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.

Bad medicine (Part 2)

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

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

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

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

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

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