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Alert Number 162

Transparency in Clinical Trials: Your Life Depends on It

Date: May 22, 2006

If at first you don’t succeed, try and try again.

Great advice, but not when drug manufacturers use this philosophy to keep doing clinical trials until they get the results they are looking for, almost by happenstance, and choose to publicize only the results that are beneficial to their bottom-line.

A couple of years ago there was a huge expose: it appeared that Paxil, an anti-depressant drug prescribed to children, may have caused several teenagers to commit suicide. Selective and biased reporting of clinical trial results contributed to the avoidable tragedy. The Paxil episode has exposed a potentially dangerous information gap: the ability of the pharmaceutical industry to conceal study results that are not to their marketing advantage, results that suggest their drug may be ineffective or potentially hazardous.

There were three Glaxo studies that when combined clearly showed increased suicidal tendencies in kids taking the drug. The only one of the three trials published (in the prestigious Journal of the American Academy of Child and Adolescent Psychiatry) was one that showed Paxil worked as advertised in reducing depression. This report labeled suicidal thoughts as “emotional lability.” But there were two negative Paxil studies and these studies never saw the light of day and their results were not published in professional journals. Based on the positive published report, doctors could and did prescribe Paxil for children. An estimated 2.1 million prescriptions were written in 2002.

Turning closer to home, are you aware that way too many clinical trials in CLL are done whose results are never published? Call me a cynic, but I expect this happens more often when the results are lackluster or downright disappointing.

Sure, there are the sound bites at conventions, word of mouth testimonials by patients, glowing press releases that herald the day is near when a cure can be had, cheap at the price. These less-than-complete disclosures span the gamut: from overworked but sincere researchers who procrastinate and just have not gotten around to writing up their results, all the way to out-and-out snake oil hucksterism. Even in expert institutions with strong ethics boards, there is a little thing called human nature: we tend to be more eager and willing to get on the soap box and talk about the successful trials, and there are so many excuses why we do not get around to writing up the negative results of the trials that did not pan out, or the pesky and unexpected side effects no one expected.

Another aspect of human nature is summed up in the phrase “Beauty is in the eyes of the beholder”. Single institution clinical trials, especially Phase-2 trials that are done with no well matched control group, are particularly susceptible to this danger. Witness the avalanche of bad press fludarabine is getting these days. Not long ago, based mostly on single arm studies, it was hailed as the greatest drug ever invented for CLL, a clear “gold standard” and slam-dunk choice for frontline therapy. Chlorambucil? That was so old fashioned! Well, more recent multi-center trials with randomized design and well matched controls have begun to raise serious questions. Do the higher response rates with fludarabine come at the expense of more toxicity, infections, secondary cancers, and the last straw, no better overall survival? The final results are not in yet, but I think the fat lady has begun to hum.

Moral of the Story:

  • We have not yet come up with a no-risk therapy in CLL. Anyone who says they have the sure way of curing you with no fuss and no muss, is lying through his / her teeth. Or riding high on an ego binge.
  • Don’t bet the farm on single institution and early stage studies, especially those that have not been put through the peer review process of publication in good journals.
  • Anecdotal testimonial do not make for statistically valid conclusions. Remember, only healthy and happy patients wax eloquent on chat rooms, the sick (or dead!) ones are too busy being sick or dead to bother about writing about their experiences. At least, not until they get their lawsuits in place.
  • Gambling should be done in Vegas, not when choosing your next CLL therapy.
  • If you are asked to participate in a clinical trial and are given the bum’s rush and asked to sign consent forms without having had a chance to think things over and discuss the pros and cons with your own trusted advisors, we suggest you run away real fast.
  • Jargon in the patient information and consent forms has you flummoxed? Send us a copy of the documents. We have become pretty good at reading the jargon, and when needed we have a dozen experts on our unofficial advisory board to whom we can turn to help get things sorted out.
  • I am a big fan of capitalism. But capitalism also means that you should be aware of the money trail. There is a lot of money riding on clinical trials, and lots of researchers whose reputations and lucrative careers ride on the results of successful results. Nothing wrong with that, but just be aware of these agendas, and make sure your own agenda as a patient trying to live a long and healthy life does not get screwed in the process of other agendas getting in the way.
  • No one, absolutely no one, should be above the requirement of transparency and accountability when it comes to human clinical trials. I don’t care how famous the institution or how big the rock-star status of the doctor. If our public scrutiny of clinical trials is considered offensive by some doctors and institutions, I think that very stance proves my point. Ethical researchers have nothing to hide and do not get huffy when questions are asked by patients or the press.

The Reuters report below highlights some of these issues.

Be well, stay smart,


Press Report

WHO Seeks Greater Openness in Clinical Drug Trials

Reuters Health Information 2006. © 2006 Reuters Ltd.

GENEVA (Reuters) May 19 - The World Health Organization (WHO) called on Friday for all clinical drug trials to be registered from the outset and to help prevent companies from hiding negative findings.

A U.S. survey on Thursday showed that seven in 10 doctors were more worried about the safety of drugs they prescribe after a series of recent high-profile scares, including the withdrawal of arthritis pill Vioxx in 2004.

The medicine was taken off the market by its manufacturer Merck & Co after a clinical trial showed it doubled the risk of heart attack and stroke after 18 months' use.

"Registration of all clinical trials and full disclosure of key information... are fundamental to ensuring transparency in medical research and fulfilling ethical responsibilities to patients and study participants," said Dr. Timothy Evans, WHO assistant director-general.

The Geneva-based health body plans to set up a registry "platform" -- or portal -- through which access could be gained to several hundred trials' registries run globally by corporations, institutions and hospitals.

At the same time, the agency set out a 20-point check list for the sort of information to be included in any registry.

Asked about the Vioxx case, Evans said the WHO plan could have made a difference had it been operating because side-effects associated with Vioxx had not been fully reported and information had been difficult to access.

"This will not prevent adverse events associated with drugs and vaccines. (But) it will provide the public with a greater access... which will perhaps decrease the likelihood of those adverse events happening," he told journalists.

As things stand, researchers can opt to wait until they are well advanced in their work before filing anything.

While the individual registers would continue to exist, the WHO's platform would provide a single entry point to find out about research concluded or in progress.

The new measures could also help boost efficiency in research by cutting down the risks of duplication.

"Above and beyond building trust through transparency, more comprehensive knowledge on what is being done will allow for efficiencies to be gained by making sure that results are much more easily accessible," Evans said.

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