Bad Medicine (Pt4)

cont’d…

A few years back I was volunteer non-emergency driver for Red Cross ambulant patients going to clinical appointments. The car was fully booked, and the third for the backseat was my last pickup. They had an an older Left Ventricle Assist Device, with huge powerpack. “Would you all squeeze up on the backseat to make room for the artificial heart?”

Talking to the new client en route to the Alfred’s Heart Failure clinic, ‘Chris’ went to the same Uni as me. Did the same course! I tell my anecdote of mathematician Tom Peachey, how I’d been restoring an old BSA and was tardy in attendance at lectures by this angry little man. “You’ll fail and make nothing of your life, Kirwood“, but I shrugged – I was on my way to 98% … Chris agreed, Tom annoyed him too, “so I slept with his girlfriend“.

Karma. Tom may’ve been ultimately right about me, but Chris sure was heartless!

In the most privileged portion of my career, working at the HyperMed clinic with high level of autonomy in dealing with seriously ill patients, there was a fatality. The deceased, Craig, was stage9 MS, and there is no stage10 *. He’d been rushed to ICU repeatedly, including an airlift from the Latrobe Valley. At the committal for trial pathologist Dr Sarah Parsons claimed cause of death was “Too much oxygen“. The planet certainly would benefit if we evolved to breathe CO2 instead, and I hope her team at Monash are working on this. Sure O2 is a vasoconstrictor, which is why hyperbaric is under pressure of around 30ft underwater – every moist tissue then carries oxygen. And this isn’t quackery – Monash’s physicians at the Alfred hospital also have novel uses for hyperbaric eg adjunct therapy in cancer. Perhaps The Age journo misunderstood Sarah’s evidence (after all, she claimed I had ‘no medical background’ despite the court transcript showing I’ve two decades as a skifield paramedic and a postgrad Dip in Clinical Research)?

Craig also suffered epilepsy. Dr Parson seemingly hasn’t heard that Sudden Unexplained Death in EPilepsy (SUDEP) is actually a thing, despite Prof Chris Semsarian hailing from Sydney and his ‘Post-Mortem Review and Genetic Analysis of SUDEP Cases’ begins: “Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death and is characterized by an absence of any identifiable cause of death…” (Brain Pathology, 2010). And he goes on to point the finger at familial long QT syndrome genes.

QT-interval-long

The QT interval is the time for the heart’s ventricle to get the signal to pump, and then recharge. Long QT can cause otherwise healthy people to suddenly die, and is the #1 monitoring of concern in ‘first-in-humans’ drug trials. The anti-epileptic drug Lyrica/pregabalin is known to lengthen QT in rabbits, but there’s no data in humans. When Pfizer’s Phillip Berry was asked where’s this key safety info, the reply was Dunno. Yet he received Medicine Australia’s Code of Conduct Award in 2013! Pfizer’s chief pharmacist Manal Nessim also couldn’t help. Cardiologists notice this danger however: Pregbalin induced recurrent syncopal attacks with prolong QT interval – PubMed (nih.gov)

The US FDA’s approval letter of Lyrica for neuropathic pain section Safety Q19 “Has the applicant submitted adequate information to assess the arythmogenic potential of the product e.g., QT interval studies?” is answered NA. And Q25 “Have narrative summaries been submitted for all deaths and adverse dropouts?” is answered No (will request from sponsor).

Craig was on many drugs, including Lyrica. But the chiropractor killed him, right everyone?

* Stage classification is now obsolete.

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Cochrane and Gotzsche

Marcellus: Something is rotten in the state of Denmark (Hamlet 1.4.5)

These words, spoken to Horatio and Hamlet as they look upon wanton and drunken behavior, which has destroyed the nation’s reputation, are apt to the sacking of Danish Prof Gotzsche by the Cochrane Collaboration – the gold standard in medical evidence. Archie Cochrane founded an independent scrutineering of medical trials in 1993, so as to impartially evaluate claims of drug efficacy. Rules and tools for trainsmashing data from systematically gathered results are intended to provide an overview of pros and cons. Peter Gotzsche was an early appointee, directing the Nordic Centre of six neighbouring countries. The last half a dozen years has seen increasingly vocal criticism of commercial influence, and doubters of the Cochrane ideal often focused on mental health solutions. Gotzsche was stubbornly strident in criticism of psychiatry, disregarding my advisory sent 5th Nov ’14 that his condemnation of the profession as being the most lucrative for industry kickbacks was wrong – per his reference it was actually 4th most (in Australia 2009), with rheumatology #1. The download of a chapter ‘Pushing children into suicide with happy pills’ , linked in the flyer for his 2015 Mentalaz tour, concludes thus: Our citizens would be far better off if we removed all the psychotropic drugs from the market, as doctors are unable to handle them.

Followon book to ‘Deadly Medicines and Organised Crime’

Not that the rheumies were off the hook. Peter’s 1989 ‘Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal anti-inflammatory drugs in rheumatoid arthritis’ warned that “the quality of RCT trials in rheumatology may be so weak that it may be impossible to place any confidence in the … conclusion“. And on pg84 of Deadly Medicines “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 CME 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.” Gotzsche aint a team player. Tugwell co-authored with Gotzsche, as well as 19 times with revered Cochrane founder Dave Sackett, whose HARLOTplc article at least gave humour to the reality that their business is for profit.

This month Cochrane’s Governing Board sacked Gotzsche, sparking outcry and protest resignations by 4 other of its 13 members. Six weeks earlier he’d written a critique of a Cochrane review for the HPV vaccine’s efficacy against cervical cancer. Peter’s team had worked on this since Jan 2017, when their analysis protocol was published. Points of disagreement raised were uncontroversial and moot, other than that the outcome of concern only developed after such a long time that surrogate indicators of lesions were instead analysed as being predictive of protection. Rather than dismissal being an exasperated or last straw reaction, the timing was merely coincidental. The Board’s statement informs us that lawyers had been on Gotzsche’s case since March, with a QC conducted independent review underway a month before publishing of the HPV challenge caused contention.

I suggest coincidence, rather than ruse, since the February trigger was possibly a letter attacking a Cochrane chief editor – Andrea Cipriani of the Common Mental Disorders group, over their recent review of 21 anti-depressants as being flawed and untrustworthy. However that team declare no conflicted-interest, and perusal reveals no alarming endorsements. Yet there’s no reference to the unwarranted attack or its target in the Board’s attempt at damage control – is this to protect the privacy of an innocent party, from their shaming by a woefully ill-informed press? Another, diplomatically worded re-analysis of Cipriani’s earlier 2009 anti-depressant report did highlight shortcomings of trial quality assessments, cautioning against the endorsement given for Pfizer’s Zoloft.

The muddy waters turn darkly Stygian.  Cipriani is Prof of Psychiatry at Oxford, which also homes Cochrane’s Pain & Palliative group under Prof Robert Andrew Moore (aka RAM, aka Andrew Moore), whose authoring name varies with context – independent and impartial, or sponsored spokesperson. There’s much overlap between pharmacotherapies with these groups, notably duloxetine/Cymbalta. Cochrane Editor-in-Chief David Tovey would be aware of the industry influence, since he acknowledged an email in March 2015 titled: ‘A 2nd Cochrane group is recruited’ – complaining about the rheumatology group and also including this: [Dr Nnoaham’s] 2008 Cochrane review on TENS for chronic pain and fibromyalgia was censored by your organisation’s Pain, Palliative and Supportive care (PaPaS) editors. Who are excellent examples of transparency, by not hiding their allegiances. Phil Wiffen and Andrew Moore et al chose to include a Pfizer employee in 2010 when conducting their own review into anti-convulsants for pain – surprisingly finding that “For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy..” (quoting the 2013 update). They reckon duloxetine’s pretty good too – http://www.bmj.com/content/348/bmj.g139/rapid-responses (well you would if you were paid as a consultant by Eli-Lilly, wouldn’t you?)

Grounds for disallowing Nnoaham’s complementary therapy review were that it shall be split into two reviews of TENS – one for fibromyalgia, and one for neuropathy. Except that Wiffen and Moore’s 2013 ‘Lamotrigine (an antiepileptic drug) for chronic neuropathic pain or fibromyalgia’ is an allowable combo! PaPaS also censored an unfavourable review of Pfizer’s gabapentin & pregabalin for pain relief in fibromyalgia on the grounds that lead author Nurcan Üçeyler had been paid speaker’s fees by Pfizer at neurology conferences. However Cochrane’s rule that neither the majority of authors nor the lead can be on the manufacturer’s payroll was also broken by their 2014 review into Neurontin/gabapentin, although Moore then complied in their 2017 update – by re-arranging the order of names to put Phil Wiffen first.

This is a coverup of misconduct. A façade. Gotzsche was certainly going beyond boundaries of expertise, and using his senior position within Cochrane to add weight to his personal opinions, which is contrary to the spokesperson policy allowing only statements on behalf of the collaboration. Years of emotive rants took a toll on his reputation – a tragic folly, when misconduct was there for all to see.

Disclaimer: I consider that the psychiatric profession takes prescribing of psychotropic meds VERY seriously, but worry about GPs playing at amateur shrink on the basis of dubious research evidence. I do not endorse Prof Gotzsche’s attitude, best expressed in his memo to Dr Dawson “Incidentally, I found out that some one has written about you and the way you treated my paper about the 10 myths in psychiatry. See attached [‘Asshole of the day – George Dawson MD’]”. George seems rather professional, actually: http://www.youtube.com/watch?v=ZyINjdCXkAQ

 

 

 

 

 

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Excluding opium, (which the Creator himself seems to prescribe… as if it were foreseen that wherever there is hunger to be fed there must also be a pain to be soothed) … I firmly believe that if the whole materia medica [medical drugs], as now used, could be sunk to the bottom of the sea, it would be all the better for mankind,—and all the worse for the fishes. Harvard Medical School dean, 1860

This is a man who hadn’t experienced the wonder of penicillin, or appreciated commercialization of aspirin for quick and easy pain relief, so the quote from Oliver Wendell Holmes Sr is merely quirky. The opioids have become contentious today, as though dictated by fashion, but dissent on the merit of miraculous pills is a constant. Psychiatrist and pharmacovigilante David Healy wrote with exasperation on the irresponsible prescription of meds for mental health, using images of hanging victims to drive home their accompanied risk of suicidality. After an outcry his next post ‘Spectre of Dissent’ used pictures of self-immolation, such as a Buddhist monk protesting the Vietnam war, in order to emphasise the seriousness of medication harm, legally, by doctor’s orders.

Movie ‘The Constant Gardener’, based on actual events.

In 1996 Pfizer rushed researchers to trial their experimental antibiotic Trovan at a meningitis outbreak in Nigeria. Ethical approvals were forged, and the drug trial comparator was only administered at 1/3rd the standard dose. Similar numbers of recipients of Trovan died as those in the (undertreated) control group, and the FDA approved the drug for adults although not for children. Within one year, over 100 cases of acute liver failure led to withdrawal of any approval. The Nigerian govt was given $75m to settle the case. The horror/thriller plot of the film, described by its author thus: “by comparison with the reality, my story [is] as tame as a holiday postcard“, stemmed from Pfizer’s damage control by discrediting the Nigerian prosecutor – done in collusion with the US ambassador. Considering that the corpse shown hanging had their genitals cut off and stuffed in its mouth as an inducement to keep quiet, wow.

This was a human rights abuse. “Happens all the time” was the response of Monash’s School of Public Health biostatistics Professor to my concern at another atrocity. Billion dollar fines have been about as worthless as a tax on criminality. A cost of doing business. Trump’s appointee to head up the FDA, Scott Gottlieb, was universally acclaimed as a good choice. But his ‘user-pays’ concept of charging pharma for their time, $905m for reviews  in 2017, has been accompanied by a threefold drop in rejections since 2010.

Does fast-tracking approvals carry a greater risk?

Undoubtedly, yes. But that must be weighed against the harm of delay. A dozen years are easily lost between the translational research breakthrough, through safety and then comparative benefit studies, before availability to the public. The question of risk vs benefit becomes a moot point though, when regulators are not sufficiently independent from industry influence. The Drug Utilisation SubCommittee reports to PBS on the subsidies for the market, the consumer patients testing ground. It’s chaired by a Professor who’s taken Pfizer sponsorship for a study, and writes on the benefit of branded over generic, but omits mentioning the commercial conflict of interest. Double standards are rife.

State AMA President doesn’t advertise, eh?

Under AHPRA rules, testimonials are banned: no reviews, or views on a service provider. Head of Victorian AMA, Dr Julian Rait knows it’s OK for a review on a third party website that he does not control – Google reviews clearly aren’t promotional. They can be brutal. Sharing experience is very much in the public interest, and Rait’s recent reply to my memo on open disclosure (‘Duty of Candour’) was appropriately candid. Telstra’s HealthEngine is an alternative service however it is indeed an advertising & booking service, since negative reviews are edited out.
The non-response on this matter from AHPRA chair Dr Joanna Flynn (an aide stating that “All registered medical practitioners are expected to abide by the [Good practice] code)” is merely wishful. And they endorse HealthEngine’s censorship, ostensibly to remove clinical performance ratings, but in effect encouraging a smokescreen for shoddy conduct.

In the UK there’s a statutory Duty of Candour – when a medical error is made, a conciliatory conference is enforceable. It affords a learning opportunity for the contrite doctor, although apologies are non-prejudicial i.e. not an admission of guilt. Our regulatory body in Oz maintains exclusivity on registered practitioners – no public ratings, and all complaints dealt with behind the scenes. An incredible dismissal of an AHPRA complaint and then an expert physician making contentious, unsubstantiated on-air comments led to my testing procedural rigour through such a complaint. Again, dismissed as it was “reasonable for the Prof to proffer an opinion“.  Except that this wasn’t a personal, but a professional, opinion that was disparaging to complementary medicine.

Perhaps medicine will one day be called before a Royal Commission, so as to expose the kickbacks paid to advisors, much as financial services has been. I’m overwhelmed by the ‘smoke and mirrors’, and am off to do a ‘snow job’ myself. A real one, as an honorary ski patroller, at the mountain retreat of Mt Stirling. I’ll return after contemplation of humanity’s evils. Geoff

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Bad Medicine (Pt3)

What does (S)-3-(aminomethyl)-5-methylhexanoic acid do for you? That depends on whether you’re a doctor prescribing Lyrica, a pharmaceutical company making pregabalin, or a patient:

Stop the drug, swelling goes.  © Canadian Medical Ass’n

 

It’s four years since my last incredulous post on the alliance between researchers and Pfizer, a collusion formalized in business collaboration at Monash University in Jun ’17. This revisit begins with the TGA (equiv to US FDA) Product Info for health professionals on Lyrica/pregabalin as of Sept ’16. The first condition of painful Diabetic Neuropathy (PDN) lists 5 completed studies in Table 1, showing pain was halved for ~26% of those administered 150mg, and ~45% if on 600mg. This would encourage doctors to increase dosage up to the maximal 600mg daily (double that allowed in the US). The most frequently reported side-effects are weight gain, dizziness and sleepiness. The manufacturer has checked on driver safety, but research simply doesn’t encompass a thought that harms should be measured systematically: Prof Nadine Attal replied to my concern with “I agree… because the methods used to assess side effects are seldom standardized, particularly as regards cognitive effects of drugs“. This is an obvious pharmacovigilance problem, but another risk lurks. Pg13 of the TGA brochure informs doctors that less than 4% of trial participants suffered peripheral oedema (pictured). None of their advice is referenced, so let’s fact-check.

Peripheral Oedema/swelling

Pfizer reported in ‘A Comprehensive Drug Safety Evaluation of Pregabalin in Peripheral Neuropathic Pain’ that they’d run 13 Randomised Controlled Trials of Lyrica for PDN up to May ’12. Somewhat surprising that the TGA only found 6, which also included independent investigations. Oedema was reported in 9% of neuropathy patients. The manufacturer paints a harms picture that’s doubly worse  than the govt regulator does! One Pfizer trial continued for another year with volunteers, of whom 16% reported oedema (10% resolved inside 2 months). Oedema is associated with congestive heart failure, so it matters. And the worsened circulation is associated with non-healing ulcers in diabetics, and that can lead to amputation. Wondering what have you got to lose by starting with this drug – a foot, perhaps? Regardless of adverse events/side-effects, stopping the drug resolves that issue – but at the end of any study there’s limited data captured on withdrawal effects.

Addictiveness

Enriched Enrollment Randomised Withdrawal is a legitimate study design, whereby everyone is dosed and only responders continue into the trial. If it didn’t work for you, goodbye. This means that the group randomized to placebo go through withdrawals, and Pfizer ran this protocol thrice (twice including DPN). After an avg of 400mg daily for a month, then 150mg for one week tapering, pain was marginally worse in the placebo group after a month. 2.5% of the Lyrica group withdrew due to adverse events compared with 6.5% of the placebo arm, hinting at withdrawals suffering. The same protocol with backpain participants finished with both groups reporting the same level of pain, although the withdrawal arm experienced worsening sooner. The endpoint is in accord with the PRECISE study’s finding that Lyrica doesn’t work for backpain.

A lengthier and larger study was run, but this time concomitant meds other than paracetamol were disallowed. Previously patients had continued their own opioids or gabapentin (a Lyrica predecessor), but now the effect of withdrawal was pronounced – some 2 months of worsened pain. Interestingly this study team included Dr Cory Toth *, who’s had 9 papers retracted due to fabricated results. The team then ran a study without Toth, which showed no benefit whatsoever for Lyrica in PDN.

 

Placebo group suffering withdrawals from run-in period

Another protocol requiring drug withdrawal is the crossover design. This study on pre-diabetic neuropathy , again funded by Pfizer, shows a pain spike lasting just 1 week upon switching from drug to placebo.

© 2016 Wolters Kluwer

Another PDN crossover study is intriguing – worse withdrawals were suffered going from placebo onto pregabalin in the first week, altho’ actual withdrawals from the drug lasted 3 weeks. Again, the outcome was of a nearly worthless drug, but it’d seem that the fear of losing relief from pain (even if just an imaginary benefit) caused hurtful anguish.

© 2015 Wolters Kluwer

An independent review aggregated 15 trials up until Mar ’16 and concluded …”an overall small effect size with significant heterogeneity in the findings. Reporting bias was a particular concern, due to the high number of unpublished studies.” The 5 TGA examples chosen in their approval decision were an obvious cherrypick of the best results from the picture, being Refs: 17, 18, 19, 21, and 22. It seems that the benefit is arguably small, and data on withdrawals is limited. A recent review on Lyrica’s abuse potential coincides with transfer to Class C schedule in the UK underway, informed by little more than frequent discovery in prisons. Public forums are informative: this group, including recreational users, has a couple of hundred user comments… http://www.bluelight.org/vb/threads/531159-Lyrica-Withdrawal/page8 ** Surprisingly, a ‘comprehensive’ report in Oct ’17 came up with only 4 reported cases of withdrawal symptoms ever, where usage had been within therapeutic guidelines. The gulf of understanding between medicine and its recipients widens. Impressive commentary from the Trump-appointed FDA head on their concern with Lyrica notes that monitoring Bluelight is a gauge of potential for abuse.

Although not the decision makers, patients were treated to $USD344m of Lyrica TV advertising in 2016 (per Nielsen). Half of which was promoting use in diabetic pain. Small comfort can be found in Pfizer’s report that glycaemic control is only fractionally worsened. I do not feel the need to examine every condition for which Lyrica is approved – one instance of systemic failure suffices. For more on the politics of pain, you’d have to ask Chronic Pain Australia’s President or Executive Director as to why they refuse to share this article with their membership: read on…. Geoff Kirwood GDip Clin Research

* Cory apologized, but whether he was ‘sincerely’ sorry is questionable (Confidence Interval bounds not given): “I am significantly apologetic”. His resignation isn’t mentioned on the faculty page, and vice-dean MacQueen accepted his declared failure to oversee his 9 instances of data manipulation. She consults to Pfizer. Scott Reuben went to jail for fraud in 21 papers, which must exceed the threshold of acceptable levels of mistakes. Colleagues Buvanendran and Kroin on Reuben’s retracted pregabalin study went on to publish a favourable study on pregabalin. Paid for by Pfizer.  However it doesn’t taint the evidence base, oh no, no, no.

** Bluelight  is dedicated to drug harm reduction, and is named after the flame of crystal meth.

 

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2015 blog cont’d…. Another massive campaign to discredit the authors of the PACE study into three ME/CFS interventions is underway. Over 12,000 signed the first petition to request retraction of supposed claims that some one quarter ‘recovered’ – even though the Lancet paper clearly states potential to just ‘moderately improve outcomes’, specified per the Mayo Clinical Significance Consensus. Another lobbying is underway, so far 6,300 have signed a demand to the GMC regulators that the study doctors be disciplined – suggesting 10 years custodial penalty for the crime of Fraud. The gist of concerns is than consequent to PACE report practitioners have distressed sufferers from ME/CFS with callous disregard. Claim is even made of “… harm done to children being forced to go to school and being subject to child protection plans“. This irrational outburst references the Tymes Trust’s Jane Colby regarding the potential for healthcare authorities to intervene so as to enforce adherence to clinical guidelines after PACE recommendations.

First in GP Sarah Myhill’s complaints beginning on pg 7 of 25 are that PACE “has effectively determined CFS/ME as a psychological condition“. Recall that the interventions detailed in the Lancet article were: Cognitive Based Therapy (CBT) with a psychologist; Graded Exercise Therapy (GET) with a physio; Adaptive Pacing (APT) with an Occupational Therapist (OT); and against a control group receiving standard care from a CFS specialist. CBT and GET were significantly better for fatigue and functioning, while APT was no better than the control/placebo. The authors state clearly: “The effectiveness of behavioural treatments does not imply that the condition is psychological in nature.” Dr Myhill’s 2012 reprimand by GMC and recently concluded cautionary period must be considered in grading her opinions, when the disciplinary ruling declared: “statements in relation to contraception and breast cancer screening that were factually incorrect; clinically unsubstantiated; and contrary to national guidelines. In so doing she used her position as a registered practitioner to exploit patients’ lack of medical knowledge by arousing ill found fears for their health.” Myhill’s website promotes powerlifting as High Intensity Training – but not for ME/CFS, where diet and detox are advised. And vaccinating is discouraged.

Another line of advocacy comes from Tuller, Geraghty, Wilshire et al. The link has a number of articles, including the PACE authors’ refuting of complaints re research quality. More telling is the activist’s collated manuscript ‘Rethinking the treatment of chronic fatigue syndrome’, which begins with an allegation that the Randomised Controlled Trial did not control nuisance variables, such as contact hours. This is alarming. ‘Control’ in this situation means that the intervention was compared with a control group, not their idea that control be applied so as to enforce participant compliance. The scientific complaints differ over time, but this paper zeroes in on statistical analysis in that the published protocol considers every possible comparison between therapies, and the Bonferroni principle requires stronger levels of proof ie the more permutations (ie 6 pairwise comparisons), the greater likelihood of a random fluke (odds of 1 in 125 actually) supporting the hypothesis of a therapy being better than the control ie standard care. The pairwise tests were a change to the stats plan, by dropping consideration of combo-therapy eg is APT and GET better than GET alone etc….explained as being overly convoluted.

Access to raw data was achieved by activist’s FoI request. Looking at their re-analysis of supplied data in Table1, people improved most under two therapies. No argument. The control group also did over time, where a placebo or Hawthorne effect can result from the satisfaction of working with supportive professionals towards a solution.

To the impartial eye, CBT and GET worked ‘better’

 

 

Expert opinions and agendas at play

Independent commentators are worth noting: OT Bronnie Thompson admires the study, but is concerned that their APT protocol failed to set goals to work towards. Their envelope of maximal activity was fixed within a ‘disabled identity’ focused on what COULDN’T be achieved, a problem noticed by Prof Leonard Jason. His Energy Envelope Theory relies upon success in avoiding crashes being inducement to better achievements in future. This is similar to Feldenkrais practice, progressing away from fear of movement through progressive challenges. Medical journalist Dr Norman Swan discusses the unprecedented outrage in the patient community with a study author and journal editor, but only considers the absence of harm during the trial (1% of all treatment arms reported worsening conditions). They suggest that activists hijacking the CFS community does them harm, without stopping to think about why there is even an outcry and whether their GPs are at fault.

It is obvious that distress results from unsympathetic doctors who’ve simplified the study conclusion as “get active, get counseling, and get out of my practice“. Indeed, practitioners proudly state conviction in their ability to discern CFS patient agendas. “I often use it as a diagnostic tool for MUPS (Medically Unexplained Physical Symptoms), that I get irritated by patients.” A vulnerable population then becomes prey to peddlers of solutions that are accompanied by rather more sympathetic caring. At a patient forum Dr Daniel Lewis agreed with Tuller’s complaint that the participant inclusion criteria of ‘Oxford Research’, rather than ‘Canadian Consensus’, was the problem. They weren’t suffering real ME/CFS, whatever that is. He sells meditation courses targeting chronic fatigue or pain in general however, without quibbling about specific diagnoses in attendees. Likewise a clinician’s summit unanimously supported their client’s grievances against PACE conclusions being given as guidance to doctors.

Personal injury specialist legal firm Maurice Blackburn sponsors Australia’s Emerge ME/CFS foundation, and seeks litigants who’ve been refused disability payment. They also advertise on SBS TV, who have requested patient’s stories for a program. CFS guru Dr Jacob Teitelbaum initially took a rational stance that PACE results were being misinterpreted in the media, but five years later joined the herd by stating in his blog: “… the PACE trial that wrongly concluded that CFS patients should be treated with psychotherapy.” Other experts such as Jose Montoya just focus on their research.

The study team took the controversy onboard, replying with rational argument to editorial letters. It then seemed that the time was ripe to shoot themselves in the foot. Perhaps the declared conflicted interest of team member’s consulting to insurance companies, presumably over disability payouts, made the Lancet article just a testing of the waters. Another writeup appeared, declaring ‘Recovery is possible!’ much as Chamberlain did in saying “Peace in our time”. And war broke out.

This wasn’t the only investigation into exercise as therapy for CFS. Last year’s update to the meta-analysis of 7 trials affirmed the results, every one of them showing benefit for reported Fatigue. But once again, researchers do themselves no favours with clinicians or patients: the publishing/editorial group is Cochrane’s ‘Common Mental Disorders’ .

My thoughts

CFS is an unmet challenge to medicine. There’s no fix, only symptom relief. LowDose Naltrexone relieves the brain fog (presumed to result from glial inflammatory response), beta-blockers may be used against POTS in orthostatic intolerance (light-headedness upon arising), and supplements such as CoQ10 or D-Ribose aid mitochondrial energy production. Post-exertional malaise is a constant however, which reinforces the lost sense of identity that was once based upon our function. Patient experience is of an invariant, and lifelong struggle. For anyone else we experience affliction as mostly transitory, even chronic illness can go into remission upon treatment. They who experience anxiety attacks, also know there’s moments of achievement. Joy counters sadness, emotions rise and fall again. It is possible to mentally step back and observe thoughts and sensations that may come and go, without attaching identity or sense of self to such temporary states. This is infinitely harder when the disease is so poorly understood.

CBT and GET offer slight improvement, a readiness for future solutions rather than idling whilst deconditioning – where practitioner’s pushing of anti-depressant meds worsens weight gain. Meanwhile however, you’re powerless prey to commercialism.

Right of Reply & Disclosure

Dr Lewis’ office has never replied to my correspondence. SBS passed a message on to their producer. David Tuller wrote back that the trial authors assumption of the CFS sufferer’s [de]reconditioning biased their choice of interventions offered, which is fair comment. If only there were better answers to this perplexing problem.

I’m married to a MUPS, and like others I know well, am struck by their hitherto overachieving.

 

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Are you a morning person?

Series 7 episode 1 of Michael Mosley’s BBC program ‘Trust Me, I’m a Doctor’ featured a study comparing gardening against yoga against mindful meditation in beating stress. The outcome was an objective measure – salivary cortisol, for which the latter activity outscored all others. 😮 Wow! But sadly, this trial hasn’t ever been written up for publication, and furthermore the premise of showing increased cortisol awakening response (CAR)  as indicative of de-stressing  is counter to the evidence. Trust me, I’m a skeptic.

Dr Mosley as coach for the Rat Race

From the beginning. Cortisol is a restorative hormone – the benefits of the synthetic corticoid, prednisolone, in suppressing auto-immune response are well understood. In evolutionary terms it’s a clever output from an activated fight/flight HPA axis, halting anti-inflammatory effects so as to concentrate energy and strength. Focus on survival, consequences be damned. It shows a strong peak half an hour into the morning, the CAR, as we prepare to take on the world. It’s so consistent, that it’s been analysed for decades. The CAR peak is flattened when in pain, or fatigued – that makes sense. “Think I’ll sit this battle out, Genghis  – tell the truth, I’m pretty knackered“. But there’s half a dozen studies showing that CAR is boosted in stressful circumstances, such as angrier teachers preparing for work or ‘Perceived work overload and chronic worrying predict weekend-weekday differences in the cortisol awakening response‘.

The Mosley program had results consistent with another, scientifically rigorous trial of yoga. The CAR peak indeed up-regulates after gentle ‘Yoga as Awareness’ classes, just as it does when making ready for battle. Though counter-intuitive, this is the lesson. Meditation isn’t just avoidance, a cozy retreating into a safe place. It’s a pep talk for the body, giving gratitude for past valour, ready for a call of “Once more unto the breech, good friends” (Henry V). A similar increase in morning cortisol resulted from an 8-week Mindfulness program delivered to military helicopter pilots – complementing and enhancing their readiness for a stressful workday.

Humans are not deterministic – the feedback mechanisms are a workaround to any change. To take a pill, or supplement, on the simplistic basis that it has a directly measurable effect shown in clinical studies overlooks the complexity of the body systems that maintain our balance (homeostasis). Mindful meditation and stress both alter CAR in identical ways, yet have opposite effects on your wellbeing. To navigate the contradictory claims there’s only one answer – treat mind&body holistically. Integrative Medicine practitioners are being supplanted by accredited wellness coaches, providing lifestyle counsel but without reliance on a script pad. America’s healthcare travails have fostered two dozen accredited university courses, and the same from private suppliers, for Health & Wellness Coaching. theMindfulGap.com.au is also servicing this need.

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The influx of Chinese to the Californian goldfields brought with them homegrown remedies for the pain and inflammation of their labour. So impressive was the effectiveness of their snake-oil, that an entrepreneur also made extracts from the local rattlesnakes. It was ineffectual, and sales events were followed by the salesman’s hasty exit. But Chinese water-snake’s oil is 20% EPA – more than that from our preferred source of omega-3, salmon. It’s vital for the species in the cold conditions, whereas the rattlesnake’s blood has no issue with glugging up in the desert.

Why the history lesson?

It’s because Harvard Med School has just blogged that fish-oil supplements are worthless as preventatives. This surprised me, since my BP reduces markedly on the minimal dosage of 2000mg fish oil, twice that obtained from an ACE inhibitor. Sure, that’s just a surrogate outcome and not reflective of survival into senility. So is the research from American Heart Association to be trusted? Our Heart Foundation’s never untangled themselves from industry ties, so….

The detailed article needs to be read from bottom to top, starting with declarations of conflicted-interest. Dariush Mozaffarian has received no grants or support from industry? That’s not what Mozza’s CV says on pg8&10: $83k from Pfizer to trial Lipitor in ’02, and $5.1m from GSK & SigmaTau pharmaceutical companies to trial fish oil on cardiac patients. His collaborator on that one, Jason Wu also forgot to disclose same in the article. He’s done a lot of work with the George Institute, a partner in the Australian public’s generously sponsoring of a $5m NHMRC trial of Lipitor. Pfizer and SigmaTau also ran a 5 year trial of omega-3 supplements on twelve and a half thousand elderly patients having cardiovascular risk factors, finding no advantage conferred to survival rates. That’s a big study, and pretty generous of Pfarma.

You have to wonder: why do we pay to study Pfarma’s meds, and they pay to study the competition?

The Harvard expert Eric Rimm’s quoted in their blog: “Taking fish oil… may not only have no benefit, it may even have some risks that we don’t realize because we haven’t studied them.” And they’re the ones dismissing complementary medicine for its supposed lack of evidence base to claimed benefits! Dr Rimm’s Pfizer-sponsored study on erectile dysfunction is a rerun of the  Heart Foundation’s apologists Grenfell and Banks advisories to take Pfizer’s infamous blue pills OR DIE. Despite this geek’s degree being Computer Sc, he’s pulled $400k to study floppys, and is now a Professor of Medicine.

In the movie ‘Dope’, drug-hustling Malcolm is fixated on Harvard. For the easy money?

It’s ironic to think that better treatments were available in the Wild West, and those cowboys had no problems with shooting their gun.

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Out of control at the PROM

I’ve flashed back to the 80s, when jokes could be made about mass shootings, which is also a terribly long stretch from the actual theme. The PROM under consideration is the Patient Reported Outcome Measure, which divests control of medical studies from institutions and doctors – and gives it to the community.
History backtrack: after the WW2 Nuremberg trials, and other human rights violations in the name of research, a number of principles were established ~’81 including mandatory oversight by a Human Research Ethics Committee (called an Institutional Review Board in the US). Atrocities became a rare event, but governance was still lacking. Drug studies with displeasing outcomes were buried, and exclusively positive results biased efficacy reports in favour of the pills. A 2-pronged approach was advocated by AllTrials among others, first being registration of every trial upfront and second being reporting of all these publicly visible studies. The former worked since journal editors were in accord that unregistered trial’s reports would never be published. Reporting of negative outcomes remains problematic however, having half the likelihood of being published than a positive outcome has. And when the pre-eminent BMJ charges authors £2000 to publish, why would you continue to spend on the failures? *

It’s also expensive to run long term real-world studies (phase IV), when TGA/FDA approval only requires short term results from a ph III study, and subsequent investigations of the market such as by Australia’s Drug Utilisation Sub-Committee are quite inconsequential. Lyrica is the only drug in the top20 by expenditure which has no treatment effect other than symptom masking. Its promotion has put prescription rates far ahead of market projections, but reviews don’t consider what health benefit is being achieved.

Covington has since taken down their gloating, boastful article

In the US health insurers are driven by commercial imperative to recover monies wasted on meds marketed on the basis of deceptive trials. Eli-Lilly paid out $1.2bn in ’06 and $1.4bn in ’09 for inappropriate promotion of antipsychotic Zyprexa. Yet consumer litigation against Eli-Lilly’s antidepressant Cymbalta failed, despite prevalence of harm being indicated by eleven and a half thousand members joining FB group ‘Cymbalta Hurts Worse’.

I’ve written on this matter previously. Over 600,000 thousand subscribers to PatientsLikeMe.com (PLM) are now ‘donating their data towards a cure’, to use their recruiting hook. Clearly this is most applicable to diseases of uncertain etiology, eg participating fibromyalgia sufferers have grown from 20 to 96 thousand in the past few years. That five-fold increase surpasses the 50% increase in total PLM subscribers over the same period, reflecting this syndrome’s perplexing of established medicine’s oracles. The intent of PLM is to find those in a similar situation and share your successes or seek their support. Such power in numbers also encompasses pathology results, wellbeing scores, medication regimes, BMI, personal factors eg stress… but unless you’d care to test ethical waters by typing individual records into a statistical processor, the interface given to the public doesn’t allow queries such as meds vs outcomes – it previously did, until I sent a memo to management thanking them for their database. Sorry 😦 This is a business, and those insights are sold to industry. But the current patient-centric mantra popular with Health Depts eg Safer Care Victoria raises interest in the worth to the consumer of their treatments, hence initiating tracking via PROM. Monash have been early adopters, but the collection guidelines aren’t yet available. Interested product vendor ePROM/OceanEHR integrates outcome collection with myHealthRecord portability, which is an unmitigated IT disaster largely due to its being a challenge to a clinic’s jealous guarding of your medical records.

‘Patient Reported Outcome Measures in Rheumatic Diseases’, 2016 edited by Yasser El Miedany has a chapter on survey instruments for fibromyalgia that may be useful to researchers. But no mention of community forums such as PLM. OMERACT (Outcome Measures in Rheumatology) is a biennial conference, upcoming in NSW from 14th May ’18. It has 14 pharmaceutical companies for sponsors. Again, there’s no consideration of community, and focus is wholly on identifying symptoms for patient classification. Disengagement with chronic illness sufferers is increasing, so continued disinterest in the huge patient support groups is foolishness.

* The Journal of Negative Results ceased publication in Sept 2017, claiming that their mission of reform was successful. Meanwhile a journal for negative results, Null Hypothesis is being launched. The truth is out there, somewhere.

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Beyond Belief

If a belief is taken beyond the safety of rational thought, it’s then an act of faith. Brave and bold, but delusional. I’d argue that medicating is well down this path – devoutly taking risks with side-effects, perhaps even shortening lifespan, yet ‘smoke and mirrors’ is a fair description of the governance in clinical research. A blog on a fabricated conclusion in an NHMRC sponsored study is linked, and my notification of the misconduct to the publishing Arthritis Care & Research journal editor Dr Gary Firestein was never acknowledged. Likewise concerns about deception in drug trial PRO-HEART (linked) to the manager of research also went unanswered, and were subject to a Freedom of Information legal demand for disclosure. The Austin Hospital refused the FoI on the grounds of ‘trade secrets’, despite donated monies to peak bodies Beyond Blue and Heart Foundation sponsoring the scam.

A third matter is detailed below, and these were chosen from this site’s 43 posts to submit to Public Library of Science as a manuscript exemplifying medical research scams. Publication assistant Rebecca Green replied that “unfortunately such a paper would fall outside the scope of PLOS Medicine“. Dirty research can’t be retracted, furthermore making the case for a multitude of scandals won’t be published. Enough to shake one’s confidence in the system? Ditto the BMJ, even Accountability in Research journal were uninterested in research fraud criminality.

Impunity in both corrupting the medical evidence base and inappropriate commercial allegiance has led some to crossing of the boundary from immoral to illegal.  ‘Dog and pony show’ is another idiom pertinent to NHMRC funded program BackTrack. BackTrack-dogjumpDSC_0477Managed by qualified dogcatcher Bernie Shakeshaft, their modus operandi is to attend a rural court where juvenile offenders have run out of warnings, and are due for detention. An alternative offer is made for these feral kids to voluntarily labour on a remote farm, where they’ll also be taught to handle dogs. This goes down well with the Magistrate “… if I can forward them to a structured program like BackTrack, I certainly feel like there would be less recidivism.” In 2013 while Bernie’s brother, University of NSW (UNSW) Prof Shakeshaft, was on the NHMRC council their grant application “This study quantifies the benefits/costs of combining cognitive-behaviour therapy with a community-reinforcement strategy to reduce substance-related harms among young Indigenous Australians” was approved for $386771. A year later Bernie took off on a study tour of the USA, Canada and Italy. Bernie’s been done for Driving Under the Influence, so has learnt by experience the perils of alcohol abuse. But he’s naïve about CBT, and the majority of incarcerated kids aren’t Indigenous. This is revealed in a book submitted by Helena Pastor for her PhD by observation from the local Uni. An excerpted page Wild_Boys_—-_(Pg_253) describes physical abuse and isolation from both social workers and community elders.

The majority of finance comes from the philanthropic Vincent Fairfax Foundation. So besides taking Aboriginal kids away from their community support, these souls are in Christian hands. This situation is ongoing, not some historical ‘taking the children away’. Barnaby Joyce redirected $200k from Indigenous Affairs to these criminals (harsh? The AFP described the affair as ‘fraud’, which I understand to be a crime).

A report was produced, ‘The Feasibility of Embedding Data Collection into the Routine Service Delivery of a Multi-Component Program for High-Risk Young People’ *, which described their use of a routine survey. This sufficed for NHMRC, whose Ethics & Governance dept disclaimed accountability for their spend of our funds “…allegations of misconduct would need to be addressed by raising your concerns with the research institution through which the research was conducted.” Director of Integrity at UNSW, Bronwyn Greene, has been working on her answer to this since May 5th. So too has bureaucrat David Baragry, whose previous diplomatic statement was careful not to tread on toes in Canberra: “The Ombudsman has the discretion not to investigate certain complaints… respects the role, expertise and decisions of the NHMRC and … tends to consider only questions related to the NHMRC’s administrative processes.” Then Minister for Science & Research, SEN Kim Carr, recognizing the need for an Office of Research Integrity left the task to the key funding bodies NHMRC and Aust Research Council to establish an independent review body. They did so, but within their own organisations. This Committee, ARIC hasn’t replied either. In its first year 2011 it accepted only one complaint against its NHMRC parent, then rejected all allegations but for a procedural matter regarding sending of a letter. It’s not listed under https://www.nhmrc.gov.au/about/nhmrc-committees but buried as a paragraph in the NHMRC Annual Report – the latest stating on pg98 that one matter was dismissed, and another is an ongoing investigation. That’s about all they have to show in five years (check the reports for yourselves: search for nh15, nh162, nh166, nh169 & nh172). The cries of dissent are more voluble – links available from http://www.bmartin.cc/pubs/plagiarismfraud.html are a start.

19th Oct update: After the UNSW and ARIC four missed dates that they’d offered as targets for a response, it’s obvious that this will be stonewalled rather than whitewashed. Pity, since we miss out on the comedic material unearthed by America’s ORI being taken to court by a fraudster… “Dr. Sauer admitted that the images in his publications and grant applications were knowingly and intentionally falsified, but denied culpability, claiming that a member of an anti-gene technology activist group had falsified Dr. Sauer’s data in order to subvert gene-technology research.  As evidence for his claim, Dr. Sauer submitted an uncorroborated declaration purportedly by an individual named “Rune Dreser,” who allegedly stated that he had hacked into Dr. Sauer’s computers and altered Dr. Sauer’s research results.  The declaration, written in German and purportedly notarized by a notary in Germany, did not contain the notary’s name, and the signature of the notary was illegible.  Noticing this irregularity, the HHS attorney for ORI emailed the notarial office in Germany to inquire about the authenticity of the notarization.  The director of the notarial office responded that the notary seal and signature were most likely forgeries. ”

1st April: comedy gold from UNSW – when offered right-of-reply to a manuscript documenting their history of research misconduct eg  harbouring of Khachigian, they came back with a ‘Strictly Confidential’ status report (which said that nothing had been done yet, after 9 months).

* Int. J. Environ. Res. Public Health 2017, 14, 208; doi:10.3390/ijerph14020208

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Having it both ways

In earlier critiques of Bad Medicine I’d wondered at the contradiction of regulatory authorities handing down $bn punitive fines for wicked off-label promotion of meds, while sponsoring trials that potentially expand the range of approved conditions and thus the on-label market. Part(3) of this series on pregabalin/Lyrica concludes herewith.

In 2011 the Pharmaceutical Benefits Scheme refused Pfizer a subsidy for Lyrica on the grounds that none of the studies thus far had shown efficacy against neuropathic pain. Just 12 months later, they changed their mind. What new data could have influenced this, when the drug’s ineffectiveness was already the source of a joke on its side-effect of dizziness (Schwindel, translated in German)? Significant adverse events of dizziness and somnolence were manifest at the lowest dosage of 150mg consistently in 38 trials  ‘The adverse event profile of pregabalin: A systematic review and meta-analysis of randomized controlled trials’ (Zaccara & Specchio et al, 2011).

Courtesy of rheumatologist Dr L.Kirsch MD, Jun 2012

 

This somewhat contradicted Pfizer’s sponsored investigation into Lyrica:  ‘Cognitive effects of pregabalin in healthy volunteers’  (Stalinsky, Storzbach & Muniz 2009) offering a conclusion of “… negative cognitive effects and neurotoxicity complaints”. The drug only works (wirksam) to relieve pain at larger doses, at which point there’s been an exponential increase in Schwindel.

Pfizer’s 2012 re-submission to PBAC had two new studies; Boyle, Gribble & Johnsen et al , finding “…there was a significantly higher number of adverse events in the pregabalin treatment group. Conclusions: There was no significant difference in analgesic efficacy between amitriptyline, duloxetine and pregabalin.“, and Trial 1107 – an unpublished, internal study run by Pfizer. I’ll repeat that. The former showed no superiority of the med over amitriptyline, a 50 year-old mainstay known as Endep, furthermore it had worse side-effects. And the in house report …. one can only hope that it was run with more probity that their Trovan trial, best described as a crime against humanity. In summary – this one piece of evidence, from behind closed doors, sufficed to allow “The PBAC recommended an Authority Required (Streamlined) listing of pregabalin (all strengths) for the treatment of refractory neuropathic pain not controlled by other drugs on the basis of acceptable cost-effectiveness compared with placebo in patients dissatisfied with their current pain relief.”

There was another study submitted to PBAC, a comparison showing pregabalin as better than amitriptyline in cancer pain. At a dose of 600mg – at which point conscious state is altered.

What else changed from 2011? Dr Suzanne Hill, co-editor of ‘Evaluating Pharmaceuticals for Health Policy and Reimbursement’ *, was appointed chair of PBAC. This went down well with the pharmaceutical industry. She’s since returned to WHO in the Expert Committee on the Selection and Use of Essential Medicines , replaced with Prof Andrew Wilson per command of Health Min Sussan Ley – who’s been recently forced to resign due to misconduct. I have no idea if governance has improved, nor can inform as to whether it ever existed.

The drug really didn’t work. The 2012 NHMRC grants round allocated $0.62m (plus topups) to try Lyrica for sciatica – leg pain from back nerve damage. Last month PRECISE’s results were posted: no benefit over placebo, and 40% reported the adverse side-effect of Schwindel. Pfizer still won though – they didn’t have to pay for the study. In the interim, the musculoskeletal team of experts had railed against alternative approaches such as imaging – although that’s done with a view to inspecting the problem source for potential intervention at the site. Dr Hill’s colleague at WHO, Prof Lisa Bero didn’t ever respond to concerned memos regarding the probity of PRECISE, nor to complaints about the Monash/NHMRC cases of misconduct.

On the one hand, we trust pharma to do the studies, and on the other, we fund universities to do the studies on their behalf. Win, win for the industry.

*Page 37: “There is evidence that the research methods of trials sponsored by drug companies are at least as good as the trials sponsored by public resources, and in many cases they are better“, referencing Bero – “Study design in drug company sponsored clinical trials better than in research where no stated sponsorship”  in her thoughts. My opinion is that trial 1107 should publicly release the names of researchers, or am I asking too much? They’re kept secret, and bound by confidentiality, per NCT00407745: “There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI’s rights to discuss or publish trial results”.

 

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