Two New Independent Reports on the Death of Dan Markingson, But Now What Will Happen?

Years after his death, there is now a little more clarity about the clinical trial in which Dan Markingson was enrolled when he died.  Whether this clarity will have any impact remains to be seen.

We most recently posted about the aftermath of Mr Markingson's death here, (and see posts in 2013 here, and in 2011 here.)  Very briefly, Mr Markingson was an acutely psychotic patient enrolled in a drug trial sponsored by Astra Zeneca at the University of Minnesota.  His enrollment was said to be voluntary although at the time he enrolled he had been under a stayed order that could have involuntarily committed him to care.  Despite his mother's ongoing and vocal concerns that he was not doing well on the study drug and under the care of trial investigators, he continued in the trial until he died violently by his own hand.  After his death, his mother Mary Weiss, friend Mike Howard, and University of Minnesota bioethics professor Carl Elliott campaigned for a fair review of what actually happened.  University managers not only rebuffed their concerns, but harshly criticized Professor Elliott, and ended up reprimanding him for "unprofessional conduct."

Two New Reports

In the last few weeks, two new independent reports on the case appeared.  Both vindicated the concerns and questions raised by Mary Weiss, Mike Howard, and Prof Elliott.

Association for Accreditation of Human Research Protection

One, called for by the University of Minnesota faculty senate, was by the Association for Accreditation of Human Research Protection,  and said that the university left research subjects "susceptible to risks that otherwise would be avoidable" (see this Minneapolis Star-Tribune article.)  Furthermore, according to a post in the Science Insider blog from the American Association for the Advancement of Science, it said,

[T]he external review team believes the University has not taken an appropriately aggressive and informed approach to protecting subjects and regaining lost trust,

Also, it said the university has been

assuming a defensive posture. In other words, in the context of nearly continuous negative attention, the University has not persuaded its critics (from within and outside the University) that it is interested in more than protecting its reputation and that it is instead open to feedback, able to acknowledge its errors, and will take responsibility for deficiencies and their consequences.

Finally, it noted a "climate of fear" in the Department of Psychiatry.

Office of the Legislative Auditor for the State of Minnesota

The second report, available in full here,was from the Office of the Legislative Auditor for Minnesota.  If anything, it was more damning. Its summary included,

the Markingson case raises serious ethical issues and numerous conflicts of interest, which University leaders have been consistently unwilling to acknowledge. They have repeatedly claimed that clinical research at the University meets the highest ethical standards and dismissed the need for further consideration of the Markingson case by making misleading statements about past reviews. This insular and inaccurate response has seriously harmed the University of Minnesota’s credibility and reputation.

It seemed to affirm in detail nearly all of Weiss', Howard's and Elliott's concerns.  It recommended that the University should suspend new psychiatric drug trials until the problems it identified were remedied (see Star-Tribune article here.)

Vindication, but Will It Lead to Progress?  

Taken together, these reports vindicate the work of Mr Markingson's mother, friend, and academic watchdog Professor Elliott and their supporters.  As the Star-Tribune reported,

'Over the past eleven years the University of Minnesota has made us feel as if we have no voice, no rights and absolutely nothing remotely called justice,' wrote Mike Howard, a close friend to Markingson’s mother, in a letter in the audit. 'This report is the first step toward accountability.'

The Minnesota Post added the response of Professor Elliott and a colleague,

'It’s nice to have an independent confirmation of what we’ve been telling the university for five years, but which they have refused to listen to,' he told MinnPost on Thursday.

Elliott said he is not convinced, however, that Kaler and other university leaders are going to take responsibility for what happened in the Markingson case — or take the necessary steps to fix the problem going forward.

'One of the most worrying findings in the report was the widespread belief on campus that the university leadership doesn’t care about human study subjects,' he said.

Leigh Turner, another U bioethicist who has also been outspoken about the issues raised by the Markingson case, expressed similar concerns. 'Can we expect reform from the very people who have done nothing for the past several years?' he said in a phone interview.

'I hope there’s some change,' he added. 'But the fact that [Markingson died in 2004] and it’s now 2015, I think hope has to be tempered with a dose of realism. There are some very powerful forces interested in minimizing the findings and suggesting that there are only minor things that need to be done.'

It appears there a several major remaining questions.

What Were the Underlying Causes?

Although both reports went into some detail about what happened to Mr Markingson, they seemed not to dwell on why it happened.  They did not seem to address relevant contextual factors, policies, and decisions.  For example, the report by the Office of the Legislative Auditor included,

We understand that the University of Minnesota has been and should continue to be an institution that delivers not only high quality medical care but also engages in cutting edge medical research— research that does pose risks to human subjects. In addition, we do not question the appropriateness of the University obtaining money from pharmaceutical and other medical companies to support that research. However, in every medical research study—whether supported with public or private money—the University must always make the protection of human subjects its paramount responsibility.

However, as we and many others more erudite have discussed frequently, clinical research that evaluates products or services made by the commercial sponsors of the research has proven to be highly susceptible to manipulation by these sponsors to increase the likelihood that the results will serve marketing purposes, and suppression if the manipulation fails to produce the wanted results.  Commercial sponsors often strongly influence the design, implementation, analysis and dissemination of clinical research.  Often their influence is mediated by financial relationships with individual researchers and with academic institutions who seem more and more beholden to outside sponsors, that is, by conflicts of interest.  The report by the Auditor noted pressures, including financial pressures on the physician who ran the study in which Mr Markingson was a subject to enroll more patients and keep them enrolled.  To protect patients better in the future, in my humble opinion the relationships among commercial sponsors, academic medical institutions, and individual researchers need further consideration.  Is the easy money supporting research coming from commercial firms with vested interests in the outcome of that research really worth the risks of biased results, hidden results, and to research subjects?   

Will Anything Change and Will Anyone be Held Accountable?

Once these two reports were delivered, it now seems to be up to university managers to make needed changes.  In general, these are the same managers who are described above as so "defensive," who not only ignored complaints, but appeared to try to silence those who complained.  If they are left in charge, why should we expect them to make any meaningful changes?  Instead, should they  not be held accountable for their actions?  

Will the University Cease Hostilities Against Dr Elliott?

Again, as noted above, university managers did not merely disagree with Professor Elliott.  They disparaged him, appeared to try to intimidate him, and reprimanded him.  It seems at the very least he is owed an apology.  So far, nothing in the news coverage suggests he has or will receive one.

Will Anyone Notice? 

So far, this case has gotten good coverage in Minnesota media.  However, it has largely been ignored in the national media.  Beyond Minnesota, I could only find mention in some blogs, e.g., in PharmaLot by Ed Silverman, and in Forbes by Judy Stone.  I have seen nothing in any US medical or health care journal, although the British Medical Journal did cover it in a news feature.  This case clearly has global implications, and ought to be considered one of the most important cases illustrating the perils of commercially sponsored human research, but it remains proportionately anechoic.

Summary

The latest reports seem only to confirm that clinical research at major academic institutions has gone way off track.  It now seems that in their haste to bring in external funding, university administrators and the academic researchers who are beholden to them have sadly neglected the protection of their own patients.  As we have said ad infinitum, true health care reform would turn leadership of health care organizations over the people who understand and are willing to uphold the mission of health care, and particularly willing to put patients' and the public's health, and the integrity of medical education and research when applicable, ahead of the leaders' personal interests and financial gain.

ADDENDUM (25 March, 2015) - See also numerous posts by Professor Elliott on the Fear and Loathing in Bioethics blog,  by Bill Gleason in the Periodic Table blog,  and by Mickey Nardo on the 1BoringOldMan blog. 

ADDENDUM (30 March, 2015) - Note that after receiving offline comments, I changed the first paragraph to emphasize the clarity is about the trial, rather than the patient's death, and second paragraph to clarify that the order to commit was stayed.

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. 

The University of Minnesota, Where Nothing Can Go Wrong, Go Wrong, Go Wrong...

As noted on the Periodic Table blog, the administration of the University of Minnesota continues to believe all is well with its clinical research activities.  A recent internal review said there was nothing more to investigate about the unfortunate death of a psychiatric patient years before. So should we all be relieved?

It will take an extensive review of the case to ultimately suggest we should not at all be relieved.  The case raised important concerns about the validity of clinical research, and whether it violates the trust of its patient-subjects.  These concerns had not been addressed before the university's most recent review, and thus seem even more pointed after its recent non-investigation.

Background: the Untimely Death of Dan Markingson

In May, 2008, the (Minnesota) Pioneer Press ran a series of articles about the untimely death of Dan Markingson which occurred while he was enrolled in a randomized trial sponsored by AstraZeneca (the CAFE study) at a site at the University of Minnesota.  The first article in the series made the following major points:

Mr Markingson had given his consent to be enrolled despite evidence that he was actively psychotic

He started having visions of killing his mother in the storm. Markingson was taken Nov. 12, 2003, to Regions Hospital in St. Paul, but it had no open psychiatric beds. He was then transferred to the University of Minnesota Medical Center, Fairview.

Weiss said discussions about research started right away at the hospital. Markingson was placed in Fairview's Station 12, a new unit at the time created to treat psychotic patients and screen them for research. Olson and Dr. Charles Schulz, head of the U's psychiatry department, helped launch the unit in part to enhance the hospital's startup schizophrenia program and meet the U's mandate to bring in more research dollars.

Olson first recommended on Nov. 14 that a Dakota County District Court commit Markingson to the state treatment center in Anoka because he was not fit to make decisions about his care. He wrote to the court that Markingson was convinced his delusions were real and that he wasn't mentally ill.

The doctor changed his opinion about the commitment in less than a week, telling the court Markingson had started to acknowledge the need for help.

Reversals by patients are common, Olson explained in an interview with the Pioneer Press last month. Schizophrenics often arrive for treatment with delusions and denial but change their outlook while hospitalized.

A judge agreed Nov. 20 with Olson's new recommendation, requiring Markingson to follow the doctor's treatment plan. The next day, Markingson signed a consent form to be part of a national anti-psychotic drug study, Comparison of Atypicals for First Episode, or CAFE.

His mother's multiple complaints that while in the study, Markingson was not getting better and not getting proper treatment were ignored

Weiss' letters to Olson and Schulz, who was a co-investigator in the study, urged them to consider different treatment options for her son, which would have disqualified him from the study. But the doctors were unconvinced by her pleas.

In particular, she wrote with strange prescience,

'Do we have to wait until he kills himself or someone else,' she asked three weeks before his suicide, 'before anyone does anything.'

There was evidence that Markingson was not getting optimal treatment

In retrospect, it was not even clear that Markingson was taking his study medications prior to his suicide:

An autopsy showed no medication in Markingson's bloodstream, and a coroner's photo showed a sealed bottle of his medication. Had he been taking his drugs?

Study officials could have been fooled. They only counted drugs left in pill bottles instead of testing blood levels in patients.

Suggestions that financial conflicts of interest influenced trial investigators' actions

The initial news article raised questions whether the study investigator had been unduly influenced to keep Markingson in the study by financial concerns:

CAFE was an early opportunity at the U for Olson to add research experience to his academic credentials. The U had recruited him in 2001 for his expertise in schizophrenia.

It was a slow start. Olson recruited one patient in 2002, and CAFE study leaders considered dropping him altogether, according to monthly recruiting summaries. Olson and the university had been dropped from a previous study because of low recruiting numbers, the doctor later said in his court deposition.

Exchanges between local and national study officials made it clear that there was pressure for results and a 'risk' that the study would be shut down if it didn't recruit enough patients.

Note that:

As Subject 13, Markingson was worth $15,000 to the U, with some of that going to Olson's salary and the psychiatry department. Switching or adding medications could have disqualified Markingson and halted payments to Olson and the department from AstraZeneca.

Overall, the study offered $327,000 to the U and an opportunity to raise the profile of its schizophrenia program.

An accompanying Pioneer Press article indicated that both Dr Olson, and the Chair of Psychiatry, Dr S Charles Schulz, were receiving considerable financial support from AstraZeneca and other pharmaceutical companies at the time of the study.

Olson received $220,000 from six companies since 2002, including $149,000 from AstraZeneca, according to the state records. Schulz received $562,000, including $112,000 as a researcher and consultant to AstraZeneca.

Olson said his AstraZeneca money went straight to the U but did support his salary. Markingson's full participation in the yearlong study meant up to $15,000 for the university.

Did the lawsuit's results indicate nothing was wrong?

Mr Markingson's mother sued the University of Minnesota and AstraZeneca, but (per the first Pioneer Press article),

The lawsuit ended this year after a judge ruled that the university had statutory immunity from such lawsuits and that AstraZeneca shouldn't stand trial because there was no convincing proof that its drug caused Markingson's death. Weiss settled with Olson, the only defendant left. She said she was granted $75,000, which went entirely toward legal bills.

Note that the results did not address the university's or its administration's role.

Dr Carl Elliott Takes Another Look

Thus the case appeared to end, with no real reconsideration of how medical schools' dependence on commercial funding of clinical studies, and how individual faculty members' financial relationships with drug, device, and biotechnology firms may affect research done on human beings.

However, in September, 2010, Mother Jones published an article by Dr Carl Elliott, a University of Minnesota bioethicist, which raised further questions about the case.

I talked to several university colleagues and administrators, trying to learn what had happened. Many of them dismissed the story as slanted and incomplete. Yet the more I examined the medical and court records, the more I became convinced that the problem was worse than the Pioneer Press had reported. The danger lies not just in the particular circumstances that led to Dan's death, but in a system of clinical research that has been thoroughly co-opted by market forces, so that many studies have become little more than covert instruments for promoting drugs

Major design defects of the CAFE study:

It barred subjects from being taken off their assigned drug; it didn't allow them to be switched to another drug if their assigned drug was not working; and it restricted the number of additional drugs subjects could be given to manage side effects and symptoms such as depression, anxiety, or agitation. Like many clinical trials, the study was also randomized and double-blinded: Subjects were assigned a drug randomly by a computer, and neither the subjects nor the researchers knew which drug it was. These restrictions meant that subjects in the CAFE study had fewer therapeutic options than they would have had outside the study.

In fact, the CAFE study also contained a serious oversight that, if corrected, would have prevented patients like Dan from being enrolled. Like other patients with schizophrenia, patients experiencing their first psychotic episode are at higher risk of killing themselves or other people. For this reason, most studies of antipsychotic drugs specifically bar researchers from recruiting patients at risk of violence or suicide, for fear that they might kill themselves or someone else during the study. Conveniently, however, the CAFE study only prohibited patients at risk of suicide, not homicide. This meant that Dan—who had threatened to slit his mother's throat, but had not threatened to harm himself—was a legitimate target for recruitment.

As Dr Elliott noted, this appeared to be yet another example of manipulation of clinical research designed to make the sponsors' products look better, a topic we have frequently discussed on Health Care Renewal:

A 2006 study in The American Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals, found that 90 percent of them came out positively for whichever company had designed and financed the trial. This startling result was not a matter of selective publication. The companies had simply designed the studies in a way that virtually ensured their own drugs would come out ahead—for instance, by dosing the competing drugs too low to be effective, or so high that they would produce damaging side effects. Much of this manipulation came from biased statistical analyses and rigged trial designs of such complexity that outside reviewers were unable to spot them. As Dr. Richard Smith, the former editor of the British Medical Journal, has pointed out, 'The companies seem to get the results they want not by fiddling the results, which would be far too crude and possibly detectable by peer review, but rather by asking the 'right' questions.'

This was likely what was going on with the CAFE study:

Although the documents unsealed in the Seroquel litigation do not specifically mention the CAFE study in which Dan was enrolled, they do suggest that AstraZeneca planned to establish Seroquel as the "atypical of choice in first-episode schizophrenia,' according to a 2000 'Seroquel Strate'y Summary.' A later document titled 'Seroquel PR Plan 2001' discusses the agenda for an advisory panel meeting in Hawaii. Among the potential topics were the marketing of Seroquel to first-episode patients, adolescents, and the elderly. The document refers to these populations as "vulnerable patient groups."

Even more alarming are internal documents suggesting that AstraZeneca was designing clinical trials as a covert method of marketing Seroquel. In 1997, when Dr. Andrew Goudie, a psychopharmacologist at the University of Liverpool, asked AstraZeneca to fund a research study he was planning, a company official replied that 'R&D is no longer responsible for Seroquel research—it is now the responsibility of Sales and Marketing.' The official also noted that funding decisions would depend on whether the study was likely to show a 'competitive advantage for Seroquel.'

Were study subjects protected?
So, as Dr Elliott wrote,

Many clinical studies place human subjects at risk—at a minimum, the risk of mild discomfort, and at worst, the risk of serious pain and death. Bioethicists and regulators spend a lot of time and energy debating the degree of risk that ought to be permitted in a study, how those risks should be presented to subjects, and the way those risks should be balanced against the potential benefits a subject might receive. What is simply assumed, without much consideration at all, is that the research is being conducted to produce scientific knowledge. This assumption is codified in a number of foundational ethics documents, such as the Nuremberg Code, which was instituted following Nazi experiments on concentration camp victims. The Nuremberg Code stipulates that an 'experiment should be such as to yield fruitful results for the good of society,' and 'the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.'

But what if a research study is not really aimed at producing genuine scientific knowledge at all? The documents emerging in litigation suggest that pharmaceutical companies are designing, analyzing, and publishing trials primarily as a way of positioning their drugs in the marketplace. This raises a question unconsidered in any current code of research ethics. How much risk to human subjects is justified in a study whose principal aim is to 'generate commercially attractive messages'?

Conflicts of interest
Of course, university faculty pushed to bring in more external funds to support their careers (see this post) by university leaders with their eyes on the bottom line may not be too critical of the intricate designs of the studies they need to do to continue their academic careers, and whether such studies are really meant to promote science and improve patient care, or position products in the marketplace, especially when the same companies are paying them as consultants, speakers, etc.

In fact, Dr Elliott found reasons to make such concerns specific to the case of Mr Markingson's untimely death:

Olson had another financial reason to maintain good relations with AstraZeneca. According to a disclosure statement for a 2006 conference, he was a member of the AstraZeneca 'speaker's bureau,' giving paid talks for the company. He had similar arrangements with Eli Lilly and Janssen, the makers of the other atypicals being tested in the CAFE study, as well as Bristol-Myers Squibb and Pfizer. In addition, Olson was working as a paid consultant for Lilly, Janssen, Bristol-Myers Squibb, and Pfizer.

Bioethicists Demand an Investigation

So eight University of Minnesota bioethicists, including Dr Elliott, wrote a letter to the University administration demanding an investigation, as reported in December, 2010, by the Minneapolis- St Paul Star-Tribune,

In a letter to the board Monday, the professors questioned whether U psychiatrists lacked ethical judgment in enrolling the victim, Dan Markingson, a schizophrenic who may have lacked the wherewithal to consent to research. They also questioned whether financial incentives from AstraZeneca, the drugmaker funding the study, presented conflicts for the researchers, Dr. Stephen Olson and Dr. S. Charles Schulz.

At the time, the administration promised a serious response:

U leaders will take the letter seriously and take the protection of human research subjects seriously, said the U's general counsel, Mark Rotenberg.

But then almost immediately indicated its bias:

'The fact that this is tragic doesn't mean the treating physicians did anything wrong,' he said.

What, Us Worry?

It did not take long for Mark Rotenberg to decide that there was nothing more to worry about. As reported in February, 2011, by the Pioneer Press:

in a Monday letter to Elliott and colleagues, the chairman of the U's board of regents wrote 'we do not believe further university resources should be expended re-reviewing a matter such as this, which has already received such exhaustive analysis by independent authoritative bodies.'

'Our general counsel has provided us with the extensive reviews of this case that were performed over the years by a number of independent experts and governmental units,' chairman Clyde Allen Jr. said in the letter. 'Each and every one of these reviews resulted in the same conclusion: there was no improper or inappropriate care provided to Mr. Markingson, nor is there evidence of misconduct or violation of applicable laws or regulations.'

Of course, since Mr Rotenberg is responsible for, among other things, reducing the university's legal liability, one could see how he might not want to delve further into this case.  As we noted earlier, it is not clear that previous "exhaustive" investigations asked the questions that needed to be asked, or had access to all the relevant data.  The issues are not whether their was criminal conduct, or even civil liability, but whether the university is presiding over good science and protection of research subjects?

So we should be worried, of course, that commercial firms sponsor research on human beings mainly to serve marketing objectives, and that university faculty and administrators go along, allowing their formerly prestigious universities' names to be added to the research in exchange for the money they so much want to keep themselves living in the style to which they are accustomed. We ought to be particularly worried when these universities seem to forget about their mission to find and disseminate new knowledge in favor of defending the work that continues to bring in the money.

Thus, physicians, researchers, patients, and the public ought to be very skeptical about clinical research sponsored by commercial firms with vested interests in the research turning out a particular way, and even about research not sponsored by such firms, but done by researchers who have personal financial ties to such firms. Worse, patients ought to be extremely skeptical about the motives of researchers who want to enroll them in trials when the researchers have financial ties to commercial firms whose products could be promoted through such trials, and especially when such firms are sponsoring the trials.

As a long-time advocate for evidence-based medicine, whose advancement depends on the continuing creation of valid research evidence from clinical research, it is heart-breaking to have to make these recommendations, but they will be necessary until there is better assurance that clinical research is being done to advance science and patient care, not the commercial interests of the sponsors and the researchers.

Until academic medicine becomes more open about how and why it is doing clinical research, such skepticism is warranted.

However, I will end with a ray of hope. If the administrators and faculty do not get it, the student journalists do. Read these words in an editorial in the Minnesota Daily:

Of course, the University has maintained neither it nor anyone involved in the case did anything wrong, an odd claim to make after the Minnesota Legislature unanimously passed a law that prohibits exactly what happened and named the law after Markingson.

The University seems to think that because it was not held liable in court for Markingson’s death, it did nothing wrong. This is false; it is a cynical excuse to keep corporate drug money flowing into the University.

The regents’ decision fundamentally undermines our mission: Supposedly, the University is 'dedicated to … the search for truth.' But the letter makes it clear that corporate research cash is more important to the University than patient safety and transparency.

Refusing to set up an independent investigation is a willfully ignorant attempt to sweep the Markingson case under the rug and damages the integrity of the entire University.

Perhaps it is time for the state legislature to take another look at this issue.

True health care reform would separate clinical research, that is, research done on human beings, from the commercial interests of health care corporations and the people who work for them.

ADDENDUM (18 March, 2011) - See this post by Naomi Freundlich on the Health Beat blog.

Conflicts of Interest in Clinical Research - Bold Thinking in the Journal of General Internal Medicine

The Joournal of General Internal Medicine has published a significant study and an important editorial on conflicts of interest affecting clinical research.

The article (Weinfurt KP, Friedman JY, Allsbrook JS et al. Views of Potential Research Participants on Financial Conflicts of Interest: Barriers and Opportunities for Effective Disclosure. J Gen Intern Med 2006; 21:901-906.) reported on research that used focus groups to question patients and prospective patients about their understanding of and preferences concerning disclosure of potential conflicts of interest (COI) affecting clinical research in which they might participate. Parenthetically, although the participants were given explanations of numerous species of COI, some significant ones were omitted, notably service by researchers on boards of directors of the companies sponsoring research, and conflicts affecting contract research organizations and for-profit institutional review boards (IRBs). The study produced some disturbing findings, particularly:

• Some participants were initially unaware that such conflicts could even exist.
• Participants found certain kinds of more complex financial relationships hard to understand even after considerable explanation.
• Some participants did not want to hear about conflicts because they were afraid doing so would remove their illusions that the researchers were trustworthy.
• Participants noted that extremely sick patients might be too desperate to care about COI.

The commentary (De Vries R, Elliott C. Why Disclosure? J Gen Intern Med 2006; 21: 1003-1004.) began with a discussion of some recent cases in which "financial interests have arguably placed subjects at risk." These included the TGN 1412 trial run by Parexel for the now bankrupt TeGenero (see our most recent post here), and trials run by SFBC International (see our most recent post here).

The editorial's summary of the effects of financial interests on clinical research was notable:

Medical research, once largely the province of academic researchers working in universities, has become a multinational corporate enterprise. Only about a quarter of clinical research now takes place in academic settings; academic researchers themselves have considerable financial ties to industry; and even the ethics review of clinical trials has become a major commercial enterprise.

How can a research subject be sure that the emphasis on 'return on investment' will not translate into a dangerous trial?

Summarizing the results of the study by Weinfurt et al, the editorial then suggested that "it is not irrational" for research subjects to "distrust disclosure as a remedy for conflicts of interest."

It then went on to summarize some recent research by cognitive psychologists. Cain and colleagues' experiments showed that disclosure of conflicts of interest did not lead those to whom the disclosure was made to be appropriately skeptical of advice provided by those with the conflicts. Even more important, after making disclosure, those with conflicts tended to say things that appeared even more biased by their own conflicts, as if "disclosure had given them moral license to exaggerate." The psychology researchers concluded "the solution to the bias created by conflict of interest is not simply to disclose the conflict, which makes bias even worse. Rather, the solution is to eliminate the financial conflicts."
So, "the important ethical question raised by conflicts of interest is not, as Weinfurt and his colleagues seem to assume, 'should researchers disclose?' but rather 'why has disclosure become such a popular way of managing financial conflicts of interest in medicine?'" Furthermore, "a more cynical explanation of the popularity of disclosure suggest that it is a 'remedy' for financial conflicts of interest that allows those conflicts to stay in place. Thus it does nothing to threaten the existing funding arrangements for clinical research."
Finally, "what is being overlooked here is the need to protect the welfare of potential research subjects. The real problem raised by industry-funded research is that the pursuit of financial gain might leader researchers to place subjects at risk in dangerous studies."

Bravo to the Journal of General Internal Medicine for publishing something so bold.

In my humble opinion, De Vries and Elliott are exactly right. Full disclosure, which is rarely practiced, might tell us about the extent of conflicts of interest affecting research, but it does nothing to manage these conflicts. The only real way to manage these conflicts is to eliminate them.

We need to drastically revise our system of funding clinical research. Clinical research should not be directly funded by, supervised, or implemented by organizations with a financial stake in the outcome. We need to develop a funding mechanism that funds clinical research as a resource that benefits all the people, and a cohort of researchers who will do their work well and honestly, devoid of financial arrangements with organizations that might benefit if their results turn out one way or the other.

Updates on Commercially Sponsored Drug Research: "A Morally Flimsy Foundation to Advance Medical Knowledge"

There are new developments in several stories we have been following about commercially sponsored drug research done on human subjects.

Studies on Ketek (Telithromycin) Done by Pharmaceutical Product Development for Sanofi-Aventis

We recently discussed how results of study of Ketek (Telithromycin) done by Pharmaceutical Product Development for Sanofi-Aventis may have been affected by misconduct, including one conviction for fraud, by some of the physicians paid to enroll patients. Although the results of this trial were never published, they have been cited in the clinical literature.

Now Reuters has reported that Sanofi-Aventis is in talks with the US Food and Drug Administration (FDA) about strengthening the warning label on the drug. A report from PharmaLive said that US Senator Charles Grassley (R-Iowa), chair of the Senate Finance Committee, is pressing the FDA for more information on how it handled the approval of Ketek. The letter said,

the Committee continues to investigate the extremely troubling allegations related to , among other things, the approval and post-market [sic] surveillance of telithromycin (Ketek) by the Food and Drug Administartion. One of the most troubling allegations is that the FDA approved Ketek with full knowledge that some of the clinical safety data supporting its approval was beset by systemic data integrity problems. While the FDA takes its time negotiating with Sanofi-Aventis to decide what drug risk information the public should know, it is completely mystifying why a fraudulant clinical trial is reference in safety information on the FDA's web-site.

The Disastrous Trial of TGN 1412 Done by Parexel for TeGenero

We have previously posted, most recently here and here, about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill. We had previously noted allegations that there was reason to think prior to this trial that TGN 1412 would pose risks to human subjects.

The BBC interviewed several experts who also felt that TGN 1412 should have been regarded as a risky drug from the outset. For example, it quoted Dr David Glover, "it may be that it [the adverse effect] was unpredicted by the tests that were done. I believe from the basic science it was predictable." Professor David Winter, of the Laboratory of Molecular Biology in Cambridge said that "those testing TGN 1412 may have been lulled into a false sense of security by the fact that it did not seem to harm monkeys - but it was wrong to make too many assumptions based on animal experiments." In response, TeGenero "said it was an 'oversimplification' to suggest that the side effects could have been predicted in advance."

Multiple Clinical Trials Done by SFBC International

We have posted before about the troubles of contract research firm SFBC International We started by posting about allegations that private, for-profit clinical research firms, including SFBC International, supervised by for-profit institutional review boards (IRBs), were doing sloppy and shoddy work. We then noted allegations that SFBC International had tried to threaten or intimidate research subjects who talked to reporters about such poor research practices. Furthermore, we discussed how a review commissioned by the company found that a top executive, Jerry Seifer, SFBC International's Vice President for Legal Affairs, threatened participants in clinical studies who had talked to the press with deportation. Seifer, it turns out, had been the subject of past regulatory sanctions by federal regulators. In addition, study participants in a trial of an immunosuppressant drug carried out by the firm's Canadian subsidiary, SFBC Anapharm, acquired tuberculosis after exposure to another participant with active disease, despite their complaints to Anapharm staff. More recently, we noted that Seifer had resigned, and the company's stock price had fallen. Finally, we noted allegations that 20 people, including trial participants and staff at SFBC International's Montreal facility acquired latent tuberculosis after exposure during trials.

Per Bloomberg News, SFBC International just announced it will shut down its facility in Florida that was the location of allegedly sloppy and shoddy research practices noted above. In fact, the Miami-Dade County Unsafe Structures Board gave the company 60 days to "file a permit to demolish its Miami facility.... The company said it would appeal the ruling and may file [for] an injunction." Bloomberg quoted Kenneth Goodman, Director of the University of Miami's bioethics program, who had toured the Miami area facility,

This is going to send a signal through the entire drug industry that human-subject protection is not a nicety or a courtesy, but a bold-faced moral and legal requirement.
What I saw was a research mill where vulnerable poor and uneducated people were being enticed into taking medical risks to make a living. That's a morally flimsy foundation to advance medical knowledge.

Summary

The cases of the Ketek trial, the TGN 1412 trial, and various trials done by SFBC International have rarely been juxtaposed, except on Health Care Renewal. However, their juxtaposition suggests

• Physicians and patients should be extremely skeptical of the results of drug research carried out by contract research organizations sponsored by pharmaceutical companies, since the design and implementation of such studies may not be what they seem. Other evidence that commercial research sponsors may manipulate the design of studies, the analysis of their data, and the dissemination of their results should only add to this skepticism (see most recent post here).
• People should be extremely wary about signing up as subjects for such trials, since their risks may be worse than they realize
• We ought to rethink the social desirability of the current relatively unregulated system of having human clinical research sponsored by commercial firms with interests in their results.

We are clearly on a "morally flimsy foundation to advance medial knowledge."

Nigerian Committee Criticizes Pfizer's 1996 Study of Trovan

The Washington Post reported on an investigation by a Nigerian committee on a drug trial done by Pfizer Inc. in that country in 1996. The trial was of the drug trovafloxacin (Trovan), an antibiotic whose the US Food and Drug Administration has recommended be restricted to patients with severe infections because of its high risk of liver toxicity.
The issues were:

Pfizer selected the patients at a field hospital in the city of Kano, where the children had been taken to be treated for an often deadly strain of meningitis.
Pfizer contended that its researchers traveled to Kano with a purely philanthropic motive, to help fight the epidemic, which ultimately killed more than 15,000 Africans.
Pfizer had told authorities that a Nigerian doctor directed the experiment. The committee, however, found that researchers from Pfizer's U.S. office controlled the trial, and the inexperienced Kano doctor, Abdulhamid Isa Dutse, was the principal investigator 'only by name.'
The panel said an oral form of Trovan, the Pfizer drug used in the test, had apparently never been given to children with meningitis. There are no records documenting that Pfizer told the children or their parents that they were part of an experiment, it said.
Dutse admitted that he created a letter after the experiment purporting to show that the test had been approved in advance by a Nigerian hospital's ethics committee. He then backdated the letter to March 28, 1996 -- a week before Pfizer's experiment began.
Pfizer used the letter as a key justification for the trial in discussions with reporters and submitted it to the FDA.
The Post previously reported that the hospital had no ethics committee in March 1996 and that the letterhead stationery used was not created until months after the experiment's conclusion.
The former director of Nigeria's version of the FDA said the agency had been unaware of the experiment. He told the panel that he viewed the conduct of the trial by Pfizer as an act of deception and misuse of privilege.'
The report said the treatment of two children during the experiment represented unspecified 'serious deviations' from the trial's protocol and concluded that those deviations compromised their care.
Pfizer's experiment was 'an illegal trial of an unregistered drug,' the Nigerian panel concluded, and a clear case of exploitation of the ignorant.'

Pfizer's response was,

Pfizer contended that its researchers traveled to Kano with a purely philanthropic motive, to help fight the epidemic, which ultimately killed more than 15,000 Africans. The committee rejected that explanation, pointing out that Pfizer physicians completed their trial and left while 'the epidemic was still raging.'
Executives at Pfizer, the world's biggest drug company, said they had not seen the report. After reviewing a copy, they responded in a two-page statement:
'The Nigerian government has neither contacted Pfizer about any of the committee's findings nor are we aware that the committee has approved a final report. Therefore it would be inappropriate for the company to respond to specific points in the document.'
'However, as we have stated repeatedly over the past several years, Pfizer conducted this trial with the full knowledge of the Nigerian government and in a responsible way consistent with Nigerian law and Pfizer's abiding commitment to patient safety.'

Why it took so long for this report to be made public is unclear.

The Washington Post recently obtained a copy of the confidential report, which is attracting congressional interest. It was provided by a source who asked to remain anonymous because of personal safety concerns.
Aspects of the affair remain mysterious, such as why the report remains confidential. The head of the investigative panel, Abdulsalami Nasidi, said in a brief telephone conversation from Nigeria, 'I don't really know myself' why the report was never released.
Dora Akunyili, director of the Nigerian drug control agency, said she did not know why the report remained confidential but added that her agency had independently concluded that 'these people did not have authority to conduct the trial.'

It sounds like Pfizer CEO Hank McKinnell (see related post here) has another big issue to deal with, albeit retrospectively. This story sounds another warning that physicians and patients need to be skeptical about how clinical research sponsored by commercial firms was actually implemented.
The Post further reported,

Last week, Rep. Tom Lantos of California, the senior Democrat on the International Relations Committee, described the report's findings as absolutely appalling' and called on Pfizer to open its records.
Lantos said he expected to introduce a bill requiring U.S. researchers to give regulators details of tests they plan in developing countries.

Maybe that would help, but problems with implementation of clinical research have obviously also occured in developed countries. (Some recent cases mentioned on Health Care Renewal were those of the US based study of telithromycin [Ketek], and the TGN 1412 calamity in the UK.)

What Did Parexel Tell the Participants in the TGN 1412 Trial?

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill. We recently reported an account of an interview with one of the participants which serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects (see post here).

Bloomberg news just reported on the consent form used in the trial, raising even more issue about what the participants were told or understood about what could happen to them. These issues are summarized below.

Risks Not Revealed - Bloomberg showed the form to several medical ethicists. Michael Goodyear stated, "they [the trial investigators] failed to to adequately disclose the degree of uncertainty around a first-in-man trial. The risks were well known. They were not disclosed in the consent form." Arthur Caplan, of the Center for Bioethics at the University of Pennsylvania, said, "they hid the most serious threats with bland language." Parexel countered only by saying that the UK Medicines and Healthcare Products Regulatory Agency (MHRA) "has done an exhaustive inquiry of Parexel and confirmed that the trial was run according to the approved protocol." However, Bloomberg noted "the agency says its investigation didn't include a review of the consent form."

Participants Questions Deflected - Bloomberg reported that study participant Raste Khan claimed that Parexel staff deflected questions, saying "we're in a bit of a push. Can you sign now, and I'll explain it all to you."

Proportion of Patients to Receive Placebo Not Explained - Khan also said, "They didn't tell us how many placebos there were, so I just thought it was 50/50." Caplan called this a "'major' ethical violation to withhold the actual chance of receiving the drug."

Drug Not Described Clearly in Lay Terms - The drug was described as "a 'monoclonal antibody,' which means that it is an antibody (a naturally produced protein) that has been designed by scientists to target a particular type of cell -- in this case, a type of white blood cell called T-cells.'' Caplan retorted, "I've read a lot of consent forms and I don't understand this." Goodyear noted that the consent form never clearly said what the drug would do, specifically never stating that the drug would stimulate the immune system, and suggested that comparing the drug to aspirin and ibuprofen was also misleading.

Adverse Effects Minimized - "Parexel's consent form says the drug, called TGN 1412, was designed to treat arthritis, other inflammatory illnesses and leukemia. The form says that 'no significant side effects had been seen in the animal studies.' "I think it was misleading not to tell participants that that this drug was genetically engineered from hamster cells and that it was designed to alter their immune system,"' commented Goodyear. "Reasonable people would think twice before allowing an experimental drug to change their immune system.''
Furthermore, the form described a cytokine burst as akin to hives. Goodyear responded, "Since monoclonal antibodies are know to cause Cytokine Release syndrome, which can be fatal, and Parexel was not even planning for this, the subjects should have been warned." Parexel's response, again was "the MHRA found no deficiencies during its inspection of Parexel's Phase I unit at Northwick Park Hospital that would have contributed to the adverse reactions experienced by the study volunteers.''

Possible Coercion - "Ethicists say the consent document exploited the participants' need for cash. The first page of the consent document says participants can leave the trial at 'any time without giving a reason and my rights will not be affected.'' On page 9, the document says, 'If you leave the study and exercise your right not to give a reason or are required to leave the study for non-compliance, no payment need be made to you.'
'That's very coercive language,'' says Greg Koski, 56, a physician and former head of the U.S. Office for Human Subject Protection, interviewed by phone April 5. 'It's a bait and switch.'"

Failure to Identify Ethics Committee Which Approved the Trial - " Parexel's TGN 1412 consent form omitted the name and contact information for the Brent Medical Ethics Committee, which approved the consent form and supervised the trial." Caplan noted, "The participant needs to know who to contact. There has to be a source of independent advice. They are defeating the entire purpose of having an ethics committee if you can't find it.'' The MHRA investigation did not cover the role of the ethics committee.

Referral to an Irrelevant Pamphlet - " Parexel's consent form advised subjects to read a pamphlet published by Consumers for Ethical Research, a London-based advocacy group. Naomi Pfeffer, chair of the organization, says the booklet shouldn't be used for healthy volunteers as it was written as advice to sick people considering treatment through a clinical trial."

Revelations about how Parexel failed to inform, or misinformed subjects in the calamitous TGN 1412 trial, coupled with previous reports about how SFBC International, another contract research organization, treated its trial subjects (most recent post here), suggest that commercial contract research organizations need to be much more closely regulated and supervised than they are now. And it may be time to question the whole notion of commercial firms doing clinical trials of drugs and devices.

Addendum (14 April, 2006): The Lancet just published a lead editorial that summarized the TNG 1412 trial, and concluded, "the TGN 1412 events indicate that urgest change is needed in the approval processes and regulation of phase I trials of biologic agents." [Anonymous. Urgent changes needed for authorisation of phase I trials. Lancet 2006; 367: 1214.]

The TGN 1412 Trial "Raises a Number of Big Red Flags"

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill (see our most recently here). The International Herald Tribune has done some investigative reporting on this trial.

First, the Tribune confirmed that TeGenero, the manufacturer of TGN 1412, was aware prior to the trial of the possibility that subjects might undergo "cytokine release syndrome" after taking the drug. This syndrome had apparently been observed in some animal testing, although the species of primates tested did not manifest the syndrome. TeGenero, however, felt that this reaction was "not expected," in the human trial.

The Tribune interviewed a survivor of the trial, who stated:

• He believed "he was participating in a fairly standard trial of a painkiller like ibuprofen, for arthritis."
• He said that "the novelty of TGN 1412 never came up in upbeat pre-trial briefing, adding: "I had no idea it altered the immune system.'"
• "At Parexel's orientation meeting there was little time to read the study's 11-page consent form before signing, Rob O. said. Headaches and bruising were listed as potential side effects, as well as the possibility of a severe allergy. But that risk was downplayed."
• Once the trial was underway, the investigators continued to dose subjects even after the first subjects had started to experience adverse effects. "About the time Rob. O's infusion started, at 9:10 am, the first patient had actually passed out in the adjacent room...." charged one of the subjects' attorneys.
• Since the trial, "the companies [TeGenero and Parexel] have been unwilling to meet with the trial subjects or provide more data...."

The Tribune quoted Dr Michael Ehrenstein of University College London, who said that human research on TGN 1412 was "a high risk strategy." Michael Goodyear, described as an oncologist and medical ethicist at Dalhousie University, Halifax, Nova Scotia, Canada, said that the conduct of the trial "raises a number of big red flags."
Nonetheless, Dr Ezekiel Emanuel, Chief of Clinical Bioethics at the US National Institutes of Health (NIH) , said "This is a terrible tragic event but so far I don't see any clear ethical problems." (Note that Emanuel formerly expressed indignation when the NIH made conflict of interest rules more stringent, so that his secretary would no longer be allowed to keep stock holdings in health care companies worth more than US $15,000, as noted in this post.)
In my humble opinion, this newspaper article raises further serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects.
Hopefully, further investigations will afford more transparency, and will lead to improved conduct of trials that put the interests of patients ahead of the imperative to "speed your product through clinical development." (The latter phrase is currently a promise made by Parexel on its web-site.)