Dr Malcolm Kendrick

� The road to Damascus

� Why are data distorted◦ The power of ideas

◦ The desire to fit in/maintain the status quo

◦ The power of the expert

◦ Money

◦ Mistakes are made…but not by me

� How data are distorted

� Modern medicine represents the single greatest technical/scientific achievement of mankind◦ Antibiotics

◦ Hip replacements

◦ Heart valve replacements

◦ Modern anaesthetics

◦ Insulin/diabetic treatment

◦ …and far too many more to mention…BUT

� The MRC study

� Main aim of the trial was to determine whether ◦ drug treatment of mild hypertension* in men and women aged 35-64 years reduced the rates of

� Stroke

� Death due to hypertension

� Coronary events

� 17,354 patients were recruited

� 85,572 patient years of observation

*phase V diastolic pressure 90-109 mm Hg

BPBPBPBP lowering medicationlowering medicationlowering medicationlowering medication PlaceboPlaceboPlaceboPlacebo

Fatal strokes 18 27

Fatal Coronary events 106 97

Stroke + MI deaths 124 124

Deaths 248 253

http://www.ncbi.nlm.nih.gov/pubmed/2861880

� ‘Men occasionally stumble over the truth, but most of them pick themselves up and hurry off as if nothing had happened.’

Winston Churchill

� The power of ideas

� The desire to fit in/maintain the status quo

� The power of the experts

� Money

� Mistakes were made….but not by me

‘Why do people insist on defending their ideas and opinions with such ferocity, as if defending honour itself? What could be easier to change than an idea?’

‘The most resilient parasite is an idea.’

J.G Farrell

Inception - The movie

Wilfred Trotter

‘The mind likes a strange idea as little as the body likes a strange protein and

resists it with similar energy. It would not perhaps be too fanciful to say that a new idea is the most quickly

acting antigen known to man.’

Leo Tolstoy

‘I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth, ……if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives.’

‘When I entered medicine, I did not realize that there was such intense

pressure to conform. But we learn early on that there is a decorum to medicine, a politeness.

A hidden curriculum teaches us not to disturb the status quo. We are trained to defer to authority,

not to question it. We depend on powerful individuals and organizations and are taught that

success does not often come to those whoask uncomfortable questions or suggest

new ways of providing care….

‘I have heard of junior faculty who were told that questioning key assumptions of the field, even with evidence, would result in threats to funding and support.’

� ‘A note to my younger colleagues – be brave ’

Harlan M. Krumholz, MD, SM (Editorial in Circulation)

Writing in this week's British Medical Journal (BMJ), Canadian-based researcher, David Sackett, said that he would "never again lecture, write, or referee anything to "never again lecture, write, or referee anything to "never again lecture, write, or referee anything to "never again lecture, write, or referee anything to do with evidence based clinical practice". do with evidence based clinical practice". do with evidence based clinical practice". do with evidence based clinical practice".

Sackett is not doing this because he has ceased to believe in evidence based clinical practice but, as the BMJ comments, because he is worried about the power of experts in stifling new ideas and wants the retirement of wants the retirement of wants the retirement of wants the retirement of experts to be made compulsoryexperts to be made compulsoryexperts to be made compulsoryexperts to be made compulsory....

‘According to the founder of Evidence Based Medicine, experts are hindering the healthy advancement of science.’

Those who challenge conventional views or vested interests in science are likely to encounter difficulties.

A scientific dissenter should first of all realize that science is a system of power as well as knowledge, in which interest groups play a key role and insiders have an extra advantage. Dissenters are likely to ignored or dismissed.’

Brian Martin ‘Strategies for Dissenting ScientistsStrategies for Dissenting ScientistsStrategies for Dissenting ScientistsStrategies for Dissenting Scientists.’ Journal of Scientific Exploration. Vol. 12. No. 4. 1998. pp. 605-616

� Dr. Cleeman: (Chairman) has no financial relationships to disclose.

� Dr. Grundy: has received honoraria from Merck, PfizerMerck, PfizerMerck, PfizerMerck, Pfizer,,,, Sankyo, Bayer, Merck/ScheringSankyo, Bayer, Merck/ScheringSankyo, Bayer, Merck/ScheringSankyo, Bayer, Merck/Schering----Plough, Kos, Plough, Kos, Plough, Kos, Plough, Kos, Abbott, BristolAbbott, BristolAbbott, BristolAbbott, Bristol----Myers Squibb, and AstraZenecaMyers Squibb, and AstraZenecaMyers Squibb, and AstraZenecaMyers Squibb, and AstraZeneca; he has received research grants from Merck, Abbott, Merck, Abbott, Merck, Abbott, Merck, Abbott, and and and and GlaxoGlaxoGlaxoGlaxo Smith Kline.Smith Kline.Smith Kline.Smith Kline.

� Dr. Bairey Merz: has received lecture honoraria from Pfizer, Merck, and KosPfizer, Merck, and KosPfizer, Merck, and KosPfizer, Merck, and Kos; she has served as a consultant for Pfizer, Bayer, and EHC (MerckPfizer, Bayer, and EHC (MerckPfizer, Bayer, and EHC (MerckPfizer, Bayer, and EHC (Merck); she has received unrestricted institutional grants for CME from Pfizer, Procter & Gamble, Novartis, Wyeth, AstraZeneca, and BristolPfizer, Procter & Gamble, Novartis, Wyeth, AstraZeneca, and BristolPfizer, Procter & Gamble, Novartis, Wyeth, AstraZeneca, and BristolPfizer, Procter & Gamble, Novartis, Wyeth, AstraZeneca, and Bristol----Myers Squibb Myers Squibb Myers Squibb Myers Squibb Medical Imaging; she has received a research grant from MerckMerckMerckMerck; ; ; ; she has stock in Boston Scientific, IVAX, Eli Eli Eli Eli Lilly, Medtronic, Johnson & JohnsoLilly, Medtronic, Johnson & JohnsoLilly, Medtronic, Johnson & JohnsoLilly, Medtronic, Johnson & Johnson, SCIPIE Insurance, ATS Medical, and Biosite.

� Dr. Brewer: has received honoraria from AstraZeneca, PfizerAstraZeneca, PfizerAstraZeneca, PfizerAstraZeneca, Pfizer, Lipid Sciences, Merck, Merck, Merck, Merck, Merck /Merck /Merck /Merck /ScheringScheringScheringSchering----PloughPloughPloughPlough, , , , FournierFournierFournierFournier, Tularik, Esperion, and NovartisNovartisNovartisNovartis; he has served as consultant for AstraZeneca, Pfizerfor AstraZeneca, Pfizerfor AstraZeneca, Pfizerfor AstraZeneca, Pfizer, Lipid Sciences, Merck, Merck/ScheringMerck, Merck/ScheringMerck, Merck/ScheringMerck, Merck/Schering----PloughPloughPloughPlough, Fournier,Fournier,Fournier,Fournier, Tularik, Sankyo, NovartisNovartisNovartisNovartis....

� Dr. Clark: has received honoraria for educational presentations from Abbott, AstraZeneca, BristolAbbott, AstraZeneca, BristolAbbott, AstraZeneca, BristolAbbott, AstraZeneca, Bristol----Myers Squibb, Merck, and PfizerMyers Squibb, Merck, and PfizerMyers Squibb, Merck, and PfizerMyers Squibb, Merck, and Pfizer;;;; he has received grant/research support from Abbott, AstraZeneca, Abbott, AstraZeneca, Abbott, AstraZeneca, Abbott, AstraZeneca, BristolBristolBristolBristol----Myers Squibb, Merck, and Pfizer.Myers Squibb, Merck, and Pfizer.Myers Squibb, Merck, and Pfizer.Myers Squibb, Merck, and Pfizer.

� Dr. Hunninghake: has received honoraria for consulting and speakers bureau from AstraZeneca, AstraZeneca, AstraZeneca, AstraZeneca, Merck, Merck/ScheringMerck, Merck/ScheringMerck, Merck/ScheringMerck, Merck/Schering----Plough, and PfizerPlough, and PfizerPlough, and PfizerPlough, and Pfizer, and for consulting from Kos;Kos;Kos;Kos; received research grants from AstraZeneca, Bristolfrom AstraZeneca, Bristolfrom AstraZeneca, Bristolfrom AstraZeneca, Bristol----Myers Squibb, Kos, Merck, Merck/ScheringMyers Squibb, Kos, Merck, Merck/ScheringMyers Squibb, Kos, Merck, Merck/ScheringMyers Squibb, Kos, Merck, Merck/Schering----Plough, Novartis, and Pfizer.Plough, Novartis, and Pfizer.Plough, Novartis, and Pfizer.Plough, Novartis, and Pfizer.

� Dr. Pasternak: has served as a speaker for Pfizer, Merck, Merck/ScheringPfizer, Merck, Merck/ScheringPfizer, Merck, Merck/ScheringPfizer, Merck, Merck/Schering----PloughPloughPloughPlough, Takeda, Kos, BMSTakeda, Kos, BMSTakeda, Kos, BMSTakeda, Kos, BMS----SanofiSanofiSanofiSanofi, and Novartis; , and Novartis; , and Novartis; , and Novartis; he has served as a consultant for Merck, Merck/ScheringMerck, Merck/ScheringMerck, Merck/ScheringMerck, Merck/Schering----Plough, Plough, Plough, Plough, SanofiSanofiSanofiSanofi, Pfizer, Pfizer, Pfizer, PfizerHealth Solutions, Johnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & Johnson----Merck, and AstraZeneca.Merck, and AstraZeneca.Merck, and AstraZeneca.Merck, and AstraZeneca.

� Dr. Smith received institutional research support from Merck;Merck;Merck;Merck; he has stock in Medtronic and and and and J&J.J&J.J&J.J&J.

� Dr. Stone: has received honoraria for educational lectures from Abbott, AstraZeneca, BristolAbbott, AstraZeneca, BristolAbbott, AstraZeneca, BristolAbbott, AstraZeneca, Bristol----Myers Myers Myers Myers SquibbSquibbSquibbSquibb, , , , Kos, Merck, Merck/ScheringKos, Merck, Merck/ScheringKos, Merck, Merck/ScheringKos, Merck, Merck/Schering----Plough, NovartisPlough, NovartisPlough, NovartisPlough, Novartis, Pfizer, Reliant, and Sankyo; he has served as a consultant for Abbott, Merck, Merck/ScheringAbbott, Merck, Merck/ScheringAbbott, Merck, Merck/ScheringAbbott, Merck, Merck/Schering----Plough, PfizerPlough, PfizerPlough, PfizerPlough, Pfizer,,,, and Reliant.

http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04_disclose.htm

NOTHING!

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

….the following disclosures should have been reported:

“Dr Mora reports receipt of travel accommodations/meeting expenses from PfizerPfizerPfizerPfizer;;;;Dr Durrington reports provision of consulting services to HoffmanHoffmanHoffmanHoffman----La RocheLa RocheLa RocheLa Roche, delivering lectures or serving on the speakers bureau for PfizerPfizerPfizerPfizer, and receipt of royalties from HodderHodderHodderHodder Arnold Health PressArnold Health PressArnold Health PressArnold Health Press; Dr Hitman reports receipt of lecture fees and travel expenses from PfizerPfizerPfizerPfizer, provision of consulting services on advisory panels to GSK, GSK, GSK, GSK, Merck Sharp & Merck Sharp & Merck Sharp & Merck Sharp & DohmeDohmeDohmeDohme, Eli Lilly, Eli Lilly, Eli Lilly, Eli Lilly, , , , and Novo NordiskNovo NordiskNovo NordiskNovo Nordisk,,,, receipt of a grant from Eli LillyEli LillyEli LillyEli Lilly, and delivering lectures or serving on the speakers bureau for GSK, GSK, GSK, GSK, Takeda, Takeda, Takeda, Takeda, and Merck Sharp & Merck Sharp & Merck Sharp & Merck Sharp & DohmeDohmeDohmeDohme; 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 PfizerPfizerPfizerPfizer,,,,and provision of consultancy services to EdwardsEdwardsEdwardsEdwards, MAPMAPMAPMAP, and NuPatheNuPatheNuPatheNuPathe; Dr Demiccoreports having stock/stock options with PfizerPfizerPfizerPfizer; Dr Clearfield reports provision of consulting services on advisory committees to MSD MSD MSD MSD and AstraZenecaAstraZenecaAstraZenecaAstraZeneca; Dr Tonkin reports provision of consulting services to PfizerPfizerPfizerPfizer, delivering lectures or serving on the speakers bureau for NovartisNovartisNovartisNovartis and RocheRocheRocheRoche, and having stock/stock options with CSLCSLCSLCSL and Sonic Health CareSonic Health CareSonic Health CareSonic Health Care; and Dr Ridker reports board membership board membership board membership board membership with MSD MSD MSD MSD and receipt of a grant or pending grant to his institution from AmgenAmgenAmgenAmgen.

http://jama.ama-assn.org/content/307/16/1694.3.full?etoc

� Astrophysics◦ No one dies…although it can get very expensive –think Hubble Space telescope with an incorrectly aligned mirror

� Medicine◦ Many can die…

S Strict bed rest after an MI…

S ‘In 1912, Dr James Herrick (1861–1954) of

Chicago published in JAMA

S “Clinical features of sudden obstruction of the

coronary arteries.”

S In that article, he stated, """"The importance of The importance of The importance of The importance of

absolute rest in bed for several days is absolute rest in bed for several days is absolute rest in bed for several days is absolute rest in bed for several days is clearclearclearclear

postinfarctionpostinfarctionpostinfarctionpostinfarction…….…….…….…….

‘The patient is to be guarded by day and night nursing and helped in every way to avoid voluntary movement, or effort.’

Thomas Lewis

S As Dr Braunwald then observed ‘…unfortunately, “ a few days became six weeks,” with a 30% in-patient mortality for acute myocardial infarction in his time of training.

S “On early-morning rounds to draw bloods, I'd find that some of our patients had slipped away quietly in the night in some of the rooms off to the side,” he lamented.’

� 30% in-patient mortality after an MI

� Now, about 9%

� Around 10% caused by strict bed-rest

� That would be ~ 100,000 additional deaths per year in the USA alone (men only)

� Conservative estimate from 1920 – 1965, worldwide…..

� Fifteen million

� Miasma/germ theory

� Radical mastectomy

� Removal of toxic colon

� Stress as primary cause of stomach ulcers

� Coronary artery bypass surgery?

� Non-acute PCA?

� The cholesterol hypothesis?

� Ideas are very powerful and important to us all, we fight to maintain them

� Experts have enormous influence, and they will almost always support the status quo

� Money

� In medicine, admitting to mistakes can be too painful

� ‘A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.’

Max Plank

� Research that isn’t done, or strangled at birth

� Peer review

� Editorial control

� Attacks on sceptics

� Manipulation of published data◦ Not publishing negative results◦ Not releasing negative data◦ Not publicising negative data◦ Creating a solar system where the Earth is at the Centre◦ If you don’t like the data, ignore it◦ Use of relative risk◦ Use of the term ‘life saving’

� Richard Smith, the recently retired editor of BMJ (formerly the British Medical Journal), has written that he required…

“…almost a quarter of a century editing . . . to wake up to what was happening." Noting that it would be far too crude, and possibly detectable, for companies to fiddle directly with results, he suggested that it was far more important to ask the "right" question. ‘‘‘‘It's Not the Answers That Are Biased, It's the QuestionsIt's Not the Answers That Are Biased, It's the QuestionsIt's Not the Answers That Are Biased, It's the QuestionsIt's Not the Answers That Are Biased, It's the Questions.’.’.’.’

http://www.washingtonpost.com/wp-dyn/content/article/2008/07/14/AR2008071402145.html

‘Smith, Bero and others have catalogued these "tricks of the trade," which include…� testing your drug against a treatment that either does not work or does not work very well

� testing your drug against too low or too high a dose of the comparison drug because this will make your drug appear more effective or less toxic

� publishing the results of a single trial many times in different forms to make it appear that multiple studies reached the same conclusions

� and publishing only those studies, or even parts of studies, that are favourable to your drug, and burying the rest.

Richard Horton (Editor, Lancet)

‘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.’

� Austrian study◦ ‘Why Eve Is Not Adam: Prospective Follow-Up in 149,650 Women and Men of Cholesterol and Other Risk Factors Related to Cardiovascular and All-Cause Mortality.’

◦ In men under the age of 50, and in women from the age of 50 onward, low cholesterol was significantly low cholesterol was significantly low cholesterol was significantly low cholesterol was significantly associated with allassociated with allassociated with allassociated with all----cause mortality, showing cause mortality, showing cause mortality, showing cause mortality, showing significant associations with death through cancer, significant associations with death through cancer, significant associations with death through cancer, significant associations with death through cancer, liver diseases, and mental liver diseases, and mental liver diseases, and mental liver diseases, and mental diseasesdiseasesdiseasesdiseases.

� Journal of Women’s Health Journal of Women’s Health Journal of Women’s Health Journal of Women’s Health Volume Volume Volume Volume 13, Number 1, 13, Number 1, 13, Number 1, 13, Number 1, 2004200420042004

0

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Mortality Rate vs. Mortality Rate vs. Mortality Rate vs. Mortality Rate vs. Variable?Variable?Variable?Variable?

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BMI < 18.5 BMI 18.5 - 24.9 BMI 25 - 30 BMI 30 - 35 BMI > 35

Mortality Rate vs. Mortality Rate vs. Mortality Rate vs. Mortality Rate vs. BMIBMIBMIBMI

� ‘Excess ‘Excess ‘Excess ‘Excess deaths associated with underweight, deaths associated with underweight, deaths associated with underweight, deaths associated with underweight, overweight, and obesityoverweight, and obesityoverweight, and obesityoverweight, and obesity.’ .’ .’ .’

� ‘Overweight was Overweight was Overweight was Overweight was not not not not associated with excess associated with excess associated with excess associated with excess mortalitymortalitymortalitymortality.’ .’ .’ .’

� 86,094 less deaths; 95% CI, -161,223 to -10,966

http://www.ncbi.nlm.nih.gov/pubmed/15840860

Dear Mister Ravnskov,

I read with interest your letter in the BMJ, in the 20 September issue of 2008.

� You state that cholesterol has nothing to do with the incidence of cardiovascular disease in individuals with familial hypercholesterolemia. You also state that the effect of statin therapy is grossly overstated and that women do not benefit and that the benefits are easily outweighted by side effects.

� If this was a joke, I could have laughed about your statements heartily, but they are in If this was a joke, I could have laughed about your statements heartily, but they are in If this was a joke, I could have laughed about your statements heartily, but they are in If this was a joke, I could have laughed about your statements heartily, but they are in fact criminal and bordering on the insanefact criminal and bordering on the insanefact criminal and bordering on the insanefact criminal and bordering on the insane. I am aware of the fact that you have advised a mother with a daughter suffering from FH to feed her organic vegetables and that the link between cholesterol and early heart disease did not exist in FH but was in fact due to a tendency to blood-clotting.

� I suggest you read the work that my colleague Dr. Sijbrands and myself published in the BMJ in 2001* as well as the article published in BMJ last week. I also suggest you take good notice of the JUPITER results that I published together with Dr. Paul Ridker in the NEJM last week. These 3 studies completely contradict all of your ridiculous contentions. completely contradict all of your ridiculous contentions. completely contradict all of your ridiculous contentions. completely contradict all of your ridiculous contentions.

� In fact, I insist that you refrain from any advice to any patient anymore. You are lucky In fact, I insist that you refrain from any advice to any patient anymore. You are lucky In fact, I insist that you refrain from any advice to any patient anymore. You are lucky In fact, I insist that you refrain from any advice to any patient anymore. You are lucky not to live in the Netherlands. I would have dragged you to court. not to live in the Netherlands. I would have dragged you to court. not to live in the Netherlands. I would have dragged you to court. not to live in the Netherlands. I would have dragged you to court. I have cared for patients with familial hypercholesterolemia since 1987 and I have seen the terrible devastation that this disease can bring to families. I have also seen what the introduction of statins has done and your nonsense is creating an anger in me that I and your nonsense is creating an anger in me that I and your nonsense is creating an anger in me that I and your nonsense is creating an anger in me that I have not experienced for a long time. have not experienced for a long time. have not experienced for a long time. have not experienced for a long time.

Professor Dr. J.J.P. Kastelein

S “If “If “If “If this was a joke, I could have laughed about this was a joke, I could have laughed about this was a joke, I could have laughed about this was a joke, I could have laughed about your statements heartily, but they are in fact your statements heartily, but they are in fact your statements heartily, but they are in fact your statements heartily, but they are in fact criminal and bordering on the insanecriminal and bordering on the insanecriminal and bordering on the insanecriminal and bordering on the insane....

S …completely …completely …completely …completely contradict all of your ridiculous contradict all of your ridiculous contradict all of your ridiculous contradict all of your ridiculous contentions. contentions. contentions. contentions. I I I I insist that you refrain from any insist that you refrain from any insist that you refrain from any insist that you refrain from any advice to any patient anymore. You are lucky advice to any patient anymore. You are lucky advice to any patient anymore. You are lucky advice to any patient anymore. You are lucky not to live in the Netherlands. I would have not to live in the Netherlands. I would have not to live in the Netherlands. I would have not to live in the Netherlands. I would have dragged you to courtdragged you to courtdragged you to courtdragged you to court....

S …your …your …your …your nonsense is creating an anger in me nonsense is creating an anger in me nonsense is creating an anger in me nonsense is creating an anger in me that I have not experienced for a long that I have not experienced for a long that I have not experienced for a long that I have not experienced for a long time.”time.”time.”time.”

S ‘What is remarkable to me is that this man [Peter Goetzsche] calls himself a scientist since he obviously and knowingly ignores the scientific method in order to further his own agenda, whatever that may be.

S I cannot believe he is so intellectually deficient that he cannot grasp the plethora of evidence that so strongly supports the benefit of screening. What then drives him so blindly in his crusade to convince us all that the world is flat?’

S To become infamous as a contrarian, standing lonely on the curvature of the earth as he denies it is spinning under his feet? Or is it something even more petty? An all-consuming hatred and jealousy of Laslo Tabar, whose impeccable trial facilitated by meticulous record keeping and a socialist society provides a setting unparalleled in the world for a scientific trial?

S What is tragic and makes [Peter Goetzsche]’s ravings sinister is that I am sure his influence has I am sure his influence has I am sure his influence has I am sure his influence has resulted in women’s unnecessary deathsresulted in women’s unnecessary deathsresulted in women’s unnecessary deathsresulted in women’s unnecessary deaths….

S Letter by Daniel Kopans to Laslo Tabar. ‘Mammography screening: truth, lies and controversy.’ pp 89-90: ISBN-13 9781846195853

� Ben Goldacre ‘Bad Pharma’

� Up to 2007 no controls

� Pharma forum research

� FDAAA Certification to Accompany Drug, Biological Product, and Device Applications or FDAAA Certification to Accompany Drug, Biological Product, and Device Applications or FDAAA Certification to Accompany Drug, Biological Product, and Device Applications or FDAAA Certification to Accompany Drug, Biological Product, and Device Applications or SubmissionsSubmissionsSubmissionsSubmissions

� The recently enacted U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007), Title VIII, Section 801 mandates the expansion of the clinical trials data bank (ClinicalTrials.gov). The new provisions require additional information to be submitted to the databank, including expanded information on clinical trials and information on the results of clinical trials. Additional information for individuals or organizations registering clinical trials in the ClinicalTrials.gov data bank is available on the National Library of Medicine (NLM) Protocol Registration System (PRS) website.

� One FDAAA provision in Section 801, 42 U.S.C. 282(j)(5)(B), requires that a certification form accompany certain human drug, biological, and device product submissions made to FDA. At the time of submission of an application under sections 505, 515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355, 360e, or 360j(m)), or under section 351 of the Public Health Service Act (PHS Act) (21 U.S.C. 262), or submission of a report under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), such application or submission must be accompanied by a certification that all applicable requirements of section 402(j) of the PHS Act have been met. Where available, such certification must include the appropriate ClinicalTrials.gov identifiers (NCT numbers).

� Based on the timeframes under which the new FDAAA submission requirements take effect, the certifications must be submitted to FDA beginning no later than December 26, 2007no later than December 26, 2007no later than December 26, 2007no later than December 26, 2007. The official certification form, Form FDA 3674 entitled "Certification of Compliance, under 42 U.S.C. § 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. § 282(j)),” is now available on FDA's Web site. The Federal Register notice (TXT) (PDF) announcing the clearance process for the form under the Paperwork Reduction Act (44 U.S.C. 3507(j)) is also available…….. BLAH, BLAH, BLAH……

http://dl.dropbox.com/u/4219544/ISMPP%20survey%20poster_1November2011.pdf

� ‘…the withholding of data has never been adequately dealt with, either by legislation or by codes of conduct in the drug industry. The Cochrane Collaboration has repeatedly failed to gain access to full data from trials of oseltamivir performed by Roche, despite the fact the UK government spent £500m on stockpiling the drug, they say.’

BMJ Oct 27BMJ Oct 27BMJ Oct 27BMJ Oct 27thththth 2012 2012 2012 2012 volvolvolvol 345 345 345 345 pppppppp 3333

� ‘Governments cannot continue to ignore this international scandal.’

Ben Goldacre

S ‘Eligible patients who completed a pre-randomization run-in phase on active treatment were randomly allocated to receive simvastatin (40 mg daily) or matching placebo tablets.’

S 60,000 in pre-randomisation but only 20,000 took part

http://www.ncbi.nlm.nih.gov/pubmed/10329064?dopt=Abstract

…in around 360,000 men who were screened for the Multiple Risk Factor Intervention Trial (MRFIT), every 1 1 1 1 mmolmmolmmolmmol/L lower blood total /L lower blood total /L lower blood total /L lower blood total cholesterol was cholesterol was cholesterol was cholesterol was associated with about a associated with about a associated with about a associated with about a 50505050% lower risk of death % lower risk of death % lower risk of death % lower risk of death from coronary from coronary from coronary from coronary heart heart heart heart disease, irrespective of blood cholesterol disease, irrespective of blood cholesterol disease, irrespective of blood cholesterol disease, irrespective of blood cholesterol at at at at baseline.baseline.baseline.baseline.

� The higher the cholesterol level, the greater the risk of death. This is linear (log linear)

S To date, the lower limit of cholesterol that still results in risk reduction is unknown, although many experts have theorized that it may be at an LDL-C level of 1mmol/L

(A)Absolute reduction in LDL cholesterol (mmol/l) and absolute reduction in risk of major cardiac event (MCE).

Prepared by: British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association Heart 2005;91:v1-v52

.

(A)Absolute reduction in LDL cholesterol (mmol/l) and absolute reduction in risk of major cardiac event (MCE).

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/heart-disease-risk-reduction/

Hazard ratio CVD vs.…

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Hazard ratio CVD vs. cholesterol levelsHazard ratio CVD vs. cholesterol levelsHazard ratio CVD vs. cholesterol levelsHazard ratio CVD vs. cholesterol levels

Jacobs et al: ‘Report of the Conference on Low Blood Cholesterol: Mortality Associations.’ Circulation Vol: 86, No 3 Sept 1992

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Women 50 - 64

Women > 64

Cholesterol levels vs. CHD risk in womenCholesterol levels vs. CHD risk in womenCholesterol levels vs. CHD risk in womenCholesterol levels vs. CHD risk in women

‘Western Diseases their emergence and prevention’Edited by H Trowell, D Burkitt. 1973’

S Efficacy Efficacy Efficacy Efficacy of cholesterolof cholesterolof cholesterolof cholesterol----lowering therapy in lowering therapy in lowering therapy in lowering therapy in 18, 18, 18, 18, 686 686 686 686 peoplepeoplepeoplepeople with with with with diabetes in 14 diabetes in 14 diabetes in 14 diabetes in 14 randomised trials of randomised trials of randomised trials of randomised trials of statins: a metastatins: a metastatins: a metastatins: a meta----analysis.analysis.analysis.analysis.

S ‘Recently, two large trials of statin therapy in people with diabetes have been reported: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin Dependent Diabetes Mellitus(ASPEN), and the German Diabetes and Dialysis Study (4D).’

The Lancet, Volume 371, Issue 9607, 117 - 125, 12 January 2008

S ‘Since both of these trials reported unpromising results, we considered whether their inclusion would have been likely to change our conclusion.’

S So both studies were ignored

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2753.2011.01767.x/pdf

S Treat 100 people with a blood pressure lowering agent for one year vs. placebo

S End of the study one person dies in the treatment arm, two die in placebo arm

S Absolute risk reduction 1%

S Relative risk reduction 1 vs 2 (50% RRR)

S Treat 1000 people

S End of study 1 person dies in treatment arm vs. 2 in placebo arm

S Absolute risk reduction 0.1%

S Relative risk reduction 50%

S Etc

S ‘Compared to those who received placebo, patients receiving the drug rosuvastatin had a 48% reduction in stroke, a 46% reduction in the need for interventions to reopen blocked blood vessels, and a 20% drop in all cause mortality.

S ‘The extent of reduction in death, heart attacks, and stroke is larger than we've seen in any trial I can remember.’

Dr. Steven Nissen

MIMIMIMI

Placebo: 68686868 MIs resulting in 6666 deathsStatin: 31313131 MIs resulting in 9999 deaths

StrokeStrokeStrokeStroke

Placebo: 64646464 strokes resulting in 6666 deathsStatin: 33333333 strokes resulting in 3333 deaths

Stroke + MIStroke + MIStroke + MIStroke + MI

Placebo : 12 12 12 12 deaths from stroke and MIStatin: 12121212 deaths from stroke and MI

Professor Michel De Logerilhttp://archinte.ama-

issn.org/cgi/content/full/170/12/1032

‘Although it is quite unusual that the burden of calculating cardiovascular mortality is placed on the readers, all methods used,

however, lead to the same conclusion: there is no significant difference in cardiovascular

mortality between the 2 groups in the JUPITER trial.’

S There were 8901 in the placebo arm at the start of the trial, and another 8901 in the statin arm. The number of those dying in each arm was 235/8901 vs 190/8901…

S Which is 2.64% vs. 2.14%

S An absolute difference of 0.5%

S This could also be represented as NNT = 200 over 2 years of treatment. (NNT 400 for one year)

http://www.bbc.co.uk/news/health-17221910

� ‘Women diagnosed with cervical cancer as a result of a smear test have a far better chance of being cured than women who do not go for tests, a Swedish study suggests. The researchers found a 92% cure rate after a smear test diagnosis, compared with 66% for symptoms-based diagnoses.’

� Robert Music, director of Jo's Cervical Cancer Trust, said the research highlighted the importance of attending cervical screening.

"Cervical cancer is largely preventable thanks to cervical screening which saves 5,000

UK lives a year. And for those diagnosed,

survival rates are good if the disease is caught early…”

S Regularly screened 71717171 deaths, out of 431 diagnosed cases

S Not screened/irregularly screened 106 106 106 106 deaths, out of 409 diagnosed cases

S

S Total difference = 35353535

� Total number of screening tests

� 2,500,000 women

� Three years

� Total 7,500,000

� 7,500,000/35

� 214,285 cervical smears for every case of cervical cancer ‘cured’

86

88

90

92

94

96

98

100

102

Start Year 1 Year 2 Year 3 Year 4 Year 5

Simvastatin

Placebo

� "This is a stunning result, with massive public health implications. We've found that cholesterol-lowering treatment can protect a far wider range of people than was previously thought, and that it can preventpreventpreventprevent strokes as well as heart attacks."

� “In this trial, 10 thousand people were on a statin. If now, an extra 10 million high-risk people worldwide go onto statin treatment, this would save about 50,000 lives each yearthis would save about 50,000 lives each yearthis would save about 50,000 lives each yearthis would save about 50,000 lives each year- that's a thousand a week.”

http://www.ctsu.ox.ac.uk/~hps/pr.shtml

86

88

90

92

94

96

98

100

102

Start Year 1 Year 2 Year 3 Year 4 Year 5

Simvastatin

Placebo

89

90

91

92

93

94

95

Year 4 Year 5

B

A

Simvastatin

Placebo

89

90

91

92

93

94

95

Year 4 Year 5

B

A

Simvastatin

Placebo

c

� Taking a statin for five years results in 1.8% living for around four months longer, on average

� For 98.2% the statin had no effect

� The average increase in life expectancy after five years is 14 days

� You cannot ‘save lives’

� You may delay death – perhaps to die of something else

� You do not know if you will be in the 1.8%

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

www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020124

J Ionnadis. ‘Why most published research findings are false’

Dr Marcia Agnell

“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

Scientists are usually too careful and clever to risk telling outright lies, but instead they push the envelope of exaggeration, selectivity and distortion as far as possible. And tolerance for this kind of untruthfulness has greatly increased over recent years. So it is now routine for scientists deliberately to ‘hype’ the significance of their status and performance and ‘spin’ the importance of their research.

Bruce Charlton: Professor of Theoretical Medicine

� Conclusion: ‘‘Spin’’ was identified in about half of press releases and media coverage. In multivariable analysis, the main factor associated with ‘‘spin’’ in press releases was the presence of ‘‘spin’’ in the article abstract conclusion.

Misrepresentation of Randomized Controlled Trials inPress Releases and News Coverage: A Cohort Study.

� Independent review body – with statutory powers

� Individuals (you) need to be more sceptical

� All studies need to be reported using the same measures

Men < 49

Men > 650

0.5

1

1.5

2

Chol <

4.8Chol

5.4Chol

5.9Chol >

6.4

1.28

1 11.24

1.28

1 1 1.04

1.75

1 1 1Men < 49

Men 49 - 64

Men > 65