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.

Reticence Around Unveiling Clinical Trials

Posted on October 17, 2016 by Tapan Ray

While scanning through various publications, we now get to know, almost at regular intervals, about new clinical trials capturing the newer ways of treating different ailments. Such information instils an invigorating hope in the minds of doctors and the patients alike, to more successfully and predictably fight the battle against diseases in the ongoing pursuit for a better quality of life.

However, for independent and impartial assessment of any new drug before it comes to the market, an ethical and transparent process of unveiling clinical trials, sans any reticence whatsoever, are absolutely essential. Only this process would be able to satisfactorily establish, beyond an iota of doubt, the safety and efficacy levels of, especially, the new drugs. To move in that direction, the fundamental requirements will be diligently recording and publishing all types of data – positive, not so positive, and also negative, arising out of all clinical trials, conducted anywhere in the world, for the same drug.

Thus, there should be a system of open access to all clinical trial data, as each trial is completed. Otherwise, pharma companies’ publication bias, overwhelmingly on positive results, would continue, as alleged by many across the world. It is worth noting that over 60 percent of all clinical trials for new drugs are sponsored by the pharma and biotech companies.

There isn’t any dearth of examples of new drugs’ getting not just the required regulatory approval, riding on the back of robust ‘positive’ clinical trial data on safety and efficacy, but also becoming highly dependable money-spinners for the companies, and in no time, as it were. These cash churning new brands would also get well protected for monopolistic pricing all through their respective patent life, and sometimes even after that, in various different ways.

Nevertheless, at a later date, mostly post patent expiry, not all pre-launch new drug trials could be universally accepted as robust and conclusive, especially on their efficacy and safety claims. On the contrary, a number of detailed and deep-stick independent studies indicate that some new drugs are, in fact, much less effective, if not ineffective, and cause more serious side effects than what were published earlier.

Hence, some critical questions are now being asked by many stakeholders, with greater assertiveness than ever before and backed by solid evidence, in this arena. Although it has now started creating a snowballing effect, still, nothing much seems to have changed on the ground, just yet.

Why aren’t all clinical trial results, and for all new drugs not still published, or otherwise made available for public scrutiny, unveiled, and of course after protecting any reasonable commercial interest? Does business consideration, then continue to prevail over the need for transparency in clinical trial data disclosure for patients’ health and safety? The sneaking fear behind the reasons of this reticence of pharma players, in general, continues to torment many. I shall discuss this point in this article backed by recently published data.

Not a recent trend:

This isn’t a recent trend either, and continuing for decades, without any effective remedial measures by the appropriate authorities. I would give just a couple of examples, one from 1998 and the other from 2014, to drive home this point.

A British Journal of Clinical Pharmacology (BJCP) article, published way back in August 1998 would vindicate this point. This study revealed the following on clinical trial data:

“Substantial evidence of selective reporting was detected, since trials with positive outcome resulted more often in submission of final report to regulatory authorities than those with inconclusive or negative outcomes.”

Another study published on September 10, 2014 in the Journal of American Medical Association (JAMA) states as follows:

“Thirty-five percent of published reanalysis led to changes in the findings that implied conclusions different from those of the original article about the types and number of patients who should be treated.”

That said, I shall now focus on a very recent controversy in this area, related to a blockbuster drug that has now gone off-patent.

A contemporary example:

Statin class of drugs, especially, Atorvastatin is one of many such examples.

Pfizer launched Atorvastatin with the brand name Lipitor in early 1997. At that time, it was the fifth in the statin class of drugs for the treatment of hyperlipidemia.

It was launched on the back of a 1996 clinical study that concluded, Lipitor reduces bad cholesterol significantly more than the other statins, from the very onset of treatment to as long as the treatment continues. After that it’s a history in the pharma industry, Pfizer marketing turned it into the best-selling drug ever, in the history of pharmaceuticals, so far.

Over 14.5 years, Lipitor reportedly made over US$ 125 billion in sales, and provided up to a quarter of Pfizer Inc.’s annual revenue for years.

Product claim – then:

Claiming that in ‘one year alone, statins reduced numerous cases of cardiovascular-related complications and saved thousands of lives’, a Pfizer Paper on “The Value of Statin”, reiterated the drug’s role both in the treatment and prevention of Coronary Artery Diseases (CAD). I am quoting below from this paper to cite just one example each – treatment and prevention:

In a study of patients with Coronary Artery Disease (CAD) statin therapy reduced the relative risk of mortality by 50 percent in those > 80-years-old, 44 percent in those 65- to 79-years-old, and 30% in those < 65 years old, compared to CAD patients in the same age group not taking statin therapy (Ref. Chloe, Allen A., et al. ‘Statin Therapy Is Associated With Reduced Mortality Across All Age Groups of Individuals With Significant Coronary Disease, Including Very Elderly Patients’. JACC. 40: 10; 1777-1785)

An analysis of 18 trials, including 56,934 patients, primarily without CVD, demonstrated statins conferred a relative risk reduction (RRR) in all-cause mortality by 14 percent and stroke by 22 percent (Ref. Statins for the primary prevention of cardiovascular disease. Cochrane Database System Review. 2013 Jan 31; 1:CD004816).

Research findings for the same drug – now:

Among several other publications on statins, a July 26, 2015 article, published in the ‘World Journal of Cardiology’ concludes as follows:

“History has proven otherwise, and the global prevalence of Coronary Heart Disease (CHD), despite worldwide statin usage and cholesterol lowering campaigns, has reached pandemic proportions. Coronary heart disease is an extremely complex malady and the expectation that it could be prevented or eliminated by simply reducing cholesterol appears unfounded. After twenty years we should concede the anomalies of the cholesterol hypothesis and refocus our efforts on the proven benefits of a healthy lifestyle incorporating a Mediterranean diet to prevent CHD.”

To give one more example, let me quote from a contemporary study, published on June 12, 2016 in the ‘BMJ Open’, which also comes to a similar conclusion, as follows:

“High LDL-C (Low-Density Lipoproteins – Cholesterol) is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (i.e., that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.”

Examples of other drugs:

Lipitor should not stand out as a solitary example, in this field. To establish this point, let me now put forth, just as illustrations, a few more examples of similar bias on positive results in clinical trial publications, besides many others.

An October 4, 2016 article titled, “Big Pharma’s Role in Clinical Trials”, published in the ‘Drug Watch’, quotes several other companies sailing in the same boat, as follows:

The Cochrane Collaboration, a nonprofit organization based in London that reviews health care information, concluded that unlike its promotional claims, Roche’s Tamiflu only shortened symptoms of influenza by one day, and it did not prevent hospitalizations or complications from influenza.

AstraZeneca reportedly paid US$ 647 million in lawsuit settlements for failing to inform the public of Seroquel’s side effects.

Takeda Pharmaceuticals reportedly settled lawsuits claiming the company’s anti-diabetic drug Actos caused bladder cancer, for US$ 2.37 billion.

In July 2012, GlaxoSmithKline reportedly pleaded guilty and agreed to pay US$ 3 billion to settle charges brought by the U.S. Department of Justice for failing to report clinical data on its anti-diabetic drug Avandia.

Johnson & Johnson was reportedly accused of hiding some dangerous side effects like, diabetes, substantial weight gain, stroke and gynecomastia – or breast development in boys for its product Risperdal – used to treat schizophrenia and bipolar disorder in adults and adolescents and autism spectrum disorders in children and adolescents. The company reportedly settled claims in Kentucky, Texas and Montana for a total of more than US$ 340 million and settled multiple cases in Pennsylvania for undisclosed amounts.

As reported by ‘Financial Times’ on February 03, 2015, Novartis was accused of manipulating trial data in favor of its anti-hypertensive drug – Diovan, and concealing side-effects associated with its Tasigna – for leukemia treatment. As a result, the company reportedly faced a temporary suspension of its business in Japan, as punishment for alleged manipulation of clinical trial data.

Possible reasons:

The above ‘Drug Watch’ article attributed several reasons to positive data bias in publications, as follows:

Researchers publish positive findings more often than negative findings as a result of human bias. Scholars want their work to contribute to medical advancement and not deter it.

Researchers do not want to put their time and energy into writing studies about negative results.

Journals seek positive results, and publish them more quickly to increase publicity.

Trial sponsors want to publish positive results to increase profit.

The article emphasized, “Big Pharma funds 60 percent of all clinical trials, and takes advantage of its power to persuade researchers and influence institutions. The result is an under-informed, and misinformed medical community giving advice to patients with false or incomplete data. The byproducts of industry cover-ups are scores of deaths and millions of dollars in industry profits.”

Indian scenario:

India is also not immune from such alleged wrongdoings. Indian clinical trial organizations have also been accused of trial related scams, and that too on a mega scale, reaching beyond the shores of the country. I am quoting below two such recent examples:

In August 2015, the European Union reportedly banned the marketing of around 700 generic medicines for alleged manipulation of clinical trials conducted by the domestic research company GVK Biosciences. This was reported as the largest EU-wide suspension of sales and distribution of generic drugs ordered by the European Commission that was applicable to all its 28 member nations.

In July 2016, the European Medicines Agency (EMA) reportedly recommended suspending the sale of dozens of generic medicines over concerns about “flawed” studies that were conducted by the Semler Research Center, located in Bengaluru. Many of these drugs are sold by Novartis and Teva Pharmaceuticals.

In September-October 2015, US-FDA also found “significant instances of misconduct and violations of federal regulations by the same research center, which includes substitution and manipulation of study subject samples.”

This year, the World Health Organization (WHO) also had issued a notice to Semler for the same reasons. After, examining the company’s computer servers, early and late last year, WHO reportedly found a spreadsheet file containing detailed instructions for manipulating drug samples that were used in clinical trials for its clients.

It is even more unfortunate that such malpractices are continuing, even after the Supreme Court of India’s widely reported observation in early 2013 that ‘Uncontrolled clinical trials are causing havoc to human life.’ The apex court of the country made this remark in response to a petition filed by the human rights group Swasthya Adhikar Manch (SAM).

The upshot:

Recent scrutiny of all original clinical trial findings of many new drugs by the independent experts, including statins, even if taken just as raising controversies, the question would still remain, why did such controversies not surface much earlier, or during the product patent life? No company would possibly be willing to unveil the fact behind this raging debate.

The good news is, pharma companies operating in Europe and the United States have decided to share trial data with qualified researchers, effective 2014, presumably in response to mounting pressure from clinical trial transparency campaigners, for quite some time.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) have jointly released a set of principles detailing plans to allow greater access to information from clinical trials. However, it fell short of public availability of all clinical trial data. Let’s wait, watch and hope that this seemingly good intent would be translated into reality by all their member companies.

Some pharma companies and their trade associations continue to raise issues of the various legalities against related to public disclosures of all trial data. Nevertheless, it is worth noting that in April 2014, a legislation was approved in Europe by the European Parliament to increase transparency in clinical trials by making the trial results publicly available. EMA was commissioned by the European Parliament to create a database where all interested parties could view comprehensive data from clinical trials. The transparency rules for the European Clinical Trial Regulation entered into force on January 1, 2015 and apply to clinical trial reports contained in all marketing authorization applications submitted on or after this date. On March 3, 2016, EMA announced the detailed guidance on the requirements for pharmaceutical companies to comply with the agency’s policy on publication of clinical trials data for all medicines. Chapter Three of this publication gives guidance to companies on how to anonymize clinical reports for the purpose of publication.

The EMA initiative of transparency of clinical trial data aims at ensuring that drug companies are aware of what is expected of them, and that they are ready for the publication of these critical data.

Besides Europe, in the United States too, though there is a clear mandate of the federal government that all clinical trial results related to serious or life-threatening diseases require to be published and uploaded on ClinicalTrials.gov – the database of the Government covering all clinical trials in America. However, this government mandate also seems to be hardly followed, both in its letter and spirit, according to reports. Similar scenario, reportedly, still prevails in most other developed countries, as well. India does not seem to be any different in this matter, either.

Intriguingly, the whole issue continues to remain polemical, with more number of initial clinical trial conclusions reportedly turning out to be not as transparent as these ought to be, carrying a significant bias towards positive treatment outcomes.

As a result, prevailing reticence around unveiling all clinical trials, including those of blockbuster drugs, is eventually pushing many patients to the brink of much avoidable and unforeseen serious health risk.

By: Tapan J. Ray

The Curious Conundrum of New Drugs Approval Process

Posted on January 18, 2016 by Tapan Ray

Fathoming the details of just a short span of time, not going beyond the last 10 years, I find from the published data that many new drugs, such as, Alatrofloxacin, Aprotinin, Drotrecogin alfa, Lumiracoxib, Propoxyphene, Rofecoxib, Rosiglitazone, Sibutramine, Tegaserod, Tetrazepam, were withdrawn from a number of important global markets. Quite a few of those were withdrawn also from the world market.

The key reason for almost all these withdrawals was serious safety concerns for the patients while using these medicines. Interestingly, some of these new molecules were withdrawn even after attaining the blockbuster status, such as Rofecoxib.

Tens of thousands of patients have died only because of this reason, according to reports.

It is widely believed by the experts in this area, if full public disclosure of the entire data of drug clinical trials was made, most of these new drugs would not have seen the light of the day and without putting many patients’ health safety in jeopardy.

All this is a part of a curious conundrum in the new drug approval process, across the world, for various reasons. In this article, I would try to dwell on this issue.

Voices against this ‘unethical practice’ getting louder:

On December 22, 2015, ‘CBC News’ published an interesting article, titled “Researcher issues ‘call to action’ to force release of hidden drug safety data: Bringing drug industry data into the light of public scrutiny.”

The article echoed the same belief of other global experts and, in fact, went a step forward. It categorically reiterated, if full disclosure of the entire data of drug clinical trials is made public, medical practice might have been quite different.

To drive home this point, the article cited the example of the arthritis drug rofecoxib (Vioxx), which has been linked to tens of thousands of deaths related to heart attacks.

It highlighted, although this risk was very much known to the regulatory authority of the United States, the relevant data was not released to the public for an impartial scrutiny.

Quoting different sources, the paper observed, almost half of the drug trials remain secret and the studies that are published, overwhelmingly report results that make the drug in question look good.

Independent experts’ views differed from the innovator companies:

In some cases, when researchers were able to see what is hiding in the filing cabinets of the drug innovator companies, a different picture altogether emerged on the overall profile of those drugs.

One group looked at 12 antidepressants, comparing the published studies with the internal US FDA assessments. They found that 94 per cent of the published studies were positive, as compared to 51 per cent, when they included all of the studies assessed by the drug regulator.

Based on a detailed study, the authors concluded, without considering all the data, drug effectiveness can often be exaggerated, leading doctors and patients to assume that the medications work better than what they actually do. The ongoing practice of the drug players may help them to significantly diminish the risks, related to the benefits offered by these medicines.

A few months ago, another group analyzed the data from an unpublished drug company study about the effect of Paxil on teen depression and found that the drug did not work and was not safe for the patients. This result completely contradicted the original, unpublished study on this drug.

A crusader emerged in Canada:

Interestingly, the same article, as above, states that Mathew Herder , the health law associate professor at Dalhousie University in Halifax, Canada is now taking up the fight. He is now “calling on other doctors, researchers and journalists to bombard Ottawa with their own demands for drug industry data, using the new legislative lever called the ‘Protecting Canadians from Unsafe Drugs Act,’, which was passed late last year in Canada.

He has also created a template to help doctors, researchers and journalists access drug safety data at Health Canada. Herder reportedly could even include biomedical researchers, doctors who prescribe medicine, investigative journalists pursuing questions about drug safety, and other activists and patient groups.

This example is worth imbibing elsewhere.

The ‘Rule Books’ are in place, though with loopholes:

To curb such alleged patient unfriendly practices of the innovative drug manufacturers, while obtaining the marketing approval of new drugs, various rules and procedure were put in place, by various authorities.

I shall deliberate below a few of these rules, and enough loopholes therein, enabling the interested parties to hoodwink the external experts, at the cost of patients.

International Clinical Trials Registry Platform:

Much before Herder, following a ministerial summit on Health Research in 2004, a World Health Assembly Resolution passed in 2005 called for unambiguous identification of all interventional clinical trials. This resolution led to the establishment of the ‘World Health Organization (WHO) International Clinical Trials Registry Platform’. It collates information on trials that have been notified in a network of clinical trial registries.

According to W.H.O, “The registration of all interventional trials is a scientific, ethical and moral responsibility”.

In the latest version of the Declaration of Helsinki, it reiterates, “Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.”

It unambiguously states, “Researchers have a duty to make publicly available the results of their research …. Negative and inconclusive as well as positive results must be published or otherwise made publicly available”.

Understandably, W.H.O statement underscores, “There is an ethical imperative to report the results of all clinical trials, including those of unreported trials conducted in the past.”

It is worth mentioning here that on January 1, 2015, by a new policy on publication of clinical data, ‘European Medicines Agency (EMA)’ also decided to proactively publish all clinical reports submitted as part of marketing-authorization applications for human medicines, by the by pharmaceutical companies.

Big Pharma's serious apprehensions on greater Public transparency:

Before finalization of the above policy, EMA sought comments on its draft from various state holders. On September 5, 2013, in its remarks on the draft, ‘The European Federation of Pharmaceutical Industries and Associations, EFPIA’ expressed its apprehension about the public health safety oriented proactive move by the EMA as follows:

“We are worried by a move towards greater transparency of clinical trials data that appears to be putting transparency – at whatever cost – ahead of public health interests. Our detailed response to the EMA draft policy speaks to this concern. While EFPIA values other voices and opinion in the conversation surrounding clinical trials data, we believe there are better alternatives than what the EMA is presenting.”

This is of course understandable. That said, it also gives satisfaction to note that EMA did not wilt under any pressure on this score, whatever the anecdotal might of the external force be.

Gross non-compliance, endangering patients’ health safety:

Although, the standards and requirements of “Public Disclosure of Clinical Trial Results” have been well specified now, and even in most of the Big Pharma websites one can find disclosure norms of clinical trial data, their overall compliance on the ground, is still grossly inadequate, endangering patients’ health safety.

An article published in the BMJ Open on November 12, 2015 titled, “Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012”, well captured the magnitude of this issue.

Nevertheless, the study analyzed just a subset of drugs approved in a single year, 2012. The researchers only examined whether clinical trials were registered and reported, not what that data suggested about how the drugs worked.

The paper reported the results as follows:

“In 2012, the US FDA approved 39 novel new medicines, known as NMEs, and 35 novel drugs. Combining these lists, the FDA approved a total of 48 new drug entities, 15 of which were sponsored by 10 large pharmaceutical or biotechnology companies with market capitalizations valued over US$19 billion. A total of 342 trials were conducted to gain regulatory approval of the 15 drugs, 24 of which were excluded from our analysis, leaving 318 trials involving 99 599 participants relevant to our study, a median of 17 trials per drug.”

Based on the findings, the authors concluded asunder:

“Trial disclosures for new drugs remain below legal and ethical standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal and ethical standards and the quality of medical knowledge.”

Simultaneously, The Washington Post in an article of November 12, 2015, titled, “How pharma keeps a trove of drug trials out of public view”, summarized this report by highlighting to the general public that one third of the clinical trial results that US FDA reviewed to approve drugs made by large pharmaceutical companies in 2012, were never publicly reported.

Unethical practices skewing medical science:

On July 25, 2015, ‘The Economist’ published an article titled, “Spilling the beans’. It highlighted again that the failure to publish the results of all clinical trials is skewing medical science.

This article also brought to the public attention that half of the clinical trial results are never published over several decades. It broadened the discourse with the observation that this specific unwanted practice, distorts perceptions of the efficacy of not just drugs, but devices and even surgical procedures too, in a well planned and a systematic manner. What is most important to note is, it has seriously compromised with patients’ health interest, across the world.

It keeps on happening, as there are no firm obligations on the part of drug companies for making public disclosure of all such data, both for and against, though all these data are required to be filed with the regulatory authorities. Hence, the overall assessment of the drugs, weighing all pros and cons, is just not possible for any outside expert agency.

For granting necessary marketing approval, the designated authorities, at least theoretically, ensure that the drugs are reasonably safe, and have, at least, ‘some beneficial effects’. However, the prescribing doctors would continue to remain ignorant of the untold facts, the article states.

According to ‘The Economist’, although in the United States the relevant laws were modified, way back in 2007, to address this issue, it still remains as a theory, the actual practices in this regard are mostly not so.

Despite vindication no tangible outcome yet:

As I said earlier, this fact got vindicated through extensive research by the ‘BMJ Online’ article and many other contemporary medical publications.

For example, the evidence released earlier on April 10, 2014 by the Cochrane Collaboration of London, UK, also shows that a large part of negative data generated from the clinical trials of various drugs were not disclosed to the public.

Again, like Vioxx, though the US FDA was aware of all such data, for a well known drug Tamiflu, unfortunately the prescribing doctors were not. As a result, the U.S. Centers for Disease Control and Prevention (CDC), which doesn’t have the same access to unpublished data as the regulators, recommended this medicine not being able to evaluate it holistically.

However, as the findings from the unpublished clinical trials eventually surfaced, CDC expressed serious apprehension on the overall efficacy of Tamiflu, quite contrary to the assessment of the concerned big pharma player.

Hence, despite quite a large number of vindications by the experts, no tangible outcome has been noticed on this pressing issue, just yet.

Conclusion:

Based on all this discussion, the moot question that springs up: Why do the doctors still prescribe such drugs, even after being aware of the full facts?

In this regard, an article titled, “Big Pharma Plays Hide-The-Ball with Data”, published in the Newsweek on November 13, 2014 raised a very valid question.

It commented, even if Tamiflu does nothing, and there is just a slight chance of life-threatening side effects, why was it approved by the US FDA, in the first place?

Even more intriguing is: Why do the doctors continue prescribing these, especially after the Cochrane Collaboration took the Tamiflu’s maker, Roche, to task about many of its claims, in April 2014.

Incidentally, the Cochrane Collaboration is widely regarded as one of the most rigorous reviewers of health science data. It takes results of multiple trials, looks for faults and draws conclusions. It doesn’t accept funding from businesses with a stake in its findings.

The answer to this question may perhaps be too obvious to merit any elaborate discussion here.

Be that as it may, this curious conundrum of ‘New Drug Approval’ with ‘Partial Public Disclosure of Clinical Trial Data’ needs to effectively addressed, without further delay. If not, patients’ health interest would continue to get seriously compromised with the continuation of prevailing laxity in its implementation process by the drug regulators.

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

Data Manipulation: Leapfrogging Dangerously Into Clinical Trial Domain

Posted on August 3, 2015 by Tapan Ray

Over the last several years, repeated allegations of gross data manipulative practices, detected by global drug regulatory agencies, such as USFDA and MHRA, have shaken the Indian pharma exporting companies hard.

This has been hurting the overall business performance of most of these players, considerably, besides other consequential fallouts

Significant numbers of pharma manufacturing facilities of different scale and size have been receiving ‘Import Alerts/Warning Letters’, at regular intervals, from the overseas drug regulators. All such steps have resulted in refusal of entry of medicines manufactured in those plants into the importing countries. As on date, most of these bans are for the United States (US), some for the United Kingdom (UK) and now a fresh one that covers all the 28 countries of the European Union (EU).

Consequently, the drug export performance of the country has started moving south, as I indicated in my blog post of September 29, 2014, titled “Make in India…Sell Any where in The World”: An Indian Pharma Perspective.

While looking at the future, the situation seems to be even more concerning than what is generally envisaged today, as it involves many homegrown local pharma behemoths, including the topper of the Indian pharma league table – Sun Pharma.

Time to take the bull by the horns:

These are regular and serious episodes of allegedly deliberate wrong doings involving life saving medicines. It is about time that without further delay the Indian Government and the country’s drug regulators accept unequivocally that there is something fundamentally wrong in this area that needs to be set right urgently.

To come out of this peril soon, competent authorities need to first ascertain without squandering much time on the utopian “conspiracy theory”, whether this seemingly uncontrollable issue falls under:

Technical incompetence
Inadequate resource deployment
Or just an outcome of generally all pervasive and a very Indian “Jugaad” mindset

It could well be a mix of all the three above factors in different proportions.

‘Data manipulation’ dangerously leapfrogging into clinical trial domain:

So far, incidences of alleged data falsification were restricted mostly to drug manufacturing activities. Alarmingly, it has now leapfrogged into the immensely important domain of ‘Clinical Trials’, based on which the drug regulators decide on the ‘Marketing Approval’ of medicines for patients’ consumption, wherever required.

If the Government does not nip it in the bud, ruthlessly and now, it has the potential to heavily impact the innocent patients even costing their precious lives.

What it means commercially?

According to Pharmaceutical Export Promotion Council (Pharmexcil), the Indian pharmaceutical industry could lose around US$1 – US$1.2 billion worth of exports due to the latest decision of the European Union to ban 700 generic drugs that earlier received European Union (EU) clearance for sale in their member countries.

According to Pharmexcil, Europe accounts for US$3 billion out of total Indian pharma exports of US$15.4 billion, which includes both APIs and formulations. This is the first time, when there has been a negative growth in pharma exports to the EU.

Unrolling the GVK Bio saga:

On July 22, 2015 Federal Institute for Medicines and Medical Products of Germany reportedly posted the notice (in German language) of ban of 700 generic drugs effective August 21, 2015. This ban would be applicable to all 28 EU member nations.

Accordingly, from the above date, all these drugs of both the Indian and multinational companies for which clinical trials were done by India’s Hyderabad based GVK Biosciences, cannot be distributed or sold by pharma companies, wholesalers, drug stores and other outlets in the EU, as indicate in the above notice. This would be the largest ban of generic drugs imposed by the European Union, as it comes into effect.

This ban is reportedly the ultimate outcome of an inspection in 2014 by the French authorities of the GVK site that handled the clinical trials for those 700 drugs. The French inspectors found that a number of electrocardiograms were falsified by GVK Bio employees as part of 9 approval studies between 2008 and 2014.

Following this finding, earlier on January 23, 2015, by a Press Release, the European Medicines Agency (EMA) had announced that a number of medicines for which authorization in the European Union (EU) was primarily based on clinical studies conducted at GVK Biosciences in Hyderabad, India, should be suspended.

Though GVK Bio has disputed the claims, it has reportedly set aside up to US$6.5 million for new studies on these drugs.

Indian Government blames ‘vested interests supporting Big Pharma’!

Interestingly, on July 23, 2015, The Financial Express reported, “the Modi government has asked the heads of India’s diplomatic missions in EU member countries and at the European Commission (EC)-level to take up the issue with the concerned authorities and ensure that it is not ‘blown out of proportion’ by ‘vested interests’ supporting the Big Pharma (innovator drug companies).”

However, it is even more interesting that earlier on April 16, 2015, quoting the CEO of GVK Biosciences Private Limited Reuters reported, “India may go to the World Trade Organization (WTO) if the European Union does not reconsider a decision to suspend the sale of about 700 generic drugs that were approved based on clinical trials by GVK Biosciences.”

It is noteworthy, despite the above public announcement, between April and July 2015, India has not lodged any complaint to the WTO on this mega ban in EU, involving clinical trials conducted by GVK Biosciences.

In my view, any tangible immediate outcome of the Indian diplomatic move, particularly on this ban in the EU, as reported above, appears rather unlikely, if at all.

The rigmarole continues:

The narrative of alleged gross falsification of sensitive clinical trial data does not end here. Almost replicating what happened earlier with frequent incidences of drug manufacturing data manipulation, the same rigmarole now leapfrogs into another important domain with similar intensity.

On June 30, 2015, close on the heels of the above GVK Biosciences saga, the World Health Organization issued a ‘Notice of Concern’ after inspection of Chennai-based Contract Research Company, Quest Life Sciences facility.

It also brought to light, critical deviations from GCP (Good Clinical Practices), over data integrity, subject safety and quality assurance and in gross violation of procedures during clinical trials for HIV drugs, such as, Lamivudine, Zidovudine and Nevarapine dispersible tablets from Micro Labs.

WHO inspectors reportedly found that “two-thirds of electrocardiograms performed on patients were duplicates with dates and names changed by the company”.

The WHO letter also underscored, “These issues appear to be systemic in nature and occurring many times over a significant period of time, and not only as a one-time incident for the study submitted to WHO.”

Again, almost depicting the past, there does not seem to be any perceptible and strong regulatory interventions in India in this regard, event after the above ‘Notice of Concern’ from the WHO.

Could assume a snowballing effect:

This situation may eventually assume a snowballing effect, when data related malpractices in clinical trials would catch up with drug manufacturing related data manipulation detected by the foreign drug regulators in India. I have just given an example of its continuation in the clinical trial domain.

The following are a few examples of just the last six months of 2015 of the continuation of the same in the drug manufacturing area:

Cadila Pharmaceuticals Limited:

In a letter dated February 25, 2015 to Cadila Pharmaceuticals Limited, the USFDA wrote that in the pharma manufacturing facility of the company, located at 294 GIDC Industrial Estate, Ankleshwar, Gujarat, their (USFDA) investigator identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of Active Pharmaceutical Ingredients (APIs). Those deviations cause the APIs manufactured there to be adulterated, in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with CGMP.

Emcure Pharmaceuticals Ltd.:

On July 13, 2015, by an ‘import alert’ posted on its website, the USFDA announced that the regulatory agency had barred imports from Hinjewadi manufacturing plant in Maharashtra of Emcure Pharmaceuticals Ltd., after their inspection revealed the company was not meeting manufacturing quality standards.

Aurobindo Pharma Ltd.:

Again, according to a July 22, 2015 media report, “Hyderabad-based Aurobindo Pharma is the latest addition to an expanding list of Indian drug firms that have come under the scanner of the US health regulator.” In this case also the USFDA reportedly raised issues related to the quality management systems of the company.

Business sustainability could be in jeopardy:

There are ample evidences that manipulations of specified drug quality standards, are making even the large home grown pharma companies to pay through the nose. In fact, it has already cost some of these companies an arm and a leg, at times jeopardizing even their very existence. One such company is Ranbaxy. The issues related to data fudging of Ranbaxy have been so complex and widespread that its recent acquirer Sun Pharma has already started struggling to keep its neck above water with this brand new acquisition.

According to July 27, 2015 media reports, GVK Biosciences are also in parleys to sell the business, following EU drug regulators’ serious allegations of clinical trial data manipulation at its Hyderabad facility.

Again, media reports of July 30, 2015 indicated that hit by the USFDA imposing import ban on three of its manufacturing facilities, Ipca Laboratories reported 86 per cent decline in net profit for first quarter ended June 30, 2015.

Though, some domestic pharma companies are still out of it, with grace, if this overall menace remains unchecked and not intervened by the Government, it could cost the nation dear, at least when it comes to near term exports business growth and global disrepute for the delinquency.

Are medicines for domestic consumption safe and effective?

When such rampant data manipulation can take place for ‘export quality’ of drugs, what about the quality standards of medicines, which are manufactured for consumption of local patients?

Despite intense furore on this subject, Indian drug regulators at the Central Drugs Standard Control Organization (CDSCO), very strangely, do not seem to be much concerned on this critical issue, at least, as perceived by majority of the stakeholders. It appears from the precedents, our drug regulators seem to act promptly, mostly when the Supreme Court of the country directs them for any specific action for public interest.

Considering blatant violations of GMP and GCP standards that are increasingly coming to the fore related to ‘export quality’ drugs in India, and that too only after the inspections by the foreign drug regulators, the following questions float at the top of my mind:

Why no such warnings are forthcoming at all from the Indian drug regulators?

Does it mean that the level of conformance to GMP and GCP is hundred percent for all medicines manufactured and clinically evaluated in India for the consumption of local patients?

If yes, why such incidences are not uploaded to the CDSCO website, just like USFDA?

If not, why?

Conclusion:

Increasing incidences of repeated GMP and GCP violations by the Indian drug exporters, as enunciated mostly by the USFDA, MHRA and now EMA are, in turn, fueling the apprehensions of many Indian stakeholders on the quality manufacturing and clinical evaluation of those drugs in the country.

In the critical public health safety area, there does not seem to be any room for diplomatic maneuvering by the Government, whatever is its financial impact on the drug exports performance of India.

This can be corrected, only if the Indian pharma industry and the Government, in tandem, wish to move in the right direction. Searching for justifications within imaginary ‘vested interests’ and self-created ‘conspiracy theory’ would be futile and counterproductive.

Making the wrongdoers swallow strong bitter pills would help salvaging the seemingly uncontrollable regulatory situation. Additionally, it would stop inviting disrepute to the country that the world was referring to, even until recently, as the ‘pharmacy of world’.

Any attempt to trivialize the situation, could meet with grave consequences and prove to be foolhardy. The emerging scenario ultimately may even compel the local doctors and hospitals to avoid prescribing drugs of those companies involved in such wrong doings against patients’ interests. This actually happened earlier with Ranbaxy, though briefly. It is also possible that many erudite patients on their own may request the doctors to prescribe equivalent drugs of pharma MNCs, enjoying better brand equity in this regard.

Drug quality related avoidable malpractices and attempted hoodwinking to regulators, are taking place at a time when Prime Minister Modi is going global to give a boost to his much publicized ‘Make in India’ campaign.

In the current aspirational business climate of the country, it is an irony that alleged ‘Data Manipulation’, which was so far confined to pharma manufacturing activities in India, instead of getting mitigated, is now leapfrogging into the related clinical trial domain too, with utter disregard to patients’ health safety interest and the reputation of the country.

By: Tapan J. Ray

Pharma Outlook 2015: A Glimpse Of Some Drivers and Barriers

Posted on January 5, 2015 by Tapan Ray

Looking ahead, the brand new year 2015 appears quite interesting to me both from the global and also from the local pharmaceutical industry perspective. In this article I shall try to give a glimpse of some of the important drivers and barriers for success of the industry as the year unfolds, based on recent and ongoing developments.

Let me start with the global outlook of 2015, where in the midst of all gloom and doom of the past years, I notice formation of a distinct and new silver lining, mainly due to the following two reasons:

1. Record number of new drugs approval in 2014 spanning across10 therapy areas:

As indicated in its website, USFDA has approved 41 novel medicines in 2014, which is 14 more than the previous year and is the second highest after 1996 that witnessed 53 approvals. Many of these new drugs are with blockbuster potential.

According to another report, the European Medicines Agency (EMA) has also recommended 82 new medicines in 2014, which though includes generic drugs in its list. However, this number too shows an increase from 79 in 2013 and 57 in 2012.

According to January 02, 2014 report from Forbes, very interestingly, infectious diseases dominated with 12 approvals (27 percent), cancer with 8 approvals (18 percent), followed by rare diseases with 5 (11 percent). Just two of these new approvals are for Hepatitis treatment and the rest are for bacterial, fungal, viral, and parasitic infections.

AstraZeneca received the highest number of 4 approvals followed by Eli Lilly with 3.

2. Patent expired blockbuster drugs in 2015 would have low generic impact:

Though drugs worth sales turnover of US$ 44 billion would go off patent in 2015, patent expiries will have minimal impact on the top line as 2015 sales will grow close to four times that of patent losses. Following are the top 10 drugs among those:

No.	Brand	Company	Disease	Sales2013 (US$ Bn)	Patent Expiry
1.	Lantus	Sanofi	Diabetes	7.9	Feb 2015
2.	Abilify	Otsuka/Bristol-Myers Squibb	Schizophrenia/ Other neurological conditions	7.8	April 2015
3.	Copaxone	Teva	Multiple sclerosis	4.33	Sept 2015
4.	Neulasta	Amgen	Infection reduction in cancer patients on chemotherapy	4.4	Oct 2015
5.	Tracleer	Actelion	Pulmonary arterial hypertension	1.57	Nov 2015
6.	Namenda	Actavis	Alzheimer’s disease	1.5	April 2015
7.	Avodart/Jalyn	GSK	Benign prostatic hypertrophy	1.34	Nov 2015
8.	Zyvox	Pfizer	Gram-positive bacterial infections	1.35	May 2015
9.	AndroGel	Abbvie	Low testosterone	1.03	Early 2015
10.	Synagis	AstraZeneca	Monoclonal antibody to prevent respiratory syncytial virus infection in infants	1.1	Oct 2015

(Compiled from FiercePharma data)

As a significant number of these drugs are biologics, such as Lantus, Abilify, Neulasta and Synagis, the generic impact on those large brands, post patent expiry, would be minimal, at least, for several more years.

However, Lantus sales could soon be impacted, as its biosimilar versions from Boehringer Ingelheim and Eli Lilly have already received approval in Europe, and may be launched in the United States, as well.

Biosimilar versions of other drugs that will go off patent in 2015, do not seem to be anywhere near launch soon to make immediate dent in the sales of the original biologics. I had deliberated on various possible reasons for delay in biosimilar entry, especially in the US, in my earlier blog post of August 25, 2014, titled “Scandalizing Biosimilar Drugs With Safety Concerns”

Taking all these into consideration, EvaluatePharma has estimated that out of patent expiry related sales turnover of US$44 billion, just around US $16 billion would get impacted in 2015 by their generic equivalents.

Global market outlook 2015:

According to IMS Health, spending on medicines will reach nearly $1,100 billion in 2015 with a growth rate of 3-6 percent over the last five-year period.

According to EvaluatePharma, the overall outlook of the global pharma industry in 2015 and beyond is expected to be as follows:

A dozen products launched in 2015 are forecast to achieve blockbuster sales by 2020

Drugs treating high cholesterol and heart failure will dominate the field with a combined 2020 sales forecast of US$8 billion

Sovaldi and its combination product Harvoni will take the number one worldwide seller spot with forecasted sales of $15.3 billion in 2015

Patent expiries will have minimal impact on the top line as 2015 sales will grow close to four times that of patent losses

Financing climate appears friendly and deals will continue at a steady pace but M&A activity unlikely to match the frenzy of 2014

Moreover, Oncology therapy area brings a huge promise with novel immuno-oncology drugs. As Reuters have reported, Merck & Co’s Keytruda and Bristol-Myers Squibb’s Opdivo, which work by blocking a protein called Programmed Death receptor (PD-1), are the first in a coming wave of immuno-therapies that analysts believe could generate annual sales of more than US$30 billion a year.

Indian pharma industry outlook 2015:

Indian pharmaceutical industry, dominated by branded generic drugs, is estimated to register a turnover of around US$ 33.8 billion with an average growth of 10.3 percent in 2014 – 2018 period, according to Deloitte. Increasing number of diagnosis and treatment of chronic ailments, fuelled by ascending trend in the per capita income, would be the key factors to drive this double-digit growth rate.

In 2013-14, pharma exports of the country with a turnover of US$ 14.84 billion grew at a meager 1.2 percent, which is the slowest growth in nearly the last 15 years. Pharmexcil attributed its reason to USFDA related regulatory issues and increasing global competition. India still stands exposed in this area, unless meaningful corrective measures are taken forthwith. It is worth noting, although India exports drugs to over 200 countries in the world, the United States (US) alone accounts for about 25 percent of India’s pharma exports.

Key issues and challenges in ‘The Exports Front’:

Generic drugs currently contribute over 80 percent of prescriptions written in the US. Around 40 percent of prescriptions and Over The Counter (OTC) drugs that are sold there, come from India and account for around 10 per cent of finished dosages in the US.

Almost all of these are cheaper generic versions of patent expired drugs, which are mainly produced in around 200 USFDA approved drug-manufacturing facilities located in India. Hence, India’s commercial stake in this space is indeed mind-boggling.

Indian drug exports were taking place satisfactorily without any major regulatory hitches since quite some time. Unfortunately, over the last few years, mostly the Federal Drug Administration of the US (USFDA) and the United Kingdom (UK)’s Medicines and Healthcare Products Regulatory Agency (MHRA) have started raising serious doubts on the quality of medicines manufactured in India, creating an uncertainty on drug exports in those countries.

To overcome this critical issue and keep marching ahead with distinction in the drug exports front, Indian pharma would require to successfully dealing with the following two areas:

A. Data integrity:

Since quite a while, USFDA has been raising serious concerns on ‘Data Integrity’ in their previously approved production facilities of a large number of Indian pharma players. The details of each of these concerns are available in the USFDA website.

This worrying development is now posing a huge threat to future growth potential of Indian drug exports, as in this area the Indian government had set an objective, in its strategy document, to register a turnover of US$ 25 billion in 2014-15. In all probability, it would fall far short of this target at the end of this fiscal, predominantly for related reasons. However, the good news is, considering the criticality of the situation, the Indian government is now working with the USFDA to resolve this problem.

I discussed a part of this area in my Blog Post of September 29, 2014 titled “Make in India…Sell Any Where in The World”: An Indian Pharma Perspective

B. Credibility of Clinical Trial Data from India:

Credibility of ‘Clinical Trial Data’ generated by the domestic players in India, has also become a cause of great concern, as the regulators in France, Germany, Belgium and Luxembourg suspended marketing approval for 25 drugs over the genuineness of clinical trial data from India’s GVK Biosciences.

Key issues and challenges in ‘The Domestic Front’:

Though 2015 would also witness the following important issues and challenges, meeting with this challenge of change should not be difficult with a proper mindset and right strategies:

A. The Drug Price Control Order 2013 (DPCO 2013):

Change in the mechanism of drug price control from earlier ‘cost based’ to newer ‘market based’ one and the specified provisions to neutralize inflationary impact of the input costs on the bottom line, based on the WPI, have already been considered as welcoming changes for the industry. As a result, despite implementation of the DPCO 2013, the pharma shares continued to do well in 2014 despite doomsayers’ predicaments, not just in the past, but even today.

I believe, the DPCO 2013 would not cause any significant negative impact further in 2015 on the performance of pharma companies, as the price controlled drugs would in all probability continue to be around 20 percent of the total pharma market. Moreover, now annual price increases are linked to the WPI for the controlled products and the companies can increase prices of remaining 80 percent of decontrolled products, upto 10 percent every year, irrespective of inflationary trend.

That said, due to huge inter-brand price differences, in July 2014 the National Pharmaceutical Pricing Authority (NPPA) had brought under price control 50 more cardiovascular and anti-diabetic drugs in addition to 348 drugs that featured under price control in the DPCO 2013.

If the pharma players do not take note of such abnormal inter-brand price variation of the same drugs without meaningful reasons, there could possibly be further move by the NPPA in this direction.

Additionally, any mechanism for patented products’ pricing, if announced in 2015, would have far-reaching impact, especially on the MNCs marketing such drugs.

B. Unethical practices in Clinical trial:

In the Clinical Trial arena of India, responding to a Public Interest Litigation (PIL), the Supreme Court of the country and separately the Parliamentary Standing Committee had indicted the drug regulator and charted out some action areas. The Parliamentary Committee in its report had even mentioned about a nexus existing between the drug regulator and the industry in this area.

Driven by the directives of the Apex Court of the country, the union ministry of health of the government of India has already strengthened some areas of past laxity in drug regulatory control, such as mandatory registration of clinical trials, constitution of committees to oversee the trial approval, its execution and above all ethical treatment of patients, including compensation.

Although, these are all requisite measures to create an appropriate longer-term eco-system for clinical trials in India, it has reportedly ruffled many feathers, such as CROs in the country who work mainly for pharma MNCs and some global pharma players too. This is mainly because of inordinate delays in drug approvals during the regulatory rectification process, besides cost of clinical trials going up. An orderly drug regulatory environment must prevail, instead of allegedly ‘free for all’ clinical trial environment in the country, costing many innocent lives and livelihoods. Responding to this changing clinical trial environment, some MNCs have already articulated that they are reconsidering their drug trial strategy in India and some Indian players, possibly with vested interests and echoing similar sentiments, are also saying that they would shift their clinical trial projects out of India, which would adversely impact the country’s clinical trial industry.

Be that as it may, it appears now that under the directive of the Supreme Court of the country, the decisions taken by the government in clinical trial area are irreversible, for the long-term interest of the country.

C. Intellectual Property (IP) issues:

Reacting to some well-justified measures taken by India in the IP area to make healthcare affordable to all, the US and its some key allies, continuously pressured by their powerful pharma lobby groups, continue to push India hard to broaden the IP protections. ‘Big Pharma’ lobbyists are reportedly trying to compel India to amend its IP laws that would suit their business interest at the cost of patients.

Fortunately, many stakeholders, including media, have started raising their voices against such strong-arm tactics, further fueling the credibility erosion of ‘Big Pharma’ and creating important pressure groups for the government.

Simultaneously, concerned pharma MNCs are also seeking legal recourse over issues mainly related to the section (3d) and Compulsory Licensing of the Indian Patents Act. However, most of the judicial verdicts vindicate the quality of decisions taken by the Indian Patent Office (IPO) in these areas.

Though very unlikely, any amendment or tweaking of the existing patent laws of India in 2015 would provide an unfair advantage to MNCs with negative impact on public health interest.

D. Uniform Code of Pharmaceutical Marketing Practices:

Compared to the actions that are now being taken by the law enforcers overseas against pharmaceutical marketing malpractices, India has been showing a rather lackadaisical attitude in these areas, until recently. It astonishes many that unlike even China; no pharmaceutical company has been investigated thoroughly and hauled up by the government for alleged bribery and other serious allegations of corrupt practices.

However, frequent reporting by the Indian media had triggered a debate in the country on the subject. A Public Interest Litigation (PIL) on this subject is now pending before the Supreme Court for hearing in the near future. It is worth noting that in 2010, ‘The Parliamentary Standing Committee on Health’ also had expressed its deep concern by stating that the “evil practice” of inducement of doctors by the pharma companies is continuing unabated as the revised guidelines of the Medical Council of India (MCI) have no jurisdiction over the pharma industry.

The Government, until recently, has shown no active interest in this area either, though the new Union Health Minister, J.P. Nadda decried the unethical nexus between the doctors and pharma companies, amounting violations of medical ethics in the country. He reportedly has stated that in majority of the cases, the pharma companies are luring the doctors by giving gifts and other benefits for prescribing the brand of medicines of their choice to the patients.

As the saying goes, ‘better late than never’, on December 12, 2014, the Department of Pharmaceuticals (DoP) of the Government of India announced details of the ‘Uniform Code of Pharmaceutical Marketing Practices (UCPMP)’, which would be effective across the country from January 1, 2015 for all pharma players to implement, across India.

However, I reckon, the document in its current form is rather weak in its effective implementation potential. Meaningful and transparent deterrent measures to uphold public health interest are also lacking. The entire process also deserves a well-structured monitoring mechanism and digital implementation tools that can be operated with military precision. I discussed this issue in my Blog Post of December 29, 2014, titled “India’s Pharma Marketing Code (UCPMP): Is It Crafted Well Enough To Deliver The Deliverables?”

On UCPMP a survey done by E&Y has highlighted the following points, besides other areas:

More than 50 percent of the respondents are of the opinion that the UCPMP may lead to manipulation in recording of actual sampling activity.

Over 50 percent of the respondents indicated that the effectiveness of the code would be very low in the absence of legislative support provided to the UCPMP committee.

90 percent of the respondents felt that pharma companies in India should focus on building a robust internal controls system to ensure compliance with the UCPMP.

In my view as well, the self-regulatory measures prescribed in the UCPMP of the DoP are unlikely to make any significant impact in 2015, unless pharma companies start focusing on building robust internal controls system to ensure compliance with the UCPMP.

Conclusion:

I would now put on the balance of probabilities, the new ‘Silver Linings’ of the Global pharmaceutical industry as discussed above, the issues and challenges of 2015 for the Indian pharma and also other important factors that I have not been able to discuss in this article. The overall emerging picture depicts that the pharma industry, both global and local, would fare much better than what it did in the recent past, provided the industry, as a whole, does not continue to ignore the storm signals outright.

Thus, based on the available data, the year 2015, as appears to me, would provide an enormous opportunity with promises of an interesting time ahead that the pharmaceutical industry should try to leverage on…and then cherish it for a long while…most probably as a turning point of the same ball game with different success requirements.

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.

Would ‘Regenerative Medicine’ Shape The Future Of Global Healthcare?

Posted on December 22, 2014 by Tapan Ray

Just the last week, on December 19, 2014, international media broke the news of regulatory approval of the first stem cell treatment by the European Medicines Agency (EMA).

The Agency reportedly has recommended an Orphan Drug – Holoclar of the Italian pharmaceutical company Chiesi Farmaceutici S.p.A for the treatment of moderate-to-severe Limbal Stem Cell Deficiency (LSCD) caused due to physical or chemical burns to the eyes in adults. LSCD can lead to blindness, where Holocar works in around 80 percent of cases.

The EMA decision to approve Holoclar will now be sent to the European Commission for market authorization.

As reported, this new generation treatment takes a small sample of the patients’ healthy cornea, removes the stem cells and grows them until there are sufficient numbers to put back into the eye. The cells themselves then repair the damage.

Experts consider this development as very significant step forward, as stem-cell therapies are now being tried mostly in the laboratory environment and clinical trials.

Treatment with Stem Cells – A new paradigm:

A stem cell is defined as an undifferentiated cell of a multicellular organism that is capable of giving rise to indefinitely more cells of the same type, and from which certain other kinds of cell arise by differentiation.

Stem cells are, therefore, immature cells that can be induced to transform into tissue or organ-specific cells and are classified as per their source, such as Embryonic Stem Cells (ES) from early human embryos, fetal stem cells from aborted fetus; adult stem cells from tissues, skin and bone marrow; cord blood cells from umbilical cord and even fatty tissues.

In human developmental biology, extensive scientific research over many years has led to the discovery of human stem cells.

Regenerative Medicine:

This terminology is generally used for new medical advances in which an understanding of the human genome allows the use of the body’s own mechanism to heal it. This may include new pharmaceuticals and the ability to create new cells that could be implanted into patients to replace diseased or missing tissues.

The science of ‘Regenerative Medicine’ is increasingly being considered as an emerging medical space aimed at the treatment of those diseases that are usually classified as degenerative, incurable and irreversible. As it appears today, this science would unfold a new paradigm, where patients can expect cure for many serious ailments, such as, spinal injuries, heart disease, Parkinson’s, Alzheimer’s disease and even diabetes, besides many others.

Some promising developments:

Besides the recently EMA approved new treatment, as mentioned above, examples of just a few more promising developments in research with the stem cells, are as follows:

- Possible cure for Type 1 diabetes:

According to an international report of October 9, 2014, for the first time, after 23 years of research, Harvard University has been able to manufacture millions of beta cells required for transplantation. It could mean a cure for diabetes and the end of daily insulin injections for patients living with Type 1 diabetes. Around 10 per cent of all diabetes is Type 1, but it is the most common type of childhood diabetes.

The report indicated, the stem cell-derived beta cells are presently undergoing trials in animal models, including non-human primates, where they are still producing insulin after several months.

Another report of April 2014 indicates that for the first time, scientists have successfully replaced the damaged DNA of a type 1 diabetes sufferer with the healthy genetic material of an infant donor. When these cells are injected back into the diabetic patient, it is expected that they will begin to produce insulin on their own.

- Transplant of embryonic human stem cells on patients with macular degeneration partially restored vision:

Another study published in ‘The Lancet’ in October 2014 stated that scientists in the United States have announced that single transplant of stem cells has helped restore the sight of patients suffering from incurable forms of blindness due to Age-related Macular Degeneration (AMD). Currently no effective treatments exist for this eye disorder, which can cause complete blindness due to the loss of light-receiving photoreceptor cells in the retina.

To recreate a type of cell in the retina that supports those photoreceptors, the new treatment uses stem cells derived from embryos that are only a few days old and have the ability to develop into any kind of tissue in the body. However, the transplants have proved controversial because they use stem cells derived from spare human embryos left over from IVF treatment.

- A cure for heart failure could be just a few years away:

Yet another international report of May 01, 2014 states, by injecting human stem cells into the organs of macaque monkeys, scientists have been able to regenerate their damaged hearts by up to 40 per cent in just a few weeks. Thus, it appears now that a cure for heart failure could be just a few years away and would mean that even people who are “bed-bound” with heart failure could be “up and about” again within a few weeks.

As on date, the heart muscle cannot be repaired, making people with severe heart failure necessarily wait for heart transplant. Of course, if the patients are willing and can afford so.

Debate around stem cell research:

Like many other research areas involving biological science, a raging debate has also commenced globally on several sociopolitical, cultural and ethical issues involving the use of stem cells as therapy.

Many clinical research related issues too are now surfacing on the use of human embryos, manipulations and modifications in stem cells research.

Apprehension of misuse, especially through cloning, had prompted many governments, India included, to ban reproductive cloning, keeping therapeutic cloning open for research.

However, arriving at a broader consensus in this area does not seem to be an insurmountable problem, in any case, as things stand today.

Research on stem cells and regenerative medicine in India:

Though it may sound almost unbelievable, India is now considered to be in the forefront of stem cells research and its use in a limited manner.

Indian Government under Indian Council for Medical Research (ICMR) and the Department of Biotechnology (DBT) has already set up a number of stem cell research institutions across the country. These institutions have already commenced valuable research in this area. DBT had granted more than Rs 300 Crore over the previous five years to be used in basic and applied research in stem cell technology.

According to one August 2014 report from ‘Business Insider’, several stem cells research initiatives are ongoing both in public and the private sectors in India.

A few examples, as reported, are as follows:

Public initiatives:

The National Centre for Cell Research (NCCR), Pune, has worked on stem cell trans differentiation into pancreatic islets.

Research at All India Institute of Medical Science (AIIMS) and Postgraduate Institute of Medical Education & Research (PGIMER), is ongoing on retinal degeneration and stroke.

National Institute of Immunohematology (NIIH) has been able to differentiate umbilical cord-derived mesenchymal stem cells into cardiomyocytes or cardiac muscles.

The National Centre for Biological Sciences (NCBS) in Bangalore, part of the Tata Institute of Fundamental Research, also works closely with the government on stem cells research.

The Government of India had set up The Centre for Stem Cell Research (CSCR) in 2008 in collaboration with Christian Medical College, Vellore, with the intention of using stem cell science for understanding human diseases and development of stem cell-based therapies. Interestingly, it also runs a training program for scientists and students of stem cell research. CSCR will also carry out clinical trials with stem cells produced under current good manufacturing practice (GMP) conditions.

Private initiatives:

Reliance Life Sciences obtained permission to use on large-scale stem cells sourced from the patient’s body for therapy.

The LV Prasad Eye Institute, Hyderabad, has developed corneal limbal stem cells.

Sankara Nethralaya Stem Cell Research Center, Chennai, is working on retinal and corneal stem cell application and immunoregulatory properties of stem cells.

Hospitals such as Dr KM Cherian’s research facility in Medville have used stem cells from bone marrow to help regenerate the heart.

Besides, Indian rules and law permit the usage of one’s own banked stem cells. Several storage facilities such as Life Cell, Reliance Life Sciences, Cryobanks International and Stemade for dental stem cell storage have also come up.

Stem cells research guidelines in India:

In India, ICMR-DBT Guidelines for Stem Cell Research are in place. These guidelines have been laid down to ensure that research with human stem cells is conducted in a responsible and ethically sensitive manner and complies with all regulatory requirements pertaining to biomedical research in general and stem cell research in particular.

Since it is a rapidly evolving field of science, the recommendations may change with time.

All types of research and clinical trials in stem cells would require to be registered with and obtain prior permission and approval of the National Apex Committee (NAC) and the Institutional Committee (IC-SCRT) for Stem Cell Research.

It is notably important that the guidelines categorically states that only stem cell research, basic and translational, is permitted but not therapy.

NAC- IC-SCRT permits therapy usage in patients only through approved and fully monitored clinical trials. Stem cells cannot be used as therapy without appropriate regulatory approvals in India.

Conclusion:

Currently, most treatments for non-infectious chronic ailments only delay the disease progression and associated complications. There is virtually no cure for most of these diseases, which include, spinal injuries, heart diseases, Parkinson’s, Alzheimer’s disease or even hypertension, asthma or diabetes.

Regenerative Medicine would not just bring down the cost of healthcare and the disease burden significantly, but would also help increasing the economic productivity of a nation considerably.

Currently, medical research of the highest order in this area is mostly being conducted by various academia of global repute along with the industry. This emerging trend sends a clear signal that ‘Regenerative Medicine’ is now strongly poised to give an altogether new shape to the future of global healthcare, adding unique dimensions.

Consequential paradigm shift in the field of healthcare, I reckon, would herald the dawn of a brand new era, setting in place a whole new commercial ball game, the like of which the world has never witnessed, ever before.

By: Tapan J. Ray

Scandalizing Biosimilar Drugs With Safety Concerns

Posted on August 25, 2014 by Tapan Ray

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

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

Innovating hurdles to negate the impact:

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

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

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

Intense lobbying to push the envelope:

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

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

Mounting protests against industry move:

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

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

Global pharma investors also raising voices in support of biosimilars:

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

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

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

Among other points, the letter reiterates:

Though the important role of biologics in treating cancer, rheumatoid arthritis, anemia, multiple sclerosis and many other conditions is well recognized, the costs of these medicines are on an unsustainable trajectory, with some biologics costing as much 22 times more than other drugs. This critical issue seriously impedes patients’ access to biologics, as well as, acceptance by providers and insurance companies.

Biosimilars hold the promise of lowering costs of treating conditions for which biologics are indicated. At the same time, the recent adoption of a regulatory pathway to approval of biosimilars in the US market and the continued growth of biosimilars in the European Union, Japan, Canada, Australia and South Korea, pose a formidable business challenge for the companies that market patented biologic medicines.

Financial experts project that biosimilars too have the potential for significant market penetration and attractive returns on investments.

Assigning different INN would communicate to providers that the biosimilar is less effective, prompting them not to prescribe this class of medicines and making it difficult for the pharmacists to dispense too. Besides, different names could lead to prescribing errors.

In short, the boards of directors of the pharma and biotech majors were urged by these investors to use the following principles to guide their decision-making related to biosimilars:

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

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

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

The WHO proposal:

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

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

Biosimilars go through stringent regulatory review:

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

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

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

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

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

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

The market potential of biosimilars:

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

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

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

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

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

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

India:

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

Current global usage of biosimilars:

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

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

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

Source: Pharmaceutical Product Development

Conclusion:

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

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

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

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

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

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

By: Tapan J. Ray

PILMAN

A Tapan Ray Website

Tag Archives: EMA

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Pharma Outlook 2015: A Glimpse Of Some Drivers and Barriers

Would ‘Regenerative Medicine’ Shape The Future Of Global Healthcare?

Scandalizing Biosimilar Drugs With Safety Concerns