1

June 26, 2006

" The recommendation also broadens the definition of conflict of interest beyond just those with financial relationships with commercial interests to include subspecialists, who derive a substantial portion of their income from certain types of care. Greenfield acknowledged that thisexpansion may cause consternation among some organizations."

JAMA 2011

Conflict of interest

‘a set of conditions in which professional judgment concerning a primary interest (such as patient’s welfare or validity of research) tends to be unduly influenced by a secondary interest.’

Statin Sales and Cholesterol Guidelines

• National Cholesterol Eduction Program (run by the NIH) lowered recommended LDL level from 130 to 100 mg/dl

• Add 7 million people to the 36 million already encouraged

• $26 billion drug group• Guidelines written by nine experts

Statin Sales and Cholesterol Guidelines

• 8 out of 9 had financial conflicts of interest• Each of the 8 experts had on average ties to

seven companies• Justified?

– 1000 Women on Lipitor had an increased CHD risk

– No evidence that statins protect women without heart disease

2

Influence of Industry sponsors

• Authors were contacted and questioned regarding financial relationships with calcium channel manufacturers.– 96% of the supportive authors had financial relationships– 60% of the neutral authors had financial relationships– 37% of the critical authors had financial relationships

• Industry sponsorship and pro-industry conclusions are significantly associated (OR=3.6, 95% confidence interval: 2.63-4.91)

N-Engl-J-Med: 1998: 338:101-6 BMJ. 2007 Dec 8;335(7631):1202-5. Epub 2007 Nov 1

When controlling for other characteristics of meta-analyses in multiple logistic regression analyses, meta-analyses that had financial ties to one drug company remained more likely to report favourable conclusions (5.11, 1.54 to 16.92).

GTR

• Company funded trials: 55.8% complete root coverage

• Non-company funded: 33.2% complete root coverage

J. Periodontol. October 2003

Sensodyne

School A 77(82%) 12

22 (28%) 58Other

94

80

+ -

Odds ratio: 9.6 95% confidence interval: 3.6- 25.4 P < 0.0001

Industry up/Academia Down

• 1980: 32% industry funded• 2000: 62% industry funded• 2/3 of academic institutions hold equity in

start-ups

JAMA, 2003, p. 454

Nature 441, 22-23 (4 May 2006) | doi:10.1038/441022a; Published online 3 May 2006

The quiet rise of the clinical contractorMore and more drug trials are being farmed out to contractors, but who's

benefiting from the change? Meredith Wadman investigates.

Figure from Nature 441, 22-23 (4 May 2006)

3

Nature vol. 441 18may2006 - 264

“Evidence-Based Clinical Practice”

• Step 3: Is the study sponsored by an organization that may influence the study design or results?

John P. Geyman, Richard A. Deyo, Scott D. Ramsay (2000)

“Why most Published Research Findings Are False”

• Corollary 5: The greater the financial and other interests and prejudices in a scientific field, the less likely the research findings are true.

John P. A. Ioannidis, 2005PLoS Med 2(8): e124

“Patients volunteer for trials, but finances and career motives decide what get published

Peter Gøtzsche

Nature, Vol 440 16 March 2006

Evidence-based medicine is valuable to the extent that the evidence is complete and unbiased

N Engl J Med January 17, 2008Turner et al., p.252

Promoting evidence

4

“If we put horse manure in a capsule, we could sell it to 95% of these doctors”

Harry Loynd, Past President of Parke Davis and Company

From the book “Hooked” by Howard Brody

I am excited to also share that at J&J we are launching a new program for faculty called JETPack (Johnson & Johnson Educational Tools Package) which was designed to provide evidence-based content using a multimedia surround sound approach.

Colgate, Forsyth enter research partnership…

“To advance research in oral health and its effects on overall systemic health by creating the Colgate-Forsyth Center for the Advancement of Global Oral Health”

5

ADA, AMA collaborate on oral and systemic health media conference

Posted 02/23/2006

By Jennifer GarvinNew York—"Who benefits from medicine and dentistry working together? The patient!"

http://www.ada.org/prof/resources/pubs/adanews/adanewsarticle.asp?articleid=1815

“UBC Gains $5 Million for Hi-tech Oral Health Centre”

• “A $5-million gift from a world leader in esthetic dental products to the University of British Columbia's Faculty of Dentistry will be recognized with the naming of a new oral health facility.1

1. http://www.publicaffairs.ubc.ca/media/releases/2006/mr-06-025.html2. http://www.pennwelldentalgroup.com/display_article/301097/54/none/none/IndNw/Company,-dental-school-form-partnership?host=www.proofs.com

“Company, dental school form partnership”

• November 14, 2005• Nobel Biocare, a leader in innovative esthetic

dental solutions, and New York University College of Dentistry, the largest dental school in the U.S., will cooperate to integrate a dental implant therapy and esthetic dentistry curriculum into all four years of the NYU predoctoral dental education program.

6

WSJ NYT, January 25, 2006

DRUG FIRMS ACCUSED OF

BIASING DOCTOR’S TRAINING

DRUG FIRMS ACCUSED OF BIASING DOCTOR’S

TRAINING

Rosiglitazone

• In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03)

• 10 of millions of prescriptions• Physician who prescribed relied on single

dimension of glycemic control

Volume 356:2457-2471 June 14, 2007Psaty and Furberg, NEJM 2007

“GSK is trying to halt falling sales”

7

GHOST WRITING

Minimize impact of negative evidence

8

May 16, 2002 FDA“that has never happened”

9

Danish Chewing Gum Saga: Honeymoon

• Company provided chewing gums for study

• Data peek; no good results; may upset plans for selling company

Danish Saga II; Threats

• The company -this was poor research (they had the protocol in advance)

• Company threatens authors including legal action

• The rector patronizes the authors; drop ‘this small project’ publishing

• Dental School Dean tells rector that he can make the authors retract abstract (IADR Vancouver 1998)

Danish Saga III:

• Authors agree to retract abstract if provided with letter from rector saying that this retraction is done in the interest of the university and not as an indication of poor research. Rector agrees and provide the letter.

• Dental School Dean sends an “anonymous” fax to a journalists showing “retraction”

• Anonymous fax has ‘sender number’ and this was uncovered by the University Board.

Danish Saga IV

• The authors managed to keep their right to publish, but had to keep silent on the news and abandon their right to defend themselves publicly.

• Situation backfires– Dental School Dean fired– Rector left when his term was over.

Danish Saga (documentation)

Newspapers:– Dandy dropper sag mod Aarhus Universitet (Dandy drops case against

Aarhus University) http://jp.dk/indland/article791922.ece– Tvivlsom documentation (Doubtful documentation)

http://jp.dk/indland/article791089.ece– Aftale kan stoppe artikel (Deal can stop article)

http://jp.dk/indland/article791204.ece– Tandlægechef angriber forskere (Ex-dean attacks researchers)

http://jp.dk/indland/article790805.ece– Aarhus Universitet går til Kammeradvokaten (Aarhus University ask

attorney) http://jp.dk/indland/article790851.ece– Forskere: Dandy havde sagt ja til offentliggørelse (Researchers: Dandy

had said yes to publication of results) http://jp.dk/indland/article800701.ece

Painkiller trial halter over health scare

Nature 432/23/30 December 2004

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Published versus FDA evidence

• Meta-analysis on 12 antidepressants on 12546 patients

• Published studies: 0.37 (95% CI: 0.33-0.41)• Unpublished studies: 0.15 (95% CI:0.08-0.22)

January 17, 2008

Conflict of interest and Paxil• Paxil ($55 million/year)• 2.1 million US youngsters had Paxil prescribed• “Spitzer sues drug giant for deceiving doctors” (Nature, 2004)• Not disclosing four negative studies• “If 20 studies are done, one is likely to show significance by

chance. If that’s the only one to get published, and I don’t know that there were 19 other studies with different results, it really skews the perception and ultimately alters clinical care” Dr. David Fassler – pediatric psychiatrist.

“The messenger under attack --intimidation of researchers by

special-interest groups.”

Deyo RA, Psaty BM, Simon G, Wagner EH, Omenn GS.

N Engl J Med. 1997 Apr 17;336(16):1176-80.

11

Clinical ProgressionDeath

HIV-1 Immunogen

53(4%) 1209

53 (4%) 1212Placebo

1262

1265

+ -

Khan. et al. JAMA 2000, vol. 284 17 – p. 2193

Million-dollar lawsuit against Kahn and University of California…

Medtronic

• Aneurysm: stent(AneuRX) versus open surgery

• 55,000 people a year get treatment• Is AneuRX associated with higher long-term

mortality (0.40% versus 0.18%)?

Article published by FDA staff

– May 7; article on higher death rate on line– Use of confidential information (A company will

only reveal the data that it thinks is essential for doctors to know.

– Criminal and civil sanctions against the editors of the “Journal of Vascular Surgery”

– Medtronic funds the society’s aneurysm screening program

– On June 8, the journal removed the paper

“Is Academic Medicine for Sale?”*

• Prevention of publication of adverse events or negative results– Rezulin (diabetes drug) and liver failure (391

deaths) (Reported by Bodenheimer).– Vioxx, Avandia,

* Dr. Angell, Former Editor of N-Engl-J

IBM

• Chemicals used in chip fabrication

• 33,000 former IBM workers + 18,000 deceased IBM workers

• ~20% increased risk for kidney cancer

• “IBM expressly reserves all of its rights to take any appropriate action”

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Fixing the black hole

“A tipping point of sorts may have occurred in the spring of 2004. … legal action filed by attorney general of the state of New York, Eliot Spitzer, on June 2. The AG accused the giant drug firm GlaxoSmithKline of fraud.

Howard Brody, Hooked, 2007

June 2, 2004

“The researchers had to file a Freedom of Information request with the US Food and Drug Administration. And the information they finally received was imcomplete: crucial data were missing for several studies that failed to find a significant benefit of the drug compared with the placebo.”

“Require international cooperation and enforcement by regulatory authorities”

p. 1 Natuire

Paxil ($55 mil/yr)• 2.1 million US youngsters had Paxil prescribed• “Spitzer sues drug giant for deceiving doctors”

(Nature, 2004)• Not disclosing four negative studies• “If 20 studies are done, one is likely to show

significance by chance. If that’s the only one to get published, and I don’t know that there were 19 other studies with different results, it really skews the perception and ultimately alters clinical care”

Dr. David Fassler – pediatric psychiatrist.

13

CMAJ. 2009 Feb 3;180(3):291-7.

Roche plunges on poor trial resultBy Miles Johnson Published: April 23 2009 03:00 | Last updated: April 23 2009 03:00

Roche , the Swiss drugmaker, suffered its biggest one day fall in 19 years yesterday after a disappointing clinical trial for one of its key treatmentsFinancial Times

Lipid Lowering Drug and Mortality

Mortality

Drug 68 (3.57%) 1839

71 (3.74%)Placebo

1906

1900

+ -

JAMA, 1984

1828

NNT=591

It is now indisputable that lowering cholesterol with diet and drugs can actually cut the risk of developing heart disease and having a heart attack

Rifkind, Time magazine 1984

Creating Doubt

14

“…the tobacco industry’s strategy was embodied in a script written by lawyers. Every tobacco company executive in the public eye was told to learn the script backwards and forwards, no deviation allowed. The basic premise was simple –smoking had not been proved to cause cancer. Not proven, not proven, not proven –this would be stated insistently and repeatedly. Inject a wedge of doubt, create controversy, never deviate from the prepared lines.”

A question of intent – David KesslerFull page add in NYT November 29, 2004

Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E.The Johns Hopkins School of Medicine, and The Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2223, USA. ermiller@jhmi.eduAnn Intern Med. 2005 Jan 4;142(1):37-46. Epub 2004 Nov 10.

NYT,Tuesday January 22,2008 NYT,Tuesday January 22,2008

15

Scavengers

• Freedom of information act was required• Two drugs could not be investigated• Missing data

True fulfillment .. will require international collaboration and enforcement by regulatory authorities – an unprecedented degree of organization and commitment. It is a daunting goal, but one worthy of the struggle

Nature Editorial Vol. 452 7183 6 March 2008

Laws and regulations

• Registries of RCTs

• FDA panels have to disclose conflicts of interest

• Authors & researchers have to disclose conflicts of interest

• Limits on gifts

• University policies

• Journal policies

• Professional organization policies

Conflicts of interest may bias findings

• Follow the money• Conflicts of interest can bias findings• Look for evidence of independent DSMB• Establish Data and Safety Monitoring Board

(DSMB)• Look of assurances in terms of policies of

journals, professional organizations, research institutions, etc.

FudgingNORWEGIAN RADIUM HOSPITALNovel approach: Jon Sudbø simply invented his test subjects.

Nature 439, 248-249 (19 January 2006) | doi:10.1038/439248bDoctor admits Lancet study is fictionEmma Marris

Faked data keeps spotlight on peer review.

NewsNature 439, 248-249 (19 January 2006)

16

News of the WeekSCIENTIFIC MISCONDUCT:

FRAUD UPENDS ORAL CANCER FIELD, Casting Doubt on Prevention Trial

Jennifer Couzin and Michael Schirber

Science 27 January 2006:Vol. 311. no. 5760, pp. 448 - 449

17

Monitoring of Failure Rates after a Switch in Implant

BrandsWilliam Becker - Burton Becker –

Philippe Hujoel

Switch

X y P-value

Surface Proprietary A Proprietary B

Implants failed/placed (%) 33/816 (4%) 46/ 661 (7%) 0.023

Mean Days to failure (sd) 212 (200) 179 (191) 0.453

Median days to failure 163 118

Interquartile range of failure 73 127

Intervention 08NOV99-14APR09 07MAY05-23FEB10

“There is no way of knowing who is right because we don’t have the data,” said Dr. Kevin J. Bozic, a professor of orthopedic surgery at the University of California, San Francisco.

“While producers of implanted heart devices have a voluntary system in which outside panels investigate problems, American makers of orthopedic devices do not” NYT - June 20, 2010