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An Emerging Yo-Yo Syndrome With Biosimilar Drugs

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Competition from Biosimilar drugs poses a threat of a combined revenue loss of estimated US$ 110 billion of those pharma players who are still enjoying market monopoly with patented biologic brands. This is expected to surely happen, in the long run, if the signals picked up from the evolving scenario continue to stay on course.

Simply speaking, generic versions of original biologic drugs are termed as Biosimilars. These are large protein molecules, created from living organisms following complex processes. Thus, it is significantly more expensive to develop and market biosimilar drugs, as compared to any small molecule generic chemical ones. 

Hurdle creation and the core intent: 

Despite these complexities, for quite some time, global original biologic drug players had initiated intense campaign to create tough hurdles in the process of regulatory and marketing approval for biosimilar drugs, predominantly raising safety concerns. A simultaneous campaign was also launched among doctors and the payers in the developed countries, stoking the same fear, to forestall the overall acceptance of biosimilar drugs.

When drug regulators of different countries are solely responsible to ensure patient safety of any drug, why are the global pharma companies, and their trade associations are continually shouting from the roof top expressing concerns in this regards? It is often seen that such campaigns become more intense, when it comes primarily to block or delay the entry of biosimilar, many generic drugs and some IP related issues in a country. Umpteen number of such examples are available from India, Europe, United States and many other countries. Many would agree that in such cases, the core intent is as important as the issue.

I discussed on those hurdle creating campaigns in my article in this Blog, on August 25, 2014, titled, “Scandalizing Biosimilar Drugs With Safety Concerns”. Hence won’t dwell on that again here.

The campaign yielded results:

This campaign of global bio-pharma majors to restrict the entry of lower priced biosimilar drugs into the market, immediately after patent expiry, has been successful to a great extent, so far. Let me now give below a recent example, from credible sources, to vindicate this point.

Although, the world’s number 1 drug in sales – Humira (Adalimumab), with a turnover of US$ 15 Billion in 2015 (IMS Health), is going off patent in December 2016, no biosimilar version of Adalimumab is ready, just yet, to compete with this profit churning blockbuster biologic brand, in the United States. More interestingly, according to another report dated July 14, 2016 of the Wall Street Journal (WSJ), even on the verge of its product patent expiration this year, U.S. sales of Humira rose 32 percent to US$ 2.2 billion in the first quarter this year, with over 16 percent jump in its prescription volume.

It is worth noting, Humira was first approved in 2002, and has long been one of the most profitable drugs, globally, contributing around 60 percent of Abbvie’s total revenue even in the last year.

The industry may well argue, in a situation like this, how can a pharma company possibly decide to remain within the ambit of just patent protection, even if it leads to sacrificing other stakeholders’ interest? That’s a ‘business ethics’ issue, and is beyond the scope of this article.

The beginning of a yo-yo syndrome:

At the very outset, let me mention that the term ‘yo-yo syndrome’ has been coined to refer to something that moves up and down quickly, or something that changes repeatedly between one level and another.

Keeping this into perspective, some of the big bio-pharma companies, such as, Amgen, which have been, reportedly, trying hard to block the on-time entry of biosimilar drugs, through litigations and lobbying, could stand as good examples in this area.

For instance, Amgen, on the one hand, seem to be vigorously shielding its over US$10 billion of annual biologic sales from the biosimilar competition through powerful lobbying. Whereas, on the other, it commenced developing its own biosimilar drugs, to reap a rich harvest from the available opportunities.

According to an Associated Press report on July 12, 2016, a panel of Food and Drug Administration advisers of the United States has voted unanimously in favor of Amgen’s version of AbbVie’s Humira. While not binding, the recommendation could help the USFDA approval of the knockoff drug.

According to reports, the companies now working on Humira biosimilars, include Novartis, Mylan and Baxter.

India did it, but a tough road ahead:

On December 9, 2014, international media flashed across the world a great news item from the Indian pharma industry: “The first biosimilar of the world’s top-selling medicine Humira (adalimumab) of AbbVie has been launched in India by Zydus Cadila.” That said, let me hasten to add that Humira does not have a valid product patent protection in India.

Yet another good news is, according to a Press Release of Biocon dated July 15, 2016, its India made Insulin – Glargine was launched in Japan on the same day by its partner FUJIFILM Pharma Co., Ltd. (FFP).

These are excellent developments, and music to many ears. However, on the flip side, intense legal battle on various regulatory grounds against the Indian biosimilar drug players, by the makers of original biologic to protect their own turf of market monopoly, has also commenced with associated acrimony.

Earlier, the Swiss drug major – Roche had objected to Biocon’s referring to Herceptin at an international scientific conference, related to clinical trial results of its own ‘biosimilar’ version Herclon (trastuzumab).

On April 2016, responding to Roche’s complaint, the Delhi High Court ordered changes to the packaging labels of the brands sold by Biocon, and other bio-pharma companies in India, such as, Reliance Life Sciences and Mylan. The court also raised questions about the DCGI’s approval processes for biosimilars, and restrained the companies from using Roche’s data related to the manufacturing process, safety, efficacy and tests.  

More recently, this issue between Roche and Biocon, over breast cancer drug trastuzumab has reportedly taken another acrimonious turn with both the companies approaching the Delhi High Court on charges of contempt of court.

Roche reportedly also alleged contempt over Biocon using the name ‘Herceptin’ in the approval process of its trastuzumab drug in the United States. According to reports, Biocon is currently conducting Phase III clinical trials for marketing approval of its trastuzumab in the U.S.

Thus, to carve out a niche in the biosimilar space of the world, Indian pharma has made some good progress. Alongside, taking note of many contemporary factors and development in this area, a lurking apprehension too did creep in. It raises an awkward and uncomfortable question – do the Indian companies have pockets deep enough to overcome the expensive legal and regulatory challenges thrown by the global biologic drug makers to protect their market monopoly status for expensive drugs, much longer than what they deserve?

Let me keep my fingers crossed.

Critical global speed-bumps for biosimilar entry:

Besides, many other hurdles, as I highlighted in my article of August 25, 2014, the intricate patent shield beyond original patent expiry, is a major speed bump for biosimilar drugs’ smooth global market entry. 

Maintaining the same example of Humira, a well crafted patent-shield strategy was implemented to extend market monopoly of this brand, at least for another decade. Although, the main patent of Humira expires in December 2016, it is reportedly well shielded, at least, with 70 other patents till 2027, as many reports indicate.

This is possible because, according to a January 19 2016 report by Bloomberg, the U.S. patent office in the same month rejected Amgen’s effort to knock out two patents on AbbVie’s anti-inflammatory bestseller Humira. Amgen hoped to get its Humira competitor to market by 2017. This is a bad news for other biosimilar drug makers too.

Nevertheless, the good news is, in May 2016, the Patent Trial And Appeal Board (PTAB) announced that it would embark on a review of Coherus’ challenge of Humira’s ’135 methods patent. Experts believe, even if it the PTAB upturns Humira’s IP shield, AbbVie could appeal, which could take another year or so.

Recent status:

So far, after the biosimilar guidelines were put in place for the first time in the United States, a Novartis version of Amgen’s Neupogen, got USFDA approval in March 2015, only after so many delays and protracted litigations. Novartis is also trying to to do the same for Amgen’s Enbrel. Pfizer too won the U.S drug regulator’s approval in April 2016 for a version of Johnson & Johnson’s Remicade, but the product is still not available for sale.

Currently, some constituents of Big Pharma, such as, Amgen, Novartis and Pfizer have started warming up for manufacturing copycat versions of blockbuster original biologic drugs of other companies.

High quality biosimilars:

These new biosimilars are of top quality. Even USFDA could not find any meaningful differences in the key parameters, such as, efficacy, safety, potency and purity, between the original biologic drugs and their biosimilar versions.

According to a July 12, 2016 Bloomberg report, in several cases USFDA finds the clinical results of biosimilar drugs are robust enough to support ‘extrapolation’. This could support approval of these biosimilar drugs for all indications that the original biologic brands treat, without requirement of separate clinical trials for each, facilitating the approval process and accelerating their market entry.

With these developments, the high voltage lobbying campaigns of the original biologic makers, and their trade associations, both to the drug regulators and doctors, are expected to lose steam, if not ultimately die down altogether. 

However, the protracted and fierce legal battles of the originators, creating various intricate patent shields, to enjoy a brand monopoly for a much longer period, are expected to continue, if not turn fiercer.

The question of price advantage with biosimilars:

Currently the cost advantage provided by the biosimilar drugs over the original biologics, does not come anywhere near to what we see for small molecule generic drugs, post patent expiry. 

For example, Zarexio of Novartis has been priced 15 percent less than the original Neupogen of Amgen. It is generally believed that in the united states this difference would continue to be around 15 to 30 percent, in the near future. Whereas in Europe, the difference is higher, as the governments regulate their prices.

In India too, the difference in the pricing trend is currently, more or less, similar. 

Nonetheless, the above report of Bloomberg had quoted the global CEO of Novartis Joe Jimenez saying that biosimilar drugs would eventually cost 75 percent less than the original biologics. 

Let’s hope so.

Conclusion:

The powerful constituents of Big Pharma who decided to delay, if not stall the entry of biosimilar drugs for vested interest, have now started adopting a dual strategy. They did not have any other choice either, after President Obama’s fulfillment of his election promise with the ‘Affordable Care Act’, which, among others, facilitated charting the regulatory pathway for entry of biosimilar drugs in the United States, for the first time ever. 

Thus, on the one the one hand, these companies continued crafting robust patent-shields to extend market monopolies, even beyond the original patent expiries, through protracted and complicated litigations. While, on the other, started moving with great speed to develop biosimilar versions of the original blockbuster biologic drugs of other players, as they go off patent. This is mainly to cash-in the golden opportunities, which otherwise would go to different players.

India has made an entry into this space, but would still require a lot to do, including winning the expensive legal battles, in order to be recognized as a global force to reckon with, in the biosimilar segment.

To facilitate rapid growth, and universal acceptance of biosimilar drugs, for patients’ interest across the world, it will be interesting to follow the spread of the ‘yo-yo syndrome’ of the original biologic drug makers, as we move on.

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.

Scandalizing Biosimilar Drugs With Safety Concerns

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With the patent expiry of exorbitantly priced biologic medicines, introduction of biosimilar drugs are expected to improve their access to millions of patients across the world, saving billions of dollars in healthcare costs in the subsequent years. According to an article published in Forbes, it is estimated that the potential savings in the United States alone from just 11 biosimilar drugs over a period ranging from 2014 to 2024 could easily be U$250 billion.

However, the flip side of this much awaited development would make commensurate dent on the sales performance of original brand name biologics, now being marketed by the global pharma majors armed with patent monopoly rights.

Innovating hurdles to negate the impact:

Facing this stark reality, global innovators of biotech drugs allegedly want to fast germinate a strong apprehension in the minds of all concerned on the safety and replaceability of biosimilar drugs. Consequently, this would severely restrict the usage of this new class of products, sacrificing patients’ health interest.

To translate this grand plan into reality, garnering additional support from ten medical societies and a physicians’ group, the global players, which mostly hold various patents on biologics, reportedly urged the USFDA to require biosimilars to have distinct names from the original biologics, on the pretext that different names would make it easier for prescribers to distinguish between medicines that “may differ slightly” and also track adverse events and side effect reports that appear in patient records.

However, other stakeholders have negated this move, which is predominantly to make sure that no substitution of high priced original biologics takes place with the cheaper versions of equivalent biosimilars to save on drug costs.

Intense lobbying to push the envelope:

Interestingly, this intense lobbying initiative of big pharma to assign a distinct or different name for biosimilar drugs, if accepted by the USFDA, would provide a clear and cutting-edge commercial advantage to the concerned pharma and biotech majors, even much after their respective biologic drugs go off patent.

Thus, the above allegedly concerted move does not surprise many.

Mounting protests against industry move:

Biosimilar drug makers, on the other hand, have suggested to the USFDA to make biosimilars fall under the same International Non-Proprietary Name (INN) system, like all generic prescription drugs.  They believe that new names would create confusion and the physicians and pharmacists may face difficulties in ascertaining whether biosimilar drugs serve the same purpose with similar dosing and regimens.

The protest seems to have a snowballing effect. In July 2014, by a letter to the Commissioner Hamburg of USFDA, different groups representing pharmacy, labor unions, health insurance plans and others, have reportedly urged her not to go for different INNs for the original biologic and a biosimilar drug, for the same reason as cited above. The letter reinforces that the industry move, if accepted by the USFDA could increase the possibility of medication errors, besides adversely affecting the substitution required to bring down overall health care costs for high priced specialized biologics, thereby slowing down the uptake of biosimilars significantly.

Global pharma investors also raising voices in support of biosimilars:

Another similar and major development followed soon. A letter titled, “Investor Statement on Board Oversight of Biosimilar Issues”, written by a group of 19 institutional investors that manages about US$430 billion in assets, to the boards of several big pharma and biotech companies, flagged that some pharma majors have been scandalizing the safety concerns of biosimilar drugs. This is happening despite the fact that this class of drugs already has a well-established track record in Europe.

They emphasize that recent actions taken by some big pharma companies could raise concerns on the overall acceptance of biosimilar drugs, which would forestall any projected savings on that subject. They also reportedly expressed serious concern that shareholder interests could be adversely affected, if the pharma and biotech players pursue those policies that undermine corporate transparency and medical innovation.

The letter underscores, “Companies seeking to downplay the patient safety record of European biosimilars have also challenged the capacity of the FDA to promulgate rules and determine when biosimilars may be substituted for biologics.”

Among other points, the letter reiterates:

  • Though the important role of biologics in treating cancer, rheumatoid arthritis, anemia, multiple sclerosis and many other conditions is well recognized, the costs of these medicines are on an unsustainable trajectory, with some biologics costing as much 22 times more than other drugs. This critical issue seriously impedes patients’ access to biologics, as well as, acceptance by providers and insurance companies.
  • Biosimilars hold the promise of lowering costs of treating conditions for which biologics are indicated. At the same time, the recent adoption of a regulatory pathway to approval of biosimilars in the US market and the continued growth of biosimilars in the European Union, Japan, Canada, Australia and South Korea, pose a formidable business challenge for the companies that market patented biologic medicines.
  • Financial experts project that biosimilars too have the potential for significant market penetration and attractive returns on investments.
  • Assigning different INN would communicate to providers that the biosimilar is less effective, prompting them not to prescribe this class of medicines and making it difficult for the pharmacists to dispense too. Besides, different names could lead to prescribing errors.
  • In short, the boards of directors of the pharma and biotech majors were urged by these investors to use the following principles to guide their decision-making related to biosimilars:

-       Policy and educational information provided on biosimilars should be balanced, accurate and informed by the patient safety experience of biosimilars in the European Union and other biosimilar drug markets.

-       Lobbying expenditures for federal and state activities related to biosimilars should be fully disclosed and the boards should ensure that political activities are aligned with the interests of investors and other stakeholders.

-       Key information about any partnership or business deal related to biosimilars should be fully disclosed to investors, including information about the value, terms and duration of the deal.

The WHO proposal:

In this context it is worth recapitulating, the World Health Organization (WHO) that oversees the global INN system has held a number of meetings to resolve this issue. The WHO proposal suggests that the current system for choosing INNs to remain unchanged, but that a four-letter code would be attached at the end of every drug name. However, individual regulatory agencies in each country could choose whether to adopt such coding or not.

Let us wait to see what really pans out of this flexible WHO proposal on the subject.

Biosimilars go through stringent regulatory review:

It is important to note that the drug regulators carefully review biosimilars before giving marketing approval for any market, as these drugs must prove to be highly similar without any clinically meaningful differences from the original biologic molecules. The interchangeability between biosimilars and the original biologics must also be unquestionably demonstrated to be qualified for being substitutable at the pharmacy level without the need for intervention by a physician.

Thus, there does not seem to be any basis for different INN, other than to severely restrict competition from biosimilars.

12-year data exclusivity period for biologics – another hurdle created earlier:

Another barrier to early introduction of cheaper biosimilar drugs in the United States is the 12-year data exclusivity period for biologics.

On this issue GPhA – the generic drug makers’ group in the United States reportedly issued a statement, criticizing a paper of Biotechnology Industry Organization (BIO), saying:

“Market exclusivity acts as an absolute shield to their weak patents. Thus, from a practical perspective, extending market exclusivity beyond the Hatch-Waxman period would block the introduction of generic competition for almost 20 years, derailing any potential cost savings by Americans.”

The market potential of biosimilars:

A new report by Allied Market Research estimates that the global biosimilars market would reach US$35 billion by 2020 from the estimated US$1.3 billion in 2013. During the next four years, over 10 blockbuster biologic drugs clocking aggregated annual sales turnover of US $60 billion would go off patent in the United States and in Europe. Humira – a US$10 billion drug of Abbvie that loses patent protection in 2016 is at the top of list.

In tandem, facilitation of regulatory pathways of marketing approval for this class of drugs in many developed markets is expected to drive its growth momentum through greater market penetration and access.

Asia Pacific region is likely to emerge as the leader in the biosimilar drugs market, primarily due to heightened interest and activity of the local players. Collaboration between Mylan and Biocon to commercialize biosimilar version of trastuzumab of Roche in India and the approval of first biosimilar version of monoclonal antibody drug by Hospira in Europe are the encouraging indications.

High growth oncology and autoimmune disease areas are expected to attract more biosimilars developers, as many such biologics would go off patent during 2014 to 2019 period.

Monoclonal antibodies (mAbs) and erythropoietin would possibly be key to the growth drivers. Similarly, follitropins, interferons, and insulin biosimilars would emerge as high potential product segments over a period of time.

As we know, among the developed markets, Europe was the first to draft guidelines for approval of biosimilars in 2006. Consequently, the first biosimilars version of Granulocyte colony-stimulating factor (G-CSF) was introduced in the European Union under the regulatory guidance of European Medical Agency (EMA) in 2008. At present, there are three biosimilar versions of G-CSF available in the European market. Insulin biosimilars also show a good potential for the future.

India:

India is now well poised to encash on this opportunity, which I had deliberated in one of my earlier blog post titled, “Moving Up The Generic Pharma Value Chain”.

Current global usage of biosimilars:

Though regulatory pathways for biosimilar drugs are now in place in the United States, no biosimilar has yet been approved there. However, the US drug regulator has for the first time accepted an application for the approval of a biosimilar version of Neupogen (Filgrastim) of Amgen, which treats patients with low white blood cell counts. Sandoz has already been selling the biosimilar version of this drug in more than 40 countries outside the US.

According to the research organization ‘Pharmaceutical Product Development’, as on March 2013, at least 11 countries and the European Union (EU) approve, regulate and allow clinical trials of biosimilars. As of February 2012, the EU has approved at least 14 biosimilar medicines. The following table shows these countries by region:

Region

Countries
North America Canada
Europe E.U. (including U.K.)
Asia and Pacific China, India, Singapore, South Korea, Taiwan
Central and South America Argentina, Brazil, Mexico
Eastern Europe Russia, Turkey

Source: Pharmaceutical Product Development

Conclusion:

With the opening up of the United States for biosimilar drugs, the entire product class is expected to be catapulted to a high growth trajectory, provided of course no more allegedly concerted attempts are made to create regulatory hurdles on its path, as we move on. This is mainly because around 46 percent of the world biologic market as on 2010 was in the United States.

However, intense lobbying and power play against biosimilar or interchangeable biologics, allegedly sponsored by the big pharma, are acting as a barrier to this much awaited development solely to benefit the patients. Such activities also undermine attractiveness of investing in safer and more affordable interchangeable biologics.

It is indeed intriguing that all these are happening, despite the fact that the regulatory approval standards for biosimilars are very stringent, as each of these drugs:

  • Must be highly similar to the reference product
  • Cannot have clinically meaningful differences from the original ones
  • Must perform the same in any given patient
  • Would have the same risk associated with switching as the reference product

Thus, scandalizing biosimilar drugs by raising self-serving ‘safety concerns’ in an orchestrated manner, just to extend product life cycles of original biologics even beyond patent expiries, is indeed a very unfortunate development. In this process, the vested interests are creating a great commercial uncertainty for this new class of medicines in the global scenario.

Be that as it may, all these seemingly well synchronized moves against biosimilars, solely to protect business interest, pooh-poohing patients’ health interests, have once again caste a dark shadow on not so enviable image of the big pharma…without even an iota of doubt.

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.