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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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, but are now subject of a Freedom of Information legal demand for disclosure.

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? Have heart, the BMJ may come to the party.

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

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/