The ‘TINA Factor’: A Hotspot for Patented Drugs

Posted on December 16, 2013 by Tapan Ray

An article published in a global business magazine on December 5, 2013 mentioned that Marijn Dekkers, the CEO of Bayer AG reportedly has said at the Financial Times Global Pharmaceutical & Biotech Conference held this month that:

“Bayer didn’t develop its cancer drug, Nexavar (sorafenib) for India but for Western Patients that can afford it.”

The head honcho deserves kudos for revealing his mind upfront, while inviting two quick questions, as follows:

If that is so, why did Bayer launch Nexavar in India?
Did Bayer have any other alternative or choice for not doing so, other than negotiating for a ‘Voluntary License’?

As Bayer already had decided against any ‘Voluntary License’ for Nexavar in India, the simple answer to both the questions is : There Is No Alternative (TINA). And…that’s my ‘TINA Factor’, now a hotspot for patented drugs in India.

I shall dwell on it below, just in a short while.

Bellicose stance for high drug prices and more stringent patent regime:

Everybody acknowledges, beyond even an iota of doubt, that the contribution of the global pharmaceutical industry in the ongoing fight of mankind against diseases of all kinds, is commendable and exemplary.

However, over a period of time, as the low hanging fruits of pharma R&D are in the process of getting all plucked, raw commerce mainly driven by likes of “The Wall Street” quarterly expectations, have started overriding public health considerations involving a large section of the society, across the world, including India.

In this evolving scenario, healthcare has to be extended to almost everybody in the society by the respective Governments in power with strong support from the pharma industry. Instead, to utter dismay of many, the later seems to have opted for a bellicose stance. Their lobby groups appear to be power playing with all might in the corridors of power, to make the product patent regime of faster growing emerging markets more and more stringent, restricting smooth entry of affordable generic or biosimilar drugs increasingly difficult.

Underlying reasons for Big Pharma’s near obsession to have in place an ever stringent patent regime, defying all public health interest particularly of the developing countries, I reckon, are mainly three-fold:

Grant of product patent for any innovation irrespective of triviality
To have absolute pricing freedom for patented drugs for unlimited profits
To enjoy and extend product monopoly status as long as possible

Probably, to camouflage these intents, the reasons for high prices of patented drugs are attributed to the over-used buzz-words – fostering and re-investing in innovation, which is more often underscored as frightfully expensive.

Fair enough, in that case, let the high cost of R&D be appropriately quantified involving independent experts and made known to public. It will then not be like a jig saw puzzle for people to understand the real intent or the truth behind high drug prices. Thereafter, practical solutions need be fleshed-out putting the bright brains and minds together to make new medicines affordable to patients, across the world.

Most probably, that is not to happen, unless a legally binding system of disclosure of expenses is made mandatory for R&D, just as the ‘Physician Payment Sunshine Act’ of the United States demands public disclosure of gifts and payments made to doctors by the pharma players and allied businesses.

On the contrary, incessant efforts by vested interests still continue to keep the patented drug prices beyond the reach of common man. The following are just some very recent examples:

Another ‘defiant move’ in drug pricing:

In another recent development, US-FDA on December 6, 2013 approved Sovaldi (sofosbuvir) of Gilead Sciences Inc. This new drug is reported to be a cure for chronic infection with hepatitis C virus, without co-administration of interferon.

According to the report of July 2013 of the World Health Organization (WHO), about 150 million people are chronically infected with hepatitis C virus, and more than 350, 000 people die every year from hepatitis C- related liver diseases, across the world.

Most interestingly, Gilead Sciences have reportedly decided to keep the price of Sovaldi at a staggering US$ 1,000 (Rs. 62,000) -a-day for one tablet to be continued for 12 weeks. Thus the cost of a three month course of treatment with Sovaldi would be a mind boggling sum of US$ 84,000 (Rs.L 5.21), just for one patient.

It is worth noting that the above price/table of Sovaldi, as decided by Gilead Sciences, has started culminating into a storm of protest, almost immediately, even in the United States (US). The biggest drug benefits manager in that country – Express Scripts Holding Co. in a decisive move to drive down spending on the medicines, reportedly plans to start a price war when Sovaldi comes to market next year or early in 2015 wearing a price tag of US$ 1,000 a pill.

Further, on this seemingly defiant pricing strategy, that too for a life saving drug affecting patients belonging to all strata of the society, ‘Doctors Without Borders’ have reportedly commented: “Using patents to block affordable versions of sofosbuvir and pricing this drug out of reach of the most vulnerable groups who need it most is simply putting profits before people’s lives.”

Brewing a fresh initiative for more stringent high drug price regime:

To foist stricter pharmaceutical patent regime, making access to affordable drugs for the world’s poor increasingly challenging, an initiative is reportedly brewing afresh led by the United States (US).

Ministers of Trade from 12 countries initiated a discussion on December 6, 2013 at Singapore to meet the US deadline of forging a deal on the proposed ‘Trans-Pacific-Partnership (TPP)’ before the end of 2013.

These twelve countries – Australia Brunei, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore, USA and Vietnam, contributing 40 percent of the world economy, are expected to hammer out the TPP deal first, though other countries may hitch on thereafter.

However, after 4 days of intense negotiation, the US-led TPP talks ended on December 10, 2013, without beating into shape any deal. These countries would reportedly meet again on January 2014, in contrast to earlier plan.

The global human right groups like ‘Medicins Sans Frontieres (MSF)’ and ‘Doctors Without Borders’ have reportedly commented, “The ‘Data Protection’ period will prevent drug regulatory agencies in TPP signatory countries from referencing data needed to approve lower-cost generic versions of a protected drug, delaying competition that would lead to cheaper prices”.

In a poll commissioned by ‘Avaaz’ – a global advocacy group, reportedly 62 percent of Americans, 63 percent of Australians, 70 percent of New Zealanders, and of 75 percent Chileans opposed limiting access to generic medicines through the patent proposal in TPP.

Quite expectedly, the powerful US pharma lobby group ‘Pharmaceutical Research and Manufacturers of America (PhRMA)’ said, “It was necessary for companies to recover investments and conduct further research into new cures”.

Breath of fresh air:

The good news is that some prudent developments are also seen around in the midst of a monopolistic drug pricing scenario, offering a breath of fresh air. Some countries around the world, including an important payor in the Unites States, National Institute for Health and Care Excellence (NICE) of UK which assesses the value of drugs for NHS use, and even ‘National Development and Reform Commission (NDRC)’ of China, have now started taking note and proactive measures in different ways on monopolistic high drug prices.

A recent report highlighted that ‘National Development and Reform Commission (NDRC)’ of China would examine and regulate the price-related monopolistic practices of six industries operating in the country, including pharmaceuticals and would crack down wherever they find excessively high prices.

Can India insulate itself from pricing onslaught?

Despite growing global pressure against ‘putting profits before people’s lives’, one may arguably expect more such initiatives spearheaded by Big Pharma to make the patent regime, of especially the emerging markets, more stringent in the years ahead.

That said, ‘The TINA Factor’, which I shall now dwell upon, would probably help reinforcing the protective shield of Indian patent regime against foreseeable assaults with strategies quite similar to as cited above, denying access to new life saving drugs to most of the general population of the country.

‘The TINA Factor’ and three ‘Alternatives’ available to MNCs:

Since enactment of patient-friendly patent laws by the Parliament of India effective January 1, 2005, many global pharma companies and their lobby groups have been continuously expressing immense displeasure and strong anger in many ways for obvious reasons, just as the CEO of Bayer AG did recently.

There are, of course, a few exceptions, such as Sir Andrew Witty, the global CEO of GlaxoSmithKline (GSK), who has been publicly expressing balanced views on this subject in several occasions, so far.

Being driven by anger and possibly desperation any MNC may wish to choose one of the following three ‘Alternatives’ available to them:

Alternative 1: Do not apply for the product patent in India at all.

‘The TINA Factor’: In that case the product will be made available in a platter for the generic players to copy.

Alternative 2: Obtaining the relevant patent from the Indian Patent Office (IPO), do not launch the patented product in India.

‘The TINA Factor’: After three years from the date of grant of patent, as per the statute, the said product could become a candidate for CL on the ground that the patented invention has not been worked in India.

Alternative 3: Launch the product only at the international price.

‘The TINA Factor’: If any patented new product is not available to patients at a ‘reasonably affordable price’ or ‘reasonable requirements’ of patients with respect to the patented invention are not satisfied, again according to statutes, interested parties are free to apply for CL to the IPO, following the steps as specified in the Act. Moreover, the Government itself may issue CL in national emergencies or ‘extreme urgency’ for non-commercial use.

Considering the ‘TINA Factor’, it appears, if the new products do not conform to the ‘Indian Patents Act’ and are NOT launched with ‘reasonably affordable prices’ or ‘reasonable requirements’ of patients are NOT met with these new drugs, the possibility of their legal generic entry at much lower prices is rather high in India. CL granted by the IPO for Bayer’s Nexavar to NATCO vindicates this point.

Summing-up effects of the ‘TINA Factor’:

Many would now reckon that the ‘TINA Factor’, being a hotspot for patented drugs in India, has the potential for getting adopted by many other countries in not too distant future. Two of its palpable effects, as felt in the country so far, may be summed-up as follows:

It leaves no option to any MNC, other than launching their new products in India, especially after obtaining relevant patents from the IPO.

It also squashes apprehensions of many that discontented Big Pharma would be able stop launching patented new products in India, depriving a large number of patients of the country.

Conclusion:

‘The TINA Factor’, thus created by the lawmakers, is expected to remain undiluted, unless commensurate changes are made in the Indian Patents Act.

Not withstanding the reported anger expressed by the CEO of Bayer AG or recently reported ‘absurd pricing’ of Sovaldi, or even for that matter, fresh attempts that are now being made to cobble together a TPP deal, patented new products would continue to be launched in India, as they will receive marketing approval from the Drug Controller General of India (DCGI).

Any possibility of dilution of the ‘TINA Factor’ seems remote now, though powerful overseas pharma lobby groups are investing heavily for a change to take place in various ways.

It also does not seem likely, at least in the near to mid-term, that India would be a party to its ‘Patents Act’ diluting any ‘Free Trade Agreement’ or remain unmoved with high drug prices like, US$ 1000/tablet for life saving drugs like sofosbuvir, more so, if those are considered essential medicines in the country.

Come 2014, it appears improbable that any new Union Government would be able to garner enough numbers in the Parliament to amend Indian Patents Act, buckling under pressure of powerful lobby groups, directly or indirectly, and daring to ignore public sentiment on this sensitive issue.

Considering all these, the point to ponder now:

While abhorring pro-patients ‘Patents Act’ of India, can the Big Pharma come out with any viable alternative today for NOT launching their life saving patented new drugs in the country with the ‘TINA Factor’ prevailing?

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.

‘Big Pharma’ Prowls Falter: Triggers Off Yet Another Critical Debate

Posted on November 25, 2013 by Tapan Ray

The ‘Big Pharma’ prowls faltered yet again exposing the ‘fault line’ to all, when the GSK global head honcho, a pharma icon in his own right, Sir Andrew Witty supported the pharmaceutical policy of India, while in the country earlier this month. This support is quite in contrary to arrogant displeasure being expressed by his MNC counterparts against the pharma regime in India up until now.

Sir Andrew reportedly spoke against the usual pharma MNC practices of charging very high prices for patented medicines during an interview and said that multinationals need to look at things from India’s perspective.

The above comment, when analyzed especially in context of one of the recent actions of Big Pharma MNCs complaining in writing to President Obama against India’s prevailing pharmaceutical regime, the fault line gets clearly visible.

In this context, a recent report captured the anger and desperation of Big Pharma. This hostility vindicates the general apprehensions in India that MNCs are once again pushing for a stringent patent regime in the country, against the general health interest of Indian patients for access to affordable newer medicines.

Quoting US Chamber of Commerce’s Global Intellectual Property Center another report reconfirmed the impatient prowl of the mighty lobby group in the corridors of power. This piece states, “Recent policy and judicial decisions (Glivec judgment and Nexavar) that invalidate intellectual property rights, which have been increasing in India, cast a daunting shadow over its otherwise promising business climate.”

The ‘fault line’, thus surfaced, triggers off yet another critical debate, especially related to the slugfest on a stringent pharmaceutical product patent regime in India, as follows:

“Does Stricter IPR Regime Spur Pharma Innovation?”

Global innovator companies strongly argue that stringent Intellectual Property Rights (IPR) and stricter enforcement of IP laws have strong link with fostering innovation leading to a robust economic growth for any nation.

However, another group of thought leaders opine just the opposite. They argue that strong IPR and IP laws have little, if any, to do with fostering innovation and economic growth, as there are no robust research findings to drive home the above point.

It has been noticed that the MNC lobby groups quite often very cleverly use their magic word ‘innovation’ on a slightest pretext with an underlying desire of having a ‘very strict patent regime’ in India. Thus they seem to be trying to mislead the common man, as if India is against innovation.

Comment of the Chairman of National Innovation Council of India:

On September 15, 2012, while delivering his keynote address in a pharmaceutical industry function, Dr. Sam Pitroda, the Chicago based Indian, creator of the telecom revolution in India, Chairman of the National innovation Council and the Advisor to the Prime Minister on Public Information, Infrastructure & Innovations, made a profound comment for all concerned to ponder, as follows:

“Everyone wants to copy the American model of development. I feel that this model is not scalable, sustainable, desirable and workable. We have to find an Indian Model of development which focuses on affordability, scalability and sustainability.”

Recent Indian stand:

On March 5, 2013, the Government of India made a profound statement on the subject of ‘Innovation and Small and Medium Enterprises (SMEs)’ at the TRIPS Council meeting covering the following points:

There is no direct correlation between IP and Innovation even for the Small and Medium Industries.

The technological progress even in the developed world had been achieved not through IP protection but through focused governmental interventions.

The proponents of this Agenda Item have reached the present stage of technological development by focusing solely on the development of their own domestic industry without caring for the IPRs of the foreigners or the right holders.

After achieving a high level of development, they are now attempting to perpetuate their hold on their technologies by making a push towards a ‘TRIPS plus’ regime.

Their agenda is not to create an environment where developing countries progress technologically, but to block their progress through stringent IP regime.

It is essential that the flexibilities provided by the TRIPS Agreement need to be secured at any cost, if the people in the developing countries are to enjoy the benefits of innovations.

A Wharton Professor’s view:

As the Wharton professor of Healthcare Management Mark V. Pauly has been quoted saying that the link between patent protection and innovation has never been definitely proven.

However, Pauly reportedly is aware that the innovator global pharma companies do say, ‘If you don’t allow us to reap the benefits of our R&D expenditure, we won’t put as much into it, and we won’t invent as many great things’.

However, the Wharton Professor counters it by saying, “The problem is that nobody really knows how much less innovation there would be if there were less patent protection. We just don’t know what the numbers are.”

The above report says, according to Pauly, the onus to prove that patent protection matters should be on the drug industry itself.

He argues, “Rather than always just insisting you should never limit intellectual property protection, they really ought to develop some evidence to show that without that protection, there would be an impact on the rate of adoption of new products. Everybody has an opinion, but nobody knows the facts.“

A French Professor’s view:

In another WIPO seminar held on June 18, 2013, Margaret Kyle, a Professor at the Toulouse School of Economics and the Université de Toulouse I in France, reportedly presented preliminary findings of a study.

This paper explored in detail the impact of World Trade Organization (WTO) Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) in various areas related to the speed of launch, price, and volume of sales of drugs across countries and across different drug products.

In this study, as the above report states, Kyle analyzed the trade-off between the dynamic and static effects of Intellectual Property Rights (IPRs).

The dynamic effect of IPRs was considered as an incentive for innovation based on the general belief that patent protection, through granting market exclusivity, incentivizes companies to invest in the research and development (R&D) to develop new drugs.

On the other hand, the static effect of IPRs in the short term is that granting market exclusivity often leads to innovator companies pricing their products at levels, which will be unaffordable by a large number of patients, especially in lower-income countries.

Kyle explained that the results implied as follows:

IPRs are neither necessary nor sufficient to launch new pharmaceutical products.

The existence of a product patent does not always inhibit generic imitation, nor does the lack of such a patent necessarily deter an originator from making a product available in a given market.

Other eminent voices:

While highlighting that TRIPS-Plus intellectual property protection is passed by some developing countries in order to implement FTA obligations, another recent paper presents the following examples in support of the argument that there no correlation between strong IP laws and fostering innovation:

UK Commission on Intellectual Property Rights. Integrating Intellectual Property Rights and Development Policy. 2002. (Link)

“…Strong IP rights alone provide neither the necessary nor sufficient incentives for firms to invest in particular countries… The evidence that foreign investment is positively associated with IP protection in most developing countries is lacking.”

Robert L. Ostergard., Jr. “Policy Beyond Assumptions: Intellectual Property Rights and Economic Growth.” Chapter 2 of The Development Dilemma: The Political Economy of Intellectual Property Rights in the International System. LFB Scholarly Publishing, New York. 2003

“…No consistent evidence emerged to show that IPR contributed significantly to economic growth cross-nationally. Furthermore, when the nations are split into developed and developing countries, results to suggest otherwise did not emerge.”

Carsten Fink and Keith Maskus. “Why We Study Intellectual Property and What We Have Learned.” Chapter one of Intellectual Property and Development: Lessons from Economic Research. 2005. (Link)

“Existing research suggests that countries that strengthen their IPR are unlikely to experience a sudden boost in inflows of FDI. At the same time, the empirical evidence does point to a positive role for IPRs in stimulating formal technology transfer.”

“Developing countries should carefully assess whether the economic benefits of such rules outweigh their costs. They also need to take into account the costs of administering and enforcing a reformed IPR system”

“We still know relatively little about the way technology diffuses internationally.”

Keith Mascus. “Incorporating a Globalized Intellectual Property Rights Regime Into an Economic Development Strategy.” Ch. 15 of Intellectual Property, Growth and Trade. (ed. Mascus). Elsevier. 2008.

“Middle income countries must strike a complicated balance between promoting domestic learning and diffusion, through limited IP protection, and gaining greater access to international technologies through a strong regime… it makes little sense for these nations to adopt the strongly protectionist IP standards that exist in the U.S., the EU and other developed economies. Rather, they should take advantage of the remaining policy space provided by the TRIPS Agreement.”

“It is questionable whether the poorest countries should devote significant development resources to legal reforms and enforcement of IPR.”

Kamal Saggi. “Intellectual Property Rights and International Technology Transfer via Trade and Foreign Direct Investment. Ch. 13 of Intellectual Property, Growth and Trade. (ed. Mascus). Elsevier. 2008.

“Overall, it is fair to say that the existing empirical evidence regarding the overall technology-transfer impacts of increased IPR protection in developing countries is inconclusive at this stage. What is not yet clear is whether sufficient information flows will be induced to procure significant dynamic gains in those countries through more learning and local innovation.”

Alexander Koff, Laura Baughman, Joseph Francois and Christine McDaniel. “Study on the Economic Impact of ‘TRIPS-Plus’ Free Trade Agreements.” International Intellectual Property Institute and the U.S. Patent and Trademark Office. August 2011.

“TRIPS-Plus IPRs viewed as ‘important, but not essential’ for attracting investment. Many other factors matter like, taxes, human capital, clustering, etc.”

Patients versus Patents:

Another recent article on this subject states as follows:

“Compulsory licensing and stricter patentability standards allow domestic manufacturers to produce lower-cost versions of patented NCD medications and break into lucrative therapeutic areas, such as oncology, in which multinational drug firms are heavily invested.”

The paper clearly highlights, “If patients are pitted against patents, international support for IP protection—upon which drug firms and many other developed country industries now heavily rely—will again diminish.”

Yet another article published in The New England Journal of Medicine, July 17, 2013 states:

“Patents are government-granted monopolies. As monopolies, they can drive the prices of drugs up dramatically. For example, in 2000, when only patented antiretroviral drugs for Human Immunodeficiency Virus (HIV) infection were widely available, they cost approximately $10,000 per person per year, even in very poor countries. Today, these same medicines cost $150 or less if they are purchased from Indian generics companies…. patents cause especially acute problems for access to medicines in developing countries – not only because of low incomes but also because insurance and price-control systems are often absent or inadequate.”

A WHO Report:

To chart the way forward at the backdrop of ongoing global debate elated to the relationship between intellectual property rights, innovation and public health, the World Health Assembly decided in May 2003 to give an independent Commission the task of analyzing this key issue. Accordingly, the Director-General of WHO established the Commission in February 2004. This report titled, “Public health, innovation and intellectual property rights” was published in 2006 and articulated that neither innovation nor access depend on just intellectual property rights and highlighted, among others, the following:

Intellectual property rights have an important role to play in stimulating innovation in health-care products in countries where ﬁnancial and technological capacities exist, and in relation to products for which proﬁtable markets exist.

In developing countries, the fact that a patent can be obtained may contribute nothing or little to innovation if the market is too small or scientiﬁc and technological capability inadequate.

In the absence of effective differential and discounted prices, patents may contribute to increasing the price of medicines needed by poor people in those countries.

Although the balance of costs and beneﬁts of patents will vary between countries, according to their level of development and scientiﬁc and technological infrastructure, the ﬂexibility built into the TRIPS agreement allows countries to ﬁnd a balance more appropriate to the circumstances of each country.

India – now the most attractive global investment destination:

Trashing the anger and displeasure of pharma MNCs, as per the latest international survey, India reportedly has emerged as the most attractive global investment destination followed by Brazil and China. It is worth noting that even recently, during April- June period of 2013, with a capital inflow of around US$ 1 billion, the pharma sector became the brightest star in the FDI landscape of India.

Conclusion:

In the Indian context, a 2013 paper titled, “Intellectual Property Protection and Health Innovation: Concerns for India” published by Center for WTO Studies highlights that the regime change in the patent system has not been very supportive for improving access to medicines in India. It reiterates, it has not been established yet that a stricter patent regime in the developing countries like India, has helped health innovation and access to medicines at economically viable prices.

The paper recommends, although India is trying to incorporate all the flexibilities under TRIPS in its Patents Act, the ‘Indian Policy Makers’ should not give in to the pressure of western powers to make IPR more stringent in the country.

In the backdrop of arrogance exhibited by Big Pharma MNCs, in general, against Indian policies and judicial verdicts on this subject, the comments made by Sir Andrew on the issue, as deliberated above, are indeed profound and far reaching. However, it clearly exposes the fault line in the collective mindset of pharma MNCs, without any ambiguity.

I shall not be surprised either, if clever attempts are made now by the MNC lobby groups to negate or trivialize the profoundness of this visionary statement not just in India, but beyond its shores, as well.

Further, as stated above recent emergence of India as the most attractive global investment destination with pharma leading the deck is a point worth noting, more in the context of policy and statutes that India has decided to follow.

Be that as it may, it is beyond the scope of any doubt that innovation or for that matter encouraging innovation still remains the wheel of progress of any nation.

However, have we garnered enough evidence yet, to establish that stringent IPR regime with absolute pricing freedom would lead to fostering more innovation leading to well-being of people of the developing countries, like India?

By: Tapan J. Ray

Big Pharma Demands Transparency, Keeping their ‘Black-Boxes’ Tight and Safe?

Posted on October 28, 2013 by Tapan Ray

Pharmaceutical Industry across the globe wants absolute transparency in all government laws, policies, guidelines, transactions and overall governance. They also expect the trade environment should be predictable, non-manipulative and business-friendly. These expectations are indeed well justified and deserve whole-hearted support from all concerned.

However, when similar expectations of transparency are voiced by stakeholders in the Big Pharma business operations, that will have direct or indirect impact on public health interests, one would mostly encounter a well guarded, mammoth and impregnable ‘Black Box’, wearing a ‘Top Secret’ label, with all relevant information kept inside.

Such areas of stakeholders’ interests on Big Pharma could well be related to details, like for example:

Actual break-up of R&D expense details,
Transparency in all clinical trials data for experts review,
Patented products’ pricing rationale,
Enormous total costs of lobbying and related expenses at the global level,
Marketing spend on doctors and other decision makers, directly or indirectly, just to name a few.

Mounting curiosity:

Continuation of such opaque practices for a long time, in turn, sparks the curiosity of the intelligentsia to know more in details, especially, about the areas as stated above.

Various research studies are now coming up, with huge revelations and strong findings in these areas. All of these together indicate, it is about time for the global pharma to also demonstrate transparency in their respective business practices and corporate governances, without further delay.

If it does not happen, probably respective governments in various countries will start acting on these areas of opaque self-serving pharma business practices, with the enactment and more importantly, stricter enforcement of requisite laws and policies. President Obama Administration in the United States has already initiated some important actions in these areas with proposals and laws, like for example, the “Physicians Payment Sunshine Act’ .

The ‘Power Game’:

An interesting article of May 3, 2013 highlighted that the global pharmaceutical industry exerts incredible influence over the prescription medicines across the globe. This power, as many will know, flows from robust political contacts and influences over various important government agencies administrating the entire healthcare system, executed immaculately by expensive lobbying and PR campaigns by their globally integrated trade bodies.

Similar powerful influences also get extended to doctors and the people who matter to further their interests. These well crafted plans are reportedly executed through sponsored or paid opinion-modifying articles, ‘advertorials’, DTC advertisements (wherever legally permitted) and well-organized, seemingly third party, speeches to push the envelopes further.

Most probably, keeping such ongoing practices in mind and coming under intense media pressure, the Medical Council of India (MCI) on December 10, 2009 amended the “Indian Medical Council (Professional Conduct, Etiquette and Ethics), Regulations 2002″ for the doctors in India. Unfortunately, its implementation on the ground is rather tardy.

The above article also stated, “In fact, in the United States the industry contributes heavily to the annual budget of the U.S. Food and Drug Administration (FDA), which is charged with regulating drugs and devices made by those same companies.”

Avoidable Expenditures:

The paper indicates that in the United States alone the industry associations:

Have 1,100-plus paid lobbyists on Capitol Hill,
Allocated US$ 188 million annual lobbying budget
Doles out around US$ 14 million to political candidates every year

The report also comments, ‘Drug companies spend substantially more on marketing than they do on research and development.’

Influencing opinion against patients’ interest?

The article in the ‘drugwatch’ also states:

“Doctors are persuaded by the pharma companies to attach their names (ghost writing), against financial considerations, to favorable article on a particular drug ensuring that it is published in a well reputable medical journal.”

The author continues that ‘Ghost writings’ are being used to promote numerous drugs to influence concerned stakeholders.

In 1998, a study of the prestigious New England Journal of Medicine found that ‘out of 75 published articles, nearly half were written by authors with financial conflicts. And, worse than this, only two of the articles disclosed interests.’

Richard Smith, former editor of the British Medical Journal, was quoted saying, “All journals are bought – or at least cleverly used – by the pharmaceutical industry.”

Striking facts:

Following are some striking facts as reported in the article, as mentioned above:

“Advertising instead of research: For every US$ 1 spent on “basic research,” Big Pharma spends US$ 19 on promotions and advertising.

Distribution of free drug samples: The United States has 1 pharmaceutical sales representative for every 5 office-based physicians.

Sponsorship of symposiums and medical conventions: Drug and medical device makers spend lavishly on doctors, including covering meals, travel, seminars and conventions that may look more like vacations.”

Pressure on publications:

The paper highlights that large global pharma majors may even pull its advertisements out, if the concerned medical journal will question the accuracy of an ad. Such types of threats have very serious effects on these journals in running their businesses without getting lucrative advertisement dollars from the drug manufacturers.

Making drugs looking good:

The same article highlights:

“Quite often the academics and scientists are hired hands who supply human subjects and collect data according to the instructions from their corporate employers. Sponsors keep the data, analyze, write the papers and decide whether and when and where to submit them for publication. Drug companies have discovered ways to stage-manage trials to produce predetermined outcomes that will put their products in the best light.”

With this strategy even a bad drug can allegedly be made looking good by doing many things, like for example:

Comparing them to a placebo
Comparing them to a competitor’s medication in the wrong strength
Pairing them with a drug that is known to work well
Shortening a trial before any bad results surface
Testing in groups too small to provide valid evidence

Pay-for-delay deals:

A recent report titled, “Top twenty pay-for-delay drugs: How Industry pay-off delay generics” highlights that ‘Pay-for-delay deals’ have forced patients in the United States to pay an average of 10 times more than necessary for at least 20 blockbuster drugs.

Key findings of the analysis on the impact of pay-for-delay deals are as follows:

This practice has held back generic medicines used by patients with a wide range of serious or chronic conditions, ranging from cancer and heart disease, to depression and bacterial infection.

These payoffs have delayed generic drugs for five years, on average, and as long as nine years.

These brand-name drugs cost 10 times more than their generic equivalents, on average, and as much as 33 times more.

These patented drug companies have made an estimated US$ 98 billion in total sales of these drugs while the generic versions were delayed.

Citing example, the paper says, a pay-for-delay deal kept a generic version of the breast cancer drug Tamoxifen off the US market for nine years, while Pfizer made $7.4 billion in sales of its cholesterol-lowering drug Lipitor (atorvastatin) in 2012 alone.

The point to ponder yet again is, why such practices are being surreptitiously carried out for years sacrificing patients’ interest and without the regulators’ strong interventions, in general?

French Government has initiated a probe:

The French Competition Authority is reportedly expected to publish a report on the findings of its inquiry, initiated in February 2013, into the costs and pricing of medicines in France. The report will also look at whether industry practices are interfering with the market entry of generic drugs, including distribution arrangements between drug manufacturers, wholesalers and pharmacists.

An appreciable initiative in America, but why not in India?

There is still a simmering hope. As indicated above, President Obama’s Affordable Care Act reportedly requires that from September 2013, pharmaceutical companies will need to collect data and openly report information on payments, investment interests, ownership and items of value given to doctors and hospitals. Very unfortunately, the Department of Pharmaceuticals of the Government of India has not taken any such steps, as yet, despite the situation turning grave in the country.

The power of pharma lobby in the US:

According to a recent NYT report, in the United States, government health programs are forbidden from rejecting new drugs on cost grounds.

When the issue of drug prices came up as part of President Obama’s ‘Affordable Care Act’ debate, it was summarily rejected in Congress. Simultaneously, a move toward comparative-effectiveness studies, putting rival drugs or treatments through trials to determine which work better, was also decried.

The report highlights, the mere suggestion of the US government throwing its weight around on drug prices stirs up talk of ‘socialism’. The pharma lobby doesn’t have to look far for support in fighting that idea. In the US, the so-called ‘free market’ is trusted to regulate drug prices, despite the reality that the healthcare market is far from transparent, ‘with byzantine pricing mechanisms and costs that vary wildly region-by-region, pharmacy by pharmacy and even patient-by-patient’.

The usual supply/demand/pricing relationships do not apply to drug prices at the consumer level in the US too, just as it has been proved in India.

A large part of creation of this environment is attributed to pharmaceutical and other health-products firms, who reportedly spent a total of US$ 250 million on lobbying last year.

Big Pharma keeps failing credibility tests:

This happened very recently, when The Guardian in July 2013 reported, the pharmaceutical industry has “mobilized” an army of patient groups to lobby against plans to force companies to publish secret documents on drug trials. This is related to the news that the European Medicines Agency (EMA) could force drug companies to publish all Clinical Trial (CT) results in a public database.

The above report says, while some pharma players agreed to share data, important global pharma industry associations have resisted this plan of the EMA. The report continues, a leaked letter from two large pharma trade associations, the Pharmaceutical Research and Manufacturers of America (PhRMA) of the United States and the European Federation of Pharmaceutical Industries and Associations (EFPIA), have drawn out a strategy to combat calls by drug regulators to force companies to publish all CT results.

The strategy reportedly shows how patient groups, many of which receive some or all of their funding from drugs companies, have been drawn into this battle by these Big Pharma lobby groups.

The e-mail reportedly seen by ‘The Guardian’ was from Richard Bergström, Director General of EFPIA, addressed to directors and legal counsel at Roche, Merck, Pfizer, GSK, AstraZeneca, Eli Lilly, Novartis and many smaller companies.

The e-mail leaked by an employee of a pharma company describes a four-pronged campaign that starts with “mobilizing patient groups to express concern about the risk to public health by non-scientific re-use of data”.

Translated, as ‘The Guardian’ reported, “that means patient groups go into bat for the industry by raising fears that if full results from drug trials are published, the information might be misinterpreted and cause a health scare.”

This appears to be another classic case of vested interests working against patients’ interests.

Global lobbying started taking the center stage in India too:

With the above back-drop and lobbying scandals reportedly being surfaced in many other countries, it is about time that India puts its acts together with India-specific stricter disclosure policies, including R&D, Clinical Trials (CTs), Patented Products Pricing, Marketing Practices and Trade Lobbying.

Interestingly, to influence Government policies India’s top lobbying spenders in 2012 (US$ million) were reported as follows:

1	US Chamber of Commerce	136.3
2	National Association of Realtors	41.5
3	Blue Cross / Blue Shield	22.5
4	General Electric	21.1
5	American Hospital Association	19.2
6	National Cable & Telecom. Association	18.9
7	Pharmaceutical Research & Mfrs. of America (PhRMA)	18.5
8	Google	18.2
9	Northrop Grumman	17.5
10	AT&T	17.4
11	American Medical Association	16.5
12	Boeing	15.6

Source: The Center for Responsive Politics (Economic Times, June 4, 2013)

According to the latest lobbying disclosure reports filed with the US Senate and the House of Representatives, at least two dozen American companies and industry associations are reportedly lobbying hard with the US lawmakers on issues in India, which include:

Intellectual Property (IP)
Patent
Market access

Another recent report comments as follows:

“The US Chamber of Commerce has become a portal for dubious reports that claim India’s intellectual property regime is worse than China’s. Such “research” by paid lobbyists and disseminated through the halls of US Congress…”

Hefty fines for illegal practices, yet Black Box remains tight and safe:

In December 2010, Healthcare advocacy group Public Citizen published a report that, for the first time, documented all major financial settlements and court judgments between pharmaceutical manufacturers and the federal and state governments of the United States since 1991.

It says, almost US$ 20 billion was paid out by the pharmaceutical industry to settle allegations of numerous violations, including illegal, off-label marketing and the deliberate overcharging of taxpayer-funded health programs, such as Medicare and Medicaid.

Three-fourths of the settlements and accompanying financial penalties had occurred in just the five-year period prior to 2010. There has been no indication that this upward trend is subsiding.

10 Largest Settlements and Judgments on Big Pharma mis governance:
(Period: Nov. 2, 1010 – July 18, 2012)

	Company	Amount US$ Million	Year	Reasons
1.	GlaxoSmithKline	3, 000	2012	Unlawful promotion, kickbacks, concealing study data, overcharging government health programs
2.	Abbott	1,500	2012	Unlawful promotion, kickbacks
3.	Johnson & Johnson	1,200	2012	Unlawful promotion
4.	Merck	950	2011	Unlawful promotion
5.	Ranbaxy	500	2012	Poor manufacturing practices, falsifying data on FDA applications.
6.	Johnson & Johnson	327	2011	Unlawful promotion
7.	Boehringer Ingelheim	280	2011	Overcharging government health programs
8.	Mylan’s Dey Pharma unit	280	2010	Overcharging government health programs
9.	Elan	203	2010	Unlawful promotion, kickbacks
10.	Johnson & Johnson	158	2012	Unlawful promotion

Conclusion:

All such expenditures, including expensive lobbying and court settlement charges for illegal business practices, as mentioned above, I reckon, are wasteful and avoidable. These are mostly outcomes of self serving measures, shorn of public health interest,

If all these costs are eliminated and actual R&D expenses are reflected, in a transparent manner, there could be significant reduction in the costs of newer innovative drugs, extending their access to billions of patients, across the world.

Thus to help evaluating the innovative drugs with greater transparency, there is an urgent need for the Big Pharma to set examples by voluntarily disclosing the secrets hidden within the ‘Black Boxes’, as deliberated above. These disclosures should be made to the independent experts and the respective Governments under appropriate statutes.

Expectations of transparency in Governance should not, therefore, be restricted just to Government laws, policies and decisions, the industry should reciprocate it too, in equal measures.

To be patient-centric, transparency in governance needs to be a two-way traffic, where pharma industry should volunteer to be an integral part, sooner than later. Otherwise it may be too late for them to avoid harsh interventions of the respective regulators, as the intense pressure from intelligentsia, civil society and media, keep mounting.

That said, the question lingers:

When the ‘Big Pharma is rightly demanding transparency in all areas of public discourse, why are they so reluctant in making their intriguing ‘Black Boxes’ transparent, that too only in areas of public health interest, for fair experts review?

By: Tapan J. Ray

Drug, Patent and Hype: Quo Vadis Pharma Innovation?

Posted on October 21, 2013 by Tapan Ray

A recent research report reveals, though the pharmaceutical companies in the United States since mid 2000 have spent over US$ 50 billion every year to discover new drugs, they have very rarely been able to invent something, which can be called significant improvement over already existing ones.

As per available reports, from the year 2000 to 2010, the US-FDA, on an average, approved just 24 new drugs per year. This number is a sharp decline from the same of 1990, when on an average 31 new drugs were approved per year.

These studies throw open some important questions to ponder:

What is then the real issue with pharma innovation?
Is it declining quality or quantity (number)?
What impacts the patients more?

Quantity vs quality of innovation:

A recent paper explored whether declining numbers of New Molecular Entities (NMEs), approved in the United States (US) each year, is the best measure of pharmaceutical “innovation.”

Thus, studying in detail the NME approvals in the US during 1987 to 2011, the authors proposed the following three distinct subcategories of NMEs:

First-in-class
Advance-in-class
Addition-to-class

This classification was aimed at providing more nuanced and informative insights into underlying trends.

The paper established that trends in NME approvals were largely driven by ‘Addition-to-class’, or “Me too,” drug approvals. However, the good news is that ‘First-in-class’ approvals remained fairly steady over the study period.

Thus I reckon, there should be much greater focus with higher resource deployments for more of ‘First-in-class’ drugs research and development.

To achieve this objective with requisite wherewithal, there will be a need to drastically cut down massive R&D expenditures on “Me-too” types of so called ‘innovative’ drugs. Such drugs, carrying exorbitant price tags, creating a financial burden to the payers, could perhaps help increasing the number of innovations, but certainly not the quality of innovations to meet important unmet needs of patients in a cost effective manner.

Some facts:

In 2010, the healthcare journal Prescire rated 97 new drugs or new indications. Only 4 of these provided any therapeutic advantage over the available existing drugs. Interestingly, 19 others (1 in 5) were approved despite having more harms than benefits.

According to another analysis, “About 1 in 6 new products had more harms than benefits, while more than half of all new products provided no advantages over existing options.”

Further, a different article published in Nature Reviews indicated, “doctors were more likely to rate drugs more than a decade old as transformative.”

Decline in the quality of innovation:

In this context, Dr Mark Olfson of Columbia University and statistician Steven Marcus of the University of Pennsylvania have reportedly established as follows:

“By the 1980s new drugs were less than four times better; by the 1990s, twice as good, and by the 2000s just 36 percent better than a placebo. Since older drugs were much superior to placebo and newer ones only slightly so, that means older drugs were generally more effective than newer ones.”

While even in earlier years, newer patented drugs on an average used to be 4.5 times more effective, as compared to placebo.

The winds of change?

As a result, under the new ‘Affordable Care Act’ of President Obama, “comparative effectiveness research” by an independent research institute could well conclude that older drugs or even cheaper generic equivalents are better than the high priced patented ones, which create fortunes for the innovator pharmaceutical companies at the cost of patients and payers.

The above initiate in ‘Obamacare’, if and when fructifies, will indeed hit the ‘Me-too’ type of drug innovators, especially in the United States, very hard. Nevertheless, is a music to the ear for the private health insurance companies and the patients at large.

A ray of hope?

‘Comparative drug effectiveness analysis’, as stated above, could eventually lead to replacement of newer high priced ‘me-too’ patented drugs by older relatively low priced generic equivalents, at least, for reimbursements.

This will, no doubt, lead to huge profit erosion of the big pharmaceutical players. Hence, extensive lobbying by industry groups in top gear, against this ‘patient-centric’ proposal, is currently on, .

As the new federal healthcare law will find its roots in America, despite strong opposition from the powerful and influential pharma lobby groups, a ray of hope is now faintly seen in otherwise blatantly exploitative and rather cruel drug pricing environment.

Where hype is the key driver:

Despite enormous hype, being created and spearheaded by the Big pharma, on the ‘essentiality’ of most stringent Intellectual Property Rights (IPR) regime in a country with patent laws blatantly in favor of commercial considerations, to enjoy a monopolistic marketing climate with pricing freedom, breakthrough pharma innovations are now indeed rather difficult to come by, as we shall deliberate below.

Reasons for decline:

Many experts believe that the following reasons, among many others, have attributed to the decline in the quality of pharmaceutical R&D output:

Most important drug discoveries for mankind have already been made or in other words, the low hanging fruits of pharma R&D have already been plucked. Now not so easy and rather difficult drug targets are remaining.

In the last decade, most of pharma R&D efforts were reportedly concentrated mainly in four major disease areas: central nervous system, cancer, cardiovascular and infectious diseases.

There is a need now to focus more on poorly understood and more complex therapeutic areas such as, autoimmune diseases or complex diseases related immune system of the body, to meet greater unmet needs of patients.

Clinical trial volunteers are now more difficult to recruit and treat.

More stringent regulatory requirements for clinical trials with studies using much larger number of patients, making the clinical drug development process very expensive.

Could it be worse for Big Pharma?

The evolving situation, though very early in the day now, has the potential to turn much worse for the big pharma and good for the patients, if some key changes take place.

Many industry analysts, across the world, feel that ‘liberal’ patent laws are responsible for acceptance of minor advances over the existing products as patentable with 20 years of market exclusivity.

Thereafter, another ‘liberal’ minded drug regulatory framework allows the pharma players to market such ‘not-so-innovative patented medicines’ aggressively, enabling them to amass astronomical profits in no time at the cost of patients’ interests and payors’ financial burden , as happened in the United States and many other countries recently.

To avoid such trivial innovations the law and policy makers in the industrialized countries may well ponder as follows:

1. Align the country’s ‘Patents Act’ with similar to what Indian law makers had formulated in 2005 to avoid minor and ‘evergreening’ types of patents under section 3(d) of the Act.

2. The clinical research data must establish that the new drugs offer significantly more tangible benefits to the patients than the existing ones.

Denial of patentability for ‘me-too’ innovations and their subsequent regulatory approvals would significantly reduce the drug treatment cost with virtually no adverse impacts on patients, across the world.

If such measures are taken by the developed countries of the world and also the emerging markets, the Big Pharma would be compelled to change their respective business models, making ailing patients of varying financial status, color and creed central to their respective strategic ideation processes.

Otherwise, it is highly unlikely that anything will change for the patients from what we are all experiencing today, at least in the near to medium term.

A possible pathway:

Highly conflicting interests of Big pharma and the patients, should get resolved sooner than later and that again for the interest of both.

Thus, to find a meaningful and generally acceptable solution to this issue, there is a dire need for a much wider global debate. The deliberations, at the same time, should include possibilities of finding ways to avoid huge wasteful expenditures on pharmaceutical R&D for developing new products that offer no significant benefits to the patients over the existing ones. On the contrary, such products burden them with exorbitant incremental drug treatment costs,

The motions of the debate could well be in the following lines:

1. ‘Should United States amend its patent laws by categorically stating that a mere “discovery” of a “new form” of a “known substance” that does not have properties resulting in significant improvement in clinical efficacy, will not be patentable?

2. Shouldn’t the clinical research data must always establish that the new drugs offer significantly more tangible benefits to the patients than already available cheaper equivalents?

The positive outcome of this global debate, if fructifies, will indeed be considered as a paradigm shift in the new world order for all, hopefully.

Unfathomable reluctance:

Despite all these developments, a recent report indicated that the heads of seventeen industry associations of the United States wrote a letter to President Obama complaining, among others, India’s patents regime. This includes the most powerful, yet equally controversial, pharmaceutical lobby group of America.

The letter alleged that the recent policy decisions in India undermine internationally recognized Intellectual Property (IP) standards, which are “jeopardizing domestic jobs” in America and are unacceptable to them.

Though the details of issues were not highlighted in the letter, One concern it specifically expressed that the defeat of Novartis on the Glivec case that challenged Section 3(d) of the Patents Act of India has raised the bar on what can be considered a true innovation for the grant of patent in India.

Though this judgment of the apex court of India was widely acclaimed even globally, American Trade Association Lobby Groups seem to project exactly the opposite, reportedly, driven solely by profit motives of their members and shorn of patients’ interests

Interestingly, an article published in The New England Journal of Medicine, July 17, 2013 also states as follows:

“A patent law that treats incremental innovation and significant innovation in the same way, encourages companies to prioritize less important research over more important research.”

A diametrically opposite viewpoint:

Another school of thought leaders opine, ‘me too’ innovations will continue to remain alive and well. This will happen, even if such new products are starved of oxygen by ‘the tightening purse strings of the eventual customers’. These innovations are sustained by the stronger imperative to avoid clinical failures and to play relatively safe in the space of expensive R&D investments.

They feel that pharma players will continue to focus on to leaner drug discovery and development models to have healthier late-stage product pipelines of such types. In tandem, by cutting costs even more aggressively, as we witness today, they will find space to keep the level of risk optimal for delivering real innovation, when the time comes.

This type of business model, the experts feel is based on the belief that it is far better to acquire a product with very little innovation ensuring that it can hardly fail to be approved by the regulator. Thereafter, the concerned players may figure out ways of how payors will actually pay for it, rather than focusing primarily on acquiring a genuinely innovative ‘First-in-class’ product and then discover it has ‘feet of clay’.

For example, AstraZeneca reportedly invested a little over US$1 billion in two such products in one month: another LABA combination from Pearl Therapeutics and a prescription ‘Fish Oil’ capsule from Omthera Pharmaceuticals.

Conclusion:

Be that as it may, a large number of experts do opine, especially in the light of the above letter of the American Trade Associations that the verdict of the Honorable Supreme Court of India on the Glivec case, though does not serve the business interests of pharma MNCs, definitely signals the triumph of justice over ruthless patient exploitations. It also vindicates that this particular rule of law, as enacted by the Indian Parliament, is indeed for the best interest of the patients of India at large.

This verdict could well be construed as a huge lesson to learn and implement by other like minded countries, across the world.

Having a glimpse at the pharmaceutical innovations, which are often laced by crafty hypes created by expensive PR Agencies of the pharma lobby groups, the global thought leaders do tend to believe, rather strongly, that Section 3(d) of the Patents Act of India would encourage more ‘First-in-class’ innovations, in the long run, benefiting all.

Such a provision, if implemented by many countries, could also help saving significant wasteful expenditures towards ‘Me-too’ type pharma R&D, favorably impacting billions of lives, across the world.

That said, the question keeps haunting – ‘Sans Hype, Quo Vadis Pharma Innovation?

By: Tapan J. Ray

MNCs to Challenge MNC Patents in India: Boon for Patients?

Posted on September 16, 2013 by Tapan Ray

Close on the heels of a reasonably successful patent challenge by the German pharma Multinational Corporation (MNC) Fresenius Kabi for the breast cancer drug Tykerb of GlaxoSmithKline (GSK) in India, another MNC Mylan, with its headquarter in the United states, has explicitly expressed its plan to challenge frivolous and weak patents of MNCs, in conformance to the Indian Patents Act, to provide less expensive generic drugs to patients.

This is indeed another interesting development, which could possibly culminate into robust, cleverly crafted and fiercely competitive business strategies of many other MNCs, revolving around patent challenges in India, for business excellence in the country.

Mylan develops new products in India:

Mylan is now reportedly working with the local Indian player Biocon to develop a strong new product pipeline, which would include a portfolio of biosimilar drugs. The advanced breast cancer drug Trastuzumab (Herceptin) of Roche is just one of many in the list. Mylan has also expressed its intent to market ‘Herceptin’ at a price, which will be affordable to many more cancer patients of India.

It is worth mentioning that some other domestic Indian companies like, Reliance Life Sciences and BDR Pharma are reportedly working on generic Trastuzumab (Herceptin), besides some South Korean bio-pharma players.

Mylan has also inked an agreement with Biocon to develop and market an insulin drug derived from the global major Sanofi’s expensive patented product Lantus.

All these developments apparently augur well for India.

Weak patent?…Recapitulating Herceptin saga in india:

Though Roche decided to discontinue its patent rights for Herceptin in India, it reportedly lost this patent earlier in Europe. This vindicates the views of experts that Herceptin patent was weak, as it would probably not be able to clear the litmus test of a stringent patent scrutiny. The report, therefore, argues that core reason for withdrawal of Herceptin patent in India by Roche cannot be attributed, even remotely, to the ‘weak IP ecosystem’ in India.

To extend the patent right for Herceptin, in early September 2013, Roche reportedly announced that the European Commission has approved a new formulation of its breast cancer drug Herceptin, which allows the medicine to be administered more quickly.

A tough market, yet difficult to ignore:

For global innovator pharma majors, India still remains a tough market to crack, despite strong overseas political pressures of various types, intense collective and individual lobbying efforts and deployment of expensive global ‘Public Relations’ firms working in full steam.

Their strong success factors of the yesteryears in this area, which worked so well across the world, are getting mostly negated by the ‘evolving patient friendly IP laws’ of the emerging economies.

Considering the vast business potential of the pharmaceutical market of 1.2 billion people in India, it is now envisaged by many, more like-minded MNCs will gradually jump into this fray with similar intent of patent challenges in conformance with the Indian Patents Act 2005.

If this scenario assumes a cascading effect on a broader canvas, ultimate beneficiary will be the ailing patients, having much greater access to more affordable newer drugs for many dreaded diseases, like cancer.

Other countries too tightening up the patent laws:

To provide less-expensive generic drugs to patients, other countries also have started following India to leash astronomical prices for new drugs, especially for life threatening and intensely debilitating ailments. China has reportedly strengthened its compulsory licensing provisions already for dealing with costly drugs, paving the way to force entry of generic drugs in the Chinese market well before patent expiry.

In 2012, Indian Patent Office, in a path breaking decision granted Compulsory License (CL) to a local company, Natco Pharma, to manufacture the patented kidney-cancer drug, Nexavar of Bayer reportedly at a cost of Rs. 8,800 (around US$ 176) for a month’s therapy of 120 capsule against Bayer’s price of Rs. 280,000 (around US$ 5,600) for the same.

This is the first-ever case of CL granted in India thus far to make life saving drugs affordable to patients.

On September 3, 2012, the Indonesian government took the unprecedented step of overriding the patents on seven HIV and hepatitis treatments, citing urgent need to improve patient access. These drugs were reportedly beyond the reach of most of the patients in Indonesia.

Thailand has also used this provision more than once, and countries like, Brazil has reportedly threatened quite often for invoking CL during price negotiations of such drugs with global pharma majors.

Winds of Change in South Africa:

Now South Africa has also exhibited its firm intent to have a tight leash on the grant of pharmaceutical patents of all types.

A recent report indicates that the Department of Trade and Industry (DTI) of the Government of South Africa is calling for comments on its proposed ‘National Policy on Intellectual Property’ by October 4, 2013, which if implemented, would significantly curb patent evergreening and expand production of generics.

The same report mentions that at present, South Africa does not examine patent applications. Instead, the system allows pharmaceutical companies to obtain multiple patents on the same drug, even for inventions, which do not fall under the country’s definition of innovation. This allows the pharma players to extend their respective patent lives, blocking competition and charging exorbitant prices.

The report also points out, while in 2008, South Africa granted 2,442 pharmaceutical patents, Brazil approved only 278 in the 5 years between 2003 and 2008.

Patents revoked in India:

Since November 2010 following 8 MNC patents have been revoked in India after respective patent challenges:

Combigan and Ganfort of Allergan (for specified eye conditions)
Tykerb of GSK (for breast cancer)
Sutent of Pfizer (for liver and kidney cancer)
Pegasys of Roche (for hepatitis C)
Iressa of AstraZeneca (Anti-cancer)
Anti-asthma FDC aerosol suspension of Merck & Co (Anti-asthma)
Dulera of Novartis (Anti-asthma)

China and Brazil revoked patents:

In August 2013, just about a year after China introduced the country’s amended patent law, its State Intellectual Property Office (SIPO) has reportedly revoked the patent on HIV/AIDS and hepatitis B drug – Viread (tenofovir disoproxil fumarate) of Gilead Science Inc.

Aurisco, the largest manufacturer of Active Pharmaceutical Ingredients (APIs) in China, challenged this patent. The ground of patent revocation was that the drug lacked novelty and was not entitled to protection.

In 2008 Brazil also declared the patent of tenofovir invalid. It is worth mentioning that tenofovir of Gilead is the third-best-selling drug of the company, clocking sales of US$ 849 million in 2012.

Top 10 ‘jaw-dropping’ most expensive medicines of the world:

No.	Name	Disease	Price US$ /Year
1.	ACTH	Infantile spasm	13,800,00
2.	Elaprase	Hunter Syndrome	657,000
3.	Soliris	Paroxysmal nocturnal hemoglobinuria	409,500
4.	Nagalazyme	Maroteaux-Lamy Syndrome	375,000
5.	Folotyn	T-Cell Lymphoma	360,000
6.	Cinryze	Hereditary Angioedema	350,000
7.	Myozyme	Pompe	300,000
8.	Arcalyst	Cold Auto-Inflammatory Syndrome	250,000
9.	Ceredase / Cerezyme	Gaucher Disease	200,000
10.	Fabrazyme	Fabry Disease	200,000

(Source: Medical Billing & Coding, February 6, 2012)

The good news is, protests against such ‘immoral and obscene pricing’ have started mounting, which are expected to have a snow-balling effect in the years ahead.

Mounting global protests:

Probably due to this reason, drugs used for the treatment of rare diseases are being reported as ‘hot properties for drug manufacturers’, all over the world.

The above report highlighted a changing and evolving scenario in this area.

In 2013, the Dutch Government had cut the prices of new enzyme-replacement therapies, which costs as high as US$ 909,000. Similarly, Ireland has reduced significantly the cost of a cystic fibrosis drug, and the U.K. rejected a recommendation to expand the use of a drug for blood disorders due to high costs.

Soon, the United States is also expected to join the initiative to reduce high prices of orphan drugs as both the government and private insurers increasingly come under the cost containment pressure.

Emerging markets – the Eldorado:

Competition within MNCs is expected to be even more fierce in the coming years as the developed markets continue to slow down, as follows, due to various reasons:

No.	Country	USD Bn.	% Share	Val. Gr.
	Global Pharma Market	961	100	5
	USA	329	38	-1
	Japan	112	13	0
	China	82	10	24
	Germany	42	5	-6
	France	37	4	-8
	Brazil	29	3	6
	Italy	27	3	-8
13.	India	14	1	11

Source: IMS Knowledge Link Global Sales 2012

This compelling scenario is prompting a change in the dynamics of competition within MNCs in the emerging pharmaceutical markets. The intents of Fresenius Kabi and Mylan, as enunciated above, I reckon, are just very early signals of this challenge of change.

All these would probably help turning the tide in favor of a seemingly win-win solution to bring down the prices of patented medicines at an affordable level, improving their access to vast majority of patients in the world.

Scope for more patent challenges in India:

Quoting a study, a recent media report highlighted that only 3% of the patent applications filed in India since 2006 were challenged. The study concluded:

“This demonstrates that given the various resource constraints faced by the Indian patent office, one can never really be sure of the patent quality unless the patent is challenged.”

Therefore, this process is expected to gain momentum in the years ahead as more MNCs join the fray of patent challenges, though driven primarily by business interests, but nevertheless, would benefit the patients, in the long run.

Further, as indicated in my previous columns, a study indicates that 86 pharmaceutical patents granted by the IPO post 2005 are not breakthrough inventions but only minor variations of existing pharmaceutical products and demanded re-examination of them.

Since, most of the above patents have not been challenged, as yet, the quality of these patents cannot be ascertained beyond any reasonable doubt, as we discuss today. If challenged, some experts envisage, these patents may not be able to stand the scrutiny of section 3(d) of the Indian Patents Act.

In that sense, if the pharma MNCs with deep pockets, challenge these patents, there stands a good chance of making generic equivalents of those products at affordable prices for the Indian patients.

However, considering different degree and elements of market entry barriers, it appears, most of the patent challenges in India by the MNCs would probably be for biologics, as compared to small molecule chemicals.

Flow of newer drugs in the Indian market is now irreversible:

Taking stock of the emerging scenario, it appears, India will continue to see newer drugs coming into the market at a lower price in the years ahead, come what may. This flow seems to be unstoppable due to the following reasons:

Stricter implementation of Section (3d) of the Patents Act in India will ensure that NCEs/NMEs not conforming to this act will not be granted patents. In that case, those products will be open to generic copying by all, in India. Thus, in the absence of a market monopoly situation and fuelled by intense price competition, the patients will have access to those newer drugs.

More patent challenges of already granted patents could lead to revocation of more number of patents paving the way for entry of their generic equivalents.

If any MNC decides not to launch a new product in India having obtained its patent from the IPO, after three years, as per the statute, the same product becomes a candidate for CL in the country.

If any patented new product is launched without ‘reasonably affordable price’, again as per statute, the possibility of applications for CL coming to the IPO from the local players will loom large.

Hence, considering all these points, it appears, if the new products do not conform to the Indian Patents Act and are not launched with responsible pricing, the possibility of their generic entry at much lower prices is almost inevitable.

Conclusion:

Legal battle is expensive, even in India, and patent challenges are perhaps more expensive. All those new products, which are not patentable in India or may otherwise be challenged against other statutes of the Patents Act, will carry risks of getting caught in protracted litigations or generic competition.

MNCs with deep pockets coming forward with such intent, though may be based purely on their business interest in India, would ultimately offer spin-off benefits of affordable pricing, especially, to the patients suffering from life threatening and fast debilitating illnesses like, cancer.

That said, do all these developments unravel yet another way to improve access to newer medicines in India, signaling a boon for patients?

By: Tapan J. Ray

India, China Revoke Four Pharma Patents in A Fortnight: A Double Whammy for MNCs?

Posted on August 12, 2013 by Tapan Ray

Revocation of four pharma patents by India and China within a fortnight has raised many eyebrows, yet again, across the globe. In this short period, India has revoked three patents and China one.

While this quick development is probably a double whammy for the Multinational Corporations (MNCs) operating in both the countries, a future trend could possibly emerge by analyzing and connecting the evolving dots.

On August 8, 2013, a judicial body, the Intellectual Property Apellate Board (IPAB) of India reportedly revoked two patents of Allergan Inc on Combigan and Ganfort, both are Fixed Dose Combination (FDC) drugs of known molecules, used in the treatment of specified eye conditions. Local pharmaceutical player Ajantha Pharma had challenged these patents granted earlier to Allergan Inc. by the Indian Patent Office (IPO), alleging that the patents were obtained on false representation, the compositions were obvious ones, mere admixture of two pharmaceutical substances and not inventions.

IPAB in its order, while revoking the patent, has also said:

“The revocation of the patent was sought on various grounds that the patent was obtained on a false suggestion or representation, that it is not an invention, that it is obvious and does not sufficiently disclose and that the Section 8 of the Patents Act, 1970 was violated.”

The “respondents (Allergan Inc) have incorrectly deciphered enhancement in therapeutic efficacy as reduction in interocular pressure comparable to serial application.”

“The respondent has not shown that it had complied with the Section 8 of Patents Act, 1970.”

Though Allergan claimed to have achieved enhanced efficacy with reduced side effects for these FDCs, the IPAB did not find the claims justifiable. Interestingly, Ajantha’s product reportedly is much less expensive too. As compared to Allergan’s Ganfort drops (3 ml) costing about Rs 580, Ajanta’s equivalent formulation costs just Rs 131.

The other pharma patent revocation of the fortnight:

On July 27, 2013, IPAB revoked yet another patent granted earlier to GlaxoSmithKline (GSK)’s Lapatinib ditosylate salt of its breast cancer drug Tykerb, while upholding the patent on the original API, Lapatinib. IPAB in its order has stated that the ditosylate salt version of Lapatinib is not patentable as per patentability criteria of the Indian Patents Act.

Experts believe, with these decisions, the Indian legal system has clearly demonstrated that despite intense anger, pressure and protests mainly from the United States and Europe, to dilute public health interest related safeguards enshrined in the current Indian patent regime, the rule of law still prevails in the country for IP disputes.

Tykerb decision of IPAB follows the landmark judgment of the Supreme Court of India clarifying patentability criteria for incremental innovations.

An interesting precedent set:

In case of Tykerb of GSK, unlike other occasions, for the first time one MNC has challenged the patent of another MNC in India, instead of domestic companies doing so. The German drug manufacturer, Fresenius Kabi, instead of criticizing Indian IP law like other MNCs, had challenged the British drug maker GSK’s patent on the patentability criteria as provided in the Indian Patent Law and obtained a favorable decision from the IPAB against one of their two patent challenges on Tykerb.

A different case, yet worth mentioning:

Earlier, in late 2012, Delhi High Court while recognizing the validity of Roche’s patent for Tarceva (erlotinib), ordered that Cipla’s generic equivalent of erlotinib has different molecular structures. Hence, Cipla has not infringed Roche’s patent.

The generic version of Cipla’s erlotinib is reportedly available at a price of Rs 1,600 against Roche’s price of Rs 4,800 for Tarceva. Though this is not a patent revocation, but an interesting case nevertheless.

Other patent revocations:

Besides the only Compulsory License (CL) issued, so far, by the IPO for Bayer’s Nexavar to Natco (Cost of a pack of 120 tablets of Natco generic is Rs.8,800 against Nexavar’s Rs. 280,000), such patent challenges are now taking place in India quite close on the heels of one another as follows:

Sutent (Pfizer):

In this case, the patent for liver and kidney cancer drug of Pfizer – Sutent (Sunitinib), granted earlier by the IPO in 2007, was revoked by the IPAB in October 2012, after a post grant challenge by Cipla and Natco Pharma on the ground that the claimed ‘invention’ does not involve inventive steps.

However, on November 26, 2012 in a new twist to this case, the Supreme Court of India reportedly restored the patent for Sutent. Interestingly, at the same time the court removed the restraining order, which prevented Cipla from launching a copycat generic equivalent of Sunitinib.

The cost of 45 day’s treatment with Cipla generic is Rs. 50,000 against Rs. 196,000 of Sutent. (Source ET, April 7, 2013)

Pegasys (Roche):

Again, on November 2, 2012 the IPAB revoked the patent of Pegasys (Peginterferon alfa-2a) – the hepatitis C drug of the global pharmaceutical giant Roche. It is worth mentioning, Pegasys enjoys patent protection across the world.

Though Roche was granted a patent for Pegasys by IPO in 2006, this was subsequently contested by a post-grant challenge by the Indian pharma major – Wockhardt and the NGO Sankalp Rehabilitation Trust (SRT) on the ground that Pegasys is neither a ‘novel’ product nor did it demonstrate ‘inventiveness’ as required by the Patents Act of India.

It is worth noting, although the IPO had rejected the patent challenges by Wockhardt and SRT in 2009, the judicial body IPAB reversed IPO’s decision revoking the patent of Pegasys, costing Rs. 360,000 for a six month course of treatment for a patient.

Iressa (AstraZeneca):

On November 26, 2012, IPAB reportedly denied patent protection for AstraZeneca’s anti-cancer drug Iressa (Gefitinib) on the ground that the molecule lacked invention.

The report also states that AstraZeneca suffered its first setback on Gefitinib in June 2006, when the Indian generic company Natco Pharma opposed the initial patent application filed by the global major in a pre-grant opposition. Later on, another local company, GM Pharma, joined Natco in November 2006.

After accepting the pre-grant opposition by the two Indian companies, IPO in March 2007 rejected the patent application for Iressa Gefitinib citing ‘known prior use’ of the drug. AstraZeneca contested the order through a review petition, which was dismissed in May 2011.

Anti-asthma FDC aerosol suspension (Merck & Co):

Similar to Allergan case, on December 11, 2012 Indian Patent Office (IPO) reportedly revoked a patent granted to an anti-asthma FDC drug of Merck & Co on the ground of lack of invention, after the domestic pharma major Cipla Ltd challenged an earlier granted patent of this FDC drug.

This aerosol suspension combines three molecules: mometasone furoate, formoterol and heptaflouropropane.

A similar asthma treatment, Dulera, reportedly lost its Indian patent held by Novartis AG in 2010.

Patentability for ‘Incremental Innovations’ in India:

Patentability criteria for any ‘incremental innovation’ has been defined in the Section 3(d) of the Indian statute as follows:

“The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.”

“Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.”

Indian Patents Act prevails:

As is well known, way back in 2006, IPO refused to grant patent to the cancer drug Glivec of Novartis on the ground that the molecule is a mere modification of an existing substance known as Imatinib.

In that case, on April 1, 2013 the Supreme Court of India upheld the validity of Section 3(d), where the rules of the game for patentability of incremental pharmaceutical innovations, as captured in the Indian Patents Act 2005, were cast in stone.

Court did not disallow all incremental innovations:

Point 191 in page number 95 of the Glivec judgment very clearly states as follows:

“191. We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment.”

Thus, it should not be highlighted unfairly by concerned constituents that all ‘incremental innovations’ are not patentable in India. The above judgment just says that Glivec is not patentable as per Section 3(d) of Indian Patents Act based on the data provided and the arguments of Novartis.

Only 3% of patents are challenged:

Quoting a study, a recent media report highlighted that only 3% of the patent applications filed in India since 2006 were challenged. The study concluded, “This demonstrates that given the various resource constraints faced by the Indian patent office, one can never really be sure of the patent quality unless the patent is challenged.”

Rejection by IPO under Section 3d is minimum – is that a key issue?

Another study done by Columbia University reportedly found that out of 214 patents filed in India last year, only 3 patents were rejected by IPO exclusively for failing to prove better efficacy, as required under Section 3d. Turning this finding on its head, would it be reasonable to ponder:

Could this be a key issue for so many patents failing to pass the acid test of judicial scrutiny when challenged?

Government has no role to play in IP disputes:

The proponents of ‘no change required in the Section 3(d)’ argue, patent challenge is a legal process all over the world, where the Government has hardly any role to play in resolving these disputes. The law should be allowed to take its own course for all disputes related to the Patents Act of the country, including Section 3(d).

They also opine that India must be allowed to follow the law of justice without casting aspersions on the knowledge and biases of the Indian judiciary by the vested interests.

That said, there is certainly an urgent need to add speed to this legal process by setting up ‘Fast-track Courts’ for resolving all Intellectual Property (IP) related disputes in a time bound manner.

Pharma patents granted in India:

As reported in the media, pharma MNCs have been granted over 1,000 patents since 2005. Moreover out of 4,036 patents granted in the past six years, 1,130 have been awarded to MNCs, like:

AstraZeneca 180 patents
Roche with 166 patents
Sanofi with 159 patents
Novartis with 147 patents

It is therefore understandable, as pharma MNCs have secured more number of pharma patents they are facing larger number of litigations at this point of time.

China and Brazil revoke patents:

Last week, just about a year after China introduced the country’s amended patent law, its State Intellectual Property Office (SIPO) has reportedly revoked the patent on HIV/AIDS and hepatitis B drug – Viread (tenofovir disoproxil fumarate) of Gilead Science Inc. Aurisco, the largest manufacturer of active pharmaceutical ingredients in China, challenged this patent. The ground of patent revocation was that the drug lacked novelty and was not entitled to protection.

South Africa mulls new law to stop ‘Evergreening’:

Recently, the Department of Trade and Industry of South Africa has reportedly submitted to the South African Cabinet a draft Intellectual Property Policy with far-reaching changes to the country’s Intellectual Property Rights (IPR) for medicines in order to increase access to cheaper drugs by making it harder for companies to obtain and extend patents.

The draft includes a proposal to introduce a patent examination office to stop pharmaceutical companies from “evergreening” where companies take out new patents based on minor changes or new uses.

Currently, South Africa uses a depository system, in which patent applications are granted without extensive scrutiny. Experts believe, “this system allows companies to file multiple patents on the same medicine and extend the life of their monopoly, keeping prices artificially high.”

Innovators Angry:

In this context, the following report recently captured the anger of the innovator companies and stated that the US drug giants are once again pushing for stronger patent protection in India:

“A coalition of U.S. lawmakers and business groups outlined concerns about Indian policies as a threat to American exports, jobs and innovation in a letter to President Barack Obama on June 18. Among the business groups were the Pharmaceutical Research and Manufacturers of America and the Biotechnology Industry Association. On June 14, the top Democrat and Republican on the Senate Finance Committee urged that Kerry raise trade concerns on his visit.”

Quoting US Chamber of Commerce’s Global Intellectual Property Center another report highlighted, “Recent policy and judicial decisions that invalidate intellectual property rights, which have been increasing in India, cast a daunting shadow over its otherwise promising business climate. From the revocation of patents to the staggering rates of piracy, India stands alone as an international outlier in IP policies. This trend is bad for investment, innovation and international trade.”

Does it benefit patients?

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

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

While the ‘Trade-Related Aspects of Intellectual Property Rights Agreement (TRIPS)’ of the World Trade Organization (WTO) sets out minimum standards for the patent protection for pharmaceuticals, it also offers adequate safeguards against negative impact of patent protection or its abuse in terms of extraordinary and unjustifiable drug pricing. The levels of these safeguards vary from country to country based on the socioeconomic and political requirements of a nation, as in India.

Following table is an example of price differential between patented and generic equivalents of those molecules used in the treatment of HIV/AIDS:

1			2			3
3TC (Lamivudine)			Zerit (Stavudine)			Viramune (Nevirapine)
Price / Year / Patient in US$			Price / Year / Patient in US$			Price / Year /Patient in US$
GSK	Cipla	Hetero	BMS	Cipla	Hetero	B.I.*	Cipla	Hetero
3271	190	98	3589	70	47	3508	340	202

(Source: Third World Network, *B.I: Boehringer Ingelheim)

Patentability for ‘genuine innovations’:

A report on ‘Patentability of the incremental innovation’ indicates that the policy makers keeping the following points in mind formulated the Indian Patents Act 2005:

The strict standards of patentability as envisaged by TRIPS pose a challenge to India’s pharmaceutical industry, whose success depended on the ability to produce generic drugs at much cheaper prices than their patented equivalents.

A stringent patent system would severely curtail access to expensive life saving drugs to a large number of populations in India causing immense hardships to them.

Grant of a product patents should be restricted only to “genuine innovations” and those “incremental innovations” on existing medicines, which will be able to demonstrate significantly increased efficacy over the original drug.

Conclusion:

A study by the ‘Indian Pharmaceutical Alliance (IPA)’ indicates that 86 pharmaceutical patents granted by the IPO post 2005 are not breakthrough inventions but only minor variations of existing pharmaceutical products and demanded re-examination of them.

Since, most of the above patents have not been challenged, as yet, the quality of these patents cannot be ascertained beyond any reasonable doubt, as we discuss today.

If the apprehension, as expressed above in the IPA study has any merit, right answers to the following questions, I reckon, would help charting out the future direction for the IP ecosystem of India:

Is there a theoretical possibility of revocation of all these 86 already granted product patents, if and when challenged in a court of law?
Is the current Patents Act of India pragmatic?
Does it reasonably benefit both the innovators and the Indian patients, signifying a paradigm shift in the global IPR scenario?
Will it inspire other countries also to emulate similar IP system in the years ahead?
Will it then invite more intense ire of the global pharma innovator companies creating increasing pressure on the Indian Government to amend the current Patents Act?
Being under continuous public scrutiny, would it be feasible for any Indian Government, now or in future, in the near or medium term, to amend the Indian Patents Act due to any amount of outside pressure?
And finally, is the Act then irreversible, at least, for quite some time from now?

By: Tapan J. Ray

FDC Saga: Defiant Manufacturers, Sloppy Regulators and Humongous Inaction

Posted on July 15, 2013 by Tapan Ray

“TO SIN BY SILENCE WHEN THEY SHOULD PROTEST MAKES COWARDS OF MEN” – Abraham Lincoln

The ghost of untested, irrational and even of bizarre kind of Fixed Dose Combination (FDC) drugs, which continue to be launched, promoted, prescribed and sold freely across the length and breadth of India, has started haunting the Ministry of Health of India, yet again, in 2013.

Though the issue originated decades ago, in 1988 appropriate ‘Rule’ of the Drugs and Cosmetics Act of India was amended suitably to have a firm regulatory grip over this situation. Despite this much awaited amendment, the situation almost went astray with incessant market entry of a large number untested FDC medicines of dubious medical rationale.

A free for all situation, as it were, in the FDC arena, continued to be facilitated by blatant laxity on the part of, especially, the state drug regulators by allowing unfettered market entry of such drugs, ignoring the CDSCO directive.

On the other hand, the Central Drugs Standard Control Organization (CDSCO), despite its statutory powers, continued to suffer from humongous inaction untill the issue resurfaced again in 2007 and then of course, now in 2013.

The WHO Model:

The 2005 ʹProcedure to update and disseminate the WHO Model List of Essential Medicines, Criteria for Selection’ includes the following statement regarding Fixed Dose Combination products (FDCs):

ʺMost essential medicines should be formulated as single compounds. Fixed‐dose combination products are selected only when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety, and adherence or in delaying the development of drug resistance in malaria, tuberculosis and HIV/ AIDS.ʺ

Thus, FDCs:

Need to demonstrate clinical efficacy and safety beyond the individual drugs when given alone.

Need to ‘demonstrate bioequivalence of the single combined dose unit with the components administered in the same doses separately but concomitantly’.

‘Adherence’ aspect of WHO Model for FDCs is also important. Problems with ‘adherence’ could lead to inadequate and inconsistent dosing, which in turn could lead to development of drug resistance.

With robust and unquestionable medical rationale, FDCs are expected to provide superior efficacy and improved compliance without causing any untoward risk to patients.

A major disadvantage:

However, one of the major disadvantages with the FDCs is lack of flexibility in adjusting dose of individual ingredients, even if it is required for some patients. Internationally, most popular example is the FDCs of antiretroviral drugs for HIV infected patients like, Combivir, Trzivir, Kaletra etc.

Interestingly, in India there are FDCs for almost all disease areas from allergic disorders to Wolf-Parkinson-White syndrome (exaggerated), as it were.

Market attractiveness for FDCs in India:

The domestic market for FDCs is very large and growing much faster, in sharp contrast to the western world. The following table will vindicate this point:

% Share
Drug	2008	2009	2010	2011
Plain	55	55	55	54
Combinations	45	45	45	46
Domestic Market: USD 13 Billion; MAT Apr 2013

Source:IMS

Thus, because of growing market demand, pharmaceutical companies in India tend to market FDCs of all different permutations and combination, at times even crossing the line of any ‘sound medical rationale’. For this reason, we find in the website of ‘Central Drugs Standard Control Organization’ (CDSCO), the banned list of so many FDCs.

A messy regulatory situation:

Introduction of new FDCs does not only warrant a ‘sound medical rationale’ but also ‘strict conformance to all prescribed regulatory requirements’ for patients’ interest.

To check unfettered market introduction of potentially harmful FDCs, the Ministry of Health issued a Notification in September 1988, including FDCs in Rule 122 E of the Drugs & Cosmetics Rules (D&CR) 1945.

In effect, it removed the powers of the State FDAs to give manufacturing or marketing approval of FDCs. After the notification was issued, all manufacturers/marketers of all new FDCs are required to apply only to the Drug Controller General of India (DCGI) under Rule 122E of the D&CR 1945 as a new drug, along with the stipulated fees by way of a Treasury Challan.

Since this entire process entails appropriate regulatory data generation, besides time and expenses involved, the above ‘Rule’ was continuously and deliberately broken and manufacturing and marketing approvals for various types of FDCs falling under ‘new drug’ category were regularly sought and granted by the State Drug Controllers.

Many believe that the State FDAs were equally responsible for knowingly flouting the Law, as were the pharmaceutical manufacturers.

Patients’ safety – the foremost concern:

Despite serious concerns expressed by a Parliamentary Standing Committee, this complicity resulted in the market being flooded with ‘irrational combinations’ which posed a real threat to patients’ interest and safety. The State FDAs were reminded of the notification by the earlier DCGI.

294 FDCs were banned by the DCGI in 2007. Thereafter, the important issue of patients’ interest and safety got converted into a legal quagmire, as many FDC manufacturers chose to go to the court of law to protect their business interest and also managed to obtain a ‘Stay’ order from the Madras High Court. The matter is still subjudice.

Be that as it may, those 294 FDCs banned by the Ministry of Health of India on health and safety grounds continue to be promoted, prescribed and sold to patients across India without any hindrance, whatsoever.

Untangling the messy knot:

As the issue got entangled into prolonged litigations, the CDSCO took initiative of resolving this contentious issue again in 2009 with the help of an expert committee, involving the manufacturers.

This subcommittee cleared 48 FDCs under ‘similar FDCs already approved’, after discussing the merits and demerits, including pharmacodynamics, pharmacokinetics, side effects, dosage, medical rationale etc. of each ingredient and the combinations. The decision of the Sub Committee was then submitted to the Drug Technical Advisory Board (DTAB).

After formal approval of DTAB, these combinations are construed to be new drugs and any company wishing to market/manufacture the formulation would require submitting its Application in Form 44 to the DCGI to get approval in Form 45.

This decision was expected to send a clear signal to all concerned that resorting to any form of shortcuts to bypass strict adherence to prescribed regulatory requirements, could seriously jeopardize patients’ interest and safety. The same process was subsequently followed for the balance 142 FDCs, as well.

Thereafter, a special committee was again appointed by the CDSCO in 2013 to look into this matter in a holistic way. However, such sporadic knee-jerk reactions have failed to deliver any tangible results in this area – not just yet.

The saga continues:

Even after the above critical decision of the DTAB the saga still continues.

In March 2013, by a written reply, the Minister for Health and Family Welfare reportedly informed the Lok Sabha (the lower House of the Parliament) that in twenty three cases of new FDC, licenses have been granted by the State Licensing Authorities (SLAs) without the mandatory approval of the DCGI and action will be taken in all these cases.

However, no one seems to know, as yet, what action the Government has taken against those errant officials.

Current scenario:

Recently, the Directorate General of Health Services (DGHS) by a notification to State Drug Controllers has reportedly ordered all manufacturers of new FDC products, licensed locally before October 2012 without CDSCO permission, to submit safety and efficacy data prior to 30 August 2013.

This decision of DGHS has created a furore within the concerned FDC manufacturers, yet again, the possible outcome of which is yet to be ascertained.

The State Drug Controllers had issued manufacturing licenses for these FDCs prior to October 2012. At that time concerned manufacturers were given 18 months time period to prove efficacy and safety of these medicines to the DCGI. Regrettably, as per the above report, the DCGI has confirmed that he has received hardly any response from the FDC manufacturers till date on this regulatory requirement.

CDSCO has also stated that manufacturers, who will fail to submit the required data by the deadline run the risk of having their products banned from the market.

Before this, the State Drug Controllers were informed about this requirement on January 15, 2013.

At this point it is worth mentioning, the DCGI in October 2012 had reportedly also barred the State Drug Controllers from granting manufacturing licenses to pharmaceutical companies under brand names of the drugs, directing them to strictly issue licenses under generic name of the molecule. Additionally, he also asked the state licensing authorities not to grant licenses to combination drugs, which are technically ‘new drugs’ and fall within the domain of DCGI only.

Conclusion:

This logjam with FDCs certainly cannot continue in perpetuity, neither should such regulatory sloppiness be acceptable to any right thinking stakeholder.

All blatant violations of Drugs and Cosmetics Act of India must be stopped forthwith and the violators be brought to justice without delay. Patients’ health interest, as required by the drug regulators, is non-negotiable.

The order of DGHS asking all manufacturers of new FDCs, licensed locally before October 2012 without CDSCO permission, to submit safety and efficacy data prior to 30 August 2013, should not follow recently reported Pioglitazone type of volte face, once again, under similar outside pressure.

It is high time now for the Government to bring the unending saga of irrational and harmful FDCs, orchestrated by defiant manufacturers, encouraged by sloppy regulators and catalyzed by humongous systemic inaction, to its logical conclusion, for patients’ sake.

By: Tapan J. Ray

Pioglitazone Conundrum: Should The Drug Regulator Step Over The Line?

Posted on July 8, 2013 by Tapan Ray

Recent order of the Indian drug regulator to withdraw all formulations of the well known, yet controversial, anti-diabetic drug – Pioglitazone from the domestic market has created a flutter in the country, ruffling many feathers at the same time.

Withdrawal of any drug from the market involves well-considered findings based on ongoing robust pharmacovigilance data since the concerned product launch. To ascertain long-term drug safety profile, this process is universally considered as important as the processes followed for high quality drug manufacturing and even for R&D.

A paper titled, “Withdrawing Drugs in the U.S. Versus Other Countries” brings to the fore that one of the leading causes of deaths in the United States is adverse drug reaction. Assessing enormity and impact of this issue, the United Nations General Assembly for the first time in 1979 decided to publish a list of banned pharmaceutical products that different countries may use for appropriate decisions keeping patients’ safety in mind, as they will deem necessary from time to time.

An interesting finding:

Quite interestingly, the paper also highlights:

“There are a number of pharmaceuticals on the market in the USA that have been banned elsewhere and similarly, there are some drug products that have been banned in the United States, but remain on the market in other countries.”

Different policies in different countries:

The reason for the above finding is mainly because, various countries follow different policies to address this important health related issue. For example, though the United States will withdraw drugs based on the decision taken by its own FDA, it will also compare the action taken by countries like, UK, Japan, Australia and Sweden on the same subject.

However, many experts do believe that United Nations must take greater initiative to make all concerned much more aware about the UN list of dangerous drugs, which should be continuously updated to expect the least.

Need transparency in pharmacovigilance:

Pharmacovigilance has been defined as:

“The task of monitoring the safety of medicines and ensuring that the risks of a medicine do not outweigh the benefits, in the interests of public health.”

An article on Pharmacovigilance by A.C. (Kees) van Grootheest and Rachel L. Richesson highlights as follows:

“The majority of post marketing study commitments are never initiated, and the completion of post marketing safety studies (i.e., phase IV studies) declined from 62% between 1970 and 1984 to 24% between 1998 and 2003.”

Thus, in many countries, due to lack of required transparency in the pharmacovigilance process, harmful drugs continue to remain in the market for many years before they are withdrawn, for various reasons.

The above paper strongly recommends, “While there might be monetary benefits for each country in keeping these drugs on the market, the U.N. must step up the visibility of the withdrawal of dangerous drugs list.”

Recent Pioglitazone withdrawal in India:

Recently in India, the Ministry of Health under Section 26A of the Drugs and Cosmetics Act, 1940 has suspended the manufacture and sale of Pioglitazone, along with two other drugs, with immediate effect, through a notification issued on June 18, 2013.

As per the Drugs and Cosmetic Rule 30-B, import and marketing of all those drugs, which are prohibited in the country of origin, is banned in India. Just as in the United States, the Ministry of health, while taking such decisions in India, compares long-term safety profile of the concerned drugs in countries like, USA, UK, EU and Australia.

A Parliamentary Standing Committee of India has already indicted the drug regulator for not taking prompt action on such issues to protect patients’ treatment safety.

Pioglitazone: the risk profile:

In India:

A leading medical journal (JAPI) cautions:

“Given the possible risk of bladder cancer, physicians have to be extremely careful about using pioglitazone indiscriminately in the future.”

The JAPI article continues to state:

“We require more robust data on the risk of bladder cancer with pioglitazone and Indian studies are clearly needed. Till that time, we may continue the use of this drug as a second or third line glucose-lowering agent. In all such cases, the patient should be adequately informed about this adverse effect and drug should be used in as small a dose as possible, with careful monitoring and follow up.”

In the USA:

In 2011 The US FDA as a part of its ongoing safety review of pioglitazone informed physicians and the public that use of this drug for more than 12 months is linked to an increased risk of bladder cancer.

The USFDA review is reportedly based on “an ongoing 10-year observational cohort study as well as a nested, case-control study of the long-term risk of bladder cancer in over 193,000 patients with diabetes who are members of the Kaiser Permanente Northern California (KPNC) health plan.”

Based on this finding US FDA directed that physicians should:

Not use pioglitazone in patients with active bladder cancer.
Use pioglitazone with caution in patients who have a prior history of bladder cancer, adding, “The benefits of blood sugar control with pioglitazone should be weighed against the unknown risks for cancer recurrence.”
Tell patients to report any signs or symptoms of “blood in the urine, urinary urgency, pain on urination, or back or abdominal pain, as these may be due to bladder cancer.”
Urge patients to read the pioglitazone medication guide.
Report adverse events involving pioglitazone medicines to the FDA MedWatch program.

The moot point:

Considering the above US FDA directives in the Indian context, the moot point therefore is, whether it will be possible for the drug regulator to ensure that physicians and the patients in India follow such steps for drug safety with pioglitazone?

In Canada:

Another new Canadian study has again reportedly linked Pioglitazone with risks of bladder cancer and cautioned, “physicians, patients and regulatory agencies should be aware of this association when assessing the overall risks and benefits of this therapy.”

Pioglitazone and its combinations banned in France and Germany:

After a government-funded study, tracking diabetics from 2006 to 2009, concluded that Pioglitazone increases bladder cancer risk, the French Medicines Agency (FMA) announced withdrawal of Pioglitazone along with its fixed-dose combination with Metformin, as well.

FMA also advised doctors to stop prescribing Pioglitazone, plain or in combination, and asked patients, who are on this drug to consult their doctors immediately.

Simultaneously, German health authorities also acted on similar lines.

An intriguing comment by the Indian drug regulator:

Keeping all these in view, it is indeed intriguing to note that the Indian drug regulator is reportedly open to re-examine the case of pioglitazone and revoking its ban in India, if strong scientific evidences emerge in support of safety and efficacy of the drug.

However, the question then comes up is what more new scientific evidences that the Indian drug regulator is now expecting, especially when the pharmacovigilance studies are almost non-existent in India?

Moreover, such comments of the drug regulator not only prompt raising doubts about the fragility and hastiness of his own decision of banning Pioglitazone in India, but also amply demonstrate lack of seriousness in his part on this extremely important decision on drug safety?

‘Drug Product Liability Claims’ in India virtually non-existant:

In most of the developed countries, appropriate regulations are in place for product liability claims.

Under this law, if any patient suffers injury in any form while administering a pharmaceutical drug, the patient concerned is eligible to make pharmaceutical-drug-based product liability claims, which usually involve a huge amount of money by any imaginable standard.

These claims are based on:

Defectively manufactured pharmaceutical drugs (Types of Defective Product Liability Claims)

Pharmaceutical drugs with dangerous side effects, even though properly manufactured (Damages in Defective Products Cases.)

Improperly marketed pharmaceutical drugs. This category includes:

- Failure to provide adequate or accurate warnings regarding a dangerous side effect.

- Failure to provide adequate instructions on safe and appropriate use of the drug.

- The “bad advice”, which may have been given by the manufacturer or by a doctor, pharmacist, sales rep, or some other medical provider.

In the United States drug safety and effectiveness related litigations reportedly also include:

- Criminal and civil complaints brought by the U.S. Department of Justice.

- Lawsuits brought by state Attorney Generals and private plaintiffs under state consumer protection acts and other causes of action.

In India, closer to the above system there is a law in paper, named as “Products Liability”. This law deals with the liability of manufacturers, wholesalers, distributors, and vendors for injury to a person or property caused by dangerous or defective products. The aim of this law is to help protecting consumers from dangerous or defective products, while holding manufacturers, distributors, and retailers responsible for putting into the market place products that they knew or should have known were dangerous or defective. However, in reality, there are hardly any damages slapped by consumers on to the manufacturers in India under this ‘Product Liability’ law.

It may sound however bizarre, but is a hard fact that many drugs in Fixed Dose Combinations (FDCs) had never even gone through any form clinical trials on human volunteers before they were for the first time allowed to be marketed in India by the drug regulators.

In absence of any active steps taken by the government to educate and encourage patients to make use of this law, patients, by and large, would continue to pay a heavy price for their ignorance, keeping their mouth shut all the way, while using:

- Defectively manufactured pharmaceutical drugs.

- Pharmaceutical drugs with dangerous side effects.

- And even improperly marketed pharmaceutical drugs.

As stated before, it is worth repeating, neither is their any functional pharmacovigilance system in place in India.

Drug product liability suit for Pioglitazone in the United States:

Just to cite an example, one report indicates:

“According to court filings, all of the Actos (Pioglitazone) lawsuits pending in the Western District of Louisiana allege Takeda Pharmaceuticals failed to provide adequate warnings to doctors and patients regarding the drug’s association with an increased risk of bladder cancer. Last month (April, 2013), the nation’s first trial involving Actos bladder cancer allegations ended with a Los Angeles Superior Court jury awarding $6.5 million to a plaintiff who was diagnosed with the disease after taking the drug for four years”. However, the judge overseeing the case granted Takeda Pharmaceuticals’ request to set aside the verdict.

The report also indicates, ‘more than 1,200 Actos bladder cancer claims are pending in the Louisiana litigation. Additional Actos lawsuits have been filed in state litigations in California and Illinois.’

Indian doctors and manufacturers protest together against Pioglitazone ban:

It is equally intriguing to note, despite serious life threatening side-effect and restricted usage profile of Pioglitazone, as established internationally through robust and large clinical studies, both the doctors and the Pioglitazone manufacturers in India are urging the government to lift ban on this drug immediately, keeping the silent patient community in the front line, as usually happens all over.

A news report highlighted that ‘doctors flayed the ban on anti-diabetes drug Pioglitazone and requested the Centre to reverse its decision in interest of patients.’

Another media report highlighted, major drug makers are strongly opposing the move of the government to ban Pioglitazone, in India.

Conclusion:

Without generating another set of robust evidence proving contrary to what has been already concluded in the United States and EU based on strong supporting pharmacovigilance data, if the Indian drug regulator revokes the ban of Pioglitazone, it will be construed as a huge compromise with patients’ safety interest with this drug.

This issue assumes even greater importance, when the ‘drug product liability’ system is almost dysfunctional in India.

The other alternative of the drug regulator is to revoke the ban, wilting under combined pressure of the manufacturers and doctors and ask for safety warnings trying to emulate, as it were, what has been done by the US FDA.

In which case, with full knowledge that it is virtually impossible for any one to comply with the above US FDA requirements in India, will the drug regulator not step over the line, yet again?

By: Tapan J. Ray

PILMAN

A Tapan Ray Website

Tag Archives: Act

The ‘TINA Factor’: A Hotspot for Patented Drugs

Ministers of Trade from 12 countries initiated a discussion on December 6, 2013 at Singapore to meet the US deadline of forging a deal on the proposed ‘Trans-Pacific-Partnership (TPP)’ before the end of 2013.

These twelve countries – Australia Brunei, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore, USA and Vietnam, contributing 40 percent of the world economy, are expected to hammer out the TPP deal first, though other countries may hitch on thereafter.

However, after 4 days of intense negotiation, the US-led TPP talks ended on December 10, 2013, without beating into shape any deal. These countries would reportedly meet again on January 2014, in contrast to earlier plan.

‘Big Pharma’ Prowls Falter: Triggers Off Yet Another Critical Debate

Big Pharma Demands Transparency, Keeping their ‘Black-Boxes’ Tight and Safe?

Drug, Patent and Hype: Quo Vadis Pharma Innovation?

MNCs to Challenge MNC Patents in India: Boon for Patients?

India, China Revoke Four Pharma Patents in A Fortnight: A Double Whammy for MNCs?

FDC Saga: Defiant Manufacturers, Sloppy Regulators and Humongous Inaction