The development and launch of most biosimilars get stuck in the multiple patent web-lock, created around original biologic molecules, leading to long drawn expensive litigations.

Pricing: Following small molecule generic drugs, most payers and consumers expect biosimilar pricing too will be no different. However, in practice, most biosimilars are priced just around 15 percent to 20 percent less than original biologics.

Interchangeability: Lack of interchangeability among presently approved biosimilars in the US limits payers’ and consumer choice for a shift from the reference biologic drugs to suitable biosimilars. This virtually restricts the use of biosimilars mostly to such drug-naïve patients.

Confidence: For various reasons, the confidence and familiarity of both physicians and the consumers on biosimilars remain suboptimal. Whether relatively cheaper biosimilars can be used in the same indications as the reference biologic to the new patients – as an alternative choice, is still not clear to many of them. This situation calls for increasing awareness programs involving all stakeholders.

Manufacturing: The manufacturing process of large molecule biosimilars is quite costly as compared to small molecule generic drugs. Hence, these are unlikely to follow a similar pricing pattern, attracting as high a discount as around 80 percent, compared to original branded drugs.

Some of these barriers I have discussed in my article, titled ‘Improving Patient Access To Biosimilar Drugs: Two Key Barriers’, published in this blog on July 31, 2017.

Conclusion:

Be that as it may, drug manufacturers continue to see tremendous opportunity in biosimilars. The interest is heating up, as about six of the top 10 biologic drugs are expected to go off-patent in the US by 2019.

Despite all this, it is generally believed, the prevailing situation will change even in the US. The regulator is expected to facilitate smoother market entry of biosimilars, facing much less obstacles on the way. As many strongly believe, these are possibly an outcome of intense industry lobbying, with the high-level policy makers.  Many of these hurdles can be removed by the regulators, themselves, including drug interchangeability.

The US-FDA Commissioner Scott Gottlieb has already said in a meeting on March 07, 2018, the FDA will start educating doctors and patients to minimize clinical and other concerns related to biosimilars. Therefore, going forward, greater competition in the biosimilar space is expected to increase the long-awaited price differential, as compared to reference biologic.

With greater support from the regulators, biosimilars still show a unique promise of greater acceptance and access to patients – occasionally ‘Rigged’ maneuvers by the vested interests notwithstanding.

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.

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.

Improving Patient Access To Biosimilar Drugs: Two Key Barriers

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Novel biologic medicines have unlocked a new frontier offering more effective treatment for a host of chronic and life-threatening diseases, such as varieties of cancer, rheumatoid arthritis and diabetes, to name just a few. However, these drugs being hugely expensive, many patients do not have any access, or adequate access, to them. According to the Biosimilar Council of GPhA, only 50 percent of severe Rheumatoid Arthritis patients receive biologic medicines, even in the United States, Europe and Japan, leave aside India.

Realizing the gravity of this situation, a need to develop high quality, reasonably affordable and similar to original biologic brands, was felt about ten years ago. These were intended to be launched immediately after patent expiry of the original biologic. Such medicines are termed as biosimilar drugs. It is worth noting, even biosimilar drug development involves complex manufacturing processes and handling, while dealing with derivatives of highly sensitive living organisms.

The regulatory approval process of these drugs is also very stringent, which demands robust clinical data, demonstrating high similarity, both in effectiveness and safety profile, to original biologic brands, known as the reference product. The clinical data requirements for all new biosimilars include data on patients switching from the originator’s brand, and also between other biosimilars. Clinical evidences such as these, are expected to provide enough confidence to physicians for use of these products.

An article published in the PharmaTimes magazine in January 2016, reiterated that over the last couple of years, a wealth of supporting data has been published in medical journals and presented at global congresses, including real-world data of patients who have been switched to the new drug from the originator. This has led to a positive change in physician and patient attitudes towards biosimilars.

The good news is, besides many other regulated markets, as of May 2017, five biosimilar drugs have been approved even by the US-FDA, and several others are in the pipeline of its approval process.

That said, in this article I shall mainly focus on the two key barriers for improving patient access to biosimilar drugs, as I see it.

Two major barriers and their impact:

As I see it, there appear to be the following two key barriers for more affordable biosimilar drugs coming into the market, improving patients’ access to these important biologic medicines:

  • The first barrier involves fierce legal resistance from the original biologic manufacturers of the world, on various grounds, resisting entry of biosimilar varieties of their respective brands. This compels the biosimilar drug manufacturers incurring heavy expenditure on litigation, adding avoidable cost. A glimpse of this saga, we are ‘privy’ to witness even in India, while following Roche versus Biocon and Mylan case related to ‘Trastuzumab’. This barrier is one of the most basic types, that delays biosimilar drug entry depriving many new patients to have access to lower priced effective biologic for the treatment of serious diseases.
  • The other major barrier that exists today, involves ‘interchangeability’ of original biologic with biosimilar drugs. It simple means that in addition to being highly similar, a biosimilar drug manufacturer would require producing indisputable clinical evidence that it gives the same result for any given patient just as the original biologic. We shall discuss the reason behind this regulatory requirement later in this article. However, this is an expensive process, and the absence of it creates a barrier, making the physicians hesitant to switch all those existing patients who are on expensive original biologic drugs with less expensive available biosimilar alternatives.

The first or the initial barrier:

The first or the initial barrier predominantly involves patent related legal disputes, that can only be settled in a court of law and after incurring heavy expenditure towards litigation. Provided, of course, the dispute is not mutually resolved, or the law makers do not amend the law.

An interesting case in India:

Interestingly, in India, a similar dispute has knocked the doors of both the high court and the Competition Commission of India (CCI). From a common man’s perspective, it appears to me that the laws under which these two institutions will approach this specific issue are seemingly conflicting in nature. This is because, while the patent law encourages no market competition or a monopoly situation for a patented product, competition law encourages more market competition among all related products. Nonetheless, in this specific case CCI is reportedly investigating on the alleged ‘abuse of the regulatory process’, as it has opined ‘abuse of regulatory process can constitute an abuse of dominance under the (CCI) Act.’                                                                                            

The second barrier:

I am not going to discuss in this article the relevance of this barrier, in detail. Nevertheless, this one is also apparently equally tough to comply with. The very fact that none out of five biosimilar drugs approved in the United States, so far, has been considered ‘interchangeable’ by the US-FDA, vindicates the point.

That this specific regulatory demand is tough to comply with, is quite understandable from the requirements of the US-FDA in this regard, which goes as follows:

“To support a demonstration of interchangeability, the data and information submitted to FDA must show that a proposed interchangeable product is biosimilar to the reference product and that it can be expected to produce the same clinical results as the reference product in any given patient. Also, for products that will be administered more than once, the data and information must show that switching a patient back and forth between the reference product and the proposed interchangeable product presents no greater risk to the patient in terms of safety or diminished efficacy when compared to treating them with the reference product continuously.”

The reasoning of innovative biologic drug makers:

On this subject, the stand taken by different innovative drug makers is the same. To illustrate the point, let me quote just one of them. It basically sates, while biosimilar drugs are highly similar to the original medicine, the patient’s immune system may react differently due to slight differences between the two medicines when they are alternated or switched multiple times. This phenomenon, known as immunogenicity, is not a common occurrence, though. But there have been rare instances when very small differences between biologic medicines have caused immune system reactions that changed the way a medicine was metabolized, or reduced its effectiveness.

It further reiterates, the US-FDA requirements to establish ‘interchangeability’ between a biosimilar drug and the original one, or between biosimilars may seem like nuances, but are important because ‘interchangeability’ allows pharmacists to substitute biosimilars without consulting the doctor or patient first.

It may, therefore, indicate to many that innovative biologic drug manufacturers won’t want substitution of their expensive biologic with more affordable biosimilar drugs, on the ground of patient safety issues related to immunogenicity, though its instances are rather uncommon.

Some key players in biosimilar drug development:

Having deliberated on the core subject of this article, let me now very briefly name the major players in biosimilar drug development, both in the developed world, and also in India.

The first biosimilar drug was approved by the US-FDA in 2006, and the product was Omnitrope (somatropin) of Novartis (Sandoz). It was the same in the European Union (EU), as well. Subsequently, many other companies reportedly expressed interest in this field, across the globe, including Pfizer, Merck, Johnson and Johnson, Amgen, AbbVie, Hospira, AstraZeneca and Teva, among many others.

Similarly, in India, the major players in this field include, Biocon, Sun Pharma, Shantha Biotech, Dr. Reddy’s Lab, Zydus Cadila, Panacea Biotech and Reliance Life Sciences.

As featured on the Amgen website, given the complexity and cost of development and manufacturing, biosimilars are expected to be more affordable therapeutic options, but are not expected to generate the same level of cost savings as generics. This is because, a biosimilar will cost US$100 to US$200 million and take eight to ten years to develop. Whereas, a small molecule generic will cost US$1 to US$5 million and take three to five years to develop.

The market:

According to the 2017 report titled “Biosimilar Market: Global Industry Analysis, Trends, Market Size & Forecasts to 2023” of Research and Markets, the market size of the global biosimilar market was valued over US$ 2.5 billion during 2014, and it surpassed US$ 3.30 billion during 2016. The global biosimilar market is projected to surpass US$ 10.50 billion by 2023, growing with a CAGR between 25.0 percent and 26.0 percent from 2017 to 2023.

According to this report, gradually increasing awareness, doctors’ confidence and the lower drug cost are expected to boost the demand and drive the growth of the global biosimilar market during the forecast period. Segments related to diabetes medicine and oncology are expected to attain faster growth during the forecast period. Patent expiry of several blockbuster drugs is a major basic factor for growth of the global biosimilar market, as it may encourage the smaller manufacturers to consider producing such biologic drugs in those segments.

Conclusion:

Biosimilar drugs are expected to benefit especially many of those patients who can’t afford high cost biologic medicines offering better treatment outcomes than conventional drugs, in the longer term. These drugs are now being used to effectively manage and treat many chronic and life-threatening illnesses, such cardiac conditions, diabetes, rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn’s disease, HIV/AIDS and cancer.

However, improving patient access to high quality biosimilar drugs, at an affordable price, with increasing competition, could be a challenge, as two key barriers are envisaged to attain this goal. Overcoming these meaningfully, I reckon, will involve choosing thoughtfully a middle path, creating a win-win situation, both for the patients, as well as the industry.

Adequate competition in the biologic drug market is essential – not only among high-priced original biologic brands and biosimilars, but also between biosimilar drugs. This is so important to increase patient access to biologic drugs, in general, across the world, including India.

The current situation demands a sense of urgency in searching for a middle path, which may be created either through a legal framework, or any other effective means as would deem fair and appropriate, without compromising with patient safety, at least, from where it is today.

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.

Is Criticizing Pharma Now Just A Fad?

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Is criticizing pharma now just a fad of its stakeholders? Fathoming the right answer to this seemingly simple question may not be too easy, either, for some. The task could even be more onerous, especially when the global ‘researched based’ pharma and biotech companies, well chorused by their trade associations, are exerting serious efforts to garner the much required trust of all stakeholders on their ‘patient centric’ focus in the process of transacting business.

This often repeated pledge, as it were, on ‘patient centric’ approach is indeed praiseworthy. There’s no two opinions about it, either. The new found interest of several ‘research-based’ pharma and biologic players to develop less expensive biosimilar drugs, to possibly improve patient access to otherwise expensive biologic medicines, post patent expiry, could well be a reiteration of the same and well publicized vow, of course if not proven otherwise.

A recent example:

In the context of ‘patient-centric’ approach with biosimilar product development by the world’s largest innovative biologic drug makers, let me quote the following recent example.

On September 23, 2016, by a Press Release, the Food and Drug Administration of the United States (US-FDA) announced regulatory approval of Amjevita (adalimumab-atto) as a biosimilar to Humira (adalimumab) for multiple inflammatory diseases. This is the fourth FDA-approved biosimilar, after the new biosimilar pathway became effective in the US. Amjevita has been developed by Amgen Inc. – one of the global pioneers in the development of innovative biologic drugs.

According to US-FDA, a biosimilar is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

Although, Amjevita is biosimilar to Humira,  it has not been approved as an interchangeable product with Humira. This issue is considered as a major regulatory roadblock in the US for substitution of original biologic brands with their biosimilar equivalents, which can, therefore, be prescribed mostly to the new patients. It’s worth noting here that Humira – the blockbuster arthritis drug of AbbVie Inc. clocked a sale of US$ 14 billion in 2015, and probably will continue to do so in the foreseeable future, even long after patent expiry. I shall touch upon that point below, briefly.

It is estimated that the savings of putting just new patients on much less expensive biosimilar drugs, sans substitution of the expensive original brand, will be billions of dollars. Nonetheless, this will help reduce the cost of treatment with biologic medications, improving their access to many others.

A key barrier:

Interestingly, the barriers to following the biosimilar path are being mostly created none other than the innovative drug companies themselves, even post patent expiry, presumably to extend market exclusivity and monopoly pricing.

Arising out of one such key barrier, in the form of patent litigation, Amgen’s Amjevita, in all probability, may not be available to deserving patients for years. This could involve a protracted process of skillfully navigating through the labyrinth of legalities.

On August 05, 2016, The Wall Street Journal (WSJ) reported that AbbVie Inc. has filed a patent-infringement lawsuit against rival Amgen Inc., seeking to block sales of a lower-priced biosimilar of AbbVie’s top-selling, now generally considered as an off-patent drug – Humira.

When the narrative gets paradoxical:

While all the ‘research-based’ drug companies claim to be ‘patient-centric’ in their business approaches, be it with the development of biosimilars or in other areas, somewhere this narrative gets paradoxical.

On September 02, 2016, Reuters reported that global ‘research-based’ companies are now ‘waging courtroom patent battles against each other over biosimilars, as the line blurs between companies known for their innovative medicines, and those that produce cheaper biotech knockoffs.’

Some of the recent high-profile examples were reported as follows:

  • Sanofi sued Merck in the US federal court over its biosimilar version of Lantus insulin with around US$7 billion in annual sales.
  • Eli Lilly reached a royalties deal with Sanofi to end a similar Lantus-related lawsuit, but their pact means the biosimilar launch was likely delayed.
  • Pfizer and Korea’s Celltrion in August beat back a court challenge from Johnson & Johnson over US$10 billion autoimmune drug Remicade, though J&J’s Janssen unit promised to appeal.
  • In a closely watched case, Novartis wants the US Supreme Court to dump a six-month marketing delay for biosimilars, in what would be the first time the high court took up a biosimilar case.
  • Samsung Bioepis, along with partner and minority shareholder Biogen Inc, filed a lawsuit against AbbVie in Britain in March to stop the US company from blocking the launch of yet another Humira biosimilar.

It is equally noteworthy, while Amgen is keen to launch its own biosimilars, the company’s aggressive legal strategy delayed Novartis’s efforts to introduce the first US biosimilar, Zarxio, before the copy of Amgen’s US $1 billion drug Neupogen finally went on sale last year.

Further, Amgen has also filed a legal suit against a biosimilar version of its Enbrel (etanercept) developed by Novartis (Sandoz), which has already received regulatory approval from the US-FDA on August 30, 2016 for multiple inflammatory diseases.

Taking these into consideration, isn’t, therefore, about time to ponder afresh, whether the innovative drug makers’ general mindset of maintaining drug exclusivity with a very high price, on techno-legal grounds, even after enjoying price monopoly over a long period of the specified time, be termed as ‘patient-centric’?

Indian scenario:

Indian players have already started developing biosimilar drugs in the country. This market offers a lucrative future opportunity considering that original biologic brands with a global turnover of around US$ 70 billion will expire by 2020.

The first biosimilar was approved and marketed in India for a hepatitis B vaccine in 2000 (GaBI Online). By now, around 30 such products have reportedly received the Drug Controller General of India (DCGI)’s approval for marketing in India. Even after the new biosimilar guidelines were framed and implemented locally, since 2012, there has not been any worthwhile legal suits filed by the global innovative biologic manufacturers, against the Indian companies or such products developed and approved in India, till 2014.

Since then, this scenario has changed with Roche suing Biocon and its partner Mylan on their biosimilar versions of Roche’s Herceptin (Trastuzumab) for breast cancer, and also making the DCGI a party to this suit. This litigation is broadly on the following grounds:

  • Non-adherence to the Indian biosimilar guidelines
  • Misrepresentation of drugs as biosimilar and passing off 

Be that as it may, its key impact is on affordable biosimilar drugs that can save more lives of breast cancer patients in India. If it is so, do such litigations demonstrate a patient-centric perspective for so important a drug, which is not even protected by a product patent in India, any longer?

Are biosimilars the only examples?

Lest I am not seen as highlighting only the instances of blocking market entry of biosimilar drugs, as sole examples of ‘patient-centric focus’, or lack of it, of many global innovative drug manufacturers, I would now expand it, just a bit. This is only to fathom the bottom-line – whether it is a ‘patients-centric’ focus, or solely a ‘profit-centric’ outlook.

‘Patients-centric’ or ‘Profit-centric’?

To get a sense on this vexing issue, it would be worthwhile for us to find out by ourselves the most appropriate reason behind each of the following. Of course it’s just an illustration. This reason could be either a ‘patient centric’ focus, or simply a ‘profit centric’ outlook. …And then let’s try to make out which way the overall balance tilts, on the ground:

  • Discovering new drugs, delivery systems, and finding new indications
  • Lack of transparency and widely reported bias towards mainly positive results in clinical trial data, both for publication and regulatory approval of various new drugs, and associated global furor.
  • Exorbitant high prices of many new patented medicines and some generic drugs too
  • Widely reported marketing/other malpractices, and associated fines paid by the respective players
  • Causing entry delay for cheaper small molecule generics and large molecule biosimilar drugs post patent expiry restricting gtreaterr patient access

What’s your relative score now?

Conclusion:

Let me sign off here by raising the following relevant questions in this area, for all of us to think and address, as we deem appropriate:

Is the narrative of ‘patient centric’ approach of the ‘research-based’ global drug companies’ now getting clearer with the widely reported credible examples, as above?

Is there still a paradox between their two different strategic business approaches – one entry into off-patent drug development, such as biosimilars, and the other in blocking or delaying entry of such drugs, whenever possible, even after enjoying a specified period of product pricing monopoly?

Does it then mean, what a large section of pharma industry constituents is now publicly demonstrating, at least in the above areas, more than negates their protracted sound bites on ‘patient centric’ focus?

Despite these facts, would pharma related criticism in this space be termed as just a fad of the stakeholders?

If not, what should be the way forward from here to ensure that remedial measures are taken in so important an area of ‘patient-centric’ outlook, soon enough?

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.