Given pharmaceutical rep information is limited to approved product information, where is the harm in promoting it?

Legal promotion: the problem of overdiagnosis

Overdiagnosis can be defined as diagnosing a ‘disease’ which would never have caused symptoms or death in a patient’s lifetime. Overtreatment  is where a treatment is given which does not benefit the patient – in the case of medication, this always costs money, and usually entails some risk of harm.

Overdiagnosis and overtreatment are increasingly being recognised as significant problems, particularly in developed nations. (Hoffman, Welch) Commercial gain by suppliers of treatment is a key driver. (Moynihan)

In 2012, departing boss of the US Medicare and Medicaid system, Dr Donald Berwick, listed overtreatment as the first of five reasons for the extraordinary 20-30 percent of US health spending he estimates as ‘waste’—as in, it yields no benefit to patients.

The glaring problem with the theory—propounded by many—that seeing all the various reps keeps the doctor up to date with every therapy, is that not one of the reps is tasked with promoting a balanced viewpoint when it comes to avoiding overtreatment. Only the independent (non-pharmaceutical-sponsored) sources of information will routinely highlight patient scenarios where the harms of treatment equal or outweigh the benefits.

Pharmaceutical reps are commendably responsible when it comes to ‘contraindications’, discussing the group of patients for whom the drug is downright dangerous. But it is simply not their job to supply evidence around the far larger group of patients whose mild disease places them in the grey area, where benefits of medication are dubious, nil or negative.

 There exists a cut-off point on every disease spectrum, inevitably ignored by drug companies and often enough by doctors, where medications simply don’t help. At that point, they do nothing. Beyond that point, they actively harm. This is true almost by definition for every medical or surgical intervention. There is pressure from multiple sources—patient, doctor, pharma, specialist, media, disease-awareness campaigns, patient advocacy groups—to nudge this point towards the midline of the spectrum. This is true for diabetes, depression, ADHD, lipid levels, cardiac stents, and deficiencies of a host of replaceable substances including testosterone, oestrogen, and various vitamins, the trendiest of which, currently, is Vitamin D. 

Coleman

Doctors who largely rely on reps to keep up to date with the newest medication brands risk missing out on, or underestimating, information which is arguably more important to their patients: the latest evidence around where NOT to prescribe. It is the independent, unbiased sources which are more likely to highlight the dangers of ‘polypharmacy’ and the need to regularly consider ceasing (‘deprescribing’) medications, particularly in the elderly. (Colyer)

Illegal promotion: the problem of off-label marketing

It is illegal for pharmaceutical reps to promote drugs for conditions which are ‘off-label’ (not approved) and our section on proven misconduct outlines some examples where this type of illegal promotion has been proven in a court of law. The Propublica website (‘Journalism in the Public Interest’) provides many further instances. However, one might suspect that cases proven in court are merely a fraction of actual occurrences.

In Australia, the Medicines Australia Code of Conduct acts as a form of industry self-regulation. According to Norris et al. in a 2005 report for the World Health Organization, one difficulty is that in most countries, self-regulation by industry tends to be concerned with anti-competitive behaviour rather than curbing promotion.

When industrial associations draw up their codes of practice they deliberately make them vague or do not cover certain features of promotion to allow companies a wide latitude. Many misleading advertising tactics are good for business. As a result voluntary codes tend to be reactive, they lack transparency, they omit large areas of concern, and they lack effective sanctions. 

Norris

Besides the direct evidence of legal fines for off-label promotion, some indirect evidence of the problem comes from studies that, rather than attempting a broad sweep of the issue, delve deeply into one small area of drug promotion in instances where previously confidential documents become available. Let’s look at three examples:

 

Case Examples

1. Promoting olanzapine to the well

Spielmans obtained internal pharmaceutical company documents about one drug, olanzapine (Zyprexa), which is approved for treatment in schizophrenia. His analysis of 358 Lilly documents detailed a strategy of promoting the drug olanzapine in dementia (unarguably an off-label indication, and one in which olanzapine treatment is known to be harmful) and for hypothetical patient examples with mild symptoms which ‘clearly failed to meet diagnostic criteria for any recognised mental disorder’. (Spielmans)

GPs who believed in good faith that they should prescribe olanzapine in their patients similar to the hypothetical examples were directly harming their patients. Yet all the GP had done was listen to the ‘evidence’ of the visiting pharmaceutical reps. The reps themselves were simply following the instructions of their employer, presumably themselves believing that nothing they were doing was incorrect or unethical.

Yet no other, independent source of medication information was promoting olanzapine in this way, so therefore patients of GPs who routinely saw reps were potentially harmed, whereas patients of GPs who used independent sources for their education were not harmed in this way.

As an aside, at least partly due to its aggressive marketing, olanzapine is one of the most profitable medications in Australia, and according to a 2013 Grattan Institute report, our PBS pricing system means that we were locked into paying 64 times more for each tablet than would occur under an ideal system. (Duckett)

There is enormous financial incentive tempting a company to educate their reps to inappropriately encourage GPs and psychiatrists to broaden the market of patients, even if that means (in Spielman’s US study) promoting olanzapine off-label, to the detriment of patients’ health.

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2. Antidepressants and antipsychotics in children

Antidepressants and antipsychotics have restricted indications in children. A 2014 study by Larkin et al. looked at off label use of antipsychotics and antidepressants in children. As in Australia, it is not illegal for doctors to prescribe ‘off-label’ but it is illegal for pharmaceutical reps to try to persuade doctors to do so.

Larkin’s study tried to tease out if the decision to carry out off-label prescribing was based not on independent evidence, but on encouragement by pharmaceutical reps.

Larkin collected before-after prescribing data from 31 US academic medical centres that introduced policies limiting ‘pharmaceutical detailing’ by drug reps to their child and adolescent psychiatrists, from 2006-2009.

The authors conclude:

After the introduction of such policies, prescriptions for off-label use of promoted drugs fell by 11 percent, consistent with the ongoing presence of off-label marketing to physicians. Prescriptions for on-label use of promoted drugs fell by 34 percent after the adoption of the policies. Conversely, prescriptions for on-label use of nonpromoted drugs rose by 14 percent, and those for off-label use of nonpromoted drugs rose by 35 percent.

These results suggest that pharmaceutical sales representatives promoted drugs not approved for pediatric use and that policies that restrict detailing by those representatives reduced such off-label prescribing.

Our results suggest that in these classes of drugs, detailing influences physician prescribing more than FDA approval does. (Larkin)

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3. Saturation marketing of gabapentin

US litigation forced Pfizer to make available 8000 pages concerning its off-label promotion of Neurontin (gabapentin). This rare window into internal documents was examined by Steinman et al.

They found:

The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues.

Research and scholarship were also used for marketing by encouraging ‘key customers’ to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results.

Conclusion: Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin.

New strategies are needed to ensure a clear separation between scientific and commercial activity. (Steinman)

While we wait for rigorous external regulation, signing the ‘No Advertising Please’ pledge is a simple strategy to help an individual doctor separate commercially driven education from independent scientific education.

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