GlaxoSmithKline's Marketing Firm Promised "Clinical Trials Could be Your Solution" to Poor Graduate Students

We have frequently raised concerns about the increasing domination of clinical research, particularly clinical trials, by those with vested in interests in the research producing particular results.  In particular, drug, biotechnology and device companies often sponsor trials meant to evaluate their own products.  Often it appears that commercial trial sponsors manipulate various aspects of research design, implementation, analysis, and dissemination to increase the likelihood of a result favorable to their interests.  Furthermore, when even such manipulation fails to produce the desired result, particular studies may simply be suppressed, that is, hidden.

Clinical Trial Participation as "Your Solution" to Graduate Students' Money Woes

A recent story, first told on the In-Pharma Technologist web site, gave an example of how trial recruitment could be gamed so as to produce more compliant study subjects. Since that web-site does not allow copy and pasting of even a few sentences of its content, I will quote, instead, from a subsequent article in the Guardian.

GlaxoSmithKline  the pharmaceuticals multinational, has apologised after being accused of playing on the hardship of unpaid interns to recruit them to take part in clinical trials.

A marketing firm working for the FTSE 100 company sought to place a blog on careers advice websites boasting that involvement in drug trials could help graduates to finance their way through unpaid work placements.

In a proposed 'guest blog' for the website Graduate Fog, an employee at TouchPoint Digital, working on behalf of GSK, wrote: 'Clinical trials could be your solution.'

The "guest blog" proposed that many graduate students "would prefer an immediate income to tide you over for the coming months."  So,

Clinical trials could be your solution. Depending on the length of the study, you could earn up to £2,000 per trial for up to 4 trials a year, plus reasonable travel expenses.

This was not a one-off,

 Touchpoint provided examples of similar articles previously published on websites targeted at students. In an email to the founder of Graduate Fog, Tanya de Grunwald, it added: 'Your readers would also benefit if there is a small link at the end of the article to the GSK website, which is the biggest pharmaceutical company in the UK, so that if they want to find out more or get answers to more specific questions they can do so.'

Excessive Inducement

The story was picked up by Ed Silverman at the PharmaLot blog in the US, who pointed out how TouchPoint Digital appeared to be supplying an excessive inducement to vulnerable subjects,

Tanya de Grunwald, who runs the Graduate Fog website in the U.K., objected to the tone of the overture. 'Some of my readers are feeling very low, vulnerable and desperate for money,' she wrote us in an e-mail after openly questioning the recruiting tactic in a note to readers on her website last week. 'Many are unemployed. Others are in low-paid graduate jobs or doing unpaid internships.'

'Suggesting that participating clinical trials is a great way to earn easy cash is not just crass – I think it’s irresponsible. Surely, the more desperate someone is for money, the more likely they are to be dazzled by the financial benefits and less careful about weighing up the risks.'

A long time ago, that is, from 2006 - 2008, we published a series of posts about how contract research organizations running clinical research projects for commercial health care firms often preyed on financially and otherwise vulnerable research subjects by offering what would appear to such people to be dazzling remuneration.  For example, we discussed the trials by SFBC International (later PharmaNet Development Group, and now apparently Inventiv Health Clinical)  in Miami that enrolled immigrants, often undocumented, under questionable circumstances and in Montreal that resulted in the transmission of active tuberculosis (see post here and links backward); and the trial by Parexel International in London that put most of its subjects in intensive care (see post here, with links backward). In 2008, as we discussed here, two articles questioning the ethics of research done under the auspices of CRO appeared in two major medical journals.  Excessively zealous recruiting designed to tempt vulnerable subjects with money appears unethical, and may be dangerous for these subjects.

How Excessive Inducement Could Lead to Invalid Trial Results

Not only is such a practice apparently unethical and dangerous, it could endanger patients outside the research projects in question by producing invalid research.  Subjects who could be dazzled by such inducements might avoid disclosing conditions which would otherwise exclude them from particular research projects, or participate in multiple projects without sufficient or any wash out periods in between, meaning that one treatment's effects could confound another.  (Note that the blog post proposed by the marketer above suggested that subjects could participate in multiple trials during one year.)  Furthermore, subjects desperate to complete studies and earn their fees might avoid reporting adverse effects to avoid the risk of premature termination of their participation, or avoid protesting questionable actions by the researchers.   

But now in the modern era of the Internet and social media, overzealous recruitment using monetary lures is still going on.  As per PharmaLot,

One expert believes the flap is not surprising, because drug makers are under pressure to maintain a steady stream of clinical trial recruits.

'Middle class folks just sit back and wait until the drug reaches the market. Poor folks are the guinea pigs in an economy that is more and more uneven, and uncertain by the day,' says Roberto Abadie, a senior researcher at the Social Networks Research Group at John Jay College, City University of New York, and author of ‘The Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects.'

A Belated Response from GSK

Apparently only after the story broke did GSK notice there was a problem.  Again, per PharmaLot,

A Glaxo spokeswoman blamed the outside marketing firm for the episode. In an e-mail, she wrote us that 'we would agree that the tone used in the ads… is wrong. It trivializes the role of clinical trials in developing new medicines and the part that volunteers play in that process. This isn’t acceptable and we’re looking into what happened.'

Whether GSK was properly supervising the marketing firm, and whether GSK had provided incentives that might have lead to overzealous recruitment were not addressed.

Summary

This story is yet another reminder that health care professionals, health policy makers, and the public at large should be extremely skeptical of clinical research sponsored (and controlled) by those with vested interests in the research results turning out a certain way, particularly clinical trials run by drug, biotechnology, or biotechnology companies meant to assess those companies' own products. However, note that very rarely do published clinical trial reports provide enough detail about subject recruitment to determine whether overzealous recruitment and undue inducements may have lead to enrollment of subjects who should have been excluded, under reporting of adverse effects, etc.

In my humble opinion, we need to reassess current policies that allows organizations with such obvious conflicts of interest to run experiments on human beings (which is what clinical trials are.)

By the way, this story is also a reminder that most big drug, device and biotechnology firms seem to be associated again and again with dodgy clinical research.   For example, see what we have previously written about GSK here.

A Call to Restore the Integrity of Clinical Research - but Will Anyone Heed it?

Concerns about suppression and manipulation of clinical research to serve vested interests have finally gotten a little more mainstream.

Background: Suppression and Manipulation of Clinical Research

For a long time, we have decried and discussed examples of manipulation of clinical research done to increase the likelihood that its results would please vested interests, often drug, device or other corporations that sponsored the research and often exerted considerable control over its design, implementation, analysis, and dissemination.  We have also decried and discussed examples of suppression of research whose results offended such vested interest, sometimes done when manipulation did not succeed in producing such pleasing results.


I wrote about suppression of research in my 2003 paper on health care dysfunction,(1)

The integrity of medical research has been violated by the deliberate suppression of its results.

That assertion was based on several important, although understandably largely anechoic cases.

I first wrote about systematic attempts to manipulate clinical research in 2005, based on Richard Smith's PLoS Medicine commentary which listed specific tactics that vested interests could use to make it more likely that research studies would provide them with favorable results.

Although striking cases of manipulation and suppression appeared more frequently starting in the 1990s, in the last few years it has become more apparent that these are widespread problems.

A Call to Restore Integrity

This week, the British Medical Journal published a special article calling for restoration of suppressed or manipulated clinical trials(2), accompanied by an editorial entitled, "restoring the integrity of the clinical trial evidence base."(3)

The article used slightly different terminology than we do, replacing suppression with invisibility, and manipulation with distortion, thus,

Two basic problems of representation are driving growing concerns about relying on published research to reflect the truth. The first is no representation (invisibility), which occurs when a trial remains unpublished years after completion. The second is distorted representation (distortion), which occurs when publications in medical journals present a biased or misleading description of the design, conduct, or results of a trial.

The article boldly asserted

Both go against the fundamental scientific and ethical responsibility that all research on humans be used to advance knowledge and are symptomatic of a general culture of data secrecy. The end result is that the healthcare, biomedical research, and policy communities may, despite best intentions and best practices, end up drawing scientifically invalid conclusions based on only those parts of the evidence base they can see.

The editorial went further, asserting that

This crisis of hidden or misreported information from clinical trials—and the resulting distortion of the clinical evidence base—is widely recognized and commonly decried. It is one of the leading scientific problems of our time, but few solutions have been put forward.

Furthermore, it concluded with a warning about the immorality of continuing on the current course,

The results of clinical trials are a public, not a private, good. The public interest requires that we have a complete view of previously conducted trials and a mechanism to correct the record for inaccurately or unreported trials. If we do not act on this opportunity to refurbish and restore abandoned trials, the medical research community will be failing its moral pact with research participants, patients, and the public. It is time to move from whether to how, and from words to action.

Thus the notion that suppression and manipulation of clinical research is a systemic, severe problem that confounds health professionals and hurts patients is no longer a concern of only a few fringe dissidents, but a matter for discussion in the foremost mainstream medical journals.

Will Anyone Heed the Call?

Furthermore, this dire problem formulation suggests the need for a strong solution, as proposed by the article, and seconded by the editorial.  Using the term "abandoned trials" for " unpublished trials for which sponsors are no longer actively working to publish or published trials that are documented as misreported but for which authors do not correct the record using established means such as a correction or retraction (which is an abandonment of responsibility)," Doshi and colleagues wrote,

We call on institutions that funded and investigators who conducted abandoned trials to publish (in the case of unpublished trials) or formally correct or republish (in the case of misreported trials) their studies within the next year.

Starting in 2005, we have repeatedly called for protection of " researchers' rights to speak truth to power," but then noted that "right now, it is more often power that speaks to truth."  The question is whether without some bigger allies, individual clinical researchers will stand up on their own to restore the integrity of clinical research.

The big reason to worry is that most of these researchers work within a context which strongly favors vested interests, rather than scientific truth, or the rights of research subjects.  The researchers who would be most likely to be able to heed the call by Doshi et al are those within academic medicine. Yet clinical research in the academic medical world now functions within a strong and deep web of individual and institutional conflicts of interests, subjects that we also have written about incessantly.

There is evidence suggesting that the majority of medical faculty,(4) and the majority of their academic departmental leaders(5) have important financial ties to the health care corporations most likely to have reason to want to suppress or manipulate research.  Furthermore, most academic medical institutions have stated their interest in increasing "collaboration" with industry, usually giving the rationale that this will lead to "innovations" that will bring better tests or treatment to patients. (See posts here,  here and here for some examples.)  Such collaboration also tends to bring a lot of money to institutional budgets.  Further collaboration with industry is likely favored by academic leaders' own financial ties to the same sorts of corporations discussed above.  Thus it should be no surprise that a study by Mello et al in 2005 suggested that most of the managers of academic medical institutions who control research contracts are willing to give significant control of of research design, implementation, analysis, and dissemination to the sponsors, not the researchers.  (See this post.) (6)


Thus, a researcher who volunteers to restore suppressed or manipulated clinical studies might become suddenly very unpopular with his or her colleagues or supervisors, and perhaps with people who are already paying him or her.

So as long as health care professionals, policy makers, and the public at large are willing to go along with the notion that academic medical institutions' "collaboration" with "industry" is absolutely necessary to foster "innovation" and hence medical progress, it is very unlikely that academic medical researchers will be willing to help restore the integrity of clinical research.  In fact, while we continue on our present course, the integrity of clinical research will probably get even worse.
 
Since questioning the integrity of contemporary clinical research might make those with vested interests who have been willing to suppress or manipulate research very uncomfortable, perhaps it should be no surprise that the paired articles in the British Medical Journal have been relatively anechoic.  For example, while one might think the publication of these simultaneous articles might get at least a little coverage in the "main-stream media," I can find not a single mention of them there.  (So far, only the Chronicle of Higher Education, MedScape the Science Insider blog and The Scientist blog have provided news coverage.)


So I hope the brave people who wrote the article and editorial are also willing to join us in decrying the web of individual and institutional conflicts of interest that have entangled health care professionals and academic medicine.  Individuals and institutions who make medical or health care decisions, or who are involved in medical and health care education and research should reveal all their conflicts of interest, at least in the interests of honesty.  Furthermore, in the interest of patients' and the public's health, clinical research meant to assess medical tests, treatments, and programs should be done completely independently from the corporations that sell them.  


References

1.  Poses RM.  A cautionary tale: the dysfunction of American health care.  Eur J Int Med 2003; 14: 123-130.  Link here..
2.  Doshi P, Dickersin K, Healy D et al.  Restoring invisible and abandoned trials: a call for people to publish the findings.  Br Med J 2003;  BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f2865  Link here.
3.  Loder E, Godlee F, Barbour V et al.  Restoring the integrity of the clinical trial evidence base.  Br Med J 2003;  BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3601  Link here.
4. Campbell EG, Gruen RL, Mountford J et al.  A national survey of physician–industry relationships. N Engl J Med 2007; 356:1742-1750. Link here.
5. Campbell EG, Weissman JS, Ehringhaus S et al. Institutional academic-industry relationships. JAMA 2007; 298: 1779-1786.  Link here.
6.  Mello MM, Clarridge BR, Studdert DM. Academic medical centers' standards for clinical-trial agreements with industry. N Engl J Med 2005; 352:2202-2210. Link here.

Minimizing Legal Liability or Upholding the Mission? - the Markingson Case Redux

There are new, and troubling developments in the long running case of Dan Markingson, the psychiatric patient and research subject who committed suicide while enrolled in a trial of anti-psychotic drugs at the University of Minnesota nearly 10 years ago.

Summary of the Case

A good quick summary of this case just appeared in the Center for Law and Bioscience blob out of the Stanford Law School. 

Dan Markingson – a vulnerable, psychotic young man – was forced to choose between enrolling in a Pharma-funded drug study or being involuntarily committed (in other words, locked up).  A UMN [University of Minnesota]  doctor enrolled him in the study despite having just determined that Dan 'lack[ed] the capacity to make decisions regarding [his] treatment,' rendering it highly unlikely that Dan could have given valid informed consent to participate.  As Dan's mother, Mary Weiss, observed his mental condition deteriorating, she repeatedly tried to have Dan removed from the trial – at one point asking  'Do we have to wait until he kills himself or someone else before anyone does anything?'  But the UMN co-investigators in the drug study refused to terminate his participation.  Shortly after Ms. Weiss made her desperate plea, Dan Markingson killed himself by cutting his own throat.

Our most recent (2011) post on the case was here.  In it we also noted that there was reason to think:
-  The design of the controlled trial was flawed.
-  Financial conflicts of interests may have influenced the trial investigators' actions, particularly their questionable enrollment of Mr Markingson in the trial and their retention of him in it despite his apparent clinical deterioration.
Despite that, when bioethicists and the University of Minnesota called for a new investigation of the trial and what happened to Mr Markingson, the university rebuffed them.

Worse, as detailed in a 2012 post in the Center for Law and Bioscience blog, not only did university officials rebuff this call, but the university general counsel, who had been operating at the heart of this case, appeared to threaten the leading bioethicist dissident, Dr Carl Elliott:

 After Carl Elliott, the University of Minnesota bioethicist, refused to drop the matter, Rotenberg asked the university’s Academic Freedom and Tenure Committee to take up the question of '[w]hat is the faculty[’s] collective role in addressing factually incorrect attacks on particular university faculty research activities?' – a question that appeared both to accuse Elliott of 'factually incorrect attacks' and to call for some unspecified action to 'address' them.  Other faculty, including the president of the Minnesota chapter of the American Association of University Professors, viewed this as an attempt to intimidate Elliott into silence.  If so, it backfired.  The story ended up in the press, putting the Markingson case back in the public eye and once again making the University of Minnesota look really bad.

New Evidence Unearthed

In 2013, Dr Elliott made public what may be important new evidence in the case.  As summarized by the Minneapolis Star-Tribune,

The professor, Carl Elliott, says he has obtained consent documents for two separate schizophrenic patients that appear to be exact copies — not just in the subjects’ apparent replies, but in the positions of the lettering on the pages.

Elliott said it is improbable that separate patients would provide identical responses to the questionnaire, which includes open-ended questions about the risks and requirements of clinical research. And that, he said, raises questions about whether the university was really examining patients to determine their ability to consent to research.

 One crucial question about the case is how a patient who was actively psychotic - out of touch with reality - could give true informed consent to participation in a drug trial.  These new documents suggest major irregularities in the process used in the trial to assure that patients did give informed consent. 

Furthermore, as reported by the Minnesota Daily, other documents that Dr Elliott found suggested problems with records that related to whether study investigators would have had legal authority to access Mr Markingson's medical records, also suggesting major problems with trial administration. 

These documents, unknown until recently, suggest new concerns with how the study in which Mr Markingson was enrolled, and during which he died, was run.  Yet, the University of Minnesota's official response to them, once again orchestrated by university counsel Mark Rotenberg, attacked the legitimacy of the documents (and indirectly, attacked Prof Elliott again), as reported by the Star-Tribune,

the university’s general counsel, Mark Rotenberg, challenged the authenticity of the documents and disagreed that study recruiters failed to obtain proper and independent consent from mentally ill patients.

'I am challenging these allegations directly,' he said. 'We have no reason to believe the consent forms were prepared inappropriately.'

As Matt Lamkin wrote in the Stanford Law and Bioscience blog,  the University's responses all through this case have been focused  not on the welfare of patients, maintaining the trust of research participants, or the integrity of clinical trials, but on the legal defense of  the University and its leaders

Despite all this (and much more), the University has never acknowledged any errors or taken any disciplinary action related to the Markingson case and has repeatedly rejected calls for an independent investigation.  That’s probably because from the start the University has handled this case as a litigation matter.  Rather than trying to determine whether there were problems with the way its personnel treated Markingson, the University has focused on minimizing its potential liability.  Accordingly, the University appears to run every inquiry related to the case through the office of its General Counsel, Mr. Rotenberg.  When Carl Elliott (my mentor as a grad student at UMN) wrote a damning article about the case in Mother Jones, the University’s response came from Rotenberg.  When UMN bioethicists called on the University’s Board of Regents to launch an independent investigation, the Regents deferred to Rotenberg.  Not surprisingly, he declined.

When you turn to your lawyer, you’re going to get a particular kind of response.  The GC isn’t in a position to take an objective look at the circumstances.  He’s an advocate.  His role is not to make sure the client has conducted itself ethically, but to minimize the client’s risk.  Asking your lawyer to respond to allegations of wrongdoing is like asking your PR flacks to do so.  Their job is to make their clients look good, not to make sure they’ve acted properly.

Note that this still begs the question of who the client is.  Is it the university, or the university's leaders?

Furthermore, as Mr Lamkin pointed out, the general counsel would appear to have a conflict of interest.  It may be he has an interest in defending his own actions, as well as those of his client(s), whether they are the university, its leaders, or both. 

In addition to Mr. Rotenberg’s role as the University’s top defender and advocate, there is another reason he cannot impartially consider requests for an investigation: the General Counsel’s Office is an important player in some of the disturbing events at issue.  As noted above, Rotenberg himself has been accused of attempting to intimidate and silence the bioethicist who has most doggedly sought an investigation.  The University’s lawyers are also responsible for the disgraceful silencing of Markingson’s mother, Mary Weiss.  After avoiding liability by arguing the University was immune from suit, these lawyers then threatened to force Weiss – whose son had died in a University doctor’s 'care – to pay the University’s legal costs of some $57,000.  The University used that threat as leverage to get Weiss to forgo an appeal of the trial court’s decision.

So as the University continues to refuse any new consideration of this this seemingly never-ending case, Dr Elliott has posted an online petition calling for an outside investigation.   We will see how Mr Rotenberg reacts to this.

Summary


A very troubling aspect of this case is that it has shown that the university leadership has seemed to care, at best, more about fending off litigation than upholding the university's mission.  The mission of the university is supposed to be discovering and disseminating the truth in a spirit of free inquiry.  Added to the mission of medical schools and university teaching hospitals is taking good care of patients, and putting the patients' interests ahead of all other concerns.  Yet, in this case, university leaders have not seemed to care whether in their haste to push back legal liability they were stepping on their faculty's academic freedom and free speech, the integrity of the medical research done at the university, and most importantly the rights of their patients and research subjects.  Furthermore, it is not clear whether they mainly feared the impact of litigation on the university, or how litigation might actually end up holding them accountable.

As Dr Judy Stone wrote in her Scientific American blog,

  it appears that UMN believes, as do many other institutions, that protecting itself from scandal and its consequences comes first and foremost and that, like the big banks, that it is too big to be punished.

Again, note that UMN cannot itself believe or protect.  People acting ostensibly on its behalf may have been protecting themselves from scandal, and believing that the size and status of their institution gave them, the leaders, impunity.

The case of Mr Dan Markingson is a continuing reminder that to reform health care, health care organizations need to be lead by people who put the health care mission first and are willing to be accountable for that mission.   I hope that eventually there is an honest investigation of this case, and a commitment to reform based on its conclusions.

See additional thoughts from Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog, on the 1BoringOldMan blog, on the Periodic Table blog, and last but certainly not least, many comments by Dr Carl Elliott on the Fear and Loathing in Bioethics blog.