Drug firms accused of distorting research

Sarah Boseley, health editor
Monday September 10, 2001
The Guardian

Thirteen of the world's leading medical journals today mount an outspoken attack on the rich and powerful drug companies, accusing them of distorting the results of scientific research for the sake of profits.

The Lancet, the New England Journal of Medicine, the Journal of the American Medical Association and other major journals accuse the drug giants of using their money - or the threat of its removal - to tie up academic researchers with legal contracts so that they are unable to report freely and fairly on the results of drug trials.

The scientists, often from cash-starved university departments, may be prevented from having access to the raw data gathered in the trial which would tell them how well or not the drug worked and whether there were side-effects. They may be given no say in the way the trial is designed and they may have only limited participation in interpreting the results. 

"These terms are draconian for self-respecting scientists, but many have accepted them because they know that if they do not, the sponsor will find someone else who will. And, unfortunately, even when an investigator has had substantial input into trial design and data interpretation, the results of the finished trial ma  be buried rather than published if they are unfavourable to the sponsor's product," says the commentary which will run this week in 12 of the journals. The British Medical Journal is running a separate editorial with the same message.

The editors say that the study produced for publication may be skewed in the interests of the pharmaceutical company, which hopes to make big profits from a new drug. It is also a betrayal of the patient who has agreed to take part in what he or she believes is research to help find new and better treatment s for disease.

Richard Horton, editor of the Lancet, said the editors hoped to start a debate over what patients are told when they sign a consent form to take part in a trial.

"The patient should know who is in control of the study. Are you - my doctor or the scientist doing the study - in control or is the pharmaceutical company in control? They are never told anything of the sort. At the moment, informed patient consent is a fabrication."

Academic scientists had little choice but to accept the restrictions imposed on them, he said, because they knew that otherwise the funding they needed for research would go to the increasing number of private contract research organisations. Those organisations last year in the USA received 60% of the research grants handed out by pharmaceutical companies.

Where the company controls the trial, the data and the writing of the study, he said, "the research will be presented to favour the product that company makes. I think it happens all the time - certainly in most papers that involve a new drug. It's obvious that that will happen. For the
company it is their profit we are talking about. There is a clash of interests".

The editors intend to take action, by requiring all authors to disclose details of their own and the sponsoring pharmaceutical company's roles in the study. Some editors will be asking for a signed declaration from the author that they accept responsibility for the trial. If the company has sole control of the data, the journals will not publish the study.
 

Guardian Unlimited © Guardian Newspapers Limited 2001 
 

http://www.redflagsweekly.com/nasstrials.html

OPENING A MEDICAL CAN OF WORMS
On Making Clinical Trials Fair

By Meryl Nass, MD

January 19, 2002 - Looking into the subject of human clinical trials and the informed consent of their subjects opens a big can of worms. 

What pops out at you immediately is how much money is spent to get a drug into the market, and how many human subjects are required.

The cost of developing one new drug today, according to the pharmaceutical industry, can typically be as much as $500 million. So, the manufacturer aims to earn this much back, plus profit, before the drug goes off patent.

In 1998, 3,278 drugs were undergoing human clinical testing. Therefore, the drug industry needs several million people per year to become subjects in drug studies. The industry also needs to get these studies completed as expeditiously as possible to recoup their investment.


As in the developing Enron story, the most desirable way to proceed is down the path of least regulation. That means most of the studies are no longer conducted in university medical centers, and many are conducted in places like China. In fact, I was recently invited to a conference to learn how to conduct clinical trials overseas.

The FDA has found that the number of overseas investigators (performing clinical trials for drugs to be licensed in the US) has increased over five-fold during the past decade.

To rapidly find subjects, private physicians are given large honoraria, often over $1,000 for each of their patients enrolled in a drug trial.Private contract-research organizations have sprung up to meet the industry’s need. Prospective subjects might be told that the drug being studied is likely to be a better treatment for their illness than already licensed drugs. The FDA has had to crack down on misinformation in advertisements for subjects.

Human subjects begin to be tested once animal studies show that the drug looks like it will be effective and probably safe. The Phase 1 study is performed, not to provide the human subjects with any benefit, but only to establish safety in the human species. If the result is positive, Phase 2 studies are undertaken in small numbers of people to further assess safety, and also effectiveness. If these results are promising, Phase 3 studies are undertaken in more (usually several thousand) people, to confirm the drug’s safety and effectiveness.


How well informed are the subjects themselves? A recent study in The Lancet by Steven Joffe at Dana Farber Cancer Center, Boston was eye-opening. Questionnaires were sent to subjects enrolled in Phase 1, 2 or 3 trials of cancer treatments at one of three Boston hospitals. Study subjects received ‘top of the line’ informed consent, with half the consent discussions lasting at least an hour.


Although 90 per cent of the participants were satisfied with the informed consent process, 70 per cent were not aware that the treatment being used had not been proven to be best for their cancer. And 54 per cent of the clinicians providing the informed consent discussion were unaware that “the main reason cancer clinical trials are done is to improve the treatment of future cancer patients.”


Since these treating doctors appeared not to recognize that participation might not be in their patients’ best interest, they are unlikely to recognize their own potential conflicts of interest in conducting the trials.


I often wondered how one gives a patient an informed consent discussion for a Phase 1 trial. How do you say that no benefit is anticipated, that the drug is not a treatment for the subject’s medical conditions? Instead, the drug is being given solely to see whether it causes harm. If the subject is paid enough (sometimes they are paid, sometimes they are not) it might not matter.


How does one honestly tell a cancer patient that you are conducting a Phase 1 trial on him? It would seem to be adding insult to injury. I’m not sure that helping the next generation of cancer patients would be my priority, in that situation. Nor would helping out my doctor.


A 1998 Lancet editorial mentioned two human studies in which healthy volunteers were fed pesticides to identify the toxic dose. One study’s purpose may have been to generate data that would lead to lowering of the safety threshold for the pesticide in the United States. Were the subjects told of the possibility that the pesticides they ingested may cause chronic neurological illnesses? Although a pesticide may be a drug (for instance, to kill parasites), in this case, the humans were part of a toxicity study that appears not to have been intended to develop a drug for human use. What were the subjects told about the purpose of the trial, and their role?


A recent case, in which a study subject died after an adverse reaction to hexamethonium used in an asthma trial, is instructive. The investigator did not consider hexamethonium a drug, and did not get permission for its use from FDA. (I knew of it as a component of antibacterial soaps.) But it had once been used as a drug, so FDA said it still was one.


A recent death in a study subject who received methionine is another example of a “non-drug”’s toxicity. Methionine is an amino acid, a component of food proteins. Given in a mega-dose, however, it caused death. What is a drug, and who is responsible for regulating the use of non-drug substances in trials?


We obviously need drugs and toxic substances to be tested adequately. The process just has to be fair to all involved. And to accomplish this, the oversight mechanisms require serious strengthening. The formation and conduct of institutional review boards that oversee clinical trials need plenty of attention.


Instead of being another rubber-stamp committee filled with harried professionals, these boards need to compensate their members adequately, and take their time to perform careful and comprehensive reviews of all human research studies. The bioethicists need to help us out and develop better guidelines for all involved. And the human subjects need to really understand all the implications of participating in a clinical trial.


Recommended Reading  Organophosphorous compounds: good, bad, and difficult. Lancet 1998. Aug 15;352 :499.

Safeguarding participants in clinical trials. Lancet 2000. June 24; 355:
2177.

Examining informed consent to cancer clinical trials. Lancet 2001. Nov 24:
358: 1742.

Joffe S, Cook F, Cleary PD. Quality of informed consent in cancer clinical
trials: a cross-sectional survey. Lancet 2001. Nov 24; 358:1772-7

Medical journals issue drug trials warning

By Victoria Griffith in Boston and David Firn in London - Sep 10 2001 00:00:00


Thirteen leading medical journals will on Monday warn that the promise of big financial rewards is corrupting human clinical trials.

The warning will be issued simultaneously in editorials by the New England Journal of Medicine, the Journal of the American Medical Association, The Lancet, and other publications in Norway, the Netherlands, Australia, New Zealand, Canada, Denmark and the US.

The editors will criticise pharmaceuticals companies for their use of private, non-academic research groups - called "contract research organisations" (CROs). CROs are fast gaining in popularity because - according to the editorials - they are cheaper and less independent than academic institutions.

In the US last year, 60 per cent of the industry's research grants went to CROs.

The editorials will assert that CROs fail to provide sufficient oversight of clinical trials. "The results of the finished trial," the editors warn, "may be buried rather than published if they are unfavourable to the sponsor's product."

Critics fear the substantial financial rewards compromise scientists' objectivity and place patients at risk.

The warning comes as the pharmaceuticals industry struggles to recover from criticism over the prices it charges developing countries for life-saving medicines and a string of high-profile recalls involving problems with treatments for obesity, irritable bowel syndrome and diabetes.

American Home Products has recently taken more than $12bn in charges to cover side-effects caused by a diet drug.

US patients last week filed a claim that GlaxoSmithKline, the Anglo-American drugs group, deliberately hid the side-effects of Paxil, its multi-billion dollar antidepressant from regulators.

Bayer of Germany is facing possible class action after its $1bn-a-year cholesterol treatment Baycol was linked to more than 50 deaths. And Pfizer, the world's largest pharmaceuticals company has been hit by charges that its clinical trials violated human rights in Africa.

The American Medical Association this year exhorted universities and hospitals to require researchers to disclose fully any financial interest they might have in products undergoing clinical trials.

The 13 publications will promise to raise their own standards for the publication of research. From now on, all authors and participants in the review process will have to reveal any possible conflicts of interest.
 

Survey reviews studies paid for by drug companies


October 23, 2002 Posted: 05:04:00 PM PDT


By LINDA A. JOHNSON, Associated Press
(AP) - The drug companies that pay for major testing of most new medicines give the participating university researchers little or no say in how the studies are designed and how the findings are handled, a survey found. The survey of 108 medical schools, published in Thursday's New England Journal of Medicine, is the latest sign of growing concern about conflicts of interest between those doing scientific research and the pharmaceutical companies sponsoring it.

"What the institutions have told us is they feel almost powerless in these contracts," said Dr. Kevin Schulman, a Duke University Medical Center professor who led the survey.While federal agencies sponsor much early research, large-scale studies of drugs' safety and effectiveness are usually paid for by the manufacturers. Typically, the companies hire medical school faculty members to carry out the studies.

But some scientists worry their lack of control could threaten the integrity of research and the safety of the volunteers participating. Among other  things, pharmaceutical companies have sponsored research that found a drug didn't work or was dangerous, then suppressed the results. Concerned about the problem, the International Committee of Medical Journal Editors in 2001 published guidelines for research contracts between medical schools and the pharmaceutical industry.

Last winter, researchers at Duke University Medical Center and Duke's law school interviewed officials at U.S. medical schools and reviewed some of their research contracts to determine how many complied with the new guidelines. Only a minority did. Schulman said researchers have less and less control over patient trials as more and more studies include dozens of medical centers, rather than just one, a strategy meant to bring results faster.

Among the study's findings:

- Researchers rarely were allowed a say in the design of the clinical trials, with only 10 percent of contracts covering how data is collected and monitored and only 5 percent covering how data is analyzed and interpreted. - Less than 1 percent of contracts guaranteed that results would be published and that an independent committee would have control over that. But 40 percent of contracts addressed editorial control of manuscripts. - Only 1 percent of contracts required an independent board to monitor patient safety. Such boards can stop a study early if the treatment is found to be harming participants.

"It is very worrying," said Mary Ann Baily, associate for ethics and health policy at the Hastings Center, a Garrison, N.Y., think tank. "The future of research and patient welfare does depend on how we approach this." Financial ties between academic researchers and industry sponsors already are under scrutiny for apparent conflicts of interest, as when researchers receive stock in a company testing an experimental drug.

Over the summer, the Pharmaceutical Research and Manufacturers of America established voluntary guidelines for clinical research, but they are "basically toothless," said Dr. Jeffrey M. Drazen, editor of the New England Journal. "The system would be better served if there were universally accepted contractual language," he wrote in an editorial.

PhRMA spokesman Jeff Trewhitt said its member companies three weeks ago started implementing new principles for operating and reporting on clinical trials that "reaffirm our commitment to the safety of research participants and a timely communication of research results."

Trewhitt said those principles cover at least some of the concerns raised in the study and recommend paying researchers in cash, not company stock. In another opinion piece, doctors wrote that such protections are critical because future medical research will depend even more closely on partnerships between universities and industry; they suggested creating a national panel to deal with conflict-of-interest issues. A third opinion piece by doctors and an industry consultant said universities must set firm policies protecting their researchers from financial influences.