Sex, Lies and Pharmaceuticals

The merging of marketing and medical science : female sexual dysfunction

As the search for the so-called ‘Pink Viagra’ continues, controversy surrounds the nature of the medical ‘condition’ such a pill would treat.

  • Do women with a low libido really have a disease called ‘hypoactive-sexual desire disorder’?
  • Does it really affect one-in-ten women as drug companies claim?

There’s already a marketed treatment for HSDD in the form of a pill called Addyi, a drug whose 2015 FDA approval came with intense debate over whether sexual desire was indeed a medical issue. Addyi has since become a commercial nonentity, in large part because women are restricted from drinking alcohol before taking it. The controversy around the drug’s approval faded along with its meager sales.

But bremelanotide, which promises a similar effect with fewer side effects, has rekindled the conversation around whether sexual desire can be a matter of pharmaceutical science.

Continue reading on stat news.

In an article in the BMJ almost 10 years ago I described the making of female sexual dysfunction as the freshest, clearest example of the “corporate sponsored creation of a disease.”1 Looking back over the past decade, it has become clear that drug companies have not simply sponsored the science of this new condition; on occasions they have helped to construct it. Corporate employees have worked with paid key opinion leaders to help develop the disease entity; they have run prevalence surveys to portray it as widespread; and they helped create the measurement and diagnostic instruments to persuade women that their sexual difficulties deserve a medical label and treatment. Drug marketing is merging with medical science in a fascinating and frightening way, raising questions about whether a new approach to defining diseases is warranted.

Continue reading on the BMJ.

Condition branding is a marketing technique in which companies develop conditions concurrently with developing drugs; examples include gastro-oesophageal reflux disease, premenstrual dysphoric disorder, social anxiety disorder, erectile dysfunction and hypoactive sexual desire disorder. Although it is illegal for pharmaceutical companies to market drugs prior to regulatory approval, there are no restrictions on marketing diseases, and industry seeks to establish a disease state in the minds of clinicians years before an expected drug launch. Continuing medical education (CME) courses are an important part of promotion prior to drug approval and have become a key marketing tool for increasing clinician receptivity to new products. We systematically identified 14 free, internet-based, industry-funded, accredited CME modules on hypoactive sexual desire disorder in women which came out before a new drug, flibanserin, was being considered for regulatory approval in the USA. Common themes in these modules included the following: Hypoactive sexual desire disorder is common, underdiagnosed and can have a profound effect on quality of life. Women may not be aware that they are sick or distressed. Simple questionnaires can assist clinicians in diagnosing the disorder. It is problematic that there are medicines available to treat sexual problems for men but not women. In fact, there is no scientifically established norm for sexual activity, feelings or desire, and there is no evidence that hypoactive sexual desire disorder is a medical condition. Hypoactive sexual desire disorder is a typical example of a condition that was sponsored by industry to prepare the market for a specific treatment.

Continue reading on the BMJ.

Chronic use of tramadol after acute pain episode: cohort study

Tramadol use is associated with a higher risk of prolonged opioid use in patients with an acute episode of pain compared with other short acting opioids, finds new research

2019 Study Abstract

Objective
To determine the risk of prolonged opioid use in patients receiving tramadol compared with other short acting opioids.

Design
Observational study of administrative claims data.

Setting
United States commercial and Medicare Advantage insurance claims (OptumLabs Data Warehouse) January 1, 2009 through June 30, 2018.

Participants
Opioid-naive patients undergoing elective surgery.

Main outcome measure
Risk of persistent opioid use after discharge for patients treated with tramadol alone compared with other short acting opioids, using three commonly used definitions of prolonged opioid use from the literature: additional opioid use (defined as at least one opioid fill 90-180 days after surgery); persistent opioid use (any span of opioid use starting in the 180 days after surgery and lasting ≥90 days); and CONSORT definition (an opioid use episode starting in the 180 days after surgery that spans ≥90 days and includes either ≥10 opioid fills or ≥120 days’ supply of opioids).

Results
Of 444 764 patients who met the inclusion criteria, 357 884 filled a discharge prescription for one or more opioids associated with one of 20 included operations. The most commonly prescribed post-surgery opioid was hydrocodone (53.0% of those filling a single opioid), followed by short acting oxycodone (37.5%) and tramadol (4.0%). The unadjusted risk of prolonged opioid use after surgery was 7.1% (n=31 431) with additional opioid use, 1.0% (n=4457) with persistent opioid use, and 0.5% (n=2027) meeting the CONSORT definition. Receipt of tramadol alone was associated with a 6% increase in the risk of additional opioid use relative to people receiving other short acting opioids (incidence rate ratio 95% confidence interval 1.00 to 1.13; risk difference 0.5 percentage points; P=0.049), 47% increase in the adjusted risk of persistent opioid use (1.25 to 1.69; 0.5 percentage points; P<0.001), and 41% increase in the adjusted risk of a CONSORT chronic opioid use episode (1.08 to 1.75; 0.2 percentage points; P=0.013).

Conclusions
People receiving tramadol alone after surgery had similar to somewhat higher risks of prolonged opioid use compared with those receiving other short acting opioids. Federal governing bodies should consider reclassifying tramadol, and providers should use as much caution when prescribing tramadol in the setting of acute pain as for other short acting opioids.

Dealing with strategies used by industry to influence scientific evidence

Commercial interests, transparency, and independence: a call for submissions

Help the move towards independence from commercial interests

A decade ago the US Institute of Medicine (IOM) issued a landmark report on conflicts of interest in research, medical education, and practice.1 Highlighting benefits of collaborations between physicians, researchers, and companies to develop new products that can improve health, the report also raised substantial concerns that extensive financial ties could unduly influence professional judgments. It concluded these financial conflicts of interest could jeopardise the integrity of science, the objectivity of education, the quality of care, and public trust in medicine. The report recommended more research on conflicts of interest, improvements in transparency, and greater independence from industry.

Today we announce plans for a stream of BMJ content to revisit these concerns and ask you to join us. A key aim is to identify and respond to commercial influences on health and healthcare, to understand under what circumstances involvement with industry is truly necessary. Where it is not necessary, we want to forge a new independence from those who make and sell products, to strengthen trust in how evidence is produced and disseminated, and to drive more rational and safer use of drugs, devices, diagnoses, and data in the public interest.

Key Points

  • Problematic relationships
  • The BMJ’s response so far
  • Call for submissions

Read

Scottish government rejects “Sunshine Act” legislation on searchable database of industry payments

A lost opportunity to have transparent information on improper financial relationships between industry and healthcare professionals

Abstract

“In February, the Scottish government formally rejected a petition to introduce legislation that would have created a searchable record of all payments to healthcare professionals from the pharmaceutical and medical device industries.

“Sunshine” legislation has been enacted elsewhere, including in the US, Australia, and Japan, and there are voluntary efforts in the UK, Germany, and Canada.

The decision is a lost opportunity for Scottish citizens to have transparent information on the financial relationships between industry and their doctors and other healthcare professionals.”…

Read Kept in the dark: Scotland rejects “sunshine” legislation, on The BMJ, 29 March 2019.

Read Scotland rejects “sunshine” legislation on searchable database of industry payments, on The BMJ, 29 March 2019.

Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses

hrHPV testing with an appropriate assay offers a promising new strategy that could increase population coverage substantially

What is already known on this topic

  • Tests performed on self samples are less sensitive and less specific than tests performed on clinician samples when using a high-risk human papillomavirus (hrHPV) assay based on signal amplification
  • Response rates for hrHPV testing are higher for self sampling kits than for conventional invitations

What this study adds

  • Tests performed on self samples are similarly sensitive and slightly less specific than tests performed on clinician samples when using a hrHPV assay based on polymerase chain reaction
  • Response rates for hrHPV testing continue to be higher for self sampling kits than for conventional invitations

2018 Study Abstract

Objective
To evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women.

Design
Updated meta-analysis.

Data sources
Medline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review).

Review methods
Accuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women.

Results
56 accuracy studies and 25 participation trials were included. hrHPV assays based on polymerase chain reaction were as sensitive on self samples as on clinician samples to detect CIN2+ or CIN3+ (pooled ratio 0.99, 95% confidence interval 0.97 to 1.02). However, hrHPV assays based on signal amplification were less sensitive on self samples (pooled ratio 0.85, 95% confidence interval 0.80 to 0.89). The specificity to exclude CIN2+ was 2% or 4% lower on self samples than on clinician samples, for hrHPV assays based on polymerase chain reaction or signal amplification, respectively. Mailing self sample kits to the woman’s home address generated higher response rates to have a sample taken by a clinician than invitation or reminder letters (pooled relative participation in intention-to-treat-analysis of 2.33, 95% confidence interval 1.86 to 2.91). Opt-in strategies where women had to request a self sampling kit were generally not more effective than invitation letters (relative participation of 1.22, 95% confidence interval 0.93 to 1.61). Direct offer of self sampling devices to women in communities that were underscreened generated high participation rates (>75%). Substantial interstudy heterogeneity was noted (I2>95%).

Conclusions
When used with hrHPV assays based on polymerase chain reaction, testing on self samples was similarly accurate as on clinician samples. Offering self sampling kits generally is more effective in reaching underscreened women than sending invitations. However, since response rates are highly variable among settings, pilots should be set up before regional or national roll out of self sampling strategies.

Whereas accuracy of new combinations of assays and self sampling devices can be evaluated in a diagnostic setting, acceptance and participation should be shown locally in a screening setting before general roll out.

Helping patients choose wisely

New UK recommendations emphasise shared decision making

As the tree of overdiagnosis has grown, efforts have been made to trim the branches. Initiatives such as Preventing Overdiagnosis, Too Much Medicine, Slow Medicine aim to increase our understanding of how it manifests itself. Efforts such as Choosing Wisely are underway to affect policy and change patient expectations and to change well-entrenched medical practices.

Abstract

Overdiagnosis and overtreatment are common, harmful to patients, and expensive. Doctors and patients tend to overestimate the benefit and underestimate harm of interventions. Choosing Wisely is a medically led campaign focusing on engaging doctors and patients in decisions about potentially unnecessary medical tests, treatments, and procedures. It started in the US in 2012 and has now been taken up in 22 countries worldwide, including the UK.

Read the full text on The BMJ, 2018.

“Helping patients choose wisely”

This statement grandly assumes that patients have no wisdom. Whilst it might well apply to many patients, there are equally many who are very well aware and informed of the best course of action to be taken.

bm Patient Karyse Day’s response, 2018.

Focusing on overdiagnosis as a driver of too much medicine

“Ironically, even though it causes harm, the effects of overdiagnosis look like benefits. People with disease that is overdiagnosed do well because, by definition, their disease was non-progressive. They are “cured” when cure was not necessary in the first place. This creates a cycle that reinforces efforts leading to more overdiagnosis. “

Healthcare is in a tailspin as the rush to offer technology and services turns otherwise healthy people into concerned patients by identifying disease that is not destined to cause them harm.

Abstract

Why overdiagnosis is hard to spot and to explain to individuals

Overdiagnosis, sometimes known as “pseudodisease,” turns people into patients unnecessarily. It identifies deviations, abnormalities, risk factors, and pathologies that were never destined to cause harm (such as symptoms, disability, or death). Overdiagnosis causes anxiety and other negative consequences of labelling; it leads to wasted resources and side effects as a result of unnecessary treatment. Here we consider overdiagnosis in asymptomatic people. Overdiagnosis also occurs (and causes harm) in symptomatic individuals when expanded disease definitions overmedicalise unpleasant ordinary life experiences, but we do not consider it here due to distinct conceptual differences between the two in terms of driving causes and ability to identify overdiagnosis in individuals.

Real but elusive trigger of too much medicine

Overtesting and overtreatment can be identified in a given patient. There is a consensus based on solid evidence that a patient with low back pain but without specific neurological signs or deficits who undergoes magnetic resonance imaging of the spine…

… continue reading on The BMJ, 17 August 2018.

Image credit newlifefoundation.

Sodium Valproate Review : Who knew What and When ?

Cumulative meta-analysis gives extra insights

2018 Abstract

Sodium valproate is licensed in the EU for treating generalised, partial or other forms of epilepsy. It has also been used to treat bipolar disorder and to prevent migraine. In February of this year, the European Medicines Agency recommended that sodium valproate should not be used during pregnancy unless no other effective treatment is available, and that it must not be used in women able to have children, unless the conditions of a pregnancy prevention programme are met. These measures to protect women and their children are welcome, but we argue that they should have been instituted several years ago, as the evidence was clear as far back as 1990 that there were risks of congenital malformations in women exposed to valproate.

Our analysis shows the value of cumulative meta-analysis, which, in our view, should be performed as standard in systematic reviews when any concerns about harms arise during the use of medications. …

…, we consider that drug companies, journal editors, prescribers and systematic reviewers have all acted too late. We, therefore, consider that from 1990 individuals should have been offered the opportunity to switch to treatments with lower risks, where they existed, and given minimum effective doses of valproate if alternative treatments were not available or advisable. In the intervening years, many women’s children will have been harmed. Manufacturers and regulators should be responsible for ensuring that cumulative analyses are carried out as part of postmarketing risk management plans.

Air pollution exposed children with mental health problems

Association between neighbourhood air pollution concentrations and dispensed medication for psychiatric disorders in a large longitudinal cohort of Swedish children and adolescents

Abstract

Objective
To investigate associations between exposure to air pollution and child and adolescent mental health.

Design
Observational study.

Setting
Swedish National Register data on dispensed medications for a broad range of psychiatric disorders, including sedative medications, sleeping pills and antipsychotic medications, together with socioeconomic and demographic data and a national land use regression model for air pollution concentrations for NO2, PM10 and PM2.5.

Participants
The entire population under 18 years of age in 4 major counties. We excluded cohort members whose parents had dispensed a medication in the same medication group since the start date of the register. The cohort size was 552 221.

Main outcome measures
Cox proportional hazards models to estimate HRs and their 95% CIs for the outcomes, adjusted for individual-level and group-level characteristics.

Results
The average length of follow-up was 3.5 years, with an average number of events per 1000 cohort members of ∼21. The mean annual level of NO2 was 9.8 µg/m3. Children and adolescents living in areas with higher air pollution concentrations were more likely to have a dispensed medication for a psychiatric disorder during follow-up (HR=1.09, 95% CI 1.06 to 1.12, associated with a 10 µg/m3 increase in NO2). The association with NO2 was clearly present in 3 out of 4 counties in the study area; however, no statistically significant heterogeneity was detected.

Conclusion
There may be a link between exposure to air pollution and dispensed medications for certain psychiatric disorders in children and adolescents even at the relatively low levels of air pollution in the study regions. The findings should be corroborated by others.

Reference.

The Guardian press releases : here, here, here, here, here, here.

Identifying research evidence relevant to clinical practice

Identifying the evidence that matters, keeping up to date and applying evidence in practice is a significant challenge for busy clinicians

When the BMJ Evidence-Based Medicine Journal was launched, about 10,500 randomised trials were indexed on PubMed. Identifying the trials that affect practice has become harder: 20 years later, over 30,000 trials are published annually. If we focused purely on systematic reviews, we would face similar problems: over 19,000 systematic reviews were indexed on PubMed in 2017.

As a result, the BMJ EBM Journal has set out to identify, and focus on, the research evidence that provides definitive conclusions and research that confirms, refutes or improves current practice.

The EBM Journal has focused on two questions:

  1. does this research apply to the patients we see in practice?
  2. and what difference could this evidence make to my patient?

In doing so, the BMJ EBM Journal can remove a substantial amount of research that does not matter.

Read Introducing the EBM Verdict: research evidence relevant to clinical practice, bestpractice.bmj, 2019.