Tag Archives: Lipitor

Reticence Around Unveiling Clinical Trials

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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  

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. 

Drugs From The Same Indian Plant: Safe For Europe, Unsafe For America, Why?

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Good number of stories on US-FDA banning several drug manufacturing facilities of major domestic players of India over serious quality related issues, have been doing the rounds since about a year and almost at a regular interval.

The quagmire has snowballed into serious apprehensions on the quality of Indian generic drugs, across the globe. Various statements of US-FDA Commissioner Margaret Hamburg, during her much talked about maiden visit to India, in February 2014, added further credence to the issue.

“If you want our market, meet our standards”:

During Hamburg’s India visit, her reported candid warning to the Indian drug exporters to America added further fuel to the above concern in India. She clearly underscored:

“If you want our market, meet our standards.”

Even in the face of this stern warning, when major drug manufacturers of India, such as, Ranbaxy, Wockhardt, Sun Pharma and some others continued to fail in meeting US-FDA drug quality standards in their respective plants, I wrote the following in one of my earlier blog posts titled, “Does India Believe in Two Different Drug Quality Standards?”:

“In a situation like this, especially when many Indian manufacturers are repeatedly failing to meet the American quality standards, the following questions come up:

  • Is the US-FDA manufacturing requirement too troublesome, if not oppressive?
  • If not, do the Indian and other patients too deserve to have drugs conforming to the same quality standards?

Answers to these questions are absolutely vital to convince ourselves, why should Indian patients have access to drugs of lower quality standards than Americans, with consequential increase in their health risks?”

The first question on ‘troublesomeness’ now partly answered?

This is because another recent media report brought to the fore that, having completed their assessment of drug manufacturing violations at Ranbaxy’s facility in Toansa, European regulators have said although deficiencies were found, they pose no risk to public health. The regulators said they were satisfied by corrective measures put in place by the company after U.S. regulators found deviations in January.

The report also highlights that this assessment of the European regulators stands in stark contrast to the response of US regulators to the deficiencies found at the same plant.

It is worth noting that US-FDA continues to restrict Ranbaxy from making and selling pharmaceutical ingredients from the Toansa facility “to prevent substandard quality products from reaching US consumers.”

The same plant meets drug safety standards of Europe, but ‘unsafe’ for America!

Quite contrary to the above stern statement of US-FDA, according to the above report from Reuters, European drug regulators commented as follows:

“The inspection team concluded that there was no evidence that any medicines on the EU market that have an active pharmaceutical ingredient manufactured in Toansa were of unacceptable quality or presented a risk to the health of patients taking them.” 

The further added, “This conclusion was supported by tests of samples of these medicines, all of which met the correct quality specifications.”

Regulatory audit standards were the same for both EU and US regulators:

It is also interesting to note from the report that according to a statement from the US-FDA:

“EMA and FDA inspected the Toansa facility using similar quality standards and underlying principles of current good manufacturing practices.”

Was the decision of US-FDA ‘import ban’ subjective?

This critical question arises because of another US-FDA statement that states as follows:

“While inspections were similar, the two regulatory authorities applied their own, differing, regulatory and legal standards to address the violations.”

Subjectivity in decision-making could encourage “Conspiracy Theory”:

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 now sold in the United States come from India. Almost all of these are cheaper generic versions of patent expired drugs. Total annual drug export of India, currently at around US$ 15 billion, is more than the domestic turnover of the pharma industry. Hence, India’s commercial stake in this area is indeed mind-boggling.

In a situation like this, the apprehension of subjectivity in the decision making process of US-FDA related to ‘import bans’, if linked with, say for example, even the missed opportunities for ‘first to launch’ generic versions of several patent-expired blockbuster drugs in the United States by Ranbaxy, could lead to much undesirable ‘Conspiracy Theory’, further souring the relationship between India and America.

As I mentioned in one of my earlier blog posts titled “Loss of Ranbaxy Gain of Big Pharma…And Intriguing Coincidences”, when the emerging dots associated with the missed opportunities for ‘first to launch’ generic versions of drugs like, Lipitor (Pfizer), Diovan (Novartis) and Nexium (AstraZeneca) are connected, an uncomfortable pattern could emerge favoring Big Pharma and obviously adversely affecting Indian companies like Ranbaxy.

The First Dot: Uncertainty over Lipitor generic launch:

Like many other large Indian players, ‘first to launch’ strategy with the new generic drugs has been the key focus of Ranbaxy since long, much before its serious trouble with the US-FDA begun in 2008. ‘Import Bans’ on two of its manufacturing facilities by the US regulator in that year created huge uncertainty in its launch of a generic version of Pfizer’s anti-lipid blockbuster drug Lipitor in 2011. On time launch of a generic version of Lipitor was estimated to have generated a turnover of around US$ 600 million for Ranbaxy in the first six months and commensurate loss to Pfizer for the generic entry.

Despite its neck deep trouble with the US-FDA at that time, Ranbaxy ultimately did somehow manage to launch generic Lipitor, after partnering with Teva Pharmaceutical of Israel.

The Second Dot: Indefinite delay in Diovan generic launch:

Lipitor story was just the beginning of Ranbaxy’s trouble of not being able to translate its ‘first to launch’ advantage of patent-expired blockbuster drugs into commercial success, thus allowing the Big Pharma constituents to enjoy market monopoly with their respective blockbuster drugs even after patent expiry.

Despite Ranbaxy holding the exclusive rights to market the first generic valsartan (Diovan of Novartis and Actos of Takeda) for 180 days, much to its dismay, even after valsartan patent expiry in September 2012, a generic version of the blockbuster antihypertensive is yet to see the light of the day. However, Mylan Inc. has, now launched a generic combination formulation of valsartan with hydrochlorothiazide.

US-FDA drug ‘Import Ban’ from the concerned manufacturing facility of Ranbaxy gave rise to this hurdle favoring the Big Pharma, as discussed above.

As a result, Novartis in July 2013 reportedly raised its guidance announcing that the company now expects full-year sales to grow at a low single-digit rate, where it had earlier predicted net sales to turn up flat. It also guided for core earnings to decline in the low single digits, revising guidance for a mid-single-digit drop.

The Third Dot: Delay in Nexium generic launch:

Ranbaxy had earlier created for itself yet another opportunity to become the first to launch a generic version of the blockbuster anti-peptic ulcerant drug of AstraZeneca – Nexium in the United States, as the drug went off patent on May 27, 2014. However, due to recent US-FDA import ban from its Toansa plant, this opportunity too seems to be fading away for Ranbaxy.

Delay in the launch of generic Nexium, which incidentally is the second-biggest seller of AstraZeneca, would make a big impact on the predator-chased company’s profit.

With the global sales of Nexium at US$ 3.87 billion and US sales at US$ 2.12 billion in 2013, retaining its monopoly status in the all-important US market beyond the end of May would not only limit a forecast decline in AstraZeneca’s 2014 earnings, but would also protect bonuses for top management of the British pharma giant, as the above report says.

Conclusion:

Let me hasten to add yet again, while highlighting the stark differences of interpretations on drug quality standards of the same plant between the European and American regulators and connecting the dots of significant missed opportunities of the Indian drug manufacturers, I do not intend to postulate any ‘Machiavellian Hypothesis’.

I just wanted to establish that both alleged ‘subjective’ decision making process of the US-FDA and coincidences of a series of missed opportunities encountered by the Indian drug manufacturers related to first to launch generics in America are now realities, which if remain unaddressed could germinate into a ‘Conspiracy Theory’, at least in some corners. This could further sour existing Indo-US relationship.

While, I am confident that the new government of India with its, so far, well demonstrated ‘Can Do’ spirit would take these critical issues up in the ensuing bilateral ministerial level meetings, an immediate and in-depth study should also be initiated with valuable inputs from the independent experts to ferret out the real reasons behind these facts, including:

  • Why are the cGMP related issues in India repeatedly arising mainly with the US-FDA?
  • Are  the requirements of the US-FDA though too onerous for the Indian drug manufacturers, yet reasonable as per global norms?
  • If so, how come the drugs manufactured in the same Indian plant though declared unsafe by the US-FDA, considered safe by the European regulators?

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.

 

 

 

Loss of Ranbaxy, Gain of Big Pharma…And Two Intriguing Coincidences

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In March 2014, the largest pharma player of India by market capitalization, Sun Pharma, became the latest of the large Indian pharma exporters facing the US-FDA ‘Import Ban’ for drugs manufactured at its Gujarat-based plant. This news came as a shocking surprise to many, including the stock market, as the home grown company has now attained an international stature being governed by a professional management team and steered by a Board that is chaired by a well-regarded non-Indian with decades of experience in the global pharmaceutical industry.

Just before that in January 2014, being slapped with the US-FDA drug ‘Import Ban’ of Active Pharmaceutical Ingredients (API) manufactured in its Toansa Plant of Punjab, the pharmaceutical business of Ranbaxy in the United States, with the products manufactured in its approved manufacturing facilities in India, came to a screeching halt.

It is worth noting that similar ‘Import Bans’ are already in place for the same company’s Dewas, Paonta Sahib, and Mohali production facilities. The combined impact of these bans now makes Ohm Laboratories plant of Ranbaxy, located in New Jersey, its sole generic drug manufacturing facility for the US market.

Considering that the US sales of Ranbaxy reportedly used to be around 57 percent of its total global turnover even in 2012, these import bans are undoubtedly a huge blow to the company, both financially as well as in terms of its business reputation.

Thus, the top priority of Ranbaxy under this situation is effectively addressing all the issues as raised by the US-FDA, especially in the area of documentation, as in the buyers’ market sellers cannot be the choosers.

A ‘Double Whammy’:

Meanwhile, prompted by theses ‘Import Bans’ on product quality ground and adding further woes to the company, the Supreme Court of India on March 15, 2014 reportedly issued notices to both the Central Government and Ranbaxy on a Public Interest Litigation (PIL) seeking not just cancellation of the manufacturing licenses of the company, but also a probe by the Central Bureau of Investigation (CBI) on the allegation of supplying adulterated drugs in the country.

Thus, it is a double whammy for Ranbaxy. The company would now require convincing the top court of the country that it manufactures and sells quality medicines for consumption of the patients in India.

However, Ranbaxy reportedly insisted that the drugs sold by it in the Indian market are safe and effective and that the company complies with all regulations of the country.

Could the situation now get even murkier?

During the process of judicial scrutiny, if the Supreme Court gets convinced with the above reply of Ranbaxy on this issue, the question that could possibly emerge is, how come the same company produces high quality drugs for the patients in India and allegedly substandard quality drugs for the patients of the United States? This could make the subject more complicated, if not murkier, internationally.

Two intriguing coincidences:

In the midst of all these, while connecting various similar looking and important dots, emerged during the last few years, a couple of clear coincidences comes to the fore, as follows:

1. Is the drug quality issue in India for exports limited only to US-FDA?

This brings us to the first interesting coincidence of drug ‘Import Bans’, involving large Indian drug exporters, coming mostly, if not only, from the US-FDA, although there are so   many other drug importing countries, including rest of the developed world.

Moreover, none of the Indian domestic companies had ever faced similar number of USFDA ‘Import Bans’ in the past, though they have been exporting to the United States from their FDA approved and inspected plants since quite a while. Therefore, it is worth figuring out why has it started happening now, that too repeatedly, and involving some of the largest global generic drug manufacturers from India.

Ranbaxy too is a large global player for generic pharmaceutical products. Besides India and the United States, the company markets its products both in East and West Europe, Latin America, Africa, Middle East, South Asia, South-East Asia and Asia-Pacific regions. Interestingly, though its saga related to US-FDA cGMP conformance in the four plants, culminating into drug ‘Import Bans’ in the United States, commenced as early as 2008, the company does not seem to have any issue with any other drug regulator anywhere in the world, not just yet.

According to the media report, UK and Australian drug regulators had commented that they are assessing the impact of the US action on Ranbaxy products sold in their countries. However, as on date Ranbaxy’s drug export to all those countries continue to remain as normal as before.

If over a period of time, it is proved that other foreign drug regulators do not have any similar quality related issues with Ranbaxy manufactured products, a serious joint evaluation of the entire chain of events related to Ranbaxy and others by the global regulatory experts would perhaps be warranted to provide a lasting solution on the subject.

2. Missed opportunities for ‘first to launch’ generic versions of blockbuster drugs:

The second coincidence is related to a series of missed opportunities, especially for Ranbaxy, related to ‘first to launch’ generic versions of several patent expired blockbuster drugs in the United States.

When the emerging dots associated with such lost opportunities for drugs like, Lipitor (Pfizer), Diovan (Novartis) and Nexium (AstraZeneca) are connected, a clear pattern emerges favoring Big Pharma and obviously adversely affecting companies like Ranbaxy.

Saga started with uncertainty over Lipitor generic Launch:

Like many other large Indian players, ‘first to launch’ strategy with new generic drugs has been the key focus of Ranbaxy since long, much before its serious trouble with the US-FDA begun in 2008. ‘Import Bans’ on two of its manufacturing facilities by the US regulator in that year created huge uncertainty in its launch of a generic version of Pfizer’s anti-lipid blockbuster drug Lipitor in 2011. On time launch of a generic version of Lipitor was estimated to have generated a turnover of around US $ 600 million for Ranbaxy in the first six months.

Despite its neck deep trouble with the US-FDA at that time, Ranbaxy ultimately did manage to launch generic Lipitor, after partnering with Teva Pharmaceutical of Israel.

The story continued with indefinite delay of Diovan generic launch:

Lipitor story was just the beginning of Ranbaxy’s trouble of not being able to translate its ‘first to launch’ advantage of patent-expired blockbuster drugs into commercial success, thus allowing the Big Pharma constituents to enjoy the market monopoly with their respective blockbuster drugs even after patent expiry.

Despite Ranbaxy holding the exclusive rights to market the first generic valsartan (Diovan of Novartis and Actos of Takeda) for 180 days, much to its dismay, even after valsartan patent expiry in September 2012, a generic version of the blockbuster antihypertensive is yet to see the light of the day. However, Mylan Inc. has, now launched a generic combination formulation of valsartan with hydrochlorothiazide.

US-FDA drug ‘Import Ban’ from the concerned manufacturing facility of Ranbaxy gave rise to this hurdle favoring the Big Pharma, as discussed above.

As a result, Novartis in July 2013 reportedly raised its guidance announcing that the company now expects full-year sales to grow at a low single-digit rate, where it had earlier predicted net sales to turn up flat. It also guided for core earnings to decline in the low single digits, revising guidance for a mid-single-digit drop.

Would it also delay the launch Nexium generic?

Ranbaxy had earlier created for itself yet another opportunity to become the first to launch a generic version of the blockbuster anti-peptic ulcerant drug of AstraZeneca – Nexium in the United States, as the drug goes off patent on May 27, 2014. However, due to another recent US-FDA import ban from the concerned plant of Ranbaxy, it now seems to be a distant reality.

That said, it has now been reported that Ranbaxy is in talks with at least two companies on sourcing ingredients for the generic version of Nexium to be able to launch its generic formulations in the United States immediately after the patent expiry.

In this context, any delay in the launch of generic Nexium, which incidentally is the second-biggest seller of AstraZeneca, would have a big impact on the company’s profit.

With the global sales of Nexium at US$ 3.87 billion and US sales at US$ 2.12 billion in 2013, retaining its monopoly status in the all-important US market beyond the end of May would not only limit a forecast decline in AstraZeneca’s 2014 earnings, but would also protect bonuses for top management of the British pharma giant, the above report says.

No Machiavellian Hypothesis:

By highlighting these coincidences, I have no intention to even attempting to postulate something like a ‘Machiavellian Hypothesis’. I just want to establish that intriguing coincidences do exist whatever may be the reasons.

Probably an in-depth study by independent experts in this field would be able to ferret out the real reasons behind these coincidences, including, why are the cGMP issues repeatedly arising only with the US-FDA?

Conclusion:

Be that as it may, delayed generic launches of Nexium (AstraZeneca) with US sales of US$ 2.12 billion, together with the same for Actos (Takeda) and Diovan (Novartis) recording a combined sales for US$ 8.55 billion, have indeed created almost a wind-fall gain for the respective ‘Big Pharma’ constituents and consequent huge losses for Ranbaxy. The first-to-file bonus on Actos alone was estimated to be more than US$ 200 million.

Though the US-FDA Commissioner Margaret Hamburg has reportedly clarified that the United States is ‘not targeting’ Indian pharma companies but just following a strict quality control regime for all products being imported into America, the following critical questions still float at the top of mind:

- Are all these missed opportunities of Ranbaxy, which favored Big Pharma immensely, just sheer coincidences of clash in timings between USFDA ‘Import Bans’ from four of its manufacturing facilities and the respective launch dates in the United States for the first generic versions of the three blockbuster drugs?

- When Indian generic drug manufacturers continue to export across the world without any problem thus far, why is a series of unprecedented ‘Import Bans’ on quality grounds now coming from the US-FDA in a quick succession decimating the image of Indian generic drug manufacturers?

At the end of the narrative, some wise men could well say that I am trying to connect the dots that do not exist at all. These are all imaginary or at best, sheer coincidences. It could well be just that, who knows? But…

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.

Threats to Indian Generics: Failing in US Inspections is Just Half The Story

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At a recent event of the American Enterprise Institute, Dr. Harry Lever, a senior cardiologist at the Cleveland Clinic in Ohio, reportedly expressed his concern based on his personal experience regarding inconsistent quality among Indian generics. As a result, he requires switching patients off them, almost routinely, for desired therapeutic effects.

Many reasons may be attributed to such medical concerns on Indian generics in the United States, however limited those may be, the core issue can nevertheless be wished away.

Back home in India, many doctors reportedly have also expressed similar apprehensions on the quality of many generic formulations produced by over 10,000 pharmaceutical manufacturers in the country.

US-FDA on its part has taken action to protect health safety of the patients in the United States through import bans of drugs manufactured in all those facilities, which failed to meet its cGMP standards during inspection.

Not an old story:

Not so long ago, just in 2013, quality related concerns with generic drugs exported by 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. Most recently, following yet another ‘import ban’ and this time for Active Pharmaceutical Ingredients (API) manufactured at its Toansa plant, Ranbaxy has suspended all shipments of APIs pending review. With this step, Ranbaxy would virtually have no access to the top pharmaceutical market of the world.

A not very responsible remark either:

Unfortunately, in the midst of such a scenario, instead of taking transparent and stringent measures, the Drug Controller General of India (DCGI) was quoted as 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 US-FDA Commissioner Margaret Hamburg was wrapping up her over a weeklong maiden trip to India in the wake of a number of ‘Import Bans’ arising out of repeated cGMP violations by some large domestic generic drug manufacturers. Whereas, Hamburg reiterated the need for the domestic drug makers of India to make sure that that the medicines they export are safe for patients, the DCGI’s above comment appears rather arrogant and out of tune, to say the least.

Just recently, on the above comments of the DCGI, the American Enterprise Institute reportedly commented, “Indian drug regulator is seen as corrupt and colliding with pharma companies…”

Failing in US-FDA inspection is just half of the story:

Around 40 percent of prescriptions and Over The Counter (OTC) drugs that are now sold in the United States come from India. All most all of these are cheaper generic versions of patent expired drugs. Total annual drug export of India, currently at around US$ 15 billion, is more than the domestic turnover of the pharma industry. Hence, India’s commercial stake in this area is indeed mind-boggling.

It is now well known, if such ‘Import Bans’ continue or grow due to shoddy compliance of required cGMP standards, there could be a serious challenges for the Indian drug exporters to salvage their reputation on drug quality for a long time to come. Consequently, this will offer a crippling blow not just to their respective organizational business outlook, but also to future drug exports of India. It is worth mentioning that drugs and pharmaceuticals are currently a net foreign exchange earner for the country.

The other half of the story:

Threats related to export of Indian generic drugs on quality parameters, as flagged by the US-FDA in India, is just half the story. The other half of the story begins in the US, instead of in India, and is related to stringent new measures taken by the same regulator in its own land to have a check on the quality of imported generic drugs consumed by the patients in America.

A recent report highlights that around twelve academic centers of the United States are now involved in the firstever widespread safety and quality evaluation of generic drugs. This program is run by the US-FDA and would continue through 2017.

This initiative has been prompted by the fact that generic drugs currently contribute over 80 percent of prescriptions written in the US. In 2014, the said program will reportedly focus on cardiovascular drugs, ADHD treatments, immune-suppressants, anti-seizure medicines, and antidepressants. The grand plan is highlighted to project the priority emphasis of the US-FDA on the quality of generic drugs, especially after it banned medicine import from four India-based facilities over a period of last nine months.

Some Examples:

- A widespread testing program of USFDA followed its 2012 finding that generic copies of antidepressant medication Wellbutrin XL did not work as good as the original. This study eventually led the largest generic drug player of the world -Teva to withdraw its generic version from the market in 2012.

- According to the report, US-FDA is now reviewing a 2013 study done by a Boston-based researcher that found widespread impurities in the generic version of Pfizer’s anti- cholesterol drug Lipitor manufactured outside of the US. The research reportedly found that some generic versions of Lipitor produced overseas were rendered ineffective as a result of manufacturing impurities. However, US-FDA action on the same is not known, as yet.

Thus, the other half of the story unfolds the reality that, even if any exporter escapes USFDA inspection in India, there is a fair chance now that the generic formulations could be tested in the US itself under the above program and if found wanting in quality parameters, concerned generic formulation could face a ban in the United States.

Conclusion:

There is nothing like tightening all loose knots in the required cGMP process for all drugs manufactured in India, without bothering much about their testing in the US. If the drug quality consciousness becomes robust in the shop floor, well before the products leave the shores of India, there is no reason why the country would face similar embarrassing incidents in future, along with a strong global furore.

The US-FDA Commissioner’s recent calling on the DCGI to join hands with the US to enforce more rigorous oversight of drug manufacturing facilities, needs to be followed up with due earnest, the above avoidable comment of the DCGI not withstanding.

The Commissioner reportedly reiterated that the US would increase the number of FDA inspectors in India from 11 to 19 as it intensifies inspections of drug manufacturing plants, simultaneously with arranging cGMP compliance related workshops for the drug exporters. The DCGI also made an announcement that India intends to increase its inspectors from 1,500 to 5,000 over the next five years.

A deepening economic spat over cheaper generic drugs, not withstanding, all these good intents to maintain a robust drug quality standard need to be translated into reality.

Trying to find ghosts nurturing dubious intentions against India, especially in areas pertaining to drug quality standards, may not augur well for the patients at large, not just of the United Stated, but for our own homeland 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.

Pharmaceutical Brand Building in a Changing Scenario: Thinking Outside the Box

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In this article, I shall explore unconventional ways of “Building sustainable Pharmaceutical Brands” thinking  outside the box, after quickly taking you through the “Challenges of Change” in the evolving dynamics of  the Indian branded generic market.

A paradigm shift has taken place:

To get insight into the future challenges of the pharmaceutical industry in general ‘Complete Medical Group’ of U.K conducted a study with a sizable number of senior participants from the pharmaceutical companies of various sizes and involving many countries. The survey covered participants from various functional areas like, marketing, product development, commercial, pricing and other important areas.

The findings in the paper indicate that a paradigm shift has taken place in the global pharmaceutical industry, where continuation with the business strategies of the old paradigm will no longer be a pragmatic approach.

The situation is not much different in India too, due to rapidly evolving change in the dynamics of pharmaceutical business environment.

Besides the above finding, my own experience also vindicates that just as today is not a mega yesterday, tomorrow will never be a mega today.

The lessons learnt:

Taking a cue from the above study, which brought out several big challenges facing the global pharmaceutical industry in general and turning it into Indian perspective particularly in the post product patent regime beginning in 2005, my submissions are as follows:

- The increasing interventions of the Government is creating an all pervasive pricing pressure both for branded generics and patented drugs in various ways. The critical issue of predictability in the business environment along with the factors related to gaining greater market access are the ‘top of mind’ concerns of the pharmaceutical players in India.

- Better understanding of the new and differential value offerings that the doctors and patients will increasingly look for beyond the physical pharmaceutical products; will indeed be the cutting edge for the winners in this new ball game.

- Top management of the pharmaceutical companies should start evaluating the long term sustainability of the current pharmaceutical business model, especially for the branded generics. They will now need to include in their strategy wider areas of healthcare value delivery system with a holistic disease management focus.

- Offering just a better choice of medication for the treatment of a disease may no longer be considered enough without further value addition. Added value with disease prevention initiatives and help managing the ‘quality of life’ of patients, especially in case of chronic ailments, will assume increasing importance in the pharmaceutical business process.

- Greater and more frequent incremental innovation across the pharmaceutical value chain will be critical success factors.

- The ability to harness new technologies, rather than just recognize their potential and  flexibility to adapt to increasingly demanding regulatory environment together with newer value requirements of the patients, should be an important part of the business strategy of any pharmaceutical company in the changing paradigm.

- More complex, highly fragmented market with cut throat competition along with various questionable sales and marketing practices, especially in the area of branded generics, demand for better, more aligned and integrated decision making process across various functional areas of the pharmaceutical business.

- Avoiding silos and empire building have long been a significant issue, especially for big pharmaceutical companies. Better and high quality strategy will include more pragmatic and efficient sales and marketing investment decisions, a robust ethics and compliance mechanism and jettisoning all those activities, which will no longer deliver intrinsic or extrinsic differential value to the stakeholders.

- Growing regulatory control in the business environment, including change in the MCI regulations for the doctors, strict implementation of long overdue ‘Uniform Code of Pharmaceutical Marketing Practices (UCPMP)’ drafted by the Department of Pharmaceuticals for the industry and recent developments in the Clinical Trial process, will prompt a drastic change in the existing business practices.

- There will be a greater need for more innovative management of the pharmaceutical communication channels, including social media, striking a right balance between ‘pushing’ information to the doctors and patients and helping them ‘pull’ the relevant information, whenever required, through various well structured processes.

Need to think outside the box:

Unfortunately, even in the changing paradigm, the fundamental way by which the pharmaceutical industry has been attempting to address all these challenges has not changed much.

Though one should hope for the best, it will not be a bad idea to have a contingency plan ready, just in case prescriptions in generic names are made mandatory in India, even if selectively. Otherwise effective marketing of branded generics may be in jeopardy.

To explore the future growth potential the pharmaceutical companies are still focusing on the areas like, new product development, conventional sales and marketing, leveraging IT in all areas of decision making process including supply chain and greater market penetration skills, to name just a few.

Though these areas are not totally irrelevant today, adhering only to such tools and responses steadfastly, do ring an alarm bell to me. In a changing  paradigm, only these tools are just not good enough for business excellence and to squarely address the new “Challenge of Change”.

The moot question will therefore be why have we not been able to address the needs of the new world order, as effectively as in the past, with these traditional tools?

More importantly, if we do not try to address today’s business issues thinking ‘outside the box’ or with ‘lateral thinking’, the implications could be rather serious in the times to come?

A different concept of “Building Mega Brands”:

Building brands, as we know, involve creating equity around an entity that delivers value to the customer, over and above the key functional properties of any product. Traditionally, the pharmaceutical companies have been largely focusing on building mega brands following widely varying strategies.

In the Indian scenario, rapidly evolving pharmaceutical business environment could make such strategies unsustainable or vulnerable, more for the branded generics, as mentioned above.

To meet those disruptive but emerging changes in the business environment, there is a need to take the conventional brand building exercises, especially for the likes of branded generics, beyond the confinement of just a single product.

A thought:

That said, I would now like to make a provocating submission.

Instead of investing huge sums in building a single product brand, can we build a larger brand with a well thought out cluster of products?

Cost efficient yet a powerful and different type of brand building process could well be thought around, say, the ‘Corporate franchise’ with a  cluster of products in different price bands for different customer segments belonging to a specific therapy category or disease area or falling in some other area, yet bonded with a strong commonality criteria?

Thus, instead of consistently watching large branded generics grow, mature and die following even an extended product life cycle, pharmaceutical companies could well explore another opportunity to build a more sustainable and a much longer term emotional equity into their brands.

Who knows, tomorrow’s list of India’s top mega brands may not be dominated by the likes of Augmentin, Corex, Monocef, Voveran or Human Mixtard, but perhaps by quite  different types of mega brands like, GSK Anti-infectives, Cipla Respiratory Care, USV Diabetic Care, Abbott Cardiac Care or Galderma Derma Care, just to cite a few examples.

‘Serum Institute Vaccines’ perhaps could well be considered as one such mega brand, incubated and grown in the pharmaceutical green field of India, over a long period of time and now known the world over.

Conclusion:

It is quite clear now that the pharmaceutical business models are undergoing an acid test and serious re-evaluation in the changing paradigm. There is a view that further changes are inevitable due to variety of factors that are squeezing both sales and profit margins, posing severe challenges to future growth at a brisk pace.

Some strategic measures to address this ‘Challenge of change’ are now being deliberated upon. However, how profound will these changes be or how effectively the pharmaceutical players counter these changes for a long term sustainability of business excellence, will indeed be quite interesting to watch.

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.