Fw: Research and Drugs How Investigators are Influenced

[Guest guest]

----- Original Message -----

From: " Ilena Rose " <ilena@...>

<Recipient List Suppressed:>

Sent: Sunday, December 23, 2001 12:04 PM

Subject: Research and Drugs How Investigators are Influenced

~~~ many thanks to JA for sending this ... and Dr. Mercola for publishing

it. ~~~

http://www.mercola.com/2000/may/21/research_and_drugs.htm

Drug companies that pay for research and clinical tests of new medicines

have been suppressing or manipulating the results. The prestigious,

peer-reviewed Journal also warned the likelihood

that drug test results will be manipulated or suppressed is even greater

when for-profit companies set up specifically to test drugs conduct the

trials.

The findings and the drug studies, along with a sharply worded editorial

where Dr. Marcia Angell raises the question " Is Academic Medicine For

Sale? " appears one week after the Journal's

publisher, the Massachusetts Medical Society, announced it would replace

her as editor with a prominent asthma researcher who has strong ties to

the drug industry.

This report comes at a time when " academic medical centers are no longer

the sole citadels of clinical research and the industry is wielding more

power in conducting large-scale drug tests. Six of the 12 investigators

interviewed cited cases of articles whose publication was stopped or whose

content was altered by the funding company. The companies are not

identified.

In one instance, a drug maker delayed publication of a study's results by

requesting changes to the manuscript to make the product look better.

During the delay, the company secretly wrote a competing article on the

same topic, which was favorable to the company's viewpoint.

Another investigator found that a drug he was studying caused adverse

reactions. He sent his manuscript to the sponsoring company for review.

The company vowed never to fund his work again

and published a competing article with scant mention of the adverse effects.

The New England Journal of Medicine -- May 18, 2000 -- Vol. 342, No. 20

The following is the full article that appears in this week's New England

Journal:

Uneasy Alliance -- Clinical Investigators and the Pharmaceutical Industry

Bodenheimer

Clinical practice is changing rapidly. New cardiovascular drugs,

antiinflammatory drugs, cancer chemotherapy, and other pharmacologic

weapons are being added to physicians' therapeutic armamentarium virtually

daily. Most clinical studies that bring new drugs from bench to bedside

are financed by pharmaceutical companies. Many of these drug trials are

rigorously designed, employing the skills of outstanding clinical

researchers at leading academic institutions.

But academic medical centers are no longer the sole citadels of clinical

research. The past 10 years have seen the spectacular growth of a new

research model. Commercially oriented networks of contract-research

organizations (CROs) and site-management organizations (SMOs) have altered

the drug-trial landscape, forcing academic medical centers to rethink

their participation in industry-funded drug research.

The infusion of industry dollars into an industry-investigator partnership

has clearly improved clinical practice. Yet the medical literature

contains many articles expressing concern about industrial funding of

clinical research. Stelfox et al. found that authors whose work supported

the safety of calcium-channel antagonists had a higher frequency of

financial relationships with the drugs' manufacturers than authors whose

work did not support the safety of these medications. (1) son

reported that results favoring a new therapy over a traditional one were

more likely if the study was funded by the new therapy's manufacturer. (2)

Cho and Bero demonstrated that articles from symposiums sponsored by a

single drug company were more likely than articles without company support

to have outcomes favorable to the sponsor's drugs. (3) Friedberg et al.

reported that 5 percent of industry-sponsored pharmacoeconomic studies of

cancer drugs reached unfavorable conclusions about the company's products,

as compared with 38 percent of studies with nonprofit funding that reached

similar conclusions. (4)

How much influence does industry have over the work and products of the

research community? Can practicing physicians trust the information they

receive about the medications they are prescribing? Does the shift from

the academic to the commercial research sector give industry too much

control over clinical drug trials?

In this report, I discuss some of the problems raised by

pharmaceutical-industry funding of drug trials, problems that may deepen

as trials are increasingly conducted by commercial organizations. I

interviewed 39 participants in the process: 6 pharmaceutical executives,

12 clinical investigators, 9 people from university research offices, 2

physicians with CROs, 8 people who have studied the process of clinical

drug trials, and 2 professional medical writers. Each interview consisted

of standard questions plus an opportunity for the interviewees to discuss

the industry-investigator relationship in a general way. Several

interviewees preferred not to allow the use of their names in the article.

The Clinical-Drug-Trial System

The Food and Drug Administration (FDA) requires manufacturers to show that

their products pass tests of efficacy and safety. (5,6) For such drugs as

antibiotics for acute infections, large populations and long time lines

are seldom needed to establish efficacy and safety. With the new emphasis

on prevention and treatment of chronic diseases, however, clinical drug

research has changed. Many people must take antihypertensive drugs and

lipid-lowering drugs for many years in order to prevent relatively few

undesired clinical end points. (7) To establish the efficacy and safety of

preventive products and products designed to treat chronic disease,

clinical trials must be large, lengthy, and conducted at multiple centers,

because a single site cannot recruit enough patients to ensure statistical

validity.

The average cost of developing one new drug is estimated to be $300

million to $600 million. (8) Of the $6 billion in industry-generated money

for clinical trials worldwide yearly, about $3.3 billion goes to

investigators in the United States. (9) Seventy percent of the money for

clinical drug trials in the United States comes from industry rather than

from the National Institutes of Health (NIH).

The Shift to Commercial Drug Networks

Until recently, the pharmaceutical industry needed academic physicians to

perform drug trials for three reasons: companies did not have the in-house

expertise to design trials themselves, academic medical centers provided

patients as subjects for trials, and companies needed the prestige of

academic publications to market their products. Lately, industry's

dependence on academia has weakened: industry employs top-level research

physicians to design and interpret drug trials, and community physicians

have become a reliable source of patients.

Moreover, pharmaceutical firms are frustrated with academic medical

centers. Most medical schools and teaching hospitals require that

industry-investigator agreements be approved by an office of sponsored

research. Slow review of industry proposals by academic research offices

and institutional review boards (which must review all trials to protect

patients' safety (10)) delays the starting dates of trials. Since academic

physicians have multiple responsibilities in teaching, research, and

patient care, trials may proceed more slowly than the pharmaceutical firms

desire. For each day's delay in gaining FDA approval of a drug, the

manufacturer loses, on average, $1.3 million. Speed is paramount for

pharmaceutical firms.

To expedite trials, industry is turning from academic medical centers to a

growing for-profit marketplace whose key players are CROs and SMOs.

(11,12,13) In 1991, 80 percent of industry money for clinical trials went

to academic medical centers; by 1998, the figure had dropped precipitously

to 40 percent. (14) Evidence suggests that the commercial sector completes

trials more rapidly and more cheaply than academic medical centers. (11)

Because multicenter trials may involve hundreds of sites and

investigators, few pharmaceutical manufacturers choose to manage the

trials themselves. CROs, which employ physician-scientists, pharmacists,

biostatisticians, and managers, offer manufacturers a menu of services.

Large drug companies often create their own study designs and contract

with CROs to develop a network of sites, implement the trial protocol at

those sites, and send report forms to the sponsoring company, which

performs the data analysis. Smaller pharmaceutical firms may hire a CRO to

manage the entire trial, including study design, data analysis, and

preparation of FDA applications and journal articles. Several hundred CROs

compete for the drug-trial business; the largest are Quintiles

Transnational and Covance.

CROs may use both academic medical centers and community physicians to

recruit patients for a trial. In the community arm of drug trials, yet

another intermediary has entered the picture, the SMO. CROs may

subcontract with for-profit SMOs to organize networks of community

physicians, ensure rapid enrollment of patients, and deliver case-report

forms to the CRO. Some trials have four layers (manufacturer, CRO, SMO,

and physician-investigator), a situation reminiscent of the multitiered

managed-care model (employer, health maintenance organization, independent

practice association, and physician). Three of the largest SMOs are

Clinical Studies Limited, Hill Top Research, and Affiliated Research

Centers. SMOs provide community-physician investigators with

administrative support and help market investigators' services to

pharmaceutical companies. (15) They have been criticized for producing

data of poor quality, inadequately training investigators, and costing

more than a system of independent sites unassociated with an SMO. (13,15)

Competition for drug-trial money has stiffened as hundreds of CROs, SMOs,

academic medical centers, and independent nonacademic sites scramble for a

larger piece of the pie. According to Gregg Fromell of Covance, a leading

CRO, " academic medical centers have a bad reputation in the industry

because many overpromise and underdeliver. " In contrast, critics,

including Dr. Sidney Wolfe of Public Citizen, view CROs and the commercial

drug-trial network as handmaidens of pharmaceutical companies, concerned

with the approval and marketing of drugs rather than with true science.

Whereas the academic and commercial drug-trial sectors can be seen as

distinct networks with conflicting cultures, they also interlock, since

CROs often act as intermediaries between drug companies and academic

investigators.

Several academic medical centers are fighting to regain lost market share,

transforming themselves into research networks to compete with the

commercial drug-trial sector. (14,16) Columbia University, Cornell

University, and New York Presbyterian Hospital have created a Clinical

Trials Network as a joint venture. With funding from both industry and NIH

sources, the network brings together academic researchers and

community-based physicians in cardiology, hepatology, neurology, and

oncology. The network has instituted required training for all

participants and has centralized contracting, budgeting, and reimbursement

systems. The network plans to be financially self-sufficient in a few

years. Director Leahey says, " Our goal is to take clinical

research back from for-profit companies and place it where it rightfully

belongs -- in networks that are partnerships between academic medicine and

community practice. We are trying to formulate a real alternative to the

for-profit drug-trial entrepreneurs. "

In 1997 the University of Pittsburgh Medical Center Health System

chartered the Pittsburgh Clinical Research Network (PCRN), a single point

of contact between industry and clinical researchers in academic and

community sites. PCRN provides the administrative procedures associated

with clinical trials in such areas as contracting,

institutional-review-board approval, and project management. Academic

research expertise and a large hospital and community-practice network

give PCRN resources unavailable to most commercial SMOs. PCRN's medical

director, Watkins, feels that " academic medical centers are sleeping

giants that are beginning to awaken and respond to industry's needs. "

Duke University and the University of Rochester are also leaders in

developing academic clinical-research networks. Some academic medical

centers will probably succeed in revamping their drug-trial business;

others will fail.

Industry-Investigator Relationships Trial Design

A company seeking FDA approval for a product often designs a clinical

trial in its research division and circulates the proposed design to

recognized investigators in that field. If the company has no in-house

expertise, outside investigators are asked to design the trial. In some

cases, company and academic investigators form a steering committee to

discuss a trial protocol. In an interview, Dr. Thierry LeJemtel, of the

Albert Einstein College of Medicine Division of Cardiology, said that 20

years ago outside investigators designed the studies, but that now

companies write the protocols and bring in outside investigators pro

forma, with little intention of changing the study design. In-house

control is more likely in the commercial sector than in the academic

sector, because of the limited expertise of many community-physician

investigators.

Sometimes an investigator will propose a drug trial to the drug's

manufacturer. Two investigators interviewed, including Cummings,

professor of medicine and epidemiology at the University of California at

San Francisco, found that companies' marketing departments, which often

rule on studies to be conducted after a drug has received FDA approval,

declined to fund clinically important studies at least partly because the

results might reduce sales of the drug.

Companies may design studies likely to favor their products. Bero and

Rennie, in an article worth study by all physicians, catalogue the methods

companies can use to produce desired results. (17)

If a drug is tested in a healthier population (younger, with fewer

coexisting conditions and with milder disease) than the population that

will actually receive the drug, a trial may find that the drug relieves

symptoms and creates fewer adverse effects than will actually be the case.

(17) Rochon et al. found that only 2.1 percent of subjects in trials of

nonsteroidal antiinflammatory drugs were 65 years of age or older, even

though these drugs are more commonly used and have a higher incidence of

side effects in the elderly. (18)

If a new drug is compared with an insufficient dose of a competing

product, the new drug will appear more efficacious. (17) Rochon et al.

concluded that trials of nonsteroidal antiinflammatory drugs always found

the sponsoring company's product superior or equal to the comparison

product; in 48 percent of the trials, the dose of the sponsoring company's

drug was higher than that of the comparison drug. (19) According to

Johansen and Gotzsche, most trials comparing fluconazole with amphotericin

B used oral, not intravenous, amphotericin B, thereby favoring

fluconazole, because oral amphotericin B is poorly absorbed. (20)

Clinical trials often use surrogate end points that may not correlate with

more important clinical end points. Companies may study many surrogate end

points and publish results only for those that favor their product.

(7,17,21)

Data Analysis

A study's raw data are generally stored centrally at the company or CRO.

Investigators may receive only portions of the data. Some principal

investigators have the capacity to analyze all the data from a large

trial, but companies prefer to retain control over this process.

A physician-executive at one company explained, " We are reluctant to

provide the data tape because some investigators want to take the data

beyond where the data should go. " Several investigators, including Dr.

LeJemtel, countered that industry control over data allows companies to

" provide the spin on the data that favors them. " In the commercial sector,

where most investigators are more concerned with reimbursement than with

authorship, industry can easily control clinical-trial data.

Publishing the Results

For academic investigators, publication in peer-reviewed journals is the

coin of the realm. For pharmaceutical firms, in contrast, the essential

product is the new-drug application to the FDA. In the absence of FDA

approval, no journal article is worth a cent to a drug company. Yet

publication in prestigious journals is important, to persuade physicians

to prescribe the company's products.

Some multicenter trials have publication committees, which may be

dominated by in-house or outside investigators, that write up the results

for publication. In other cases, the company or CRO writes the reports for

publication, circulating draft manuscripts to the investigators who will

be listed as authors. Authorship may be determined by such criteria as who

participated in designing the study, who enrolled the most patients, and

who has a prominent name in the field.

Control over Publication

Many academic medical centers review contracts between industry and

investigators, insisting on the investigator's right to publish the

trial's results and allowing the company prepublication review, with a

time limit of 60 to 90 days. Nikki Zapol, head of the sponsored-research

office of Massachusetts General Hospital, estimates that 30 to 50 percent

of contracts submitted by companies have unacceptable publication clauses

that must be renegotiated.

In a survey of life-science faculty members, 27 percent of those with

industry funding experienced delays of more than six months in the

publication of their study results. (22) Chalmers argues that the results

of substantial numbers of clinical trials are never published at all. (23)

In 1996, Canadian investigator Olivieri and colleagues found that

deferiprone, used to treat thalassemia major, could worsen hepatic

fibrosis. Apotex, the sponsoring company, threatened legal action if

Olivieri published the findings. The contract between Apotex and Olivieri

forbade disclosure of results for three years after the study without the

company's consent. An article was eventually published. (24,25)

In 1987, the manufacturer of Synthroid (levothyroxine) contracted with

University of California researcher Betty Dong to study whether Synthroid

was more effective than competing thyroid preparations. In 1990, Dong

found Synthroid to be no more effective than other preparations, including

generic preparations. The sponsoring company refused to allow the findings

to be published; the contract with Dong stipulated that no information

could be released without the consent of the manufacturer. An article was

finally published in 1997. (26)

Six investigators interviewed for this report cited cases of articles

whose publication was stopped or whose content was altered by the funding

company. In one case, according to Dr. Cummings, the company held up the

prepublication review process for over half a year, then requested pages

of detailed revisions that would have made the manuscript more favorable

to the company's official marketing position. During the delay, the

company secretly wrote a competing article on the same topic, which was

favorable to the company's viewpoint.

In another case, the drug being investigated did not work. The

investigator argued that scientific integrity required publishing the

findings. The company never refused to publish, but it stalled until the

investigator lost interest.

Another investigator, most of whose relations with industry have been

without problems, related the case of two trials of the same drug, one

more favorable to the company. Despite a protest from the investigator,

the results of the less favorable trial were never published.

A fourth investigator found that a drug he was studying caused adverse

reactions. He sent his manuscript to the sponsoring company for review.

The company vowed never to fund his work again and published a competing

article with scant mention of the adverse effects.

Dr. Curt Furberg, professor of public health sciences at Wake Forest

University School of Medicine and principal investigator in a study whose

results were unfavorable to the sponsoring company, refused to place his

name on the published results of the study, because the sponsor was

" attempting to wield undue influence on the nature of the final paper.

This effort was so oppressive that we felt it inhibited academic freedom. "

(27)

A sixth investigator recounted two examples of suppressed manuscripts

regarding negative studies whose results were sufficiently important to

publish.

In scenarios such as these, the frequency of which is unknown, companies

repeatedly delay publication, eventually exhausting investigators who are

busy with other projects. One industry executive explained that such cases

result from priority setting within the company; with limited personnel to

produce publications, certain trials take precedence over others. However,

as one investigator described it, " when results favor the company,

everything is great. But when results are disappointing, there is commonly

an effort to spin, downplay, or change findings. " A CRO executive added

that " industry obstruction to publishing is a big problem. They are

nervous if bad data comes out and gets into the mass media. " Investigators

in the commercial sector may be less concerned than those in academia with

contract clauses guaranteeing their right to publish, thereby giving

industry greater control over publications.

Authorship

In the past, publications were written by a study's principal

investigator. More recently, a practice that one might call the nonwriting

author-nonauthor writer syndrome has developed. Many interviews conducted

for this report confirmed the wide prevalence of this syndrome in

publications of drug-trial reports, editorials, and review articles. The

syndrome has two features: a professional medical writer ( " ghostwriter " )

employed by a drug company, CRO, or medical communications company, who is

paid to write an article but is not named as an author; and a clinical

investigator ( " guest author " ), who appears as an author but does not

analyze the data or write the manuscript. (28,29,30) Ghostwriters

typically receive a packet of materials from which they write the article;

they may be instructed to insert a key paragraph favorable to the

company's product.

The nonwriting author, who may be uninvolved in the research and have been

requested to author the article to enhance its prestige, has final control

over the manuscript. But many of these authors are busy and may not

perform a thorough review. This guest-ghost syndrome (31,32) is a growing

phenomenon, particularly in the commercial sector, where

community-physician investigators have little interest in authorship.

In one study, 19 percent of the articles surveyed had named authors who

did not contribute sufficiently to the articles to meet the criteria for

authorship of the International Committee of Medical Journal Editors.

Eleven percent had ghostwriters who contributed to the work but were not

named as authors. (33,34) In justifying the nonwriting author-nonauthor

writer syndrome, one industry executive explained that professional

medical (ghost) writers are well trained, that investigators may be too

busy to write, and that " nonwriting authors " are at fault if they do not

carefully review ghostwritten manuscripts. An alternative view,

articulated by , of the Institute for Health Policy at

Massachusetts General Hospital and Harvard Medical School, holds that " a

manuscript represents the accumulation of the intellectual and physical

processes conducted under the aegis of a study and should be produced by

the people who have actually been involved in the design, conduct, and

supervision of the research. " Tim Franson, Vice President for Clinical

Research and Regulatory Affairs at Eli Lilly, believes that " any parties,

be they industry staff, investigators, or others who contribute to the

content of articles should have their names listed on the article. "

Conclusions

Without industry funding, important advances in disease prevention and

treatment would not have occurred. In the words of Lee Goldman, chairman

of the Department of Medicine, University of California at San Francisco,

" companies translate biologic advances into useable products for patients.

They do it for a profit motive, but they do it, and it needs to be done. "

Investigators interviewed for this report confirmed that many

collaborations with pharmaceutical companies were conducted on a high

professional level.

But when results are disappointing for a company, conflicts may develop.

Dr. Furberg, with years of experience in industry-funded drug trials,

stated: " Companies can play hardball, and many investigators can't play

hardball back. You send the paper to the company for comments, and that's

the danger. Can you handle the changes the company wants? Will you give in

a little, a little more, then capitulate? It's tricky for those who need

money for more studies. "

Although academic-industry drug trials have been tainted by the profit

incentive, they do contain the potential for balance between the

commercial interests of industry and the scientific goals of

investigators. In contrast, trials conducted in the commercial sector are

heavily tipped toward industry interests, since for-profit CROs and SMOs,

contracting with industry in a competitive market, will fail if they

offend their funding sources. The pharmaceutical industry must appreciate

the risks inherent in its partnership with the commercial drug-trial

sector: potential public and physician skepticism about the results of

clinical drug trials and a devaluation of the insights provided through

close relationships with academic scientists.

A number of authors have recommended changes to resolve the problems of

clinical drug trials. (11,35,36,37) An essential ingredient of any

solution is increasing the independence of investigators to conduct and

publish their research. Some investigators interviewed for this article

felt that drug trials should be funded by industry but that design,

implementation, data analysis, and publication should be controlled

entirely by academic medical centers and investigators. The rise of the

commercial sector -- which reduces rather than enhances the independence

of investigators -- appears to be moving drug trials in the opposite

direction.

References on his website.