Even Smaller Countries Now Question Indian Drug Quality Standard

Posted on December 5, 2016 by Tapan Ray

India has over 135 US-FDA approved pharmaceutical manufacturing units, at present. This number is very significant ranking second behind the United States, and was driving the growth of generic drug exports in the top pharma market of the world. Riding on the wave of such stellar progress, a hubris seems to have set in the related operational areas of many Indian pharma players, especially the drug exporters.

This incredible ride continued, until a first major jolt shook all concerned in this business. It came first in the form of an unprecedented hefty fine for wrong doing, followed by the US- FDA ‘import bans’ of several drugs, manufactured around 44 different Indian drug-making facilities, since over the last five years.

The first major jolt:

Not so long ago, just in 2013, quality related concerns with generic drugs exported from India came to the fore, after Ranbaxy reportedly pleaded guilty and paid a hefty fine of US$ 500 million for falsifying clinical data and distributing ‘adulterated medicines’ in the United States.

Thereafter, US-FDA banned drug imports from Ranbaxy and Wockhardt, manufactured in all those facilities that failed to conform to its cGMP quality standards.

Those are the stories for generic formulations. It then covered the Active Pharmaceutical Ingredients (API) too. On January 23, 2014, USFDA notified Ranbaxy Laboratories, that it is prohibited from manufacturing and distributing APIs from its another Indian manufacturing facility in Toansa. With this step, erstwhile Ranbaxy had virtually no access to the top pharmaceutical market of the world.

Was it for raising the bar of quality norms?

Many of us felt and expressed that ‘import bans’ of Indian drugs due to failing quality parameters, manufactured in certain facilities of largely Indian pharma companies, are mostly due to higher stringent quality norms of the US-FDA, the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA). Nevertheless, this argument does not carry much weight, as an exporter will always have to conform to the set quality standards of the importers, whatever these are.

Indian drug regulator too made a much avoidable remark:

Unfortunately, amid such a scenario, instead of taking appropriate transparent and stringent measures, the Drug Controller General of India (DCGI) was quoted by the media saying, “We don’t recognize and are not bound by what the US is doing and is inspecting. The FDA may regulate its country, but it can’t regulate India on how India has to behave or how to deliver.”

The DCGI made this comment as the then US-FDA Commissioner Margaret Hamburg was wrapping up her a weeklong maiden trip to India, in the wake of several ‘Import Bans’ arising out of repeated cGMP violations by some large domestic generic drug manufacturers. Whereas, Hamburg reiterated the need for the domestic drug manufacturers conform to the USFDA quality standards ensuring health and safety for American patients, the DCGI’s above comment appears rather arrogant, out of tune, and was avoidable, to say the least. Instead, some serious corrective regulatory measures should have followed.

On the above comments of the DCGI, the American Enterprise Institute reportedly reacted by saying, “Indian drug regulator is seen as corrupt and colliding with pharma companies…”.

Smaller countries initiated similar action:

It now appears that this situation is going from bad to worse and malady is much deeper. Smaller countries, such as Vietnam, have recently banned products of a sizable number of domestic pharma exporters.

On September 5, 2016, a leading business daily of India reported: “Close on the heels of Prime Minister Narendra Modi’s visit to Vietnam to strengthen bilateral ties, including defense, security and trade, the ministry of commerce and industries is planning to set up a committee, along with the Central Drugs Standard Control Organization (CDSCO), to inspect Indian pharmaceutical companies which have been banned from Vietnam for exporting sub-standard drugs.”

In 2014, the Drug Regulatory Authority of Vietnam ‘red-listed’ about 50 pharma companies for alleged regulatory non-compliance in their manufacturing practices. The names included, some big names of Indian pharma industry.

Overall pharma market size of Vietnam is estimated over US$ 2 billion, and expected to grow to US$ 8 billion by 2020. A significant chunk of Vietnam’s pharmaceutical market comprises of generic drugs, where India used to be a major exporter. In the recent years, however, Indian pharmaceutical product exports to Vietnamese market have dipped considerably, reflecting the effects of the ban, with exports declining by 12 percent to US$ 146 million in 2015-16 from US$ 165 million in the previous fiscal year, the report said.

It was envisaged, especially after the Prime Minister’s visit to Vietnam, this situation will improve notably. However, just as what happened with the USFDA on related issues, there has been no change in the overall situation in this case, either.

Further, on November 23, 2016, yet another Indian Business news daily reported that 39 Indian drug companies have been blacklisted by Vietnam for quality standard violations, along with some others in Bangladesh and South Korea. The Vietnamese regulator has listed the names of all blacklisted companies on its website, without specifying in detail the exact reason behind the bans. The Indian products include, antibiotics and anti-rabies vaccine, among others. The latter was also reportedly banned by the World Health Organization (WHO), in January 2016.

What is more intriguing, despite the Union Ministry of Health and the Ministry of Commerce and Industries of India being aware of it, the issue seems to have drifted beyond reasonable control of the Indian regulators.

Some local companies still not acting:

On Feb 24, 2016, the US and the EU drug regulators reportedly called upon India’s pharmaceutical sector to step up efforts to improve manufacturing standards, and ensure the reliability of data, if it wishes to maintain its dominance in the generic drug industry. In the report, the director of the office of surveillance at the USFDA – Russell Wesdyk was quoted saying, “some Indian companies are still not taking enough steps to identify risks and failures at their firms.”

“Data integrity really sounds-off alarm bells for us. If you see data integrity on the surface, there is likely a lot going on underneath,” the foreign drug regulators reportedly commented.

These comments are profound, especially considering that India supplies about 33 percent of medicines sold in the United States, and nearly a quarter sold in the UK. Similar Indian drug quality related issues are now being raised by even smaller countries.

How safe are drugs for domestic consumption?

Many reasons may be attributed to quality concerns on Indian generics in the United States. Nonetheless, another question that surfaces alongside, if cGMP violations can take place for drug exports, despite rigorous compliance checks by the foreign drug regulators, what could possibly happen when the same system is so tardy in India? Are we consuming safe and effective drugs, whenever required, even within the country?

No one seems to have the right answer to this question, be because of various reasons. One such reason, out of various others, could well be how robust is data quality generated by the contract manufacturing companies? These are the core quality related issues, and can’t just be wished away, under any pretext.

Some examples:

On November 12, 2013, the DCGI was quoted saying that the investigative team of the drug regulator concluded that all the data submitted by Puducherry-based contract drug manufacturer ‘GuruFcure’, while seeking approval for manufacturing seven fixed dose combination drugs, are ‘fabricated’ and not ‘authentic’.

‘GuruFcure’, which started operations in 2007, and calls itself “one of the leading pharmaceutical formulation manufacturers in India”, reportedly used to manufacture drugs for some leading pharma MNC and Indian companies, such as: Abbott, Alkem, Glenmark, Wockhardt, Unichem, Intas Pharma, among others.

Though, as per the above media report, Wockhardt and Glenmark said that they were no longer associated with ‘GuruFcure’ at that time, the fact remains, they did market drugs produced by this contract manufacture in the past, and the patients consumed those drugs against doctors’ prescriptions. The saga continues unabated, even today.

On November 28, 2016, a major national English daily reported with a video clip that, following a crackdown since March this year, the drug regulators of seven states have alleged that 27 medicines, sold by 18 major drug companies in India, including Abbott, GSK, Sanofi, Sun Pharma, Cipla, Torrent, Alkem, Emcure and Glenmark Pharma, are of substandard quality, citing grounds such as false labelling, wrong quantity of ingredients, discoloration, moisture formation, failing dissolution test and failing disintegration test. Such allegations, though supported by laboratory test results, needs to brought to their logical conclusion. This is mainly because, media reports of this nature fuel lurking apprehension on the overall drug quality standards in India, leading to serious compromise with patients’ health and safety.

Conclusion:

Against this rather gloomy backdrop, a ray of hope comes from a report that CDSCO has started training Indian drug manufacturers in good manufacturing practices, as it tries to address concerns of the USFDA, and other drug regulators, effectively.

Quoting the DCGI, who has now apparently resolved to put together proper practices and regulation in place for the pharma industry, the report says that CDSCO has hired 500 personnel, and is expected to further train employees of other units, to ensure that high quality medicines are manufactured in the country.

These officials will visit drug manufacturing hubs of the country over the next three to four years and train employees in producing quality medicines, following proper procedures and maintaining records. I hope, this will include contract manufacturers too. The question would remain: What happens when these regulatory lapses do not take place out of ignorance or lack of experience or expertise, but are purely intentional to cut corners?

Alleged dubious quality of many drugs manufactured in India is a critical issue, both within the country and with several foreign drug regulators, such as US-FDA, EMA and MHRA, among others. It affects all those who consume such drugs.

Today, even smaller countries are questioning Indian drug quality to protect their patients’ health interest. Thus, everything, when clubbed together, sends a strong signal to the Indian drug regulator to come out of its denial mode, walk the talk, and act decisively to safeguard the interest of Indian patients too.

By: Tapan J. Ray

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

Is Criticizing Pharma Now Just A Fad?

Posted on October 10, 2016 by Tapan Ray

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

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

A recent example:

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

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

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

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

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

A key barrier:

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

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

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

When the narrative gets paradoxical:

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

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

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

Sanofi sued Merck in the US federal court over its biosimilar version of Lantus insulin with around US$7 billion in annual sales.

Eli Lilly reached a royalties deal with Sanofi to end a similar Lantus-related lawsuit, but their pact means the biosimilar launch was likely delayed.

Pfizer and Korea’s Celltrion in August beat back a court challenge from Johnson & Johnson over US$10 billion autoimmune drug Remicade, though J&J’s Janssen unit promised to appeal.

In a closely watched case, Novartis wants the US Supreme Court to dump a six-month marketing delay for biosimilars, in what would be the first time the high court took up a biosimilar case.

Samsung Bioepis, along with partner and minority shareholder Biogen Inc, filed a lawsuit against AbbVie in Britain in March to stop the US company from blocking the launch of yet another Humira biosimilar.

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

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

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

Indian scenario:

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

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

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

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

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

Are biosimilars the only examples?

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

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

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

Discovering new drugs, delivery systems, and finding new indications

Lack of transparency and widely reported bias towards mainly positive results in clinical trial data, both for publication and regulatory approval of various new drugs, and associated global furor.

Exorbitant high prices of many new patented medicines and some generic drugs too

Widely reported marketing/other malpractices, and associated fines paid by the respective players

Causing entry delay for cheaper small molecule generics and large molecule biosimilar drugs post patent expiry restricting gtreaterr patient access

What’s your relative score now?

Conclusion:

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

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

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

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

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

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

By: Tapan J. Ray

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

What Happens To Pharma’s Incredible Ride On The ‘Gravy Train’?

Posted on September 26, 2016 by Tapan Ray

India continues to be one of the fastest growing pharmaceutical market of the world with its over 40 percent of the total pharmaceutical produce is exported around the world. Over half of the total exports constitute of formulations, and the balance comprises of bulk drugs. India has been consistently maintaining its supremacy in the formulation exports since my salad days.

According to Export Statistics (2014-15) published by the Pharmaceutical Export Promotion Council of India (Pharmexcil), United States (US) is the largest market for the India’s pharmaceutical exports with a share of 27 percent of the total, followed by the United Kingdom (UK), South Africa, Russia, Nigeria, Brazil and Germany.

A red flag raised:

Up until recently, it has almost been like walking over a bed of roses in this front for Indian pharma exporters. However, it does not seem to be so now, and at least in the foreseeable future, for a number of reasons.

The Press Release of ‘CRISIL Research’ dated May 17, 2016 has also raised a red flag in this area. The report foresees growth in pharma formulations (in US dollar terms) declining sharply to 10-12 percent annually over the next 5 years, as compared with a growth of ~19% seen in the last decade.

This adverse impact will be felt mostly in the US – the largest export destination of India, followed by the UK.

I reckon, there are three basic reasons for this changing scenario, namely, pricing, quality and lesser number of branded small-molecule blockbuster drugs going off patent.

The ride on the ‘gravy train’:

Pharma companies across the world consider that doing business in the US market would provide them a lot of money without facing any head wind, fundamentally driven by the drug pricing freedom in the country, as compared to any other market of the world.

This unfettered freedom of charging a hefty price premium in the largest pharma market of the world, on an ongoing basis, has been a critical factor of attraction for many pharma players to do business in the US, coming from various corners of the globe, including India, just as honey attracts the bees, as it were.

Thus far, it has been an incredible ride on the ‘gravy train’, as it were, for most of them.

However, ongoing activities of a large number of drug companies, dominated by blatant self-serving interests, have now given rise to a strong general demand for the Government to initiate robust remedial measures, soon. The telltale signs of which indicate that this no holds barred pricing freedom may not be available to pharma, even in the US, any longer.

In this article, I shall focus mainly on this point, drawing both global and local examples, as this development has a strong potential to add more to the existing miseries of many Indian drug exporters, of course in tandem with many other large MNCs.

Some recent developments:

The April 21, 2016 issue of ‘The Financial Times’ quoted Joe Jimenez, the Global Chief Executive (CEO) of Novartis, where he said that pharma companies can no longer count on the “hockey-stick” trajectories for new products in the US. This is primarily due to the aggressive control of the drug expenses by the insurers and other healthcare payers, besides lawmakers and the public at large, of this most lucrative pharma market of the world.

As Jimenez said in the report, yesterday’s business model that pharma companies have followed since long, has now changed, slowing the pace of growth of innovative patented products in the US.

This trend is now heading north, primarily driven by the consolidation among the US insurers and healthcare providers. Consequently, the payers are making effective use of their greater bargaining power over the drug companies, especially to avail new incentives for cost savings, as provided in President Barack Obama’s Affordable Care Act, the article highlights.

To give a feel of it, I am quoting the example of a Novartis drug from the same ‘Financial Times’ article. It states, “Entresto, a treatment for heart failure, launched last year on the back of stellar clinical trial results, has so far sold more quickly in Europe than the US, marking a reversal of usual patterns in the pharma industry.”

A key differentiator in global ranking:

In this emerging scenario, all global companies will be adversely impacted for increasing pricing pressure in the US market.

This factor remaining the same for all the pharma players in the world, one of the key differentiating factors that would now play even more important role, is the richness of the advanced stage R&D pipeline of each innovator company.

For example, according to ‘Evaluate Pharma World Preview 2016, Outlook to 2022’ report, the overall R&D pipeline value of Roche is US$ 43.2 billion, far ahead of the same of Novartis’ US$ 24.1 billion and AstraZeneca’s at US$ 23.2 billion, followed by Eli Lilly, AbbVie, Pfizer, Sanofi, Celgene, Biogen and J&J and in that order. As a result, Roche is expected to overtake Novartis and Pfizer in the ranking by 2022, just when the global pharma industry would possibly cross as US$ 1Trillion mark.

Currently Novartis, though quite a small player in the Indian Pharmaceutical Market (IPM) holding the rank of 23 (AIOCD Pharmasofttech AWACS retail audit report, MAT August 2016), is number three in the global ranking, just ahead of Roche.

Indian generic players to feel the heat:

According to the Reuters report of September 11, 2016, US Department of Justice has sent summons this month to the US arm of Sun Pharma – Taro Pharmaceutical Industries Inc. and its two senior executives seeking information on generic drug prices. In 2010, Sun Pharma acquired a controlling stake in Taro Pharmaceutical Industries.

On September 14, 2016, quoting a September 8, 2016 research done by the brokerage firm IIFL, ‘The Economic Times’ reported that some large Indian generic drug manufacturers, such as, Sun Pharma, Dr. Reddy’s, Lupin, Aurobindo and Glenmark have also hiked the prices of some of their drugs between 150 percent and 800 percent in the US. This invites even more apprehensions in the prevailing scenario.

As I wrote in this Blog on September 12, 2016, the subject of price increases even for generic drugs has also reverberated in the ongoing Presidential campaign in the US.

The Democratic Party’s presidential nominee – Hillary Clinton has already promised, if elected in November 2016, she would constitute an ‘Oversight Panel’ to protect the consumers of her country from hefty price increases for long-available life-saving drugs.

Import bans:

In the midst of all this, import bans of a large number of formulations and bulk drugs by the US-FDA from several manufacturing facilities of Indian drug manufacturers of various scales and sizes, have further compounded the future risk potential of Indian pharma business growth in the US.

As investors are raising concerns, the following comment of the Co-Chairman and Chief Executive of Dr. Reddy’s Laboratories, reported by ‘Financial Express’ on August 24, 2015, well captures the pharma business risks in this area:

“The U.S. market is so big that there is no equivalent alternative. We just have to get stronger in the U.S., resolve our issues, build a pipeline and be more innovative to drive growth.”

However, this still remains a good intent. It is worth noting, for most Indian pharma exporters, the US is the single largest export market, with a stake, as high as nearly half of most of these companies’ annual revenue, and probably much more in profit, both of which are now showing a declining trend.

Price control coming in the UK:

On September 15, 2016, the Department of Health of the United Kingdom (UK) reportedly introduced a new Bill in Parliament to use its statutory power to limit the price of generic medicines where competition in the market fails, and pharma companies charge the NHS unreasonably high prices.

The Bill would also allow the government to apply penalties for non-compliance and to recover any payments owed through the courts following a right of appeal to a tribunal. The penalties can be a single penalty not exceeding £100,000 or a daily penalty not exceeding £10,000.

UK drug regulatory authorities had also announced import bans of APIs and formulations from some manufacturing facilities of a couple of leading Indian drug manufacturers, but on a lesser scale as compared to the USFDA.

Action in EU:

As reported by Bloomberg on July 22, 2016, The European Medicines Agency (EMA) has called for a halt to sales of hundreds of medicines that were tested in India, after an inspection of a research site found “substitution and manipulation” of the study samples. The affected companies include both large Indian and multi-national players.

According to a PTI report of July 27, 2015, after this incident Pharmexcil estimated that exports worth US$ 1-1.2 billion are likely to be affected, if cancellation of 700 generic drugs by the EU stands.

Conclusion:

All these developments, particularly on pricing and mostly in the US, could have a retarding effect on the business growth trend of a large number of global and local pharma companies.

Focusing nearer home, the evolving scenario in the world’s top pharma market, viewed together with what’s happening in Europe, both on pricing and the data integrity fronts, send a strong cautionary signal to the Indian drug exporters, in general.

Inadequate remedial measures could unleash this pressure to reach a dangerous threshold, impacting sustainable performance of the concerned companies. On the other hand, adequate remedial action, both strategic and operational in nature, could lead to significant cost escalation, with no space available for its neutralization through price increases, gradually squeezing the margin.

As I see it, ease of doing pharma business in these top export markets will no longer be quite the same as in the past. Many believe, pharma industry has invited these measures sans perceptible self-control, over a long period of time.

Is it mostly a self-inflicted injury of the industry players? The drug companies, in general, don’t believe so. Will this change be irreversible? Only the future could unravel this. However, regarding the possibility of future US Government legislation on drug pricing, it’s now a wait and watch game for the stakeholders. On a shorter time-frame, the ghost in this area, would keep haunting globally, primarily for business in the US market, at least, till the end of this year.

However, for the Indian pharma exporters, pricing appears to be just one among several other critical issues, especially, in the two most lucrative markets of the world. The overall situation in this area, by and large, remains unchanged till today, besides expression of a plethora of good intents.

Thus, pharma analysts’ quest to ferret out an answer to the Gordian knot on the continuity of Indian pharma exporters’ incredible long ride on the ‘gravy train’, has also not been plain sailing, so far. Further mired by the local manufacturers’ prolonging errors of judgement, the status quo ante is expected to still remain elusive, at least, for now.

By: Tapan J. Ray

Biosimilar Drugs: First Indian Foot Print In An Uncharted Frontier

Posted on April 4, 2016 by Tapan Ray

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

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

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

Would it be a free run?

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

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

Key barriers to a biosimilar drug's success:

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

These barriers can be broadly divided in two categories:

A. Regulatory barriers:

1. Varying non-proprietary names:

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

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

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

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

2. Substitution or interchangeable with original biologics:

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

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

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

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

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

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

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

A rapidly evolving scenario in the United States:

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

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

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

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

B. Prescribers’ skepticism:

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

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

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

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

The major growth drivers:

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

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

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

Unfolding a huge emerging opportunity with biosimilars:

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

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

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

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

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

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

Conclusion:

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

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

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

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

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

By: Tapan J. Ray

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

Ease of Doing Pharma Business in India: A Kaleidoscopic View

Posted on March 28, 2016 by Tapan Ray

Ensuring ease of doing any ethical business activity in India, is a new focus area of the Government and is very rightly so. Creating ease of doing ethical pharma business too, falls under this overall national objective.

In this article, restricting myself to the drug sector, I shall deliberate on various aspects, which are now being considered by the pharma industry, related to the ‘ease of doing pharma business in India’. My discussion would cover all subsets of pharma players, irrespective of whether they fall under Multinational (MNC) or purely homegrown Indian companies, with different scales of operations – large, medium, small, or micro.

To help the Government facilitating the ‘‘ease of doing pharma business in India’, it is just not enough to make the business models for all subsets of the Indian pharma sector looking ethical, conforming to all relevant laws, policies, rules and norms. Each pharma player need also to maintain an ongoing strict internal vigil, religiously, to ensure that the requirements of high quality clinical development, manufacturing and selling practices for effective, safe and rational medicines, are properly understood and strictly followed by all the employees within the organization.

A Kaleidoscopic View:

The above situation is something that ought to happen, as the Government keeps striving to improve the ‘ease of doing pharma business’ in India. However, while looking through a Kaleidoscope, as it were, the colors of industry expectations in this area keep changing rapidly, as the new contentious issues keep emerging. Consequently, the ground reality of assessing the same, by a large section of the pharma players in India, seems to veer only around different types of just self-serving demands, expecting those to act as a powerful tailwind pushing their business interests rapidly forward.

Such expectations keep surfacing, rather frequently, from all the subsets of the pharma industry, be they MNCs and their trade associations or the Companies of purely Indian origin and their trade bodies. The accusation to the Government pertaining to all these issues, is a common one: ‘Where is the ease of doing pharma business in India?’

Citing even some recent incidents, they are voicing with equal gusto, that the root causes of all these problems lie miles outside the pharma industry. The causative factor, they indicate, is rooted at the very doorsteps of the Government, as its ministries initiate tough action to root out corruption in the pharma industry as concurrent measures, disturbing their business comfort zones, and upsetting the apple carts.

The Government has its task cut out:

I hasten to add that I have no intention to paint it as a confrontation between the Government and the pharma industry, in any way. The Government is also facing the brunt from the various stakeholders, relentlessly, for its utter negligence of public health care, and public expenditure over it.

The impact of this Government indifference, though also comes on the patients, the industry does not seem to have much to crib over it as a direct impediment to the ‘ease of doing pharma business’ in India.

Probably as a diversionary tactic, the industry keeps using this critical Government inaction in the hope of diverting the public, or media attention from its own alleged business malpractices, even at a time when these are being covered both by the national and international media, regularly. Nevertheless, the industry credibility on these issues, seems to have started waning fast, as the genie is out of the bottle.

A common punching bag of all industry dissatisfaction on the Government:

It is worth noting that despite some key differences between the MNC and Indian pharma companies, which I shall discuss later, the common punching bag of the industry dissatisfaction on various Government decisions, always has been the lack of ‘ease of doing pharma business’ in the country.

This discontentment may be well justified. I have no qualms about it. However, when this dissatisfaction gets tagged with some recent Government action, taken to protect public health interests and does not have much to do with the ‘ease of doing ethical pharma business’, many eyebrows are obviously raised.

Against some of these critical patient-centric actions, the industry continues to express its annoyance in unison, while for some other Government decisions, it speaks in different voices – some are happy ones, and the others are not so. However, the common thread of expression of all such dissatisfactions is always linked with the lack of ‘ease of doing business’ in India.

A. Where the pharma Industry in India speaks in unison:

I shall now give two major examples of the key Government decisions, that have irked the entire pharma industry immensely, and makes it voicing that those Government actions grossly violate the fundamental requirements of its smooth running of business. Is that fair? Let me analyze that below with these two examples:

1. Drug price control:

The industry, by and large, opines that individual drug company should be allowed to decide the way it would price any drug, as the market forces, especially for generic drugs, would determine its price.

Indian Parliament, the Supreme Court of India, the Government in power at different times, most of the independent experts and the NGOs, on the contrary, consider drug price control is necessary in India, especially for essential drugs. It makes high quality essential medicines affordable and accessible to the general population.

National Pharmaceutical Pricing Authority (NPPA) has also announced and explained that the competition does not work on controlling prices for pharma products, where the consumers are not the decision makers. The key prescribing decision makers for the patients are the doctors, who are mostly and unethically influenced by the drug companies having vested interest in making such decisions. This unholy nexus has been widely alleged globally, and also established through umpteen number of studies of high credibility.

Nevertheless, the doctors, from across the globe, including in India, have long disputed that any payments, if and when they receive from pharmaceutical companies, have no relationship to how they prescribe drugs.

A March 17, 2016 study of ProPublica has conclusively established that: “The more money doctors receive from drug and medical device companies, the more brand-name drugs they tend to prescribe. Even a meal can make a difference.” This study may be in the context of the Unites States, but India in this in this regard is no exception, as captured even in the parliamentary Committee reports.

Thus, conceding to high voltage pharma advocacy, made on the pretext of ‘encouraging innovation’ and ‘ease of doing business in India’, if any Government contemplates the abolition of drug price control in India is, it would make not just essential drugs inaccessible to a large section of society, but encourage blatant corrupt practices. This caution has come, besides many others, also from a Parliamentary Committee report, unambiguously. Incidentally, the present Government too strongly speaks against corruption, in any form.

Thus, I reckon, if the industry believes that the price control of essential drugs, which are for public health interest, goes against ease of doing pharma business in India, so be it.

2. Manufacturing and selling of irrational FDCs:

A Fixed Dose Combination (FDC) drug may appear irrational to drug regulators and well-qualified experts, after necessary scientific scrutiny, for various reasons. This may happen, primarily because of the following reasons:

When the medical rationale of the FDC along with the ingredient details, submitted to the regulatory authority for marketing approval, are considered scientifically inappropriate.

When the evolving medical science establishes the irrationality of the FDC after a period of time.

When the analysis of ‘Adverse Drug Event’ reports from the ongoing Pharmacovigilance studies signals a red alert.

Widespread uncontrolled misuse or abuse of FDCs, where the consumers’ health risks far outweigh the drug benefits, as provided in the drugs Act, for public health interest.

Some regulatory loopholes were misused by the drug manufacturers in the past to get the irrational FDCs approved by the State Drug Authorities, violating the new FDC regulatory approval Policy.

Any irrational FDC so identified by the drug regulators and experts, by putting a system of scrutiny in place, must be banned forthwith, in public health interest. There should not be any scope of negotiation with drug manufacturer to make the bans effective.

Incidentally, realizing the gravity of public health risks posed by irrational FDCs, even the NPPA has reportedly decided to review afresh all new applications for price fixations of FDC and examine their safety and efficacy profile.

Moving towards this direction, the NPPA Chairman, has reportedly sent back more than 200 applications for price fixation of FDCs, instructing the concerned manufacturing and marketing companies to apply again with a declaration that their formulations are not “irrational.” It was also reported that the price regulator has also brought under the lens third-party drug makers and pharma companies that outsource to them, to check illegal sales of irrational FDCs and spurious drugs.

Two key questions being raised now:

Despite all these, the industry keeps repeating, especially, the following two questions, which are worth looking at, one by one:

1. Why is the ban now?

I discussed the issue of FDC ban in my previous article in this Blog on March 21, 2016 titled, “The Recent Ban On Irrational FDCs: History Repeats Itself”.

In the above article, I also argued that large section of the industry and its associations are protesting against the Government ban of 344 irrational FDCs, and questioning vigorously, even outside the Delhi High Court – ‘why is the ban now?’

The point ‘why now’ is absolutely irrelevant, as not taking any action ever, against a wrong doing ignored over a long period time for whatever reasons, does not confer any regulatory legitimacy to an irrational FDC formulation to be considered as a rational one for all time to come, and thereby, exposing patients to serious health risks, knowingly.

2. Why is this ban so sudden, and in some cases after decades?

Sudden banning of drugs, which are in the market for a long time, is not a recent Indian phenomenon in India. In 2011, according to a report, in the world’s largest pharma market – the United States, the FDA banned 500 prescription drugs that had been on the market and working for decades. USFDA ban also happened suddenly, and that includes cough syrups too. Thus, it is intriguing, why is this fuss created by the Industry in India now?

In the midst of it, one odd, knee-jerk, apparently ‘spoon-fed’ and ill-informed editorial in some Indian business daily, raises more questions about its real intent, rather than help finding answers to the poorly sketched problems.

I would hope, the Government would stay firm and be able to convince the Delhi High Court today, i.e. on March 28, 2016, with its robust data-based arguments, accordingly.

Be that as it may, in my perspective, if the industry still believes that bans of irrational FDCs to protect public health interest, as decided by the independent experts after long and structured deliberations, would go against ‘ease of doing pharma business’ in India, so be it.

B. Where the pharma industry in India speaks in different voices:

As stated above, there are several other key areas, where the MNC and Indian Pharma players have sharp differences in their perspectives. Despite these differences, the aggrieved section does not even blink a bit to attribute those Government actions to the lack of ‘ease of doing pharma business’ in the country.

In this area, I shall give just the following three examples:

1. The Patents Act:

MNCs say that section 3 (d) of the Indian Patents Act 2005, which is aimed at curbing patent ever-greening or frivolous inventions, is against the ease of doing business in India. However, the Indian Pharma players, do not think so, at all. Similar disagreement also exists in other critical areas too, such as, ‘Data Exclusivity (DE)’ and ‘Compulsory Licensing (CL)’.

Thus, in my opinion, if some ‘public health interest’ related provisions of the robust Indian Intellectual Property (IP) Act, such as, section 3 (d), DE and CL, are considered as going against the ‘ease of doing pharma business in India’ by the MNCs, so be it.

2. Mandatory Uniform Code of Pharma Marketing Practices (UCPMP):

Need to have a mandatory UCPMP, though, is reportedly supported by the MNCs, Indian pharma players do not seem to be quite in sync with this idea. I am not sure, whether the delay in the announcement of mandatory UCPMP, almost in every 3 months, has any coincidence with it or not. However, the reality is, no one still knows clearly, when would it definitely come, if at all.

Media reports on pharma MNC support to mandatory UCPMP, and repeated reiteration that its members in India rigidly follow the IFPMA Code of Marketing Practices, though commendable, seem to grossly lack in credibility.

Interestingly, despite the existence of this code and high-decibel vouch for its rigid conformance, maximum number of MNCs have been fined billions of dollars, by the Government in various countries, for alleged gross marketing and other business malpractices. It has been happening over a long period of time, and is being reported by the international media, frequently.

What is really happening, especially, on the so called total support of ethical marketing practices by the MNCs? Are they trying to create just good optics by craftily framing and supporting such showpiece codes, and blatantly defying these to achieve self-serving goals? The voice gets shriller, even when they are being levied hefty fines, after getting caught red handed, as reported by the global media? I guess, the future would ultimately unfold the reality. But would it, at all?

The Indian Scenario:

Even in India, such alleged marketing malpractices involving even a top pharma MNC have often been reported by the media. Just to illustrate, “Prescribe a drug maker’s medicine and get a free vacation”, reported a news article. There are several other similar reports too. Hence, the credibility of pharma MNC statements regarding strict conformance to ethical marketing codes, ably formulated by the well-known pharma trade associations, such as, IFPMA, appears to be very low, if exists at all.

The well-reputed medical Journal BMJ in one of its articles titled, “Corruption ruins the doctor-patient relationship in India”, published on May 8, 2014, expressed serious concern on this issue.

It concluded that corruption, kickbacks and the nexus between doctors and pharmaceutical firms are rampant India. This eventually prompted the BMJ, in June 2014, to launch a campaign reportedly called ‘Corruption in Medicine’.

On this issue, way back in May 08, 2012, even the Indian Parliamentary Standing Committee on Health and Family Welfare in its 58th Report, placed before the Parliament on May 08, 2012, expressed its serious concern.

Indian lawmakers, recommended in the report that the Department of Pharmaceuticals (DoP) should take decisive action, without further delay, in making the UCPMP mandatory, so that effective checks could be ensured on ‘huge promotional costs’ and the resultant add-on impact on medicine prices. Unfortunately, despite a change in the Government in 2014, UCPMP has still not been mandatory.

It is anybody’s guess, despite all these reports, what type of external pressure, if at all, the DoP is still facing to put in place a robust mandatory UCPMP with strong deterrent measures.

Under this backdrop, in my view, if mandatory UCPMP having enough teeth, to curb ongoing blatant marketing malpractices to protect patients’ health interest in India, is considered by any as going against the ‘ease of doing pharma business in India’, so be it.

3. Drug manufacturing quality:

Enough discussions have already been made on import ban of USFDA from over 45 drug manufacturing facilities of Indian Companies, of all sizes and scale of operations, on the ground of drug quality standards. USFDA considered drugs manufactured in those banned facilities are unsafe for the consumption of American patients. Some other foreign drug regulators, from the developed countries, have also taken similar action.

Taking advantage of this development, it was reported that attempts are indirectly being made to establish that MNC marketed generic drugs are superior to similar ones, manufactured even by the large Indian drug producers.

The fact, apparently, is quite different. MNCs operating in India has not come under the USFDA scanner in this regard as much, probably not because of their far superior drug manufacturing quality standards in India, as compared to even the best of their Indian counterparts. I reckon, it is mainly because, very few MNC drug manufacturing facilities in India export India manufactured drugs for consumption in the United States.

It may not, therefore, make any real sense to conclude that MNC marketed generic drugs in India, either manufactured my themselves or under loan & license or under a third party, are generally better in quality than the similar ones manufactured even by the large Indian manufacturers.

In any case, I feel that there is a huge scope for Indian drug regulators to ensure uniformly high drug quality standards. This is necessary for Indian patients’ health and safety. There also should be stringent regular quality audits in all drug manufacturing facilities in India, where non-conformance with prescribed standards would attract serious punitive measures. The Union Ministry of Health, together with the State Governments would require increasing the number of auditors accordingly.

However, the reality is, many Indian drug manufacturers have expressed that maintaining stricter drug manufacturing standards (cGMP) would involve huge expenditure, which they will not be able to afford. Consequently, this would go against the ‘ease of doing pharma business’ in India.

Again, in my view, if the stringent regulatory requirements for maintaining high drug manufacturing standards in India to protect public health interest, is considered as going against the ‘ease of doing pharma business’ in India, so be it.

Conclusion:

Improving ‘ease of doing pharma business’ in India is an absolute necessity, just as all other businesses. Pharma sector deserves it very badly too, as it has been experiencing excruciating delay in multiple regulatory clearances. Single window clearances of all applications, with a much greater sense of urgency, without bureaucratic red tapes and avoiding other unnecessary delays, is certainly the way forward for India. It would require urgent policy reforms, maintaining a right balance between, public, consumers and business interests.

Pharma sector is not all villain, either, by any yardstick. It is instrumental in saving and improving the quality of lives of so many people across the globe, since a very long time, with its both innovative and generic medicines. All must acknowledge it, and the Government does it too, openly, several times.

That said, the space of focus of the pharma industry appears to be getting increasingly narrowed down to more of its self-serving acts, and in their hard selling, through hugely expensive advocacy campaigns, even at the huge cost of attracting frequent self-defeating scathing criticisms, across the world.

At the same time, the Governments in different times hugely disappointed its citizens, in charting a clear road map for quality and affordable health care for all in India, along with appropriate budgetary allocations and policy reforms, and thereafter, in its implantation with military precision.

However, that doesn’t mean, in any way, while facilitating ‘ease of doing pharma business’ in India, the Government would turn a blind eye on the rapidly breeding corruption in the pharma business practices, and give in to unjustified industry muscle-flexing, sacrificing the health interest of its citizens in the country.

While looking through this Kaleidoscope, it appears to me, if the pharma sector considers the appropriate Government actions to protect public health interest, against the unacceptable industry practices, would also go against the ‘ease of doing pharma business’ in India… Well, so be it.

By: Tapan J. Ray

For Drug Safety Concern: “Whistleblower’s Intention Should Be Nationalistic”

Posted on March 14, 2016 by Tapan Ray

In the recent weeks, three significant developments related to the Pharmaceutical Industry in India, have triggered rejuvenated concerns in the following critical areas:

A. Overall drug safety standards in the country

B. Self serving interest, rather than patients’ interest, dominate the prescribing decisions

C. Government assurance to American Trade Organization on ‘Compulsory License (CL)’ in India.

These important issues fall under three key regulatory areas of India, as follows:

The Central Drugs Standard Control Organization (CDSCO)
The Medical Council of India (MCI)
The Indian Patent Office

It is worth mentioning here that the Department Related Parliamentary Committee on Health and Family Welfare in its 59^th Report, placed before both the houses of the Parliament on May 08, 2012, on the functioning of the Central Drug Standards Control Organization (CDSCO), begins with the following observations:

Medicines apart from their critical role in alleviating human suffering and saving lives have very sensitive and typical dimensions for a variety of reasons. They are the only commodity for which the consumers have neither a role to play nor are they able to make any informed choices except to buy and consume whatever is prescribed or dispensed to them, for the following reasons:

Drug regulators decide which medicines can be marketed
Pharmaceutical companies either produce or import drugs that they can profitably sell
Doctors decide which drugs and brands to prescribe
Consumers are totally dependent on and at the mercy of external entities to protect their interests.

Most importantly, all these concerns, if not properly clarified and appropriately addressed by the Government, soon enough, have the potential to create an adverse snowballing impact on the uniform access to affordable quality medicines, for all sections of the society in India.

Under this backdrop, I shall discuss in this article briefly, my perspective on each of these critical areas, as they are today, and not just the drug safety concerns.

The headline of this article is expected capture not only the prevailing mood of some key regulators, but also their inertia to address critical healthcare concerns and above all how the core public health related issues are getting lost, and the trivial ones are gradually occupying the center stage.

A. Overall drug quality and safety  standards in India:

A Public Interest Litigation (PIL) suit, filed against the Drugs Consultative Committee and the Central Drugs Standard Control Organization (CDSCO), was listed on the Supreme Court website for hearing on March 11, 2016.

The PIL has been filed by one Dinesh Thakur, requesting the Supreme Court to lay down guidelines by which manufacturers could be made liable for violating drug standards and also give a direction to the government to set up a ‘Drug Approvals Review Committee’ for examining criminality in the manner in which faulty drug approvals were granted.

Many may recall that the same Dinesh Thakur worked for Ranbaxy from 2003 for two years, and is now the Chief Executive of MedAssure Global Compliance based in Florida, US. Thakur’s Company now advises pharma manufacturers on drug safety and quality standards.

As reported by Reuters, Thakur had earlier exposed how the erstwhile largest drug maker of India, Ranbaxy Laboratories, failed to conduct proper safety and quality tests on drugs and lied to regulators about its procedures. Consequently, USFDA fined Ranbaxy US$500 million for violating federal drug safety laws, and making false statements to the US regulator.

This news report further states: “Indian Parliamentary Committee, thereafter, reportedly demanded an investigation and the drugs regulator committed to one in 2013. Thakur received a statement from the health ministry last year, seen by Reuters, showing no inquiry had begun.”

On the last Friday, however, the Supreme Court of India refused to entertain this PIL of Dinesh Thakur, saying it does not have time to adjudicate academic issues, such as, need for guidelines to regulate quality of medicines.

The core issue:

The core issue here is not at all the above PIL, not at the very least. The issue is the much reported concern being expressed, over a period of time, regarding the drug safety standards in India. The reasons include breach of of data integrity, and gross violation of the ‘Good Manufacturing Practices’ standards. Such instances are being detected, almost regularly, by the foreign drug regulators, in several manufacturing facilities run by many large and small Indian drug producers.

It is well vindicated by the fact that around 45 Indian drug manufacturing plants have been banned by the USFDA alone, from shipping generic drugs to the United States, as these were considered unsafe for consumption of patients in the US. Some other foreign regulators too had taken similar action, citing similar reasons. The USFDA website specifies the details of gross violations made in each of these cases.

Ironically, all such facilities can manufacture and sell their drugs in India, as they conform to the quality requirements of the Indian drug regulator. Consequently, the Indian patients consume even those medicines, which are considered unsafe by the USFDA for American patients, innocently, as and when prescribed by the doctors.

Arising out of these incidents, when asked about the drug safety standards in India, and the public health-safety, instead of giving credible and action oriented answers for public reassurance, some of the apparently brazen replies of the DCGI are quite stunning for many stakeholders, both within and outside the shores of India.

I would now quote below just a few of those replies, just as examples.

“…Whistleblower’s Intentions Should Be Nationalistic” - DCGI:

According to Reuters, it has received the following response from the Drug Controller General of India (DCGI), on the above PIL related to the drug safety standards in India:

“We welcome whistleblowers, we have got great respect, but their intentions should be genuine, should be nationalistic… I don’t have any comment on this guy.”

Thus, many industry watchers feel that in a situation like this, the honorable Supreme Court of India would possibly require to intervene, just as what it did on alleged ‘Clinical Trial’ malpractices in the country or for drug price control, solely for public health interest.

The same attitude continues:

Such brazen response of the Central Drug Regulator, and that too on a serious subject, is indeed bizarre. It becomes increasingly intriguing, as the same attitude continues without any perceptible meaningful intervention from the Ministry of Health.

For example, on February 22, 2014, in the midst of a more intense scenario on a similar issue, instead of taking transparent and stringent measures, the DCGI was quoted by the media commenting:

“We don’t recognize and are not bound by what the US is doing and is inspecting. The FDA may regulate its country, but it can’t regulate India on how India has to behave or how to deliver.”

On February 26, 2014, presumably reacting to the above remarks of the DCGI, the American Enterprise Institute reportedly commented, “Indian drug regulator is seen as corrupt and colliding with pharma companies…”

Such apparently irresponsible and loose comments keep continuing, despite the 2012 report of the Parliamentary Committee of India alleging collusion between some pharmaceutical companies and officials of the CDSCO, which oversees the licensing, marketing and trials of new drugs. The report also commented that the agency is both chronically under-staffed and under-qualified.

Some possible remedial measures:

As the saying goes, “better late than never”, considering all these continuing developments, it is about time to reconsider some of the key recommendations of Dr. R. A. Mashelkar Committee on a similar subject and make amendments in the relevant Act accordingly, soon, to facilitate creation of a robust with high accountability ‘Central Drugs Authority (CDA)’. It would introduce a centralized licensing system for drug manufacturing, along with stringent drug safety standards; besides, sale, export and distribution of drugs. Perhaps, the draft bill on CDA is now lying in the heap of archival documents with the change in Government.

Why does India need CDA?

I believe, the formation of a robust CDA with high accountability, besides meeting with drug safety concerns, would provide the following significant benefits, both to the Industry and also to the Government:

Achieving uniform interpretation of the provisions of the Drugs & Cosmetics Act & Rules
Standardizing procedures and systems for drug control across the country
Enabling coordinated nationwide action against spurious and substandard drugs
Upholding uniform quality standards with respect to exports to foreign countries from anywhere in India
Implementing uniform enforcement action in case of banned and irrational drugs
Creating a Pan-Indian approach to drug control and administration
Evolving a single-window system for pharmaceutical manufacturing and research undertaken anywhere in the country.

B. Self serving interest dominates the prescribing decision:

That the self serving interest, rather than patient interest, dominate the prescribing decision, was vindicated by a key announcement of the Medical Council of India (MCI) last month.

In February 2016, apparently succumbing to continuous and powerful external pressure, the MCI announced an amendment in a clause of its Code of Ethics Regulations 2002, exempting doctors’ associations from the ambit of its ethics code, as applicable to doctors now across the country. Prior to the amendment, this section used to read as: “code of conduct for doctors and professional association of doctors in their relationship with pharmaceutical and allied health sector industry”.

In other words, it means that the professional associations of doctors will no longer come under the ambit of ethics regulations, legitimizing their indulgence in the identified unethical and corrupt practices, by receiving gifts in cash or kind from the pharma or healthcare industry.

A large section of the key stakeholders believes that this amendment would help creating an additional large space for the pharmaceutical marketing malpractices to thrive, unabated, at the cost of patients.

The latest report of the Parliamentary Standing Committee on MCI:

In its 92nd Report, the Department-Related Parliamentary Standing Committee on Health and Family Welfare titled, “The Functioning of Medical Council of India”, presented to the Rajya Sabha and laid on the Table of Lok Sabha on 8th March, 2016, the Committee observed on this amendment as “an action that is ethically impermissible for an individual doctor cannot become permissible, if a group of doctors carry out the same action in the name of an association.”

The report also noted the failure of MCI to instill respect for a professional code of ethics in the medical professionals and take disciplinary action against doctors found violating the code of Ethics, etc.

The Committee called for a complete restructuring of the MCI, since it believes that the Council has failed as a regulator of medical education and the profession. Casting serious aspersions on the functioning of the MCI, the house panel of the Parliament recommended that the Act under which the MCI was set up be scrapped and a new legislation be drafted “at the earliest”.

The report castigated the health ministry:

The lawmakers castigated the Health Ministry in this report saying, “The committee also finds it intriguing that instead of intervening to thwart attempts of MCI at subverting the system, the ministry meekly surrendered to MCI.”

While summing up, the report states, “the Committee exhorts the Ministry of Health and Family Welfare to implement the recommendations made by it in this report immediately and bring a new Comprehensive Bill in Parliament for this purpose at the earliest.”

How will it pan out now?

I reckon, it will now be immensely interesting now for all concerned to follow, how does the Government deal with this report to curb, among others, the strong interference of mighty and powerful vested interests to continue with the rampant pharma marketing malpractices, at the cost of patients in India.

C. Reported Government assurance on ‘Compulsory License’:

On March 3, 2016, a media report quoted a submission by the US Chamber of Commerce to the office of the US Trade Representative (USTR) as follows:

“While the Government of India has privately reassured (American) industry that it would not use compulsory licenses for commercial purposes, a public commitment to forgo using (this) would enhance legal certainty for innovative industries.”

This is an interesting development, primarily because there are a number of legal provisions for granting Compulsory Licenses (CL) in the Indian Patents Act 2005, including, when a drug is not widely available, extremely expensive and some other situation. In some these provisions, law should follow its own course and there is no legally permissible scope for Government’s administrative interference. Grant of CL for Nexavar of Bayar is one such example, and incidentally, that’s the sole CL that India has granted, so far, from the date of amendment of the country’s Patents Act in 2005.

Thus, a blanket assurance of not invoking any of the provisions of the CL, as provided in the Indian Patents Act 2005, if true, would possibly require to pass through intense legal scrutiny, as that would adversely impact the access to key medicines in a necessary situation, for the public health interest.

So far, India has amply demonstrated to all, time and again, that the country does not grant a CL at the drop of a hat. That situation should continue to encourage and protect innovation.

Nevertheless, “a written public commitment to forgo using the CL provisions for enhancing legal certainty for innovative industries,” as demanded by the US Chamber of Commerce, appears to be unreasonable, goes against the spirit of India’s Patents Act, and perhaps is not legally tenable either, unless the IP Act is amended accordingly in the Parliament.

Conclusion:

All these three areas, as discussed above, are critical from the healthcare perspective of the country.

Ironically, while deliberating on the subject, the capability, credibility and competence of some of the key regulators of the country, are being repeatedly questioned. These doubts emanate not just from Tom, Dick and Harry, but from an illustrious spectrum of constitutional institutions of India, spanning across the lawmaking Parliament, through its various committee reports, to the ultimate legal justice provider – the Supreme Court of India, through is various orders and key observations.

Regrettably, in this specific space, which is primarily related to healthcare, nothing seems to be changing on the ground, since long. The same tradition continues, without any visible sense of urgency, even from the Government.

On the contrary, we now read a new genre of comments, even from a key regulator, on the stakeholder concerns. For example, reacting to concern on drug safety standards, instead of articulating tangible actions to usher in a perceptible change, the chief action taker reportedly specified a totally judgmental and an outlandish requirement: “…Whistleblower’s intentions should be Nationalistic.”

Together with these incidents, the key public healthcare concerns of India too, are now apparently getting drowned in the high decibel ‘Nationalistic’ versus ‘Anti-nationalistic’ cacophony. But, the hope still lingers… for a change…for our nation’s sound health!

By: Tapan J. Ray

Marketing Off-label Use of Drugs: A Path Much Abused?

Posted on November 30, 2015 by Tapan Ray

As many would know, prescribing any medicine for disease conditions that are not approved by the drug approving authorities while granting its marketing approval, is generally termed as ‘off-label’ use of drugs.

It is also a usual practice in most of the regulated markets of the world that once the drug regulators give marketing approval of a medicine, which is indication-specific, physicians are free to prescribe these as they deem necessary. However, the drug manufacturers can seek prescription support from the doctors only for the indications as approved by the appropriate government authorities.

Even the USFDA had articulated, “the best way to address any concerns that the information about those (off-label) uses is not reaching medical practitioners is to get those uses in the labeling. We believe that the risks of allowing drug companies to distribute journal articles and other information about off label uses far outweigh any benefits.”

Since long, most of the drug regulators across the world, including the Drug Controller General of India (DCGI) have prohibited the sales promotion for unapproved uses of drugs to doctors. Nevertheless, the practice continues ignoring its serious consequences.

Monitoring of ‘off-label’ use is challenging:

Monitoring of off-label use of medicines is quite challenging too by the drug regulators, especially in India, where post marketing surveillance is generally just on paper.

In this regard, a recent research study that I shall refer to below in this article, has quite appropriately suggested, “Future electronic health records should be designed to enable post market surveillance of treatment indications and treatment outcomes to monitor the safety of on and off-label uses of drugs.”

As India intends to move towards the ‘Digital’ space, this suggestion would be quite implementable by the DCGI, as the ‘Smart Cities’ start coming up.

Some examples of extensive off-label usages:

According to the study done by a team of experts in medical information – Iodine, using the top drugs by number of monthly prescriptions, the following is a list of 4 medications with surprising off-label uses:

Drug	Approved Indication	Off-label Indication
Abilify (Aripiprazole)	Schizophrenia, Bipolar Disorder, Major Depressive Disorder (adjunctive), Autism-related Irritability, Agitation associated with Schizophrenia or Bipolar Mania, other	Insomnia
Lyrica (Pregabalin)	Management of: neuropathic pain associated with diabetic peripheral neuropathy, post herpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury; adult patients with partial onset seizures (adjunctive)	Anxiety
Namenda (Memantine)	Moderate to severe dementia of the Alzheimer’s type	ADHD, OCD
Synthroid (Levothyroxine)	Low thyroid hormone levels, some types of goiters, management some types of thyroid cancers	Depression

Off-label use and increasing risks of drug safety:

In its November 02, 2015 online issue, JAMA Internal Medicine published an article titled, “Association of Off-Label Drug Use and Adverse Drug Events (ADE) in an Adult Population.” The objective of this study was to monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population.

This particular study assumes importance, as off-label use of prescription drugs without strong scientific evidence has been identified as an important contributor to preventable Adverse Drug Events (ADEs), especially in children. However, despite concerns in this regard, no systematic investigation on the effects of off-label drug use in adult populations is being performed, regularly.

The detail analysis of this study reveals that not only is the benefit of off-label prescription is uncertain, but the risks of ADEs could make the ‘risk-benefit ratio’ quite unfavorable. So much so that in a large number of cases, no drug treatment will be a much better option.

According to the authors, the risk for ADEs grew as the number of prescription drugs the patient used increased. For example, patients using eight or more drugs had more than a 5-fold increased risk for ADEs compared with patients who used one to two drugs.

The study involving 46,021 adult patients, receiving 151,305 prescriptions between January 2005 and December 2009 was done in Canada. Of those prescriptions, more than 10 percent were prescribed for off-label use. Interestingly, out of that group, more than 80 percent prescriptions were for off-label uses without any robust scientific evidence supporting the use.

Based on the findings the researchers concluded that off-label use of prescription drugs is associated with ADEs.

The article suggested:

Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence.

Future electronic health records should be designed to enable post market surveillance of treatment indications and treatment outcomes to monitor the safety of on and off-label uses of drugs.

Pharma industry strongly opposes off-label use, when it suits them:

Interestingly, pharma industry vehemently opposes off-label use of drugs, when it suits them.

To give just a couple of examples, recently a new law that permits prescribing of drugs for off-label uses in France has reportedly been strongly opposed by the pharmaceutical industry in Europe.

Pharma trade associations argue, “the above move of France is directly in opposition to European Union’s laws that prohibit member states from supporting off-label use for economic purposes, and is a trend that undermines the current regulatory framework and could put patients’ health at risk.”

Besides France, they have also submitted a complaint against Italy to the European Commission over the country’s new off-label rules.

Common methods followed for off-label marketing:

The other side of the story is that, reportedly many pharma companies continue promoting off-label uses of drugs aggressively, for significant commercial gains.

According to ‘The Centers for Medicare & Medicaid Services (CMS) – a federal agency within the United States Department of Health and Human Services, some of the off-label drug promotion methods of the pharmaceutical companies are as follows:

• Paying incentives to sales representatives based on sales for off-label use

• Paying kickbacks to physicians to prescribe drugs for off-label use

• Disseminating misleading posters promoting off-label use

• Paying physicians:

- To pretend to be the authors of articles about off-label uses when the articles were actually written by manufacturers’ agents

- To serve as members of “advisory boards” promoting off-label use

- To travel to resort locations to listen to promotions about off-label use

- To give promotional lectures in favor of off-label use to fellow practitioners

• Publicizing studies showing efficacy of off-label uses, while suppressing studies showing no efficacy.

Even the Uniform Code of Pharmaceutical Marketing Practices (UCPMP) of the Government of India does not allow such sales and marketing practices. But these all continue to happen, unabatedly.

A path much abused?

Although most of the drug companies publicly advocate self regulation to avoid unethical marketing practices, the situation on the ground is much different, across the world.

The following are just a few examples of serious business consequences faced by some of the well-known global pharma and biotech majors, besides many others, from the United States Department of Justice, for alleged off-label promotion of drugs:

On November 4, 2013, Johnson & Johnson (J&J) was asked to pay more than US$ 2.2 billion to resolve criminal and civil liability arising from allegations relating to the prescription drugs Risperdal, Invega and Natrecor, including promoting for uses not approved as safe and effective by the USFDA and payment of kickbacks to physicians and to the nation’s largest long-term care pharmacy provider.

On July 30, 2013, Wyeth Pharmaceuticals Inc., a pharmaceutical company acquired by Pfizer, Inc. in 2009, agreed to pay US$490.9 million to resolve its criminal and civil liability arising from the unlawful marketing of the prescription drug Rapamune for uses not approved as safe and effective by the USFDA.

On December 19, 2012, Amgen Inc. pleaded guilty and paid US$762 million to resolve criminal liability and false claims allegations.

On July 2, 2012 GlaxoSmithKline LLC (GSK) pleaded guilty and paid US$3 billion to resolve its criminal and civil liability arising from the company’s unlawful promotion of certain prescription drugs, its failure to report certain safety data, and its civil liability for alleged false price reporting practices. This resolution is the largest health care fraud settlement in the US history and the largest payment ever by a drug company, so far.

On May 7, 2012, Abbott Laboratories Inc. pleaded guilty and agreed to pay US$1.5 billion to resolve its criminal and civil liability arising from the company’s unlawful promotion of the prescription drug Depakote for uses not approved as safe and effective by the USFDA. This resolution is the second largest payment by a drug company and includes a criminal fine and forfeiture totaling US$700 million and civil settlements with the federal government and the states totaling US$800 million. Abbott also was reportedly subjected to court-supervised probation and reporting obligations for Abbott’s CEO and Board of Directors.

On October 21, 2011, Pfizer Inc. agreed to pay US$14.5 million to resolve false claims allegations related to its marketing of the drug Detrol.

On June 10, 2011, Novo Nordisk was asked to pay US$25 million to resolve allegations of off-label promotion of Novoseven.

On September 30, 2010, Novartis agreed to pay US$422.5 million to settle criminal and civil investigations into the marketing of the anti-seizure medicine Trileptal and five other drugs. The government accused Novartis of mislabeling, paying illegal kickbacks to health care professionals through speaker programs, advisory boards, entertainment, travel and meals.

Hence, it appears that the path followed by many pharma players to inform the doctors about the judicious off-label use of drugs only in circumstances where approved treatments have failed, is being much abused.

A conflict of interest?

Many doctors believe that there is also a distinct upside for off-label use of drugs, as flexibility of a physician to prescribe drugs off-label offers important advantages too, especially in circumstances where approved treatments have failed. This is indeed true and indisputable.

However, the reality is, many pharma industry, in general, actively encourage off-label use of drugs for commercial benefits through expanded use of their respective brands.

Aggressive drug promotion for various off-label uses, reportedly being so widespread and indiscriminate, many physicians can’t even remember the approved indications of drugs. Hence, they do not necessarily go for off-label use only when approved treatments have failed. In this context, on November 23, 2015, ‘The Wall Street Journal (WSJ)’ in an article titled, “Risk of Off-Label Uses for Prescription Drugs” reported as follows:

“A 2009 study published in the journal Pharmacoepidemiology and Drug Safety found that 1,199 physicians in a national survey were able to identify the FDA-approved indication of 22 drugs only about 55% of the time. The physicians surveyed included primary-care doctors and psychiatrists.”

On the other hand, the patients generally expect that the prescribed drugs will be safe. They want to administer evidence based approved medicines. Some of them have even started expressing that these evidences must also be disclosed to them.

Hence, there seems to exist a clear conflict of interest in this matter between the patients, drug manufacturers and perhaps the doctors, as well.

Conclusion:

The magnitude of general off-label use of drugs is reportedly increasing and is likely to increase further, exposing patients to increased risks of ADEs. Although the business consequences of getting engaged in this unwanted process indiscriminately could at times be quite adverse, in the balance of probability between slim chances of getting caught, and expected creamy return, many pharma players continue to feel that this risk is worth taking.

Therefore, the moot question that needs a pragmatic answer is, for patients’ safety, when the global and local pharma majors talk about prescriptions of only impeccable evidence based medicine, do they walk the talk?

By: Tapan J. Ray

Does India Produce ‘World Class’ Medicines, For All?

Posted on October 12, 2015 by Tapan Ray

India has already achieved a staggering number In terms of quantity or volume of generic medicines that it produces not just for India, but for many developed, developing and poorer countries, across the world. For this reason, India is popularly known as ‘The Pharmacy of The World’. No one questions this number at all, rather looks at India with a sense of admiration in this regard.

Nevertheless, for driving this volume growth trend further north, in a consistent and sustainable way, Indian pharma sector must ensure that its huge volume growth engine remains firmly placed on a solid bedrock of ‘world class’ drug quality, always. Any compromise in this crucial area, could strike a critical blow to this ‘tower of national pride’.

Ongoing several embarrassing incidents related to the drug manufacturing quality standards in India, are increasingly fueling the apprehension, whether or not India produces ‘World Class’ medicines for all patients across the world, independent of any other criteria, financial or otherwise. The debate has now taken an interesting turn, especially after near confirmation of this apprehension by the top drug regulator of India.

In this article, I shall discuss this important issue that hugely impacts all of us, giving my own perspective to it. Let me begin with one of the most recent incidents on the subject, involving the numero-uno of Indian pharmaceutical industry.

An overseas new product launch got prematurely aborted?

On September 25, 2015, by a Press Release, Sun Pharma Advanced Research Company Ltd. (SPARC) announced a major set back for the company. The set back may not be so much in terms of the company’s estimated revenue loss, but more on public perception across the world, about the manufacturing quality standards followed even by the top most pharma company of India.

SPARC made a public announcement through media that on March 2015 it had received a final approval from the Food and Drug Administration of the United States (USFDA) for the anti-epileptic drug – Elepsia XR (Levetiracetam extended-release tablets 1000 mg and 1500 mg). However, in the Complete Response letter (CRL) to the company’s New Drug Application (NDA) for the product, the USFDA has revoked its earlier approval, citing that the compliance status of the manufacturing facility was not acceptable on the date of approval. Elepsia XR is to be manufactured at Sun Pharmaceutical Industries Ltd (SPIL)’s Halol facility in Gujarat, the announcement said.

Sun Pharma had reportedly indicated in June 2015 that the Company had been working “very aggressively” to find partners for the product. It had “some advanced discussions” and aimed to launch the drug by the second half of fiscal 2016.

The international media lapped it up and reported this development with eye-catching headlines, one such was:

“India’s Sun Pharma research arm sees FDA nod for Elepsia XR yanked by FDA on manufacturing.”

Not a one-off isolated incident:

This matter can no way be treated as a one-off and an isolated incident, as it fits in well with a series of similar events, spanning over the last few years.

Looking at these disturbing adverse reports from the foreign drug regulators on the drug manufacturing quality standards in India, together with recent comments of the Indian drug regulator on the subject, serious health safety concerns on overall drug quality in the country, are being expressed now. The concern includes the local patients in India, as well.

Can the core issue be wished away?

Up until today, USFDA has altogether warned 39 manufacturing sites of 27 Indian pharma companies for breach of data integrity and not following specified manufacturing quality standards. The agency has also expressed that it treats these as potentially dangerous medicines for the consumption of patients in the US.

In 2015 alone, USFDA has reportedly detected such serious ‘short comings’ with 6 Indian drug makers, till September. A report from Financial Times (FT) states that the above numbers do not include the testing facilities facing sanctions from the European Medicines Agency (EMA) in the GVK Biosciences related cases or from the World Health Organizations (WHO).

What is most worrying, none can possibly still fathom, if these alleged ‘reprehensible’ manufacturing practices are restricted to just a few players or are all pervasive across the Indian drug industry.

When the foreign regulators, such as USFDA and Medicines and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom (UK) continue raising the red flags on the manufacturing standards of the top pharma players of India, including the numero uno, a chilling sensation flows through the spine, as it were. The moot question that comes up: Are all the drugs manufactured in India safe for the local patients, offering desirable efficacy?

Keeping these in perspective, would it be prudent to wish away the drug quality related critical issues, raising a conspiracy theory against the US or EU or suspend discussions on any Foreign Trade Agreement (FTA)? I don’t reckon so, and would touch upon this point in course of my discussion below.

The murmur among the US doctors:

According to an article from Reuters of March 18, 2014, titled “Unease grows among US doctors over Indian drug quality”, some US doctors are also expressing concerns about the quality of generic drugs supplied by Indian manufacturers, following a flurry of recalls and ‘import bans’ by the USFDA.

This concern has been prompted by the fact that India supplies about 40 percent of generic and over-the-counter drugs used in the United States, making it the second-biggest supplier after Canada.

Not much complaint from the Indian doctors:

This is intriguing. Despite so much of furore of the regulatory agencies in the US and EU on the Indian drug quality standards, not much concern on the same has been expressed by the medical practitioners in India, just yet.

It appears, by and large, Indian doctors believe that branded generics are generally of good quality, and the quality of generics without a brand name is not as reliable, always.

This logic is beyond my comprehension. How come just fixing a brand name on a generic formulation makes it more acceptable in terms of quality, when both branded generics and generics without a brand name, have obtained the same regulatory approval from the same drug regulators in India and following the same regulatory process?

As you will see below, the situation has changed further now, especially after the admission of the DCGI about non-compliance of global manufacturing quality standards by majority of the formulation manufacturers in India, as reported by the media. The only silver lining to it is that whatever is being currently manufactured in India, presumably meets the regulators approval in conformance to the Drugs and Cosmetics Act of the country, without any credible data to the contrary.

Does India produce drugs of ‘World Class’ quality for all?

The key question that is being raised today: Does India produce ‘world class’ drugs and for all? This is mainly because, manufacturers of ‘world class’ drug quality always aim at competing for quality on the best global standards to remain competitive in the international markets, in all parameters. This should hold good even for the domestic Indian market, for all drugs, consumed by all the local patients, irrespective of their financial status.

A lurking fear keeps lingering, primarily apprehending that Indian drug manufacturing quality related issues are not confined only to the importers in the developed world, such as, the United States, European Union or Canada. There is no reason to vouch for either, that such gross violations are not taking place with the medicines consumed by the patients in India or in the poorer nations of Africa and other similar markets.

A recent international study on Indian drug quality:

The following study further aggravates the angst.

The September 2014 ‘Working Paper 20469’ of ‘The National Bureau of Economic Research (NBER)’ Cambridge, USA, titled “Poor Quality Drugs and Global Trade: A Pilot Study’, epitomizes the following:

Experts claim that some Indian drug manufacturers cut corners and make substandard drugs for markets with non-existent, under-developed or emerging regulatory oversight, notably Africa.

The study assessed the quality of 1470 antibiotic and tuberculosis drug samples that claim to be made in India and were sold in Africa, India, and five mid-income non-African countries and found:

– 10.9 percent of these products fail a basic assessment of active pharmaceutical ingredients (API)

- The majority of the failures are substandard (7 percent) as they contain some correct API but the amount of API is under-dosed.

– The distribution of these substandard products is not random, they are more likely to be found as unregistered products in Africa than in India or non-African countries.

Claiming that the findings are robust, the NBER study points towards one likely explanation that Indian pharmaceutical firms and/or their export intermediaries do indeed differentiate drug quality according to the destination of consumption.

Incomprehensible?

The above facts are alarming, especially when these flow from a survey report of a credible international institution. This is incomprehensible too, as all these are medicines, and are meant to be for relief or cure of ailments that the patients are suffering from, irrespective of whether they are from the developed, developing or poorer countries.

If it is still happening today, why are those manufacturers allowed by the Indian drug regulators to discriminate between the patients of the developed countries and the developing world, including India, to meet the same health care needs? This is absolutely cruel by any standard, undoubtedly.

‘As you sow, so shall you reap’:

Just as the above well-known proverb says that the actions or deeds repay in kind, reasonably frequent ‘import bans’ by the foreign drug regulators on drug quality norms, has probably prompted booming generic drug exports of Indian pharma now slowing down to US$15.3 billion in 2014-15, from US $14.84 billion in 2013-14.

Along side, these avoidable incidents have significantly dented India’s image as the ‘pharmacy of the world’, manufacturing affordable and high quality generic formulations for the patients across the world.

Indian drug regulator too now thinking afresh?

Yet another relevant question comes up. What happens, if during treatment of serious ailments such drugs fail to act for inferior quality? How would one possibly know in India, whether a death has occurred due to unresponsive poor quality of drugs or on account of severity of the ailments? How helpless are the patients in such a situation?

This sad feeling gets even stronger, when well after a prolonged defense of the high quality of drugs manufactured in India, no less than the Drug Controller General of India (DCGI), airs his second thought on the same issue. This is vindicated by recent media reports on this subject.

On September 30, 2015, a media report stated that being virtually flustered by the USFDA and the drug regulators in the European Union, the Drug Controller General of India (DCGI) would place a proposal before the Ministry of Health, within the next six months, for an amendment to the existing pharmaceutical manufacturing laws under Drugs and Cosmetics Act, 1940, and Drugs and Cosmetics Rules, 1945, in order to ‘bring them on par with international standards’.

The DCGI now believes that this remedial measure would raise drug manufacturing standards in India in line with the global cGMP standards, recommended by the World Health Organization (WHO).

Currently, out of around 8,000 drug manufacturers in India, only 10 to15 percent are following the WHO guidelines, the report stated quoting the DCGI.

The new revelation further strengthens the apprehension about quality of drugs that Indian patients are consuming in the country with a strong hope for relief from the diseases that they suffer from.

The DCGI apparently admitted it, when he was quoted saying in the above report, “India has become a pharmacy of the world. So, we cannot live in isolation and will have to meet their expectations. Our system is in the process of improving.”

DCGI statement follows an important Government decision:

It is worth noting that the above comment of the DCGI comes close on the heels of an important Government decision in this regard.

On August 12, 2015, The Press Trust of India (PTI) reported that to facilitate domestic manufacture of quality medical products, the Cabinet Committee on Economic Affairs (CCEA) on that day approved a proposal of strengthening and upgrading the drug regulatory system both at the Central and state level. The committee approved a budget of of INR17.5 billion (US$270 million) on this account.

The up gradation and strengthening of the system will also include setting up of new laboratories and training academy for regulatory and drug testing officials, the report added.

Yet Another significant development:

On October 5, 2015, in yet another significant development in this direction, the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK), by a ‘Press Release’, announced signing of a Memorandum of Understanding (MOU) with the Central Drugs Standard Control Organization (CDSCO) of India.

This agreement will increase collaboration between India and UK in the area of medicines and medical devices with the aim of further improving public safety in both the countries. It is worth noting, around 25 percent of generic drugs consumed in the UK are made in India. Hence, the concern of MHRA over the safety of those medicines is understandable.

I wrote in this Blog on USFDA ‘Import Bans’ in my article of November 11, 2013, titled ‘USFDA ‘Import Bans’: The Malady Calls For Strong Bitter Pills.’

Conclusion:

A valid question that is being asked by many in India today, why the issues like, alleged cGMP non-compliance, data fudging and falsification of other documents, especially with USFDA, have multiplied suddenly over the last few years. Why not as many of such issues were raised by the USFDA before around 3 to 4 years?

This is primarily because, of late the inspectors from the USFDA have significantly increased their efforts to ensure the drug manufacturing facilities from where both generic Active Pharmaceutical Ingredients (API) and formulations are exported to the US, strictly follow the drug manufacturing standards, as stipulated by the USFDA. The fact that India supplies about 40 percent of generic and over-the-counter drugs currently used in the United States, has prompted this requirement to safeguard health safety of the American patients.

Such stringent USFDA audits commenced in 2012, when US Congress passed the FDA Safety and Innovation Act. This legislation, among others, requires the USFDA auditing all foreign facilities that make drugs for export to the US, as frequently as it does for the domestic drug manufacturing plants. Thereafter, we have seen a spurt in the USFDA inspections of the pharma manufacturing facilities in India, where from drugs are exported to the US. Hence, there does not seem to be any other credible ‘conspiracy theory’ on this issue.

As reported in ‘The New York Times’ of February 14, 2014, the same DCGI almost brushing aside the gravity of the situation arising out of repeated ‘import bans’, commented at that time, “If I have to follow US standards in inspecting facilities supplying to the Indian market, we will have to shut almost all of those.”

The top drug regulator seems to have changed his mind since then, and presumably is thinking differently now, as the Indian media very recently quoted the DCGI saying “India has become a pharmacy of the world. So, we cannot live in isolation and will have to meet their expectations. Our system is in the process of improving.”

This is a good omen, especially for the patients in India. If and when it gets translated into reality, with Kudos to the DCGI, we all would feel very proud saying, “The Pharmacy of the World now produces the World-Class drugs, for all” …God willing!

By: Tapan J. Ray

PILMAN

A Tapan Ray Website

Tag Archives: USFDA

Even Smaller Countries Now Question Indian Drug Quality Standard

Is Criticizing Pharma Now Just A Fad?

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.

What Happens To Pharma’s Incredible Ride On The ‘Gravy Train’?

Biosimilar Drugs: First Indian Foot Print In An Uncharted Frontier

Ease of Doing Pharma Business in India: A Kaleidoscopic View

For Drug Safety Concern: “Whistleblower’s Intention Should Be Nationalistic”

Marketing Off-label Use of Drugs: A Path Much Abused?

Does India Produce ‘World Class’ Medicines, For All?