Medical journals are an extension of the

marketing arm of drug companies

Richard SmithChief executive, United Health Europe

Formerly editor BMJ

Agenda

• Editors are all at it• Observations on the drug industry• Advertising• Trials

– Mostly drug company funded– Rarely produce results unfavourable to the company– Easy to get the results you want– Manipulating the journals

• Four stories of manipulation• Reprints• Supplements• “A better relationship?”

Richard Horton, editor, Lancet

• “Journals have devolved into information laundering operations for the pharmaceutical industry”

• New York Review of Books, March 11, 2004

Marcia Angell, former editor, NEJM

• “ [The pharmaceutical industry] has moved very far from its original high purpose of discovering and producing useful new drugs. Now primarily a marketing machine to sell drugs of dubious benefit, this industry uses its wealth and power to co-opt every institution that might stand in its way, including the U.S. Congress, the Food and Drug Administration, academic medical centers, and the medical profession itself."

Jerry Kassirer, former editor, NEJM

• “In On the Take, Dr. Jerome Kassirer offers an unsettling look at the pervasive payoffs that physicians take from big drug companies and other medical suppliers, arguing that the billion-dollar onslaught of industry money has deflected many physicians' moral compasses and directly impacted the everyday care we receive from the doctors and institutions we trust most.”

• OUP promotional blurb

Editors of PLOS Medicine: “Prescription for a healthy journal”

• “We have decided not to be part of the cycle of dependency that has formed between journals and the pharmaceutical industry, an industry that focuses overwhelmingly on the most profitable drugs, thus sidelining many of the world's health problems. Medical journals have allowed their interests to become aligned with those of the pharmaceutical industry by printing advertisements for drugs, publishing trials designed by drug companies' marketing departments, and making profits on reprints used as marketing tools.”

The drug industry

• Has invented virtually all the new drugs in the past 50 years--although Mrcia Angell says that they “feed off” public investment in science

• Hugely profitable and politically powerful• Global• Business model—new drugs plus increased revenue

from existing drugs—failing: productivity crisis (fewer new drugs; marginal benefits) plus political pressure on price increases

• “Drug companies turning into banks.” Charles Medawar• Response: more marketing; perhaps mergers to create

“monopolies” around

The drug industry

• US based companies spent $15.7 billion on promotion in 2000

• Since 1995 research staff down by 2%, marketing staff up by 59%

• A fifth of staff are researchers but two fifth are marketing staff

• Industry spends about $10 000 per doctor on promotion

Advertising

• In most countries drug companies can advertise only to doctors

• Lucrative market for doctor only publications paid for entirely by advertising

• Many free publications to doctors—making them reluctant to pay for anything

• Major journals receive a substantial income from drug advertising—and most have copies that circulate free paid for by drug advertising—or sponsored subscriptions, some with false covers

• Makes them nervous about upsetting advertisers—hard to quantify that nervousness

Advertising

• The ROI on advertising in encouraging doctors to prescribe particular drugs is greater than that for drug reps

• The advertising is often misleading

Study in the Annals of Internal Medicine

• 109 ads from 10 major journals• Reviewed by two physicians from the

relevant specialty and a clinical pharmacist against FDA guidelines

• Information on efficacy and side effects unbalanced in 40%

• Would have recommended against publication in 28%; substantial revision in a third

• Wilkes MS, Doblin BH, Shapiro MF. Pharmaceutical advertisements in leading medical journals: experts' assessments. Ann Intern Med 1992;116: 912-9.

Spanish study

• 264 different advertisements for antihypertensive drugs and 23 different advertisements for lipid lowering drugs selected from six Spanish medical journals

• Two reviewers looked at 102 references• In 44% of ads the promotional statement was not

supported by the reference—most commonly because the slogan recommended the drug in a patient group other than that assessed in the study

• Villanueva P, Peiro S, Librero J, Pereiro I. Accuracy of pharmaceutical advertisements in medical journals. Lancet. 2003;361: 27-32.

Should journals carry advertising?

• No– Misleading– Distorts prescribing patterns– Demeans the journal, reducing its credibility

• Yes– Provides income for journal and may carry fewer

strings than other sources (for example, from owners)

– Doctors discount advertising– Doctors will receive promotional messages anyway

and at least ads are better than what drug reps may say behind closed doors

Should journal peer review ads?

• Yes– Many are known to be misleading– Reduces credibility of the journal to publish

misleading ads– Distorts prescribing, bad for patients

• No– Doctors discount advertising– Tight regulation (at least in the UK)– Hard to do properly (and peer review is weak

anyway)– Better to use resources on the journal itself– Readers can criticise advertisements

Other deals available to advertisers

• Favourable editorial mention in exchange for an ad

• Will publish a particular paper if advertisers place an ad

• Ad alongside paper• Tell advertisers what will be in the journal• “Advertorials”• Product news• Keep out unfavourable studies• Ads on editorial pages, false covers, messages

direct to individual readers

Trials in journals

• Much more valuable to companies than advertisements (many other outlets for ads)

• Credibility of the journal attached—the opposite of being discounted

• Worldwide distribution• Possibly massive media coverage

Two thirds of trials in major journals are funded by the drug industry (Egger M, et al, BMJ

2001; 323: 773)

J ournal Total trials % drug trials

AIM 20 65

J AMA 47 64

Lancet 82 67

NEJ M 83 74

BMJ 48 31

Companies get the results they want

• Study of 56 studies of non-steroidal anti-inflammatory drugs

• Not one was unfavourable to the company

• All showed the manufacturer’s drug to be as good as the comparison or better in terms of efficacy or toxicity

• Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, et al. A study of manufacturer supported trials of non-steroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994;154: 157-63.

Companies get the results they want

• 30 studies compared studies funded by the pharmaceutical industry with results of studies funded from other sources

• Five of the studies looked at economic evaluations and in every study the results were favourable to the pharmaceutical company

• 16 studies looked at clinical trials or meta-analyses, and 13 had outcomes favourable to the companies

• Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167-70.

Companies get the results they want

• Overall studies funded by companies four times more likely to have results favourable to the sponsor than studies funded by others

• 13 of the studies examined the quality of the research

• None found the quality of drug company sponsored studies to be inferior

• 4 found that the research funded by the industry was of superior quality

Why do companies get the results they want?

• Hypothesis 1: companies selectively fund research on better drugs. No.

• Hypothesis 2: Quality lower not in the methods but in the questions asked.

• Hypothesis 3: Companies make inappropriate comparisons—comparing their drugs with poor drugs or drugs used at the wrong dose.

• Hypothesis 4: Publication bias in that favourable studies are more likely to be published—by companies or journals

The methods of HARLOT

• 13 methods to get the results you want• Trial against placebo• Trial against treatment known to be inferior• Trial against low dose of competitor• Trial against high dose of competitor (to give

advantages on toxicity)• Equivalence or non-inferiority trial that is too small

to show a difference from competitor drug• Use multiple endpoints and select the ones that

give positive results• Subgroup analyses and select positive results

Publishing strategies

• Suppress (don’t write up) negative studies• Publish positive studies more than once—perhaps in

supplements• Do multicentre trial and publish results of individual

centres—perhaps selectively• Publish different outcome measures at different times• Publish different follow periods at different times—3

month results, one year, two year• Publish positive results in major journals and negative or

neutral results in minor journals• Combine results of trials in ways that are favourable

Odansetron story

• 84 trials that included information on 11 980 patients

• In reality only 70 trials and 8645 patients (17% of the studies had been published more than once and the number of patients had been inflated by 28%)

• Impossible to tell from published studies• Four pairs of identical trials were published by

completely different authors without any common authorship (Misconduct)

Effectiveness of odansetron

Cox-2 story

• The three month results of the CLASS study published in JAMA in 2000 shows that Celebrex is safer than NSAIDs

• August 2001 the Washington Post reports that the FDA had the full results of the CLASS study, which contradicted the JAMA resulys

• The JAMA study had many problems• Pfizer continues to use reprints of the JAMA paper to

promote the drug• Many doctors are unaware of the trial being dicredited

Cox-2 story

• The VIGOR study reported in the NEJM in 2000 showed rofecoxib (Vioxx) to be safer than an NSAID but also showed cardiovascular toxicity

• Merck, the manufacturers, proposed that the result was explained by the NSAID protecting against heart disease

• Four years later the drug has been withdrawn because a long term placebo controlled trial has confirmed the cardiovascular toxicity

• Question: Do all Cox-2 inhibitors have these effects?

CLASS results in JAMA and with the FDA

The hormone replacement therapy

• Many observational studies suggested that HRT reduced coronary artery disease

• “Rough and ready” meta-analysis of randomised trials suggested that HRT actually increased cardiovascular events

• Torrent of abuse from the drug industry• A major trial and huge observational study

show that HRT does indeed increase cardiovascular events

Observational studies of coronary artery disease after hormone replacement therapy

A story

• Study A—compares drugs x and y; results showing x better than y published in a major journal; results showing y better than x on other (clinically more important) outcome measures not published

• Study B—x no better than y; not published• Study C—combines studies A and B (and

shows x better than y) published in a major journal

Reprints

• Enormously lucrative to journals; companies may buy $1m worth—70% profit margin

• A major source of revenue for journals publishing trials

• Handed out to doctors—selectively of course; not read, but journal brand adds lustre to selling message

• Major conflict of interest for journals: “publish this paper or lay off six editors”

Supplements

• A major source of income for some second tier journals• Often include papers presented at sponsored symposia

—often around one drug• Studies often previously published in some way• Studies selectively published• Accompanied by opinion pieces by prominent doctors

(opinion leaders in marketing jargon); the doctors are very well paid (? bought)

• The person who organised the symposium may be the editor

• Standards of supplements shown to be inferior to standards of parent journals (which may themselves be low)

Sponsored supplements

• The number of symposiums published per year increased steadily from 1966 through 1989

• 42% had a single pharmaceutical company as the sponsor

• Sponsored symposia

– more likely to have misleading titles

– more to use brand names

– less likely to be peer-reviewed in the same manner as other articles in the parent journal

– Of the 161 symposiums that focused on a single drug

• 51% concerned unapproved therapies

• 14 percent concerned drugs classified as bringing important therapeutic gains

• Bero LA, Glabraith A, Rennie D. The publication of sponsored symposiums in medical journals.N Engl J Med 1992;327:1135-40.

“Solutions”

• Public funding of head to head trials• Registers of trials• Protocol reviews• Role of sponsor made clear• Journals decline to publish trials unless

researchers control decision to publish• Journals don’t publish trials—rather results are

made available in full on regulated websites together with protocols

Conclusion

•Medical journals are an extension of the marketing arm of drug companies

•Do you agree?