Taking the easy way out

If you torture the data long enough, it will confess…..Ronald Coase (economist)

Carole is backtracking from PostGrad qualifications in Coaching, to undertake an undergrad Psychology degree.  I’m overwhelmed by the depth of statistical expertise expected of her, and despite having a GradDip in Clinical Research I draw a blank on something called factor analysis. Psychologists doing investigations gather together factors which may be influential on the patient outcome, and search for interactions in the data. Medicine doesn’t do this. In fact post-hoc analyses are anathema. Data dredging – shame! The example often given is from 1988, in the Lancet, when studying the benefit of aspirin after a heart attack it was found that subgrouping by starsign significantly affected recovery. [Laughter 🙂 ]

Subgroups behaving badly

Subgroups behaving badly

Actually, this is worth thinking about. If you’ve been told since birth the behaviours expected from a Taurean, it’s quite possible you need additional counselling to subdue the inner beast. And not simply a different med dosage. But everyone except the doctors mines data nowadays. The social sciences statistical packages are being heavily adopted by business to glean profitability trends, most notably since IBM acquired SPSS.

All clinical trials have a single purpose, ie to test a hypothesis, even if multiple outcomes are considered and when multi-arm interventions (factors) are being tested (see Bonferroni). If the analysis isn’t declared upfront in the protocol, the ensuing report will be discredited by colleagues. Worthless even, since physicians’ distrust of their peer’s integrity leads to a presumption of bias – doing unethical selective analysis so as to claim ‘Eureka’ for something, anything! Earnest conferences churn out checklists for marking studies – GRADE, CONSORT, SPIRIT, PRACTIHC, STROBE, and even specialty specific guidelines such as PEDro (for Hispanic physiotherapists?). All seemingly ensuring transparency in the system, but somehow we’re forever growing the numbers of malcontents who claim that the regulatory oversight is broken.

Myself included. The problem arises from the cartel of institutional research, and I’ve written here often about our delusional confidence.  The investment in years to attain a medical qualification, followed by the personal sacrifice of a research-entitling doctorate  leaves medicos with little choice but to play the game. I don’t have evidence as to whether the psych’s datamining or the physician’s approach to test a hypothesis yields more fruit but am concerned that despite their claims to foster creativity, the universities stultify nonconformists as we make progress by degrees. Just getting funding is enough grounds to claim a breakthrough.

This month saw the publish of the ‘Handbook of Academic Integrity’, 72 chapters and starting price $USD400. To prove there’s no sanctimony on my part, here’s a sneaky free link to half a dozen chapters.

Shameless, actually

Shameless, actually

Everyone’s guilty of wrongdoing, sin is in our nature. Doing something even more wrong here:

We’re all crazy now

PRO-logue. It’s telling that an identical German study to PRO-HEART was shutdown early. Comments by psychiatrist Andreas Ströhle and Nina Rieckmann from their Institute of Public Health : “Dr Angermann and colleagues reported that escitalopram did not reduce all-cause death or hospitalization… It is not clear why the authors expected that it would, as it does not reduce mild to moderate levels of depression… Rather, it adds to the mounting evidence that questions the risk-benefit ratio of prescribing antidepressants to patients with less than severe depression.”

Once upon a time, psychs drew a distinction between depression originating from within (endogenous) or that which arose due to circumstances (reactive). The former was treated by meds, but the market for anti-depressants has grown as the two-type concept has fallen out of favour. Pills manipulating neurotransmitter levels are a simple solution with scrip from your GP, one that doesn’t require psych expertise. The American Psychiatric Association aren’t blameless, since the criteria for mental illnesses is loosened with every release of the DSM. That manual has also expanded in order to inform practitioners of the complexity of the complex. But they have lost control in this non-infectious pandemic. Prof Peter Gotzsche is fanatical in advocating that prescriptions of such meds be reduced 50-fold, but for a less emotive perspective I suggest you follow psychiatrist Professor David Healy, or read his ‘Pharmageddon’.

Followon book to 'Deadly Medicines and Organised Crime'

Followon book to ‘Deadly Medicines and Organised Crime’

Earlier posts have complained at the fabricated conclusion that chronic pain is  manifestation of a mental illness. It was a researcher’s invented report that then conveniently led into a publicly funded trial for anti-depressants in osteoarthritis. It’s to the Royal Aust & NZ College of Psychiatry’s credit that their submission  against Medicine Aust code-of-misconduct application to regulatory authority ACCC was the only one to address perversion of research by industry. If they’re to be believed, academics are corrupted. And if Gotzsche is right, you can’t trust Patient Organisations for … “having done absolutely nothing to stop the blatant abuse of patients in industry-sponsored trials“, citing Dr Ben Goldacre’s book ‘Bad Pharma’ of 2012. It’s worse than that, as you’ll find out.

Heart Foundation Vic CEO Jennifer Johns has earlier come in for ridicule over statins, echoing her disgraced NSW President’s associations with the refined sugar industry. An Austin hospital cardiologist, in 2010 she funded her colleague David Hare and Baker IDI’s Prof Krum to trial  Lexapro as treatment for the depression that their heart failure patients are presumed to suffer, PRO-HEART. Also in this year the manufacturer’s promotion of such off-label usage cost them $USD313m in fines, with civil actions continuing. Such as 03-10395-NMG for wrongful dismissal of sales rep and whistleblower Chris Gobble, who complained to supervisors of “illegal kickbacks (i.e. paying doctors for no other reason than to induce them to prescribe Celexa and Lexapro)”. The marketing budget disclosed in the Confidential plan provided to the US Senate was $35m on speakers fees, and $36m on lunches. In one year. In one country.

The drug is also associated with hyponatremia, ie it worsens heart failure risk. None of the team answered this concern, but they were defended by the Heart Foundation’s Deidre Cope: “In regard to its Research Program, the Heart Foundation follows the NHMRC guidelines around disclosure of interest. The research funded by the Heart Foundation undergoes a rigorous peer review process involving assessment by independent, external reviewers. All funding decisions are scrutinised by an external committee to ensure that all aspects of the peer review process are consistent, transparent and ethical.” Affirming that they’re just as utterly corrupt as the NHMRC, as evidenced by Cicuttini and Wluka’s impunity.

The other half of the $820,000 raised by door-knockers and tin-shakers that PRO-HEART is costing was from Beyond Blue. No responses to approaches were provided at all. It’s too early to allege misconduct – the trial is running three years behind schedule, and a staffer thought late 2017 would see a report released. But it already stinks like something’s died. [Sep 2017 update: 2018 perhaps? BB CEO Georgie Harman states that she’s happy with the study progress – seven years after the first patient was enrolled in the 6month study]

There’s often a trite closing disclaimer in articles that if you suffer from depression, there’s phone support available at these numbers…… who’ll suggest medical advice. I’m more of the opinion that you think carefully, so have linked further material on happiness or absence thereof at http://themindfulgap.com.au/2016/02/05/the-blue-bird-and-the-black-dog/



‘The Strange Case of Dr Jekyll and Mr Hyde’ was an 1886 novel written to contrast public and private lives of a reputable gentleman. Duplicity is a constant failing, but often what’s revealed is just an iceberg’s tip above massive issues. Thanks to the only mandatory Pfarma reporting in Oz, Medicine Australia’s Education Events, we know that Pfizer spent an average of $12k on each of the 23 rheumatologists they recently sent to European and American conferences EULAR and ACR. The full reports give an insight into specialist’s lives outside the surgery, as $43.3m was spent on them in the 6 months to Sept 2015. Worse still in 2010 pharmaceutical companies reported $637m expenditure on research, but nobody knows who received the money *. There is monumental potential for conflict-of-interest as the scope of new-gen bio-agents increases (monoclonal antibody drugs, hereafter referred to as the  _mab drugs).

Tony Abbott recovers after finishing Pfarma-sponsored 'Pollie Pedal' in 2013

Tony Abbott recovers after finishing Pfarma-sponsored ‘Pollie Pedal’ in 2013

Amgen sponsored 799 events in the last 6 months. Focusing in more closely, we really can’t be sure just how safe is their anti-inflammatory _mab for arthritis, Enbrel. Regulatory authority TGA advises physicians under Adverse Effects: “In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed“. Uhuhh.

Allegations it caused Eagles frontman Glenn Frey’s death due to pneumonia can’t be verified. In the latest EULAR journal ‘Annals of Rheumatic Diseases’ Winthrop & Smolen et al suggest it’s a good idea to track outcomes of _mabs. ‘Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases’ reveals the shortcoming that “no consistent OI [Opportunistic Infection] definition was identified across [368] studies“. Hence a list of OIs was drawn up, topped by the pathogen responsible for pneumonia. The best evidence for their recommendations was the publicly accessible meta-analysis by Kourbeti, Ziakas, & Mylonakis which put the odds of infections 1.8 times higher for _mab recipients than controls (usually patients on frontline med, methotrexate)  in Rheumatoid Arthritis (RA) trials – a small but significant risk. But note that RA doubles that risk over healthy comparators already.

That’s short term though, a trial median of around 6 months for the drug to prove its worth. Aust Rheumatology Association’s Rachelle Buchbinder established the ARAD tracking database a decade ago to determine _mab safety. It’s paid for by Pfizer, BMS and AbbVie. The few reports published in journals thus far inform us of customer satisfaction such as subjective Quality of Life surveys, and that no increased risk of cancer occurs, and that herpes/shingles virus infection rates are 1.7 times higher. Specifically for Enbrel, this result came after a median of 3 years followup. So the longterm prognosis is much like the brief studies would indicate. A worsening, but hardly deadly. Glenn’s manager wisely declares he has taken legal advice to limit his accusation.

This drug inhibits TNF, a cytokine messenger that augments our innate immunity system. As understanding of the molecular basis of many diseases improves, an inflammatory aspect is a recurring theme. The prospects for treatment with anti-TNF therapy look promising, but for the fact that the body needs to be regulated by internal controls. And not shareholders, salesfolk, or Jekyll. Interestingly, a trial for Enbrel in Alzheimers found that TNF levels rose. Feedback systems are adaptive.

Future studies could well heed the EULAR belief that their “… list of infections should be considered potential indicators of alterations in host immunity, and that this list and the associated case definitions should be used to standardise reporting of OIs in future biologic and other disease modifying antirheumatic drug clinical trials“. It’d also be helpful if an outcome tracking registry reported on all OIs, instead of the trickle of data from ARAD. But unease over industry manipulation of research is fuelled by the doctors themselves. When a weakened version of the US Sunshine Act for disclosing contents of the unmarked envelope was being considered by the Aust Competition and Consumer Commission, the AMA submission sought a deferral: “A twelve month delay in implementing the ACCC’s condition would allow health practitioners to think about and plan for their ongoing relationships with pharmaceutical companies.”

Gap payments cover the weekender, the kid's schooling ....

Gap payments

EULAR 2016 is in London. The UK has an Office of Research Integrity, let’s hope some fresher ideas than creative accounting are brought home.

* Source: College of Psychiatry submission to the ACCC. They’re concerned: “Clinical research should be included in the transparency model. All payments above the threshold that are made to individual researchers, or research institutions, including hospitals, should be publicly reported. This would better enable doctors and other health professionals to interpret the research outcomes while taking into account their funding sources.”

Rage, rage against the dying of the light

… from ‘Do not go gentle into that good night’, Dylan Thomas




Before delving into the massive NHMRC research investment of public money  ($5.1m upfront) into Pfizer’s Lipitor that is STAREE, some preliminaries:

Few Australians would be unaware of the furore raised by Catalyst (The Heart of the Matter), and subsequent retraction by ABC management of the program. A couple of opinions on Dr Demasi’s journalism by Drs Briffa and Coleman, and their arguing in blog comments shows that even those in general agreement were discordant. Instead of ‘playing the ball’ and take on the well-orchestrated industry, I’ll ‘play the man’ and focus upon individual proponents of statin therapy. And their complicity. It’s a softer target due to a weakness in humanity – insatiable need for funding.
Heart Foundation CEO Jen Johns immediately warned that sales of statins would be harmed, and a month later they published a poll by their Rob Grenfell showing 10% had stopped the therapy. Their corruption is further detailed at this update, and is unsurprising given that the decade-long president is father of Pfizer’s lobbyist Andy Thirlwell. Even before the exposé aired, Prof Emily Banks had pointed the bone * thus: “It’s likely that if this program goes ahead, and it does the unwarranted undermining of statins, that there will be people who didn’t have to have a heart attack and didn’t have to die from a heart attack, who will die through reducing use of statins“. An expert in this field, having authored ‘Erectile Dysfunction Severity as a Risk Marker for Cardiovascular Disease Hospitalisation and All-Cause Mortality’, she’d be appreciative of Pfizer’s infamous blue pills for ED. Dr Grenfell concurs with a warning, “These results tell us that every man who is suffering from any degree of erectile dysfunction should be seeking medical assistance as early as possible“.

Grenfell and Tonkin et al wrote of the confusion in lipid management in May 2015 ‘Clinical Guidelines on Hyperlipidaemia: Recent Developments, Future Challenges and the Need for an Australian Review’ – considering the perspective of the American Heart Association “… the maximum tolerated dose of a statin be generally employed”, but their own concern is absence of an optimal target level: “Whilst the cost-benefit analysis of statin therapy is generally favourable, it is very sensitive to the absolute risk level of the patients selected for therapy”. Andrew Tonkin had already made his mind up in 2005 though, as chair of the Heart Foundation’s consensus Position Statement on Lipid Management a number of guidelines and criteria are given to prescribers. Along with a conflict-of-interest declaration. The same “provision of consulting services to Pfizer” should also have been disclosed in a JAMA report ‘Association of LDL Cholesterol…with Risk of Cardiovascular Events Among Patients Treated With Statins’, that was subsequently amended due to medico complaints to the journal.

Bias is a relevant fact in STAREE (STAtins for Reducing Events in the Elderly), but frequently missing. Monash colleague Sophia Zoungas should also have declared a 2007 Pfizer personal grant of $55k in articles such as ‘Treatment of Dyslipidemia and Cardiovascular Outcomes: The Journey So Far—Is This the End for Statins(?)’ advocating “the first [Randomised Controlled Trial] to determine the effects of statin therapy vs. placebo in an apparently healthy elderly cohort living independently” ie preventative Lipitor for the over 70s. This is not however, a trial designed to test a hypothesis. It’s an experiment on the elderly to see what happens. Lipitor is the hammer, let’s see if it nails aging! Extending of life is the outcome being investigated – meaning that if they’re wrong, then shortening of life may become apparent.  A successful trial is assured, since my previous example from this department shows an outcome can be invented with impunity. And worsened death rates ‘adjusted for’.

One example of deception is apparent already. In July ’14 Current Opinion in Cardiology neither professor mentions Pfizer’s backing, but offer panacea in claiming: “In a meta-analysis of observational studies, statin therapy was associated with reduction in risk of dementia, Alzheimer’s disease and mild cognitive impairment“. The cited references of Richardson et al (in response to the Lipitor label warning of additional risks, imposed by the FDA in 2012): “Published data do not suggest an adverse effect of statins on cognition.  The strength of available evidence is limited…” and a Cochrane review by McGuinness et al : “Demonstrated lack of benefit of statins compared with placebo on cognitive measures” actually contradict this claim! These issues were raised with Monash Chancellor Finkel, but the reply from his Director, Tony Calder abdicates responsibility: “The matters you allude to in your email are matters that are dealt with by University management therefore the Chancellor, as head of Council, will not be providing a response to your email.

Solving the problem of an aging population?

Solving the problem of an aging population?

Two years after Catalyst aired, a Med Jnl of Aust article advises that over the first eight months 61,000 have made up their own, negative opinion of the meds: “…changes in statin use occurred despite warnings in the Catalyst program that its content should not be taken as medical advice”. Co-author Sallie-Anne Pearson is noncommittal on consequence, having just published a study that concludes: “Deprescribing of statins may be indicated for some older people, because the evidence for benefit in primary prevention of cardiovascular disease is limited and there is an increased risk of side effects in old age.” Other, collaborative colleagues are more determined to restore Lipitor to its heyday position of the highest grossing drug. That popularity arose due to trial results on a surrogate outcome of LDL (Low Density Lipid) levels, without epidemiology data as to whether the drug improves survival rates in the community. We’re a trusting lot.

On the other hand the Brits stay true to form, by constant whinging about risks: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714436/ 😉

* Indigenous Australian’s forewarning of death as punishment

Manipulating the market.

Once upon a time, doctors were hanged for unethical human experimentation. Of 16 found guilty of war crimes, 7 were executed by hanging. Nuremberg, then Helsinki, countless other, and most recently the 2010 Singapore Statement on research ethics have convinced us that society has matured. But humanity hasn’t evolved, and the same Hippocratic oath persists.hangedDr

The forthcoming ‘Handbook of Academic Integrity’ has a chapter by Prof Vaux, whose accusation of misconduct against Uni of NSW researcher Levon Khachigian led to his standdown in 2013. That team had received $8.3m in a 2014 cardiovascular grant from NHMRC. The UNSW has just last month cleared Prof Khachigian of all charges, since: ….” breaches were the result of Professor Khachigian’s genuine error or honest oversight, not deliberate or intentional conduct.” The sacked whistleblower who brought the scandal to public attention, Dr Ying Morgan, wasn’t interviewed or requested to make a submission to the confidential inquiry. This was a case of fabricated data, whilst my previous post blogged how un-tampered data can be described howsoever as the study author chooses in order to suit their intent. Then there’s statistical adjustments.

David Vaux quotes Stanford biostatistician Prof Ioannidis, who finds procedural errors interpreting data in the majority of trial reports i.e. most studies are falsely presented. The figure given is 90%, which would mean that only 1 in 10 regulatory approved meds are truly beneficial. Deliberate obfuscation of harm also occurs, and Peter Gotzsche or David Healy are worth reading. The tutorial given at Monash in the Advanced Statistical Methods for Clinical Research subject MPH5270, on how to coverup dozens of deaths in a trial gone awry has already been discussed here . This post moves on from the blatant misconduct, to the insidious – market analysts determining what treatment you can receive.

Naltrexone blocks opioid receptors, and is approved to treat substance abuse. In 1985 Dr Bihari found that a one-tenth strength dose improved survival in HIV and postulated that the body’s endorphins were being boosted. Prof Mark Hutchinson and a team determined in 2009 that a similar molecule, naloxone alleviated chronic neuropathic pain by suppressing neural immune response to a perceived allergen attack, which has relevance in MS, fibromyalgia, Traumatic Brain Injury, and other inflammatory cytokine conditions. This led to Prof Jarred Younger of Stanford Uni trialing Lowdose Naltrexone (LdN) successfully in fibro, using a gold-standard randomised crossover protocol. The FDA didn’t accept the evidence as warranting their approval, and independent researcher budgets were never going to be able to satisfy their demands. A state of play report is available from this open-access rheumatology journal, and rheumatologist Emma Guymer visited their lab. But then reportedly told an LdN advocate that she couldn’t prescribe “for contractual reasons”. Buyers clubs solve this roadblock. There is a growing, loyal online community procuring LdN by either doctors scrip and a compounding pharmacy, or import from Canadian or Israeli sources. This established market seemingly deserves support by US insurance company rebate or else Australian PBS subsidy, so pfarma was approached to start the approval process.
Bristol Myers Squibb held the original patent for Revia/naltrexone, and after deliberating on the request for five months their Medical Director Marian Gandy determined there to be no opportunity: “I have explored the options with our global teams who determine the development programs for our products and regret to inform you that there are no plans to seek any further indications for ReVia“.

Bad drugs are pushed, good drugs are withheld. The system is so broken that suggested reforms, such as voluntary conflict-of-interest declarations, can only ever be window-dressing. That’s right – disclosing commercial allegiance is opt-in, since Australia has no equivalent to the US Sunshine Act. Nor an Office of Research Integrity where Dr Morgan could present her allegations. Because as PM Abbott said, “We’re open for business”.

Your life in their hands

An expression often applied to surgery, but physicians playing God is equally relevant to manipulation by mental health practitioners. Except that it’s Quality of Life that’s at stake. Institutions once committed difficult persons, but today medicating provides that confinement. Mostly beneficial in mental illness, mostly harmful otherwise.

So drawing the line for treatment carries grave responsibility. Complaints of this example of insitutional malpractice I detail here have however, been dismissed by  all governance authorities. In concluding that “Mental health is associated with changes in foot pain. Clinicians dealing with this population should consider the contribution of mental health in their management and treatment of foot pain” the connection is made – unless pain improves, it’s psych. The final page emphasizes the viewpoint, “the results from this current study suggest that foot pain could be related to mental health in the same manner as other chronic musculoskeletal conditions“. *
Except that the author’s data shows no significant association.
The report linked contains an untruth. Table 1 shows that mental health isn’t the factor – but rather it’s Vitality , or energy, which is determinant of recovery. The difference of 12 points equates to an increased likelihood of inability to work due to fatigue of over 60%, according to one validation of the SF-36 (Quality of Life) Vitality scale. Limitations of a self-report survey in judging someone to be suffering mental illness aside, this is a fabricated conclusion. And one which suits the purposes of the Professors in their subsequent trial of an anti-depressant in treating arthritis. This is no maverick opinion – Anita Wluka is musculoskeletal editor for BioMedCentral, and her department hosts the musculoskeletal group for the Cochrane Collaboration. It’s not a typo, else the ‘corresponding’ author would acknowledge the error. Nor did the editor of Arthritis Care & Research care to reply, indeed there appears to be no integrity underpinning the evidence base used by every doctor. The university ethics committee overseeing the study answered my challenge but only after four months had lapsed and I’d been suspended by the Dean, for causing distress to these academics by my complaints. Designated integrity advisor Prof Stephen Holdsworth hasn’t responded.

The misconduct isn’t confined to Monash either, Melbourne University obesity expert Joey ‘Mr Big’ Proietto contributed to the study, so their ethics committee was questioned. The only response was: “Due to the [Business Improvement Program] restructure which resulted in this office losing staff we are unable to reply to your request immediately. We will endeavour to respond as soon as possible. Thank you for your understanding“.

 The study was jointly funded by National Health and Medical Research Council and the Royal Aust College of Physicians. NHMRC Director of Grants Saraid Billiards isn’t fussed by misconduct within her alma mater: “we would anticipate that the institution would manage the allegation of research misconduct in accordance with Part B of the Code “. Rheumatology Assigner Academy and coincidentally co-author Prof Flavia Cicuttini could have taken this handpass, but perhaps too busy allocating funds and simultaneously consuming same? RACP “… has rigorous application, review and reporting procedures to ensure a fair and equitable process. …. but the College does not enter into correspondence regarding its decisions.”, according to research manager Laina De Winne. Spokesperson for federal Treasurer Hockey is concerned at budgetary drain, but “As this matter falls directly into the portfolio responsibilities of the Minister for Health the Hon Sussan Ley, Mr Hockey has asked me to refer this matter through to the Minister for her attention.” Joe’s been sent offshore, as our Govt does with many other children of refugees. Office of shadow Health Minister Cath King informs me that the complaint system is working: “Should you wish to pursue your concerns relating to potential conflicts of interest in the grants application process for NHMRC funding, I would encourage you to raise them with NHMRC directly .”

Evidence-based medicine Prof Paul Glasziou is overwhelmed by the extent of fraud: “Good luck with pursuing this. As I now focus on NON-drug interventions and the overall waste in research processes, I no longer get involved in individual problems in drugs research (as that would consume 10,000% of my time!)“. Adjunct Prof Ken Harvey of Medreach agrees, “As Paul Glasziou noted, it is difficult for those of us concerned about such matters to take up every case. The same, regrettably, applies to NH&MRC and University research and governance bodies although you certainly deserve a reply.” He suggested writing to the publishing journal editor, something attempted thrice without response. “Oh dear“, said Ken.

Members of the team are now collaborating with Mandana Nikpour and Andrew Tonkin on a trial of atorvastatin for arthritis, OAKS. Lipitor remains the world’s highest grossing drug on record, and Pfizer quite generous in granting early career kickstarts of $50-55,000. Mandy’s shy regarding her CardioVascularLipids grant, since it’s not declared in an article with Prof Rachelle Buchbinder ‘Should patients with systemic sclerosis-related pulmonary arterial hypertension be anticoagulated?’ (Internal Medicine Jnl of May 2013 ) even though Pfizer’s apixaban is suggested and a favourable result from her registered trial ACTRN12614000418673 will boost sales of their Eliquis. Again as with pregabalin/Lyrica trial PRECISE, NHMRC sponsored.

Arguably harmful except in the population who’ve already had a heart attack or angina, statins have one certain side effect. Fatigue. Which perpetuates the arthritic pain cycle, but Anita wasn’t going to tell you that. Pharmacology and rheumatology are bedfellows who’re profitable partners.

* Copyright © 2014 by the American College of Rheumatology

New Romantics FB3 actually wrote this about Thatcher-era Britain so the soundtrack doesn’t warrant linking, but the title suffices to illustrate a theme. In the mid-60s Canadian cystic fibrosis patients were entered onto a tracking registry, and other countries followed suit. The US foundation extracted outcome reports and used it to rank treatment centers, and the UK NHS mandates recording of all clinic attendance thus facilitating cross-country reporting. The best practice evidence revealed in this way is certainly less biased than any Cochrane review, since it’s also completely non-selective.
A more commercially oriented registry has been built at the for-profit PLM described here a few months ago. An FAQ encourages sufferers to ‘donate their data’ towards finding a cure, and this raises the intriguing idea of their vested interest overriding concerns about case confidentiality.

It’s not such a new idea. Grand rounds are a tradition in teaching hospitals, and case studies or series present de-identified but intimate details for elucidation of a condition. They’re win-win situations. Research institutions can also bend privacy rules to their own means – such as through ‘opt-off’ implied consent. Registries.org.au shows the benefit of, and reliance upon full capture of clinical care outcomes for quality monitoring.
On the other hand, requests to the Director of Grants at NHMRC for the identities of reviewers approving research funding applications (in order to scrutinize for conflicts-of-interest) are denied – using as disclaimer “confidentiality of applications and that (sic) all personal information is dealt with in accordance with our obligations under the Privacy Act”. Their oxymoronic Principles of Peer Review of articles 2 “All stages of peer review are transparent” and 6 “Participants respect that confidentiality is important to the fairness and robustness of peer review” contradiction is exposed when a falsified report is challenged, posted in detail here. For anyone wishing to draw on a correlation between mental health and chronic pain, for all eternity, that study can be cited. The artificial construct of epidemic mental illness results in inadequate treatment available to those genuinely suffering, and a pill-popping panacea instead of fruitful therapy.

Similarly secret, we are invariably blinded to identities of the peers for a peer-reviewed journal. The commercial imperatives of publishing have been exposed by luminaries such as the BMJ editor, who, following a quarter of a century as chief executive wrote in open-source PLoS: ‘Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies’. Studies on the peer review process also show this form of governance is a fallacy. It seems to have been lost that the purpose of research is to improve outcomes, and that the data belongs to the patient rather than their drug dealer. Ownership has underpinned the ethical guideline of ‘beneficence’ instituted after Nuremberg, and accountability was promised by the institution when informed consent is granted by study participants.  That consent can’t be withdrawn posthumously if it doesn’t work out as expected.
Militant united voices can redress the present disempowered situation, only tolerated out of the individual patient’s desperation to obtain effective treatment for which they’re handsomely rewarding their service provider. That’s my dream. The reality is that a petition to draw the attention of our Health Minister, raised on the forum representing a (conservatively) estimated 600,000 fibromites managed only a few thousand signatures. As to whether meekness, or ignorance of commercially driven bias is to blame I’d suggest the former. Even if ‘doctor’ no longer translates from the Latin ‘teacher’, their authority is nonetheless unassailable.

Doctoring the evidence

If your doctor is any good, they’re users of theCochraneLibrary.org founded by Sir Iain Chalmers, whose online book I’ve previously linked. Reports of treatments are gathered systematically, to avoid cherry-picking of that evidence which is more favourable to pre-conceived ideas. An assessment of bias follows formal rules, and a statistical meta-analysis (trainsmashing) of outcome results conveys confidence limits in the solution. All reviews are written to the same format and lay folk can benefit from this collective wisdom (if they’ve learnt from reading Testing Treatments), since they’re altruistically distributed in many countries. 1424312_368966716574253_1835599297_n
Authoring is an act of selflessness by prestigious experts in their field, although displeased editors can dismiss any work if it disagrees with their perspective. Fibromyalgia was considered too different an etiology from neuropathy to jointly consider a common treatment, even though the Cochrane group editor published his own ‘Oxycodone for Neuropathic Pain and Fibromyalgia’ a fortnight earlier. The same team included a Pfizer employee when reviewing anti-convulsants for acute and chronic pain, yet more hippocratic hypocrisy.
Co-founder Prof Peter Gøtzsche published in 2013 the exposé: ‘Deadly Medicines and Organised Crime: How Big Pharma has Corrupted Healthcare’, an excerpt from pg84 follows. ”A rare admission that doctors’ opinions are for sale to the highest bidder was provided by Canadian rheumatologist Peter Tugwell, who wrote a letter to several major companies soliciting funds for (Continuing Medical Education) conferences on behalf of an organisation called OMERACT: We think that support for such a meeting would be very profitable for a company with a worldwide interest in drugs targeted in these field. The impact of sponsorship will be high…” This is the very same Cochrane’s Prof P.Tugwell who co-authors with musculoskeletal editor Prof Rachelle Buchbinder on OMERACT progress. After the 12th biennial conference we’re yet to discover how rheumies intend to measure outcome improvement – seemingly a major impediment to actually doing any investigations into treatments. May’s junket to Budapest has yet to be reported (10 months later), but watch for a breakthrough report (once the holiday photos have been put in order) at: http://omeract.org/conference_proceedings.html
The weblinked chapter ‘Pushing children into suicide with happy pills’ is preceded by ‘Psychiatry, the drug industry’s paradise’, opening with a delusional claim that “Psychiatrists are also ‘educated’ with industry’s hospitality more often than any other specialty”. Citation given is Ray Moynihan’s “suspicion”,  in turn citing a report co-written with Lisa Bero and submitted to BMJ but not published. Their précis of Medicines Australia Education Event reports actually found psychiatrists to be 5th placed in per head promotional spending, back in 2008. In the most recent report rheumatology is clearly the most rewarded specialty – sponsored by pharma with $1mil to attend overseas conferences and another $1mil for pain management seminars at home. Sadly, the sanctimonious supply of evidence for your doctor’s decisions is dirty at the source.

It’s not apparent just who the leading pushers of happy pills may be, but the anti-depressant amitriptyline/Endep has two trials on the go – Flavia Cicuttini hopes to fix backpain and Anita Wluka sees opportunity in osteoarthritis. These rheumies from Buchbinder’s department at Monash are hosting the Melbourne leg of Peter’s Mentalaz 2015 tour, and despite NHMRC public funding of their studies the justifying proposals for this 54-year old drug are secret (requesting memo response: “the protocol is not in the public domain”). Easy money – Prof Cicuttini is listed in the Assigner Academy, which determines the members of the Peer Review Panels for grant approvals. Their recent review of the accumulated evidence  ‘Are depression, anxiety and poor mental health risk factors for knee pain?’ states that one high-quality study was found correlating depression with 4.4% of variation in osteo knee pain & disability scores (r=0.21), ie 95.6% of pain perception was attributable to other factors (notably self-efficacy). Their 2014 report ‘Relationship Between Mental Health and Foot Pain’ concludes that “Mental health is associated with changes in foot pain”. Which omits the keyword ‘not’, since the Mental Health domain of the Mental Component Summary was nonsignificant – however the Vitality domain (survey items Pep & life, Energy, Worn out, Tired) was the determinant of deterioration. The implication that ongoing pain is associated with mental illness (survey items Nervousness, Down in dumps, Peacefulness, Blues & sadness, Happiness) is plain, dumb wrong.

Hardly good reasons to step out of specialty and into psych, so what are the risks? Tolerable, but after dry mouth weight gain is 2nd worst  – tho’ a mobility scooter will fix that.  They also cited three “high-quality” * trials of Cymbalta/duloxetine for knee osteo, but two of these were conducted by the manufacturer. Mmm, you can just smell that quality. It’s also a riskier drug than Endep due to addiction – the US FDA has classified Cymbalta Withdrawal Syndrome, and (shhh, don’t tell anyone) suicide risk (the FDA concealed deaths during trials behind “Some clinical trial data are considered trade secrets, or commercially protected information“). Is amitriptyline any good for pain? A Cochrane review of trial results for neuralgia states “The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many patients“. Will it work for you? Until pharmacogenomics comes into maturity, read the tealeaves …. or ask for a quick serotonin bloodtest to judge for yourself whether you’re deficient.

Conflict of interest declaration: I’m distrustful of physicians due to a conviction that secretive money flags corruption, and alternative therapies hold greater promise for this reason alone.

* Rather than rely upon CONSORT or GRADE standard checklists, PEDro assessed ‘quality’. Sí, this is true. Not even the late, great Dave Sackett could fictionalise better material.
PS Questions as to who’s watching the watchers overflows onto an earlier post. And did I mention that NHMRC Director of Grants is Monash alumnus?

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.
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.

Prestigious journal The Lancet Vol 359 Issue 9315 page 1442 uses a historical example to remind us to critically judge the Doctor’s ℞. In 1745 the Royal Physician recommended tobacco smoke enemas for victims of drowning during immersion therapy sessions – their being conducted as a treatment for mania. The modified bellows were subsequently provided at stations alongside the Thames river by The Institution for Affording Immediate Relief to Persons Apparently Dead. In an 1840 Kennisgeving (Notice) the Mayor of Rotterdam exalts those responsible for a successful resuscitation by rectal fumigation with a tabaksrookklisteer, after which the practice declined – since it was determined that nicotine was toxic.
I’m not sure that I can do this comedic material justice. If your health practitioner holds you underwater too long, they’re equipped to blow poison up your anus and that’ll restore life? klisteertabak There’s no reports of rectal tobacco usage on Antipodean shores for the countless victims of drowning during the settling of the colony. And it’s not known whether British Tobacco influenced medical adoption of the toxic weed as a cure-all. Nor do we descendants of convicts know whether inappropriate inducements are behind current prescriber’s choices. Lacking an equivalent of the US Sunshine Act for open payment disclosure between pharma and researchers, sponsorship remains cloaked in secrecy. Likewise it hasn’t been deemed necessary to copy America’s Office of Research Integrity, seemingly more prudent to deal with misconduct offline.

Medicine Australia’s Transparency Working Group was unable to reach consensus on a roadmap to setting something up in around abouts a coupla years. Health Ministerial policy is strictly hands-off, shown in a Feb 2014 reply to concerns of specific misconduct “[ahem]…. The Department is supporting an industry-led implementation advisory group that is guiding work to strengthen self-regulation including through the design and development of shared communication systems and a common complaints mechanism“. That’s a relief! I was worried that this matter was being managed by the cleaners because none of the TWG members endorsed the Transparency Model, and the Discussion Paper hasn’t been heard of since the month previous when the TWG was disbanded. And while reform languishes under whichever carpet it was swept, we must trust in our antidepressants as truly beneficial. There’s nothing to prove otherwise – death certificates do not have provision for medication regimes. Similarly so long as any medical procedure wasn’t in the previous 24 hours, the Coroner needn’t be told about that either. The offer proposed (and subsequently accepted) in Edition 18 of Medicine Australia’s (MA) voluntary Code of Conduct submission to the ACCC, being for reports disclosing consultancy payments from Aug 2016 means the clock for direct kickbacks has only two years left to run. That’s real self-regulated progress. Although the loophole exempting payments to researchers via an institution requires that we add to our lexicon “Trust me, I’m a Vice-Chancellor”.
MA Education Event reports disclose that healthy funding is indeed available, to specialists. Amongst Pfizer’s 1490 payments in the last reporting year was over a million dollars spend in sending 34 rheumatologists to conferences in the US and Europe, and 1-day pain management seminars locally. How apt that their Immunology Business Manager’s qualification is commercial pilot with a marketing degree! I’m unaware as to whether pregabalin was promoted, but can’t imagine any material presented had been sourced locally (there being almost* no fibromyalgia research conducted in Australia). ProPublica ‘Dollars for Docs’ 2012 scrutiny of Pfizer’s global corporate citizenship showed just $USD2.8m for travel alongside $USD144.2m for research. These ex gratia payments recognise that our Aussie rheumies are more world weary than world class. I nonetheless trust that that one day we’ll convulse with laughter at the arcane and archaic ℞ of anti-convulsants Lyrica and Neurontin for an autoimmune disorder.
* A survey in 2012 of seven Monash outpatients using pregabalin found diminished anxiety. Higher levels of trust also, no doubt.