Category Archives: Conflicts of Interest

Medical censorship in the twenty first century

“If liberty means anything at all, it means the right to tell people what they do not want to hear.” George Orwell.

Many of you may be aware of an article published in the Lancet on the eighth of September. ‘Interpretation of the evidence for the efficacy and safety of statin therapy.’1 It caused a media stir, and I was asked to appear on a few BBC programmes to argue against it – tricky in two minutes. At one stage I was cut off when I attempted to bring up the issue of financial conflicts of interest amongst the authors. The lead author of this paper was Professor Sir Rory Collins.

In truth, I have been awaiting this article for some time. In fact, I am going to reproduce here a blog I wrote on February 16th 2015, predicting exactly what was going to happen, who was going to be involved, and (in broad terms) exactly what they were going to say:


A humiliating climb down – or a Machiavellian move?

Some of you may have seen a headline in the Sunday Express Newspaper ‘Statin, new safety checks.’ The subheading was ‘Oxford professor who championed controversial drug to reassess evidence of side effects.’

Those of you who read this blog probably know that the professor in question is Sir Rory Collins. He, more than anyone, has championed the ever wider prescription of these drugs. He has also ruthlessly attacked anyone who dares make any criticism of them.

You may remember that last year he tried to get the BMJ to retract two articles claiming that statins had side effects (correctly called adverse effects, but I will call them side-effects to avoid confusion) of around 18 – 20%.

He stated that these articles were irresponsible, worse than Andrew Wakefield’s work on the MMR vaccine, and that thousands would die if they were scared off taking their statins by such articles. Ah yes, the old ‘thousands will die’ game. A game I have long since tired of.

Is this story ringing any bells yet? The truth was that both articles quoted a paper which stated that 17.4% of people suffered adverse effects. So, yes, a pedant would say that the 18 – 20% figure was wrong – although not very wrong. Certainly not worth a demand of instant retraction, and apology, which is a very drastic step indeed.

Anyway, below is a short description of the findings of an independent panel set up by Fiona Godlee, editor of the BMJ, regarding the Rory Collins attacks:

“As previously reported, Rory Collins, a prominent researcher and head of the Cholesterol Treatment Trialists’ (CTT) Collaboration, had demanded that The BMJ retract two articles that were highly critical of statins. Although The BMJ issued a correction for both papers for inaccurately citing an earlier publication and therefore overstating the incidence of adverse effects of statins, this response did not satisfy Collins. He repeatedly demanded that the journal issue a full retraction of the articles, prompting The BMJ’s editor-in-chief, Fiona Godlee, to convene an outside panel of experts to review the problem.

The report of the independent statins review panel exonerates The BMJ from wrong doing and said the controversial articles should not be retracted:

“The panel were unanimous in their decision that the two papers do not meet any of the criteria for retraction. The error did not compromise the principal arguments being made in either of the papers. These arguments involve interpretations of available evidence and were deemed to be within the range of reasonable opinion among those who are debating the appropriate use of statins.”

In fact, the panel was critical of Collins for refusing to submit a published response to the articles:

“The panel noted with concern that despite the Editor’s repeated requests that Rory Collins should put his criticisms in writing as a rapid response, a letter to the editor or as a stand-alone article, all his submissions were clearly marked ‘Not for Publication’. The panel considered this unlikely to promote open scientific dialogue in the tradition of the BMJ.””1

To provide a bit more context at this point, you should know that for a number of years, people have been trying to get Rory Collins to release the data he and his unit (the CTT), holds on statins. [The CTT was set up purely to get hold of and review all the data on statins, it has no other function].

He has stubbornly refused to let anyone see anything. He claims he signed non-disclosure contracts with pharmaceutical companies who send him the data, so he cannot allow anyone else access. Please remember that some of the trials he holds data on were done over thirty years ago, and the drugs are long off patent. So how the hell could any data still be ‘confidential’ or ‘commercially sensitive’ now?

[The concept that vital data on drug adverse effects can be considered confidential, and no-one is allowed to see it, is completely ridiculous anyway. But that is an argument for another day.]

Now, amazingly, after running the CTT for nearly twenty years, Collins claims that ‘he has not seen the full data on side-effects.’ In an e-mail to the Sunday Express he stated that ‘his team had assessed the effects of statins on heart disease and cancer but not other side effects such as muscle pain.

Let that statement percolate for a moment or two. Then try to make sense of it. So, they have got the data, but not bothered to look at it? Or they have not got it – which surely must be the case if he hasn’t even seen it. Give us a clue. Either way, Collins states he has not assessed it.

Despite this, he still managed a vicious attack on the BMJ for publishing articles, claiming statins had side effects of around 20%. This was an interesting stance to stake, as he now claims he has no idea what the rate of side effects are? In which case he should make a grovelling apology to Fiona Godlee immediately.

What is certain, and must be reiterated, is that Rory Collins has consistently refused to allow anyone to see the side effect data, or any other data, that that the CTT may, or may not, hold. See e-mail below from Professor Colin Baigent to the ABC producer MaryAnne Demasi (she was trying to get the CTT to confirm that they would not release data, Colin Baigent is, or was, deputy to Rory Collins)

From: colin.baigent@xxxxxxxxxxx

To: maryannedemasi@xxxxxxxxxxxx

Subject: RE: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

Date: Tue, 24 Sep 2013 17:02:23 +0000

Dear Maryanne

The CTT secretariat has agreement with the principal investigators of the trials and, in those instances where trial data were provided directly by the drug manufacturers, with the companies themselves, that individual trial data will not be released to third parties. Such an agreement was necessary in order that analyses of the totality of the available trial data could be conducted by the CTT Collaboration: without such an agreement the trial data could not have been brought together for systematic analysis. Such analysis has allowed the CTT Collaboration to conduct and report all of the analyses on efficacy and safety that have been sought directly or indirectly by others (eg by Dr Redberg in her papers on the efficacy and safety of statins in primary prevention, and in questions raised by the Cochrane Collaboration). Hence, the CTT Collaboration has made available findings that would not otherwise have emerged.

I would be very happy to ring you at whatever time is convenient for you in order to help you to understand our approach, and then address in writing any residual concerns. It would be a shame if we were not able to speak as this would be the most effective way of explaining things.

Please let me know where and some times when I can reach you, and I will endeavour to telephone.

Colin Baigent.

I put the word safety in bold in this copied e-mail. You will note that Professor Colin Baigent does not say that that the CTT do not have these data on safety. He just says that the CTT won’t let anyone else see any data.

If they do have it, why have they not done this critically important review before, as they have had much of the data for over twenty years. If they don’t have it, how exactly is Rory Collins going to review it – as he states he is going to? Sorry to keep repeating this point, but I think it is absolutely critical.

Picture the scene in a lovely oak panelled office in Oxford, the city of the dreaming spires….

Professor Collins:             ‘Hey guys, you’re just not going to believe this, but a researcher just found a big box in the airing cupboard, and guess what, it has all the safety data in it….phew.’

Professor Baigent:           ‘Ahem… Why that’s lucky Professor Collins, now we can do the safety review.’

Professor Collins:             ‘Ahem… Indeed, Professor Baigent, we can. So, let’s get cracking shall we?’

And lo it has come to pass that after all these years Professor Collins has deigned to look at the safety data. This review shall, in Collins own words ‘be challenging.’ But you know what. I really don’t think they should bother, because we all know exactly what they are going to find….

That they were right all along, statins have no side effects. Hoorah, pip, pip. Nothing to see here, now move along.

A.N.Other Researcher:                    ‘Please sir, can anyone else see these data that you hold, to ensure that you are being completely open and honest?’

Professor Collins:                               ‘Don’t be ridiculous, these data are completely confidential.’

At this point I feel that I should ask how much do you, gentle readers, believe you can trust a review by Collins, on the data that Collins holds, on behalf of the pharmaceutical industry. Data that no-one else can ever see. [And the data from clinical trials on side effects is totally inadequate anyway].

Were I to be given the task of finding someone to review the safety data on statins, Professor Sir Rory Collins would not be the first person I would ask. He might even be the last.

1: http://www.forbes.com/sites/larryhusten/2014/08/02/no-retraction-for-you-review-panel-exonerates-medical-journal-in-statin-kerfuffle/

P.S. Actually, he would be the last.


I do not claim to be Nostradamus here. What was going to happen was obvious. The script had been written a long time ago. It was only a question of when, not if, it happened.

However, whilst the article itself is nothing new… and believe me, there is nothing new here. Just the same data stretched into three hundred references, and mind-blowing statistical obfuscation. It does, however, contain a few new Alice in Wonderland statements, such as the following:

‘If information on a particular outcome is not available from a randomised trial because it was not recorded, that would not bias assessment of the effects of the treatment based on trials that did record that outcome.’ How can this statement be made? For the first twenty years of trials on statins, no-one had noted that statins increase the risk of type II diabetes. It was not, as far as could be seen at the time, a problem.

Then, in a later study, JUPITER, all of a sudden it was found that there was a significant increase in type II diabetes. Now, it turns out that all statins increase the risk of type II diabetes. Had JUPITER not recorded the incidence of type II diabetes, this would never have been noticed. The cynics among you might say that they recorded this in the hope that the incidence would actually go down.

Here we have a perfect example of an outcome not recorded in the vast majority of statin studies. Had it been, it would have significantly biased the assessment of treatment. We also find that after two trials, 4S and HPS, found an increase in non melanoma skin cancer2, this outcome was not recorded, ever again, in statin trials. Outcomes certainly cannot make a difference if you do not record them. But if you did bother record them – who knows what might have happened.

This type of logic litters this Lancet paper, along with straw man argument after straw man argument. However, the purpose of this blog was not to discuss the evidence, such as it is, such as we are allowed to see, but to highlight why this paper was written and published. For this I shall turn to the editorial, accompanying the paper, written by Richard Horton. Who is the editor of The Lancet.

Read this, and be afraid, for it is the most frightening thing you will read this year. Possibly this decade and maybe the entire century as is a direct attack on human freedoms. Whilst couched in the usual life destroying scientific prose, what he is saying is that any who questions current accepted medical dogma should be very tightly controlled, and probably should not be allowed to publish anything at all.

The entire editorial is an exercise in trying to silence any dissent with what some might view as threats and bullying. This, I think, is the key paragraph (my emphasis in bold).

‘The debate about statins, as for MMR, has important implications for journals. Some research papers are more high risk to public health than others. Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review. The risk of publication should be explicitly discussed and evaluated. If publication is agreed, it should be managed with exquisite care.’

Now that, when you strip it down, is basically censorship.

Despite the seriousness of what Richard Horton is proposing, it is amusing to know what his published views on peer review might be, consider his statement that ‘Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review’:

‘The mistake, of course, is to have thought that peer review was any more than a crude means of discovering the acceptability — not the validity — of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong.’ https://en.wikipedia.org/wiki/Richard_Horton_(editor)

Anyway, you can read the editorial in full here (http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)31583-5.pdf). In addition to the paragraph highlighted above, I would like to draw your attention to a couple of other very worrying statements in the closing parapgraphs:

The Committee’s [Committee on Publication Ethics COPE] decision [not to investigate statin critics as demanded by ‘concerned’ scientists] points to a serious gap in UK science—the lack of a central institution where scientists who wish to question the actions or ethics of other scientists or scientific institutions can go. Allegations of research misconduct are best investigated by the institution where the original research took place. But that principle does not apply for some organisations, such as scientific or medical journals.

With no independent tribunal to consider allegations of research or publication malpractice, a damaging dispute has been allowed to continue unresolved for 2 years, causing measurable harm to public health.

The debate about statins, as for MMR, has important implications for journals. Some research papers are more high risk to public health than others. Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review. The risk of publication should be explicitly discussed and evaluated. If publication is agreed, it should be managed with exquisite care.

Authors and editors should be aligned on the messages they wish to convey, and every eff ort must be made to avoid misinterpretations and misunderstandings in the media. Editors also have to separate their roles as gatekeepers and campaigners. It is tempting to publish science that confirms pre-existing beliefs, especially if those beliefs underpin a campaign. Two ongoing campaigns—against Too Much Medicine and for Statin Open Data—continue to imply that statins are overused and that hidden harms remain to be exposed. As the Review we publish makes clear, the best available evidence indicates that neither statement is true.

Would this be the same Richard Horton, editor of the Journal, the Lancet,  who wrote? ‘Journals have devolved into information laundering operations for the pharmaceutical industry.’3

Would this be the Richard Horton who said? “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”4

And would this be the same man who followed it up with?

‘The apparent endemicity of bad research behaviour is alarming. In their quest for telling a compelling story, scientists too often sculpt data to fit their preferred theory of the world. Or they retrofit hypotheses to fit their data. Journal editors deserve their fair share of criticism too. We aid and abet the worst behaviours. Our acquiescence to the impact factor fuels an unhealthy competition to win a place in a select few journals. Our love of “significance” pollutes the literature with many a statistical fairy-tale. We reject important confirmations. Journals are not the only miscreants. Universities are in a perpetual struggle for money and talent, endpoints that foster reductive metrics, such as high-impact publication.’4

Couldn’t have put it better myself. Yet, despite the fact that Richard Horton knows that much of the research is flawed and distorted by ‘flagrant conflicts of interest’ he still seems to believe that the statin studies, uniquely in history, are perfect – and cannot be questioned in any way. “Doublethink means the power of holding two contradictory beliefs in one’s mind simultaneously, and accepting both of them.” (George Orwell).

What do other editors think of this latest paper? Well, we have the thoughts of Fiona Godlee (editor of the BMJ), and Rita Redberg (editor of the Journal of the American Medical Association). I will supply a few quotes from them in an article published in Medpage Today (http://www.medpagetoday.com/cardiology/cardiobrief/60122):

‘More generally, Godlee and Redberg lamented the absence of independent verification of the statin data. Redberg said that “none of the CTT data has been made available to other researchers, despite multiple requests.” “No one has seen these data except the trialists.” Godlee agreed. “Ideally all clinical trial data should be available for third-party scrutiny,” she said.

Godlee’s also noted that “this is not an independent review, this is a review by the trialists.” Redberg went further, saying that “the long declaration of interests is telling. The Oxford Clinical Trials Unit receives hundreds of millions of pounds of support from the pharmaceutical industry.”

Godlee said that the need for independent review is especially pressing in this case, given the public health implications of the call for widespread use of statins for primary prevention. Redberg went even further and observed that “all of this data is from industry-sponsored studies, with concern for bias.”

As they went on to say

‘Redberg also pointed out some unintended consequences of statin usage. “Data shows that people on statins are more likely to become obese and more sedentary over time than non-statin users, likely because people mistakenly think they don’t need to eat a healthy diet and exercise as they can just take a pill to give them the same benefit (Sugiyama et al. JAMA IM 2014). So it seems this review affirms that many healthy people who feel perfectly well can take a pill every day, not live any longer, suffer any number of adverse effects, all to treat the ‘disease’ of LDL. I maintain the best way to reduce cardiac risk is to eat a Mediterranean-style diet, get regular physical activity, don’t smoke, and enjoy yourself.”

Godlee also emphasized the limitations of primary prevention. “Evidence about poor adherence to statins has long been known,” said Godlee. “People don’t want to take a drug forever. The problem didn’t arise with the BMJ study.”

It also seems likely that the Lancet paper exaggerated the benefits of primary prevention. The long-term benefits of primary prevention in the paper were based on modeling. The calculated benefits might have been a best-case scenario.’

In short, they did not think much of this paper, and Fiona Godlee was particularly concerned about the censorship element:

‘Godlee rejected the comparison of the BMJ papers to the Lancet Wakefield paper and objected to the idea that it’s too dangerous to publish papers critical of statins. “Where do you stop and where does that begin?” she wondered. She also pointed out that public concern over statins in the U.K. became elevated, not after the publication of the BMJ papers, but after Collins brought attention to the papers in a public denunciation of the papers on the BBC.

“We have to allow debate, I don’t know where you would draw the line,” she said. “In terms of public debate, the statin debate is fascinating and deserves airing.”

So, thank goodness for them. I shall stop now, although there is much still to say, because this blog is already very long and people may fall asleep reading it. However, I think this is such an important issue – potential censorship in medical research – that I felt I absolutely had to write something. So, here it is.

I shall finish on two things. Firstly, to state the Uffe Ravnskov, who has been a long-term campaigner against the cholesterol hypothesis, and statins, had one of his books, burned, during a live television debate. I do not have any footage, but here is my attempt to replicate the scene using a photograph from the past.

pic1

Secondly, here is a list of some of the conflicts of interest of the authors of the paper.

Declaration of interests

JA, CB, LB, RC, JE, RP, DP, and CR work in the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford. The CTSU has received research grants from Abbott, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Schering, and Solvay that are governed by University of Oxford contracts that protect its independence, and it has a staff policy of not taking personal payments from industry (with reimbursement sought only for the costs of travel and accommodation to attend scientific meetings). RC is co-inventor of a genetic test for statin-related myopathy risk, but receives no income from it. DP has participated in advisory meetings for Sanofi related to PCSK9 inhibitor therapy in his previous employment. The CTT Collaboration, which is coordinated by CTSU with colleagues from the University of Sydney, does not receive industry funding. JD has received research grants from, and served as a consultant to, Merck and Pfizer. GDS hast twice received travel and accommodation funding and honoraria from Merck; DD receives compensation for serving on data monitoring committees for clinical trials (including of statins) funded by Abbvie, Actelion, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Sanofi , and Teva. NW and ML are inventors of a combination formulation for the prevention of cardiovascular disease that includes a statin, covered by patents licensed to Polypill in which they both hold shares and which owns the website polypill.com. SMac has received research grants for research on statins and polypill development from Bristol-Myers Squibb and BUPA. SMar is co-inventor on a pending patent for a LDL cholesterol estimation method, and has served as an advisor to Sanofi, Regeneron, Quest Diagnostics, Pressed Juicery, and Abbott Nutrition. NP has received research grants and honoraria for participating in advisory meetings and giving lectures from Amgen, Lilly, Menorini, and Merck. PR has received investigator-initiated research grants from Amgen, AstraZeneca, Kowa, Novartis, and Pfizer. PSa has received research grants and honoraria for consultancies from Amgen and Pfizer. LS has undertaken advisory work unrelated to statins for AstraZeneca and GlaxoSmithKline. SY has received a research grant from AstraZeneca through Hamilton Health Sciences. AR declares that George Health Enterprises, the social enterprise arm of The George Institute, has received investment to develop combination products containing statin, aspirin, and blood-pressure-lowering drugs. JS has received grants from the National Health and Medical Research Council, Australia; Bayer Pharmaceuticals; Roche; and Merck Serono. RB, SE, BN, IR, and PSa declare no competing interests.

[This list is far from complete. Paul Ridker, for example was (and may still be) a board member of Merck Sharp and Dohme, the maker of simvastatin at the time. Something he failed to report in a paper entitled: ‘Association of LDL Cholesterol, Non-HDL Cholesterol and Apolipoprotein B level with risk of cardiovascular events among patients treated with statins: A meta-analysis.’6 And something he has not mentioned here either.]

 

1: http://www.thelancet.com Published online September 8, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31357-5

2: Hung SH, Lin SC, Chung SD. Statins use and thyroid cancer: a population based case-control study. Clin Enodocrinol (Oxf) 2014 published online 30 July 2014,doi:10.111/cen.12570

3: Richard Smith. “Medical journals are an extension of the marketing arm of pharmaceutical companies.” Public library of Science. (May 17, 2005).

4: http://www.thelancet.com Vol 385 April 11, 2015

5: http://www.medpagetoday.com/cardiology/cardiobrief/60122

6: Correction. “Unreported Financial Disclosures in: Association of LDL Cholesterol, Non-HDL Cholesterol, and Apoliprotein B levels with risk of cardiovascular events among patients treated with statins: a Meta-analysis.’ JAMA. (April 25, 2012].

What causes heart disease – part XIII

Heart disease and inflammation.

A few people have sent me links to a recent paper called ‘Inflammation and Atherosclerosis.’ This was published in Circulation, and the authors were: Peter Libby, MD; Paul M. Ridker, MD; Attilio Maseri, MD. Remember two of the names.

Here is a relatively long section of the abstract:

‘Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis.

Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors.

Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.http://circ.ahajournals.org/content/105/9/1135.full

This paper interested me for a number of reasons. I focused down for a few moments on the phrase ‘Atherosclerosis, formerly consider a bland lipid storage disease…’ Does this mean that the world is moving on… Atherosclerosis has nothing to do with lipids e.g. LDL a.k.a. ‘bad cholesterol’? Now that would be something. Especially as it was published in the mainstream CV journal ‘Circulation.’

It seems that these authors are trying to shift the thinking away from cholesterol to inflammation. However, before discussing anything else I wanted to point out something that most people may have missed – by looking at a bit of background on the authors. First, Paul Ridker, who ran the JUPITER study, and who is a hugely influential cardiologist.

It should be noted that Paul Ridker has a major interest in moving thinking about atherosclerosis from a lipid storage disorder to an inflammatory condition. Because he has patent on the high sensitivity CRP test (C-reactive protein).

‘Dr Ridker is named as a coinventor on patents filed by the Brigham and Women’s Hospital that relate to the use of inflammatory markers in cardiovascular disease.’ http://circ.ahajournals.org/content/108/12/e81.long

What this means is that every time someone uses a high sensitivity CRP test, Paul Ridker becomes a little bit richer. However, in this paper, this massive financial conflict of interest is not mentioned. Instead, we get Acknowledgements:

This work was supported in part by grants from the National Heart, Lung, and Blood Institute to Drs Libby (HL-34636, HL-48743, and HL-56985) and Ridker (HL-58755 and HL-63293), and by the Leducq Foundation (to Drs Libby and Ridker). Dr Ridker is also supported by a Distinguished Scientist Award from the Doris Duke Foundation. Dr Maseri is supported by a grant from Fondazione Internazionale di Ricerca Per il Cuore onlus

No conflicts Dr Ridker? Mind you, Paul Ridker does have considerable form in not disclosing his financial conflicts. Some years ago, the Journal of the American Medical Association JAMA, was forced to publish a statement on ‘Unreported Financial Disclosures’ that were spotted in paper ‘Associations of LDL, Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B levels With Risk of Cardiovascular Events Among Patients Treated with Statins: A meta-analysis.’

This statement mentioned many, many conflicts that the authors had failed to mention at the time. The section on Dr Ridker reads thus:

‘…Dr Ridker reports board membership of Merck Sharp and Dohme and receipt of a grant or pending grant to his institution from Amgen.’ [Amgen, as you may know are pushing PCSK-9 inhibitors]. This is covered in my book Doctoring Data.

Just to spell this out in a little more detail, Paul Ridker was an author on a meta-analysis of statins, yet failed to report that he was a board member of a pharmaceutical company (Merck) that marketed statins.

In truth, the moment I saw a paper promoting the ‘new idea’ that atherosclerosis is all due to inflammation, my antennae started to twitch. Especially when I knew that Paul Ridker was involved. A man who holds patents on a test for the inflammatory marker that we should be using.

I then immediately wondered, Is Paul Ridker now running a clinical trial on behalf of a pharmaceutical company, looking at the use of an anti-inflammatory agent to treat CVD. So, I had a little look round the internet. And guess what. Paul Ridker is, indeed, running a trial on an ant inflammatory for the treatment of CVD. The CANTOS study http://www.thecantos.org/steering-committee.html If you look down the list those on the committee running this study, you will find that Peter Libby is also on the steering committee. A conflict that remained unmentioned in the Circulation paper either.

What is the drug, it is Canakinumab. Here, from Wiki:

Canakinumab (INN, trade name Ilaris, previously ACZ885) is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.

Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the U.S. Food and Drug Administration (FDA) on June 2009[4] and by the European Medicines Agency in October 2009.CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.

Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial was completed in October 2009. Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease, gout and coronary artery disease. It is also in trials for Schizophrenia. In gout it may result in better outcomes than a low dose of a steroid but costs five thousand times more. https://en.wikipedia.org/wiki/Canakinumab

I thought I would highlight the final sentence, just to give you some idea of the potential cost of this drug, should it ever be marketed for the treatment of CVD.

I know that this may seem a diversion. However, I have been around the world of cardiovascular research for long enough to take nothing at face value. Here is a paper suggesting that atherosclerosis has little or nothing to do with lipids. It is primarily due to inflammation. Which is a reasonable hypothesis. But guess what, one of the authors has a patent for an inflammatory marker. He and another author are running a clinical study, funded by Novartis, on the use of an anti-inflammatory agent in CVD.

However, just because there is money in the background, it does not necessarily mean that everything written is wrong. Perhaps inflammation truly is the underlying cause of atherosclerosis. Many other people have been saying this for years. Some of them, I know, certainly believe it from a purely objective scientific perspective. For example, Duane Graveline – who writes a great deal about CVD on his blog www.spacedoc.com, and is also a friend. He fully believes that atherosclerosis is an inflammatory condition, and he has no horse in the race.

My own take on this matter is slightly different. Yes, if you have a high C-reactive protein (CRP) level, this means that there is inflammation going on within the artery, and this is a sign of increased CVD risk. This is true, but what does it mean? Is the inflammation causing the CVD?

Whenever I see anyone stating that inflammation is a cause of anything I simply change the word inflammation to the word ‘healing,’ to see how sensible it then sounds. Inflammation is, in most cases, the way the body heals itself after injury. If you twist your ankle, it will become swollen and inflamed. The injury comes first, then you get the inflammation/healing. You would be hard pressed to state that inflammation causes twisted ankles.

Of course, there are some conditions where the inflammation itself can become greater than the original problem. Just to name three: Asthma, Crohn’s disease and Rheumatoid arthritis. In these diseases the body’s inflammatory/healing system becomes revved up, and starts attacking itself. This out of control inflammation can then lead to further problems downstream e.g. joint destruction. Such conditions are often ‘treated’ or controlled by anti-inflammatory agents e.g. steroids.

Equally, if you have Systemic Lupus Erythematosus (SLE), this is an ‘inflammatory’ disease, and you also have a severe vasculitis (inflammation of vasculature). As mentioned before SLE can raise the risk of CVD, in young women, by up to five thousand per cent. Case proven? Inflammation causes atherosclerosis?

No, I don’t think so. The sequence in SLE is that the vasculature is damaged (the endothelium is damaged). This stimulates the body to try and heal the damage. The healing is what we call inflammation and the C-reactive protein level goes up.

Get rid of the inflammation, and you will not be treating anything. You will simply be interfering with the healing process, and the CVD will, most likely, accelerate. Even if C-reactive protein levels go down, along with any observable inflammatory action.

If I may return for a moment or two to twisted ankles. To quote Dr Mirkin:

‘When I wrote my best-selling Sports medicine Book in 1978, I coined the term RICE (Rest, Ice, Compression, Elevation) for the treatment of athletic injuries. Ice has been a standard treatment for injuries and sore muscles because it helps to relieve pain caused by injured tissue. Coaches have used my “RICE” guideline for decades, but now it appears that both Ice and complete Rest may delay healing, instead of helping.’

As he goes on to say:

‘Anything That Reduces Inflammation Also Delays Healing [I cannot resist stating that, this is because inflammation is healing]

Anything that reduces your immune response will also delay muscle healing. Thus, healing is delayed by:

  • cortisone-type drugs,
  • almost all pain-relieving medicines, such as non-steroidal anti-inflammatory drugs like ibuprofen
  • immune suppressants that are often used to treat arthritis, cancer or psoriasis,
  • applying cold packs or ice, and
  • anything else that blocks the immune response to injury.’ http://www.drmirkin.com/fitness/why-ice-delays-recovery.html

At least Dr Mirkin has had the grace to admit that he was wrong. RICE reduces inflammation, but interferes with healing.

I am pretty certain that exactly the same thing will happen with ‘inflammation’ in CVD. I can state this with relative confidence, because the most powerful anti-inflammatory agent known to man are steroids/corticosteroids. Corticosteroids e.g. prednisolone, or hydrocortisone are potent anti-inflammatory agents, they are all based on the natural stress hormone cortisol – produced in the adrenal glands. Steroids = corticosteroids = cortisol (just about).

Cushing’s disease is a disease whereby too much cortisol is produce in the adrenal glands, usually due to a small tumour that overproduces the hormone. So, if you have Cushing’s disease, you have a powerful anti-inflammatory agent coursing through your blood vessels – at all times. And what is the effect of this on CVD?

‘In patients with Cushing’s syndrome (CS) cardiovascular complications determine a mortality rate four times higher than in an age- and gender-matched population.’ http://www.ncbi.nlm.nih.gov/pubmed/15579193

The same thing happens when you prescribe steroids, for various conditions:

‘Individuals who use glucocorticoids and exhibit iatrogenic (caused by the medicine) Cushing’s syndrome should be “aggressively” targeted for early screening of cardiovascular (CV) risk factors, say researchers.

Laurence Fardet (University College London, UK) and colleagues found that individuals with iatrogenic Cushing’s syndrome who were prescribed glucocorticoids had a significantly higher incidence of CV events (including coronary heart disease, heart failure, or ischemic cerebrovascular events) than individuals prescribed glucocorticoids without iatrogenic Cushing’s syndrome, or those not prescribed glucocorticoids.

Indeed, Cushing’s syndrome patients prescribed glucocorticoids had a CV incidence rate per 100 person-years at risk of 15.1 compared with 6.4 and 4.1 in those without Cushing’s but who were prescribed glucocorticoids and those not prescribed glucocorticoids, respectively.

Multivariate analysis revealed that iatrogenic Cushing’s patients had a 2.27-fold increased risk for coronary heart disease, a 3.77-fold increased risk for heart failure, and a 2.23-fold increased risk for ischemic cerebrovascular events.’ http://www.news-medical.net/news/20120807/Cushinge28099s-patients-must-be-screened-for-heart-disease.aspx

Proving a medical hypothesis is never that simple. However, if you believe that CVD is due to inflammation, then the world’s most potent anti-inflammatory agents ought to decrease CVD risk. Instead, it increases it by at least 400%. [Far more in some studies]

Other anti-inflammatory agents, known as Non-steroidal anti-inflammatories (NSAIDs) also greatly increase the risk of CVD. Vioxx (a potent NSAID), launched then pulled off the market, was estimated to have killed over one hundred thousand people in the US alone, from increasing CV risk.

In short, if CVD is primarily a disease of inflammation, then potent anti-inflammatory agents ought to reduce the risk. Instead they increase it massively. There is no doubt that inflammation is associated with CVD. Equally, if you measure C-reactive protein (a marker of inflammation), a high level is associated with a higher risk of CVD. However, it is not a cause, and if you try to reduce inflammation you will almost certainly increase the risk of CVD, not decrease it.

Ergo. Inflammation is sign of active CVD. That is all.

Lowering cholesterol – an urgent Christmas appeal

A reader of this blog sent me this e-mail message that she had just received:

This is a special Cholesterol e-News Bulletin asking for your help to draw your urgent attention to a recent decision by NICE that is of great concern to us.

There has been significant progress in the management and treatment of cardiovascular disease (CVD) over the past two decades, which has resulted in an overall decline in CVD deaths in the UK. Heart disease still remains one of the UK’s biggest killers. Over half of all UK adults have raised cholesterol increasing their risk of cardiovascular disease; leading to heart attacks and strokes. Not only does it have a devastating impact on patients and their families, but it also places significant burden on our health service and wider economy.

Innovative new medicines, such as PCSK9 inhibitors, are an exciting development in the treatment of cholesterol, with little known side effects and very good scientific evidence that they work to significantly reduce the levels of bad cholesterol in those at high risk of CVD.

NICE reviewed the first of these PCSK9 medicines and recommended that it should not be available for NHS patients.

HEART UK is concerned by NICE’s recent decision to turn down the use of the first of the PCSK9 medicines. This means patients will not have access to the best possible treatment options to help lower the levels of bad cholesterol, particularly those at high risk such as people with an inherited high cholesterol condition called Familial Hypercholesterolaemia.

NICE are conducting a second round of consultation, closing on Tuesday 8th December, before issuing final guidance. On behalf of the patients in England adversely affected by this decision, please join HEART UK’s efforts to reverse this decision and allow PCSK9 inhibitors to be more freely available for NHS patients.”

NICE = The National institute for Care and Health Excellence. Let us not dwell for too long upon that self-aggrandizing title. NICE was set up in the UK, initially to look at whether or not various healthcare interventions represented good value for money, or poor value for money.

For reasons beyond the understanding of man, they plucked a figure from the sky one day (well not a figure, a range) from £20 – £30K ($33 – $48K) per year. If the intervention cost more than £20 – £30K/year to provide one added year of full quality life, then they turned it down. [One year of full quality life = 1 QALY (quality adjusted life year)]. And breathe.

Of course, NICE make all sorts of exceptions (all cancer drugs get funded no matter how much they cost, or how useless they are – go figure) and the way NICE words out how much interventions actually cost/ per QALY is complete nonsense in many cases. Be that as it may, they do make an effort to say ‘How much!’ ‘You must be joking,’ Reject…bong!

If NICE do say, reject, bong! This basically means that the drug will not be prescribed to anyone in the UK. In addition, such is the influence of NICE that many other countries use their decisions as an important guide for what they will do with regard to funding. So if NICE turn a drug down, this is very bad news from the manufactures or said drugs.

Now, when it comes to the new cholesterol lowering agents (PSCK-9 inhibitors) the manufacturers have a problem. Which is that they cost around £4 – £8K ($6.4 – $12.8) per year, per patient. Now, at those sort of costs, you are going to have to have some seriously impressive benefits. At present, however, the manufacturers have no data on mortality, or morbidity. Which makes the current cost per QALY = infinity. Just slightly above the NICE thresholds.

For those who read my blog you will know that I wrote the following in ‘Changing the definition of Familial Hypercholesterolaemia.’

At present I would think that the response of NICE (to PCSK-9 inhibitors) would be ‘Are you out of your tiny little minds. Why the [[…] insert swear work of choice here], would we fund this?’ At least I would certainly hope this would be their response. Imagine if everyone on statins in the UK, around seven million, changed to PCSK9 inhibitors This would cost £56 billion pounds [$80Bn] a year. A tidy little sum. Half of the entire NHS budget.

As it turns out NICE did turn down the first PCSK9-inhbitor, no surprise there. And this is where HEART UK comes in….

Before going any further I should state that there are, currently, two PCSK9-Inhibtors launched/launching. They are Repatha ‘evolocumab’ made by Amgen. And Praluent ‘alirocumab’ to be co-marketed by Sanofi and Regeneron. They are, to all intents and purposes, identical drugs doing identical things. Remember the names Amgen and Sanofi. Amgen and Sanofi….

Now HEART UK states that it is a charity. HEART UK – The Cholesterol Charity – campaigns to increase general public and policy makers’ awareness of raised cholesterol as a major public health concern. We campaign to keep action on cholesterol at the forefront of the health debate.’ 1

Where do HEART UK get their funding from. Difficult to tell precisely. They claim to get money from public donation… how much? It’s a secret. What I do know is that they receive a very large amount of funding from companies that have cholesterol lowering products. So, for example Nestle, who make Shredded Wheat, pay HEART UK money, and HEART UK says stuff like

‘HEART UK dietician Linda Main said: “Shredded Wheat and Shredded Wheat Bitesize are low in saturated fat and can play an important role in a heart healthy diet and HEART UK is delighted that these products are supporting National Cholesterol Month and the Great Cholesterol Challenge.’2

Kerching!

Of course, when it comes to cholesterol lowering PCSK9-Inhibitors are the big daddies, with the big, big, budgets. So, you would expect that Amgen and Sanofi would be very, very, close to HEART UK. Well, if you expected that, you would be right. If you want to visit the HEART UK website, and look at the sponsors of their conference we have3:

Sanofi:                     Exclusive conference sponsor

Amgen:                   Sponsored symposia 1

Sanofi:                    Sponsored symposia 2

Amgen:                   Privileged sponsor…etc.

And now, to bring the two strands of this little tale together. NICE have just turned down the first PCSK9-inhbitor and so we have HEART UK reaching out to everyone that they know, or have contact with, to plead with them to sign a petition ‘On behalf of the patients in England adversely affected by this decision, please join HEART UK’s efforts to reverse this decision and allow PCSK9 inhibitors to be more freely available for NHS patients.’ Sob. But what about Tiny Tim?

Some people, were they to be truly cynical, would allege that HEART UK may not be trying to get NICE to reverse their decision on PCSK9 – inhibitors, for the great good of humankind. But because they are being paid large sums of money by the manufacturers of PCSK9-inhbitors. Shame on anyone for thinking such a thing. With Christmas coming this should be a time of peace and happiness. Such cynicism has no place in my thoughts. No sirree.

[And for my Christmas quiz the reader with the best answer to the following question will have it published on my blog. ‘What is a health charity, and should they be allowed to accept sponsorship from pharmaceutical companies?’]

1: http://heartuk.org.uk/policy-and-public-affairs

2: http://heartuk.org.uk/latest-news/article/press-release-shredded-wheat-to-support-heart-uks-national-cholesterol-mont

3: http://heartuk.org.uk/news-and-events/meetings-conferences/heart_uk_annual_conference/sponsors

The longest journey

Whilst on a short break I picked up the Times Newspaper on Friday the ninth of October. There were two headlines. The main one was ‘Fizzy drinks giant pays millions to diet experts.’ On the other side of the page was ‘Revolution for FIfa after Blatter gets red card.’

The fizzy drinks company was, of course, Coca Cola. I wondered why the headline did not say ‘Coca Cola pays millions to diet experts.’ Perhaps that was just a step too far to upsetting a major advertiser. Although I note that the picture of Sepp Blatter had a large Coca -Cola sign above his head. So, somebody at the Times clearly has a sense of humour.

Now I looked at these headlines and I thought, as I find myself doing most of the time nowadays. Corruption, corruption, corruption everywhere. Sepp Blatter is almost heroic in his ability to brush aside allegations against him and his organisation. ‘I knew nothing about anything.’ Seems to be his defence. Well, if he didn’t know anything he’s incompetent, if he did, he is corrupt. I suspect both.

As for Coca Cola. They just pay ‘experts’ large sums of money, and the expected messages flow forth. According to the Times article they set up the European Hydration Institute to promote… hydration. Which sounds quite innocuous and nothing to do with Coca-Cola at all.

However, guess which drinks people should hydrate themselves with. Why…. Let me think. They get a Professor Ron Maughan to state the dehydration was an ‘unrecognised danger’ for drivers. Drivers should regularly stop and buy drinks to ensure they are properly hydrated with drinks such as… Why… let me think.

Of course, by pretending the European Hydration Institute is some sort of independent academic body, such messages are not simply seen as adverts for Coca Cola, Oasis, and suchlike. This arm’s length marketing is a very old trick now. Heart UK is a charity which is dedicated to warning of the dangers of cholesterol. Heart UK ruthlessly promotes cholesterol lowering as the most important function of the medical profession. Of course it is almost entirely funded by pharmaceutical companies who make cholesterol lowering drugs. [I would say entirely funded, but I am not absolutely sure about this].

Various experts give talks on behalf of Heart UK, paid for by Heart UK, then claim they receive no money from the pharmaceutical industry. Which is, of course, technically correct. They do not receive money from the pharmaceutical industry. Heart UK receives money from the pharmaceutical industry, they then pay the expert, and the expert need not even declare a conflict of interest. ‘How dare you say that I take money from the pharmaceutical industry, you dirty knave…. I did this work for a charity. A charity I say.’

This is also how Sir Rory Collins works. He runs the Clinical Trial Service Unit (CTSU) in Oxford. It runs trials that are almost entirely funded by the pharmaceutical industry. Nearly three hundred million pounds sterling ($500m) over the last ten years or so. He states he receives no money from the pharmaceutical industry, and therefore is not biased in any way. Once again…Industry pays CTSU, CTSU pays Sir Rory Collins = no payment from industry and no conflicts of interest. And if you believe that.

Wherever you look. Wherever I look it is the same old story. Experts are inevitably bought and paid for by one company or another. The messages that come out are universally supportive of the company’s products. If you are not sufficiently supportive the companies will go find something else to turn into an ‘expert.’

As the Times reports ‘In 2013 Spanish researchers found that scientific papers on sugary drinks that were sponsored by or had potential conflicts of interest with the food and drink industry, including Coca-Cola were five times more likely to find no link with obesity than similar papers that were independently funded. They recommend “special efforts to preclude funding by parties with vested interests at all levels.’

In truth, I don’t care that much about Fifa and the endemic corruption thereof. If people can be bribed sufficiently to hold a World Cup in Qatar, average summer temperature 50c, the world is not going to come to an end. Although a few footballers might. Obviously, it would be better if the countries with the best bid actually won, but no-one is going to die. Probably.

However, if companies such as Coca-Cola can fund research that distorts science and promotes the consumption of sugary drink, and helps to create millions upon millions of people with type II diabetes then this is very serious stuff indeed. The increase in morbidly and mortality could end up bankrupting health services around the world.

I know that all organisations and companies, if they are not properly policed, will end up travelling the road to corruption. It seems an immutable law of commerce. In a way I don’t blame the companies. They are, by their nature wolves. If I have a thousand sheep in a field and find the wolves circling, I do not say the wolves, ‘now, really, I do not want you to eat the sheep. Do you promise?’

Wolves: ‘Yes, we promise.

Shepherd: ‘Good.’

Next day, shepherd arrives, sheep mostly eaten, wolves fat. Well, what do you expect? Wolves eat sheep. It is what they do. If you want to stop this happening, build a bloody great fence, or buy some guns, or both. Don’t rely on wolves to suddenly start acting like sheepdogs.

No, I don’t blame the companies for being companies. I blame our politicians. It is only they who can create a system of policing and punishment that will stop companies corrupting researchers, or corrupt researchers demanding money from companies. Yes, this is not a one way street. You can’t have corruption if researchers don’t take bribes.

Unfortunately politicians seem perfectly uninterested in corruption in the medical field. Is it because they themselves are being bribed. I am certain that this is part of it. In the UK large numbers of MPs are non-exec directors of private health companies, and the corporate world swirls around and within the political arena far, far, too closely. Before the last election David Cameron stated that lobbying would be next great scandal.

He says nothing of the sort now, yet lobbying and manipulating on behalf of large corporations has become worse and worse. The UK has not yet reached the situation in the US where lobbyists outnumber politicians by about a hundred to one…. Or thereabouts. And when politicians stop being politicians they immediately become lobbyists. But we heading in that direction.

So where are we? A long, long way down the longest road. The road that ends with everyone in any position of power becoming, essentially, a spokesman for large corporations, where there is no-one left who can or will do anything to stop it. Because, sadly, they are all in it together. I write that last sentence and think, oops, have I just become a conspiracy theorist. Then I think. No, I am not a conspiracy theorist, I am simply Winston Smith.

Study 329 – where the hell is the outrage?

To quote from the BMJ ‘No correction, no retraction, no apology, no comment…’

Study 329 was started in 1994 by Smith Kline Beecham, which shortly become part of the larger conglomerate Glaxo Smith Kline (GSK). Study 329 looked at the use of paroxetine, an anti-depressant, in adolescents with depression.

Following this study paroxetine was promoted and marketed heavily by GSK as demonstrating, in the words of GKS marketing materials: ‘REMARKABLE Efficacy and safety’. Over two million prescriptions were then written for children and adolescents in the US.

However, in 2002 the FDA considered study 329 to be a ‘failed trial.’ In 2003 the UK recommended that paroxetine should not be used in children and adolescents with depression because it increased the risk of self-harm and potentially suicidal behaviour.

In 2004 the FDA placed a black box warning on all antidepressants in adolescents and children stating that they increased the risk of suicidal thinking and suicidal behaviour in these groups. In 2012 GSK finally agreed to pay £2Bn for fraudulently promoting paroxetine.

But the story does not end here. A group of researchers, who had been heavily critical of this trial, finally managed to get hold of the raw data and carried out a re-analysis under the restoring invisible and abandoned trials (RIAT) initiative. Yes, this saga has been a long one.

The reanalysis was recently published in the BMJ with sadly predictable results. The primary conclusion was that ‘Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was increase in harms in both groups.’

This is in stark contrast to the original trial results. When it was first published it appeared to demonstrate very clearly that paroxetine was both safe and effective in adolescents with depression. According to GSK it demonstrated ‘.remarkable efficacy and safety’ However, using exactly the same trial data, reanalysed by independent researchers, we now find that paroxetine was both useless and damaging.

So, what has been the consequences for those involved in the initial trial and the writing up thereof? For those who read the BMJ, you will know that I am now quoting verbatim here:

  • Despite subsequent FDA and MHRA warning about increased risks of suicidal thinking and behaviour and GSK receiving a record fine, partly for illegal off-label promotion of the drug, the original report has not been retracted or even had a correction
  • Academic and professional institutions have failed to publically address the many allegations of wrongdoing
  • None of the named authors had intervened to correct the record. An internal enquiry by the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) concluded that no further action was necessary
  • Brown University remains silent over its involvement in the study. It refuses even to confirm or deny whether any investigation took place1

I will add to this that a co-author of study 329, Karen Wagner, named eight times in the 2011 US Department of Justice complaint against GSK, is currently the president elect of the American Academy of Child and Adolescent Psychiatry – whose journal, the JAACAP, is where the original study was published.

Taking stock. What do we have? A study was done, and published, demonstrating that paroxetine was safe and effective. The trial data were heavily promoted, resulting in millions of children and adolescents being prescribed paroxetine.

The reality is that this drug was completely ineffective and increased the risk of suicide (amongst other things). This has all been known for many years. The latest re-analysis simply confirms everyone’s worst fears.

So surely someone, somewhere, got punished? No they did not. Not only that, but the original published study has not even been retracted. It still sits in the medical database. A young and innocent researcher could come across it, and reference it, and use data from it to support a grant application for a study to use antidepressants in children.

If this were not all completely and absolutely one hundred per-cent fact, you might think we have a possible plot line for a dystopian novel here. A story of terrible corruption where large corporations can distort data through one hundred and eighty degrees, and get away with a fine. A world where bent researchers promote research that results in more children committing suicide, and then move on positions of greater power and authority – with no censure from anyone. To become presidents of major medical societies, for example.

Frankly I don’t think I would dare to write a novel with a plot so completely outrageous. Surely someone, somewhere, would be punished for this behaviour. Surely the paper would be retracted. Surely a co-author of such a study would not be in line for a prestigious position. Surely the public would rise up in outrage.

In truth, it seems, nothing is going to happen at all. I must dig out 1984 and read it again, just to depress myself even further.

1: BMJ 2015;351:h4629

The Augean Stables – part II

It has become clear that much of medical research is flawed, and so inherently biased that much of it/most of it simply cannot be relied upon. One of the strongest critics of this current situation is a brilliant statistician, Professor John P Ionnadis. His seminal paper on the subject of medical research, which is nearly ten years old now, was entitled ‘Why Most Published Research Findings Are False ‘. I include the abstract here:

‘There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias1.’

Has his work been contradicted by anyone? The answer would be a resounding… no. In fact, all that has happened over the last ten years is more and more confirmation that medical research has become worse.

This is an incredibly worrying situation, yet very few people seem in the slightest bothered. The status quo remains in status. When new medical studies come out the press continue to regurgitate the findings as though they are unquestioned gospel. Experts have maintained their status as demi-gods, to be fawned upon as though their work is beyond any possible reproach.

Guidelines, the ones that instruct doctors on how to treat various conditions, are still published without any provisos. Guidelines which are based on evidence that… ‘may often be simply accurate measures of the prevailing bias.’ But woe betide any doctor that fails to follow said guidelines, for they may well be struck off the medical register. In the US, you could end up in jail.

All of these things are bad enough, and there are many other problems. However, in this blog, I want to focus on another issue. Namely, what about placebo controlled studies? Just to make it clear, for those who know a great deal about this area, I am not looking at the issue of ‘what the hell is in placebos anyway, cos it sure as hell ain’t inert substances.’ Whilst the fact that you cannot find out what manufacturers actually put in placebos, which should be inert ‘sugar pills’, but most certainly are not, is extremely important, that is an issue for another day.

Today’s issue is as follows. We have reached a situation in medical research where it may never be possible to find out if certain treatments actually work. Sub-header… ‘And in which case we are all doomed.

Here is the context. Once a treatment has been found to be superior to a placebo, it will be deemed unethical ever to carry out a placebo controlled study ever again. That may not mean much to many people, so I shall expand – using a concrete example (yes, statins again).

If placebo controlled studies have shown that statins reduce the risk of heart disease, and for the sake of argument let us accept that this is true, where does this leave us? It leaves us in the position whereby, if anyone wanted to set up a study to try and disprove that statins are no better than placebo, they will never be given permission to do so.

Why not? Well, before you are allowed to carry out a clinical study, you have to present it to an ethics committee. This committee will look at the proposal and decide if it is indeed ‘ethical.’ Exactly what this means is up for debate. However, if you decided to study the speed at which cars need to run into children, to result in a fifty per cent mortality rate, I imagine you would be turned down by the ethics committee.

More prosaically, if you have found that statins reduce the risk of dying of heart disease vs placebo, then you will no longer be allowed to do a placebo controlled statin trial ever again. The reason for this is that you have already ‘proved’ that statins are superior to placebo. So it will argued that any volunteer placed in the placebo arm of your study would be suffering avoidable harm. Bong! Ethics committee says no. We know statins work, so it is unethical not to give them.

The only studies the ethics committees will allow would be statins vs. statins and a new drug. Equally you would not be allowed to study a new drug vs. placebo, at least not for an indication where statins had shown a benefit. Because everyone ‘at risk’ should be on a statin already.

Now, I have some sympathy for pharmaceutical companies in this situation. If statins reduced the risk of heart disease by 50% (made up figure), then any new drug can only provide an incremental benefit over statins – there is only 50% possible benefit left. So you need to study more people, over a longer period, to demonstrate superiority over statins. A higher hurdle than statins had to get over to be approved.

In another way, obviously, I have less sympathy. Let us suggest that all of the statin trials were biased. Let us further suggest that statins do not have any benefit over placebo. Is there any evidence for this? Well, the only major non pharmaceutical funded study on statins vs placebo was ALLHAT-LLP. Which was run by the National Institutes for Health (NIH). It was reported thus:

‘Washington, DC – Surprising results of an unblinded but randomized comparison of pravastatin (Pravachol® – Bristol-Myers Squibb) vs “usual care” in patients with hypertension and moderate hypercholesterolemia enrolled in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) show that pravastatin did not significantly reduce either all-cause mortality or fatal or nonfatal coronary heart disease (CHD) in these patients.’

So, no benefit at all. This study was immediately attacked by all the ‘experts’ and dismissed as being useless, not enough LDL lowering, not enough difference from standard care blah, blah. Nothing to see here, move along.

However, I find it interesting that the only statin study which was not funded by the pharmaceutical industry was completely negative. You may even believe that this would give people pause for thought. If so, silly you.

Where does this leave us though? Well, as already stated, you can never, ever, do another statin vs placebo study. For it would be unethical to do so. You can never do a cholesterol lowering study on any other drug vs placebo either, for it would be unethical to do so. If the statin trials were all correct and unbiased and without the slightest doubt attached to them….fine. If, however, these trials were simply accurate measures of the prevailing bias then we are completely screwed.

This leaves us in a situation whereby if we test other drugs against statins, we are testing a drug against a drug that we cannot be certain has any benefits at all. So, what can we prove? Nothing. Which means that the very foundations of all future research in this area have been built on a bog.

So, what can we do? Carry on believing that all the research done is correct and above any suspicion of bias and manipulation. If so, fine, but you may have trouble sleeping at night. If not, you are going to have to tear apart all of the research that has been done, and do it again. I think that makes the task of Hercules look pretty easy.

1: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0020124

2: http://www.medscape.com/viewarticle/785851

The Augean stables

For many years it was possible to start a clinical trial, on a drug, without telling anyone that you were doing so. Then, if it turned out to be negative you could just slip it under the carpet and never let anyone know you were doing it. This is what happened with many antidepressant trials. Positive, publish. Negative, bury. Unsurprisingly, the results for antidepressant treatment looked pretty damned good.

Another little trick was to keep the primary end-point of the trial secret. To explain. Say you started a study on statins where you most wanted to look at the effect on overall mortality – whether taking statins meant more people were alive at the end of the study, than those taking a placebo. In this case overall mortality would be the ‘primary end-point’.

You could also measure other outcomes, or end-points. For example, you see how many people were admitted to hospital with angina, or how many people needed an angiogram and/or stent. Or how many people suffered a non-fatal heart attack or stroke. You can, in fact, measure many different things. These would usually be called secondary end-points.

Up until fairly recently, if you failed to reach your primary end-point – the term normally used for this sorry state of affairs would be ‘failed to reach statistical significance’ – you didn’t need to let anyone know. You could just say. ‘Oh look, the number of episodes of angina was significantly reduced, as was hospitalisation for chest pain and the rate of non-fatal strokes.’ Success!

Man on Clapham omnibus:          ‘But, but, I thought you said the trial was going to look at overall mortality.’

Pharmaceutical company:           ‘How do you know that, we never told anyone what the primary end-point would be.’

Yes, I know, pharmaceutical companies cannot speak. But you get the general idea.

Now, if you start trawling around your data, you can almost always find something somewhere got better. And if something else got worse, you can just fail to mention it. Essentially, therefore, unregistered clinical trials are not worth the paper that they are written on. Especially, of course, if they never got written on any paper at all.

In the year 2000 the major US group the National Heart, Lung, and Blood Institute (NHLBI) decided that any studies they were going to fund (these are non pharma company studies) must register all end-point/primary outcomes, before the study started. This means that the trial investigators could not manipulate the results post-hoc.

A group of researchers recently looked at 55 large clinical studies funded by the NHLBI between 1970 and 2012 to see if the transparency rules had made any difference. What they found should shake the foundations of medical research…but it almost certainly won’t:

  • 57% of studies (17/30) published before 2000 showed a significant benefit in the primary outcome
  • 8% (2/25 trials published after 2000 showed a significant benefit in the primary outcome

As the researchers said ‘The requirement of prospective registration in ClinicalTrials.gov is most strongly associated with the trend towards null clinical trials. The prospective declaration of the primary outcome variable required when registering trials may eliminate the possibility of researchers choosing to report on other measures included in a study. Almost half of the trials [published after 2000] might have been able to report a positive result if they had not declared a primary outcome in advance.1

Pharmaceutical companies have been asked to register trials since 2005.

At this point I am going to try and join two thoughts together. Almost every study done on blood pressure lowering, blood sugar lowering and cholesterol lowering was done before the year 2005. I only choose these three areas as they are the three area of maximum drug prescribing in the world. Billions upon billions are spent in these areas, hundreds of millions are ‘treated’.

The evidence used for this mass medication of the Western World is demonstrably, horribly, biased. Had companies been forced to register their trials prior to publication, positive results would have been reduced by at least 49%. Almost certainly far more. You could put this another way around and say that it very likely that only 8% of studies would have been positive.

We do not know which trials would have been positive, or which negative. Yet we have based the entire edifice of drug treatment, of hundreds of millions of people, on unreliable nonsense. The study in PLOS is only the latest demonstration of this fact. The database of medical research – everything until at least 2005 is a gigantic festering mess. It needs to be stripped out and cleansed.

Do you think this is too strong?

Well I shall now quote Dr Marcia Angell, Dr Richard Horton and Dr Richard Smith. Editors of, respectively, the New England Journal of Medicine, the Lancet and the British Medical Journal. The three highest impact factor journals in medical research.

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgement of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as editor of the New England Journal of Medicine.’ Marcia Angell.

‘The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.’ Richard Horton

‘The poor quality of medical research is widely acknowledged, yet disturbingly the leaders of the medical profession seen only minimally concerned about the problems and make no apparent efforts to find a solution.’ Richard Smith

Who, in a position of power, will finally wake up and realise that the vast database of medical research stinks of bias and manipulation. Who can we call upon to take up the gigantic and painful task of clearing out the Augean stables?

1: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132382

Conflict of interest – not just about money

There is a major spat going on at present around Conflict of Interest. The New England Journal of Medicine (NEJM) appears to be backtracking on the issue, and they are talking about relaxing their rules. The British Medical Journal (BMJ) is very ‘heavy’ on Conflict of Interest (COI) and has been somewhat critical of the NEJM approach – to say the least. See 13th June edition of BMJ.

To give you a flavour, one article in the BMJ has the title ‘Backtracking on conflicts of interest: a very bad idea… A series of articles in the New England Journal of Medicine has questioned whether the conflict of interest movement has gone too far in its campaign to stop the drug industry influencing the medical profession. Here three former NEJM editors respond with dismay.’

My sympathies are almost entirely with the three former editors: Robert Steinbrook, Jerome Kassirer and Marcia Angell. I think bias, and resultant distortion of medical research is a massive problem. So massive that it has become difficult to believe most of the research that is published. I am not alone in my concerns. Here is what Richard Horton (Editor of the Lancet), has to say on the matter:

‘The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.’

A half of medical scientific research may be untrue… think on the implications of that for a moment. However, before you focus all your efforts on trying to expose financial conflicts of interest as the solution to all problems, you need to take several steps back. Here are just two of the elephants in the room:

  • Just because someone is getting paid, does not mean they are saying or doing anything that is biased, or distorted. So, by introducing punitive rules on payment from the industry, you could be punishing everyone who has ever received any money, when many of them have done nothing wrong.
  • It is incredibly simple to set up structures that allow money to be paid to a ‘charity’, or a University Department, that can then be filtered down to an opinion leader who can then state, quite truthfully, that they receive no money from the industry. So, if you are going to look for conflicts, you are going to have a dig considerably deeper than looking for a direct transfer of money from pharmaceutical company to doctor. And that is tricky to enforce.

There is also another major issue here, which no-one seems to have discussed at all. Which is that money is most definitely not the only currency available when it comes to ‘bribes.’

At present, COI is seen in very simple terms. A conflict of interest is that someone (usually an international expert in, say, psychiatry) is paid lots of money by a pharmaceutical company. They then say exactly what the pharmaceutical company has written down on a piece of paper for them to say e.g. ‘This new product depressagon is completely safe, highly effective, has no side-effects, and I believe that depressagon should be use, first line, in anyone with depression. Thank you, where’s my cheque.’ The last three words are usually silent.

The International expert then sits on a guidelines committee for depression, and encourages all the other members of the panel to put depressagon on the list of first line drugs to be used in depression – and any other mental illnesses they can think of. At which point the Acme Pharmaceutical Company Inc. makes twenty billion dollars a year from depressagon. Which means that the one hundred million paid to the offshore account of said expert can be considered money well spent.

Of course, it is never as crude as this. Paying people money to say what you want them to say is considerably more subtle and nuanced. A raised eyebrow here, a small cough in the correct place there, an embarrassed silence round the table… the rules of playing the game are complex and never written down anywhere. In fact, if you have to ask how to take part, you don’t get invited.

However, urbane, crude, or not, there is still an assumption that the currency of COI is money, specifically money that ends up the experts bank account (directly, or indirectly). This is nonsense. There are many other things on offer. The most important of which is…power.

If you can work with the industry to attract several hundred million to your University for research; if you can be the lead investigator in several major international studies, then you will gain prestige, influence and power. The University may create an entire department as your plaything. You can have fifty new staff members, you will be asked to sit on prestigious committees. You can advise Governments on health policy.

Money….money. Who needs that? To quote Kevin Spacey playing Francis Underwood in House of Cards:

‘Such a waste of talent. He choses money over power. In this town, a mistake nearly everyone makes. Money is the Mc-mansion in Sarasota that starts falling apart after 10 years. Power is the old stone building that stands for centuries. I cannot respect someone who doesn’t see the difference.’

Up to now, all discussions about Conflict of Interest have focussed purely on payment in money. As if this is the only reason why someone may, ever, be influenced. When a medical expert states proudly they are not paid by pharmaceutical companies this may or may not be true. Tracking the flow of money into and out of Universities and medical charities is a complex old game.

However, no-one seems to have grasped a very important concept. You don’t have to pay someone money to manipulate them. They can be rewarded, instead, with power and influence. Conflict of Interest is about far more than money, and we should stop pretending otherwise.

You’re killing my patients (again)

Some of you may remember that the Australian Broadcasting Corporation (ABC) ran two programs in 2013 about saturated fat and statins. The messages were that saturated fat does not cause heart disease, and statins have more side effects than were reported in the trials, and could do more harm than good in patients at low risk of heart disease.

Massive outrage ensued, at least in Australia, a faraway country of which we know little. However, the battle is important for us all. For it is about crushing free speech and stomping on any criticism of medical ‘experts.’ Which is a very dangerous thing indeed.

After internal investigation, ABC pulled both programs and apologized profusely. Even though they could find nothing wrong with the programme on saturated fat, and only one of seventeen objections was upheld. And this objection was, in my opinion, a relatively minor issue (see a previous blog on the matter).

Just to refresh your memory. Here is the only point in which the programs were felt to have misrepresented the facts, followed by my comment at the time.

‘The program’s treatment of use of statins in secondary prevention focused solely on mortality benefits in a way that reinforced the view that statins were overprescribed and their benefits exaggerated. The principal relevant perspective that statins have wider benefits for this group was not properly presented. This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.’

My Comment: [Turning this into English. What the committee believe they found was that the second Catalyst program ‘Cholesterol drug war’ did not mention that statins have benefits on non-fatal outcomes e.g. non-fatal heart attack, and non-fatal stroke. By failing to emphasize this point it was judged that the program gave a misleading perspective on the overall benefits of statins (in secondary prevention).]

However, all of this was represented as follows:

ABC takes down Catalyst heart disease episodes after review criticism Controversial TV program on cholesterol-lowering statins found to have breached editorial standards.

‘Two episodes of the TV science program Catalyst will be removed from the ABC’s website after an internal review found the program had breached editorial standards on impartiality.

The controversial Catalyst program on statins and heart disease, The Heart of the Matter, was attacked by health experts even before it aired last year.

The presenter of ABC radio’s Health Report, Norman Swan, warned “people will die” as a result of the TV program’s messages about heart medications.

Swan, whose criticism of the program has been vindicated by the independent Audience and Consumer Affairs Unit report, had said the program made him “really angry” because it might affect Indigenous Australians, who are especially likely to suffer from high cholesterol.’ {P.S. Norman, indigenous Australians have lower cholesterol levels than the surrounding population}.

If this was all you had heard about the matter you would assume that ABC had done a very shoddy job, with sloppy and potentially dangerous reporting. Yet all of this ‘howling villagers with pitchforks’ attack was based on a single issue. It should be emphasised that, at no point did the programs suggest that anyone should stop taking a statin, or that statins should not be used in high risk patients.

But the vicious attacks did not stop here, oh no. Now we have a paper in the Medical Journal of Australia, reported yesterday, as follows:

Today, researchers from the University of Sydney and the Australian National University report on the impact of another Catalyst program. In October 2013, Catalyst broadcast a segment highly critical of statins, a class of drug used for lowering cholesterol.

The program questioned the link between cholesterol and heart disease, and suggested the benefit of statins in preventing cardiovascular disease was exaggerated.

There was extensive criticism of the program, including from the ABC’s own Norman Swan and the ABC later removed the episodes from the Catalyst website after an internal review found that the episodes had breached its impartiality standards.

The new report in the Medical Journal of Australia used Pharmaceutical Benefits Scheme data of 191,000 people and found an immediate fall of some half a million fewer statins dispensed to patients in the eight months following the Catalyst broadcasts.

The authors wrote:

This translated to an estimated 60,897 fewer people taking statins over the eight months examined. If patients continue to avoid statins over the next five years, this could result in between 1,522 and 2,900 preventable, and potentially fatal, heart attacks and strokes.

One of the study authors, Associate Professor Sallie Pearson, Scientific Director of the Centre of Research Excellence in Medicines and Ageing at the University of Sydney, said:

What is particularly concerning is that this drop in use was seen in people who were at high risk of cardiovascular disease – for example, those who were also taking medications for diabetes. Heart attacks and strokes are the main killers of people with diabetes.

Statins are recommended for people at high risk of cardiovascular disease because they have been shown to be effective. Like all medications, they have risks and benefits and should only be used as recommended.

The study authors wrote:

Even though the observed effect was relatively small, the prevalence of statin use in Australia and their established efficacy means that a large number of people are affected, and may suffer unnecessary consequences.

Why would anyone have done such a study? The only possible reason is that it was a deliberate effort to destroy any possibility of anyone ever criticising statins again? The whole thing is appalling and disgraceful.

At no point (to restate this yet again,) did the programs suggest people at high risk (secondary prevention) of heart disease stop taking statins. Yet, as you can see, the main attacked focussed on the fact that there was a reduction in people taking statin, in those at high risk of heart disease. What nonsense. Yesterday I wrote the following in a comment on an Australian website ‘The Conversation.’1

Here is the kind of delicious irony we should all enjoy. To quote Sallie Pearson, one of the study authors. ‘What is particularly concerning is that this drop in use was seen in people who were at high risk of cardiovascular disease – for example, those who were also taking medications for diabetes.’

Oh my God, people with diabetes are giving up statins. Well, as statins increase the risk of diabetes by 46%* then it would not be surprising to find a significant number of people with diabetes giving up statins. After all, it would have been, in many cases, the statins that gave them the diabetes in the first place. So, giving up the statins would probably have ‘cured’ their diabetes. And as we all know, to quote Sallie Pearson again…’Heart attacks and strokes are the main killers of people with diabetes.’ Yes, indeed.

Pursue this line of argument for too long and madness shall surely follow.

*The use of statin treatment could increase risk of type 2 diabetes by 46%, as a result of decreases in insulin sensitivity and insulin secretion, according to researchers from the Institute of Clinical Medicine in University of Eastern Finland. http://www.pharmaceutical-journal.com/news-and-analysis/statins-increase-risk-of-type-2-diabetes-study-suggests/20068064.article

P.S. When it comes to statins, 75% stop taking them in the first year anyway. So the Catalyst programme would have been but a drop in a very large ocean. http://www.statinusage.com/Pages/key-findings-and-implications.aspx

P.P.S. As you will see, most people stop taking statins due to adverse drug effects which, according to the programmes critics, do not really exist.

1: https://theconversation.com/abcs-2013-catalyst-program-may-contribute-to-up-to-2-900-heart-attacks-and-strokes-43177

A humiliating climb down – or a Machiavellian move?

Some of you may have seen a headline in the Sunday Express Newspaper ‘Statin, new safety checks.’ The subheading was ‘Oxford professor who championed controversial drug to reassess evidence of side effects.’

Those of you who read this blog probably know that the professor in question is Sir Rory Collins. He, more than anyone, has championed the ever wider prescription of these drugs. He has also ruthlessly attacked anyone who dares make any criticism of them.

You may remember that last year he tried to get the BMJ to retract two articles claiming that statins had side effects (correctly called adverse effects, but I will call them side-effects to avoid confusion) of around 18 – 20%.

He stated that these articles were irresponsible, worse than Andrew Wakefield’s work on the MMR vaccine, and that thousands would die if they were scared off taking their statins by such articles. Ah yes, the old ‘thousands will die’ game. A game I have long since tired of.

Is this story ringing any bells yet? The truth was that both articles quoted a paper which stated that 17.4% of people suffered adverse effects. So, yes, a pedant would say that the 18 – 20% figure was wrong – although not very wrong. Certainly not worth a demand of instant retraction, and apology, which is a very drastic step indeed.

Anyway, below is a short description of the findings of an independent panel set up by Fiona Godlee, editor of the BMJ, regarding the Rory Collins attacks [This has appeared on my blog before]:

“As previously reported, Rory Collins, a prominent researcher and head of the Cholesterol Treatment Trialists’ (CTT) Collaboration, had demanded that The BMJ retract two articles that were highly critical of statins. Although The BMJ issued a correction for both papers for inaccurately citing an earlier publication and therefore overstating the incidence of adverse effects of statins, this response did not satisfy Collins. He repeatedly demanded that the journal issue a full retraction of the articles, prompting The BMJ’s editor-in-chief, Fiona Godlee, to convene an outside panel of experts to review the problem.

The report of the independent statins review panel exonerates The BMJ from wrong doing and said the controversial articles should not be retracted:

“The panel were unanimous in their decision that the two papers do not meet any of the criteria for retraction. The error did not compromise the principal arguments being made in either of the papers. These arguments involve interpretations of available evidence and were deemed to be within the range of reasonable opinion among those who are debating the appropriate use of statins.”

In fact, the panel was critical of Collins for refusing to submit a published response to the articles:

“The panel noted with concern that despite the Editor’s repeated requests that Rory Collins should put his criticisms in writing as a rapid response, a letter to the editor or as a stand-alone article, all his submissions were clearly marked ‘Not for Publication’. The panel considered this unlikely to promote open scientific dialogue in the tradition of the BMJ.””1

To provide a bit more context at this point, you should know that for a number of years, people have been trying to get Rory Collins to release the data he and his unit (the CTT), holds on statins. [The CTT was set up purely to get hold of and review all the data on statins, it has no other function].

He has stubbornly refused to let anyone see anything. He claims he signed non-disclosure contracts with pharmaceutical companies who send him the data, so he cannot allow anyone else access. Please remember that some of the trials he holds data on were done over thirty years ago, and the drugs are long off patent. So how the hell could any data still be ‘confidential’ or ‘commercially sensitive’ now?

[The concept that vital data on drug adverse effects can be considered confidential, and no-one is allowed to see it, is completely ridiculous anyway. But that is an argument for another day.]

Now, amazingly, after running the CTT for nearly twenty years, Collins claims that ‘he has not seen the full data on side-effects.’ In an e-mail to the Sunday Express he stated that ‘his team had assessed the effects of statins on heart disease and cancer but not other side effects such as muscle pain.

Let that statement percolate for a moment or two. Then try to make sense of it. So, they have got the data, but not bothered to look at it? Or they have not got it – which surely must be the case if he hasn’t even seen it. Give us a clue. Either way, Collins states he has not assessed it.

Despite this, he still managed a vicious attack on the BMJ for publishing articles, claiming statins had side effects of around 20%. This was an interesting stance to stake, as he now claims he has no idea what the rate of side effects are? In which case he should make a grovelling apology to Fiona Godlee immediately.

What is certain, and must be reiterated, is that Rory Collins has consistently refused to allow anyone to see the side effect data, or any other data, that that the CTT may, or may not, hold. See e-mail below from Professor Colin Baigent to the ABC producer MaryAnne Demasi (she was trying to get the CTT to confirm that they would not release data, Colin Baigent is deputy to Rory Collins)

From: colin.baigent@xxxxxxxxxxx

To: maryannedemasi@xxxxxxxxxxxx

Subject: RE: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

Date: Tue, 24 Sep 2013 17:02:23 +0000

Dear Maryanne

The CTT secretariat has agreement with the principal investigators of the trials and, in those instances where trial data were provided directly by the drug manufacturers, with the companies themselves, that individual trial data will not be released to third parties. Such an agreement was necessary in order that analyses of the totality of the available trial data could be conducted by the CTT Collaboration: without such an agreement the trial data could not have been brought together for systematic analysis. Such analysis has allowed the CTT Collaboration to conduct and report all of the analyses on efficacy and safety that have been sought directly or indirectly by others (eg by Dr Redberg in her papers on the efficacy and safety of statins in primary prevention, and in questions raised by the Cochrane Collaboration). Hence, the CTT Collaboration has made available findings that would not otherwise have emerged.

I would be very happy to ring you at whatever time is convenient for you in order to help you to understand our approach, and then address in writing any residual concerns. It would be a shame if we were not able to speak as this would be the most effective way of explaining things.

Please let me know where and some times when I can reach you, and I will endeavour to telephone.

Colin Baigent.

I put the word safety in bold in this copied e-mail. You will note that Professor Colin Baigent does not say that that the CTT do not have these data on safety. He just says that the CTT won’t let anyone else see any data.

If they do have it, why have they not done this critically important review before, as they have had much of the data for over twenty years. If they don’t have it, how exactly is Rory Collins going to review it – as he states he is going to? Sorry to keep repeating this point, but I think it is absolutely critical.

Picture the scene in a lovely oak panelled office in Oxford, the city of the dreaming spires….

Professor Collins:   ‘Hey guys, you’re just not going to believe this, but a researcher just found a big box in the airing cupboard, and guess what, it has all the safety data in it….phew.’

Professor Baigent:  ‘Ahem… Why that’s lucky Professor Collins, now we can do the safety review.’

Professor Collins:   ‘Ahem… Indeed, Professor Baigent, we can. So, let’s get cracking shall we?’

And lo it has come to pass that after all these years Professor Collins has deigned to look at the safety data. This review shall, in Collins own words ‘be challenging.’ But you know what really don’t think they should bother, because we all know exactly what they are going to find….

That they were right all along, statins have no side effects. Hoorah, pip, pip. Nothing to see here, now move along.

A.N.Other Researcher:       ‘Please sir, can anyone else see these data that you hold, to ensure that you are being completely open and honest?’

Professor Collins:               ‘Don’t be ridiculous, these data are completely confidential.’

At this point I feel that I should ask how much do you, gentle readers, believe you can trust a review by Collins, on the data that Collins holds, on behalf of the pharmaceutical industry. Data that no-one else can ever see. [And the data from clinical trials on side effects is totally inadequate anyway].

Were I to be given the task of finding someone to review the safety data on statins, Professor Sir Rory Collins would not be the first person I would ask. He might even be the last.

1: http://www.forbes.com/sites/larryhusten/2014/08/02/no-retraction-for-you-review-panel-exonerates-medical-journal-in-statin-kerfuffle/

P.S. Actually, he would be the last.

Can we believe any medical research – at all?

I have now finished my book, to be called ‘Doctoring Data.’ It has taken a long time to write, mainly because I had to bring together hundreds of different strands of thinking and research. Each strand seemed to get longer and longer as I attempted to pursue them to the end. In many cases I never really found the end.

Some ideas just keep stretching away forever and I had to give up, or else the book would have become a million pages long. And I was told three hundred and ten was to be my limit – or something like that. As if my genius could be contained to a mere hundred thousand words, or so.

Anyway, the main purpose of the book was to look at medical research and data, and try to make some sense of it for those who are interested in looking beyond a medical headline. The book was, at least in part, inspired by a paper written by John Ionnadis.

It was entitled ‘Why most published research findings are false.’ You can easily find it on the internet by searching the title. It is currently the most downloaded paper in recent medical scientific literature

The shortest summary of his paper is, as follows:

Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.’ J Ionnadis.

How can it be, you may think, that most published research is false? Surely research is the one area of human endeavour where bias and dogma are ruthlessly hunted down and destroyed. A scientific finding is a scientific finding….is it not? Did Francis Bacon die in vain?

As Dogbert might say. Hahahahahahahahahahaha!

Or you might be best to pay attention to the quote from Friedrich Nietzsche. ‘There are no facts, only interpretations.’ Of course, he was a bit bonkers, but there is an awful lot of truth to what he said. Especially in medical research. Facts are the most tricky little blighters to get hold of. Interpretation, however, that is stated as fact all over the place

Surely, though, we have ways to ensure that research is pure and objective, such as peer-review. A system of using respected ‘experts’ to check and approve papers before publication. This will weed out papers that are flawed, will it not. Well, here is what Richard Horton (editor of the Lancet) has to say on peer-review:

The mistake, of course, is to have thought that peer review was any more than a crude means of discovering the acceptability — not the validity — of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong.’

There we are, nice and reassuring to know that peer-review is such a fabulous system. As for the quality of published research itself, here is one of my favourite quotes by Drummond Rennie, at the time the Deputy Editor of the Journal of the American Medical Association.:

‘There seems to be no study too fragmented, no hypothesis too trivial, no literature citation too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too selfserving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print.’

A view supported from a slightly different angle by Dr Marcia Agnell, who was the editor of the New England Journal of Medicine for two decades. This was, and remains, the single most powerful and influential medical journal in the world. At least it is, when it comes to citations and impact factor:

“It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.” Dr Marcia Agnell

Here is a further view on the issue by Richard Smith, editor of the BMJ for many years. He wrote this in his blog:

Twenty years ago this week the statistician Doug Altman published an editorial in the BMJ arguing that much medical research was of poor quality and misleading. In his editorial entitled, “The Scandal of Poor Medical Research,” Altman wrote that much research was “seriously flawed through the use of inappropriate designs, unrepresentative samples, small samples, incorrect methods of analysis, and faulty interpretation.” Twenty years later I fear that things are not better but worse…

…The poor quality of much medical research is widely acknowledged,” wrote Altman, “yet disturbingly the leaders of the medical profession seem only minimally concerned about the problem and make no apparent efforts to find a solution.”

Altman’s conclusion was: “We need less research, better research, and research done for the right reasons. Abandoning using the number of publications as a measure of ability would be a start.”

Sadly, the BMJ could publish this editorial almost unchanged again this week. Small changes might be that ethics committees are now better equipped to detect scientific weakness and more journals employ statisticians. These quality assurance methods don’t, however, seem to be working as much of what is published continues to be misleading and of low quality. Indeed, we now understand that the problem doesn’t arise from amateurs dabbling in research but rather from career researchers.’

So, Ionnadis states that most research findings may often be simply accurate measures of the prevailing bias. Current and past editors of the three most respected and powerful medical journals in the world confirm that medical research is warped, biased and flawed and, in many cases simply not believable.

Would this be very evidence used by NICE* to tell us which drugs to use – for example. Why, yes it would be. So be afraid, be very afraid. For an idiotic politician (sorry for the tautology) recently made this announcement1.

‘A Labour government could reduce variation in access to drugs and procedures by making it mandatory for commissioners to follow national clinical guidelines, Andy Burnham has revealed.’ Andy Burnham was, at one time Secretary of State for Health. His is now shadow secretary of state for health. So, if the UK votes for Labour, it will mandatory for all doctors to follow the guidelines based on the evidence that comes from clinical trials.

Oh Joy.

*NICE stands for the National Institute for Care and Health Excellence. It is supposed to review all evidence for various healthcare areas and decree what is best practice. What NICE says tends to get taken up in many, many, other countries as their views are widely respected and acted upon.

1: http://www.hsj.co.uk/news/exclusive-labour-could-make-nice-guidance-mandatory/5076286.article

What is a conflict of interest anyway?

Whilst away on my holidays I have been watching the battle between the BMJ and Professor Sir Rory Collins. A couple of years ago I watched the battle between Professor Sir Rory Collins and the Cochrane Collaboration. A month ago I was taking part in the battle between various professors and cardiologists and Professor Sir Rory Collins.

He, as you probably know, thinks statins are wonder drugs that should be prescribed to almost everyone. Actually, that is not entirely true. He doesn’t believe they should be prescribed to almost everyone. He believes that they should be prescribed to everyone.

He thinks statins have no adverse effects at all. In fact, they actually make people feel better when they take them. He viciously attacks anyone who might dare to suggest otherwise, and has accused them of killing people by frightening them off taking these uniquely lifesaving medications. This has been the basis of his attacks over the last couple of years.

Now, he might really believe all this to be true. In fact, I think he probably does. Of course, he might not believe it to be true, but he is just saying it anyway. One of the great frustrations of life is that you can never know what another person is really thinking. You can guess all you like, but it is only ever a guess.

The problem that we have here is that Professor Sir Rory Collins runs a unit called the Clinical Trials Service Unit at Oxford. This unit has received nearly £300m ($500m) in funding from pharmaceutical companies over the years. Without this funding, his unit would be very much smaller. It probably would not exist at all.

Now, you could say that this makes Professor Sir Rory Collins utterly dependent on pharmaceutical company funding, and therefore you should not believe a single word that he has to say about anything to do with statins, and other such drugs. He is completely corrupted.

You could counter argue that this is a ridiculous stance to take. His is a highly motivated and ethical researcher who works with the industry, purely in order to develop effective medicines that will help humanity. After all he is both a Sir and a Professor.

You could say that his Knighthood and professorship are completely irrelevant, and simply ask the following question. Why does he say he has no conflicts of interest to declare. Why does he state that he receives no money from industry. Why has he never admitted to the association between himself, the CTSU, of which he is a director, and £300m in drug company funding? Why does he never disclose these financial interests? Why not, indeed?

His argument, I believe, is the following. If the pharmaceutical industry pay the CTSU, who then pay him, he is not actually being paid any money directly by the pharmaceutical industry. So he has no conflicts of interest to declare. Discuss. [Shouldn’t take long].

Whether or not you think his is conflicted (and I do), this discussion leads into a rather more complicated area. What is the purpose of declaring that you have a conflict of interest in the first place? What does it matter if you are paid money by someone else who has a vested interest in making sure that certain things are said, and done.

Now, you may think the answer is simple. If Professor Sir Rory Collins states he has a conflict of interest e.g. the unit he runs is paid £300m by the industry, we can then….. We can then…..We can then what?

Believe nothing that he says about statins. Believe everything that he says. Believe most of what he says. Believe a bit of what he says. The problem is that there are only two rational positions here.

  • Believe everything
  • Believe nothing

How can you believe most, or a bit, of what Professor Sir Rory Collins says? Which bits could you ignore, which bits could you pay attention to? How could you possibly know? The answer is that you cannot.

Which then leads onto the next question. Why do medical journals, and suchlike, demand that researchers, lecturers and authors declare their conflicts of interest? What does this achieve? If having a conflict means that the author/researcher is biased, then surely the article cannot be published – as the journal is accepting a biased piece of work. Believe me, properly done, bias is impossible to spot. It’s like hearing the dog that didn’t bark.

On the other hand, if conflicts of interests mean nothing. In that you can have financial conflicts of interest, but this makes no difference to anything you say or do – why bother demanding that the conflicts of interests are declared.

In short, I cannot see what declaring a conflict of interest achieves.

Man on the Street 1: ‘Oh, I see Professor Sir Rory Collins unit has received £300m in funding from the pharmaceutical industry. Most interesting. However, this clearly makes no difference to anything he has to say on the matter.’

Man on the Street 2: ‘Oh, I see that Professor Sir Rory Collins unit has received £300m in funding from the pharmaceutical industry. Clearly he is corrupt and biased and I shall pay no attention to any he has to say.’

Man on the Street 3: …. ‘I shall believe 82% of what he has to say.’

Man on the Street 4: …..’I shall believe 23% of what he has to say.’

Which of the men on the street has the right idea? There is no way to tell, without becoming a mind reader. At present, when it comes to conflicts of interest, we just have a gigantic fudge. So long as people declare their conflicts they are then free, it seems, to do anything they like. Carry out research, write papers, sit on guideline committees, advise the Government and NICE. Declaring the interest…what? Makes the possibility of bias disappear?

But what should really happen. My view is relatively simple. I have said it before, and will say it again. If you get paid money by the pharmaceutical industry then, fine. I have no problem with that. Good for you. Buy that luxury ski chalet in the Alps if you want. Indoor swimming pools are lovely things to have. Have both – you will certainly be able to afford it.

However, once you have taken the money, directly or indirectly, you should not be allowed to sit on guidelines committees e.g NICE. Nor should you be allowed to educate your fellow doctors on best forms of drug treatment, or act as a Government advisor on healthcare matters – or suchlike. Because you are, even if you don’t think you are – and get very angry with anyone who suggests that you might be – biased.

This nettle needs to be grasped, and it needs to be grasped soon. I am not a great believer in absolutist positions, as they tend to block the compromises that are necessary for things to work in life. However, when it comes to conflicts of interest I think that the only possible position to take is absolutist. If you are paid money by the pharmaceutical industry, you cannot be appointed to a position that allows you to influence how drugs are used. End of.

Catalyst crushed?

“A lie gets halfway around the world before the truth has a chance to get its pants on.”
Winston Churchill

ABC takes down Catalyst heart disease episodes after review criticism

Controversial TV program on cholesterol-lowering statins found to have breached editorial standards1

And that, as the Guardian reported, seems to be pretty much that. Here is some of the accompanying text.

‘Two episodes of the TV science program Catalyst will be removed from the ABC’s website after an internal review found the program had breached editorial standards on impartiality.

The controversial Catalyst program on statins and heart disease, The Heart of the Matter, was attacked by health experts even before it aired last year.

The presenter of ABC radio’s Health Report, Norman Swan, warned “people will die” as a result of the TV program’s messages about heart medications.

Swan, whose criticism of the program has been vindicated by the independent Audience and Consumer Affairs Unit report, had said the program made him “really angry” because it might affect Indigenous Australians, who are especially likely to suffer from high cholesterol.’

If this was all you had heard about the matter you would assume that ABC had done a very shoddy job, with sloppy and potentially dangerous reporting. Well, this is all very interesting. However, if you were to criticise sloppy reporting you could start with the Guardian report itself.

To begin with there were two programs, covering different issues, one of which had nothing to do with statins at all. However, the Guardian headline suggests there were two episodes ‘on statins and heart disease’. Not true. The first episode discussed whether or not saturated fat consumption caused heart disease. This episode was called ‘dietary villains’. It had nothing whatsoever to do with statins. The internal review found that this episode contained no errors. (Yet still it is being taken down?)

The second mistake the Guardian made is to accept Norman Swan’s statement that Indigenous Australians are especially likely to ‘suffer from high cholesterol’. Well this is complete rubbish. In one of the very few studies to report cholesterol levels in this population, published in the BMJ, the average cholesterol levels were very low (around 4.4.mmo/l)2. Lower than in any Western country.

Really, dear Guardian reporter, you ought to check your facts before writing such stuff – as should Norman Swan. But hey, checking facts is very time consuming, I think you will find. Moving on, I should also point out that you cannot ‘suffer’ from high cholesterol as there is no level of cholesterol that causes any symptoms. Mind you, if it were possible to ‘suffer’ from high cholesterol then the Swiss, with an average cholesterol level of 6.4mmol/l, would be suffering mightily. [Instead of having an extremely low rate of heart disease.]

Blimey, a few short paragraphs, and this article is already full of cock-ups. Of course, if you decide to go through anything with a fine toothcomb you will be able to pick up all sorts of errors. Writing scientific stuff is not easy. There is always a choice between absolute factual accuracy and providing the broader picture.

There is another choice between which facts to include, and which to exclude. Because of these inevitable tensions, and difficulties, if you want to attack any study, article, TV program, you will always find some traction. Sure as eggs is eggs, any program criticising statins was bound to be attacked mercilessly. Dr Uffe Ravnskov, a long time statin critic, had his book burned live, on air, in a Finnish TV studio. Part of a highly scientific debate, no doubt.

As a disclosure of interest, I did help the programme’s producer, and presenter, Dr Maryanne Demasi with questions and background information whilst she was putting the Catalyst programs together. I tried to give her as much factual information as possible. The day after the programmes came out, I wrote her this e-mail on 31st October 2013:

Maryanne,

Just seen part II. Brilliant, well done…….. I feel a sense of pride being able, in a small way, to help you put this together.

I now hope that you are viciously attacked, because that means you have won. (And it also means that thincs has won). Be ready – I suspect the attacks have already started.

She wrote back on the 4th of November:

Malcolm

OMG!! I am getting attacked in the media. They’re out for blood!!

Where do I hide??!!

Since then, the attacks have been relentless, from many directions. Page after page of criticism from the National (Australian) Heart Foundation (NHF). Withering attacks by the likes of Norman Swan – who seems to have set himself up at the ultimate arbiter of science in Australia. Somehow or other. Despite the fact that he believes people ‘suffer’ from high cholesterol, and has no idea about risk factors for heart disease in Indigenous Australians.

These attacks were battered backwards and forwards until my brain began to overheat. I provided supportive information to counter the criticism. As did several others. Point after point was refuted. It became quite exhausting.

Eventually, it seems ABC effectively caved in and removed the programmes. Why, I am not sure. The judgements on the programmes were almost entirely supportive – with a single exception, which I shall get to. Here, for example, was the commentary on the first programme on the link between saturated fat and heart disease.

Accuracy and impartiality

Episode 1 – ‘Dietary Villains’

The role of dietary saturated fats in heart disease has been controversial since the theory was first postulated at the beginning of the twentieth century. Notwithstanding the lack of definitive proof, mainstream medical organisations such as the National Heart Foundation (NHF) believe there is enough good quality evidence to recommend a diet low in saturated and trans fats…

In our view, the program could have done a better job of teasing out the mainstream perspective to leave audiences better informed.

However, in our assessment this did not amount to a breach of the impartiality standard in the first episode because judgements about impartiality require a number of factors to be weighed. While there were problems with structure and tone:

1. The factual information in the program was accurately presented and the reporter has demonstrated that she diligently sought and considered a variety of views on the subject. No material inaccuracy has been demonstrated by any complainant.

2. The principal perspectives were presented.

3. Neither position was endorsed by the program.

4. Neither perspective was misrepresented.

5. The nature of the program necessitated that the unorthodox theory was given more time and explanation. The Code does not require that they receive equal time, nor that every facet of every argument is presented.

As an important aside, I find it fascinating that the committee accepted that there is no ‘definitive proof’ that saturated fats cause heart disease. Check.

Yet, in a complete rupture of logic, the report stated that the ‘National Heart Foundation believe there is enough good quality evidence to recommend a diet low in saturated and trans-fats.’

Well, if there is enough good quality evidence, there must be, by definition, definitive proof. Either one statement is correct, or the other. They cannot both be, as they are mutually contradictory. This I am afraid is the level of thinking that goes on here. As expected, there is no criticism of the National (Australian) Heart Foundation for recommending a diet for which where is no ‘definitive proof.’ ‘It’s okay, they believe there is enough good quality evidence, and they are good chaps. So that is good enough for me.’

This is the usual kowtowing to the experts. If the roles had been reversed, Catalyst would have been crucified for promoting dietary advice based on nothing at all. Yet, the NHF are completely let off the hook with this pathetic statement.

‘Notwithstanding the lack of definitive proof, mainstream medical organisations such as the National Heart Foundation (NHF) believe there is enough good quality evidence to recommend a diet low in saturated and trans fats.’

Hang your heads guys. What is sauce for the goose should also be sauce for the gander.

And what of other ‘complaints.’ Here is another judgement, from this very, very, long document:

Did the program incorrectly state that it had sought comment from Merck Sharp & Dohme?

Complaint

Catalyst reported that it sought comment from MSD. MSD says that no contact was made.

Assessment

Catalyst has provided emails demonstrating that it approached MSD for responses to a number of detailed questions. MSD replied that it would not comment on the specific questions and stated only that:

‘MSD is committed to ethical research and abides by the principals of good clinical practices. All clinical trials and their protocols undergo review by hospital ethics committees.’

We are satisfied that Catalyst contacted MSD for comment and they declined to provide specific responses to allegations.

Conclusion – No breach of section 2.1.

Basically, MSD lied. They complained that no-one had sought any comment from them. It turned out this was nonsense, they were simply telling porkies. Any criticism of the company? No.

Here is another of the complaints:

Undue favouring of the perspective that saturated fats do not cause heart disease by raising cholesterol – part I – Code of Practice sections 2.2 and 4.5

Complaint

The hypothesis that eating saturated fats can increase cholesterol levels which in turn can cause heart attacks is widely accepted by the medical community and is the basis for most official dietary advice. Some medical researchers and physicians believe the hypothesis is flawed – Catalyst presented and examined their criticisms.

Complaints, including from the National Heart Foundation, allege the analysis lacked balance and omitted critical evidence…..

Assessment

We are satisfied on the basis of our review that the program’s scepticism towards the diet-heart hypothesis was not unjustified and its presentation of an alternative approach did not amount to an undue favouring of that approach.

Conclusion – No breach of section 4.5, no breach of 2.1

Are you getting some sense of what happened here? In point after point, it turns out that the Catalyst programmes had not, in any way, got anything wrong. Nothing, zip, nada. If you are so inclined, you can read the whole report3. To save you the trouble I have pulled out all the complaints, and added in the conclusions in as concise appendix as I can manage. [There is also a short appendix to make it clear what the Codes of Practice mean].

COMPLAINTS

[There were a total of twelve separate complaints, looking at seventeen possible breaches of editorial standards]

1: Ancel Keys’ population studies were misrepresented – Part I – Code of Practice section 2.2

Conclusion – No breach of section 2.2

2: Mediterranean Diet & The Lyon Diet Heart study – Part I – Code of Practice section 2.2 (Did the program accurately describe the Lyon Diet Heart study?)

Conclusion – No breach of 2.2

3: Misrepresentation of the composition of margarine in Australia – Part I – Code of Practice sections 2.1 & 2.2

Conclusion – No breach of section 2.2

4: Inaccurate description of the structure of polyunsaturated and saturated fats – Part I – Code of Practice section 2.1

Conclusion – No breach of section 2.1

5: Misrepresentation of the National Heart Foundation & Dr Grenfell – Part I – Code of Practice section 2.2

Conclusion – No breach of section 2.2.

6: Undue favouring of the perspective that saturated fats do not cause heart disease by raising cholesterol – part I – Code of Practice sections 2.2 and 4.5

Conclusion – No breach of section 4.5, no breach of 2.1

7: Misrepresentation of the 4S trial data – Part II – Code of Practice section 2.2

Conclusion – No breach of section 2.1 or 2.2

8: Merck Sharp & Dohme (MSD) – Part II – Code of Practice section 2.1 (Did the program incorrectly state that it had sought comment from Merck Sharp & Dohme?)

Conclusion – No breach of section 2.1.

9: Unfair characterisation of Australia’s medicines industry – Part II – Code of Practice sections 2.1 & 4.5

Conclusion – No breach of section 2.1 or 4.5.

  1. Failure to provide material context by not disclosing the commercial interests of some of the experts featured – Parts I & II – Code of Practice section 2.2

Conclusion – No breach of section 2.2.

  1. Failure to provide material context in relation to use of statins and undue favouring of view that statins do more harm than good – Part II – Code of Practice 2.2, 4.5 and 7.6

Did the program unduly favour an anti-statin viewpoint in its presentation of the evidence for the benefits and harms of statins?

Conclusion – Breach 4.5; No breach 2.2; No breach 7.6 (4.5 Do not unduly favour one perspective over another.)

  1. The program falsely claimed that the National Heart Foundation had ‘signed off’ on Catalyst’s evidence (PM 31/10/13) – Code of Practice sections 2.2 & 4.4

Conclusion – corrective action required, no breach 4.4

Twelve complaints about seventeen possible breaches of conduct, one upheld (I don’t think I have ever written anything that accurate in my life). There was another part of the report where the judgment is so weird that I cannot understand it. I defy anyone else to understand it either. You can read the whole report if you wish, and see what you think.

It seems to be saying that stratifying risk in primary prevention of heart disease is something that is contentious, but a lot of doctors believe in it, so it should have been mentioned. Something with no evidence to support it, that happens to be believed in by a number of doctors, should be presented as what….the truth? That bit is bonkers. It seems they thought they should say something, but descended into gibberish.

When you get down to it, the judgement is that there was a single breach. Represented thus:

‘The program’s treatment of use of statins in secondary prevention focused solely on mortality benefits in a way that reinforced the view that statins were overprescribed and their benefits exaggerated. The principal relevant perspective that statins have wider benefits for this group was not properly presented. This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.’

Turning this into English. What the committee believe they found was the second Catalyst program ‘Cholesterol drug war’ did not mention that statins have benefits on non-fatal outcomes e.g. non-fatal heart attack, and non-fatal stroke. By failing to mention this point it was judged that the program gave a misleading perspective on the overall benefits of statins (in secondary prevention).

And that, ladies and gentlemen, is that. Perhaps not quite the crushing indictment you thought. Now, you must remember that this committee was starting from scratch, knowing bugger all about the area of statins and heart disease. Given this, they didn’t do too badly. But on the point about non-fatal strokes and non-fatal heart attacks they failed to spot the Elephant in the room. An Elephant that I need to describe to you.

Pharmaceutical companies hide data

The elephant in the room is that, when it comes to data on statins (and most other drugs), we are completely reliant on pharmaceutical companies to provide it. Increasing attempts have been made to get them to release all the data they have, but this has proven virtually impossible. Recently, we have seen a battle over the Roche drug Tamiflu:

‘The British Medical Journal (BMJ) has alleged that pharmaceutical giant Roche is deliberately hiding clinical trial data about the efficacy of oseltamivir (Tamiflu) in patients with influenza. The journal says global stockpiling and routine use of the drug are not supported by solid evidence and alleges that Roche concealed neurological and psychiatric adverse events associated with the neuraminidase inhibitor drug.

In an open letter from Fiona Godlee, MD, editor-in-chief of BMJ, to Professor John Bell, FRS, HonFREng, PMedSci, Regius Professor of Medicine at Oxford University in the United Kingdom and a Roche board member, published online October 29, Dr. Godlee reminds Bell of concerns that were initially voiced in 2009 about the reliability of Tamiflu research.

At that time, BMJ published an updated Cochrane review of neuraminidase inhibitors in healthy adults. That study “took the view that, since eight of the 10 [randomized controlled trials] on which effectiveness claims were based, were never published, and because the only two that had been published were funded by Roche and authored by Roche employees and Roche-paid external experts, the evidence could not be relied upon,” Dr. Godlee writes.’ [From medline, needs registration to view]

To quote the Cochrane collaboration on this matter:

“Patients around the world are being harmed because clinical decisions on their health care are skewed by the absence of clinical trials data,” said Mark Wilson, CEO of The Cochrane Collaboration, in announcing this new partnership. “For 20 years The Cochrane Collaboration has been working to give clinicians, researchers and patients the best possible evidence-based information to help them make informed decisions, and it is a scandal that we still do not have access to all trials data so that we can be confident in our conclusions…”4

Many people find it difficult to believe that companies just hide the data. But they did, and do, and shall do into the future, I would imagine. The 4S study, the single most positive study on statins ever done, by a long way, is more than slightly worrying in this respect. To quote from a blog by Dr Walter Ferneyhough, discussing the 4S study:

‘Did I mention the study bias. Well, it was funded by Merck (the pharmaceutical responsible for simvastatin (a.k.a. Zocor)), was monitored by the Scandinavian subsidiaries of Merck, and the data analysis was performed by Merck. A financial disclosure (conflicts of interest) of the researchers were not given, which is odd, since most studies provide this information.’5

If you believe that there is no possibility that the industry might present biased data, or fail to provide data that is not positive about their products, then you can sleep soundly in your bed…..you poor deluded fool. The reality is that negative studies are not published. Even when a study is positive the ‘raw’ data are held by the pharmaceutical companies. They release what they like, and keep secret what they like. Perfectly legal, so I am reliably informed.

When it comes to statins, this is highly significant when it comes to the issue of Serious Adverse Event (SEA) data. To explain this in a bit more detail, because the terminology here is confusing.

Drugs can cause adverse effects e.g. flushing, pain, headaches. These are known as drug related adverse effects. They are commonly called side effects, but this is inaccurate. A side effect can be positive, or negative.

On the other hand there are Serious Adverse Events (SAEs). SAEs include deaths. They also include nasty things such as a non-fatal MI, or a non-fatal stroke. Things that could be prevented by a statin. So that is good news for statins. However, an SAE could also be an episode of Rhabdomyolysis, or liver damage requiring hospitalisation, or Transient Global Amnesia, or tendon rupture. These could be caused by the statin, and would therefore be bad news for statins.

As you can see, after mortality, SAEs are the next best measure of how beneficial, or harmful, a product might be. Whilst pharmaceutical companies are delighted for us to have the data on positive SAEs, they are completely silent on the data on negative SAEs. Here is what the Cochrane collaboration first had to say on the matter, after they tried to get hold of the data from the statin trials:

Are SAEs reported in the major lipid-lowering trials?

SAE data were sought in the major placebo-controlled trials published up to September, 2001 using statins (5 trials)3-7 or fibrates (5 trials).8-12 Remarkably, only one study, the AFCAPS trial,3 reported total % SAEs in the treatment and placebo groups. In this study, lovastatin was compared with placebo in patients without cardiovascular disease (primary prevention). Similar total % SAEs were reported for the lovastatin, 34.2%, and placebo groups, 34.1% (RR = 1.0 [0.94-1.07]). What this indicates is that the 1.4% absolute risk reduction in total MI or CV death (see Table Letter #27) has been negated by an absolute risk increase in other SAEs. No information is provided as to what these other SAEs might be. The only other trial that reported anything approximating SAEs was the coronary drug project (CDP), a secondary prevention trial. This trial reported the percentage of patients ever hospitalized at 5 years: 55.1% for clofibrate and 52.4% for placebo (RR = 1.05 [0.99-1.12]).

Later on, they had this to say:

‘How can CHD (Coronary Heart Disease) SAEs decrease, but not total SAEs?

All CHD events are SAEs and are counted in both categories. Therefore a reduction in major CHD SAEs should be reflected in a reduction in total SAEs. The fact that it is not suggests that other SAEs are increased by statins negating the reduction in CHD SAEs in this population. A limitation of our analysis is that we could not get total SAE data from all the included RCTs. However, we are confident that the data from the 6 missing RCTs would not change the results, because they represent only 41.2% of the total population and include ALLHAT-LLT10, where one would not expect a reduction in total SAEs; in that trial there was no effect on mortality or cardiovascular SAEs.6

Yes, these reports from the Cochrane collaboration are getting a bit old now. But so are the placebo controlled statin trials, the ones that are used to support all the guidelines on the use of statins. So, when you get down to it, the fact is this. Serious adverse events are simply not reported from the major statins trials, the data are not released.

Which means that the data that are reported are completely skewed. Yes, statins (in secondary prevention) can reduce non-fatal MI and non-fatal strokes. But they increase other unpleasant things by approximately the same amount.

Now, let me take you back to the judgement on the Catalyst program.

‘The program’s treatment of use of statins in secondary prevention focused solely on mortality benefits in a way that reinforced the view that statins were overprescribed and their benefits exaggerated. The principal relevant perspective that statins have wider benefits for this group was not properly presented. This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.’

The committee that sat in judgement of the Catalyst programme was, in my opinion, very fair in the vast majority of what they said. But on this issue they got it terribly wrong. I cannot really blame them, for they probably cannot believe that critical trial data on SEAs are simply withheld. It cannot even be seen by independent researchers.

Because you probably do not believe that this can possibly be true either, I am about to do something that I possibly should not. I have taken advice from a number of people on this, and the views are contradictory. I am about to reveal e-mails that I was sent, and I have not sought permission to do so. Frankly, I know that if I did I would never get permission from all the parties involved [as you will understand once you have read them]. However, I think they are of such enormous importance that people should know they exist, in order to make their own minds up.

The e-mails come from the following discussion. Whilst making the Catalyst programme, Maryanne Demasi contacted Professor Colin Baigent from the Cholesterol Treatment Triallists Collaboration (CTT). The CTT are Oxford based group that hold all the data from the statin trails (Exactly how much, and in how much detail, I have no idea). They are hugely influential, and their meta-analyses form the basis for guidelines on the use of statins around the world. In the UK, the latest NICE guidance will be based entirely on them.

I have known for some time that the CTT will not release the data that they hold, to anyone. But when I speak to journalists they don’t really believe me, much eye-rolling occurs. So, please read on, and find out the truth for yourself. [The only editing I have done to this e-mail trail is to remove all contact details, apart from the address of the CTSU which can be easily found]. You can amuse yourself by spotting the point where the lawyers get involved in drafting the e-mails.

 

To: Enquiries at CTT
From: Maryanne
Sent: 22 September 2013 05:05
Subject: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

Hi, I am a medical reporter for ABC TV AUSTRALIA and I am doing a report on statins in primary and secondary prevention.

I have interviewed Harvard Dr John Abramson about the over use of statins within the population and also the lack of transparency of data when it comes to clinical trials.

In the interview he mentions the CTT collaborators being one group who have access to individual data but will not share their data with the public or other researchers even though they’ve been asked.

Prof Rita Redberg from University of California San Francisco supports these statements.

I would like a comment from CTT collaboration regarding Dr Abramson’s and Prof Redberg’s statements please?

Why has the CTT Collaborations refused to release all the data requested of them?

Kind Regards
Maryanne Demasi
Producer
ABC TV AUSTRALIA

 

To: Maryanne Demasi
From: Colin Baigent – CTT
Date: Mon, 23 Sep 2013 21:37:01 +0000
Subject: FW: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

Dear Maryanne

Drs Abramson and Redberg are incorrect in stating that the Cholesterol Treatment Trialists’ (CTT) Collaboration has not shared data on the effects of statin therapy in healthy people. Comprehensive analyses of the effects of statins in people at low risk of heart disease or stroke were published (and widely publicised) in the Lancet in 2012, and directly addressed questions about the balance of benefits and risks of statins in such people. The work showed clearly that statins are of net benefit even among those with no previous history of cardiovascular disease.

I would be pleased to discuss this issue with you over the telephone if this would be helpful. I can be reached on +44…

Colin Baigent
Professor Colin Baigent
MRC Scientist & Hon Consultant in Public Health

Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU)
Richard Doll Building
Old Road Campus
Roosevelt Drive
Oxford OX3 7LF

 

To: Rita Redberg and John Abramson
From: Maryann
On Sep 23, 2013, at 2:51 PM

Hi Rita and John,

Both of you mentioned in the interviews that the CTT collaborators don’t give full access to their data to public but the deny this. Please see below and respond as soon as possible please?

Many thanks

 

To: Maryanne Demasi
From: John Abramson
24/09/2013

To: Maryanne, Jim Wright

Maryanne,I have forwarded this to Jim Wright, who is the Co managing director of the Therapeutics Initiative in British Columbia. He has direct experience re ctt data sharing. I do not want to speak for him, but I believe he will be interested in the email below from Dr. Baigent.

Best wishes,
John

 

To: Maryanne Demasi
From: Rita Redber
24/09/2013

Publishing data that they have analyzed is NOT at all the same as giving full access to the public, or to other researchers. In whatever they publish, they maintain control and access to their data, the analyses etc. I am referring to the fact that CTT will not make their data available to any colleagues and other researchers who wish to study risks and benefits of statins. THe CTT data is not accessible publicly.

Rita

 

To: Colin Baigent
From: Maryanne Demasi
24 September 2013 00:50

Hi Colin, thanks for your time. 

I wasn’t referring to the published data, its the unpublished data. Dr Redberg has been specific:

“Publishing data that they have analyzed is NOT at all the same as giving full access to the public, or to other researchers. In whatever they publish, they maintain control and access to their data, the analyses etc. I am referring to the fact that CTT will not make their data available to any colleagues and other researchers who wish to study risks and benefits of statins. THe CTT data is not accessible publicly.”

Comment?

Cheers
 Maryanne

 

To: Maryanne
From: Colin Baigent
Tue, 24 Sep 2013 10:44:01

Dear Maryanne

This is again incorrect. The trials participating in the Collaboration contributed their data to the combined database on the understanding that the data would be held securely and that analyses would be  discussed and agreed by the collaborators before they are conducted. We meet annually, and discuss proposals for new analyses at those meetings. We welcome suggestions for new analyses from scientists who are not formally part of the Collaboration. If, after discussion, such proposals are felt to be scientifically worthwhile (and are feasible) they are conducted by the Secretariat, and the work is shared with collaborators (which then includes those who proposed the analyses).  It is important to recognise that data from participating trials are not owned by the Collaboration, but remain the property of the trial sponsors, so we are not able to provide unlimited access to the combined database. We do, however, provide a mechanism through which the data can be utilised for public benefit.

I hope this is helpful.

Colin Baigent

 

To: Colin Baigent
From: Maryanne Demasi
24 September 2013 13:26

Hi Colin,

Thanks for your moments. I just want to be clear about how i interpret your email.

The data from the clinical trials is “owned” by the trial sponsors – the statin manufacturers.

Hence, the CTT researchers can’t give full disclosure of the data to the public because the trial owners won’t allow them to? Correct?

Maryanne

 

To: Maryanne Demasi
From: Colin Baigent
Date: Tue, 24 Sep 2013 12:30:22

Dear Maryanne

No, this is again incorrect. I think it may be more efficient if you were to call me so that I can explain the process to you. If you wish to speak then I can be reached at the direct line below.

Colin Baigent

 

To: Rita Redberg, Jim Wright, John Abramson
From: Maryanne
Date: Tue, 24 Sep 2013 22:32:28

Hi Dr Redberg, Dr Abramson and Dr Wright

I wrote to the CTT collaborators (Colin Baignet) a second time specifying that its is the “unpublished” data that they are withholding.  His email is below.  Is it possible that I am asking the wrong CTT collaborators?

Am I missing something?

Regards

Maryanne

 

To: Colin Baigent
From: Maryanne Demasi
Tue, 24 Sep 2013 22:09:39

Unfortunately, I don’t have access to a work phone as its late here in Oz.  Also, our lawyers will want to see all these emails to ensure there hasn’t been a misunderstanding or misrepresentation of your position.  I will have to further clarify further with Prof Redberg, Dr John Abramson and Dr Jim Wright from the Therapeutics Initiative in Canada who all claim that the CTT collaborators do not give full disclosure of their data to the public and other researchers.  They have gone on record with this so the matter must be clarified.

Can you explain why they would say something like this?

Maryanne

 

To: Maryanne Demasi
From: Colin Baigent
Tue, 24 Sep 2013 17:02:23

Dear Maryanne

The CTT secretariat has agreement with the principal investigators of the trials and, in those instances where trial data were provided directly by the drug manufacturers,  with the companies themselves, that individual trial data will not be released to third parties.  Such an agreement was necessary in order that analyses of the totality of the available trial data could be conducted by the CTT Collaboration: without such an agreement the trial data could not have been brought together for systematic analysis. Such analysis has allowed the CTT Collaboration to conduct and report all of the analyses on efficacy and safety that have been sought directly or indirectly by others (eg by Dr Redberg in her papers on the efficacy and safety of statins in primary prevention, and in questions raised by the Cochrane Collaboration). Hence, the CTT Collaboration has made available findings that would not otherwise have emerged.

I would be very happy to ring you at whatever time is convenient for you in order to help you to understand our approach, and then address in writing any residual concerns. It would be a shame if we were not able to speak as this would be the most effective way of explaining things.

Please let me know where and some times when I can reach you, and I will endeavour to telephone.

Colin Baigent

 

To: Colin Baigent
From: Maryanne Demasi
24 Sep 2013, at 22:41

Hi Colin,

I am happy to talk to you.  Ive just arrived at work but understand if its too late in London to call you?!

I have to be honest.  I’m not sure why you keep saying my interpretation of the situation is incorrect because the way I read your last email, it tells me that “individual trial data will not be released to third parties”. (that is a direct quote from the email).

I completely understand the reasons why the CTT can not release this information but the purpose of this correspondence was to confirm that the comments of Prof Redberg, Dr Abramson and Dr Wright were factually correct – that they were not making false statements.

They explained that this is the problem with the data from clinical trials – that drug companies “own” the information and will only release what they want rather than having full disclosure of all the data to the public.

Regards

Maryanne Demasi

 

PHONE CALL WITH COLIN BAIGENT NOTES

I had a follow up conversation with Colin.  He stressed that while the CTT made an agreement with the drug companies not to give full disclosure of the individual data to third parties, the CTT had a very important role in providing doctors with the best information available.  He hoped that my report did not undermine the workings of the CTT.

 

To: Maryanne Demasi
From: Jim Wright
26/09/2013

To: Maryanne Demasi

The truth is that Colin agreed for me to send a student to do that analysis in 2007.  When the student Michelle Wong arrived there he would not let her have access to the data and do the analysis.  We would have done the analysis differently and had a better idea of whether the benefits outweighed the harms in low risk people.  I am not convinced by their 2012 analysis, which is based on little or no harm.

Kind regards,

Jim Wright
Editor-in-Chief
Therapeutics Letter

 


Postscript

So now you know that no-one can see the data. Now you also know that the criticism of the Catalyst programme was unfounded. Balance on the ‘non-mortality’ data on statins is impossible as the data on SEAs are hidden. Yes, know the things that statins can prevent e.g. non-fatal heart attacks, but we do not know the equal and opposite things they cause.

The reality is that, if you all did present the data on non-fatal CV events prevented with statins, you would be presenting catastrophically flawed data. Biased, and unbalanced. Yet, Catalyst is told that this is what they should have done.

I know that nothing anyone says will make any difference to ABC now. They just want the attacks to go away. However, I hope that a few thousand more people are now aware of the truth of this matter.

References (may require site registration or membership to access)

1: http://www.theguardian.com/media/2014/may/12/abc-takes-down-catalyst-heart-disease-episodes-after-review-criticism

2: http://bmjopen.bmj.com/content/3/1/e002308.long

3: http://about.abc.net.au/wp-content/uploads/2014/05/Catalyst-Heart-of-the-Matter-ACA-Investigation-Report.pdf

4: http://www.cochrane.org/features/cochrane-signs-alltrials-initiative-campaign-registration-and-reporting-all-clinical-trials

5: http://www.drfernyhough.ca/Cardiovascular%20disease/files/tag-cardiovascular.html

6: http://www.ti.ubc.ca/newsletter/serious-adverse-event-analysis-lipid-lowering-therapy-revisited

 

 

 

Conflict of Interest at the CTT?

What is a conflict of interest? One definition is thus: ‘A conflict of interest is a set of circumstances that creates a risk that professional judgement or actions regarding a primary interest will be unduly influenced by a secondary interest.’

Or, in my simple world. ‘Someone pays you money. You then say or do things that you would not have said or done, if they hadn’t.’ The secondary interest doesn’t have to be directly monetary. It could be a promise of a promotion, or an invitation to be chairman of an important committee, or a chance to meet someone famous, or watch a world cup final, or suchlike.

However, for the sake of keeping things simple, we are talking about money here. We are talking about pharmaceutical companies paying money to medical ‘experts’, who may then say or do things that they would not otherwise have said or done.

The first problem is, thus. How do you know they would not have said or done it anyway? If the dairy industry paid me a million pounds to say ‘Dairy foods do not cause heart disease.’ This would be a bonus. Because it is what I believe, it is what I say already, and you really don’t need to pay me a million pounds to say it. [Although I am open to offers].

However, if I was paid a million pounds and I then said ‘dairy foods to do not cause heart disease’, and you discovered that the dairy industry had paid me a million pounds, what would you think? I know exactly what you would think. ‘I trusted him, now it turns out he is just lining his wallet, the same as everyone else.’ Some would state this more vehemently than others. However, any reputation that I have would never be the same again. There would always be that loss of trust. That doubt.

The people we admire and trust the most do not take backhanders. Pity.

For many years, pharmaceutical companies paid doctors ‘honoraria’, which is just a posh word for money. The doctors happily stuffed said honoraria into their bank balances, and no-one seemed much bothered. You did not need to declare any financial interests, and the only limitation on how much you got paid was your perceived value to the companies.

Your value was measured in a few different ways:

1. Ability to influence other doctors – your status as an ‘opinion leader’
2. Your quality as a speaker at meetings and/or ability to set up and run clinical trials
3. Your influence within the healthcare system i.e. do you advise Governments on treatment, do you sit on committees that advice NICE, or the Food and Drugs Administration (FDA)
4. Your position on Guideline committees. Can you play a key role in writing the guidelines that other doctors have to follow e.g. drug x a must be used first line in all patients with condition y.

These things are, of course, all linked. As an expert you start on rung one and two, and then move onto three and four. Your progress up this ladder requires very close links with the industry. You cannot influence other doctors if you haven’t done research, and it is very difficult to do research without industry funding. If not impossible.

At a certain point in the process, you become exceedingly important to the industry. In fact there are companies who support the pharmaceutical industry whose entire raison d’etre is to manage Key Opinion Leaders (KOLs).

According to Dan Mintze, senior director, heartbeat experts, “The management of KOLs needs to be broader than identifying, segmenting, influence mapping and working with clinicians in order for products to gain clinical approval. Rather a comprehensive KOL solution which includes the identification and appropriate engagement of KOLs who impact market access decisions e.g. KOLs who serve as Government or payer advisory board members (see figure 3) should be adopted.” Such pharma-KOL engagement will lead to the development of value messages that can help pharma to access the market faster, gain quicker product adoption, and increase bottom line performance.’ [my words in bold]  Original PDF here

The more you increase bottom line performance, the more you are worth, and the more you get paid. Strangely, some left-wing commies a.k.a ‘people’ began to object to this cosy relationship. A bit too much potential for the situation whereby… a primary interest will be unduly influenced by a secondary interest.

Luckily this problem was instantly solved, amid scenes of wild rejoicing, by ensuring that doctors who did major studies, or wrote articles and suchlike, must disclose their conflicts of interest. Once this had been done there was nothing to worry about, ever again. [joke]
Although, what we are supposed to do with a disclosure of interest has never really been explained. As a Swedish doctor wrote to me:

‘While we are at this: I have often wanted to ask the purpose of revealing possible/probable conflicts of interest. Just what are we supposed to do with that editorial caveat? Does it mean the data might be suspect? If the editors want us to know it is suspect then why do they publish it?

If it means we should interpret the data with caution, can someone tell me how one is to be cautious. Does it mean one believes none of it or does one believe some of it? If the latter then which part do we believe and/or which do we not believe. Just how are we supposed to judge these things, after having been warned to beware?

Indeed, what are we supposed to do? The other problem is that, whilst doctors are meant to declare their conflicts, quite often they do not. Here is an addendum taken from the Journal of the American Medical Association.

It was in response to an article which was written by a number of authors, who did not see to need report any of their conflicts. Some eagle eyed readers wrote in to complain, and the journal responded thus [I put in bold those companies who would have benefitted financially from the original paper]:

Unreported Financial Disclosures in: ‘Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins: A Meta-analysis.’

….the following disclosures should have been reported: “Dr Mora reports receipt of travel accommodations/meeting expenses from Pfizer; Dr Durrington reports provision of consulting services to Hoffman-La Roche, delivering lectures or serving on the speakers bureau for Pfizer, and receipt of royalties from Hodder Arnold Health Press; Dr Hitman reports receipt of lecture fees and travel expenses from Pfizer, provision of consulting services on advisory panels to GlaxoSmithKline, Merck Sharp & Dohme, Eli Lilly, and Novo Nordisk, receipt of a grant from Eli Lilly, and delivering lectures or serving on the speakers bureau for GlaxoSmithKline, Takeda, and Merck Sharp & Dohme; Dr Welch reports receipt of a grant, consulting fees, travel support, payment for writing or manuscript review, and provision of writing assistance, medicines, equipment, or administrative support from Pfizer, and provision of consultancy services to Edwards, MAP, and NuPathe; Dr Demicco reports having stock/stock options with Pfizer; Dr Clearfield reports provision of consulting services on advisory committees to Merck Sharp & Dohme and AstraZeneca; Dr Tonkin reports provision of consulting services to Pfizer, delivering lectures or serving on the speakers bureau for Novartis and Roche, and having stock/stock options with CSL and Sonic Health Care; and Dr Ridker reports board membership with Merck Sharp & Dohme and receipt of a grant or pending grant to his institution from Amgen. (original JAMA correction here.)

As you can see, Paul Ridker had board membership with Merck Sharp and Dohme, and simply forgot the mention it. The authors’ collective punishment? Well, you have just seen it. Essentially, there is no punishment. A bit of momentary embarrassment, soon forgotten. [Although not by everybody, guys].

However, the steady pressure for doctors to provide disclosures of interest has had one major impact. It has made it a bloody site more difficult to know where the conflicts of interest might actually lie.

For it has been decreed….I don’t know who decreed, or agreed it, that if you are paid money directly by a pharmaceutical company, or say a PR company working for the industry, you have a financial conflict of interest that you must/should declare.

However, if you work for an organisation such as the Cleveland Clinic, or the Clinical Trials Research Unit (CTSU) in Oxford things are different. The clinic is paid money by the industry, and then the clinic pays you. This means that you are not conflicted in any way. You need not declare anything. Why?

I don’t know who stated that this is acceptable. As with most things in this area we are in a shadow world full of ghostly apparitions that elude your grasp. ‘They said it was fine.’ And who, exactly, are they. There is no oversight committee here, no investigations carried out, no rulebook, no punishment. Just a very woolly gentlemen’s agreement amongst the great and the good of medical research.

However, because it has been agreed, in some mysterious way, that ‘second hand’ payments are fine, it means that those working at the Cleveland Clinic, the CTSU, and suchlike, feel able to state that they have no financial conflicts – at all. Even if the organisation they work for earns hundreds of millions, or billions, in industry funding.

If those working at the CTSU do, somehow, find themselves working directly with the industry, they now give any money they might have eared to charity. To quote their rules on the matter:

Guidelines for CTSU staff with respect to honoraria and any
other payments offered and share ownership

——-

d: If an honorarium is declined, the intended CTSU recipient can still mention that a
corresponding amount might be donated to a specific charity.

A corresponding amount to a specific charity. What charity?

‘I guess if I had any advice for reporters, I would say, ask your local university if they’ve set up any associated [non-profit organizations]; many universities have an associated charity or foundation through which they solicit donations from corporate sponsors to support medical research. Find out about who those corporate sponsors are. Unfortunately, many universities set up these associated charities and foundations in such a way that they don’t have to disclose much publicly – ask about that, you know, try to push.’  (original article here)

Push away, but I don’t expect you will get very far.

Anyway, we are now supposed to believe that highly qualified and very influential KOLs, who work at the CTSU in Oxford, carry out work on behalf pharmaceutical companies for no payment, whatsoever. This is just charity work. Helping impoverished pharmaceutical companies is the same, really, as helping starving orphans in Africa.

Strangely, it appears that the CTSU doesn’t mind in the least that their staff are spending large chunks of their professional life helping pharmaceutical companies – out of the goodness of their hearts. The CTSU gets nothing; the pharmaceutical companies get nothing, other than a warm glow in their hearts. Meanwhile a ‘specific charity’ is doing rather well. Whatever that specific charity may be?

Of course the CTSU itself does rather well from the industry. Just for carrying out one of their many studies, REVERSE, they received £96million ($155million) from Merck Sharp and Dohme.

Yet, despite the huge sums of industry money sloshing about in the CTSU there are absolutely no conflicts of interest going on here. We are told this by none other than the CTSU itself. No-one is paid money directly by the industry in any way. So that is fine.
As Robbie Burns said: ‘O, wad some Power the giftie gie us to see oursels as others see us. It wad frae monie a blunder free us.’

As a sort of footnote to this blog, you may be interested to know that the Cholesterol Treatment Triallists Collaboration (CTT) in Oxford is probably the most influential organisation in directing the management of CV disease around the world.
The ACC/AHA guidelines launched last year in the US are based on the latest CTT meta-analysis; as are the latest NICE guidelines in the UK. The Cochrane Collaboration, which is also highly influential world-wide, changed their guidance on the use of statins in primary prevention, based on the CTT meta-analysis.

In short, if you want to identify a group of KOLs who can truly increase ‘bottom line performance’, you will not find any organisation more powerful than this. Best of all, CTT have absolutely no conflicts of interest with the pharmaceutical industry either. If you want to contact the CTT about any of this, you can e-mail them at: CTT@ctsu.ox.ac.uk

The pharmaceutical industry now controls NHS policy – hoorah.

I noticed the other day that the pharmaceutical industry have managed to achieve something they could surely once only have dreamed of. Creating policy documents. Here is the offending headline from the Guardian newspaper:

NHS hires drugmaker-funded lobbyist

As the secondary headlines say:

‘Conflict of interest concerns as Specialised Healthcare Alliance (SHCA), funded by pharmaceutical companies, advises NHS England.’

A lobbying organisation with links to some of the world’s biggest pharmaceutical companies and medical equipment firms has been asked by NHS bosses to write a report that could influence health policy, it has been reported.’

It seems lobbying is now ‘so five minutes ago.’ Who needs a lobbyist when this organisation, the Specialised Healthcare Alliance (SHCA), which is entirely bought and paid for by the pharmaceutical industry, has been commissioned to write a report on funding specialised services for the NHS.  Services worth £13,000,000,000.00p (£13Bn/$20Bn) per year.

The article does point out, though, that we are misguided to think that this could be in any way an issue. For John Murray, the director of the SHCA, a lobbyist, and author of the report, has made it clear that:

.…..there was no link between his lobbying business and the SHCA other than providing secretariat services and said the SHCA “never takes a position on particular products or treatments in any of its activities”.

John (Pinocchio) Murray’s nose is now in the Guinness Book of Records for being the longest nose ever recorded on a human being, at seven point three miles. He is a lobbyist, paid for by pharmaceutical companies, and his organisation never takes a position on particular products…..hahahahahahahahahaha. Well then, sack him immediately for being useless…. sack him for failing to do what he is handsomely paid to do.

The final part of this newspaper report, which I savoured, is the following:

‘James Palmer, clinical director of specialised services at NHS England, said he was aware of Murray’s role as a lobbyist but “there are no opportunities for lobbying in the process of forming clinical policy”.’

This, of course, is true. There are no opportunities for lobbying in this particular process of forming clinical policy. Once a lobbyist starts to write clinical policy, they have moved well past the annoying requirement to lobby anyone. For the lobbyist has now managed to become the very person that they should be paid to lobby.

Instead of trying to influence someone who may not listen to him, he can just talk to himself…. Imagine that this short section of imagined dialogue is like Smeagol talking to Gollum in Lord of the Rings (Smeagol and Gollum are, or course the same person):

John Murray: ‘We must put the following phrase into the report, my precious. A “clear commitment” to “disinvest in interventions that have lower impact for patients” in favour of “new services or innovations”.

John Murray: “But why would you like me to put this in the report, wont this harm the hobbits? Hobbits have been kind to me…yes they have.”

John Murray: ‘I needs it in the report you fool. I represent precious pharmaceutical companies that are bringing new products onto the market. We needs to ensure that there will plenty of money to pay for them. So they must stop paying for stupid old fashioned treatments…yes, they must, foolish Hobbits.’

John Murray: ‘But won’t the kind Hobbits be worried this will just look like lobbying.’

John Murray: ‘Don’t be so stupid. How can the nasty Hobbits accuse me of lobbying? I am their friend, and I am trying to help them…yes I am.. Yes John Murray likes the friendly Hobbits. John Murray want to help the Hobbits, yes he does.’

John Murray: ‘You are so clever Smeagol, our master will be pleased.’…….

Duchess: ‘You’re thinking about something, my dear, and that makes you forget to talk. I can’t tell you just now what the moral of that is, but I shall remember it in a bit.’

“Perhaps it hasn’t one,” Alice ventured to remark.

“Tut, tut, child!” said the Duchess. “Everything’s got a moral, if only you can find it.”