What drug has generated over $130 billion in sales?

Lipitor

Ethics and Professionalism:The Integrity of Medicine: Part II

Medical Industry and Medical Practice

Richard L. Elliott, MD, PhD, FAPAProfessor and Director, Medical Ethics

Mercer University School of MedicineAdjunct Professor

Mercer University School of Law

Follow-up to Research Ethics Questions on cases/groups? The integrity of medical research

– Last hour – ethics and the protection of research subjects• Tuskegee, IRBs

– Today – another threat to our integrity• Medicine and the medical industry

Tomorrow – threats to our integrity from within– Abuse of trainees– Impaired physicians

Relationships with the Pharmaceutical Industry

How good is the evidence in Evidence-Based Medicine?– Publication bias

• Negative studies• Adequate review in industry funded journals• Duplicate publications

• Ghost writing What are we teaching?

– Influence over content of medical education• CME talks, lunches

What are we prescribing?– Influence over prescribing practices

• Free samples, gifts, DTC advertising

JAMA 2001;286(23):2947-55

Similar Effectiveness of Paroxetine, Fluoxetine, and Sertraline in Primary Care

K Kroenke et al. JAMA 2001;286:2947-2955 ARTIST: A Randomized Trial Investigating

SSRI Treatment 573 depressed adult patients 37 clinics 1999 Open label, randomized study Sponsored by Eli Lilly

ARTIST - Comparative Outcomes per Eli Lilly

No statistically significant differences in clinical outcomes

No differences among anxious-depressed patients

No differences among older patients No differences in patient satisfaction

Rankings of All Measures at 3 and 9 Months

Paroxetine Fluoxetine Sertraline

Best 7 15 58Middle 27 39 14Worst 39 19 1

p<10-21

ARTIST

Rare example of reporting a positive study as negative

What influence did Eli Lilly have on editorial decisions?– Choice of reviewers?– Referral to JAMA statistician?

Why did JAMA publish this?

(A Few) Big Pharma Scandals Vioxx death data submitted to FDA concluded

no significant risk Intent-to-treat deaths in RCTs for Alzheimer’s

– Subjects 34/1069– Placebo 12/1078 – Hazard ratio 2.99

Vagal nerve stimulation and editorials– Editor wrote favorable opinion piece, did

nor disclose financial interests

Rosiglitazone (Avandia) Peak sales $2.5 billion 2006 2007 meta-analysis of 42 triels

– OR MI 1.43 (95% CI, 1.03 - 1.98; P = 0.03)– OR death from all CV causes 1.64 (95% CI, 0.98 to 2.74; P

= 0.06) Recent meta-analysis confirmed risk Senate concluded GSK knew of risks, withheld data from FDA FDA voted not to withdraw – one member of panel later found to

have been paid by GSK Meta-analysis (BMJ 2010) that commented on two meta-

analyses found authors who had conflict more likely to give favorable opinion of risks (RR 3.5-6.5 depending on analysis)

Publication Bias Perlis et al. Am J Psychiatry 2005;162:1957-60 162 randomized, double-blind, placebo-controlled

clinical trials between 2001-2003 AGP, AJP, J Clin Psych, J Clin Psychopharmacology 60% received funding from industry 47% authors reported potential conflict of interest Those with potential conflict of interest were 4.9 times

less likely to report negative results (6/75 vs. 26/87) Comparable results in non-psychiatric literature

Effectiveness of Antidepressants 74 FDA-registered trials of 12 antidepressants approved

between 1987-2004 74 trials, 38 positive (statistically significant benefits for drug

over placebo)– 37/38 published

Of 36 FDA-deemed negative trials:– 22 never published– 11 published in manner to appear positive– Only 3 negative trials published

Turner et al. NEJM 2008;358:252-60 Thus, the published evidence for the efficacy of

SSRIs is vastly different from the results of all trials:– 48/51 trials positive vs. 38/74

Efficacy of Cardiovascular Drugs

Results published in NEJM, JAMA, Lancet– 2000-2005

If study funded by for-profit, 67.2 % favored newer treatment

If study funded by non-profit, 49% favored newer treatment

Ridker PM, Torres J:  JAMA 2006; 295. 2270-2274

JAMA. 2003;290:921-928 370 randomized drug trials from Cochrane data base Experimental drug recommended as treatment of

choice in 16% of trials funded by nonprofit organizations, 51% of trials fundedby for-profit organizations (P.001; 2 test).

Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events.

Publication of Clinical Trials 451 study protocols submitted to one

research committee 375 publications resulted from 233

protocols (publication rate 52% - 233/451 protocols)

Odds ratios for publication:– Non-commercial funding 2.4– Commercial funding 0.7

Von Elm et al. Swiss Med Weekly

Reducing Publication Bias Authors must have submitted trial to

clinicaltrials.gov– Negative results available

Authors must report potential conflicts of interest– But funding sources can be buried in a

long list of honoraria, speakers bureaus, research funding, …

Mandatory reporting of payments from medical industries

How effective are author disclosure policies?

JAMA. 2011 Mar 9;305(10):1008-17– Reviewed 29 most recent meta-analyses in highest impact

medical journals involving RCTs of pharmacological treatments. 2/29 MAs reported on potential conflicts among RCT authors. Conclusion: Journals might require CoI disclosure, but MAs relying on RCTs do not use this info

Otolaryngol Head Neck Surg 2009 Sep;141(3):311-5– 25% of publications reviewed had disclosure discrepancies

between disclosures at annual meeting presentation and subsequent publication

J Vasc Surg. 2011 Sep;54(3 Suppl):55S-8S– Inconsistent disclosures in 27% of disclosures

Peer Review

Peer review – supposed to ensure submission has scientific validity and ethical integrity

“Peer review” is a term used loosely by some.– The editor/symposium chair looked at it

Peer Review One criterion for quality in a publication is peer review Reviewers are selected randomly from a pool of pre-

qualified experts having no conflicts of interest – avoids preselecting outcome of review– Some studies are so specialized that few experts

exist and cannot be assigned randomly– Conflicts can be buried in a list of funding sources

Blinded review: Authors are removed from reviewers copies– Not hard to identify some authors based on

references, previous work

Ghost Writing and Guest Authors

Ghost writer – person not identified who was involved in significant data or writing process

11-13% of articles – Flanagan et al. JAMA 1998;280:222– Ross JAMA 2008;299:1800

“Hundreds of articles” The Observer Dec 7, 2003 Guest author – inclusion of author who had minimal or no

involvement in data or writing– Often honorarium– 16% research articles, 26% review articles, 21% editorials

ARTIST study? Nemeroff, Text published by APA, written by drug company

affiliate

Influence of Industry on Scientific Conclusions

Effects of passive smoking – harmful? 106 reviews 39/106 (37%) of reviews concluded no harm

– 29/39 (74%) of these reviews had tobacco affiliations 67/106 (63%) of reviews concluded passive smoke harmful

– 2/67 (3%) had tobacco affiliations Similar results in other biomedical research – affiliation with

industry is best predictor of pro-industry finding (odds ratio 3.60) Artist study? Barnes et al. JAMA 1998;279:1556 Bekelman et al. JAMA 2003;289:454

Evaluating bias in a publication or presentation

Lo JAMA 2013;310(10): 1019-1020 Options for managing a condition,

including generics and lifestyle changes; risks/benefits compared?

Limitations for studies of new drugs?

Accuracy of Advertising 69 journal advertisements 50.2% claims provided no source to support When sources cited, 65% claims supported Efficacy claims supported 53.2% Can you believe claims in medical journal

ads?– Flip a coin

Spielman et al. J Nerv Ment Dis 2008;196:267

Physicians and the Pharmaceutical Industry

Relationship(s) often mutually beneficial Gifts Educational funding Research support Information Samples

Gifts from the Pharmaceutical Industry Industry spends approximately

$10,000/physician/year 97% residents carry at least one item

with industry logo Six gifts/year 14 meals/year

– Much higher at MCCG Wazana and Primeau Psych Clin N Am 2002;25:647

Steinman et al. Am J Med 2001;110:551MDs believed only 16% of other MDs unaffected by gifts, but 61% believed they were unaffected. Similarly, MDs believed 40% of there colleagues were at least moderately influenced by gifts, but very few believed they were similarly influenced.

Industry CME and Prescribing Patterns

$2.45 billion spent on continuing education for health professionals in 2006– $1.4 billion paid for by industry (57%)

2011 75% CME providers received commercial funding

After event, 4-5x greater prescribing of product

Formulary Requests 40 physicians who requested a formulary addition

from January 1989 through October 1990. Control physicians were 80 randomly selected physicians who had not made requests.

Physicians were more likely to have requested that drugs manufactured by specific companies be added to the formulary if they had met with pharmaceutical representatives from those companies (OR, 13.2; 95% CI, 4.8 to 36.3) or had accepted money from those companies (OR, 19.2; 95% CI, 2.3 to 156.9)

Pharmaceutical Research and Manufacturers of America (PhRMA) Guidelines

Pre-2002– Golf, honoraria for attending presentations, trips, games

2002– Meals modest, without guests– Gifts of modest value (<$25-100) and primarily of benefit to

patient care or practice 2009

– No gifts (pens, notepads, stethoscopes, lights, etc.) which have value independent of patient education

– May have office meals

AMA and the Pharmaceutical Industry

Gifts should primarily entail a benefit to patients and should not be of substantial value

Individual gifts of minimal value are acceptable if work-related

Some are calling for rejection of all gifts, meals, speaking honoraria, GME support

Supports National Clinical Trials Registry– Trials begun after 7/05 will be considered for

publication only if publicly registered

Marcia Angell “It would be naïve to conclude that bias is

only a matter of a few isolated instances. It permeates the entire system.”

“Physicians can no longer rely on the medical literature for valid and reliable information.”

“Clinicians just do not know anymore how safe and effective prescription drugs really are, but the products are probably nowhere near as good as the published literature indicates.”– Angell M:    JAMA 300. 1069-1071.2008

AMSA Scorecard Conflict of Interest Policies at Academic Medical

Centers (http://amsascorecard.org/) Gifts/Industry relationships

– Gifts, consulting, speaking, disclosure Samples, purchasing, access Education

– On/off campus, industry support, curriculum MUSM Grade “C” `Not widely disseminated to faculty/trainees

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