Tuesday, August 19, 2008

Seeding Trials: Misled in Translation?

Translational research- defined as research aimed at bringing discoveries in the basic sciences into clinical practice, is often divided into two types: T1 and T2. This blog is almost entirely focused on the former, which involves testing laboratory discoveries in human beings. 

Often lost in the glitter of T1, however, is the nettlesome challenge of taking clinical findings and translating them into community practice. Such T2 research in many cases involves 'phase 4' studies: trials that test a drug that has already been licensed by regulatory authorities.

A few years ago, I organized a research ethics symposium at McGill on phase 1 and phase 4 studies, titled "Dirty Business?" because such studies are often perceived as the most ethically suspect (the former because of their risk-benefit balance, the latter because they are often drug promotion masquerading as science).

The current issue of Annals of Internal Medicine features an article "The ADVANTAGE Seeding Trial: A Review of Internal Documents" (August 19, 2008) where Kevin P. Hill and co-authors show that Merck ran and published the ADVANTAGE study primarily to promote Vioxx sales(gasp!)  rather than to answer a question about the drug's performance.

In an editorial accompanying the article, editors Drummond Rennie and Harold Sox condemn such "seeding trials" and offer a series of recommendations for ending this abuse of study volunteers and health care professionals. Specifically, they urge physicians and IRBs to "ask... about the study hypothesis and whether it addresses a settled question... they should look for clues [that it does]: such as a sttudy with an open label design, no control group, a very large projected enrollment relative to the importance of the question, a short-term study of a chronic disease, a study of an already approved drug...."

Rennie and Sox couch the ethical problem with seeding trials as one of risk– "few physicians would knowingly enroll their patients in a study that placed them at risk in order to provide a company with a marketing advantage." But in my opinion, IRBs are reasonably good at sniffing out risk and harm.  Where they underperform is in assessing value. In my experience, IRBs seem to take the attitude "if nobody is going to get hurt, what the heck?" Phase 4 studies are generally harmless– probably more so than typical medical practice. What is troubling about them is that they are often valueless and– in the case of seeding studies– deceptive as well. And current review procedures at IRBs, focused as they are on risks rather than ends, are ill equipped (and frankly unmotivated) to staunch such unethical conduct. (photo credit: nutmeg66 2007)


Vioxx Side Effects said...

My name is Tony Gomez and i would like to show you my personal experience with Vioxx.

I am 56 years old. Have been on Vioxx for 2 years now. Everybody that works for the fda that oked this drug should be put in jail.

I have experienced some of these side effects -
heart attack hardening of the arteries and nerve damage in my feet

I hope this information will be useful to others,
Tony Gomez

Anonymous said...

It's known within the pharma industry as 'publication planning':

Published on www.brainblogger.com

The Human Injury of Lost Objectivity

If I were to rate the corruptive tactics performed by big pharmaceutical companies during my intimate experience with them , the frequent and intentional strategy of implementing fabricated and unreliable results of clinical trials performed by others possibly tops the list of corruptive tactics by the pharmaceutical industry that sponsors such trials. By this atrophy of the scientific method absent of authenticity that has been known to occur, harm and damage is possibly done to the health of the public. Most would agree that the science of research should be sound and as aseptic as possible- completely free of deliberate and reckless interference. However, it appears, money and increased profits can be a catalyst for disregard for human health with the clinical trial process that is largely unregulated. This is particularly a factor on post-marketing studies of various pharmaceutical companies, as some pharmaceutical corporations seem to be deliberately conducting nothing less than seeding trials- with about a 50 percent tax credit for these trial sponsors. Trials that are pointless and void of scientific benefit.

Decades ago, clinical trials were conducted at academic settings that focused on the acquisition of knowledge and the completely objective discoveries of drugs and devices to benefit mankind. Then, in 1980, the Bayh-Dole Act, Public Law 96-517,was created, which allowed for such places with their researchers to profit off of their discoveries that were performed for pharmaceutical companies and others in the past. Furthermore, such academic institutions were coerced to license patented inventions to those pharmaceutical companies that will then commercialize these discoveries paid for in large part by the taxpayers who funded this research to a degree.

This resulted in the creation of for-profit research trial sites without any academic affiliation that are called Contract Research Organizations. CROS utilize primarily community patient care clinics whose staff are absent of any research training compared with the former researchers that existed decades ago. Because of this structure, the clinical trial investigators of these pharmaceutical sponsored trials are likely novice compared with academic researchers. This, of course, happens with intent by the sponsor who can and does control all aspects of the clinical trial protocol at the site locations of a clinical trial that the pharmaceutical company structures and even gives the trial the title they want for their marketing purposes.

These quite numerous CROS are in fact for- profit, with some CROs making billions of dollars a year, and this market continues to grow.

The trials conducted at such places again are sponsored by pharmaceutical companies that control and manipulate all aspects of the trial being conducted involving their particular drug chosen to be studied. Etiology for their deception regarding this manipulation is because the pharmaceutical company that sponsors such a trial is basically creating a marketing tool for this drug of theirs to be studied in this manner. This coercion is done by various methods of deception in subtle and tacit methods. As a result, research in this protocol of the sponsor ensures favorable results of the sponsor’s medication that is involved in the clinical trial they clearly own. These activities are again believed to be absent of true or applied regulation to any degree, and therefore have the autonomy to create whatever they want to benefit the pharmaceutical sponso. There likely is a collusive relationship between the sites, the CRO, and the sponsor, as this whole system is planned beforehand by the pharmaceutical sponsor of their clinical trial to again be utilized to increase the market share of the drug studied that they promote.

Guest authorship has been known to be aggressively recruited by sponsors by paying a known opinion leader to sign off on the completed clinical trial. Furthermore, the pharmaceutical sponsor recruits investigators to be used for this function of what ultimately is a fabricated clinical trial protocol. The trial manuscript and protocol design is prepared by those employed by the drug company sponsor upon specific direction of this sponsor on how this should be prepared. The medical program coordinator of a particular sponsored trial is an actual employee of the sponsoring drug company and also may act as the publisher, manuscript version reviewer, and the clinical trial director who works with the drug company’s hired CRO editors whose objectives are to benefit the sponsor. Typical and ultimate cost of the final manuscript of the trial to the sponsor created by the hired CRO and the recruited ghostwriters exceeds 1000 dollars per page, some have said. Merck engages in this behavior, which shocked many, as they were always viewed as an ethical pharmaceutical company that always placed patients over profits. Apparently, this is no longer the case. There are other well known and large pharmaceutical corporations that consider this plan of action standard operating procedures to ensure growth of their drugs.

Further disturbing is that once the creation of the trials is completed, the research paper is often composed with specific directions by the sponsor to writers known again as ghostwriters. These people are usually not identified and acknowledged by the sponsor, and may not be trained in clinical research overall, as they are simply freelance writers. One does not need research training or certification in order to perform this function. Rarely do clinical trial ghostwriters question their instructions about their assignment, which is clearly deceptive and undocumented by the pharmaceutical sponsor. Also, these hired mystery writers are known to make about 100 grand a year performing this deception full time.

This activity removes accountability and authenticity of the fabricated clinical trial even further. The corruptive act is finally completed by the sponsor hiring again a known thought leader as an author to have their name be placed on the trial, while this hired author likely had absolutely no involvement with the trial, or even reviewing the trial is not asked or required by the hired author, others have said.

To have the trial published, the sponsor has been known to pay an obscure journal, and the sponsor bribes the journal in a few ways, such as the sponsor purchasing from a selected journal thousands of reprints of their study from the journal, for example. Again, how often this process is performed is unknown, yet frequent enough to create hundreds of such false writers mentioned earlier and progressively growing research sites to receive the support the pharmaceutical industry. So benefits of pharmaceuticals that are studied in such a malicious way potentially can harm patients and their treatment options along with clear safety risks as a result of this process.

The purchased reprints of the fabricated clinical trial are then bought by the sponsor of the study from the medical journal they hired to publish this trial. The reprints are eventually distributed to the sponsor’s sales force to share the content with prescribers, with the sales force completely unaware about this manipulation that has occured with such a trial that benefits the drug they promote for their employer. As a bonus, the sponsor may agree to pay the chosen medical journal to advertise their products to be placed in this journal as well.

Such misconduct discussed so far impedes research and the scientific method with frightening ethical and harmful concerns, as stated previously. If so, our health care treatment options with drugs that are claimed to have benefits that may not exist are now unreliable in large part due to such corruptive situations, as well as the absence of objectivity that has been intentionally eliminated with trials produced in this way.

More now than ever, meds are removed from the market or are given black box warnings due to the damaging effects of drugs approved by the FDA. We as citizens need to dig deep and ask why this is occuring.

Transparency and disclosure needs to happen with the pharmaceutical industry for reasons such as this as well as many others, in order to correct what we have historically relied upon for conclusive proof, which is the scientific method. More importantly, research should be conducted in a way that the sponsor cannot in any way interfere in such ways described in this article, which would require independent clinical trial sites with no involvement from the maker of the drug studied in a clinical trial.

And clearly, regulation has to be enforced not selectively, but in a complete fashion regarding such matters. Public awareness would be a catalyst for this to occur, after initially experiencing a state of total disbelief that such operations actually are conducted by such people, of course. We can no longer be dependent on others for our optimal health.

Knowledge is power, and is also possibly a lifesaver.

“Ethics and Science need to shake hands.” ……. Richard Cabot

Dan Abshear
Author’s note: What has been written was based upon information and belief.