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Pharma Branding At Tough Times

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“About two-thirds of drug launches don’t meet expectations. Improving that record requires pharmaceutical companies to recognize the world has changed and adjust their marketing accordingly.” This appeared in an article – “The secret of successful drug launches,” published by McKinsey & Company in March 2014. There isn’t any recent evidence, either, that this situation has improved now.

Even innovative drugs no longer guarantee a commercial success, as greater competition is building up there, as well. Today, the number of such drugs per indication has risen by 37 percent since 2006 making the task tougher, according to another article of McKinsey & Company, titled ‘Why innovative products aren’t enough for a successful pharma launch,’ brought out in August 2017.

Top marketers’ intimate involvement in these launches, backed by robust marketing strategies notwithstanding, large scale ‘brand failures’ or rather ‘branding failures,’ still remains unavoidable. Although, its telltale signs are more often visible immediately after launch, but may happen even several years after.

Pundits are just not scratching their heads, but doing extensive research to fathom why it happens. However, with changing times – the market dynamics and the research outcomes/inferences keep changing too. And that will be the focus of my today’s discussion in this article, while I explore various facets of the same.

Is pharma branding just a marketing exercise?

That pharma branding is not just a marketing exercise and its failure at any stage – from launch to even years after, I reckon, isn’t the sole responsibility of the pharma marketer. This is mainly because, doctors would ideally prefer to prescribe specific pharma brands and patients would feel confident to use those, because of successful construction of a positive brand bias. Which in turn creates a higher perceived efficacy and a low anticipated safety concern with the brand.

Although, it will be right to assume that good pharma marketers are solely responsible for the creation of this intangible brand asset, but the tangible intrinsic brand value should necessarily be ingrained into each dose of the same that patients consume, always.

Thus, tangible brand value creation, its maintenance, if not enhancement, span across many other functional domains of a drug company. Some of these include, unbiased reporting with expected disclosures of all clinical trial results, maintaining a robust and highly efficient supply chain network or high-quality manufacturing facilities, besides a few others. Evidences exist that irrational pricing could also result in a kind of brand failure. Considering these aspects in totality, creating a positive bias during a pharma brand-building process, is a collective responsibility, and not just of the marketers.

Why creating a positive brand bias is a collective responsibility?

There are ample examples to substantiate that creating a positive stakeholder bias during its brand-building process, is a collective responsibility. Let me illustrate this point by drawing a few examples of branded failures prompted by supply-chain network, disclosures on clinical development and of course perceived ‘irrational’ pricing that falls basically in the marketing domain. It is worth noting, similar incidents may also be related to the manufacturing process, even for top selling generic drugs.

Supply-chain: In the beginning of 2008, serious adverse drug events, some even fatal, were reported with Heparin (Baxter), which used to be widely used as an injectable anticoagulant. Around 80 people died from contaminated Heparin products in the U.S. The US FDA reported that such contaminated Heparin was detected from at least 12 other countries. The primary reason of the same was a serious breach in the supply-chain integrity.

Disclosures on clinical trial results: On 30 September 2004, Vioox (rofecoxib), a non-steroidal anti-inflammatory drug (NSAID) that had been on the market since 1999, was suddenly withdrawn by its manufacturer MSD, owing to concerns about its effect on cardiovascular health.

‘Irrational’ pricing: Like a lot of new cancer drugs, Zaltrap (aflibercept) wasn’t cheap carrying a price tag of USD 9,600 a month. But its price was quickly taken down. This followed some serious public flak, such as, doctors from Memorial Sloan-Kettering (MSK) wrote a blistering review for The New York Times in November 2012. They declared that MSK was taking the drug off the institution’s formulary, because less expensive and just as good alternative angiogenesis inhibitors were available. Although, Sanofi initially defended the price, it subsequently backed down, cutting down the price by half.

Manufacturing process: On September 13, 2019, the FDA announced that preliminary tests found low levels of N-nitrosodimethylamine (NDMA) in ranitidine (Zantac), a heartburn medication. Consequently, almost all companies, including Novartis (through its generic division, Sandoz), GSK, Apotex and many others announced its withdrawal from a large number of markets. Interestingly, these announcements came after a Connecticut-based online pharmacy informed the FDA that it had detected NDMA in multiple ranitidine products under certain test conditions. The NDMA impurity was believed to have been introduced by changes in the manufacturing process. There are several other well-reported examples, as well.

These examples vindicate that creating a positive brand bias remains a collective responsibility throughout the product lifecycle. And it involves several functional areas of drug companies. That said, let me now focus on the creation of a positive bias for pharma brands.

Creating a positive brand bias:

Skillful creation of a positive brand-bias, supported by high quality – tangible and intangible value offerings, is the net outcome of any successful branding process. It augments stakeholder confidence, leading to an increased prescription generation, alongside a favorable patient experience.

More often than not, a positive brand-bias successfully brings into being greater perceived brand-efficacy and higher perceived brand-quality, with lesser anticipated safety concerns. Consequently, the process invigorates an emotional bonding with customers for a long-term brand-loyalty. A positive brand-bias also creates a strong brand equity that often helps in working out a good pricing strategy for the company.

An interesting strategy prescribed – recently:

The October 8, 2019 issue of Fierce Pharma featured an article on creating a positive brand-bias with “Prime and prompt” marketing strategies, outlined by CMI/Compas.

According to Changing Minds: ‘Priming works by providing people with information that is easily brought to mind. The prompt that brings the information to mind can be an implanted and specific trigger or can be an associated term that will naturally bring back the primed information.’ Illustrating the point, it adds: ‘Prime-and-prompt can be a bit like firing a gun, where priming cocks and prompting pulls the trigger.’

Putting this concept in the pharma industry perspective, the CMI/Compas officials explained in the above article, ‘pharma marketers can create primes with product messages that condition people to recall their product when they need medicine or are diagnosed with a condition.’

Hence, a pharma marketer’s adroitness in the ‘priming’ strategy helps ‘prompt’ the desirable action, such as, going to a doctor to ask about a product. Hence, the persuasion technique is termed – ‘prime and prompt’, the paper explained. Naturally, the question that follows: what are the key principles behind this strategy?

Key principles behind ‘prime and prompt’ strategy:

As elucidated by the Changing Minds, when thinking and deciding, we are influenced by related information from the past. At that time, our memories would supply that information, which helps us understand, make sense, decide and act on the subject at hand. Thus, those things that come at the top of mind will have a more immediate and disproportionate influential effect, while those things which are long forgotten may have little or no effect.

It further adds: ‘Priming is driven by implicit memory, where recall is entirely unconscious as the person ‘just knows’ without having to think hard or otherwise put effort into remembering or working things out.’

How to apply the ‘prime and prompt’ strategy in pharma?

It’s no-brainer that to use ‘priming’ in the persuasion process, say for increasing prescription support, the marketers need to provide stakeholders with relevant information beforehand, and more importantly, in a different setting. And only thereafter, they need to focus on a normal brand persuasion strategy. One may most appropriately comment, this is easier said than done in the drug industry.

Taking a cue from the above interview with the CMI/Compas officials, some of the broad steps of the ‘prime and prompt’ strategy, I reckon, may be summarized as follows:

  • Consistent messaging through omnichannel media achieving target reach and frequency, as I had explained before.
  • For intended top of mind recall, a combination of print, digital, social, search, display at appropriate places and in TV, especially for OTC drugs, should consistently surround the target audience for ‘priming.’
  • According to a recent research, the most highly rated ‘priming’ spots for pharma ads for physicians are medical journals, conferences and the likes. Similarly, for patients, appropriate displays at doctors’ clinics and similar places also appeared to be one of the top-rated ‘priming’ spots.

Consequently, a well thought-out ‘priming’ strategy, skillfully executed – based on research findings, is expected to be effective. It will then help trigger desirable ‘prompts’ for the target-audience, augmenting a successful branding process. However, it comes with a caveat that the tangible intrinsic value of the brand, especially those which originate in other functional areas, don’t get compromised or changed in any way.

Conclusion:

Branding exercise in the pharma industry has never been more challenging, as it is today – both for innovative and generic drugs. As stated above, the number of innovative drugs per indication has risen by 37 percent since 2006, making the market competition tougher. Likewise, product proliferation with cut-throat pricing for branded generics, is also making the generic drug marketers grasping at straws, as it were.

In this challenging situation, creating a positive stakeholder bias for brands, as the net outcome of the pharma branding process, is a collective responsibility. Any non-marketing misstep in the tangible brand value offering, could sweep a brand away to oblivion – not just during launch, but at any stage of its life-cycle. Pharma marketers will of course be solely responsible to create the critical intangible brand assets, such as a positive stakeholder bias for brands.

At this tough time for pharma branding, several fresh marketing concepts like, ‘prime and prompt’ are now being seriously evaluated. Thus, I reckon, its also a time for astute marketers in the pharma industry to test the water, in pursuit of excellence.

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.

 

Drug Quality Imbroglio And ‘Culture of Bending Rules’ in India

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“Bottle Of Lies Exposes The Dark Side Of The Generic-Drug Boom” – re-emphasized the book, released in May 2019.  This confirms, the raging debate on the questionable quality of many generic drugs manufactured in India and involving several top domestic pharma companies, is a never-ending one. Numerous articles also ascribe many different reasons to this saga, leaving an overall impression – as if, blindfolded persons are trying to describe an elephant, touching and feeling different parts of the animal’s body, each at a time.

Let me illustrate the point with the Bloomberg article of January 31, 2019. It reported, “Culture of ‘Bending Rules’ in India Challenges U.S. Drug Agency.” And further commented: ‘The FDA confronts creative improvisation in the world’s largest generic-drug exporter.’ Curiously, according to the above report it seems to be a general belief among many, even within India.

This article will take into account the above apprehension – specifically raised against Indian drug manufacturers of both branded and non-branded generics. Accordingly, my focus will be on just three points – as possible causative factors for this critical issue:

  • Is it an India specific concern – thus related to ‘Indian cultural mindset’? or it’s a global issue, involving both Indian multinational drug manufacturers.
  • Is it a systematic attempt to create a perception bias against low-cost generic drugs, worldwide?
  • Are generic drug makers resorting to such unacceptable shortcuts due to increasing margin pressure?

Having deliberated these points, I shall try to outline a set possible remedial measures to address this issue in a holistic way, ensuring a win-win outcome. Let me first explore, whether or not this issue is specific to India, involving Indian drug manufacturers.

Is the issue India specific?

Is the issue of questionable quality of generic drugs, irrespective of whether they carry a brand name or not restricted to the shores of India? One can find its answer in the same report, as quoted above. A yearlong investigation by Bloomberg News into the generic-drug industry concluded, ‘FDA inspections at factories from West Virginia to China have found reason to doubt the data meant to prove drugs are safe and effective.’

One possible reason for such perception could be, since India is predominantly a branded generic market, voices decrying ‘questionable’ safety and efficacy of cheaper non-branded generic drugs, are too loud. Nevertheless, amidst all this, who’s who of branded generic manufacturers continue getting caught on the wrong foot by overseas regulators in the quality quagmire. Ironically, multinationals are also included in it.

Multinationals are also included in such quality quagmire:

There are several examples of non-compliance to requisite drug quality standards by multinational drug companies. Let me illustrate the point with an example that involves a top global pharma player.

The March 04, 2019 ‘Warning Letter’ of US-FDA for the Irungattukottai (Tamil Nadu) plant of Pfizer in India, clearly said: “Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.”

This is not a solitary example of Pfizer’s generic hospital injectables manufactured in this plant. According to a media report dated July 17, 2018, twice before US-FDA had cited manufacturing and testing issues in this facility, containing 11 observations of the regulator, such as, workers “manipulated test sample weights to obtain passing results” for both batches of raw materials and finished product. It is a different matter that the company, later on, decided to close this plant for commercial reasons. Be that as it may, negative perception of generic drug quality is indeed an issue that needs to be addressed without further delay, holistically.

Studies have captured negative perception of generic drugs:

That this is a perception, has been well – elucidated along with its implications, in several studies. A few of which are as below:

A BMJ article concluded: “A significant proportion of doctors, pharmacists and lay people hold negative perceptions of generic medicines. It is likely these attitudes present barriers to the wider use of generics.” It further added, “Negative perceptions of medicine quality along with other drivers contribute towards choosing more expensive medicines in the private sector.”

Endorsing this point, yet another BMJ article inferred: “Negative perceptions of generic medicines and preferential promotion of branded medicines over generics by pharmaceutical companies could influence prescriber behavior and affect trust in healthcare provided in public services. To succeed, access to medicine programs need to systematically invest in information on the quality of medicines and develop strategies to build trust in healthcare offered in government health services.”

Again, in a separate survey of over 2700 physicians on perceptions of generic drugs, more than 23 percent of respondents expressed negative perceptions about their efficacy and nearly 50 percent. reported negative perceptions of generic drug quality. In the same survey, patients also expressed concerns that the lower cost of generics is associated with reduced medication quality.

Although, the above survey was conducted in the United States, the current situation in India, I reckon, is no different, but with one caveat. Here, preferential promotion of branded generic medicines over cheaper non-branded equivalents, by the respective drug manufacturers, could significantly influence prescriber behavior. Therefore, the question that follows: Is this perception-creation based on facts?

Is the negative perception fact-based?

Although, even the US-FDA clearly states that: ‘A generic medicine works in the same way and provides the same clinical benefit as its brand-name version”, I did try to find some conclusive evidence depicting brand name drugs are superior to their cheaper generic equivalents. While doing literature searches, two types of results emerged – there are studies that do not find any significant difference between generic drugs and their branded equivalents. At the same time, a few other studies do suggest that there is a difference between these two, but admitting that these studies are not conclusive. Let me give below examples of each.

No quality difference found between generic drugs and the branded variants: 

I shall quote here three studies, out of which one is India specific. The analysis reported in the above BMJ article, found that ‘the generic and branded variants of the medicines tested were of comparable quality.’

Another study, published by PLOS Medicine on March 13, 2019 also said, “In this study of 8 drug products conducted using 2 large US commercial insurance databases, we observed that use of generics provided comparable clinical outcomes as the brand products.”

An India specific researchon the same also reported, most generic and branded drug users believed that their drugs were effective in controlling their ailments with no significant difference in reported adverse effects and drug adherence.

Slightly different results were also reported with generics, but not conclusive:

One such study questioned, whether generic drugs are truly equivalent to the brand-name versions.This article was published on January 2019 by Harvard Health Publishing with the title, “Do generic drugs compromise on quality?”

This article quoted a Canadian study, published in the October 2017 issue of ‘Circulation: Cardiovascular Quality and Outcomes’, which found that patients who took generic versions of three different blood pressure medications in the months after the generic drugs became available saw increased rates of drug-related side effects.

Was it due to a perception bias?

To ascertain whether or not there is a perception bias, let us look into the following details of the same study along with its conclusion.

In this study, the researchers ‘looked at the numbers of emergency room visits and hospitalizations for 136,177 individuals ages 66 and over (60% of them women) who used any of three blood pressure medications: losartan (U.S. brand name Cozaar), valsartan (Diovan), and candesartan (Atacand). The investigators examined data for the periods 24 months before and 12 months after the generic versions of these medications went on the market. And found that before the generic versions became available, about one in 10 people taking the blood pressure drugs had to go to the emergency room or be hospitalized each month. In the month after each of the generics went into use, the rates of these adverse events went up: 8% for losartan, almost 12% for valsartan, and 14% for candesartan.’ The study authors commented, this might suggest performance differences between the brand-name and generic drugs.

However, analyzing this study, the Harvard article suggested further probe on the question: Did it result from quality problems with the generic versions of these medications or were there other factors that occurred in this time frame?

Another research, aimed at finding, whether patients are more adherent to generic statins than brand-name statins (lovastatin, pravastatin, or simvastatin) and whether greater adherence improves health outcomes, also concluded, “An 8% reduction in the rate of the clinical outcome was observed among patients in the generic group versus those in the brand-name group.” This also wasn’t a conclusive one, either.

Nevertheless, the key point of a ‘perception bias’, is captured in a separate study, where the researchers did find higher rates of psychiatric hospitalization for patients taking generic and AG escitalopram and sertraline, compared with those who initiated the brand-name product. Importantly, they noted that these outcomes were likely due to either residual confounding or generic perception bias.

No quality difference also found between branded and non-branded generics in India:

There are studies, which captured no quality difference between branded generics and non-branded generics in the country. One such India specific study concluded: “Quality of branded-generics is same as for their branded version. The study highlights the need to modify the drug price policy, regulate the markups in the generic supply chain, conduct and widely publicize the quality testing of generics for awareness of all stakeholders.”

Thus, so far, we have seen in this article that concern on quality of generic drugs is neither India specific, nor is it related to ‘Indian cultural mindset.’ And this is, undoubtedly, a global issue, involving both Indian and multinational drug manufacturers. There are also ample evidences available that a systematic attempt is being made to create a perception bias against low-cost generic drugs, worldwide. Let us now look at the third possible causative factor, as I listed above.

Is it due to margin pressure on generic drugs?

The answer to this question was deliberated in an article titled, ‘Generic drug makers feel pinch as prices crumble,’ published in the Financial Times on August 17, 2017. Quoting a top global financial analyst, it reported – global generic drug industry, where Indian manufacturers are major players,has maintained roughly 30 per cent operating margins over a long period of time, with improvements year on year. But, since last few years, there has been a margin degradation, which may possibly further go down – even lower than what it is today.

The article further highlighted, a round of consolidation among their main customers in the US: the wholesalers, have escalated the problem.  Many of these groups have clubbed together to form “mega buyers”, known as general purchasing organizations, that can command large discounts. Moreover, for the US market, another area of ‘concern’ is that the US-FDA has identified boosting competition in the generics market as one of its main priorities. As this reform opens up, it could squeeze the generic drug margins further.

Many envisage that intense cost cutting measures, could have transgressed in the drug quality assurance area, aggravating this issue. Although, it needs to be verified through credible studies, curiously, some signs of improvement in this area has recently been reported.

That said, there appears to be a strange coincidence between recent reports on Indian drug makers showing improvement in USFDA inspection outcomes and attempts to increase generic drug companies and some of their top executives slapped with price-fixing lawsuits in the U.S.This needs to be studied further.

The way forward:

The negative perception of generic drugs, in general, and non-branded generic drugs, in particular, is most likely a well-crafted business issue, rather than a genuine patient safety concern. It calls for an immediate two-pronged approach:

  • Vigorous awareness and educational campaigns on safety and efficacy of generic drugs targeted to patients, medical and paramedical professionals.
  • New regulatory measures, especially the following five:

- No pricing pressure or price control in any form of generic drugs

- Abolish brand names for generic drugs

- Make generic prescription compulsory to boost intense competition and thereby     reducing the price.

- Restrict the number of ingredients in FDC not more than two or three

- Make Uniform Code of Pharmaceutical Marketing Practices (UCPMP) mandatory.

Conclusion:

Thus, the questionable quality of generic drugs is not an India specific concern and involves both Indian multinational drug manufacturers. This is also evident from the analysis, as quoted above, that underscores, ‘FDA inspections at factories from West Virginia to China have found reason to doubt the data meant to prove drugs are safe and effective.’ Many studies have revealed that there is a systematic attempt to create a perception bias against low-cost generic drugs, worldwide.

A sequence of remedial measures, as described above, also include fostering competition, instead of introducing government controls on prices of generic drugs with stringent regulatory oversight being in place.

Thus, the so called ‘belief’ that the ‘culture of bending Rules’ is culpable for dubious generic drug quality in India, is more akin to a strong perception, prevailing in India, rather than based on any scientific analysis related to this issue. This ought to change with a well-coordinated intervention – for patients’ health interest sake.

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

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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.