by Dr.Harald Wiesendanger– Klartext
What the mainstream media is hiding
Using medicines “off-label” outside their approval often makes medical sense, sometimes even necessary. However, it is always highly risky – and extremely lucrative. Encouraging doctors to do this opens up a “huge deal for manufacturers, which includes targeted disinformation,” as a former pharmaceutical executive admits.
When authorities approve a new drug, it is always only for a specific area of application: a disease, a symptom, or a group of people – for example, for acute pain in adults. It is also determined how it has to be administered – for example, as a tablet, as a tincture, or as an injection under the skin – how it is to be dosed, and how long it is to be used. For each application applied, the pharmaceutical company must submit study results showing that the proposed application is effective and safe.
In practice, however, a drug also proves to be helpful for indications or patient groups other than those originally intended. The pharmaceutical company could then also apply for approval for this. Because this procedure is time-consuming and expensive, manufacturers often do without it. So it happens that doctors use many medicines “off label” contrary to what is stated in the package insert – under certain conditions, for example, when an unapproved drug has proven itself for this purpose, such as an antiepileptic for migraine, an antidepressant for an anxiety disorder – or when an illness cannot be adequately treated with approved medication.
In principle, every doctor is free to use off-label products. He should even opt for it if he believes the drug in question is the best treatment option for a particular patient. However, if serious side effects occur, the manufacturer is not liable, but he himself.
That’s the theory. It sounds reasonable, and it is, as long as medical considerations alone decide on off-label applications.
Targeted disinformation for profit
But from the manufacturer’s point of view, profitability counts: Every expansion of application areas increases sales, and every hesitation reduces them.
And this is also what the pharmaceutical representative is concerned with when he visits the doctor. He expends a great deal of energy on incitements to use drugs in a risky manner outside of the area for which they are approved. (1) Because off-label use opens up a “huge business that includes targeted disinformation” for pharmaceutical companies, as a former Eli Lilly CEO admits. (2) In many medical fields, especially in pediatrics, geriatrics, oncology, and psychiatry, the majority of drugs are used off-label – an average of 40 to 60 percent of all prescriptions. (3)
However, because treating physicians can be held accountable for any side effects in such cases, many people hesitate. In order to loosen this brake, well-trained pharmaceutical representatives always keep suitable recommendations from well-informed “experts” and specialist societies as well as reprints of acceptable “scientific studies” ready to hand in their briefcases.
Admittedly, it is now expressly forbidden to advertise off-label applications, even in the USA. Nevertheless, large pharmaceutical companies repeatedly accept enormous fines, sometimes in the billions, in order to test and routinely exceed the limits of these legal regulations. GlaxoSmithKline took the lead in July 2012 with a $3 billion fine. Apparently, it pays off.
Therapeutic blind flight with unsuspecting guinea pigs
Millions upon millions pay for it with their health, even their lives. For example, feeding antipsychotics off-label to older people with dementia “knowing full well that they can lead to heart attacks and strokes and sudden death is nothing more than euthanasia,” as the Wall Street Journal denounces. (4)
Even more shameful are many off-label prescriptions of psychiatric drugs for children. “The paradoxical reality is: the smaller and sicker the child, the less often it gets an officially approved drug,” writes medical journalist Martin Lindner about the therapeutic blind flight with unsuspecting guinea pigs. “Pediatricians in private practice use 10 to 30 percent of the drugs they prescribe outside the market license. In children’s hospitals, the proportion increases to around 50 percent. And in neonatal wards, up to 90 percent of the substances can be administered off-label. (…) A recent study in almost 40 French pediatric practices confirms that off-label treatment increases the rate of side effects, sometimes more than three times that of approved therapy.” (5) It remains to be seen that the benefit will be multiplied to the same extent of proof.
An eye opener: the Cytotec scandal
The Cytotec scandal at the beginning of 2020 made it clear to anyone who wants to see how extremely dangerous off-label use can be. Pfizer’s gastric protection against ulcers officially disappeared from the market, at least in Germany, in 2006. Nevertheless, every second German maternity hospital continued to use it (6) because it had turned out by chance that the active ingredient misoprostol promotes labor quite reliably. However, Cytotec was not approved for this at all, especially not in the widespread, supposedly tried and tested dosage, which in the delivery rooms was often two to four times higher than the value of 25 micrograms recommended by the World Health Organization. In several cases, this led to serious complications during childbirth: the uterus ruptured, a “squall of labor” set in, babies were born with brain damage, and mothers and newborns died.
No authority had warned against it; none had intervened. The import of Cytotec was only stopped in April 2021. (7)
Neurontin: an antiepileptic for almost everything
When it comes to off-label business, big pharma is always guaranteed to pay off – even if, as an exception, breaches of the law are draconically sanctioned, as in the case of Neurontin. (8) The blockbuster with the active ingredient gabapentin was only approved for treatment-resistant epilepsy. Nevertheless, Pfizer advertised it for no fewer than 48 other indications – including migraines and other pain conditions, ADHD, restless legs syndrome, bipolar disorders, and alcohol and drug addiction. To do this, the company used manipulated and incompletely published data from studies that it had sponsored itself. (9)
Of course, Pfizer did not rely solely on the powers of persuasion of its pharmaceutical representatives. Bringing Neurontin to the public off-label was the primary purpose of so-called “further education” events, at which handsome fees sometimes flowed for the speakers and the participating doctors. They were lured by luxury trips to Florida, Hawaii, or the Olympic Games, among other things. (10) Anyone who produced a particularly large number of Neurontin prescriptions was allowed to act as a top-paying speaker or act as a “consultant.” Money also flowed to doctors who lent their names to articles in which ghostwriters on Pfizer’s services “proved” how fabulous Neurontin works beyond its licensing limits. (11) Renowned opinion leaders in mainstream medicine – including university department heads, heads of research programs, and clinical departments – raked in princely rewards for speaking up about off-label prescriptions, asking and receiving between $10,250 and $158,250. One-handed in a whopping $308,000 for eloquently promoting Neurontin at conferences. (12)
In 2004, to avert impending indictment, Pfizer admitted to violating the law and paid a fine of $430 million (13) – a paltry figure compared to the $2.7 billion the company made with Neurontin in 2003 alone; a year later it was $3 billion. (14) Around 90 percent of sales came from off-license applications. (15)
Abuse of freedom of therapy
The pill industry cleverly takes advantage of a professional privilege of the doctor: his freedom of therapy. Nobody can dictate how he should be treated. He alone chooses and decides how to help. He is always primarily committed to the individual patient, whose peculiarities he must take into account to the best of his knowledge and belief; he may also have serious, well-founded misgivings about a common practice.
But freedom does not mean arbitrariness. A doctor is subject to the duty of care; he must be guided by specialist medical standards and constantly undergo further training so that he remains up to date with the latest medical knowledge. Drug manufacturers are more than happy to help him with this: Shouldn’t a doctor who conscientiously explores therapy options take note of the grandiose advantages of drug XY, its pleasantly harmless profile of side effects, how pharma-financed courtesy studies and specialist articles ordered by paid desk workers fool him? Wouldn’t it be profoundly unethical to deny a suffering person seeking help the tremendous opportunities that the drug opens up for them? Isn’t a physician neglecting his continuing education responsibilities by ignoring the very latest pharmaceutical breakthroughs, the latest breakthrough pill innovation?
Manageable liability risk
Doctors indeed take considerable risks when they use medicines for indications for which they are not approved: they are liable for damage caused by the medicine. However, liability only applies if it can be proven that he has failed to comply with the obligations mentioned. Drug manufacturers provide him with the necessary “evidence” that he has fulfilled them: by manipulating studies, a corrupted trade press, training, and further education institutions brought into line, bought opinion leaders and relevant bodies on the “state of research” determining the relevant “evidence”. . Big Pharma is using a clever dual strategy to eliminate medical scruples about off-label therapies: On the one hand, it gives doctors “evidence-based” reasons to exceed approval limits. On the other hand, she provides him with the necessary alibis in case something goes wrong.
Off-label also saves manufacturers billions in costs. Why start expensive and lengthy clinical trials when the preparation has long “proven” itself in everyday use?
(Harald Wiesendanger)
Remarks
More in Harald Wiesendanger: The health care system – how we see through it, survive and transform it, chap. 6: “Trained demigods” and chap. 7 “Insatiable Renters.”
1 A. Fugh-Berman/S. Ahari: “Following the script: how drug reps make friends and influence doctors,” PLoS Medicine 4 (4) 2007: e150; M. A. Steinman/G. M. Harper u.a.: “Characteristics and impact of drug detailing for gabapentin”, PLoS Medicine 4 (4) 2007: e134; A. F. Shaughnessy/D. C. Slawson/J. H. Bennett: “Separating the wheat from the chaff: identifying fallacies in pharmaceutical promotion,” Journal of General Internal Medicine 9/1994, S. 563–568.
2 John Virapen: Nebenwirkung Tod, 5. Aufl. 2009, S. 193.
3 Bernadette Tansey: “HARD SELL: How Marketing Drives the Pharmaceutical Industry “(2005), www.sfgate.com/health/article/HARD-SELL-How-Marketing-Drives-the-2676193.php, abgerufen am 25.11.2016.
4 Barbara Martinez/Jacob Goldstein: “Big Pharma Faces Grim Prognosis, “Wall Street Journal, 6.12.2007.
5 Martin Lindner: „Versuchskaninchen“, Die Zeit Nr. 36, 31.8.2006.
6 https://projekte.sueddeutsche.de/artikel/gesundheit/im-wehensturm-e688113/?reduced=true; https://www.br.de/nachrichten/deutschland-welt/geburtseinleitung-aerzte-geben-gefaehrliche-tablette,Rq6JTvb, abgerufen am 12.2.2023.
7 tagesschau.de: Importstopp für umstrittenes Medikament Cytotec, https://www.tagesschau.de/investigativ/br-recherche/cytotec-importstopp-101.html, abgerufen am 3. April 2021. Im Cytotec-Fall war es ausnahmsweise der Hersteller selbst, der die Notbremse zog: Vom Markt genommen hatte Pfizer das Medikament mit der Begründung, der “Missbrauch” sei zu hoch.
8 C.S. Landefeld/M.A. Steinman: “The Neurontin Legacy – Marketing through Misinformation and Manipulation,” New England Journal of Medicine 360/2009, S. 103-106. Auszug; M.A. Steinman u.a.: “Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents”, Annals of Internal Medicine 145 (4) 2006, S. 284-293. Volltext.
9 S.Swaroop Vedula u.a.: „“Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use”, New England Journal of Medicine 361/2009, S. 1963-1971; arznei-telegramm 39/2008, S. 121; https://www.iqwig.de/veranstaltungen/2009-11-27_becker-brueser_objektive_forschung_ist_nicht_moeglich.pdf
10 Bernadette Tansey: “Huge penalty in drug fraud: Pfizer settles felony case in Neurontin off-label promotion, “San Francisco Chronicle 14.5.2004
11 M. Petersen: “Suit says company promoted drug in exam rooms, “New York Times 15.5.2002; Marcia Angell: The Truth about the Drug Companies: how they deceive us and what to do about it, New York 2004.
12 M. Petersen: “Suit says company promoted drug in exam rooms, “New York Times 15.5.2002.
13 B. Tansey: “Huge penalty in drug fraud, “a.a.O.
14 http://forum-gesundheitspolitik.de/artikel/artikel.pl?artikel=1489
15 B. Tansey, a.a.O.; O. Harris: “Pfizer to pay $430 million over promoting drug to doctors “, New York Times 14.5.2004; Jeannev Lenzer: “Pfizer pleads guilty, but drug sales continue to soar, “British Medical Journal 328/2004, S. 1217.
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This text is part of a series of articles with the following additional contributions:
1) Trained demigods – How doctors become drug dealers
2) Visit from the Rep – Mendacious Friendship based on the script
4) Off-label – Breaking boundaries as routine
5) Bought observer – the doctor as a “researcher.”
6) Well kicked – When doctors let themselves be greased
7) “As you do to me, so do you” – reciprocity as the secret of success
8) Softened – education and training as brainwashing
9) Insatiable Renters – The uncanny power of paid opinion leaders
10) Among Gorillas – Silverbacks call the shots
11) As KOL to the Golden Nose – Why “Key Opinion Leaders” have taken care of it
Off-label use, off-label, drug approval, Neurontin, Gabapentin, Cytotec, Cytotec scandal, Freedom of therapy, Harald Wiesendanger, Medical liability