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An ethicist walks into a bar…

… it hits them in the shins, as they made no effort to step over it. Annoyed, they claim that the bar used to be lower, and if it’s to be raised then they must be the ones giving approval to do so.

I submitted a manuscript detailing efforts to expose three cases of medical research fraud and misconduct (a fabricated conclusion at odds with the data; a scam funded by NHMRC; and a buried trial of antidepressants in Heart Failure – using a drug that worsens HF) to three journals. It was rejected by Dr Sarah Edwards of ‘Research Ethics’; Dr Shamoo of ‘Accountability in Research’; and Israel, Allen & Thomson of ‘Research Ethics Monthly’. One case was conceded by the University HREC as a one-off mistake, all others stonewalled.

The Cochrane Collaboration claims to be impartial in their scrutiny of such, biased studies. For two years I’ve fruitlessly raised a concern that the Professor heading their Pain and Palliative Support group was on the Pfizer payroll, but after including evidence that two other groups include analyses by authors secreting industry sponsorship there was a response. Governance officer Veronica Bonfigli onsent the issue to the Integrity Editors.

That was six weeks ago.

Their gold standard is more apt a description of monetary reward, than of excellence.

Token displays of integrity are seen everywhere that collectives are formed to take responsibility for adherence – no worse an example then the Vatican. Altruistic priests, like committed doctors, are constrained by their hierarchy. Their walled city of committees provides cover for a multitude of sins.
I’m a novice, having learned only from my mistakes, failures of integrity. Inspiration comes from Padmasiri De Silva’s book, An introduction to Buddhist Psychology and Counselling: “The replacement of genuine moral reflection by procedures and protocols finally paralyses people’s capacity for moral reflection“. It’s a superb work, even though overladen with Pali (Sanskrit-like) terms – since many concepts haven’t an acceptable English translation.

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Sheeple

Right to terminate lives?

The sight of feral MAGA supporters taking to the streets in an attempted mass extinction event, protesting their constitutional right to dumb it down, has me musing on US vs Australian psyche. CoVID-19 new case rates here have dropped 9-fold after mandated stay-home ‘unless …..’, and we’re meekly compliant. However the USA’s outstanding effort to hold #1 spot in having the most fatalities isn’t world leadership to aspire to. Likewise, mandatory seatbelt laws beginning in 1970 were proven successful in dropping our roadtoll, whereas in 16 of 50 States Americans still can’t be pulled over by police for not wearing one.

There’s a flipside. Medication harms are hardly ever brought to our TGA’s attention by consumers, and the Database of Adverse Event Notifications (DAEN) is worthless. For the #1 worst drug for numbers of reported side-effects in the USA in 2015, Xarelto, the DAEN lists 123 Australian complaints for their beloved dying as a result of it. The US FDA site at fis.fda.gov is a simple dashboard, and shows 15,557 died – most bleeding from their arse. Bummer!

With a 13:1 population difference (and ignoring prescription rates for now), Americans are ten times more likely than ‘Strayans to cry ‘bloody murder’ at their doctor. For the choice to prescribe Xarelto is difficult to justify.

Old-school anti-coagulant warfarin, in use since 1954, and likewise clopidogrel, are each still prescribed three times as much as Xarelto in 2017, have a fraction the number of adverse events. They’re roughly 20 times safer, and even the newer alternative of Eliquis is killing Xarelto in the marketplace – but at a slightly lower rate in the hospitals. So why was an older friend suffering a leg clot just put onto Xarelto as first option? Lacking the transparency brought by Obama’s Sunshine Act, I can’t comment on whether pharmaceutical company sponsorship influences Australian Dr’s prescribing patterns. It’s fair to speculate that Johnson and Johnson had to adopt aggressive marketing tactics in order to overcome the hits to business from vaginal mesh implants, and opioid & Risperdal (anti-psychotic inappropriately promoted as a sedative in nursing homes) damage.

Partnered with Bayer in marketing Xarelto, J&J last year settled out-of-court for $USD775m for failing to adequately forewarn of bleeding risk.

*Disclaimer. The author didn’t even study biology at school, but a sense of smell for rat (o/dosed on warfarin?) developed doing a Master of Clinical Research at Pfizer’s partner Monash Uni.

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2014© Medscape staff surveyed physicians on ethical issues, finding less than half confessed to a weakness for a freebie. That’s encouraging to drug reps, since influencing just a few Key Opinion Leaders pays dividends. So long as the flock all think alike, this being exemplified by a disclosure. The practitioner failing to practice what he preaches!drugreps
Dr Justin Coleman boldly challenged pharma thru his official position with Royal Aust College of GPs, fronting a well-publicised ‘no reps’ in the surgery campaign which raised ire among his fellows. Seriously, who’d ever believe wealthy physicians could be bought with a Bic? A humour-laden registrar tutoring session blogged recently under ‘Uncertain Dealings’ raises doubts. “Thus, when a patient complains of a painful lower back, my eventual diagnosis, after a thorough history and examination, is ‘low back pain’…. And, as for assuming my intervention of massage or gabapentin directly causes the pain’s eventual resolution, well…call me Dr Doubt!” Bon mots over a patient suffering pain aside, this is revealing. Gabapentin is an anti-convulsant for epilepsy, which happens to also fix everything – if Pfizer’s offlabel marketing is to be believed. Fines for such of $430m in 2004, $142m in 2010, and $615m (including $325m class settlement) in 2014 were just incidental costs alongside their promotional budget. The best evidence from Cochrane states that less than half of those with postherpetic neuralgia or diabetic neuropathy will obtain pain relief. So uncertainty over cause leads to a stab (glad he didn’t become a surgeon) that the pain originates from damaged nerves, and an indirect consequence of a hundred Pfizer Aust pain presentations to doctors in the previous 6 months just happens to be a prescription for Neurontin. And a little rub down there, in case of a herniated disc perhaps.

There’s been 6 studies into gabapentin for nociceptive pain, ie hurting without malfunctioning nerves, and all the results were suppressed by the company. They weren’t published, because they were negative. This disturbed Kaye Dickerson sufficiently to inspire a 57 page dissertation on the gabapentin, with a few hundred pages of supporting appendices.
The white knight * can offer no other assistance, and how did this come to pass? A letter from Pfizer Aust in 2003 prefaces the corporate strategy – avoid offlabel fines by investing in more approval trials. Dawn Carroll was recruited by Pfizer in ’07 and co-authored an updated Cochrane review in ’10, which was surprisingly favourable to their products gabapentin and pregabalin for chronic pain. All up, she’s published 50 articles with the Pain & Palliative Support group of Cochrane’s Editorial boardmember Prof Andrew Moore. Moore’s 2014 article for Jnl of the American Medical Association, ‘Antiepileptic Drugs for Neuropathic Pain and Fibromyalgia’ confirms that marketing-based medicine penetrates everywhere: “The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain and the National Institute for Health and Care Excellence recommend gabapentin and pregabalin as first-line treatments for neuropathic pain. These results support the recommendations.”

The future holds little promise, since a check of registered ANZ Clinical Trials of gabapentin for bad backs tells us Pfizer is comparing gabapentin against pregabalin for sciatica – which won’t offer us much of a choice (they’re related drugs having identical mechanisms). The obvious difference is that pregabalin is more expensive – the fine for offlabel promotional bribery was double that of its stablemate, at $USD2.3bn

I’d ridiculed medicine’s adoption of the caduceus previously. Perpetually going in circles makes the ouroboros – the snake eating itself, a more appropriate motif.

*Justin claimed in a memo that his example was an ironic motif, because he campaigns against industry influence on prescribers such as for gabapentin.  I value his opinion on popular culture as an illustrative means, and intend to  incorporate same next month. But perhaps the somewhat more socially critical Southpark, than the sagely Gandalf.

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Framework or Façade?

Introduction. A decade ago the outlook for a diagnosis of HIV positive had turned, due to anti-retro viral drugs. Well-meaning folk were concerned that the therapy elevated cardiovascular risk, so a large multi-centre trial was initiated to record death rates if the drug were titrated to a minimal dosage.  The endpoint of interest was rarely achieved, since backing off therapy let the AIDS virus go viral. The job of burying the bodies was given to the biostatisticians.

Studies have found that 37% of statistics are made up on the spot….[Reliable source]
To explore manipulation of medical research, here’s a hypothetical. Investigators studying obesity and fitness in schoolchildren ensure that prior to athletic tests, carbohydrate loading is provided per specifications from endurance sports nutritionists. The broadly aged kids are given portions appropriate to their size, and field times adjusted for calorific energy levels. Remarkably, BMI had very little effect on athletic results. Heartened by this interventional study, the makers of V-Bomb (corn syrup based energy drinks) sponsor an observational report: Making An Impact – Zoom & Effort (or MAIZE) study. Parents supervised the event, where prior to the test V-Bomb was dropped off with family groups for optional consumption. This was a short run and block of a padded bag, measuring the force of collision. The greatest impacts were delivered by the largest consumers of the energy drink, and an outstanding effort by Georgie ‘Porgie’ P&P (participant privacy protected) saw him approached by the football coach for a fullbacker position.
ppt
I hope a laugh was scored at overriding commercial interest in a fictional scenario, but seriously wonder at the trust placed in our medications. We don’t believe that influence is applied to drug trials, since we haven’t been fully informed of the extent of sponsorship. Past editor of the British Medical Journal Richard Smith’s article ‘Is the pharmaceutical industry like the mafia?’ argues “… that drug companies are doing what is expected of them in maximising financial returns for shareholders, but doctors and academics are supposed to have a higher calling.”

Inspecting the integrity issues arising from ‘CD4+ Count–Guided Interruption of Antiretroviral Treatment’ in the New England Jnl of Med, Nov 2006 raises questions about ‘supposed to’. This example of misconduct is unclouded by any allegations of pharma interference – the medicos created a smokescreen all by themselves. Testing whether episodic use of antiretroviral drugs (ART) against HIV was safer in long term than continuous usage, the strategy’s disastrous results showed the opposite to a benefit  and the trial was stopped. But not because participants in Strategic Management of ART (SmART) were dying. It was stopped only once the hypothesis was proven false – the hazard ratio fell on the ‘bad luck old chap’ side of the line pictured here. The doctors kept waiting for cardiovascular results, but uncooperative participants kept snuffing it for another reason – AIDS. The end of the abstract’s results paragraph plays down the magnitude of the 2.6-fold worse risk, in that after adjusting for CD4+ and HIV counts the hazard confidence interval now nudged the 1.0 (no statistically significant risk) level. Sorry? The effect of the treatment strategy, after adjusting for the effects of the treatment (ART maintains CD4+ counts and inhibits virus growth) is supportive of the null hypothesis … this introduces another acronym, WTF!!! The second to fourth confidence range pictured in each of the three outcomes are these ‘fixed’ figures, shown alongside the true unadjusted (conveniently using a log scale, where the fourfold risk of “fatal or nonfatal opportunistic disease” just appears as a doubling). Another study finding: the more spin applied to the figures, the better they look. Thousands of lives were shortened, but after adjusting for the fact that everybody dies anyway no harm was done.

23 co-authors signed off on this article and NEJM editors have also been remiss, but worse is to come. The planned six-year trial was abandoned after four years due to the sixth meeting of the data safety monitoring board (DSMB) finally deciding that the strategy worsened, rather than improved outcomes. Look up Chart A of Figure 2 in the report to see that this was apparent after just a few months. A statistical power prediction of a result this bad gives the answer that only 35 unfortunate events would suffice to call it quits. A total of 2720 HIV-positive men and women were allocated to the risky treatment group, and left underdosed whilst the disease progressed. Furthermore there’s a page listing 712  SmART medicos who agreed to the study protocol, which minimizes the number of looks the independent DSMB takes at progress results (according to an O’Brien Fleming spend function*). But if a DSMB adheres to International Conference on Harmonisation guideline E9 by not discussing the interim analyses with SmART then those spend rules become void. The DSMB can investigate every event, confidentially. And when death is a primary outcome, why did it take four years instead of four months to call ‘whoops’? 2720-35/712= an average of 3.8 lives harmed per doctor. Hippocratic oath, WTF!

My next posts will move onto the half-hearted disclosure of conflict-of-interest problems, then will explore fabricated conclusions thereafter … standby.

* A biostatistical way of saying that it spoils the surprise for the researchers upon study conclusion.

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Bad medicine (Part 2)

Lyrica/pregabalin continued…… Integrity of research is maintained under an accord struck with journal publishers, whereby trial results will only ever be reported if the goal is declared upfront when the study is registered with a govt agency. This ensures inconclusive or negative results aren’t hidden in secrecy, and thus trial NCT00333866 in 2009 is open to scrutiny – a sponsor’s restrictive agreement on investigators publishing or discussing trial results notwithstanding. Under the leadership of Lynne Pauer (a Pfizer Director) 73 facilities worldwide randomly allocated fibro patients to either placebo control or else one of three dosages of pregabalin. 30% dropped out over the 14 weeks, and only the 450mg dosage yielded a statistically significant result in efficacy for pain. Paracetamol was allowed as a rescue therapy, surprisingly the amount needed for pain relief increased with higher dosages of pregabalin. Data from this and other trials was analysed by Oxford University who determined the Number Needed to Treat at 450mg to obtain one person benefiting by a moderate 30% reduction in pain intensity was eleven. On the other hand, worsening side-effects with increased dosage led a rheumy with a sense of humour to plot the Schwindel.

Pfizer has a patent thru’ to Dec 2018 on Lyrica however, and if all you have is a hammer then everything looks like a nail. American audiences are aware of their ad campaign which follows the “Here’s your answer, regardless of your problem” school of thought. Diabetic neuropathy? The ads announce “No worries”, although others are concerned about suicidality. And NonSignificant result study at 300mg dosing shows it’s every bit as good as placebo in reducing pain. whack-a-mole

Writing in the Medical Journal of Aust this year, rheumatologist Prof Rachelle Buchbinder complains that NationalHealth&MedicalResearchCouncil “funding is disproportionally low compared with the burden of these (musculoskeletal) conditions”. Her co-author Prof Chris Maher should impress then, in obtaining a $618,590 NHMRC grant for the PRECISE study trialing pregabalin as a treatment for sciatica. Coincidentally, The Age newspaper published on 24th July their promotional article against standard care claiming that: “This month the prestigious NEJM published a paper reporting that steroid injections are no more effective than a sham …”, but if you read Friedly and Jarvik et al’s report the placebo was lidocaine.  Yeah right, an anaesthetic is a sham control! Experts condemned the trial, writing: “This critical assessment shows that this study suffers from a challenging design, was premised on the exclusion of available high-quality literature, and had inadequate duration of follow-up for an interventional technique with poor assessment criteria and reporting.” Discouraging guided lumbar injections is pleasing to a Govt cutting health funding in 2015, since imaging is expensive. Pills can keep the pain at bay. 

PRECISE trial protocol cites Pfizer’s  Dr Zahava Gabriel on the cost-effectiveness for pregabalin, who previously participated in a team providing supposedly independent evidence with ‘A Systematic Review and Mixed Treatment Comparison of the Efficacy of Pharmacological Treatments for Fibromyalgia’ – whose conclusion “confirms the therapeutic efficacy of pregabalin”. The NHMRC’s funding submission includes the justification: “Currently there is limited, direct, high quality research to inform the use of pregabalin in the treatment of people with sciatica. A small prospective randomised trial of patients with chronic low back pain (n = 36), which included some patients with sciatica, suggested that pregabalin may produce a statistically significant reduction in back pain in the short term”. The cited pilot study by Romano & Mineo et al wasn’t placebo controlled – patients being allocated to consecutive periods on either pregabalin, an NSAID celecoxib, or both. The least improvement was shown by the pregabalin only group, so surely Maher’s colleague Prof Ric O’Day would endorse additional celecoxib therapy (especially after having served on Pfizer’s advisory committee)? Unless coming off-patent next year resulted in a commercial decision to dump Celebrex? A supposed risk of cox-2 inhibitors cardiovascular disease hasn’t been investigated, which makes Pfizer’s March 2014 contest against generic manufacturers in Court appear financially risky (tho’ rash judgements are rather clouded by memories of Vioxx corruption! 2015 update here suggests that 200mg is a safe dosage).

Money appears to be not a factor in NHMRC deliberations, otherwise $4.6bn in sales of Lyrica last year would have deemed that Pfizer themselves can reinvest to break a new market with backpain. Hopefully they’ll read other New England Jnl of Medicine articles before gifting in future. 

Regulatory compliance appears to have been taken to an all-time low within health research ….. obedience to industry! It also shows how hit and miss medicine is based on commerce rather than science – pregabalin having been developed as an anticonvulsant for epilepsy echoes Pfizer’s subsidiary Searle re-purposing of misoprostol (declared protective against ulcers by Dr Fred Silverstein & co) for inducing labour. A $70m birth injury litigation set a record, and spawned an industry for lawyers suing hospitals for off-label use of mistoprostol.

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Mud slinging (Part 1)

Listening is a fastrack to learning. Time spent with arthritis sufferers in Moree thermal pools informed me of the benefits of medicinal marijuana after hearing how an elderly couple inadvertently spent too long in a pungent smoke filled café at Nimbin. Indeed, the largest number of reviewers at fibromyalgia-reviews.com cast an overwhelmingly endorsing vote for the weed. The side-effects preclude living a normal life, however reality has always been overrated and opt-out for many. Winfried Häuser led an investigation into evidence-based interdisciplinary guidelines across Germany, Israel and Canada but cautiously advised undertaking research by clinical trial of cannabinoids before addressing licensing. Mineral springs or balneotherapy were recommended though, an idea which was extended by researchers at the University of Pisa who compared the short-lived relief of a thermal treatment with the enduring benefit of a mudbath, in the journal of Clinical and Experimental Rheumatology.

IMG_1745Bazzichi and Lucacchini et al didn’t rely on subjective opinion of symptoms, rather going so far as to apply salivary protein analysis to differentiate an improved therapy. Justification enough for a trip to the murky sulphurous pools of Ngawha in New Zealand – their ‘Doctor’ being pictured. Not only have this team listened to their patients’ stories, but they’re cognizant of expert skepticism and the demands of evidence base. To no avail unfortunately, since founder of the Arthritis Research Centre Prof Fred Wolfe in his fmperplex.com blog derides the study as about as useful as a Chianti/Riesling comparison… “Really! Does anyone really think that mud baths are a truly useful therapy for FM? What also caught my eye was all of the ‘sophisticated’ and expensive tests that were done and what it all costs.” A cost benefit analysis requires a crystal ball for evaluating future returns from the pioneering work in proteomic salivary analysis. Thus far it’s proven useful in distinguishing Sjogren’s syndrome from other sicca syndromes such as presented by fibromites.  Relief from this discomfort of dry mouth compounded by the nuisance of a runny nose (non-allergic rhinitis) is one of the attractions of guaifenesin as a treatment, besides its neurological effects. Again lampooned on fmperplex as “Quackery”, but another unfortunate discard of babe with the dirty bathing water. Arif Donmez and team from Istanbul Dept of Medical Ecology concede that their clinical trial of a balneotherapy course, showing a diminishing improvement during 9 months of followup may have been influenced by residual benefit of a break from the daily grind. Pain was objectively measured by inflicting it with a dolorimeter however, which would have erased pleasant memories! Ouch!!

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