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no significant difference in analgesic efficacy between amitriptyline, duloxetine and pregabalin.“, and Trial 1107 – an unpublished, internal study run by Pfizer.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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2014© Medscape staff surveyed physicians on ethical issues, finding less than half confessed to a weakness for a freebie. That’s encouraging to drug reps, since influencing just a few Key Opinion Leaders pays dividends. So long as the flock all think alike, this being exemplified by a disclosure. The practitioner failing to practice what he preaches!drugreps
Dr Justin Coleman boldly challenged pharma thru his official position with Royal Aust College of GPs, fronting a well-publicised ‘no reps’ in the surgery campaign which raised ire among his fellows. Seriously, who’d ever believe wealthy physicians could be bought with a Bic? A humour-laden registrar tutoring session blogged recently under ‘Uncertain Dealings’ raises doubts. “Thus, when a patient complains of a painful lower back, my eventual diagnosis, after a thorough history and examination, is ‘low back pain’…. And, as for assuming my intervention of massage or gabapentin directly causes the pain’s eventual resolution, well…call me Dr Doubt!” Bon mots over a patient suffering pain aside, this is revealing. Gabapentin is an anti-convulsant for epilepsy, which happens to also fix everything – if Pfizer’s offlabel marketing is to be believed. Fines for such of $430m in 2004, $142m in 2010, and $615m (including $325m class settlement) in 2014 were just incidental costs alongside their promotional budget. The best evidence from Cochrane states that less than half of those with postherpetic neuralgia or diabetic neuropathy will obtain pain relief. So uncertainty over cause leads to a stab (glad he didn’t become a surgeon) that the pain originates from damaged nerves, and an indirect consequence of a hundred Pfizer Aust pain presentations to doctors in the previous 6 months just happens to be a prescription for Neurontin. And a little rub down there, in case of a herniated disc perhaps.

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

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

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

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