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Disease-mongering: Any which way to find a market

By branding impotence ‘erectile dysfunction’ and heartburn ‘gastro-oesophageal reflux disease’, pharma companies turn commonplace conditions into threatening diseases to market existing drugs or new drugs of doubtful or no utility. This article, by S Srinivasan, is an eye-opener on the extent to which drug companies obfuscate, bribe, offer kickbacks and make irrational, harmful, useless and even banned medicines

The pharma industry is a good example of how looking at all science and technology-based business endeavours purely as profit-making machines ends up swallowing itself, a harakiri of sorts that sets it on a collision course with the very people -- the sick and the needy -- that it needs to survive. This is happening at a time when the rate of innovation, discovery of really useful new molecules, is falling rapidly. So there is desperation aboard the pharma ship: about finding new uses and new markets for existing molecules, and overstating the usefulness of newly arranged molecules of doubtful or no utility.

Today the general public -- literate and illiterate -- is somewhat aware that corporate misdemeanours are a given and that consumers and end users need to be constantly on the lookout. Still, very few of us are aware of the extent to which drug companies obfuscate, bribe, offer kickbacks and make irrational, harmful, useless and even banned medicines. Or that they appoint doctors as key opinion leaders to give false certificates about the efficacy of their products. Or that they take cooperative doctors on exotic holidays and more, conduct unethical and unscientific clinical trials and selectively report the findings.

In this article, I illustrate how corporations ensure that drugs find their market. The tactics they use are astonishing for their brazenness as much as they are depressing for their venality -- even if one thinks from previous experience that these are par for the course. Specifically, I discuss two phenomena: disease-mongering and ghostwriting. 

Disease-mongering: “The corporate construction of disease”

One of the important ways drug companies make money is by telling people they are sick even when they are passing through one of life’s many normal transitions. A collection of papers published in the April 2006 issue of PLOS Medicine discusses this practice of “disease-mongering”, something that suits both the industry and the medical profession, as it helps in medicalising problems. In 2004, an editorial in the journal Bulletin on Drug and Health Information (BODHI) referred to a number of instances in the US of “branding” medical conditions, quoting from an article by Vince Parry, ‘The Art of Branding a Condition’ in the journal Medical Marketing & Media. Some examples from these articles:

When Warner Lambert invented a condition called ‘halitosis’ -- which makes ordinary bad breath sound serious, sales of Listerine rose from US$100,000 to US$4 million in six years.

In the 1980s, Glaxo needed to expand its market for ranitidine (brand Zantac) and created a condition called ‘gastro-oesophageal reflux disease (GERD)’ a serious sounding name for heartburn, an age-old complaint. The company also set up the Glaxo Institute for Digestive Health, which in due course led to a PR exercise, Heartburn Across America. Annual sales of Zantac peaked at US$2 billion.

“Capturing impotence in an acronym

During the 1990s, Pfizer had to create a market for sildenafil citrate (Viagra). It labelled the broader condition of impotence ‘erectile dysfunction’ (ED). Calling impotence ED probably caused less embarrassment to shy patients as they could now discuss a medical problem called ED with their doctors!

Manufacturers of fluoxetine (brand Prozac, a serotonin re-uptake inhibitor, SSRI) marketed it for ‘premenstrual dysphoric disorder’, a new name for a severe form of premenstrual syndrome, a routine hormonal transition. The marketing strategy was to frame the “disease prevalence to maximise the size of the medical problem”. Pfizer even set up an organisation called Impotence Australia to host advertisements of SSRIs in the media -- the logic presumably being that depression is caused, among other factors, by impotence. In the US, SSRI antidepressants have been widely promoted through what is called direct-to-consumer advertising. In a 2005 paper published in PLOS Medicine, Jeffrey Lacasse and Jonathan Leo observe: “The impact of the widespread promotion of the serotonin hypothesis should not be underestimated. Antidepressant advertisements are ubiquitous in American media, and there is emerging evidence that these advertisements have the potential to confound the doctor-patient relationship.” 

“A legendary example of this condition-branding strategy was the development of Xanax (alprazolam) for panic disorder in the 1970s,” writes Parry. “In DSM-II, panic disorder fell under the broad category of anxiety neurosis. Without a well-branded condition, patients experiencing panic attacks often went to cardiologists, thinking their problem was a heart condition, only to be labelled ‘cardiac complainers’ and hypochondriacs due to a lack of physical pathology. Dr David Sheehan, a pioneering thought leader in the field of panic, helped characterise the condition and push for a new way to diagnose and treat it. Upjohn, the makers of Xanax, helped fund this early research, as well as publications and speaking tours to cardiologists to help raise awareness of the heart-brain connection in the minds of panic disorder patients. Xanax was the only benzodiazepine to be studied that showed clear evidence of effectiveness. Through an unrestricted grant to the National Institute of Mental Health, a three-day thought leader conference resulted in a published consensus on the diagnostic criteria of panic disorder and how best to treat it.”

Australian journalist/researcher Ray Moynihan has documented the media’s promotion of drugs. In an article ‘Selling Sickness: The Pharmaceutical Industry and Disease-Mongering’, in BMJ in 2002, he and his co-authors note that, in Australia, baldness in men was medicalised by Merck to sell its hair-growth drug finasteride (Propecia); Merck funded a new International Hair Study Institute so that men could wise up to the bald truth by consulting their doctors. Hair loss, the public was told, could lead to panic and other emotional difficulties and even have an impact on job and wellbeing. Needless to say there were several articles around 1998-2002 in the media about the life-threatening process called hair loss!

Moynihan also notes that irritable bowel syndrome, a common functional disorder, found a drug in GSK’s Lotronex (alosetron hydrochloride). GSK used a “medical education” firm In Vivo to shape medical and public opinion -- with a plan that included setting up an “advisory board”, consisting of pre-selected “key opinion leaders” in each Australian state. The campaign was stopped because the USFDA recommended withdrawal of the drug after reports of serious and sometimes fatal adverse reactions. FDA investigators discovered that use of Lotronex could result in ischaemic colitis, a potentially life-threatening condition which is caused by reduced blood flow to the colon. Additionally, the drug can cause severe constipation, which can result in a ruptured bowel. As of October 2000, there had been 91 reported cases of hospitalisation (many more likely went unreported) in which some patients required surgery and at least five died. As a result, GSK agreed to remove the drug from the market in November 2000. However, the USFDA, facing pressure from desperate patients, announced on June 7, 2002, approval of a supplemental new drug application that allows restricted marketing of Lotronex to treat only women with severe diarrhoea-predominant irritable bowel syndrome. And in 1997, Roche started promoting its antidepressant Aurorix (moclobemide) as a valuable treatment for “social phobia”. Its PR company issued a press release saying more than 1 million Australians had a “soul-destroying condition” called social phobia. Soon Roche’s promotion of Aurorix became case study material for positive action in marketing circles.

Disease-mongering in India

There are plenty of examples of disease-mongering in the Indian scenario.

Piracetam is promoted for vague conditions like “intellectual decay,” “social maladjustment,” “lack of alertness,” “changes of mood,” “deterioration in behaviour” and in “learning disabilities in children associated with the written word”. The recommended duration of treatment for the last indication is “entire school year” in a dose of “3 g per day”, or seven to eight capsules of 400 mg daily. If the drug is administered as recommended, parents must buy at least 2,700 capsules at a cost of Rs 12,775 per year. Claims of the drug’s efficacy include the treatment of sickle cell anaemia, stroke and vertigo. In Britain, Piracetam is permitted for use in just a single indication, a rare disorder called cortical myoclonus, and only as an adjunctive therapy. Its use is contraindicated for adolescents under the age of 16. An editorial in the July 2005 issue of MIMS India points out that “the drug is contraindicated in hepatic and renal impairment, during pregnancy and lactation. It is to be used cautiously in (the) elderly. Its side-effects include: diarrhoea, weight gain, insomnia, nervousness, depression, hyperkinesis and rash. It can interact with warfarin and result in bleeding. Piracetam is not marketed in the United States”.

The same MIMS India editorial notes that buclizine is promoted as an appetite stimulant. The drug is not commercially available in the US and is restricted worldwide for treatment of migraine in combination with analgesics. Internationally reported adverse effects include drowsiness, blurred vision, diarrhoea, difficulty in passing urine, dizziness, dryness of mouth, tachycardia, headache, nervousness, restlessness, hallucinations, skin rash and upset stomach. Bottles of buclizine in India do not contain either the package insert or the patient information leaflet.

E Merck found that the Government of India’s price control on its Vitamin E medicine Evion, selling some Rs 35 crore, was getting uncomfortable: the National Pharmaceutical Pricing Authority (NPPA) had placed Vitamin E under the Drugs Price Control Order. The NPPA fixed price (inclusive of all taxes) was Rs 9.20 for Vitamin E 200 IU and Rs 14.82 for 400 IU, for a 10-capsule strip. In 2009, E Merck found a good way to get out of this jam: it added wheatgerm oil and some omega fatty acids and called it a dietary supplement, thereby escaping the price control order -- dietary supplements are not drugs according to one interpretation of the law (not true, if you go by the definition of a ‘drug’ in the Drugs and Cosmetics Act of India). The new dietary supplement is made under licence of the Prevention of Food Adulteration Act, reserved for food products like achars and masala powders and jams. The new price of the ‘improved’ product: Rs 60 for a 10-capsule strip. Other companies routinely do this by tweaking their ingredients to escape price control. Lost in the brouhaha is whether Vitamin E has any role as a drug or as a dietary supplement, especially at the dosages indicated, and whether it should have been licensed in the first place by the Drugs Controller General of India (DCGI).

Vaccines: Products in search of a market

Ever since hepatitis B vaccines started being made by Indian companies, starting with Shanta Biotech of Hyderabad, the classes of people who ‘need’ this vaccine have been expanding; the Ministry of Health and Family Welfare would have us believe that it is a bigger problem than AIDS. India now has a glut of hepatitis B vaccine manufacturers -- all in search of a market -- and some are on the verge of closing. They have succeeded in convincing policymakers that the vaccine must be given to all newborns by including it in the National Immunisation Programme. The business media have gleefully reported this as a “shot in the arm” for the ailing vaccine industry.

Among the other vaccines knocking on the door is the HPV (Human Papilloma Virus) vaccine advocated as a tool to fight cervical cancer, which is linked to HPV. In 2009, two “demonstration projects” of the HPV vaccine, collaborations between the government and PATH International, were launched in Gujarat and Andhra Pradesh. In April 2010, they were shut down following reports of unethical practices. The vaccine is known to be effective only against lesions caused by specific HPV types; its known protection against HPV is only for five to six years though it is promoted for lifelong immunity; protection against cervical cancer can only be known in 30-40 years, which is how long it takes for cervical cancer to develop; it is expensive -- Rs 9,000 for three shots -- with possible booster shots later. Does this make sense in a public health system that allocates Rs 12.50 per capita for government health insurance?  

Merck went one step further, advocating mandatory vaccination. Women In Government (WIG), a recipient of Merck funding, has introduced Bills in 20 US states, in one case writing the legislation, in another case getting an executive order issued requiring vaccination for all girls entering the sixth grade, unless parents opt out. If Merck’s Gardasil becomes routine, the $360 course will generate annual sales of $3.2 billion by 2010.

Charlotte Haug makes a very important point relevant to the introduction of all new drugs, vaccines included, in her 2009 article in the Journal of the American Medical Association,‘The Risks and Benefits of HPV Vaccination’: “When do physicians know enough about the beneficial effects of a new medical intervention to start recommending or using it? When is the available information about harmful adverse effects sufficient to conclude that the risks outweigh the potential benefits? If in doubt, should physicians err on the side of caution or on the side of hope? These questions are at the core of all medical decision-making. It is a complicated process because medical knowledge is typically incomplete and ambiguous. It is especially complex to make decisions about whether to use drugs that may prevent disease in the future, particularly when these drugs are given to otherwise healthy individuals. Vaccines are examples of such drugs, and the Human Papilloma Virus (HPV) vaccine is a case in point… When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit. Patients and the public logically expect that only medical and scientific evidence is put on the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed. The balance will also tilt if the adverse events are not calculated correctly.”

Ghostwriting

No man but a blockhead ever wrote, except for money. -- Samuel Johnson, 1709-1784

Premarin and Wyeth

On August 5, 2009, the New York Times was one of several newspapers across the United States reporting that Wyeth Pharmaceuticals engaged a medical writing company to produce 26 articles from 1998 to 2005 pushing Premarin as Hormone Replacement Therapy (HRT) in women. The work was ‘outsourced’ to Design Write that employed writers to write them and forward them to top experts, mostly academics in obstetrics and gynaecology, who looked at them, okayed them with minor changes and submitted them to journals under their own names. That Wyeth was involved in funding the articles was not of course mentioned.

Ghostwritten articles are read by physicians who take them as independent proof that the companies’ drugs are safe and effective. The company’s attorney acknowledged that the articles were part of a marketing effort, but said that they were also fair, balanced, and scientific. Wyeth, the world’s No 12 pharmaceutical company by sales, is being bought this fall by No 1 drug maker Pfizer.

Rofecoxib and Merck

Merck did a lot to promote rofecoxib. It suppressed data on the drug’s adverse effects, especially the increased risk of heart attacks and possible death. And it refused to withdraw the drug when it should have. Part of Merck’s “marketing” efforts were supplanted by ghostwriting, according to Joseph Ross, a doctor at Mount Sinai School of Medicine, New York, who, with his colleagues, scrutinised 250 documents relating to rofecoxib created between 1996 and 2004, released by Merck. Ross and his co-authors conclude, in a 2008 article in JAMA: “This case study review of industry documents demonstrates that clinical trial manuscripts related to rofecoxib were authored by sponsor employees but often attributed first authorship to academically affiliated investigators who did not always disclose industry financial support. Review manuscripts were often prepared by unacknowledged authors and subsequently attributed authorship to academically affiliated investigators who often did not disclose industry financial support.”

Fake journals

Merck Sharpe & Dohme (Australia) (MSD[A]) went one step ‘better’: it published an entire fake journal called the Australasian Journal of Bone and Joint Medicine, paying an undisclosed sum to Elsevier to produce several volumes of a publication that had the look of a peer-reviewed medical journal but contained only reprinted or summarised articles, most of which presented data favourable to Merck products, with no disclosure of company sponsorship (‘Merck Published Fake Journal’; posted by Bob Grant on http://www.the-scientist.com/blog/display/55671). “I’ve seen no shortage of creativity emanating from the marketing departments of drug companies,” Peter Lurie, deputy director of the public health research group at the consumer advocacy non-profit Public Citizen, said after reviewing two issues of the publication. “But even for someone as jaded as me, this is a new wrinkle.”

George Jelinek, an Australian physician and long-time member of the World Association of Medical Editors, commented that the “average reader” (presumably a doctor) could easily mistake the publication for a “genuine” peer-reviewed medical journal. “Only close inspection of the journals, along with knowledge of medical journals and publishing conventions, enabled me to determine that the journal was not, in fact, a peer-reviewed medical journal, but instead a marketing publication for MSD(A).”

He also stated that four of the 21 articles featured in the first issue he reviewed referred to Fosamax. In the second issue, nine of the 29 articles related to Vioxx, and another 12 to Fosamax. All of these articles presented positive conclusions regarding the MSD (A) drugs. “This is straightforward marketing,” he said.

Ghostwriting in medicine is clearly unethical. Dr Richard Smith, former editor of the BMJ and former chief executive of the BMJ Publishing Group, admitted in a 2005 article in PLOS Medicine: “We are being hoodwinked by the drug companies. The articles come in with doctors’ names on them and we often find some of them have little or no idea about what they have written,” he wrote. “When we find out, we reject the paper, but it is very difficult. In a sense, we have brought it on ourselves by insisting that any involvement by a drug company should be made explicit. They have just found ways to get round this and go undercover.”

“Articles in medical journals,” says S Sismondo, also in PLOS Medicine,in 2007, “have real effects upon physician prescribing behaviour, which is why pharmaceutical companies invest so much in their publication. Journal articles are heavily used in detailing, to validate claims and rebut worries. Even independent of detailers, responsible physicians and medical researchers search the literature to gather evidence about the best treatments. Published scientific articles are the sources of medical information with the highest authority. Systematic reviews and meta-analyses almost all start with the published literature -- so even fully independent reviews are influenced by ghostly activities. Therefore, the ghost management of journal articles is a step in the intervention into medical practice.”

Ghostwriting befuddles the truth. Psychiatrist Daniel Carlat comments on his blog: “As with baseball players on steroids, when companies pour marketing money into ghostwriting campaigns, they change the rules of the academic game. The playing field is no longer level; the drug company’s version of the truth gains the upper hand. Sometimes, their truth really is the truth, but sometimes it’s a carefully crafted lie. Sorting it out is difficult even for physicians who specialise in the area being written about. It’s essentially impossible for the average generalist physician, to say nothing of patients who did not have the advantage of attending medical school.”

Concluding remarks

Disease-mongering and ghostwriting are two sides of the same coin. In an ideal world these things ought to be corporate crimes of the highest order. They involve perjury as much as playing with people’s lives, giving false hope by selling dishonest cures. That companies do such things is probably to be expected. That doctors and medical professors should aid and abet is a crime against humanity -- one that is likely to increase with medical college seats being retailed for Rs 1 crore and more in India. This is another horror against which even activists do not seem to be raising their voice.

(This article draws upon material from (The Revised) A Layperson’s Guide to Medicines. LOCOST, Vadodara, 2006; Ray Moynihan and Alan Cassels: Selling Sickness: How The World’s Pharmaceutical Companies Are Turning Us Into Patients. New York: Nation Books, 2005; MIMS India various issues, PLOS Medicine, 2005)

(S Srinivasan is Managing Trustee, Low Cost Standard Therapeutics (LOCOST), a non-profit and small-scale pharma in Vadodara)

Infochange News & Features, December 2010