Dan and his mom, Mary Weiss

This research ethics series uses the story of Dan Markingson’s participation in a clinical trial of anti-psychotic drugs at the University of Minnesota, his suicide 2004 while participating on the study, and subsequent events as a case study in which to explore various aspects of clinical trial conduct. In previous posts, I’ve looked at issues of “good clinical practices” and ethics: consent, investigator responsibilities and conflicts of interest. Then I examined the university’s response and then turned to the importance of careful documentation of consent. Next, I explained how I was transformed by Dan’s story from looking at it simply as an objective case lesson in clinical trial ethics, to an advocate for an independent investigation of the University of Minnesota. In a more recent post, I shared reactions to the announcement that Mark Rotenberg, the UMN’s General Counsel, was leaving Minnesota to assume a similar post, now as Counsel and Vice-President at Johns Hopkins University. Most recently, I have asked Dr. Jeffrey Lieberman, who was Principal Investigator on the CAFE and CATIE trials, to address concerns that have been raised about the ethics and conduct of that trial.

Remember when University of Minnesota General Counsel Mark Rotenberg proclaimed the University’s innocence, stating that Dr. Carl Elliott’s concerns “have been reviewed by Federal, State, and academic bodies over the last five years, including the FDA, the Hennepin County District Court, the Board of Medical Practice and Minnesota Attorney General’s office, and the University and its IRB?” Rotenberg insisted,  “None found fault with the University. None found fault with any of our faculty.”

Then we learned that the Board of Social Work, which issued the corrective action against Ms. Kenney, was represented by Assistant Attorney General Benjamin R. Garbe. (page eight) They cited her undertaking tasks beyond the scope of practice of a social worker—but this was clearly done with Dr. Olson’s knowledge and support. Still, the Principal Investigators, who are legally responsible for the conduct of the studies they supervise, have not been held accountable.

But there was this letter from Deputy Attorney General Michael Vanselow to Mary Weiss on May 17, 2005 that raised questions as to the credibility of Mr. Rotenberg’s claim, stating, “We are also willing to work with you and Jim Gottstein in regard to drafting some proposed legislation to address some of the systemic problems that contributed to your son’s death.” Such legislation was passed in 2009 and is known as “Dan’s Law.” This law prohibits recruiting most patients who are under a commitment agreement into clinical trials.

And remember when “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.”

The Board of the Regents, in a letter exonerating itself to concerned faculty, noted that the FDA, the Minnesota Attorney General and the Minnesota Board of Medical Practice had previously conducted investigations and reached the same conclusion. The Board deferred to Rotenberg, who again alluded to the AG’s office in his defense.

There’s one small problem with Rotenberg’s assertion that the Attorney General’s office had investigated the Markingson case and found no fault with the University—we now have definitive proof that never happened. In a just released letter to Dan’s mother, Mary Weiss, the Office of the Attorney General  confirms that it “has not made any independent investigation or determination regarding the care rendered to your son.”

In light of confirmation that Mark Rotenberg’s statements have been misleading, at best, perhaps it is time for President Kaler to rethink his defense of his General Counsel’s work and support an independent investigation.

Many ethicists, university faculty and concerned citizens—more that 2700—are calling on Governor Mark Dayton to appoint an independent investigation of psychiatry studies at the University of Minnesota. I explained my support for this here. You can add your support here.

Credits:

“Molecules to Medicine” banner © Michele Banks

photo of Dan and Mary courtesy Mary Weiss

Facets of the field

Kelly Hills (@rocza) was kind enough to call my attention to the guest post on SciAmMind by Jeffrey Lieberman, incoming president of the American Psychiatric Association (APA).

Frankly, I’m appalled by Lieberman’s post, especially as it was invited. Although masquerading as a reasoned critique, it is anything but that. Rather, the piece is self-promotional and condescending.

Rather than respond to critics of the APA’s new Diagnostic and Statistical Manual of Mental Disorders, aka DSM-5, the Bible of psychiatry with sound arguments, Lieberman stoops to disparaging characterizations of critics as “real people who don’t want to improve mental healthcare,” and that he, as  Professor and president-elect of the APA, is in a far better position to understand and solely make decisions.

Besides that it contained no data or sound arguments to his critics, the fact that Lieberman failed to disclose his own extensive conflicts of interest is quite telling, and precisely why the field of psychiatry is getting such a bad name.

I am not anti-psychiatry. I have seen the good that can come both from medications that are used judiciously and monitored carefully, and of different “talk,” insight-based therapies.

Over my decades of internal medicine practice, I have seen a shift in psychiatry that appears largely driven by reimbursement constraints and by heavy pharmaceutical detailing. Psychiatrists—and other physicians—are not reimbursed for listening carefully to patients, a time-consuming but ultimately cost-effective technique. They are paid by volume of patients seen and procedures performed, and in the case of psychiatry, effectively for medications prescribed.

To respond more specifically to Dr. Lieberman’s  assertions:

To characterize critics as “misguided and misleading ideologues and self-promoters who are spreading scientific anarchy” is rather ironic, given that it is psychiatrists who have the financial gain through promoting their field and by periodically changing the ground rules. In fact, even the DSM manual is a cash cow for the APA, costing $199 per copy. New diagnoses and coding are also opportunities to sell ancillary products, be it billing software or coding classes, as happens in some other specialties.

Dr. Lieberman complains whiningly, “No other medical specialty is targeted by such an ‘anti’ movement.” He continues, “Being ‘against’ psychiatry strikes me as no different than being ‘against’ cardiology or orthopedics or gynecology.” 
Yes, Dr. Lieberman, psychiatry is different. These other specialties, in most cases, are far more evidence based, with more readily measured outcomes.

Lieberman then asserts, in an arrogant and offensive tone, “Like most prejudice, this one is largely based on ignorance or fear–no different than racism…many people made uncomfortable by mental illness and psychiatry, don’t recognize their feelings as prejudice. But that is what they are.”
 No. Instead, having no personal gain at stake, others are looking at psychiatry more objectively than you. We are looking for data, for evidence, and are listening to the growing numbers of patients saying that they have been harmed by medications—meds often forced on them by the medical-legal system.

As Duke University’s Dr. Allen Frances notes in the Annals of Internal Medicine, “Psychiatric diagnosis is facing a renewed crisis of confidence caused by diagnostic inflation.”
 Critics are also fueled by psychiatry’s attempts to medicalize normal human behavior, such as grief.  Such efforts fly in the face of commonsense and inspire ridicule.
 Dr. Frances concludes, “These changes will probably lead to substantial false-positive rates and unnecessary treatment. Drug companies take marketing advantage of the loose DSM definitions by promoting the misleading idea that everyday life problems are actually undiagnosed psychiatric illness caused by a chemical imbalance and requiring a solution in pill form. This results in misallocation of resources, with excessive diagnosis and treatment for essentially healthy persons (who may be harmed by it) and relative neglect of those with clear psychiatric illness (whose access to care has been sharply reduced by slashed state mental health budgets).”

Even the Director of the National Institutes of Mental Health (NIMH), Dr. Thomas Insel, has rejected the DSM, stating:
“The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment.
Patients with mental disorders deserve better…NIMH will be re-orienting its research away from DSM categories.”
Conflicts of Interest

Let’s look at who stands to gain by the new DSM.
 First, there is the product itself. While I never thought I would agree with anything on Fox News (yes, this reveals recognition of my own bias), Dr. Ablow, in Be Wary of the APA, said of the new criteria, “But those labels aren’t driven just by science, but by political, economic and commercial forces within the American Psychiatric Association that may have nothing to do with the wellbeing of patients – or with reality.  
The labels in the DSM-V (like the Diagnostic and Statistical Manuals that came before it) have really become little more than the roadmap by which psychiatrists chase both insurance reimbursement and applause from special interest groups who lobby—sometimes very effectively—for one diagnosis to be included, or another to be removed.”

And Dr. Frances chides, “I believe that the American Psychiatric Association (APA)’s financial conflict of interest, generated by DSM publishing profits needed to fill its budget deficit, led to premature publication of an incompletely tested and poorly edited product. The APA refused a petition for an independent scientific review of the DSM-5 that was endorsed by more than 50 mental health associations. Publishing profits trumped public interest.

 New psychiatric diagnoses are now potentially more dangerous than new psychiatric drugs, because diagnostic expansions may lead to drug company promotions that dramatically increase the use of unnecessary medications, with high cost and potentially harmful side effects.”

Dr Lieberman states that the panel recommending the new APA definitions was carefully vetted and lacked conflicts of interest. The standards for claiming financial purity are pretty low:
 the amount they could receive from drug companies was set at $10,000 a year and  stock holdings to $50,000, excluding research grants, were allowed.

Tufts and Harvard researchers found that 57 per cent of the APA work groups drafting the manual – had links to industry. 
I know. They are just prejudiced against psychiatry. Such examination is a witch hunt.

Perhaps the most egregious  statement in Lieberman’s opinion piece occurred when he referred to prior ethical lapses and barbaric treatment of patients, saying dismissively, “However, that was then and now is now.”

Yes, Dr. Lieberman, now is now, and ethical lapses are still occurring. I have spent months following up on information from Dr. Carl Elliott and writing substantive, well-documented posts, such as that on why I now call for an investigation of the UMN Department of Psychiatry, on Conflicts of Interest and the whole series on Dan Markingson’s death, still in progress.

Surely you are aware of the controversy surrounding the UMN’s Department of Psychiatry, and particularly around conduct of the CAFE and CATIE studies. After all, you were the Principal Investigator on these multi-center studies. Are you in denial as to the ethical breaches that occurred on this study?

Why didn’t you mention in your article that you were the PI on the study that Dr. Carl Elliott, I, and others, have been criticizing?  Didn’t you feel that was relevant, or that readers would know what to make of that information?

Only buried in the fine print is mention of your research on schizophrenia and anti-psychotic medications. And even the fine print doesn’t happen to mention your having received research grants from: Allon; GlaxoSmithKline; Janssen Pharmaceutica Products, L.P. (US); Merck & Co., Inc; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Sepracor Inc.; Targacept 
Served on the advisory board for: Bioline; GlaxoSmithKline; Intra-Cellular Therapies, Inc.; Eli Lilly and Company; Pierre Fabre; Psychogenics; Received patents from: Repligen Corporation

You ask why there is mistrust of psychiatry and psychiatrists? You, sir, have just answered that by your omissions and by your undocumented attacks on your critics.

Do you believe the more than 2500 signatories, including those of three former editors of the New England Journal of Medicine, a former editor of the British Medical Journal, the editor of the Lancet, and numerous scholars from all over the world, are just prejudiced against psychiatry, when they ask for an investigation of UMN’s Department of Psychiatry by Minnesota Governor Mark Dayton?

Conclusion

So many symptoms are now being medicalized, even absurdly, grief. It makes me wonder if there a DSM 5 diagnosis for someone who is self-serving, can’t accept criticism, and believes critics are prejudiced bigots?

I was very disappointed to see Dr. Lieberman’s shallow, self-serving and evidence-free diatribe appear in Scientific American as a guest opinion. He failed to reveal important conflicts of interest. He made serious claims for which he presented no evidence. He has made thinly veiled personal attacks on his critics, without offering anything substantive to counter rationally. Dr. Lieberman has failed to offer any evidence to refute assertions that Dr. Elliot and others have made, on a point by point basis.

Dr. Lieberman, instead of  publishing evidence-free attacks on your critics, I  invite you instead to respond point-by-point to Dr. Carl Elliott’s well-documented assertions regarding ethical lapses and other problems  in the CAFE and CATIE trials, on which you were the lead investigator.

Credits:

Psychiatry tag cloud – Scrag/wikipedia

“Molecules to Medicine” banner © Michele Banks

Bristol Stool Chart

This weekend, the proverbial s**t hit the fan over the Food & Drug Administration’s (FDA) decision to require an Investigational New Drug (IND) application for stool transplants—formally known as “fecal microbiota transplants (FMT)”—for the treatment of C. difficile colitis. “C. diff,” as it is known, is a severe inflammation of the bowel complicating treatment of other infections with antibiotics or treatment with chemotherapy.

There have been excellent discussions of this issue by Maryn McKenna, Mike Edmond and a twitter exchange this weekend with Eli Perencivich (@eliowa), Carl Zimmer (@carlzimmer), Amesh Adjala (@AmeshAA, myself and others, captured in Maryn’s Storify. But once again, as an experienced infectious disease clinician, I’d like to weigh in on the impact of the FDA’s decision, as I can offer a different perspective.

Over the last 10 years of my practice, I saw a change in the patients I treated for C. diff. More patients were affected, they were generally more severely ill, and the infection became increasingly difficult to treat. It went from responding to a brief course of Flagyl (metronidazole), to more prolonged and very expensive courses of oral Vancomycin, to the infection now often being refractory to therapy.

Treatment with stool transplants, while not commonplace, was more often entertained for patients with chronic and recurrent infections. In the past several years, I began to see more patients who relapsed despite prolonged oral Vancomycin, and who became very debilitated and unable to recover from their other infections and illnesses, due to the severe and persistent diarrhea. I also began to see patients floridly septic from C. diff, occasionally needing emergency surgery to remove their colon (colectomy).

It is these severely ill patients who changed my thinking about this illness and caused me to wonder whether we shouldn’t be treating severe cases of acute C. diff with stool transplants. I reasoned that it was a better alternative to an emergency colectomy.

Others appear to have had the same idea, and there are now occasional case reports about using FMTs as first-line treatment^⁠. There are barriers to doing so, however:

First, there is the “ick” factor. Thus far, resistance to transplants I have recommended has not come from patients or their families, who are desperate for relief. It has come from other health care workers, especially physicians, who seem to find the idea particularly distasteful.

There is cost and time—while the “medicine” is inexpensive and readily available, current recommendations are that the stool donor be tested for a variety of infectious diseases at a cost of $1500-2000.^⁠ There might be a week’s delay, while the donor is tested for hepatitis and other infections, particularly if the need arises at a community hospital that relies on sending out specimens for lab testing.

And now there is the new FDA requirement for an IND, which will be the coup de grace for this treatment.

The FDA has now decided that stool transplants, colloquially known now as “FMT” to not offend sensibilities, meet the definition of a biologic therapy and therefore fall under their regulatory purview. Because it is not an approved therapy, they will now require an IND be submitted for each proposed use.

Except perhaps for academic settings with an extensive infrastructure, INDs are incredibly burdensome, time-consuming, and expensive for an independent practitioner to obtain. They involve hours of paperwork (my office practice consisted of me and 1-1.5 secretaries; who has time?).

Unresolved questions

Yes, there are many questions involving FMT that do warrant further study. For example, what is the best diluent for the stool? Saline or water or milk or other? What is the most efficacious route of administration—colonoscopy vs enema vs nasoduodenal tube?

Ironies

There is better efficacy data for this FMT treatment than for many things that we do to our patients. In fact, according to a freshly released article in Clinical Infectious Diseases^⁠, “Ninety-two percent of patients experienced resolution, 89% after a single treatment, and 5% after retreatment due to failure or relapse.” Some studies have reported even better results, up to 94%.^⁠

As Boston Infectious Disease expert Dr. Paul Sax notes: “A person struggling with C diff can walk into any pharmacy, Whole Foods, Trader Joe’s, GNC, etc, and spend a small fortune on various probiotics, the efficacy of which is marginal at best.”^⁠

Similarly, stem cell “treatments,” which are far more dangerous and expensive, are unregulated, and deserve considerably more attention from the FDA. The same holds true over probiotics and many “nutritional supplements” with widespread advertising to patients.

I have done clinical research in a variety of settings and am all too familiar with both with the labor involved in completing an IND and the FDA’s admirable goal of improving patient safety. I admire their intent, but believe their efforts are seriously misplaced here. Frankly, having been immersed in reading about clinical research ethics scandals, particularly at the University of Minnesota’s Department of Psychiatry, my gut reaction to the news of the IND requirement was, “Doesn’t the FDA have anything better to do?” Wouldn’t their efforts be more likely to result in improved patient outcomes if they looked first at areas where there is evidence to suggest that known problems exist?

I think it is reasonable for the FDA to provide guidance and to try to collect data in some standardized format so that we can learn more about best approaches. My understanding is that individual physicians will have to develop and submit their own plan for treatment—which is both burdensome and will not result in any generalizable conclusions. While the FDA says that in emergencies, physicians can seek urgent approval, rather than wait for a 30 day turnaround time on their IND submission, in practical terms, this isn’t going to happen.

At a minimum, I would suggest the FDA exclude non-academic/non-research centers from the IND requirement, or centers that want to perform less than X number of procedures per month. They should also exclude attempts at emergency use of FMT from burdensome IND submissions.  Perhaps they could develop, with clinicians, a simple data checklist or CRF, which needn’t be more than 1 page, and would gather standardized data for analysis of otherwise anecdotal treatments.

Otherwise, physicians will increasingly give patients directions for home do-it-yourself (DIY) treatments, which families can administer to patients in the privacy of their homes. But then the sole data will come from some ambitious citizen science group, and acutely or seriously ill hospitalized patients, too ill to be treated at home, will be deprived of potentially life-saving treatment.

Then, the FDA’s stated goal of patient safety will sadly backfire, and result in unnecessary patient deaths.

Credits:

Bristol Stool Chart mug courtesy Butt Fudge Sundae

“Molecules to Medicine” banner © Michele Banks

Editorial control

On Mother’s Day, May 12, ethics Professor Carl Elliott had an Op-Ed published by the Minneapolis Star Tribune, “The University of Minnesota Research Case Needs Scrutiny.”

The Star Tribune began to post comments, the first being:

Minnesoda73 May. 12, 13 6:10 PM

The University of Minnesota has investigated itself and found itself innocent. It has nothing to gain by doing this. When the UM makes a mistake, it always does the right thing. Stop the U bashing.

A bit later, there was:

meegwichMay. 13, 13 5:06 AM

I’m confused; the principal investigator of the drug study treating the young man worked at the UMN, for the UMN. The young man was only treated under the drug protocol at the University and after his death the doctor settles a malpractice suit filed against him by the young mans mother but the University walks because they claim immunity. Then, the doctor claims that as a state employee of the University he’s entitled to immunity from punitive damages from the malpractice settlement because the state doesn’t allow employees to pay punitive damages even when they’re warranted. So how can the psychiatrist settle a malpractice suit and admit fault, all the while working at the U-MN, and the U can’t find any wrongdoing. How does the U explain the psychiatrist settling a malpractice suit in the death of his patient, and they can’t find a thing wrong.

And then:

luxaeternaMay. 13, 13 8:50 AM

The case was investigated by the MN Attorney General, the MN Board of Medicine, and the Federal Government (FDA). They found no wrongdoing on the part of the U. How many more investigations are needed?

Since I pride myself on now knowing a bit more about this case than the average Joe, after seeing some of the ignorant comments, I thought perhaps I could provide some clarification. I promptly wrote this response, which I publish here, as the Star Tribune has refused to publish it:

“Governor Dayton,

I could not agree more with Dr. Carl Elliott and the Markingson family’s plea that you appoint an independent panel to investigate apparent ethical breaches at the clinical research program of the UMN’s Department of Psychiatry.

Since December, 2012, when I first began to explore the case in depth, I have been increasingly appalled by the numerous ethical breaches that have been uncovered. My own research on the case, studies of documents, and interactions with the UMN General Counsel’s office has transformed my perspective from a totally objective, journalistic and academic orientation to that of advocacy to not only correct this particular injustice, but likely similar breaches involving other vulnerable patients in UMN studies.

In my series at Scientific American, “Molecules to Medicine” column, I’ve looked at issues of “good clinical practices” and ethics: consent, investigator responsibilities and conflicts of interest. Then I examined the university’s response and then turned to the importance of careful documentation of consent. Next, I explained in some detail how and why I was transformed by Dan’s story from looking at it simply as an objective case lesson in clinical trial ethics, to an advocate for an independent investigation of the University of Minnesota. I then shared my dismayed reaction to the announcement that Mark Rotenberg, the UMN’s General Counsel, was leaving Minnesota to assume a similar post, now as Counsel and Vice-President at Johns Hopkins University. Most recently, I posted an essay in memory of the anniversary of Dan’s death.

I have no doubt that Dr. Elliott will continue his research and writing about the UMN. I know that I will, too, because although it is time-consuming and at times tedious, I write a lot about clinical trial ethics and there is a lifetime of learning to be had here. Most importantly, seeking justice on this case is the right thing to do.

Governor Dayton, part of my appeal to you is because of the brush off I got not only from the UMN Counsel’s office, but more unexpectedly and disappointingly, from the Minnesota Attorney General’s office.

I understand that the UMN has powerful lobbying groups and brings in a great deal of money to the state. The question is, how much blood do they have to have on their hands before anyone in power in Minnesota will step up and do the right thing. There appears to be a cult-like culture at UMN reminiscent of that seen at Penn State with the cover up of their sex abuse scandal. We all know how that came down.

The cat’s out of the bag on this one. When you have a petition calling for an investigation signed by “nearly 2,500 people, including three former editors of the New England Journal of Medicine; the editor of the Lancet; a former editor of the British Medical Journal, and the former health and disability commissioner of New Zealand,” as well as “More than 200 experts in medical ethics and related disciplines [who] also have signed, including six members of the Institute of Medicine and the medical historian who uncovered the Guatemala syphilis studies, which resulted in an apology by President Obama in 2010,” you should know this issue is not going away.

Furthermore, critics of Dr. Elliott should recognize that he does not stand alone, given the array and caliber of people supporting this request for an independent investigation.

So Governor Dayton, please stand up and do the right thing—for Dan Markingson, for other vulnerable patients generously offering to help clinical research, and for your state. Appoint an independent panel to investigate not only this case, but the related breaches in good clinical trial conduct.

“Never doubt that a small group of thoughtful, committed citizens can change the world; indeed, it’s the only thing that ever has.”  Margaret Mead

The story gets considerably weirder from here, as was reflected on twitter yesterday:

Judy Stone ‪@DrJudyStone

@StarTribune. I tried submitting a response to bit.ly/12ukXTq and can’t tell if it got through. Suggestions? Alt address? Thx

Carl Elliott ‪@FearLoathingBTX

@DrJudyStone @StarTribune Lots of people (including me) having comments blocked on this article. What’s the story?

Carl Elliott ‪@FearLoathingBTX

Four people have emailed me to say their comments on my @StarTribune op-ed were blocked. I sense a pattern. Can’t even get my own published.

Leigh Turner ‪@LeighGTurner

@FearLoathingBTX@StarTribune My comment wasn’t posted. Still waiting…

@drjudystone my comment wasn’t posted either—

Judy Stone ‪@DrJudyStone

@FearLoathingBTX @AliceDreger @StarTribune My comments are neither vulgar nor libelous and reflect what I have written in @sciam. #gagged

Alice Dreger ‪@AliceDreger

@StarTribune Please note your comment moderator is blocking legit comments, picking and choosing, not following your stated policy. Thanks.

Judy Stone ‪@DrJudyStone

Hey @StarTribune: You’ve posted some ignorant resp to bit.ly/10m7j61 Why haven’t you posted my researched response or ans e-mail?

Billiam James ‪@billiamjames

Selective Reporting = Biased Results+Bad Conclusions. Why? @StarTribune @FearLoathingBTX @DrJudyStone @deborahblum @yobluemama2 @AliceDreger

Carl Elliott ‪@FearLoathingBTX

@DrJudyStone @StarTribune I emailed your comments to the opinion page editor, again without success.

Alice Dreger ‪@AliceDreger

@FearLoathingBTX @DrJudyStone @StarTribune What’s that old saying? Just because you’re paranoid doesn’t mean they’re not out to get you.

Judy Stone ‪@DrJudyStone

@AliceDreger @FearLoathingBTX @StarTribune Add “Hell hath no fury like a woman scorned.” … or who lost her only son in #UMN clinical trial

While episodically tweeting my frustrated messages, I also tried several times to e-mail the Star Tribune. I got this response:

“If you have not heard from us further within 10 days, feel free to place your material elsewhere. (If timeliness is a factor, we will do our best to take it into account.)”

This am, I received a polite note informing me they would not publish my response to Dr. Elliott, essentially as they did not feel it added anything to the dialogue.

I bring this to your attention because, rather than educate readers and engage them with intelligent conversation and stimulate a healthy exchange about the University’s behavior, the Minneapolis Star Tribune missed a huge opportunity. Whether intentional or not, they appeared to be selectively censoring comments supportive of Dr. Elliott throughout the day, only posting them after considerable ill will had developed, including multiple e-mails to their op-ed department and biting back and forth on twitter. All of this makes the paper look bad and fuels suspicions about the University, which are already growing.

So @StarTribune, if you want to really contribute substantively to the discussion about the UMN’s Department of Psychiatry and help both your community and your paper’s stature, put an investigative reporter on this story. There is so much more serious reporting to do–and so many unanswered questions. Maybe you’ll win a Pulitzer.

And readers, you can find the petition asking Governor Dayton to appoint an independent investigation of apparent research misconduct at the University of Minnesota here.

Credits:

Censorship image: Andréia/Flickr

“Molecules to Medicine” banner © Michele Banks

Angel of Grief

This research ethics series uses the story of Dan Markingson’s participation in a clinical trial of anti-psychotic drugs at the University of Minnesota, his suicide 2004 while participating on the study, and subsequent events as a case study in which to explore various aspects of clinical trial conduct. In previous posts, I’ve looked at issues of “good clinical practices” and ethics: consent, investigator responsibilities and conflicts of interest. Then I examined the university’s response and then turned to the importance of careful documentation of consent. Next, I explained how I was transformed by Dan’s story from looking at it simply as an objective case lesson in clinical trial ethics, to an advocate for an independent investigation of the University of Minnesota. In the most recent post, I shared reactions to the announcement that Mark Rotenberg, the UMN’s General Counsel, was leaving Minnesota to assume a similar post, now as Counsel and Vice-President at Johns Hopkins University.

Today is the 9th anniversary of Dan Markingson’s death. No matter the year, the yahrzheit (as known in my tradition) always seems to grow in oppressiveness as the day approaches, like a summer thunderstorm, and then there is release and scent of fresh air and renewal. It is, for many, a time of deep reflection, as one tries to find meaning in the death and loss.

I have never met Mary Weiss nor Mike Howard, Dan’s family, yet as I have learned and written about Dan’s tragic death at the hands of the University of Minnesota, I feel like I have come to know them on some deep level.

I struggle with my own losses. It is at these times that I envy those who believe in an afterlife and being reunited in a “better” place, something that is incomprehensible to me. I am comforted, though, by rituals, and the rhythm of seasons and nature. . .by some readings, and by contemplating legacies.

As I write this, I flashed back to a powerful story I heard on NPR many years ago, called “Shattered but Still Whole.” It was recounted by Saki Santorelli at a meditation workshop I attended and in his book Heal Thy Self.

“Next we hear about a sculptor. A large, powerfully built man who fabricates and welds metal, building huge and sometimes towerlike structures. We find out that this sculptor lost his leg some years ago, is unable to wear a prosthesis, and continues to sculpt with one leg. He is asked if his work now is different from when he had two legs. The man responds clearly, deliberately. “This is what I do now. This is normal.” We come to find out that this sculptor has been chosen to create the centerpiece of the exhibit. He has sculpted a sphere out of stone, perhaps marble or granite. We are told that it was perfect, with an uninterrupted, smoothly polished surface. After the sphere was completed, the artist smashed it, then put it back together with bolts, metal fasteners, and bonding agents. Now–full of fractures–it is sitting in the middle of the gallery, in the middle of America, labeled SHATTERED BUT STILL WHOLE.”

The only book about death and grieving that ever touched me was Naomi Levy’s “To Begin Again.” She encourages us, “No matter what we have lost in our lives, there is always something that survives to start over with. There is always some shard, some shred of hope, some way to begin again.” And she, too, talks about our lives being shattered, asking, “What are we to do with the broken pieces of ourselves? All too often we try to ignore them, deny them, or obliterate them, never realizing that they will be with us for the rest of our days on this earth. We try to bury our shattered parts because we see them as a sign of weakness, as a painful reminder of our vulnerability. But our broken pieces are a seat of wisdom and insight and compassion within us. They are holy and sacred and ought to be preserved.”

So Mary’s life has been shattered by the death of her only son. There is no sense to be made of this.

The only thing that we can offer this mother, still grieving, is that Dan has left a legacy. Although Dan died 9 years ago, his memory and lessons from his death are not fading. Instead, there is a growing sense of outrage. There is now a petition to Governor Mark Dayton calling for an independent investigation of the University, which has garnered almost 2500 signatures, including those of three former editors of the New England Journal of Medicine, a former editor of the British Medical Journal, the editor of the Lancet, and numerous scholars from all over the world. I hope that Dan’s family will find some small consolation knowing that his story has reached thousands, all over the world, and that the lessons of his tragic death in this clinical trial—which seems so unethical to many—are being used to inform numerous students of research and ethics.

As Robert Kennedy said, not that long before his tragic death, “Each time a man stands up for an ideal, or acts to improve the lot of others, or strikes out against injustice, he sends forth a tiny ripple of hope, and crossing each other from a million different centers of energy and daring, those ripples build a current that can sweep down the mightiest walls of oppression and resistance.”

Mary, have hope. Dan’s legacy is growing and will have a lasting impact. It already has.

To take action:

Sign the petition to Governor Mark Dayton calling for an independent investigation of the University on Change.org, via the hyperlink.

Dr. Carl Elliott has generously offered to educate groups or classes about bioethics and this case. He can be reached at the Center for Bioethics.

Credits:

Angel of Grief image Scott Loftesness

“Shattered but Still Whole,” courtesy Saki Santorelli, from Heal Thy Self

Yahrtzeit candle – Elipongo/wikimedia

“Molecules to Medicine” banner © Michele Banks

Roller coaster

Of the roller coaster of emotions that has marked the past few weeks, personally and for the nation, one talk at TEDMED tied them all together for me, with the theme of our interdependence and how much we can accomplish if we work together.

I’d like to share with you several seemingly unrelated events, with a commonality that crystallized for me at TEDMED.

Preface: For me, this chapter started a little earlier, with a late night call that my daughter had fallen and was in an Emergency Room several hours from where I live. Fortunately, a friend went with her, and then my brother and her housemates got her back home and carried her in…along with her x-rays, which she was able to transmit to me. I’m an Infectious Disease doc, yet even I recognized that her shattered ankle would need prompt surgery; the other may soon. The poor judgment of the ER to discharge someone with bilateral ankle fractures, who was unable to bear weight, to a handicapped-inaccessible house with no one to care for her was impressive. So much for ensuring a safe discharge plan, and looking at patient’s needs in a holistic context.

So my husband and I drove to the big city, he and her friends carried her down the stairs and laid her on a mattress in the back of our van, and we drove her to Cumberland. We had strong, generous friends who met us here to help unload her. With knowledge gleaned from my patients and practice, and my husband’s creativity, we were able to cobble up a hospital room in our living room, including a hoist, since she was totally non-weightbearing. Our daughter promptly had surgery  by an excellent team at an independent surgicenter. It was a good experience and reminded me of the sense of community I used to have here—before a hospital merger destroyed that. (The old Memorial Hospital where I had my practice was a secular community hospital with a grassroots, non-hierarchical, collaborative feel. It merged with Sacred Heart some years ago, adopting an authoritarian, top-down management style, among other changes. There was considerable concern about the imposition of Catholic religious directives on care in the entire rural region. The merger divided the community and led to an exodus of physicians and nurses from the health system, myself included. Some of those disillusioned with the Western Maryland Health System have opened independent surgicenters, giving patients a welcome option for health care).

With great ambivalence, I then left home to fulfill my patient care commitment at a Pittsburgh area hospital, torn between maternal concern and professional obligations—an unresolved conflict for many working mothers.

~ ~ ~

Team Todd Leukemia logo

Another tragedy struck the week before TEDMED, when a close family friend died of Acute Lymphoblastic Leukemia. We’d known Troy Todd for almost 30 years, since he was a teen; he helped build our home and care for our young children. There was a tremendous outpouring of support in the community for Troy and his family, with several fundraisers; everyone loved him. At his funeral, the Pastor’s eulogy was “Can a UPS driver change the world?” The answer was resounding. One of Troy’s friends described him as “someone who just didn’t do their job but actually cared about people. He remembered everyone’s names, Remembered everything about our family, and never complained about delivering our heavy packages to the top floor. Troy was encouraging and infectious….you wanted to smile because he was smiling. He never missed a beat!” But the young Vicar recounted Troy’s most hopeful legacy. In this community of ~20,000, there were three bone marrow drives, and 278 people signed up in a bone marrow donor registry. While no match was ever found for Troy, his most fervent wish was that he would help find a donor to save someone else’s life.

~ ~ ~

Fast forward to the shock of the Boston Marathon bombings with the juxtaposition of the horror of the carnage in our midst and the heroism and generosity of bystanders, other runners, and first responders. Stories continue to emerge of acts of kindness and courage, as well as the remarkable skill of the medical and surgical teams at the Boston hospitals.* That there have been no further deaths is astonishing.

Eli Beer/United Hatzalah

And from that, I had a sudden rapid immersion in the whirlwind of thought provoking, glitzy talks at TEDMED. I liked the conference much more than last year—and will have more to say about specific sessions shortly. But one of the last sessions brought it full circle for me. Brazen Eli Beer spoke of the successes of the Israeli emergency response system, United Hatzalah (Rescue). This is a volunteer response network that has an impressive response time of only 3 minutes—and now has a goal of reducing that by half, to just 90 seconds. The volunteer medics (all EMTs, paramedics, MDs) are equipped with ambucycles —specially equipped motorcycles—rather^⁠ than relying on ambulances.^⁠ The cycles are fast, maneuverable, and well-equipped with emergency medical equipment, enabling EMTs to arrive and initiate emergency care well before the average of 12-15 minutes for an ambulance. With perhaps typical modesty, Beer notes describes his “lifesaving flash mob:” “Our response is the fastest in the world. We call our approach a lifesaving flash mob. On motorcycles, traffic doesn’t stop us. Nothing does.”

NowForce LifeCompass

The underlying technology enabling the efficient, rapid response was also quite impressive. Using cell phone GPS, dispatchers are able to send alerts out specifically to the 5 closest EMTs to an accident—and can even identify specific volunteers with the requisite level of expertise to send.^⁠ They treated more than 200,000 people last year; 42,000 had life-threatening conditions.

~ ~ ~

The response to the Boston Marathon bombing, on an individual and community level, brought out the best in our country.

When I see the broader political response of fear-mongering, hate-filled anti-immigrant rhetoric, I am sickened. It is the same with calls to dispense with the Constitution and civil liberties under the guise of enhancing “security.” And even more so with Congress and the draconian cuts to Head Start, aid for seniors, and safety net programs, at the same time displaying corporate greed and self-righteous arrogance and entitlement like some kind of macho mating ritual.

There was another stark reminder of this contrast in values yesterday, described in Ezra Klein’s Wonkblog post.^⁠ He recounts a highly successful program, Health Quality Partners (HQP), that “has reduced hospitalizations by 33 percent and cut Medicare costs by 22 percent.” At the same time, seniors are cared for and visited weekly by a nurse, providing medical care and human contact with an old-fashioned caregiver. This is not sexy, high tech care. It is care with a capital C and a human touch. It works, it helps the poor and elderly—and so it will likely lose its funding.

In addition to its emergency services, United Hatzalah provides a similar service for seniors as does HQP. Theirs is a small pilot program, Ten Kavod ^⁠(The Twilight of Heroes), which provides weekly visits to the elderly to monitor their health and well-being.

United Hatzalah reaches across barriers of race, religion, and income—both among their volunteers and the people they serve. They are attempting to broaden use their model—including to Brazil and India.

Community building. Connections. Collaboration.

That was the message of Troy’s life…and of Boston’s resilience. That was the message of United Hatzalah. And that was a major theme at this year’s TEDMED.

Credits:

Thanks to Heather Stone and Suzanne Todd for permission to tell their stories.

Thanks to the Boston Globe for their superb coverage of the Boston Marathon bombing and aftermath.

Roller coaster: Lee Haywood/Flickr

Eli Beer: courtesy Sandy Huffaker/ TEDMED

LifeCompass screenshot: courtesy NowForce

“Molecules to Medicine” banner © Michelle Banks

-Edmund Burke

Hear no Evil

One month ago, Mike Howard, family friend of Dan Markingson, who committed suicide while participating in a clinical trial at the UMN, launched a petition requesting that Governor Mark Dayton launch an independent investigation of research misconduct in the university’s psychiatry department. Since that time, the petition has garnered almost 2000 signatures, from a range of people, including mental health professionals, families affected by mental illness, both non-affiliated Minnesota residents, and from prominent scholars from all over the world. A sampling of comments follows, below.

This Monday, the University of Minnesota dropped a bombshell of an announcement—that Mark Rotenberg, the General Counsel, would be leaving to pursue a similar opportunity at Johns Hopkins University in Baltimore.

This announcement has taken many observers by surprise…yet the Minnesota Post notes that the petition has been signed by “a veritable Who’s Who of top academics here and abroad,” after consent documents from different patients surfaced that were inexplicably identical, raising more alarming questions about possible research misconduct. The Post continues, “And so it is perhaps natural for his departure to occur while he’s in the headlines.”

Good vs Evil

The Star Tribune spoke with Rotenberg about how he “has navigated the dual roles of general counsel, defending the U as well as investigating its wrongdoing.” Rotenberg responded, “You need on the one hand to be a defender, an adviser, a counselor, a trusted partner…And on the other hand, you must also be a government lawyer who protects the public interest when the client is engaged in, or alleged to be engaged in, bad acts. If you fail at either task, you’re not doing your job.”

President Kaler stated that Rotenberg “has epitomized the kind of integrity and accountability that all public institutions like ours strive for.” As the comments on the petition reveal, not everyone shares that assessment.

For a countervailing view, see Bill Gleason’s tender farewell and reminiscences.

What do you make of this turn of events?

Signatories to the petition include three former editors of the New England Journal of Medicine, former editor of the British Medical Journal, the editor of the Lancet, and numerous scholars from all over the world.

Here is a representative sampling of comments. If you wish, you can add your voice to the petition.

The protection of research participants is an issue that concerns everyone.

Francoise Baylis   Dalhousie University, Halifax, Canada

As an American academic residing and teaching ethics in Israel, I am concerned about the possibility of such serious misconduct and suspected cover-up in a respected American university, especially one supported by the state!

Norm Zohar          Bar-Ilan University, Jerusalem, Israel

I am a professional bioethicist, and to me the attitude of the university to bend any rule to forestall an investigation is appalling.

Christian Munthe         University of Göteborg, Sweden

This is exactly why the Nuremberg Code was developed and why the principle of informed consent is #1 on the list of 10 standards.

Elisabeth Clark             Montreal, Canada

I’m a University of Minnesota alum and I’m outraged by the school’s response to this scandal… There is substantial evidence of multiple forms of misconduct, some of which are felonies. The trial’s coordinator has been censured. The Minnesota legislature passed a law to avoid some of these exploitative practices in the future…

To call this merely shameful would be wholly inadequate. There must be a thorough and independent investigation of the University’s treatment of Dan Markingson, its conduct in related litigation, and its attempts to intimidate critics into silence. If, as it appears, University employees committed criminal acts, they should be prosecuted. And if the University’s counsel withheld documents and/or knowingly produced altered or faked documents in litigation, those attorneys should be disbarred.

Matt Lamkin               Stanford University

Attended U of MN Medical School. then U of MN Psychiatry Residency – ashamed of the Psychiatry Department – have been in private practice since 1977 – Have seen first hand the hijacking of Psychiatry by BigPharma.

David Bransford MD      Grand Rapids, Mn

As a faculty member at a University (Penn State) now notorious for failing to investigate abuses, I find the refusal of the University of Minnesota to confront this scandal sadly familiar. Granted that the abuses that occurred here were of a very different nature unfolding in very different circumstances, our experience should nonetheless be evidence enough for any institution that the only way forward when abuses have occurred is a thorough, transparent investigation conducted by an independent authority.

Jesse Ballenger   Pennsylvania State University, State College, PA

The institutional stonewalling on the part of University of Minnesota, and the further horror of suing Mary Weiss for legal fees is staggering. Please investigate this case.

Sarah Lewis                  Dover, NH

As a bioethics and law professor, I have been profoundly disappointed and dismayed by the lack of serious investigation by the University of Minnesota and various US agencies mandated to protect human research subjects into what happened in the Dan Markingson case and in other cases of alleged breaches of research ethics and research subject protection standards at the University of Minnesota. There clearly are sufficient indicia to warrant a full fledged investigation, yet the University and other agencies seem to be hiding behind formal procedural rules to avoid any further inquiry. This is unacceptable for any academic institution, let alone a publicly funded institution.

Trudo Lemmens   University of Toronto, Canada

The largest employer in the state should take better care of Minnesotans.

George Hoagland  Duluth, MN

It is a blatant misuse of state, economic, and institutional power that has resulted in at least one death.

Matt Levine                  Minneapolis, MN

An independent investigation has now become absolutely necessary.
The scandal is shameful. The response of the administration of the University of Minnesota has been even more shameful.
By the way, I did my postdoctoral fellowship in bioethics at the University of Minnesota

Jing-Bao Nie                 University of Otago, New Zealand

I am a graduate (CLA, 1981) and ashamed of the way the University continues to handle this tragic case. According to the Board of Regents, Minnesota is committed “to the advancement of learning and the search for truth….” Let the whole story about Dan Markingson and the clinical trial come to light. The protection of research subjects is a matter of great public import that demands public accountability.

Joseph Davis                University of Virginia, Charlottesville

As an academic psychiatrist and a director of a psychiatry residency program, I am appalled by the circumstances surrounding this case. While I was deeply concerned about the recruitment and management of this particular study and the death of this patient, I am perhaps even more alarmed by the attempts to avoid and/or distort an appropriate and objective inquiry. When there is morbidity and mortality associated with any clinical interaction, we are obligated to make sure that we do anything and everything to make sure it doesn’t happen again. Many times this means asking for help and accepting constructive criticism. I urge the University of Minnesota to do the right thing: appoint an external panel to conduct a thorough, independent and transparent investigation.

Hal Elliott, MD    East Tennessee State U, Johnson City, TN

Society deserves honesty and transparency from researchers and the pharmaceutical companies funding them.

Nancy Hokkanen  Bloomington, MN

As an historian who has written on US experiments in both Tuskegee and Guatemala, it is imperative that when injustice happens it be acknowledged and investigated. This is not something we must do only for the past.

Susan Reverby     Women’s and Gender Studies Wellesley College

If the University has nothing to hide then an investigation into the death of Dan should be welcomed by them. Ensuring that those who are vulnerable are protected from harm is a cornerstone of research ethics – the fact that a young man who was vulnerable died during a research project demands that the circumstances leading to his death are investigated. It’s the least the University ought to do. To threaten Dan’s mother with legal action to cease her campaign smacks of the worse kind of insensitivity and arrogance.

Phillipa Malpas    University of Auckland, New Zealand

The lack of transparency and willingness to look into how research and clinical trials are conducted is, in itself, a breach of trust that casts a pall on the university and the psychiatric community. As a psychiatrist, I am deeply concerned about the widespread complicity between the profession and the pharmaceutical industry.

Laurence Kirmayer McGill University, Montreal, Canada

As a researcher, I am horrified by so many elements of this abuse of power. We must not let this go unacknowledged and unpunished, or the future of all research is at stake. People cannot make safe, well-informed decisions to participate in research if they do not know their interests will be protected. Thank you for your time and attention.

Erin Morgan Center for Victims of Torture, St. Paul, MN

I’ve been following this story, open-mouthed, as its unfolded. The very least that can be done is to shine some light into what are apparently some very murky corners.

Iain Brassington University of Manchester, England

This petition is important for more reasons than space will allow to list. Having known another participant in the Cafe study and how he and his family were treated by the researcher and the coordinator is disgusting. It was stay in the study at all costs, no recommendation for a second opinion, and no referral for any psychiatric help if he didn’t stay in the study. For the University of Minnesota to have conducted this charade for so long that they were not responsible is incomprehensible. If Governor Dayton will not listen then this petition needs to go to Washington DC.

Peter Richardson Roseville, MN

I am a researcher and advocate regarding the rights of human subjects enrolled in clinical trials research. This petition is important because we need to carefully investigate every case of possible conflict of interest. In this case, the circumstances surrounding Dan’s Markingson death are extremely serious and shouldn’t be overlooked. As citizens, we need to know that every trial is bringing a potentially new drug or treatment to the table and that the researchers are not conducting them enticed by the prospects of short term financial gain. Protecting subjects’ rights is critical because without their altruistic participation no drug development would be possible. Research subjects are assuming risks to benefit us all. The least we can do is to make sure these risks are minimized by avoiding, or investigating, every case of research malpractice. This petition won’t bring Dan back but it can make a big service by contributing to minimize some of the behaviors that killed him in the first place.

Roberto Abadie City University of New York

“When I taught at the U some years ago, we had to undergo research ethics training because of the unethical conduct of John Najarian. How did the Psychiatry Department avoid the training? Do you really want the great University of Minnesota to become an academic pariah?”

Helen Longino  Stanford University

I was the editor of the British Medical Journal and have a long standing interest in research misconduct and experience of many cases. I’d have thought that the University itself would have been keen to investigate this case–because there is clear evidence that things went badly wrong and the University would surely want to learn from a bad experience. Much might be learnt. Sadly I’ve encountered many examples of universities being unwilling to run the risk of finding serious problems with their own staff, which is why in this case an independent inquiry may be needed–but the University will have to cooperate.

Richard Smith former editor, British Medical Journal, London

I don’t care much for evil.

Jed Wolfe Los Angeles, CA

Credits:

“Molecules to Medicine” banner © Michelle Banks

Hear no Evil – M.A.S.K. Productions/Flickr

Good vs Evil-HaydenChristensenfan/Deviant Art

Drink me!

This series uses the story of Dan Markingson’s participation in a clinical trial of anti-psychotic drugs at the University of Minnesota, his suicide 2004 while participating on the study, and subsequent events as a case study in which to explore various aspects of clinical trial conduct. In previous posts, I’ve looked at issues of “good clinical practices” and ethics: consent, investigator responsibilities and conflicts of interest. Then I examined the university’s response. In the most recent post, I turned to the importance of careful documentation of consent.

I’ve experienced research in a variety of settings, from the bench in my fellowship, where I was filtering spit and nasal washings for influenza antibodies detected via laborious cell cultures, to sleeker clinical trials. I’ve conducted extensive literature reviews for my basic science research and subsequent articles, in writing my text on clinical trials, and as part of my regular patient care practice. I’m good at digging for data. But my experience digging for the truth on this series about the CAFE study at the University of Minnesota (UMN) has led me to unanticipated new frustrations and an impasse.

In this episode of my series, I share in greater detail the evolution in my thinking about the UMN’s handling of the Markingson case.

Getting to the truth

As I noted in my last post, when I started reading about this case, it was as an academic endeavor, seeking a case study for my blog. I like reading and writing about ethical stories, using a person and story to illustrate research conduct. The Markingson case, like some others, was peripherally on my radar. As I read, I became engrossed in the sleuthing as well as the tragic story, in figuring out the puzzle of “he-said-she-said.” I dove into depositions and started a timeline and spreadsheet to keep details straight. I never spoke to the principals…until March 8.

Wanting to put a more human face on my writing, that day I attempted to call several faculty members at the UMN to ask for their perspective. Only one person returned my call, politely telling me that all calls would have to be directed to Mark Rotenberg, the university’s general counsel. He didn’t return my calls either. So I e-mailed him with my questions for my most recent post. That evening, I received a call from Justin Paquette, PR Manager for the Academic Health Center and the spokesperson  for this case. I asked Paquette essentially the same things I had attempted to ask Rotenberg, and received disconcerting and evasive answers.

HIPAA

For example, as noted in my last post, there are questions raised about discrepancies in HIPAA (Health Insurance Portability and Accountability Act) forms. In a 2007 deposition of Dr. Stephen Olson, Dan Markingson’s attending physician and study investigator, Mary Weiss’ attorney notes (p. 144-5) that they (neither Weiss nor her legal team) had never been given a signed copy of the HIPAA form. In the deposition, Olson indicated that he didn’t know if there was a signed copy or, surprisingly, what the consequences were if they had not obtained a HIPAA consent. (Understanding the legal requirement to obtain a permission to access medical records, or HIPAA consent, and that failure to do so might be considered a felony is a basic concept I thought researchers were uniformly familiar with).

Yet, in response to a complaint by Mike Howard (close family friend of Dan’s mother, Mary Weiss) alleging misconduct by Dr. Olson, a signed form unexpectedly appeared in 2011—although the Fairview Hospital (the UMN campus where Dan had been admitted) medical records department certified that it didn’t have a copy of this on Dan’s chart.

Furthermore, Rotenberg’s own letter in response to Mike Howard’s complaint to the Board of Regents about Dr. Olson, states at one point that the HIPAA consent was signed November 24, yet later notes that Dan consented to participation in the trial on November 21. A date discrepancy. Rotenberg’s letter acknowledges that the HIPAA consent occurred days after Dan’s enrollment, suggesting a significant breach and possible felony.

Even if we accept that the signed HIPAA form was perhaps misfiled, I have yet to receive a response to my question about how Dan was enrolled on a trial three days before he gave consent for his records to be reviewed.

I asked Rotenberg and Paquette about the discrepancy in the evaluation to consent forms, one with a Bates number (used to identify medical and legal documents), one without. Again, they provided no explanation.

Down the garden path…

There was one response from Paquette that was particularly disturbing, given that he should be very familiar with this trial. Regarding Dan Markingson’s competency, Paquette tried to assure me that “the Court” had declared Dan competent to consent to this trial and had agreed to Dan’s participation. I countered that David Pettit, the case manager, didn’t even see Dan until 10/26/03, five days after he was enrolled on the trial. Surprisingly, Paquette reiterated it wasn’t Pettit, that “the Court had agreed to Dan’s participation.”

Perhaps this was an innocent slip of the tongue or memory. I would have expected the University’s spokesperson for this trial for several years to be more familiar with major details that are recurrently raised, and to be able to provide documents to refute specific concerns. But Paquette and Rotenberg have received multiple e-mails and calls from me since March 8 asking about this point, and have yet to provide any documentation of this claim.

I wonder if that is because there is none. In fact, Dr. Olson (deposition pages 78-79) makes the statement that he never informed the court about Dan going into the study…only that Dan’s county case manager approved it…who was never appointed until days after Dan was signed and enrolled on the trial.

That brings us to the next episode…

After reviewing the deposition again, I wondered if Paquette had deliberately misled me.

Study coordinator filling out forms

So I wrote a letter to Ben Garbe, an assistant attorney general who had represented the Minnesota Board of Social Work in their mild rebuke of the study coordinator. I raised my concerns about the puzzling responses from the university and the lack of transparency, including failure to provide documents to verify their claims.

I expressed my concern about the thinly veiled threats toward faculty. It’s not just Dr. Elliott, the University of Minnesota Professor of Bioethics and most persistent critic of the University’s handling of this case.  After all, if you ask questions, you are likely to be accused of making allegations—rather than trying to understand all sides, as General Counsel Rotenberg described Elliott’s media outreach efforts. (Mr. Rotenberg notably asked the university’s Academic Freedom and Tenure Committee to address “What is the faculty’s collective role in addressing factually incorrect attacks on particular University faculty research activities?”)
This question was widely interpreted as targeting Dr. Elliott and challenging academic freedom.

Additionally, if, as the UMN asserts there is nothing to hide, why instruct faculty not to speak with me? Or why are faculty not returning calls? Of course, typically, lawyers advise those involved in an ongoing lawsuit to refrain from speaking to the media. Such proceedings could be behind any evasiveness.

Even some other people who have expressed concern about the UMN’s behavior toward their family members have been reluctant to share more details with me, referring to admonitions from their attorneys.

And Garbe’s response? Astonishingly, he referred me back to the General Counsel’s (Rotenberg’s) office to investigate my concerns about that very office!

Fun house mirror

Some days I feel like I’m lost in a fun house with mirrors distorting everything beyond belief.

And that, dear readers, is why I have signed on to the petition to ask Minnesota Governor Dayton to launch an independent investigation of possible research misconduct in the psychiatry department of the University of Minnesota. I personally feel that multiple trials conducted by Drs. Olson and Schulz’ team should be examined, including the CATIE trial, which involved NIH. So far, 1,200+ people have signed on, from all over the world, including prominent ethicists and historians, Susan Reverby (the historian who brought unethical syphilis experiments in Guatemala to light), and three former editors of the New England Journal of Medicine. As Dr. Reverby noted, “It is imperative that when injustice happens it be acknowledged and investigated. This is not something we must do only for the past.”

see also: Petition to Gov. Mark Dayton of Minnesota to investigate psychiatric research misconduct at the University of Minnesota – started by Mike Howard (Dan Markingson family friend).

Credits:

“Molecules to Medicine” banner © Michelle Banks

Pills – ephotography

Getting to the Truth – Zoe Craft/Flickr

Coordinator filling out form – wistechcollege/Flickr

Fun house mirror – kthypryn/Flickr

Linnea Duff shows off her "famous lungs" at #ahcj13

The Association of Health Care Journalists annual conference (#ahcj13) covered a variety of topics, with lectures and panels followed by question and answer sessions. As with many conferences, it was tough to choose between competing sessions. I learned a great deal about health care, databases, and resources to help make accurately tracking data more efficient. I was glad to see several sessions covering medical reporting, particularly “Covering Medical Studies: How Not to Get It Wrong.”

As a clinical researcher, I was, as might be expected, particularly interested in the session moderated by NPR’s Scott Hensley:

What you need to know about clinical studies but were afraid to ask

I appreciated the panelist’s comments, but was frustrated that the underlying message addressed only the more positive aspects of clinical trials. Mind you, I have been generally pro-trials in my practice and my writing, but have become a bit more skeptical in recent years. I thought AHCJ was to help teach journalists and bloggers to ask the hard questions and to dig. This session, while informative, failed to do so.

Dr. Jeffrey Drazen, editor in chief of the New England Journal of Medicine, gave a largely historical perspective, focusing on the  first randomized trials to treat TB in 1931. He then fast-forwarded to the 1960s and the advent of large clinical trials and the need to improve patient safety measures for trials. I agree with Drazen that the Data Safety Monitoring Boards (DSMB) have a very valuable role in protecting patients, by overseeing the progress of clinical trials and evaluating interim data at specific endpoints, thus allowing a trial to continue, if results are not yet definitive or stopping a trial prematurely. Sometimes premature discontinuation happens because of safety concerns. Other times, a study might be stopped prematurely because trial results are so strong that the DSMB believes it would be unethical to continue enrolling more subjects (efficacy) or, conversely, for futility (the trial will never achieve statistical significance). The DSMB comes in relatively late in a trial, however—and as Drazen noted in 2010, the DSMB has sometimes been manipulated by the sponsor pharmaceutical company. Is it any wonder then that physicians are less likely to trust results labeled as coming from a pharma-sponsored study? (Unfortunately, physicians also tend to overlook the incentives or conflicts of interest NIH investigators have to get a prestigious publication).

James H. Ware, Ph.D., Professor of biostatistics and associate dean for clinical and translational science, Harvard School of Public Health raised some advantages for adaptive clinical trials and for accelerated approvals based on surrogate markers.

I would caution journalists much more strongly than Ware did to look at how strong the evidence is to support use of a surrogate marker. For example, at an earlier panel, Dr. Jerry Avorn, Professor of Medicine at Harvard Medical School and Chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital, noted that a new drug to treat multidrug-resistant tuberculosis (MDR-TB), bedaquiline (Sirturo), had received “fast-track” approval by the FDA, based on a surrogate marker, yet was associated with a 5-fold increase in deaths. Post-marketing study results are not required until 2022, and may well not be completed.

This issue of relying on surrogate markers, when we really may not have a good understanding of what they represent, is in the forefront again this week as the FDA is recommending use of surrogates be allowed to enable earlier treatment of patients for Alzheimer’s—before there is actual concrete data as to safety and effectiveness. While companies would be expected to do post-approval studies confirming the value of their drugs in real life scenarios, in fact their history of completing post-marketing studies is abysmal, and there appears to be little accountability.

Linnea Duff

One speaker blew everyone away—Linnea Duff, with her compelling story of her participation in a Phase 1 (first in human) clinical trial and battles with lung cancer. Linnea is an incredibly powerful advocate for participation in clinical trials, noting that doing so has enabled her not only to help herself but to provide a meaningful contribution to others. She has lived eight years now since diagnosis of non-smoker’s lung cancer, when there is an expected 5 year survival rate of only 15%. . .yet she notes, “I am an outlier.” She concluded, “I start every day with three simple words: I Am Alive.”

Ron Winslow, deputy bureau chief, health and science, The Wall Street Journal, had the unenviable position of following Duff’s moving talk. He observed that the number of retracted trials has gone up 10-fold in past decade – and cautioned that it is important to consider reliability and reproducibility when reporting trial results. He also soundly noted, “We don’t cover failed trials enough,” nor often put them in the context of an unmet need.

Unfortunately, due to time constraints, I was unable to provide the feedback I had hoped to in the Q&A. So, as promised there, here are more of the comments and questions for the #ahcj13 panelists on clinical trials that I had hoped to make.

Journalists (and critical readers) if you want to present your audience with a more accurate assessment of a clinical trial, you need to be asking probing questions including:

Dan Markingson & Mary Weiss

1)    Why is this trial being done? What question does it ask—and does that appear to be an important scientific question? Or is this more a marketing ploy to extend the indications for the drug? (e.g., another look-alike drug for erectile dysfunction, or the use of anti-psychotics like Seroquel for treating public speaking anxiety. [This trial, like the series I have been writing about on the Dan Markingson suicide on a psychiatric clinical trial, was conducted at the University of Minnesota.]

2)    What phase of a trial is this? Phase 1, first in human? Or post-marketing?

HIPAA vs. Pharma

3)    Are the risks of the drug proportionate to the illness being studied? For example, a volunteer for a trial for metastatic cancer might well be willing to accept more risks—and should likely be allowed to—than someone who has a relatively minor problem, especially if drugs with good safety profiles are already available.

4)    What was the make-up of the Institutional Review Board that approved the trial? Did they have the scientific depth or expertise to really understand (this is getting harder and harder as many studies require expert knowledge in an area)?

5)    What are the conflicts of interest of the IRB and its members? (Other than being paid by the study sponsor for their review and approval). What is their stance about patient protection? (See Alice Dreger’s “The Worst of All Possible IRB Worlds” and statements like that of Moira Keane, the former head of the UMN’s IRB, who stated that the IRB is not responsible for protecting clinical trial subjects.)

6)    Read the informed consent. If you can’t understand it, most participants won’t either. What safeguards are in place?

7)    If the study is being done at a university, what is the message from the university leadership? For example, I’ve been covering the death of a clinical trial participant, Dan Markingson, at the University of Minnesota, and the allegations of research misconduct. Many ethical concerns have been raised by that, and other trials done by the Department of Psychiatry there. Yet the UMN’s President Kaler recently delivered an address urging reduction in barriers to trials, and encouraging academic-industry trials.

I encourage everyone to ask these hard questions about clinical trials, as I have done with my series about the UMN. I will continue to encourage participation on meaningful trials where there are strong participant protections. And above all, I applaud Linnea Duff’s gift of participation and spirit.

Recommended reading:

Linnea Duff: Clinical trials: My next good chance and

life and breath: outliving lung cancer (for the terminally optimistic)

Previous posts in my series, A Clinical Trial and Suicide Leave Many Questions:

Part 1: Consent?

Part 2: Investigator Responsibilities

Part 3: Conflict of Interest

Part 4: The University of Minnesota’s Response

Part 5: The Case of the Mysteriously Appearing Documents

Credits:

“Molecules to Medicine” banner © Michelle Banks

Linnea Duff at ahcj13 – courtesy Ivan Oransky/Retraction Watch

Linnea Duff portrait – courtesy Linnea Duff

Dan Markingson photo – courtesy Mary Weiss

pharma cartoon – xkcd

Since I last wrote on the lapses in good clinical practices at the University of Minnesota, involving the suicide of a clinical trial participant, Dan Markingson, more disturbing documents have come to light, provided and contextualized by Professor Carl Elliott. Hard to imagine, I know…but this single case can provide a lifetime of lessons on clinical trial conduct, oversight, and ethics.

HIPAA Security Guide

This week’s episode looks at several mysterious documents, asks why some are only appearing now, and brings you more questions raised by their contents.

First, look at these HIPAA consent documents:

Single Page HIPAA in Markingson Chart Certified by Medical Records Department at Fairview April 5, 2011

Disputed HIPAA document with Signature

What do you notice?

One lacks a signature, and the Fairview Hospital medical records department is both certifying its authenticity and that there was no signed HIPAA consent page on Dan’s record. The second form—is signed and dated. The only explanation, woefully unsatisfying, comes from family friend Mike Howard, who noted: “Mary [Weiss]’s attorneys as well as Mary had received about three (3) different “Certified” sets of records and each one was different or had pages added or subtracted. So much for certification of study records.”

Now note the date on the HIPAA consent. There are a couple of concerns with this document. The first, is that this dated consent was never given to Mrs. Weiss nor her attorneys in her suit against the university. How did this magically appear in 2011, only in response to a complaint by Mr. Howard alleging misconduct by Dr. Olson?

Other documents from that suit, available on Scribd, have “Bates” numbers, which are used to identify medical and legal documents. This signed HIPAA consent lacks such an identifying number.

Mark Rotenberg, counsel for the UMN, in defending Dr. Olson and the university against charges by Mike Howard, responds to Mr. Howard’s complaint (almost a year later) by noting that the HIPAA consent was signed November 24. In that same letter, Mr. Rotenberg further notes that Dan consented to participation in the trial on November 21. So I read this as the University’s counsel confirming Mr. Howard’s assertion that Markingson’s mental health records had been released to the study coordinator, working as an agent of AstraZeneca through Dr. Olson, without Dan having signed a HIPAA release. Howard reiterates, “There is absolutely no paper document or record anywhere that states Dan agreed to be interviewed by Jean Kenney, Liz Lemke or anyone else connected with the CAFE’ study. No record in any of his hospital notes indicating that he possibly gave ‘verbal’ authorization to anyone connected with the CAFE’ study to approach him.”
I await Mr. Rotenberg’s explanation. [His office was contacted by me for this story].

There is another problem with the HIPAA consent, which, in and of itself, could represent a felony. The HIPAA regulation “requires that an Authorization contain either an expiration date or an expiration event.” This has neither. It appears that the University is at risk for significant civil and criminal penalties. A second CAFE Study family provided Carl Elliott with an identical, unsigned HIPAA consent form, and again with no expiration.

“Evaluation to Consent” forms

The next document mystery involves these forms in which Jean Kenney, the social worker responsible both for study recruitment and a psychiatric evaluation regarding a “volunteer’s” ability to understand and consent to participation, administered to patients.
Look at these evaluation forms:

Evaluation to Consent without initials

Evaluation to Consent with initials

What do you notice?

They appear identical, except for initials on one, suggesting they might have been xeroxed and used as a template.

Then a 3rd form appeared:

Evaluation to Consent-anonymous CAFE study member

It, too, is identical–but lacks initials or a hospital unit number. But it was given to Dr. Elliott by someone who, as yet, feels a need for anonymity. Other families have contacted Dr. Elliott or posted on the Community Alliance for Ethics in Minnesota Psychiatry Facebook page that they have identical forms as well, though this has not yet been definitively confirmed.

What do these duplicate forms mean?

The HIPPA forms are troublesome because they indicate possible breaches of patient confidentiality regarding psychiatric illnesses. The requirement for an expiration date was a federal requirement at the time of the study, as verified by the HIPAA web site. Each of these problems is potentially a felony.

The seemingly duplicated  evaluations to consent are even more problematic. It is implausible that patients gave identical responses to these questions of their understanding and ability to consent. Using duplicated forms would call into question the competence of the patients to consent, a contested point in Mary Weiss’ suit against the UMN. As Dr. Elliott notes, the “evaluation to consent” forms have been submitted to official research oversight bodies, which have relied on them to make judgments about the conduct of the studies.”

I would extend the concerns further. If the investigators allowed their staff to use identical forms and claim that different patients provided identical answers, then this would be far more evidence they provided inadequate oversight and did not fulfill their responsibilities as Principle Investigators. It would also call into question the work that this team did on other clinical trials, including the NIH funded CATIE trial.

The university is state and federally funded. Given that, a bit of transparency would seem in order. One of the most troublesome aspect of this case for me is the response of the University to questions being raised. In 2010, eight faculty members sent a letter to the Board of Regents requesting an outside investigation. None was done.

Dr. Elliott has bravely persisted in methodically raising concerns as new evidence emerges, each time posting documents of concern on Scribd for anyone to evaluate. He is  still requesting an outside investigation. Instead of doing so, the University has brushed aside Dr. Elliott’s concerns. In the latest example, Dr. Frances Lawrenz, the Associate Vice President for Research replied to the emergence of this new evidence:
“Our research misconduct policy has a ‘statute of limitations’ of 7 years…Since the matters covered in your letter occurred more than seven years ago, the material you present is outside the purview of the policy. In addition, your concerns about the consent evaluation process and possible HIPAA violations do not appear to fall under the definition of research misconduct (i.e., alleged fabrication, falsification or plagiarism), regardless of when the events occurred.”
[Note: I attempted to reach Dr. Lawrenz for comment and was told she would not speak with me.] I am unpersuaded with the response I subsequently received via the PR person apparently directed to call me by Mr. Rotenberg’s office.

Conclusion

It is difficult in this case, as with much of life, to tell with total certainty “where truth lies.” The reluctance on the part of the Office of Research, the Office of the President, the Office of the Counsel, and the Board of Regents of UMN to fully and transparently examine new evidence is extremely troubling, though. Without such a transparent examination, there is no guarantee that the clinical investigational staff did not commit breaches of research ethics and of law, and has not continued to do so, perhaps putting other vulnerable patients at undue risk.
When I started reading about this case, it was as an academic endeavor, seeking a case study for my blog. I did (and do not) not know any of the parties involved. Yet the more I have learned, the more outraged I have become.

I am angered by the thinly veiled threats towards Dr. Elliott (e.g., Mr. Rotenberg’s “What is the faculty’s collective role in addressing factually incorrect attacks on particular University faculty research activities?”

I am saddened by what appears to me to be violations of the trust of vulnerable patients and of research ethics. As I have become immersed in the case, it has become clear that it provides a lifetime of study and discussion about what not to do during the course of a clinical trial. It is also clear to me that more patients than Mr. Markingson likely were harmed at the UMN by: enrolling participants with contested ability to consent; having financial incentives that encourage keeping someone on a trial when it appears they are not responding well; approving and supporting protocols that have seemingly disproportionate risks, e.g. “The Use of Quetiapine (Seroquel) in the Treatment of Social Phobia: Public Speaking Environment.”

And, unfortunately, 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.

Suggested reading:

Carl Elliott’s important new letters:

Request that FDA Office of Scientific Investigation to investigate “evaluation to consent” forms for CAFE study

Letter to HHS Civil Rights About Possible HIPAA Violations

Credits:

HIPAA image: purpleslog/Flickr

Klebsiella

Great posts have been written about the “end of antibiotics” and superbugs in a variety of flavors.

Yesterday, the CDC⁠ issued an alarming warning about Carbapenem-Resistant Enterobacteriaceae, aka CRE. The enzyme that  produces the antibiotic resistance, was first identified in 2001 from an isolate of  Klebsiella. According to the new CDC report, in a 2012 survey of US hospitals, “181 (4.6%) reported one or more infections with CRE (145 [3.9%] in short-stay hospitals; 36 [17.8%] in long-term acute-care hospitals” LTACs).”

The background for the resistant bacteria’s emergence and spread across the country is well described by Maryn McKenna and Liz Szabo/USA Today (with a great infographic⁠), and won’t be repeated here.

I want to share my perspective as an infectious disease practitioner who cares for patients with these infections regularly. As I have mentioned more privately, there are cultural issues driving the emergence of resistance, especially in the U.S., first with MRSA, then VRE, and now with CRE. Warning: my observations may not be politically correct—but they reflect 30+ years of patient care. These include:

— The belief  many have that people will live forever. There used to be more of an acceptance of death. But with television/movies portraying advances in medicine unrealistically, the public now often has an expectation that their loved ones will not die. Some seem to feel that any death must be a result of medical error, and there are a number of malpractice attorneys vying for their attention with aggressive advertising reinforcing that belief.

— Pharmaceutical companies and their sales reps push doctors to use the latest wonder drugs. If a physician uses older agents, s/he is likely to be portrayed as not keeping up to date with medical advances.

— Individual “rights” above all. Physicians and families focus on the possible benefit for one patient, with little or no concern as to public health implications of treatment. This sounds harsh, but should we reconsider treatment of nonviable patients for the good of the community. This warrants thoughtful discussion.

In the hospitals where I work, patients with superbugs tend to be admitted from LTACs or nursing homes. Many of these patients are comatose and have been unresponsive for years. Some are more recently poorly responsive, often from head injuries or strokes. Common denominators are presence of urinary catheters, feeding tubes, tracheostomies (breathing tubes), and often multiple bedsores. And commonly, the families want “everything” done, no matter the cost to the patient in terms of pain and suffering, or to society. (They may never even come to visit their “loved one” but are insistent with their demands for aggressive care). Living wills may not be honored—and certainly won’t be if any family member objects. And then there is the whole “sanctity of life” argument…that results in flogging patients with no likelihood of recovery…torturing them, it often seems.

I’ve cared for patients with these superbugs. First, it was MRSA, then VRE, and now these multi-resistant gram negative bacteria, CREs. Here is an example of a report from one patient.

Antibiogram: Notice that the only antibiotic that the Acinetobacter is susceptible to (S) is colistin. The bacteria is resistant to everything else. The Proteus also is resistant to many antibiotics.

And here’s what the Acinetobacter resistance looks like nationally.

In the past couple of years, I’ve started to have to use an old antibiotic, polymixin (or colistin). There are no other options. It causes renal failure and results in the need for dialysis. While I only work part-time now, I have yet to see a patient get better and leave the health system after receiving polymixin.

The hospitals I am familiar with—one in particular—are extraordinarily careful. They are proactive in screening high risk new patients for CRE, MRSA, and VRE, and are very careful with isolation…yet breaches of isolation occasionally happen, due to medical emergencies or human error, especially as staffing is spread more thinly. There are tangible costs to the screening and isolation, but there are more intangible ones as well—it is a burden to health care practitioners to don gowns, masks, gloves, and booties when entering a room, and for the nurses, to be so attired for extended periods of time. Patients tend to get attended to less often, and to feel more isolated.

Overseas, many important antibiotics are sold over-the-counter. Here, they are squandered as growth-promoters, or marketed aggressively and unrestrainedly. At the same time as antibiotics are being misused, which leads to increasing resistance emerging, there is little incentive to develop new antibiotics, as they are only used for brief periods of time. Pharma is far more interested in the next “me, too” drug for “Low-T” or hypertension—drugs that will be taken for years—rather than one prescribed for only a week or two.

So we breed more and more resistant organisms, and squander the few good antibiotics we have left—in the name of being “pro-life” and pro-individuality. We should have restrictions on “antibiotic last rites” with specific indications for use of some antibiotics. Until there are restrictions on antibiotic use—saving them as a national security treasure—and requirements to use them judiciously, we will never control antibiotic resistance.

Suggested reading:

Maryn McKenna: ‘We Have a Limited Window of Opportunity’: CDC Warns of Resistance ‘Nightmare’

Liz Szabo and Peter Eisler: CDC sounds alarm on deadly, untreatable superbugs

The CDC’s report: “Vital Signs: Carbapenem-Resistant Enterobacteriaceae,” MMWR, March 5, 2013. 62 (Early Release);1-6

Eli Perencevich: KPC, CRE, MDR-GNR: Call ‘em what you will, but call for a national response!

The Center for Disease Dynamics, Economics, and Policy

Credits:
“Molecules to Medicine” banner © Michelle Banks

Klebsiella-wikipedia

Feel more secure?

As mentioned, I’ve been doing more traveling, and am increasingly disturbed by the growing surveillance society, from TSA’s “Security Theater” to the wider spread presence of traffic cameras and surveillance of public spaces.

Security expert Bruce⁠ Schneier has pointed out that the current system is reactive—e.g., having to remove shoes now—and so, as with malware, the “bad guys” are generally one step ahead, simply by shifting strategies. In fact, there is growing evidence that more lives are being lost because of TSA and people’s aversion to flying now that has arisen due to the hassles TSA has created, that has resulted in a return to driving, resulting in more accidents than are being saved due to any prevention of terrorist activity that might have occurred.

So some experts—and Schneier’s Harms of Post-9/11 Airline Security is a “must-read”—have urged a shift from all these scanners and examining objects as shoes, as in TSA’s drama, to more targeted focus on behavior and intelligence.

Increasing “security” surveillance are always justified by the need for more “security”.  Where is the evidence that more security makes us more secure…and at what cost?

We’ll look first at such dramatic effects in the workplace, then in other settings.

Pre-employment drug screening

Meds might trip you up...

Screening potential employees has some appeal, largely for public relations—“We are doing everything we can to provide a safe workplace!” and for perceived reduction in liability, even though there is no good data that this improves general outcomes or in medical settings.
But the downsides of such testing receive less attention.

Screening is generally conducted by a urine test. However, to avoid cheating, the specimens are obtained in humiliating ways, including either direct observation or by listening to the person void, and having the toilet contain a blue dye to avoid temptation to dilute the sample. Urine is then immediately checked for temperature and concentration. Those with “shy bladder” are commonly reported as a refusal to test.

Don't try diluting urine with this!

Screening prior to a conditional job offer has been considered a “violation of the American with Disabilities Act (ADA), which prohibits ‘‘inquiries of a job applicant as to whether such an applicant is an individual with a disability …’’⁠ Such screening is acceptable after a job has been offered, however.

Many consider screening an invasion of privacy. While safety concerns trump HIPAA, how many workers want to share all of their medical information with their employers?

Further, the implications of a falsely positive test are potentially devastating. “Despite the lack of evidence for the utility of drug testing, the impact is profound.⁠ The mere suspicion of use or, worse yet, a false positive test can have a long term, devastating impact on an individual’s life and career. Immense administrative, legal, and medical effort would be required to prove innocence once suspected of illicit use.”

Is there value to workplace drug screening?

What appears to be overlooked in the zeal for increased drug testing is that pre-employment screening tells you nothing about what is happening on the job nor if there is any impairment, which is really the key issue.
As a reminder, in the US, 42.9% of full-time workers reported that tests for illicit drug or alcohol use were required as part of “pre-hire” testing—so more than 47 million adults were subjected to testing as a condition of employment. (2004) Further, 29.6%, or 32 million full-time workers reported random drug testing at work.⁠ A 2010 study reported about 130 million drug screens⁠.

Dr. George Lundberg, former editor of the Journal of the American Medical Association and of Medscape, has long opposed screening, aptly calling it “chemical McCarthyism.” He also has criticized the “hypocrisy” of screening, given that alcohol and tobacco abuse are commonly ignored. Lundberg has noted, too, the incredible cost of screening. Tests are currently ~$45—more for confirmatory testing, and not including any administrative costs. If the 115 million full-time workers (Dec, 2012)⁠ were all tested, that would cost $5,175,000,000. As he noted some time ago, still true today, “‘This is terrific for the laboratory industry and all the attorneys who will argue these cases . . . but should we spend that kind of money?’ he wrote. ‘In fact, we have not found one proper cost-benefit analysis of this process’ in the medical literature.” Think of all the good that could be done with those monies.

Northwestern University Drs. Levine and Rennie give further excellent arguments against testing (in medicine)—again that the testing is not measuring what is really the issue, impairment:
“Drug testing is arguably less important than addressing the performance impact of overnight work, circadian rhythm disruption, and overwork. Testing does not necessarily measure impairment, abuse, or intoxication. The presence of a banned substance does not mean that cognitive impairment is present or clinical performance is impacted. Further, routinely used medicines such as decongestants, antihistamines, stimulants, and other prescribed substances can also profoundly impair functioning.”
One need only look at sleep deprivation to find considerably more impairment than that due to many drugs, yet this is a problem which is, at least in the medical field, readily dismissed or ignored by administrators or training program directors.

Drug screening as a condition of welfare?

There is understandable outrage at the thought of taxpayer monies being wasted by public assistance recipients buying drugs. (Frankly, I feel the same sort of anger when patients come in with fast food or cigarettes but say they can’t afford their meds).
Again, the wrong question is being asked. What does the data tell us? You’ll likely be surprised. First, the rate of drug use among public assistance recipients is about the same as that of the general population. Next, testing welfare recipients does not save money.
Of the 87,000 Arizonans tested for “reasonable cause,” only 1 tested positive, saving the state a whopping $560.
In Florida, where all welfare applicants were tested, 2.7% had positive screening tests. Who benefited the most from the drug testing? Not the taxpayers…

Yield of drug testing welfare recipients

The biggest winners appear to have been the owners of testing companies, such as Governor and Mrs. Rick Scott’s company, Solantic. Scott also pushed for random drug testing on state employees, although some departments found that <1% of employees failed. Ultimately, such random drug testing was ruled unconstitutional last year in Florida as being an unreasonable search.
I have found zero evidence that routine drug testing does any good for anybody other than the businesses conducting and profiting from the tests.

Drug screening as clinical research

Some have argued that widescale, untargeted drug screening is akin to conducting clinical research on an industry or population scale or to testing an individual in order to make some prediction as to their likely job performance. If examined in the context of research, we could ask if such testing would pass the muster of meeting basic ethical principles, as outlined in the Belmont report:
Respect for persons, or voluntariness—Clearly testing in order to gain employment is coercive and not freely offered. Nor is there truly an informed consent with workplace testing. There is generally no discussion either of the accuracy of the tests or of potential repercussions beyond not being hired for that specific position.
Beneficience—There is no apparent benefit to the individual being tested, so screening fails this ethical tenet.
Justice—A test or procedure is applied equally to all populations, with a fair distribution of risks and benefits among those tested. One might argue that using screening for pre-employment is unjust, as it does not predict future job performance. Selective testing “for cause” makes much more sense.

What is the value of TSA—wouldn’t real data be nice?

According to Businessweek, in “Airport Security is Killing Us,” the TSA has a budget of almost $8 billion of the $580 billion the government spent on homeland security 2002-11.
What has been the yield—the efficacy of this intervention? No terrorist was caught trying to board a plane in the US. A number of firearms were confiscated, as was one batch of explosives (apparently missed the first time). The National Academy of Science noted no data to justify the huge expenditures.

Then there is the always frustrating and intrusive experience with TSA. (I am routinely pulled aside for extra screening—my matronly appearance either seems to alarm them, or makes me an easy target for a quota.) While the unpleasantness of the TSA screening has not been shown to make us substantially safer, it has, however, been shown to increase deaths—by reducing flying and thus resulting in increased deaths from automobile accidents. Estimates vary from an increase of 242 driving fatalities per month to an excess of 500 deaths/year. TSA screenings have also had a huge negative economic impact.
Now you have to arrive at an airport two hours earlier. According to Schneier, “In 2004, the average extra waiting time due to TSA procedures was 19.5 minutes per person. That’s a total economic loss—in –America—of $10 billion per year, more than the TSA’s entire budget.”  Many—our family included—have concluded that a trip of less than about 8 hours is not worth the added aggravation and stress due to TSA, resulting in more auto travel, and increased risk.

Security theater is not limited to air travel. Since 2004 another TSA—VIPR (Visible Intermodal Prevention and Response)—troupe has emerged to perform at surface transportation hubs, including train, subway, and bus stations, as well as truck stops. Most impressively, instead of screening people boarding a train, in 2011, a VIPR team chose passengers getting off a train in Savannah, detained them and subjected them to “security” screening before allowing them to leave the station. This raised more questions about Fourth Amendment protections from unreasonable search.
In a related case involving the New York subway, MacWade vs. Kelly, the 2nd Circuit Court of Appeals ruled that random, suspicionless searches of bags were allowed as a satisfying the special needs exception to the Fourth Amendment’s protections.
Random and limited searches of bags for explosives made some sense, given reasonable concerns about terrorism in NYC subway system. That commuters could be arrested for carrying “contraband” found incidentally during such a search, seems unjustified.
Unsurprisingly, after the Savannah embarrassment, “when asked if  VIPR has ever directly resulted in discovered explosives or the arrest of suspected attackers,” the TSA response was, “Specific operational results are considered security sensitive information.” Since they are happy to trumpet their “successes,” I think we can safely take that as a “no”.

Thanks to the Patriot Act and the NDAA⁠, the government also now has extraordinary powers to detain someone without any due process. As Schneier notes, “And if you’re on a certain secret list, you cannot fly, and you enter a Kafkaesque world where you cannot face your accuser, protest your innocence, clear your name, or even get confirmation from the government that someone, somewhere, has judged you guilty. These police powers would be illegal anywhere but in an airport, and we are all harmed—individually and collectively—by their existence.” With the Patriot Act and NDAA, there is increasingly a presumption of guilt rather than innocence, and disturbing abuses of power. Most disturbingly, when President Obama was asked recently whether he claims the authority to kill a U.S. citizen suspected of being associated with al Qaeda or associated forces on U.S. Soil, he didn’t say, “No.” Obama responded, “What I think is absolutely true is that it is not sufficient for citizens to just take my word for it that we’re doing the right thing.”

There is no small irony that, in another Kafkaesque twist, people who are prevented from flying can still legally buy weapons and many of the politicians supporting security theater oppose gun control.

Broader implications and political context

DNA and Drug Testing - One Stop Shopping

Drug screens are but one example of the increase in surveillance throughout our society. Such intrusive testing inherently sets up an adversarial relationship as well. Many people likely work better in an environment of respect and trust. I’ve seen a dramatic change in the working atmosphere of some hospitals over the years, as the institutions adopt fingerprint scans to clock in and out, GPS phones that track employees’ movements, measure the response time to answer a call light, etc. These processes are dehumanizing and counterproductive.
There is one new and growing area for privacy concerns—the trend for genetic sampling of people arrested  for various crimes—and amassing a huge database, on these individuals, whether or not they are convicted of anything.

Additionally, we have no evidence that all the surveillance does anything more than have a chilling effect on society and erode our civil liberties. There is a strong push in healthcare for “evidence-based medicine.” This is the mantra of the day, and drives many decisions.

If evidence is so important for our health, why is it not the same for our civil liberties? Why do we not have to justify, with hard data, the benefits of the surveillance to anyone besides the businesses and government agencies who profit from this growing surveillance industry?

As Bruce Schneier concluded recently, “This loss of trust—in both airport security and counterterrorism policies in general—is the first harm. Trust is fundamental to society. There is an enormous amount written about this; high-trust societies are simply happier and more prosperous than low-trust societies. Trust is essential for both free markets and democracy. This is why open-government laws are so important; trust requires government transparency. The secret policies implemented by airport security harm society because of their very secrecy.”

Conclusion

The example of drug testing is but one example to illustrate the difficulty in interpreting laboratory tests and studies. More importantly, drug testing and the TSA screening processes appear structurally similar; both pretend to address large societal problems, are performances involving a lot of show, and both are ineffective sociotechnical systems.

With any test, you have to try and tease out not only the accuracy of the test in measuring the outcome you wish to examine, but also whether you are measuring the right thing or asking the right question. We need to know whether the test or intervention makes a difference, is effective, and what the cost or risk:benefit ratio is.
For example, in my field of medicine, do we want to create a culture of safety, where an RN can question a physician, or one which is authoritarian and fear-ridden?  I have worked in both, and can tell you where I would want to work or to receive care as a patient.

Do we want to have workplaces built on trust and a presumption of honesty and mutual respect, or one of constant surveillance? Do we want a presumption of innocence until proven otherwise, or one of presumed guilt?

Will we accept propaganda that all this surveillance and violations of our civil liberties—be it at the workplace, in public assistance programs, or in public spaces—somehow is for our own good, in the absence of any data?
Do we want to address the issues that have a real impact on our safety and quality of life, or hoodwink ourselves with security theater?

Readings:

Bruce Schneier’s Harms of Post-9/11 Airline Security

The Government wants your DNA-Erin Murphy

Credits:

Security cameras – Stiwwe/Flickr

Blue water in toilet – Judy Stone

Welfare drug screens – courtesy John Henry/ LowGenius

DNA-Drug testing van – courtesy SkepticalScalpel

“Molecules to Medicine” banner © Michele Banks

Under the influence?

I’ve been doing a lot of traveling recently, and am increasingly disturbed by the growing surveillance society and the misplaced reassurances that are used to assuage the public, coined “security theater” by Bruce Schneier. Here we’ll look at this drama in the context of screening for drugs of abuse. In a later post we’ll look more closely at the parallels between drug screening and the TSA. Both are problematic and neither produces the desired outcomes. We’ll look at why.

There are three key issues to consider: one is the accuracy of the test; the second are ethical concerns; the third, the societal and political context of drug testing.
In reading about clinical trials, one commonly misunderstood, yet basic concept is that of the accuracy of clinical test results—are you measuring what you think that you are? I’ve spoken about this a bit in posts about Orasure’s HIV test and turned again for a quick review to Marya Zilberberg’s “Between the Lines.”⁠ We’ll look at evidence and accuracy in a different context here, with our focus being on understanding false negative and false positive results. Drug screening is used as an example, as such screening is increasingly being used in work and social services settings, and raises similar concerns about accuracy and ethics as we see in clinical trials.

Background rates of drug use

According to the government’s Substance Abuse and Mental Health Services Administration⁠1 (SAMHSA) the rate of drug use in the US among full-time workers averaged 8.2%, ranging from 6.1% among health care workers (HCW) reporting use within the past month compared to 16.9% among accommodations and food workers and 13.7% for construction workers. Overall, rates were higher in those younger than 35. Among HCW, nurses had much higher rates than physicians, whose rates varied by specialty, being highest among anesthesiologists and emergency room staff.

Drug screening

Screening is performed in different settings and for different purposes. For example, there is routine screening of long distance truck drivers and airplane pilots, as they are considered a potential public safety risk. Screening can be done pre-employment or, more commonly, in response to a workplace accident. Toxicology screens are also commonly performed in Emergency Departments when evaluating a patient with an unexplained change in mental status or behavior.

Among full-time workers in the US, 42.9% reported that tests for illicit drug or alcohol use occurred as part of “pre-hire” testing—so more than 47 million adults were subjected to testing as part of the hiring process. (2004) Further, 29.6%, or 32 million full-time workers reported random drug testing at work.⁠ A 2010 study reported about 130 million drug screens⁠. Is this necessary? Does this make us safer?

Obviously, we want tests such as these to be accurate – to provide a valid measure of the state of the “real world”.  There are two ways in which tests such as these can be correct. They can detect true positives and true negatives:  That is, they can give a positive reading when the subject of the testing has used one of more of the drugs that are being tested for, and likewise they can give a negative [or “all clear”] reading when the testing subject has not used drugs within the testing window. They can also err in two ways: They can give a false negative, or a negative reading when the subject has actually used drugs, and they can give a false positive, or a positive reading when the subject of the testing has not used any drug.  The ability of the test to return true positives and avoid false negatives is called the “sensitivity” of the test.  Similarly, the ability of the test to return true negatives and not false positives is called the “specificity” of the test.

Urine testing

Most commonly, urine samples are used. Urine tests are very sensitive, but not very specific—this means that there are likely to be many falsely positive results. So a positive result will generally be followed up with a more expensive and specific urine (and occasionally blood) test being done for confirmation—but even among these tests, none are 100% accurate.

Urine tests have the advantage of showing drug use over a longer period of time; the drugs are also present in higher concentrations in urine than in blood. The advantage of testing blood is that it more often reflects the parent drug, rather than metabolites, and that it reflects more “real-time” use.

The likelihood of these false negative and false positive errors varies, and depends on both the accuracy of the test, and upon the expected [or “real-world”] percentage of true positive results in the group being tested. Due to a quirk of statistics, if the incidence of drug usage in the population under study is low, there will be higher likelihood of false positives. The smaller the number or % of true positives, the higher the rate of false positives.

For screening tests, false positives are estimated to occur in 5 to 10% of tests, and false negatives in 10-15%. For confirmatory tests, data has been more difficult to find. Estimates of accuracy of the drug tests are < 1% for false positive confirmatory tests, and perhaps 5% false negatives, due to where the thresholds are commonly set.* Using this as an example, and an 8% drug usage rate, we would get, in a 1000 tested workers:

About 4 people will be reported “clean,” a false negative, though they use drugs.
Of 920 who did not use drugs, 1%, or ~9 people will show up as pos.
Of 85 people who test positive, 9/85, or 10.6% will erroneously be identified as drug users. So while 1% error rate (false positive) sounds good, 10% of the positives will be false.

What drugs are being tested for?

“Testing conducted according to SAMHSA’s guidelines checks for five illicit drugs plus, in some cases, alcohol (ethanol, ethyl alcohol, booze).  These five illicit drugs are:⁠
•    Amphetamines (meth, speed, crank, “Ecstasy” (MDMA))
•    THC (cannabinoids, marijuana, hash)
•    Cocaine (coke, crack)
•    Opiates (heroin, opium, codeine, morphine)
•    Phencyclidine (PCP, angel dust)”

The typical 10-Panel Test also includes:
•    Barbiturates (phenobarbital, butalbital, secobarbital, downers)
•    Benzodiazepines (tranquilizers like Valium, Librium, Xanax)
•    Methaqualone (Quaaludes)
•    Methadone (often used to treat heroin addiction)
•    Propoxyphene (Darvon compounds)

Testing is not typically done for alcohol, hallucinogens, inhalants, steroids, hydrocodone, suboxone, or “bath salts” (an amphetamine like drug).

Drugs firms 'creating ills for every pill'

Sites also tell you the length of time that drugs can be detected in blood or urine.⁠
• Alcohol – 1 oz. for 1.5 hours
• Amphetamines – 48 hours
• Barbiturates – 2-10 days
• Benzodiazepines – 2-3 weeks
• Cocaine – 2-10 days
• Heroin Metabolite – less than 1 day
• Morphine – 2-3 days
• LSD – 8 hours
• Marijuana – casual use, 3-4 days; chronic use, several weeks
• Methamphetamine – 2-3 days
• Methadone – 2-3 days
• Phencyclidine (PCP) – 1 week
(Hair testing has extended detection time.)

While testing might pick up some drug use, a whole cottage industry has developed to sell products to defeat the testing, including urine substitutes, or giving advice as to how to beat the tests.⁠ Thus, an individual with a small amount of knowledge could circumvent scheduled screening. This is why drug screens are random, not scheduled, except for pre-employment.

Approaches to testing

SAMSHA ⁠has two different approaches to testing. One is a “zero tolerance” test, which reduces false negatives. Any level of drug detected is considered a positive (or failed) test. The other is the “cut-off” type of test—a drug may be detected in small amounts, but the test will be reported as negative (passed) if below a certain threshold.

False positives
A major concern for those who don’t use illicit drugs and for whom the repercussions of a positive test are grave, is the issue of false positives. Unfortunately, many drugs cross-react with the test, giving potentially erroneous results, especially on screening tests. For example, the USC’s Keck Hospital⁠ notes “more than 300 over-the-counter drugs and foods that can affect the test (see modified table).

**Large amounts of poppy seeds—for example, a pastry filled with poppy seeds, not a poppy seed bagel—would need to be consumed to cause a positive test. However, sophisticated testing can discern poppy seeds from opiates.”
A suspected false positive on a screening assay—designed to be highly sensitive but not very specific—is then followed up with testing by another technique. Unfortunately, no test is completely accurate, and even the “gold standard” confirmatory test, gas chromatography-mass spectometry, has false positives and is subject to performer error.

False negatives

In the balancing act, trying to avoid the costly additional testing and potential legalities of a false positive, the threshold set by some labs for reporting a test is high enough that even though drug may be present in low levels, it will not be reported. The Feds are pushing for more stringent reporting.

Other testing nightmares

There are other workplace testing procedures that erroneously punish non-users.⁠ For example, those with “shy bladder”, or those who only void small amounts, have been fired. If urine appears too dilute, employees have been subject to repeat testing and surveillance. Forensic toxicologist Dr. Vina Spiehler ⁠has been particularly critical of “arbitrary cutoffs for creatinine, saying they discriminate against women, vegetarians, the elderly, people who drink lots of water, and people of small body size. Spiehler also argued for greater safeguards for validity testing, since ‘for employees subject to urine drug screening sometimes the penalties for abnormal urine characteristics are more severe than those for the presence of drugs in their urine.’”

Conclusion

This example of drug testing is but one example to illustrate the difficulty in interpreting laboratory tests and studies. For each, you have to try and tease out not only the accuracy of the test in measuring the outcome you wish to examine, but also whether you are measuring the right thing or asking the right question.

In an upcoming post, we’ll look at pre-employment screening, its value (or lack thereof), and some of the broader ethical and societal implications of the increasing culture of surveillance.

(*Note: est of false +/- for GC-MS is based on information from toxicologists)

Credits:
Special thanks to: Dr. David Parish
Ed Smith, Drug Detection Lab
Steve Codd, Beckman Coulter
and Dr. George Lundberg
for additional background info and for helping me understand the complexities of this topic, and to my family, for their thoughtful comments.

“Molecules to Medicine” banner © Michelle Banks
Tried that – Jovike/Flickr
Urine testing – publik15/Flickr
Pills for every ill – publik15/Flickr

The "Unconference"

I had the wonderful opportunity to co-moderate two sessions at this past week’s Science Online “unconference” in Raleigh, affectionately known as #scio13. Sessions are proposed and moderated by volunteers, and there is a broad range of attendees, leading to rich discussion…and lots of fun.

#SciOctopus & Karyn Traphagen captured by Russ Creech

There were three sessions devoted to different aspects of Citizen Science. We met in cyberspace and then via a Google hangout for initial planning, then planned more details within our own session. I worked with Kelly Hills (@rocza), a woman whose energy and youth belie a wealth of diverse experiences. Our focus was to discuss “What happens when citizen scientists start doing research outside the scope of institutional review boards, medical ethical committees or institutional animal care and use committees?”

Kelly and I first struggled to define “Citizen Science” (#citsci) vs. “DIY” science and the maker crowd. Kelly describes our discussion well in her post, The Difference Between Citizen and DIY Science. From our discussions and review, it appears to us that “Citizen Science” is generally affiliated with an institution, and receives funding, support, and guidance from the mother ship. Most appear to be related to natural history or astronomy. A prime example of this would be the Cornell University’s Great Backyard Bird Count, which enlists community volunteers to help with scientific observations.

In contrast, the DIY enthusiasts are generally independent and are more likely to be unaffiliated with any formal institution. They are more often the mavericks, and may be unaware of either ethical concerns or some of the potentially troublesome implications of some of their research—or what kind of deep trouble they might find themselves in.

A couple of basic questions came up:

When do you need an ethics review?

There is a simple answer—any time human subjects are involved in research. This applies not only to direct interventions with people, but also to the use of any data or samples that can be linked to an identifiable living person? (i.e., privacy concerns, see HIPAA).

Unfortunately, the current system for research review was designed with the presumption that all research is done in academic centers or similar research institutions, via the “Institutional Review Boards” (IRBs).

Dr. Caren Cooper (@coopsciscoop) stressed the importance of proper animal care–humane and regulatory aspects–as well.

How can #citsci or #DIY explorers learn about ethics and the responsible conduct of research?

Fortunately, there are many resources now available for self-study, as well as courses. These include:

• My own text, Conducting Clinical Research: A Practical Guide for Physicians, Nurses, Study Coordinators and Investigators, now available on-line as the Aaron Swartz memorial open access pdf. Of particular relevance to this topic will be chapters four, five, and eight.
• NIH Research Ethics Training
• CITI-Collaborative Institutional Training Initiative
• Office for Human Research Protections and educational webinars by OHRP or PRIM&R

What kind of ethical review or oversight can or should be available to those not affiliated with a university?

Clearly, there can be considerable debate as to what kind of oversight should be available—while many of us cringed at the idea of a “DIY” IRB or ethics review, both institutional and commercial IRBs have had conflicts of interest and their own lapses in oversight. (e.g. University of Minnesota and the Dan Markingson case, Coast IRB, Texas Applied Biomedical (TAB) Services IRB and Celltex).

One of the problems is that IRBs generally charge on the order of $2500 for their review and seal of approval—something clearly impossible for many individuals or small groups, or for students looking to explore research. And many such researchers have no access to an institution or university. While many researchers might have no intention to publish results formally, they encounter problems if they try—access to publishing in most journals requires that the research received IRB approval. (Bastian Greshake and the OpenSnp group have reported on this here.

While we cringed at the talk of a “DIY” ethics group or IRB, it turns out that it is not hard to set one up—and a call to OHRP revealed that there is no fee and the process can generally be completed in less than 3 weeks. Instructions can be found here and more background regarding regulatory requirements are  in the Code of Federal Regulations 45 CFR 46.

Dr. Holly Menninger (@DrHolly) also noted that there are guidelines for non-institutionally affiliated researchers.

We will continue the discussion regarding Citizen Science and Ethics, and explore the possibility of providing research support (IRB and education) via an association. Please contribute to the discussion on the Science Online wiki.

Further recommended reading:

DIY Science, Art, Biotech Hackers, and Citizen Science and Research
- The Rise of Citizen Scientists and Patient Initiated Research by Kent Bottles, MD
- DIY Biotech Hacker Space Opens in NYC by Dave Mosher (Wired coverage of Genspace)
- SpotOn NYC: DIY Science – Bringing Biotech Home by Cathal Garvey (Nature SpotOn guest editorial)
- Critical Art Ensemble: Biotech
- Eduardo Kac: multimedia, communications, and biological artist. Bio Art projects.

And as Kelly noted, “When Things Go Bad, They Can Go Very Bad
Think nothing can go wrong when doing DIY science, art, and general extra-institutional experimentation? Oh, think again…
- Steve Kurtz and the Critical Art Ensemble”

Credits:

Special thanks toBora Zivkovic (@BoraZ), Anton Zuiker (@mistersugar), Karyn Traphagen (@kTraphagen) for making the awesome ScienceOnline conference possible, to Kelly Hills, my dyanamic co-moderator, and to the other Citizen Science moderators and attendees, for great discussion and provocative questions.

“Molecules to Medicine” banner © Michelle Banks.

Aaron Swartz

I continue on break from the UMN Markingson story as I try to make sense—although there appears none to be had—of the tragic death of Aaron Swartz. I am haunted and infuriated by the senselessness of his death and his persecution by overzealous prosecutors. I am also reminded of other witch hunts that were equally misguided and also led to perverse and Kafkaesque results.

In an emergency, what is your duty to care?

One case is that of Dr. Anna Pou^⁠, who was attacked by a grandstanding prosecutor, Charles Foti, in New Orleans. She was the heroic physician who stayed in a New Orleans hospital to care for her patients during Hurricane Katrina. She was exonerated of irresponsible accusations of homicide. While hers was not a federal prosecution, it sent a chilling message to healthcare workers—in a disaster, consider if your duty to care^⁠ for your patients trumps that of your other duties and is worth the risk of the destruction of one’s reputation and career, not to mention crippling legal defense bills and even a prison sentence.

In Hurricane Sandy, we again saw many heroic people who stayed to care for others, putting themselves at significant risk. There was considerable government support this time, however, unlike during Katrina. Perhaps that accounts for the difference in outcome. There needs to be some legislative protection for the good people who stay to help. Otherwise, the lesson from Katrina is that it is too dangerous to do so.

Patriot Act warning to researchers

Fear

Another example is that of Dr. Thomas Butler, who I wrote about some years ago. He was a leading researcher who, before the government attacked him, was studying treatments for plague, bearer of the “Black Death,” a bacteria that might be weaponized and used for bioterrorism. When he reported vials missing from his lab, federal agents descended on his Lubbock, Texas lab, and he was charged–and ultimately acquitted–of 69 felony counts related to bioterrorism. He served 2 years on minor unrelated, “fishing expedition” charges.

What was little mentioned at the time was that Dr. Butler is also the leading researcher responsible for developing “oral rehydration solution,” an inexpensive powder that has saved millions of lives in developing countries. This treatment, which replaces intravenous therapy for severe dehydration “is credited by the World Health Organization for saving between 2 and 3 million lives of under-4-year-olds each year around the planet,” according to Dr. William Greenough, professor of medicine at Johns Hopkins University.

Dr. Butler’s trial was apparently intended to serve as a warning to researchers that the Patriot Act concerns extended to them and would be ruthlessly applied. It has done that. It has also resulted in many researchers losing their willingness to study agents of concern, lest their lives be similarly destroyed.

I would recommend John Mangel’s thoughtful series, Plagued by Fear, in the Cleveland Plain Dealer for an excellent review of this tragic story.

“Destroying the Life and Career of a Valued Physician-Scientist Who Tried to Protect Us from Plague: Was It Really Necessary?“^⁠ reflects the analysis by many of Dr. Butler’s colleagues, including:

“Reactions in favor of Butler and expressions of concern about the handling and impact of the case have been strong, including comments from the Human Rights Committee of the National Academy of Sciences (NAS), the Institute of Medicine (IOM), the National Academy of Engineering, and the New York Academy of Sciences. The presidents of the NAS, the IOM, and the European Society of Clinical Microbiology and Infectious Diseases, as well as many prominent scientists and physicians, wrote to then Attorney General John Ashcroft to express their concern about the impact of the prosecution of Dr. Butler (the presidents of the NAS and the IOM had written only once before to an attorney general, Janet Reno, and their letter was concerned with the prosecution of Los Alamos National Laboratory scientist Wen Ho Lee).

Four academy members who are Nobel Laureates wrote, on behalf of themselves, that “this respected colleague has been subjected to unfair and disproportionate treatment.” . . .many other news sources have run stories suggesting that Butler may have been a victim of the widespread fear about (bio)terrorism and may have been singled out, presumably to serve as an example, as part of a flawed strategy to fight bioterrorism.

We think it makes very little sense to have removed from action such a knowledgeable and active clinician and clinical investigator who was working to protect us from plague–such removal is akin to shooting ourselves in the foot…

Dr. Tom Butler, a physician-scientist and member of the IDSA, respected by all colleagues who know him and his work, has been stripped of his professorship, tenure, salary, and medical license and has spent his life savings and retirement to defend himself. . . He and his family have no sources of income. His situation is a cautionary tale to all of us, especially those who work with biological agents with potential for use in bioterrorism, even if in collaboration with governmental laboratories and scientists.”

Yet Andrew McCarthy, a former federal prosecutor, saw nothing wrong with the prosecution, opining, “I don’t think it’s remotely heavy-handed. This is a time when it’s important to get the message out to the world that we’re serious about dealing with components of weapons of mass destruction.”

Dr. Butler’s colleagues have gotten the fed’s message.

Dr. Peter Agre^⁠, was a co-recipient of the 2003 Nobel Prize in chemistry, and is a member of Duke University’s faculty, recently said, “many scientists are reluctant to study these organisms because their best attempts to know and to obey applicable regulations still might land them in prison, might cost them their faculty positions, their licenses to practice medicine, or their right to vote.”

Dr. Stanley Falkow^⁠, an expert microbiologist from Stanford University, echoed Dr. Agre’s concerns, noting, “In my letter to Ashcroft, I said I couldn’t imagine why I would let my students work in this area when a simple mistake can lead to incarceration,” and “they took one of the only experts on plague in the U.S. and totally muzzled and incapacitated him.”

When I first wrote about this mockery of justice in 2006, Dr. Butler was working in a Lubbock warehouse, tagging clothing for sale, instead of continuing his valuable research or developing other life-saving therapies, as he had in the past.

“He now has no medical license and no job, and in the eyes of the US government—but not of his colleagues—he is a convicted felon. All of this because he was able to organize and complete a field trial with colleagues at the University of Tanzania that addressed the vital question of which antimicrobials would keep you alive if you were to contract plague.”

Dr. Butler has since gone back to teaching and research—in Dominica—but remains under the eyes of the feds, although acquitted of all the national security count. In 2010, the Miami International Airport was evacuated and he was detained overnight by TSA^⁠ for carrying a suspicious canister—looking remarkably like a stainless steel thermos to me. Nothing sinister was found and he was eventually released. Some have considered this to have been harassment, rather than an innocent mistake on the part of the government.

One of the fallouts from the Butler prosecution—or persecution, depending on your perspective—is that of dissuading researchers from studying bioterrorism. There is now an extensive list of infectious agents classified as “select” agents. In order to study these, special permissions and precautions must be taken under the “Patriot Act.” Ironically, some of these agents are also found in natural settings, like plague or Q fever.

Do you feel any safer now?

Prosecutorial excess

Justice?

There are common threads in these cases, particularly the two involving federal prosecutors. One striking one is that both Aaron Swartz and Thomas Butler were charged with numerous felonies—69 in Butler’s case and 13 in Aaron’s, and both individuals refused to plea bargain and accept an unjust felony conviction. Both were harassed and driven to financial ruin. Aaron faced multiple “felony counts, each of which ‘carrie[d] the possibility of a fine and imprisonment of up to 10-20 years per felony’, meaning ‘the sentence could conceivably total 50+ years and [a] fine in the area of $4 million^⁠.’ That meant, as Think Progress documented, that Swartz faced ‘a more severe prison term than killers, slave dealers and bank robbers’^⁠.”

Remember—What was Butler’s crime? Filling out paperwork incorrectly and naivete. And Aaron’s crime? Downloading too many articles with the intent of making them freely available to the public.

Both Dr. Butler and Aaron were extraordinarily bright and had worked tirelessly to better the plight of others—Butler for saving millions of lives from diarrhea due to poverty, lack of clean water and sanitation, and Aaron through making information and education available to all.

Neither had any profit motive. Perhaps that was their fatal error. After all, Carmen Ortiz’s office chose not to pursue prison terms for corporate^⁠ officers^⁠ although their actions caused actual harm to patients. Ortiz was quoted in the case of one pharmaceutical company as saying, “Forest Pharmaceuticals deliberately chose to pursue corporate profits over its obligations to the F.D.A. and the American public.”^⁠ And the cases of both Forest and Glaxo, also involved in a settlement, involved drugs that had serious side effects. St. Jude^⁠ Medical makes cardiac devices that have been plagued by problems with defibrillator leads, some leading to deaths^⁠. And yet, where clearly more harm has been done, there has been no criminal prosecution nor accountability for the responsible executives. Why the selective prosecution of this brilliant young man?

Some, as Professor Jonathan Turley^⁠, rips Ortiz’ comparison to Inspector Javert, unable to show any discretion (let alone compassion or sense of proportionality). As Aaron’s friend and mentor, Lawrence Lessig noted, “I get wrong. But I also get proportionality. And if you don’t get both, you don’t deserve to have the power of the United States government behind you.^⁠”

Others cite Ortiz’ and Assistant US Attorney Stephen Heyman’s pattern of bullying. Heyman was involved in the case of a hacker, Jonathan James, who also felt driven to suicide.^⁠

Ortiz has shown a pattern of selective prosecution.^⁠ In a recent example, she is going after a small motel owner in Tewksbury, seizing his property because drug crimes were committed there.

“U.S. Attorney Ortiz said through a spokeswoman last week that the government wanted to send a message by going after the motel. But just up the street from the Caswell, the Motel 6, Walmart and Home Depot have all experienced a similar rate of drug crimes on their properties over the years, according to Caswell’s attorneys.

And attorney Salzman says there’s one good reason Ortiz didn’t go after them.

“Mr. Caswell is a small business,” Salzman said. “A single family owned this property, didn’t have the resources to defend himself, and the U.S. Attorney’s office, looking to make an example, picked on the smallest kid on the block.”

There is a certain bitter irony that these federal attorneys are immune from prosecution or civil suits for their actions. For a damning post on how prosecutors can target people, rather than actual crimes, and how they abuse plea bargaining by bringing excessive charges, see Reynold’s “Ham Sandwich Nation: Due Process When Everything is a Crime^⁠.”

Others have noted that Ortiz’ prosecution of Swartz was not sound:

“The flaw in Ortiz’s posture has been laid bare by Chief Judge Alex Kozinski of the Ninth Circuit Court of Appeals. In United States v. Nosal, he dismissed the theory Ortiz used to go after Swartz, saying it would potentially criminalize ‘everyone who uses a computer in violation of computer use restrictions — which may well include everyone who uses a computer.^⁠’”

So we have prosecutors with extraordinary discretion as to who to target, and how aggressively to go after defendants and yet having no accountability for their actions. There’s something fundamentally wrong when prosecutors focus on easy, helpless targets so they gain easy wins to advance their careers.

On reflection, I believe in some prosecutorial discretion—the difference being that I regard brilliant, kind, selfless people like those profiled here as national treasures. They can help make our country scientifically and technologically great and help millions of people. And these courageous souls provide something our country sorely needs—a moral compass that can never be met by the military industrial complex and corporate greed. They remind us of what we have lost through the Patriot Act, the increasingly pervasive surveillance and prosecutorial excess and, most importantly, that absolute power corrupts absolutely.

Suggested reading:

Prosecutor as bully – Lawrence Lessig

The Tragic Case of Aaron Swartz: Unequal Justice for Web Activists vs Health Care Corporate Executives – Roy Poses

Edward Tufte’s defense of Aaron Swartz and the “marvelously different” -Dan Nguyen

Plagued by Fear – John Mangel

Note: The section on Thomas Butler largely appeared in 2006 on my blog.

Credits:

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Aaron Swartz

This post is in honor of Aaron Swartz. I had long considered posting my book as open access but had hesitated in doing so, even though I have long been an enthusiast about OLPC and Creative Commons.  Aaron’s tragic death prompted my urgent reconsideration and offering.

For me, it is the pictures of Aaron, the goodness and sweetness of a young man working for just, equal society through open access, that are especially haunting.

There are so many moving vignettes; I cannot write as eloquently, but was particularly touched by these:

The heartbreaking, beautiful post by Quinn Norton, “My Aaron Swartz, whom I loved,” and her plea, “Make the world that wouldn’t have killed him, please.”

“We’re going to miss your brilliant mind, your righteous heart and your sensitive soul.” Chris Hayes

Cory Doctorow’s “My obit for Aaron Swartz.”

Haunting Jay Rosen’s “…Trying to explain to myself why I was on the verge of tears all day…”

More glimpses of how Aaron touched so many people’s lives can be found at http://rememberaaronsw.tumblr.com/

There are also very powerful posts on how Aaron’s death reflects on our society and its tolerance of abuses of power:

From Alex Stamos, “I was Aaron Swartz’s expert witness, and here is the truth about his ‘crime.’”

Danah Boyd (@zephoria) on the abuse of government power noting that the Feds wanted to “make a point to the entire Cambridge hacker community that they were p0wned.”

Aaron Swartz’ “death is a good reason to revisit the 1986 Computer Fraud and Abuse Act. Chris Hayes

Dan Gillmor’s admonition: “Remember Aaron Swartz by working for open society and against government abuses.”  “Instead of despairing for @aaronsw, fight the evils he fought.”

Tim B. Lee: “Revolutionary new technologies and ideas don’t come from people with a reverence for following the rules”

And reflections of what we, as a society, have lost:

“Our society should be selecting for the Aaron Swartz’s of this world. Instead, generous and ethical behavior, especially when combined with technical brilliance, turns out to be maladaptive, indeed lethal.” Rick Perlstein

“…I am sorry indeed to live in a society where the crime of stealing  articles on 18th century monetary policy (inter alia, of course) is treated more harshly than the non-offense of terrorizing a public street through the display of firearms.

Last word: As Doctorow told the Times, we have lost someone to be missed.

Swartz, he wrote via email, was “uncompromising, principled, smart, flawed, loving, caring, and brilliant. The world was a better place with him in it.”  Tom Levenson

Tim Wu: “We can rightly judge a society by how it treats its eccentrics and deviant geniuses—and by that measure, we have utterly failed.”

Lawrence Lessig and Aaron Swartz 2002

“Aaron dead. World wanderers, we have lost a wise elder. Hackers for right, we are one down. Parents all, we have lost a child. Let us weep.”

Tim Berners-Lee

Seeing the many photos of Aaron, with his bright eyes and mischievous smile, I flashed back to a favorite high school poem:

“Elegy for Jane
(My student, thrown by a horse)

Theodore Roethke

I remember the neckcurls, limp and damp as tendrils;
And her quick look, a sidelong pickerel smile;
And how, once startled into talk, the light syllables leaped for her,
And she balanced in the delight of her thought,

A wren, happy, tail into the wind,
Her song trembling the twigs and small branches.
The shade sang with her;
The leaves, their whispers turned to kissing,
And the mould sang in the bleached valleys under the rose.

Oh, when she was sad, she cast herself down into such a pure depth,
Even a father could not find her:
Scraping her cheek against straw,
Stirring the clearest water.

My sparrow, you are not here,
Waiting like a fern, making a spiney shadow.
The sides of wet stones cannot console me,
Nor the moss, wound with the last light.

If only I could nudge you from this sleep,
My maimed darling, my skittery pigeon.
Over this damp grave I speak the words of my love:
I, with no rights in this matter,
Neither father nor lover.”

Thank you, Aaron, for making the world a better place. I have always asked my children to work for the forces of good and justice. You had the courage to do so. In your honor and memory, I have now made my own book open access. May you rest in peace and your death kindle a movement.

Credits:

Aaron Swartz – Flickr

Lawrence Lessig and Aaron Swartz (2002) / Rich Gibson / CC BY

Molecules to Medicine banner © Michelle Banks

Bowl of antidepressants

In earlier posts, we’ve looked at issues of consent, investigator responsibilities, and conflicts of interest on the case of Dan Markingson’s suicide while participating in a clinical trial of anti-psychotics at the University of Minnesota. This time, we turn to the University’s response.
Not surprisingly, the University has claimed it has no responsibility for any wrongdoing—that in fact, no wrongdoing even occurred. But there are some inconsistencies in the story and unanswered questions. There is also concern over how the University has responded to criticism. We’ll examine these issues in this post.

Background regarding the University’s response

In response to the Minnesota Board of Social Work’s “corrective action” vs. Jeanne Kenney, the social worker/study coordinator who did most of the study assessments on Markingson, the UMN’s General Counsel Mark Rotenberg stated, “As we’ve stated previously, the Markingson case has been exhaustively reviewed by federal, state and academic bodies since 2004. The FDA, the Hennepin County District Court, the Minnesota Board of Medical Practice, the Minnesota Attorney General’s Office and the University’s Institutional Review Board have all reviewed the case. None found fault with the University. None found fault with any of our faculty. Most importantly, none found any causal link between the CAFE trial and the death of Mr. Markingson.”

Yet a number of UMN faculty have remaining concerns and have requested an independent investigation. Two years ago, eight faculty members in the Bioethics Department wrote Rotenberg, citing the University’s conflicts of interest in the matter. The UMN declines to reexamine the case, saying that they have been exonerated. In October 2012, Dr. Carl Elliott, Professor in the UMN Center for Bioethics, wrote Dr. Debra DeBruin, director of the Clinical Research Ethics Consultation Service for the UMN Clinical and Translational Science Institute, again requesting a review. This time Dr. Elliott expressed concern regarding human subjects protections in other trials conducted by the psychiatry department as well. As always, Dr. Elliott’s concerns were thoroughly documented. Once again, the University has turned away.

The UMN’s claim of exoneration is complicated, and not quite accurate.

The FDA’s review of Markingson case

The FDA’s review of the case seems remarkably superficial to me. Perhaps I have more information now than they had available, accounting for differences in our conclusions. You can read the 2005 FDA report of Inspector Sharon Matson here:
Dan had been involuntarily committed for being psychotic and homicidal, and was then offered a stay of commitment to a psychiatric hospital if he followed the recommendations of his physician and social worker—all of which seems very coercive and is frowned upon by both research ethics and regulations. “The HHS regulations state that “An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence” (45 CFR 46.116)

There are also special cautions about enrolling vulnerable subjects, placing additional responsibility on the IRB, with regulations requiring them to “ensure that ‘additional safeguards have been included in the study to protect the rights and welfare’ of all subjects that are ‘likely to be vulnerable to coercion or undue influence.’ The regulations include ‘mentally disabled persons’ in this category (45 CFR 46.111(b)).”

Despite these facts, the FDA inspector concluded, “There was nothing different about this subject than the others enrolled to indicate that he couldn’t provide voluntary informed consent” (p. 9).

But remember, “On November 14, 2003 Dr. Olson signed a commitment document stating that Markingson “lacks the ability to make decisions regarding such treatment [consenting to neuroleptic drugs].”

Dan Markingson

Then, “on November 21—just two days after being deemed incapable of consenting to Risperdal (anti-psychotic treatment)–Dan was suddenly determined by Jeanne Kenney, his social worker, to be capable of consenting to a clinical trial of anti-psychotic medications.” (Groat expert report)

Despite notes documenting Dan’s failure to improve on the CAFE study, Ms. Weiss’s urgent warnings about his deterioration, and Dr. Olson’s requesting Dan have an additional 6 month stay of commitment, the FDA inspector concluded that the record “does not appear to indicate a significant decline or deterioration” (page 10).

Matson notes that Dan’s court appointed caseworker, David Pettit, approved of Dan’s enrollment, but missed that Pettit had no involvement with Dan prior to enrollment, as he had not yet even been assigned to the case until 3 days later, and didn’t see him until 5 days after he was enrolled (p 15 of Pope expert report). Even the judge issuing the commitment order had not been informed by Olson that Markingson would be enrolled in the CAFE study. (p 78-9 of Olson deposition)

Matson regurgitates Olson and Kenney’s views that participating in the CAFE study gave Markingson better care than he would have received had he not participated because of much closer monitoring—frightening, if true. (p 8 of FDA inspection report). At no point does she mention disadvantages of participation, including that the protocol prohibited changing his medication or using combinations of drugs, nor were alternative options clearly outlined. The inspector also fails to note that most studies of antipsychotics exclude patients at risk of violence, but this study did not, nor did the UMN IRB object. She states that the IRB reviewed the case and “no irregularities were noted.” (p 13) (I believe this is colloquially known as the fox guarding the hen house).

Similarly Inspector Matson notes that subjects had an assessment of their ability to consent to a protocol, but does not indicate that this was administered by the same study coordinator who was in charge of recruitment. (p 14)

Perhaps I just have the benefit of having more records and depositions than Ms. Matson did but, given all the evidence that she missed and that is new since her 2005 report, one would think that the FDA would reopen this case.

Other inconsistencies

Seroquel samples

University counsel Mark Rotenberg skillfully and disingenuously proclaimed of reviewers, “None found fault with the University. None found fault with any of our faculty.” This is true—but only as far as it goes.
I, like Carl Elliott before me, have not been able to find anything from the Attorney General’s office that exonerates the university.
In fact the Attorney General’s office clearly had concerns about the case. For one, the Board of Social Work, which issued the corrective action against Ms. Kenney, was represented by Assistant Attorney General Benjamin R. Garbe. They cited her undertaking tasks beyond the scope of practice of a social worker—but this was clearly done with Dr. Olson’s knowledge and support.

Deputy Attorney General Michael Vanselow also wrote Mary Weiss, “We are also willing to work with you and Jim Gottstein in regard to drafting some proposed legislation to address some of the systemic problems that contributed to your son’s death.” Such legislation was passed in 2009 and is known as “Dan’s Law.” This law prohibits recruiting most patients who are under a commitment agreement into clinical trials.

The IRB was not exonerated either. More accurately, a District Court “judge ruled in a partial summary judgment that the university IRB was ‘statutorily immune from liability.’”

University of Minnesota’s behavior

If there is one thing the university has excelled at in this sorry story is that of creating a climate of intimidation, both towards the plaintiff, Ms. Weiss, and towards concerned faculty.

One of the things I found sickening was that in 2008, the University countersued Mary Weiss for almost $57,000 to recover their legal fees—although they did not really win their case. Instead, they hid behind the state equivalent of “diplomatic immunity.” Further, Ms. Weiss only had 10 days in which to decide whether she could afford to appeal the case and explore her options. Fortunately, all but ~$1000 of the UMN’s countersuit was dismissed by the court administrator—but Mary had to waive her right to appeal.

As Carl Elliott aptly notes, for the UMN to file a countersuit against a grieving mother who has just lost her only child in a clinical trial at the University was not only a shameful tactic, but one clearly designed to punish Ms. Weiss for her lack of deference to them. It also sends a clear and intimidating message, akin to a SLAPP, or Strategic Lawsuit Against Public Participation.

The UMN appears to be playing the same game of intimidation in its actions towards Dr. Elliott, in response to his persistent request that there be an independent inquiry, rather than one by the UMN’s own General Counsel, Mark Rotenberg, who appears to be vying to be judge, jury, and executioner in this story. In response to Elliott’s requests, “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.”

Fortunately, Rotenberg’s heavy-handed tactics appear to have backfired. Rather than squelching Elliott, a number of faculty viewed this as another thinly-veiled attempt at intimidation. A University of Chicago Professor of Law and Philosophy, Brian Leiter, described Rotenberg’s question “a quite brazen attack on the core of academic freedom,” noting that it also illustrates “how important tenure is to protect faculty whose research adversely affects corporate interests.”  Other criticism followed. In one particularly scathing post, “Should the General Counsel at the University of Minnesota Take a Sabbatical for a Refresher Course in Constitutional Law?” attorney Michael McNabb notes, “The First Amendment prohibits the government from abridging free speech.  A state university may not exercise prior restraint on public discussion…neither the faculty nor the administration has the authority to restrict speech at a state university (of all places).”

Conclusion

At this point, we have the UMN:
- hiding behind state sovereignty protection
- denying any responsibility for the death of a clinical trial subject although the Minnesota Board of Social Work found that the coordinator, practicing under the direct supervision of a physician-investigator, performed medical assessments and procedures for which she was not qualified
-an IRB chair who states that the IRB is not responsible for protecting clinical trial subjects
-a bereaved mother who is hit with a hefty countersuit as a tactic of intimidation, and who can’t afford the cost of appeal
-a courageous and well-qualified bioethics professor, Carl Elliott, who is threatened by the UMN General Counsel for voicing his concerns
-blatant financial conflicts of interest that are seemingly swept under the carpet because of the lucrative financial benefits to the UMN

Loose ends:

There are a number of unresolved questions in my mind. Among them:
If the social worker/study coordinator was found at fault by the Minnesota Board of Social Work, why has nothing happened to the physicians supervising her and who were responsible for her actions?
Medical assessments were done by a non-medical individual, were sometimes erroneous, and records were  altered after the fact. The same coordinator and physician principal investigators (Olson and Schulz) were also involved in the CATIE trial and other NIH sponsored trials. Why have these not undergone review?
What changes, if any, have the IRB and institution made to enhance protections for vulnerable subjects?

In my concluding post, we’ll look at some of the broader implications of this study for the UMN, for NIH, and for clinical trial participation.

Credits:

Bowl of antidepressants – Carsten Schertzer/Flickr

Dan Markingson photo courtesy of Mary Weiss

Seroquel samples-Judy Stone

Molecules to Medicine banner © Michelle Banks

Dan Markingson and mom, Mary Weiss

We’ve touched on some of the many disturbing things that happened during the clinical trial on which Dan Markingson committed suicide. In my first post, I asked how a psychotic, homicidal patient who was involuntarily hospitalized in a psychiatric hospital could give an informed consent for participation in a clinical trial. There appeared to have been abuse of a vulnerable patient and extraordinary coercion—participate in this trial or be committed to a psych hospital seems to have been the bottom line.

In my second post, we looked at investigator responsibilities, delegation of authority, and Good Clinical Practice tenets, all of which were violated with no consequences.

Now we turn to the need to disclose conflicts of interest (COI), again a basic clinical research ethics principle that was violated. There are so many obvious conflicts of interest that it is hard to know quite where to start.

Physicians

The most obvious and egregious COI was that shown by Dr. Stephen Olson, who acted as both Dan Markingson’s treating physician and as Principle Investigator on the CAFÉ study. As Dr. Harrison Pope, a Harvard expert, concluded in his testimony, Olson “failed to meet the standards for good clinical practice both as a principal investigator and as the study physician for Mr. Markingson.” He failed his ethical responsibilities to Dan by:

—Enrolling him in a clinical trial he was incapable of consenting to, particularly over the objections of Dan’s mother, Mary Weiss.

— Not dropping Dan from the protocol when Dan was clearly not showing improvement.

— Not examining Dan closely and regularly. “Dr. Olson’s signature appears only twice throughout all of the study documents” from 12/8/2003 until his death 5/8/2004. (p 30, Pope testimony). According to Ms. Weiss, Dan had told her “that Dr. Olson would, at most, ‘stick his head in occasionally at study visits. The medical records confirm that impression.’” Olson likely would have had to examine Dan more frequently if he were not on a study, as he would not have had the additional staffing funded by the study to have a surrogate see his patients.

—Improperly acting as both Markingson’s study physician and treating physician

The conflict between Dr. Olson’s roles as Dan’s personal physician and as researcher is further detailed by Dr. Pope. For example, it likely kept Dan from getting a second opinion and from getting additional medications. The protocol also prohibited Olson from measuring blood levels of the anti-psychotic, which would have shown if he were being compliant in taking his meds.

Olson reportedly mislead the IRB^⁠, leading them to believe that Markingson’s enrollment had been agreed to by his case manager, when he hadn’t yet been seen by Mr. Pettit. He also failed to inform them of information about Dan’s inability to consent and that the judge had granted a stay of commitment for Dan if he followed recommendations.

The NIH website summarizes the problem succinctly: “If an investigator is also the personal health provider of the potential research participant, there may be an additional conflict of interest. A physician’s duty is to honor the best interests of the patient. An investigator must do what is best for the study. These two objectives are not always consonant. Further, potential participants may be reluctant to question the advice of a health provider on whom they depend for care.”^⁠

Olson’s involvement, and that of the department chairman and coinvestigator, Dr. Charles Schulz, appear to have been significantly driven by financial interests, though they had other incentives, too, such as increased prestige and publications.

Financial Conflicts of Interest

Sweetheart deal

There were major financial incentives for both Drs. Olson and Schulz, as well as for the university.

Dan Markingson—aka Subject 13—was worth over $15,000 to the university, had he completed the study. The CAFÉ study not only yielded $327,000, but helped generate more attention (and probably more trials) for the university’s schizophrenia program.

This particular study was structured so that patients had to complete the trial in order for the full payment to be received by the institution. Thus, dropping the patient because the study drug was ineffective, or adding additional medications, was prohibited and would have resulted in significant financial penalties—and this was not explained in the “informed consent.” Because the study period was one year, Olson had to keep Markingson on the trial to get the full payment; I suspect this contributed to his recommendation that Dan’s stay of commitment be extended to keep Dan a captive participant.

Dan was far more valuable to the University and psychiatrists as a study patient than as a regular psychiatric inpatient. As Dr. Pope noted, above, ancillary personnel could do many of the assessments. And Dan was destitute, so any care they provided him outside of the study would have had minimal reimbursement—we often didn’t feel that the payments from Medical Assistance even covered the cost of billing, let alone the medical care provided. (Note: not all of the grant money goes to the investigator. Much of it then has to be disbursed to the university for direct costs and for their administrative overhead charge, often 50% of the total grant. Physicians are also expected to generate monies to cover much of their salaries.)

According to the Pioneer Press in 2008, “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.”

Yet these significant COIs were not disclosed to study participants. When Dr. Schulz replied to anguished Ms. Weiss’ 3^rd letter (her first two went unanswered), he did not disclose that he was a principal investigator, nor did he forward her serious concerns to the IRB.

I was shocked to read Dr. Schulz’s testimony that he hadn’t even read the consent form for a study in which he was a co-investigator (and was listed on the FDA Form 1572 as being a responsible party). (p 156 Schulz deposition).

Nor was Schulz, a leading schizophrenia researcher, aware that informed consent requires disclosure of financial COIs:

“At another point, plaintiff attorney “Barden read an excerpt from a bioethics book arguing for the importance of informing patients about a doctor’s financial ties to drug companies.

“Do you agree or disagree with that statement?” asked Barden.

“I don’t agree with that statement,” replied Schulz, arguing that disclosing this information could “confuse” the situation.

“Have you had any training in biomedical ethics?” pressed Barden.

“I’ve taken the courses at the University of Minnesota that are required for us to participate in clinical research.”

“And isn’t this part of that training?”

“I’m not aware,” said Schulz. “I don’t recall that.”

CROs

Contract research organizations (CROs) are intermediaries hired by a sponsor (generally pharmaceutical) to administer a clinical trial. This used to be done by the pharma company itself. As business has gotten more competitive, they generally farm that work out now, to avoid having to have their own staff. Quintiles, responsible for the CAFÉ study, is the largest CRO, capturing 14 percent of the lucrative $11.4 billion global market^⁠.

CROs put a lot of pressure on sites to enroll. Delays in completing the approval of a new drug cost from $684,931 to $1 million per day and slow recruitment is the major factor. So they try to motivate their sites to enroll patients, sometimes with encouragement (holding them up as examples to other sites or similar recognition) or promises of further studies, sometimes by threats of having the trial taken away^⁠. They employed both tactics to manipulate the study coordinator, Jeanne Kenney, illustrated by their e-mails here and here.

While CROs can often provide helpful tips from their experience doing trials, I was flabbergasted to read, “In the CAFÉ study, for instance, a Quintiles study monitor suggested that each of the CAFÉ study site coordinators try recruiting subjects at homeless shelters.^⁠” This is so coercive and unethical, it almost defies belief. . .but the longer I am in this field (and in medicine), the more disillusioned I have become. I should no longer be surprised by anything, I’m afraid.

University

It’s not just individual researchers who benefit from industry-sponsored research. The entire university feeds happily at the trough. At University of Minnesota alone, “In fiscal 2010, business and industry sponsored $35.4 million in research spending at the U — 5.4 percent of total research expenditures of $653.6 million.”

And between 2002-8, drug companies gave “$88 million in gifts, grants and fees to Minnesota doctors and caregivers,” including $782,000 just to the University’s two psychiatrists.

The CAFÉ study initially suffered from poor enrollment—so much so that Quintiles, the CRO administering the study, had placed the site on probation and threatened to terminate it.

One Flew Over the Cuckoo's Nest

So the university established a 16 bed specialty psychosis unit at Fairview hospital, known as “Station 12,”  “in part to enhance the hospital’s startup schizophrenia program and meet the U’s mandate to bring in more research dollars.” According to a CAFÉ Study Coordinator Teleconference, on this unit “All patients are reviewed for possible research candidacy.  Research staff are in contact with nurses, case managers, and attending psychiatrists daily   Research staff attend morning report before inpatient rounds take place.  The focus is to identify any possible subjects that may be eligible for studies. This is also focused on building a repertoire [sic] with psychiatry residents, who are often much easier to approach than attendings.”

So we have a University department chairman demonstrating leadership by being unaware of basic research tenets and by saying that disclosure of financial COIs would just cause “confusion.” What an exemplary role model.

Of course, there are other COIs and pressures as well, in that successful enrollment begets publication, more fame, and more research grants from other sponsors as well. It also seems to bring considerable protection from those in power at the university.

IRB

The IRB holds a fair measure of blame in this tragedy, as well, though they have admitted no wrongdoing. The IRB is paid by the study to review the protocol and consent and, in theory, to provide oversight.

IRBs have had their own share of bad press. For example, the Johns Hopkins’ IRB received scathing criticism for failures of oversight in an asthma study that led to the death of a healthy volunteer, Ellen Roche. The Office for Human Research Protections (OHRP) temporarily suspended all federally funded research involving human subjects at Hopkins.

Even back in 1996, alarms were raised by the GAO that the workloads of IRBs were too heavy and precluded thorough review. The load on IRBs is well described in Trials and Tribulations.

Funding for IRBs comes from the study sponsors—in this case, AstraZeneca likely paid the U. Minnesota IRB fee. And while the fees are thousands of dollars, the workload of most IRBs results in just minutes spent on each protocol. (Note, individual members of a committee are not paid for their reviews. The funding goes to the institution for administrative overhead).

There are also nonfinancial ethical conflicts of interest involving IRBs. These may be due either to excessive personal involvement or prejudgment by the experts on the board, or increasingly, from competition between the PI and IRB members.

Academic institutions have an incentive to approve studies, so that they can tout that it is providing “state-of-the-art” medical care and that it has been selected as a research site over its competitors by a leading pharmaceutical company.

But IRBs have certain responsibilities. As noted even on the U Minnesota website, “The IRB reviews research projects which involve human subjects to ensure that two broad standards are upheld: first, that subjects are not placed at undue risk; second, that they give uncoerced, informed consent to their participation. The IRB works with investigators to modify projects to ensure adequate protection for its subjects’ welfare and right of self-determination. The University’s process for protecting human research subjects reflects federal regulations developed in response to such cases as the Public Health Service syphilis study and the U.S. government radiation experiments.”

Yet Moira Keane, the director of the IRB (and now a Board member for PRIM&R), responsible for overseeing the CAFÉ study, was asked in her deposition, “So it’s not the Institutional Review Board’s purpose to protect clinical trial subjects, is that what you’re saying?”

And she replied, “Yes.”^⁠

Conclusion

In the Markingson case, there are apparent conflicts of interest on multiple levels. The investigators had significant financial incentives to enroll patients—and to not alter therapy, even if a patient was not responding to therapy. Shockingly, the investigators claimed ignorance of basic ethical principles, including informing potential subjects of financial conflicts of interest.

They all claimed shocking levels of ignorance about basic research ethics, although holding positions of responsibility and authority. And, at each level, they absolved each other of any responsibility for this young man’s death.

With failures at multiple levels of supposed safeguards, and knowing that some of the same staff provided the assessments and care for patients on the AstraZeneca study as on a major NIH trial, the CATIE study, it seems essential that OHRP and an independent review examine not only the CAFÉ study, but take a careful look to see if similar breaches tainted the NIH trials.

Who will step up?

[I will continue this series in early January, looking a bit at the NIH and CATIE concerns and the University's troublesome response to this case. As Matt Lamkin just noted, "It can be difficult to keep up with the research scandals at Minnesota’s Psychiatry Department over the years," so we still have lots of questions to bring up.]

Suggested Readings:

Carl Elliott, A referenced summary of the Dan Markingson case

Jill A. Fisher, “Ready-to-Recruit” or “Ready-to-Consent” Populations?: Informed Consent and the Limits of Subject Autonomy

Jeremy Olson and Paul Tosto, Critics say drug firms’ payments to doctors are conflict of interest

William Heisel, The Markingson Files: Can pressure to recruit patients subvert a clinical trial?

Credits:

Dan Markingson photo courtesy Mary Weiss

Origami dollar heart -Thomas Hawk/Flickr

One Flew Over the Cuckoo’s Nest – Portland Center Stage

Molecules to Medicine banner © Michelle Banks

Dan Markingson and his mom, Mary Weiss

There are many disturbing things that happened during the clinical trial on which Dan Markingson committed suicide. Besides the issue of consent, or lack thereof, which I raised in my last post, one of the most disturbing aspects to me has been the lack of accountability and the apparent violations of clinical practice standards, with no consequences.

Zero accountability is how I have come to understand the outcome of this CAFÉ trial.

Clinical Research Standards—in Theory

Despite sensationalistic trials gone wrong, there are actually principles for “Good Clinical Practice,” and numerous guidelines for the ethical conduct of clinical trials. “Good Clinical Practice” (GCP) refers to International Guidelines on Harmonisation (ICH), E6 Guideline for Good Clinical Practice 1.24. This defines GCP as “A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of the trial subjects are protected.”

As part of this, there are extensive guidelines outlining the responsibilities of investigators and delegation of authority. The 2009 Guidance for Industry—Investigator Responsibilities, explicitly focuses on the supervisory responsibilities of investigators, stating, “When tasks are delegated by an investigator, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated. The investigator is accountable for regulatory violations resulting from failure to adequately supervise the conduct of the clinical study.”

The FDA also notes that inappropriate delegation includes:
“Screening evaluations, including obtaining medical histories and assessment of inclusion/exclusion criteria, conducted by individuals with inadequate medical training (e.g., a medical assistant).”
Informed consent obtained by individuals who lack the medical training, knowledge of the clinical protocol, or familiarity of the investigational product needed to be able to discuss the risks and benefits of a clinical trial with prospective subjects.”

Form FDA 1572—Statement of Investigator

In addition to the FDA guidances, all investigators on investigational studies have to sign an agreement with the FDA, called the Form FDA 1572. The 1572 is a binding contract between the investigator and the FDA, whereby the investigator makes certain commitments. Investigators are required to sign a Form FDA 1572 for any phase 1 through phase 3 study; they are up to the discretion of the sponsor for Phase 4 (post-marketing) studies. Dr. Olson had signed the 1572 for this study, assuming specific responsibilities. As I explain in my text, the 1572 is essentially a marriage contract between the investigator (PI, or Principle Investigator) and co-investigators and the FDA whereby the investigator vows to fulfill the following obligations:
•    Conduct the trial in accordance with the protocol. The PI can only change the protocol if a patient’s safety, rights, or welfare is at stake.
•    Personally conduct or supervise the investigation. If responsibilities or assessments are delegated, the PI is still responsible.
•    Inform patients that the drugs are being used for investigational purposes.
•    Report adverse events (AEs) to the sponsor, within 24 hours if they are serious AEs.
•    Read and understand the Investigator’s Brochure, the information already known about the drug.
•    Ensure that other staff members who are assisting in the trial understand their obligations.
•    Maintain accurate records.
•    Report all unanticipated problems promptly to the IRB.

Responsibilities: Theory vs. the Reality of the CAFÉ Study at the U. of Minnesota

Let’s look at the reality of what happened to Dan Markingson on the Seroquel study, and see how it stacks up to basic expectations for the conduct of a clinical trial. Dan was enrolled on a study for schizophrenia, yet the diagnosis was initially “psychosis NOS” (not otherwise specified and to rule out bipolar affective disorder). The diagnosis of schizophrenia was not firmly documented until some time after he was enrolled.

Dr. Olson clearly delegated responsibilities to someone who was not at all adequately trained to do them. A social worker, Jeanne Kenney, did most of the clinical trial assessments. Her deposition and the recent, feeble “corrective action” issued by the Minnesota Board of Social Work as penance for her role, are quite damning. For example:
—although she fully acknowledged lack of any training in biological sciences, let alone medicine, she was responsible for evaluating Dan’s “review of symptoms” and noted, incorrectly and repeatedly, that he had hyperthyroidism, rather than hypothyroidism.
—she acknowledged that Dan had ~15 lb weight loss over a relatively short time, yet did not bring this to anyone’s attention because she didn’t understand that it might be significant.
—at one point, when questioned about inconsistencies in pill counts and Markingson’s erratic compliance, attorneys asked about there having been “106 percent compliance” with medications, she responded as follows:
Q.  Did that concern you that this person is getting overmedicated?
A.  Not for one day, no. Not for one day.

Q.  Because why?
A.  I just — kind of based on our own experience of, you know, my own medications or something, if I took one, I don’t think that would be anything to scare me, and I’d never heard that taking one too many pills would hurt anyone. So –

Q.  But this was six too many pills.
A. Six too many pills was, really, they were all small doses, so it really only would have been like one pill possibly.

Q.  Possibly. But you don’t know that.
A. Well, I don’t — at the time, I didn’t know which medication…

Q. Did you notify Dr. Olson about this breach in protocol?
A: I don’t remember if I told him or not…

The Board concluded that her documentation consistently fell below the minimum standards expected for a social worker. As bioethicist Carl Elliott summarizes in “I was Just Following Orders,” “despite the fact that Kenney had no formal medical training, she apparently administered prescription drugs to research subjects and made formal judgments of the side-effects. She frequently assessed the severity of potentially dangerous adverse events such as akathisia [disturbing feeling of inner restlessness and inability to be still], and sometimes she even assigned the job to a social work intern she was supervising. According to the Board, her record-keeping was “devoid of any clearly articulated, consistent set of treatment goals” and she omitted crucial information relevant to suicide prevention. When Markingson’s mother, Mary Weiss, left “alarming voicemail messages” about her son’s condition, Kenney did not respond adequately.  Kenney also made significant mistakes about medication dosage and a medical diagnosis, and these mistakes remained in the chart until well after Markingson’s suicide, when Kenney went back and changed them. To top it all off, Kenney often signed the chart with the initials of a physician.”

Mary Weiss' plea for help

A message left by Dan’s mother, Mary Weiss, to the study coordinator, Jeanne Kenney, which warned, “Do we have to wait until he kills himself or someone else before anyone else does anything? ” Yet neither Kenney nor Dr. Olson thought this was worrisome enough to even notify the IRB, let alone to drop Dan from their clinical trial and place him on other medications, such as the Risperdal he had initially stabilized on, or Haldol, an older antipsychotic. In her deposition, Kenney acknowledges that Olson was a vulnerable subject, yet she did not feel it necessary to report his mother’s concerns to the IRB.

Given the severity of the violations of Good Clinical Practice standards and the resultant death of a clinical trial participant, what do you think would be an appropriate punishment?

Ms. Kenney received a carefully worded “corrective action” that emphasized that this was not a disciplinary action—and that only requires her to do 18 hours of continuing education and write a book report to the Board about what she had learned…and it took four years for the Board to reach this conclusion.

This response is disappointing, but not altogether surprising. Unfortunately, there is a long history of punishing low-ranking members of a unit. That they were “just following orders” has never been felt to be an adequate excuse. All too often, the leaders escape scott free.

It’s not hard to find summaries of investigator responsibility. For example, Dartmouth clinical trials website states, “The investigator is legally responsible for all aspects of the investigation and cannot delegate this responsibility to another individual.
It is common practice for investigators to delegate certain study-related tasks to employee, colleagues, or other third parties (individuals or organizations not under the direct supervision of the investigator). When tasks are delegated by the investigator, the investigator is responsible for providing adequate supervision or those to whom tasks are delegated and the investigator is accountable for regulatory violations resulting from failure to adequately supervise the conduct of the study.”

I have spent hours poring over depositions and original documents for the CAFE study, yet my review was, of necessity, incomplete, as there are thousands of pages. I did learn that Dan was told in his consent that his condition would be monitored closely by the study doctor (p 213 of Olson deposition), yet Dr. Olson only saw Dan monthly (p 164 ).  Olson was unaware of some notes from neuropsychiatric testing that said that Dan was not on medication at that time (though he was supposed to have been). (p 230-232). He was similarly unaware of clinic notes from March, 2004, that suggested deterioration. (p 243-4). Yet on April 27, he recommended extending Dan’s stay of commitment for an additional 6 months.

Pill count?

It is still unclear to me whether he made dosage adjustments after seeing Dan or if he relied on Kenney’s assessments to modify dosages. What seems clear from the depositions, however, is that Olson deferred most of the visits to others—not exactly my definition of close follow-up by your doctor. (For more about PIs—Partially-Involved Investigators or, more disparagingly, Phantom Investigators, see Elizabeth Moench’s unsettling article).

Olson did state that, at the time of enrollment, Ms. Weiss expressed concerns as to whether medication would be switched if the medication didn’t work. (p 221), and he was aware of her desperate message to the coordinator, though he did not return her call. How does Dr. Olson’s actions fit with the responsibilities he assumed towards his patient and by signing the FDA Form 1572 obligations of investigators?

Physician as Caretaker vs. Investigator

There is another troublesome aspect—that of the conflict of interest of Dr. Olson’s being both the physician responsible for Dan’s care as well as being the Principle Investigator. (While we will discuss Conflicts of Interest in more detail in an upcoming post, I want to raise this here as a particular responsibility Dr. Olson seems to have shirked). Dr. Olson acknowledged, in his deposition, that he was Dan’s personal, and only psychiatrist, and that he did not transfer his care to someone else. He also, surprisingly, admitted not knowing the term “therapeutic misconception.” (p 72)

The U. of Minnesota training module says that “recruitment of participants need to be done in a non-biased, non-power based manner. It is important that none of the participants ever feel they do not participate in the study, they will be penalized.” (p 219)

Dr. Olson failed to act in his patient’s best interests. If a patient is doing poorly on a treatment regime—be it research or not—it is customary and obligatory to look at other treatment options and to change therapies. While some of the staff say they did not detect the deterioration that caused Ms. Weiss to sound alarms, it is clear that Dan was not showing an adequate response to his treatment. Despite 5 months of treatment, Dr. Olson recommended that Dan’s stay of commitment be extended for another 6 months, conveniently allowing Dan to complete the study.

The conflict between being the primary caretaker and a researcher is something many of us struggle with regularly. That is why it is recommended that the research physician not be the patient’s primary physician. I also encountered this conflict with many of the trials I conducted, which often enrolled patients with severe and life-threatening infections. My threshold was always, “What would I want if this were my family member?” and “Can I sleep tonight without regrets?”

Conclusion

The Minnesota Social Work Board’s puny response towards Kenney is not what I find most troublesome. The thing that I am most appalled by in reviewing this tragic case is that nothing—absolutely nothing—has happened to Drs. Olson or Schulz, the IRB responsible for overseeing the trial, or the University of Minnesota.

Why not?

Credits:
Photo of Dan Markingson and Mary Weiss courtesy of Mary Weiss

Pills by e-magic/flickr

Molecules to Medicine banner © Michelle Banks

For further information on research ethics, basic courses are available through ACRP (Association of Clinical Research Professionals) and PRIM&R (Public Responsibility in Medicine and Research).

Dan and his mom, Mary Weiss

The suicide of Dan Markingson, a 26 year old man participating in a psychiatric trial, has again made the news, and will serve us for a life-time of study and discussion of research ethics, along with the TeGenero and Jesse Gelsinger cases.

Markingson began to show signs of paranoia and delusions in 2003, believing that he needed to murder his mother. He was committed to Fairview Hospital involuntarily after being evaluated by Dr. Stephen Olson, of the University of Minnesota. He was subsequently enrolled on a clinical trial of antipsychotic drugs—despite protests from his mother. This study was a comparison of atypical antipsychotics for the treatment of first episodes of schizophrenia (aka the CAFÉ study), sponsored by AstraZeneca. The study’s structure was that of a Phase 4 randomized, double-blind trial comparing the effectiveness of three different atypical antipsychotic drugs: Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine), with each patient to be treated for a year.

Esquizofrenia

After about two weeks on study treatment in the hospital, Markingson was discharged to a halfway house—again over his mother’s objections. Over the coming months, Dan’s mother, Mary Weiss, continued to express concerns about her son’s deterioration, even asking if her son might have to kill himself before anyone else would take notice…then, in fact, her son violently committed suicide on May 7, 2004, mutilating himself with a box cutter.
The University of Minnesota and their IRB have maintained that the study was conducted appropriately and that they have no responsibility for Dan’s death. Dan’s mother and bioethicist Carl Elliott believe otherwise. Elliott has written passionately about the case regularly, with major articles being here and here.

We’ll explore some of the major issues of contention in this case over several posts, as illustrative of basic clinical research principles, including adequacy of informed consent, IRB oversight, conflicts of interest, and coercion, including threats to a bioethicist whistleblower.

Consent

First, let’s look at making an “informed consent” to participate in a clinical trial. What is this supposed to mean?
Consent is supposed to be more than just a signed document. It should be a process of explaining a trial to a volunteer, including procedures to be performed, risks and benefits, and alternatives to participation. While a consent is an agreement to participate in a trial, it is different than a contract in that the volunteer may opt out of participation in a study at any time, without any adverse consequences or penalties.

While the study coordinator sometimes obtains a consent, because of the grave responsibility associated with ensuring adequate consent, I did not delegate this responsibility. I can’t speak for others.

The following elements of the informed consent agreement are required by the FDA and the International Conference on Harmonisation and are further detailed in the “Informed Consent Form Requirements Checklist” from my text, “Conducting Clinical Research: A Practical Guide…”:

• A statement that the study involves research
• The purpose of the research
• A description of the study procedures
• The time frame in which participation will occur
• A description of the procedures or treatments that are experimental
• A description of anticipated risks and discomforts, and a caveat that there may be significant unknown risks
• A description of what, if any, benefits might be reasonably expected
• Alternatives to participation that are available
• A confidentiality statement, explaining who will have access to the records and for what purpose
• An explanation of compensation (and limits) for treatment or injury
• Direction as to whom to contact for further information, including both the Principal Investigator and the IRB
• A declaration by the volunteer acknowledging that his or her participation is voluntary, that he or she is aware that no benefits will be lost should he or she choose not to participate, and that there is no penalty for early withdrawal from the study

Other elements are strongly suggested. The following elements are optional under the FDA regulations but are required by the ICH:

• An explanation that the volunteer may be dropped from the study without his or her consent, by the investigator or by the sponsor, should that appear to be in the volunteer’s medical interest or should the study be terminated early
• A description of any costs that might be incurred by the volunteer
• An assurance that the volunteer will be informed of significant new findings during the study that might affect his or her decision to continue participation
• A statement that the volunteer has received a copy of the informed consent document

The ability to provide an informed consent is dependent on a number of factors, including educational status and beliefs that derive from cultural, social, and family influences and evolve over time. An in-depth, highly recommended review is the IOM’s report Health Literacy: A Prescription to End Confusion.

Frighteningly, the level of general health literacy is quite dismal, although it is critical to accessing even routine health care. In an often-cited white paper, the Joint Commission reported that 44 percent of patients who signed an surgical consent form did not know the exact nature of the operation to be performed, and 60 to 70 percent did not read or understand the information on the form. Imagine how much worse this is likely to be for investigational clinical trials.

Consent and Research Ethics

We’ve talked before about the basic ethical principles outlined in the Belmont report:
Respect for persons, or the voluntariness of participation;
Beneficience, or benefit to the specific individual;
Justice, that “vulnerable” populations—groups including children, the indigent, the military, prisoners, pregnant women, and institutionalized—require additional protections as they are particularly vulnerable to coercion,

Consent for Vulnerable Populations

The first major question regarding Dan Markingson’s participation in this clinical trial was whether the consent was informed and properly obtained. The US Common Rule directs Institutional Review Boards (IRBs) “to include ‘additional safeguards…to protect the rights and welfare’ of ‘mentally disabled persons.’” There certainly appears to have been none here. After all, Markingson had just been involuntarily committed to psychiatric treatment. A look at the time course related to Dan’s participation raises disturbing questions.

Timeline

November 12: Dan Markingson was hospitalized on a psychiatric ward. “The diagnosis at that time was psychosis and mood disorder, and to rule out bipolar affective disorder with psychosis and schizophrenia.”Dr. Olson’s “differential diagnosis includes paranoid schizophrenia, schizoaffective disorder, and bipolar disorder with manic psychosis.” At that time, it was “noted that Mr. Markingson was felt to not have the capacity to make decisions regarding neuroleptic medication” and that he was refusing to take the prescribed Risperdal.
November 13-14: Dan agrees to take Risperdal
November 18: evaluation “no cognitive difficulties were noted which could potentially interfere with his ability to actively participate in his own treatment.”
On November 19, Dr. Olson discussed the CAFÉ  study with Dan. This same day, in a pre-petition screening, a clinical psychologist, Dr. James Jacobson, confirmed Dr. Olson’s assessment that Markingson failed to acknowledge having a mental illness and that he “is believed not to have the capacity to make decisions regarding neuroleptic medication.”
On November 20, the judge elected to stay Mr. Markingson’s commitment for a period of six months, “so long as he followed certain conditions: …(a) that he remain hospitalized, cooperative with the treatment plan at Fairview University Medical Center until medically discharged and follow all of the aftercare recommendations of the treatment team; (b) that Mr. Markingson participate in and satisfactorily complete the inpatient/outpatient treatment program and aftercare recommendations as determined by his social worker…”
On November 21—just two days after being deemed incapable of consenting to Risperdal (antipsychotic treatment), he was suddenly determined by Jeanne Kenney, his social worker, to be capable of consenting to a clinical trial of antipsychotic medications. The 10 page CAFÉ  study “consent form was read to him verbatim.” Dan then signed the consent, witnessed by Kenney, who also had responsibility for study recruitment. Curiously, he remained on Risperdal until December 5.
On December 11, when Dan had his first study visit, Dr. Olson diagnosed him with schizophrenia—conveniently one of the criteria for participation in the trial on which he had already been enrolled.
March 15, Ms. Weiss sent a certified letter expressing her concerns to the study investigators, and never received a reply.
April 9: Meeting with Dr. Olson, Jeanne Kenney, David Pettit (Dan’s Dakota County case manager), Markingson, and Ms. Weiss, who again expressed increased concerns about her son’s lack of improvement on the study medication. Dr. Olson concurred that Dan’s “ADLs had deteriorated over the last few months, and often looked more disheveled.”
An agreement was reached to extend Dan’s stay of commitment for another six months.
April 15: message left by Dan’s mother, Mary Weiss, to the study coordinator, Jeanne Kenney, which warned, “Do we have to wait until he kills himself or someone else before anyone else does anything?”
April 15-26, Ms. Weiss wrote three letters to Dr. Schulz, the study’s co-investigator, begging for help with her son’s deterioration and increasing agitation and “rage…desperately needs help in dealing with it. Please don’t wait until it comes boiling out!”
May 5, Ms. Weiss informed others that she would seek conservatorship of her son; Dan told Pettit, his case manager, that he did not want that.
May 8, 2004 Dan Markingson committed suicide.

Should Dan Markingson have been enrolled on this clinical trial?

There are several issues here. Before the obvious, “Was Dan capable of consenting?” is the question of the enrollment criteria for the trial. This was a trial for patients with the first episode of schizophrenia. Dan was initially diagnosed as having a psychosis “NOS,” or not clearly defined. It was not until December 11—almost 3 weeks after his enrollment—that Dr. Olson clearly labelled him as having schizophrenia. Also, patients with schizophrenia are at increased risk for suicide or violence, so violent ideation is typically an exclusion criteria on clinical trials. Why wasn’t homicidal ideation an exclusion on the CAFÉ trial?

Seroquel clock

What was the adequacy of Dan Markingson’s Consent?

Do you believe that Dan was able to provide an informed consent? I certainly have a number of concerns.

First, was Dan competent? After all, he was just institutionalized for being delusional and homicidal, and was denying that he had any mental illness. Several evaluations had concluded that he was incapable of consenting to taking neuroleptic (antipsychotic) drugs. The social worker, Jeanne Kenney, did the evaluation that determined that he was capable of consenting—but she was certainly not unbiased, being the study coordinator working under Dr. Olson and responsible for study recruitment. The study was on probation for poor enrollment, so there was also considerable pressure on her to boost enrollment.

There appears to have been an overwhelming level of coercion.
Dr. Olson discussed the protocol with Dan and then, the very next day, the judge stays the commitment with the condition that  he cooperate with treatment plans.

Two other problems with the written consent vs. reality of what happened are immediately evident. One is that the consent states, “If the study antipsychotic medication is not effective for you…you will discontinue from the study.” Markingson, who did not believe nor understand that he was mentally ill, was not likely able to ask to be dropped from the study, particularly when he believed that would lead to his being institutionalized. Ethically, investigators are bound to drop patients who are not improving on a study regimen. Yet this was never done.

Similarly, a standard clause in consents says, “What if we learn about new risks during the study? You will be given any new information gained during the course of this study that might affect your willingness to continue your participation. “On March 17, 2004, the study sponsor warned investigators of a new risk of Seroquel – specifically, the hyperglycemia and weight gain.” The increased risks of diabetes and metabolic abnormalities from Seroquel were never disclosed to Markingson. He should have been reconsented when this information came to light, but Kenney failed to do so.

The problems with consent are but the tip of the iceberg in this tragic story. In upcoming posts, we’ll look at the responsibilities of Principle Investigators, delegation of responsibility, conflicts of interest, and much more.

Suggested Readings:

Elliott, Carl. “I Was Just Following Orders”: a Seroquel Suicide, a Study Coordinator, and a “Corrective Action.”

Elliott, Carl. “The Deadly Corruption of Clinical Trials”

Elliott, Carl. “A referenced summary of the Dan Markingson case”

William Heisel also has excellent coverage at http://www.reportingonhealth.org, which I will be citing in upcoming posts.

Original documents including the study protocol, consent, and testimonies of expert witnesses can be found at http://www.scribd.com/MarkingsonCase/documents

Correction: This was a Phase 4 study.

Credits:

Photo of Dan and mom, courtesy Mary Weiss

Seroquel clock image – rexdownham

Esquizofrenia – RxHxS

“Molecules to Medicine” banner © Michelle Banks.

Protest over Savita Halappanavar's death - separation of Church and State

Sometimes I feel like Alice in Wonderland, staring into distorting mirrors. The ongoing fight over Plan B has again precipitated this disquieting feeling. There is such a disconnect between some stated outcomes that are claimed as being desirable and actions that don’t support that. In this case, probably most people would agree that elective abortions are unfortunate and not a desirable outcome. But how different sides would approach this problem are at polar opposites.

For example, conservative folks on the political right are using draconian measures of banning abortions—even if the mother’s life is at risk—and attacking clinics and murdering health care workers, at the same time as euphemistically proclaiming themselves “pro-life.” “Small government” proponents want to insert themselves into every aspect of a woman’s life and health, including via intrusive, medically unnecessary vaginal ultrasounds, psychological duress, and insanely stupid debates about “legitimate” rape. In contrast, many of us who are more liberal, focus our efforts on reducing the need for abortion, aiming to achieve this goal by providing education and family planning services.

Also, on the one hand, we are asking physicians to practice more evidence-based medicine, at the same time as, in the area of women’s reproduction at least, politicians are tying their hands.

Memorial rally in Dublin for Savita Halappanavar and women's rights

This issue has resurfaced in recent weeks, first with the tragic and senseless death of Savita Halappanavar, a 31 year old Hindu woman who had the misfortune to have a miscarriage “treated” in an Irish hospital imposing barbaric and antiquated Catholic doctrines on her. As well described by Dr. Jen Gunter, physicians did not perform a medically necessary abortion on a non-viable fetus, instead choosing to let a woman die painfully and needlessly from overwhelming sepsis.

Last week, the The American College of Obstetricians and Gynecologists called for birth control pills to be sold over the counter, noting that the cost and difficulty of seeing a physician to obtain a prescription is a major barrier to use of contraception.

This week, Plan B is again making headlines, as the American Academy of Pediatrics (AAP) just recommended that pediatricians provide prescriptions for Plan B to teenagers to have on hand “just in case.” Don’t get me wrong—I think this is a great step forward for health care for teens. But it falls short of what is rational, evidence-based, and necessary practically.

The battle over men’s control of women’s bodies has been going on for years, though has certainly heated up with this election cycle. Before, we even saw access to science-based information being limited through censorship and distortion even in government sources (e.g., data regarding the efficacy of condoms in preventing HIV infections and STDs were removed from the CDC’s Web site). This helped neither the rates of abortions, the teen birthrate, nor STDs and HIV to go down. At the same time as HIV prevention programs and NIH funding has been cut, funding for abstinence-only programs rose from $20 million to $167 million, despite any lack of evidence of effectiveness. To reiterate, No federal money is spent on comprehensive sex education. Even worse, since 1982, “Over $1 billion in government funding has been granted to abstinence-only programs…[which] are expressly forbidden from discussing contraception…and often contain factually inaccurate and distorted information. Those who design and operate these programs are often inexperienced, religiously-motivated and frequently have close ties to the anti-abortion movement.”

So why are we tolerating this? (For more history related to the FDA and reproductive politics, see my previous post here.)

Note that several years ago, Susan F. Wood, former assistant FDA commissioner for women’s health and director of the Office of Women’s Health, resigned because of the politicization of the agency—specifically, having the approval of Plan B emergency contraception denied, despite scientific evidence of the pill’s safety and recommendations from the FDA’s own advisory committee. Yet the same battles are still taking place.

Plan B Perspective

The irrational decision to overrule the recommendation of numerous experts appears to be based on the idea that young girls would be buying the pill without parental consent, and that such girls could not do so safely. They ignore that kids can readily buy Tylenol, which has significant liver toxicity and is often a component of deadly drug overdoses. Plan B is far safer—and also unlikely to be used routinely because, at ~$50, it is relatively expensive. They ignore the dangers of pregnancy, which are far greater…or the dangers of a teen suffering from rape or abusive parents, who certainly doesn’t need the added trauma of an unwanted pregnancy.

Plan B has the same hormone found in birth control pills, progestin, but in a larger dose. It works primarily by preventing ovulation. It does not cause an abortion. Taken within 72 hours of unprotected sex, it reduces the risk of becoming pregnant to only about 1 to 2 percent—the sooner taken, the more efficacious.

Given the clearcut and overwhelming data, I was tremendously disappointed by last fall’s decision by Secretary of Health Kathleen Sebelius’ to deny the emergency contraceptive, Plan B, over-the-counter status for women under the age of 17. This was a particular disappointment to many because President Obama had promised that decisions at the FDA would be made based on science, rather than politics. Clearly, that wasn’t the case.

President Obama expressed his concern as a parent, that his daughters must not have access to such a medicine without adult guidance. That may be true in an ideal world, but it is neither practical, nor does it bear any resemblance to the realities of many teens’ lives. The US has a higher teen pregancy rate than any other developed western country, with five times the teen birthrate in France and 2 1/2 times the rate in Canada. “Only half of the nation’s teen moms ever earn a diploma; more than half go on welfare; and more than half of the families started by teens live in poverty,” according to “Sacrificing ‘Change We Can Believe In’ for Expediency?” According to a pediatrician author of the new AAP policy, teen pregnancy perpetuates a cycle of poverty and problems, as these babies perform more poorly in school and tend to have ongoing behavior problems.

Given the safety data, the lingering educational and economic harm and the huge personal toll of unexpected and unwanted pregnancies, I am disappointed that the AAP did not go further in their recommendation. It is unrealistic to expect teens to be able to get a prescription from their physicians for emergency contraceptives. Many teens do not have access to regular medical care. Instead, the AAP and ACOG should strongly back the FDA, who already recommended OTC status for the drug for teens. And we should all send a strong message to President Obama: decisions should be based on science, not politics. You have been re-elected. Stand up and don’t overrule the FDA and data on this public health and economic issue. Make emergency contraception available to all, regardless of age.

Updates 11/30/12:

See my comments in response to a reader for further information about the application of the Catholic religious directives during miscarriages.

Also, to encourage HHS Secretary Sebelius to take action, the Union of Concerned Scientists has a new petition up, “Tell HHS Secretary Sebelius: Allow the FDA to Revisit its Plan B Decision.”

Credits & Links:

Molecules to Medicine banner © Michelle Banks

Savita protest images by infomatique (William Murphy)/Flickr

Small portions of this post appeared previously in Plan B: The Tradition of Politics at the FDA.

see also:
Plan B’s ad: “I chose a condom but it broke. Now I Have A Second Chance.”

and a superb cartoon capturing the debate, Matt Davies,’ “Which of these responsibilities is a 15 year old too young to be handed?”—a screaming baby or Plan B pill.

Antikamnia calendar

32 deaths. 461 cases…and counting. Unless you live under a rock, you probably know about the nationwide outbreak of an unusual fungal meningitis caused by Exserohilum rostratum, a plant fungus. The outbreak is now linked to a single pharmacy in Massachusetts, New England Compounding Center (NECC), which compounded a variety of drugs used for injection, including the implicated steroid.

Almost daily, we learn sordid new details, without any of the irony or salaciousness of the Petraeus affair. This week’s shockers included:

- Birds found flying around a drug storage area of Ameridose (companion company of NECC) and insects adjacent to a sterile area.

Exserohilum fungus - CDC

- Barry Cadden, president, co-owner and director of NECC, pleading the fifth amendment to avoid self-incrimination at today’s House Energy and Commerce oversight subcommittee hearings. Cadden then shamelessly left, carefully avoiding any contact with Joyce Lovelace, widow of the first victim.

- More conflicts of interest unearthed, with Cadden having been “chosen to serve on a state pharmacy board task force to write new rules for compounding pharmacies” in 2002, the same time the FDA began reviewing complaints about his company, NECC.

-According to the Boston Globe, although three top pharmacy board administrators knew that the “Illinois company chosen to monitor NECC was led by a man convicted of fraud involving a product blamed for blinding people…they did not tell board members before they voted the following month to accept the Illinois firm’s findings that New England Compounding had made satisfactory improvements.”

-The director of the state’s pharmacy board was fired for failing to alert the board that NECC was making and distributing drugs in mass quantities even though it wasn’t licensed to do so

So why are we relying on compounding pharmacies?

Compounded drugs used to be mixed by a relatively small and generally local pharmacy and are intended for a specific patient.  The law regulating compounding pharmacies, in fact requires that each compounded drug be prepared based upon a prescription from a physician for a specific patient. They are custom produced to meet specific allergies, for example, or to mask flavor. However, New England Compounding Center (NECC), was were essentially acting as a small pharmaceutical company, mass producing the steroids for injection.

Such broader production of compounded drugs was originally intended to be a response to shortages of raw materials. Due to the wide-scale shortages that have become commonplace in the last few years, a marketing opportunity has appeared that compounding pharmacies have been quick to fill. Some compounding companies have also been allowed to also continue production as less-expensive alternatives to brand name drugs.

Let’s play pin the blame on…the FDA

There’s one thing there is no shortage of in this tragic meningitis outbreak—finger-pointing. The first point of attack was, appropriately, on the pharmacy. Rather than compounding drug for an individual patient, they became a major supplier across the country. In fact, they sold large quantities of the implicated steroid product to the government itself, for the Veterans Administration. Further, while she reportedly recused herself, Sophia Pasedis was an executive for a NECC-affiliate as well as board member and former president of the Massachusetts Board of Registration in Pharmacy. This obviously raises the question as to whether a cozy relationship might have led to averted gazes.

But, as in keeping with tradition, the main question has been, “Why doesn’t the FDA regulate compounding pharmacies?” The answers are quite peculiar. First, the FDA actually doesn’t appear to have the authority to do so, according to Kevin Outterson, director of the health law program at Boston University. As collateral damage in a 2002 suit, (Thompson vs. Western States Medical Center), in a Supreme Court ruling regarding a pharmaceutical company’s advertising and free speech, the FDA lost much of its regulatory oversight of compounding pharmacies.

While the FDA is being criticized for not providing more oversight, according to Regulatory Focus, “In a case involving Franck’s Pharmacy—the same company whose products were involved in the May 2012 recall—a judge ruled FDA could “not assume it had authority to regulate compounding pharmacies.” Professor Outterson further details how the 2002 Supreme Court ruling hobbled the FDA in a recent New England Journal of Medicine article, concluding, “It’s possible that if the Supreme Court hadn’t struck down Section 503A, the tragedy at NECC could have been averted.”

So now the FDA has to wait until there is a problem before they can intervene in production by a compounding pharmacy. According to the NY Times, the International Academy of Compounding Pharmacists actually “tutored pharmacists on how to sidestep requests” for information or samples from inspectors.

Adverse reactions are not easy to detect. This outbreak was picked up early because of an astute Infectious Diseases physician at Vanderbilt, Dr. April Pettitt, who took a careful history, prompting her suspicion that her patient’s unusual fungal meningitis was related to the injections he had received.

There is no well-organized procedure for detecting adverse outcomes. Side effects are reported during clinical trials, but include relatively small numbers of patients. Post-marketing or for compounded drugs, there is only a voluntary reporting system through MedWatch. Frankly, many physicians either don’t think of this, nor will they find it very gratifying activity to complete yet more forms. And while the number of FDA analysts has held steady, the number of adverse event reports has steadily grown, along with the number of drugs available. Even when there are drug recalls, detecting lots is cumbersome and not everyone adheres to the recalls.

The FDA is in an unenviable position. While they were aware of some problems at NECC and, in fact, issued a warning in 2006, the FDA has deferred to “states’ rights”: “so long as a pharmacy’s operations fall within the scope of the practice of pharmacy (as outlined in FDA’s Compliance Policy Guide 460.200), FDA will generally continue to defer to state authorities for regulatory oversight.”

Once again, the FDA is in a no-win position. If they try to be tough enforcers, they are damned by pro-business forces, like Congressman Darrell Issa’s witchhunt report, the FDA’s Contribution to the Drug Shortage Crisis, where he criticizes the FDA warnings to manufacturers about production problems before actual outbreaks occurred, as being unnecessary. Would Issa have preferred the FDA to wait for outbreaks? Then the FDA would have been damned for not being proactive enough, which is what the consumer watchdog group, Public Citizen, has just done.

Lobbying

Lobbyists vs. Regulation

“Corporations are people, my friend,” and as such, exercised that in the Supreme course free speech case that limited FDA’s authority over compounding pharmacies. These pharmacies also have vociferous lobbyists who spend millions of dollars trying to prevent regulation; the International Academy of Compounding Pharmacists boasted of its success defeating such legislation. Previously, FDAMA prevented them from advertising their services: “The restrictions included that the prescription be unsolicited and that the providers not advertise or promote the compounding of any particular drug, class of drug, or type of drug.” Through the Thompson vs. Western States Medical Center suit challenging The Food and Drug Administration Modernization Act of 1997 (FDAMA)’s restrictions on commercial free speech, compounding pharma lobbyists were quite successful in widening their reach.

Partisan attacks occurred today targeting Dr. Margaret Hamburg, FDA commissioner, led by Rep. Joe Barton, of Texas. He forgot to mention that many compounding pharmacies and their lobbyists are also based in Texas. According to the NYTimes, Barton “is a top recipient of political donations from the industry” and is described by the compounding academy as a “dedicated” industry advocate…and been outspoken in praising compounding.” The NYTimes also notes that in 2003 ex-Rep. Tom DeLay, also from Texas, helped kill a Medicare bill regulating compounding, saying that regulating them should be left to the states.

Efforts have been made to regulate the industry, including the Safe Drug Compound Act of 2007, proposed by Senator Edward M. Kennedy, but they have consistently been defeated by compounding pharmacy  lobbyists.

The more that we learn about NECC, the role of cronyism, and lax regulatory oversight, the more sickening this web of deceit becomes. NECC knew that their so-called clean rooms, for sterile preparations, “contained bacteria or mold at levels requiring corrective action to remove contamination, according to company records,” yet they willfully ignored their findings, jeopardizing patients’ lives. Pharmacy workers turned off air conditioners at night, fostering conditions favoring growth of fungi and bacteria, and there was visible discoloration and growth on surfaces.

A scathing article in Slate notes that NECC had been repeatedly cited for failing to meet acceptable standards, and was to have received a 3-year probation and public reprimand in 2004. Craig Unger reports that the “reprimand was withdrawn by the [then Governor] Romney administration in apparent deference to the company’s business interests.” Thus, the probation was decreased to 1 year and the reprimand became “a non-disciplinary agreement that would not be reported to the National Association of State Boards of Pharmacy or other outside agencies.” According to Philip Johnston, former Massachusetts secretary of health and human services (pre-Romney), this was in keeping with the Romney administration philosophy “to have lax regulations across the board.”

Future Direction

The FDA has been attempting to reduce drug shortages by “fast-tracking” approval of manufacturing plants after remediation. The FDA also issued a pointed response to the House Oversight Committee’s report, squarely laying much of the blame for drug shortages on profit motives.

Now the FDA is being scapegoated by many, especially Republicans, for failure to oversee the compounding pharmacy industry, even though it appears to lack the authority to do so.

While I suspect there is plenty of blame to share, perhaps it might be more productive if the oversight group and “small government” representatives targeted lobbyists as well as the FDA for admonishment…but then they might not be re-elected.

As it stands now, even with fast-tracking, predictions are for serious drug shortages to continue at least through 2014, so we are likely stuck with needing compounding pharmacies.

I, for one, am a strong supporter of protecting the defenseless. As such, I believe that compounding should be limited to pharmacies producing drugs for individual patients, as was intended, and that large production centers, like NECC, should be eliminated or strictly regulated.

This outbreak surfaced just before the elections. Though they are mostly over (except in incompetent Arizona), this tragedy still illustrates stark differences in politics and approaches to governing. Do we want a laissez faire government that puts profits before people and believes in the superiority of privatization to such an extent that it waives any thought of regulatory oversight? Do we want a strong government and disaster preparedness agency through Federal Emergency Management Agency (FEMA), which is showing an exemplary response to Hurricane Sandy’s destruction, or “Heckofajob Brownie’s” pathetic and reckless response to the smaller Hurricane Katrina? Do we want an FDA with the authority and funding to protect us, or do we want to continue with a hodge-podge of individual state regulations?

The fungal meningitis outbreak is a microcosm of the decisions facing us and the opposing paths we might take. While it’s fine to want to encourage business, we need to be sure to do so without simultaneously endangering the public’s health. I hope that Congress and the Supreme Court will stop playing politics and finally give the FDA the tools it needs to protect us.

(This post has been adapted and updated from my guest post on Ed Silverman’s Pharmalot: The Op-Ed: Compounding & Laissez Faire Rules last week.)

Suggested Readings: for ongoing coverage

The Boston Globe series

Pharmalot

USA Today

Credits:

Anikamnia image Louise M. Darling Biomedical Library at UCLA

Lobbyists – Darin Barry/Flickr

Molecules to Medicine banner © Michelle Banks

Thalidomide children

I was attending World Federation of Jewish Child Survivors of the Holocaust and Descendants 24th Annual International Conference in Cleveland last week, when my aunt, herself a survivor, handed me a copy of Newsweek with a cover article, “The Nazis and Thalidomide: The Worst Drug Scandal of All Time.” The story was prompted by the drug developer, Germany’s Grünenthal, unexpectedly issuing an apology to the victims of its teratogenic drug—babies who sustained life-long wounds inflicted by their drug more than 50 years earlier.

I’ve written some about thalidomide previously, in my initial Clinical Trials for Beginners posts, (here and here). For those unfamiliar with the tale, Thalidomide was first released in 1957, with over-the-counter availability in Germany, to treat morning sickness. There were reassurances from the manufacturer that the drug was totally safe, even during pregnancy. It took several years of widespread use before the link was clearly made between thalidomide’s use in early pregnancy and the cluster of children who were subsequently born with small seal-like flippers instead of limbs (phocomelia). Thalidomide was then removed from the market. This tragic effects of thalidomide on developing embryos marks one of the most notorious failures in the history of drug development.

In a controversial move, the FDA approved thalidomide’s use in multiple myeloma in 1998. It’s also being used now for treating leprosy. Studies are in process for using thalidomide to treat the chronic cough of interstitial fibrosis, as well.

Thalidomide advertisement

We’ve discussed before that side effects often are not seen until after a drug is marketed. Since only small numbers of patients participate in clinical trials, and some adverse events occur very rarely, side effects like the phocomelia, the small flipper-like limb deformities associated with thalidomide, are not detected until post-marketing.

This brings us back to thalidomide’s resurfacing in the news. In September, Grünenthal, developer of the drug, rather inexplicably issued an apology to the victims of its drug—more than 50 years after the debacle began. Chief executive Harald Stock unveiled a bronze statue of a child born without limbs, stating, “We ask for forgiveness that for nearly 50 years we didn’t find a way of reaching out to you from human being to human being…We ask that you regard our long silence as a sign of the shock that your fate caused in us. We wish that the thalidomide tragedy had never happened.”

I found his apology to the more than 10,000 babies born with serious birth defects—including complete absence of limbs—about as touching as they, their parents and caretakers did. What these victims are asking is financial support to assist in their care and medical needs, something Chemie Grünenthal has resisted. One of the most chilling aspects of this sordid tale is the assertion that “in the immediate postwar years, a rogues’ gallery of wanted and convicted Nazis, mass murderers who had practiced their science in notorious death camps, ended up working at Grünenthal, some of them directly involved in the development of thalidomide.” One of the most reprehensible was Otto Ambros, an inventor of sarin (the nerve gas), who had been convicted of mass murder at the Nuremburg trials but was subsequently freed. After helping the US chemical industry, he went on to become chairman of Grünenthal’s advisory committee when thalidomide was developed. Newsweek’s Roger Williams and Jonathan Stone (no relation) give further horrifying details about links between Grünenthal and other Nazi’s as well, some of whom experimented on inmates at concentration camps such as Auschwitz and Buchenwald. Another former Nazi, Heinrich Muckter, received huge bonuses for rushing thalidomide to market, despite inadequate testing.

It’s no small irony that the response to the horrors of these “experiments” on innocent people led to development of the research codes of ethics, the Nuremberg Code, Declaration of Helsinki and the Belmont Report, which are the standards for all human research now.

Kati, 1946

This is my aunt, who survived Auschwitz in her teens. Miraculously, some, though not all, of our family survived. This is a more recent photo of her, from an educational exhibit in Omaha on the Holocaust.

Kati - 2008

There were several striking things about this Holocaust survivor and descendants’ conference. One was the ongoing pain and scars that still linger and are now cross-generational. Another was the survivors’ remarkable resilience. Yet another was how many have gone on into helping professions, part of their attempt at tikkun olam, or repair of the world. My father followed that path, making artificial limbs and prosthesis—almost certainly for thalidomide babies among them. It was my accompanying him on house calls to patients when I was a child that first stirred my interest in becoming a physician and my special interest in medical ethics and issues of social justice. And the conference’s final message was, “Remember…never forget…There is hope for your future.”

The take home message of the juxtaposition of this moving conference and then reading more about the Nazi connection to thalidomide is that, despite the Nuremberg trials and the development of ethical principles to guide research, we haven’t yet gotten it. It has taken fifty years for a tepid apology for thalidomide to arrive. Worse, there are still ongoing genocides throughout the world, either related to historic ethnic rivalries or, more often, related to money and greed. There are still major ethical abuses in conducting clinical trials. We seem to be confronted almost daily by evidence of our mistakes. What more will it take for us to learn and put people and ethics above power and profits?

Credits:

Thalidomide children: Luciana Christant/Flickr

Distaval ad: Duckwaill/Flickr

Photos of Kati courtesy of her and photographer David Radler

Molecules to Medicine banner © Michelle Banks

View from St. Andrews' conference room. Note they have a dock and helipad, enabling access by land, sea, or air.

Although I’ve been busy traveling again, the struggle of the Boothbay peninsula communities to keep their hospital remains constantly on my mind. I’ve written two letters to the editor of the Boothbay Register*, which I am reproducing here to update my readers, as this is an example of broader David and Goliath healthcare struggles and a case study of a crisis in rural healthcare.

The proposed closure of the ER is scheduled for April, 2013. Lincoln County Healthcare and MaineHealth have, thus far, refused requests from the community’s citizens and elected representatives to delay this execution to have time to conduct a more thorough economic impact study or explore other options.

See Hospital merger déjà vu and Big Fish Eats Little Fish- Warning for Rural Hospitals for further background.

It is important to note that if the hospital ER is closed, St. Andrews also loses its accreditation as a hospital and its designation (and considerable funding) as a rural Critical Access Hospital.

Boothbay ER closure plans smell fishy

Trauma Bay at St. Andrews' ER

As I was leaving Boothbay Harbor, Dr. Timothy Fox [medical director at Miles Memorial Hospital and St. Andrews Hospital] was kind enough to show me St. Andrews’ ER and answer some of my questions. I was very impressed with both his knowledge and how well-equipped the ER is. In fact, it has more sophisticated equipment and capabilities than we had when I left the hospital I worked at in Cumberland, Md.

Dr. Fourre [Director of Emergency Services and a Trustee of the Board of Lincoln County Healthcare] had suggested the need to close St. Andrews was due to quality concerns, but I missed seeing that. After all, most of the physicians work at both Miles and St. Andrews and some even rotate up from MaineMed. Both ERs are staffed with one physician, except for a six-hour overlap shift at Miles.

Using Sue Mello’s numbers [Boothbay Register] regarding ER visits: 390-542 patients with true emergencies (Level 1-3, defined as needing care in less than 1 hour) would need to be transferred out annually, at night, just during hours the proposed urgent care center would be closed.

So patients with a heart attack or serious problem will now have a further delay in receiving care while they are being transferred first to Miles and then in the opposite direction to Portland or Brunswick, rather than being stabilized in town. Even during the day, urgent care is not intended to accept such seriously ill patients, nor authorized even to accept ambulances, so a total of ~1500 Level 1-3, or the most seriously ill patients, would have to be taken directly to Miles annually. How does this improve the quality of care?

So what’s a small town to do?

Many tiny Critical Access Hospitals throughout the country are turning to telemedicine. I spoke with Kristi Henderson, Director of Telehealth at University of Mississippi and Dr. Rafael Grossman, head of TeleTrauma at Eastern Maine Medical Center. Of Maine’s 15 CAH, 8 use TeleTrauma, with excellent results and cost savings for all parties. Maine hospitals use telemedicine for Cardiology, Neurology/Stroke care, Pediatrics, and more.

Miles uses telemed in their ICU and is exploring use for stroke care. So telemedicine is successful solution for all parties, except for those on the Boothbay Peninsula. Lincoln County Health Care says the technology, now no more cumbersome than an iPod or iPad, is not “developed” enough for us.

Interior of BRAS ambulance

And Lincoln County Healthcare’s Cindy Leavitt incorrectly describes ambulances as “traveling ICUs.” Though our EMTs are well trained, ambulances are far from that. But that is another post.  Frankly, the more I learn about the proposal to close the peninsula’s ER, the more irrational and inexplicable I find it. And when something like this plan makes such little sense, I’ve learned to follow the money.

[Would you rather get care in the well-equipped, relatively spacious St. Andrews ER or in this ambulance--which is more roomy than most--careening on curvy country roads to Damariscotta?]

Yesterday, Joe Gelarden, Executive Editor of the Boothbay Register, accurately reflected the community’s anger and mistrust of LCH: “They feel betrayed by Lincoln County Healthcare’s decision to close St. Andrews Hospital. They resent the way Lincoln County Healthcare’s brass hid behind closed doors to make their decision. And they have a very real fear that if something should happen to them, they would be denied adequate healthcare services.”

My just-submitted letter to the editor is an open letter to Jim Donovan, the CEO of  Lincoln County Healthcare. It was written in response to the shocking report of the preliminary estimates of the increased costs of the ambulance service (aka “BRAS) and Mr. Gelarden’s description of Donovan’s strategy as “Rope-a-Dope.”

A local resident, Tom Hagan, questioned how LCH could make a sound decision to close St. Andrews without even having done the arithmetic, saying, “The headline should have been ‘St. Andrews Closing Decided Without Cost Data From Ambulance Service.’” One might say the same about the lack of an economic impact study. These lapses appear totally irresponsible.

LCH Plays Shell Game

Dear Mr. Donovan,

Please tell me again how closing St. Andrews’ ER will result in a significant cost savings for the citizens of the Boothbay peninsula and improve their quality of care, and otherwise create the best of all possible medical worlds? On the other hand, moving towards telemedicine, as is increasingly being done in rural communities throughout Maine (including Miles) and the rest of the country, has been cost-effective. So why not offer this at St. Andrews?

The delays in patients receiving care due to the transport time to Miles will certainly not improve the quality of care—(certainly not for those patients who die en route to Miles.)

And now we learn that the shift will increase the Towns’ subsidy of BRAS from:

$34,205 to $187,676.13 or an increase of 549% for Boothbay

$38,215 to $223,549.39 or an increase of 585% for Boothbay Harbor

$8,044 to $48,529 or an increase of 603% for Southport.

And that’s just for the next fiscal year. Costs are likely to continue to increase in the future due to the added costs for salaried EMTs (including health insurance), training, equipment. Would Mr. Donovan like to cover the town’s subsidies that will result?

"The Conjurer," painted by Hieronymus Bosch. The painting accurately displays a performer doing the cups and balls routine, which has been practiced since Egyptian times. The shell game does have some origins in this old trick. The real trick of this painting is the pickpocket who is working for the conjurer. The pickpocket is robbing the spectator who is bent over.

By closing St. Andrews’ ED, LCHC is playing a shell game here, as many cost savings LCHC realizes will simply be shifted to the taxpayers of the affected communities in higher taxes for increased ambulance service subsidies, and increased morbidity [illness] and mortality [death] for the Boothbay peninsula’s residents due to the additional travel time and ED wait times at Miles.

Is the ultimate plan to claim, 2 or 3 years down the road, that Urgent Care is not financially viable, and turn the entire valuable St. Andrews waterfront property into a casino or condos to subsidize local residents’ care? If this move is not a shell game, what would you call it? Aren’t shell games illegal?

*The first letter was published last week; the second has been submitted but not yet published.

P.S. to Mr. Donovan. You recently said, “I’m writing today to support the St. Andrews Task Force in its efforts to understand the demographic, clinical and patient volume trends that are significantly changing the way we (and providers everywhere) are delivering healthcare.” If this were true, you would not be rigid about an April, 2013 closure date, but would grant a stay of execution so that more thorough impact study could be done.

Credits:

Molecules to Medicine banner © Michelle Banks

Images of St. Andrews and BRAS ambulance by Judy Stone

Bosch’s “The Conjurer”/Wikipedia

That’s why, too often we rely on peer reviewers and journal editors to digest materials for us, and give us findings in a short abstract, rather than immersing ourselves in all the time-consuming and painful details.

So this week, I was excited to receive a late acceptance and be able to attend the Medicine in the Media course (aka #NIHMiM12), aptly subtitled “The Challenge of Reporting on Medical Research.” This intense course is sponsored by the NIH,  The Dartmouth Institute for Health Policy and Clinical Practice and the Department of Veterans Affairs. It is very wise investment by NIH, as it helps train media to review findings critically and to report medical findings correctly, which is no easy feat.

Lisa Schwartz and Steve Woloshin

The main instructors of the course were Drs. Steve Woloshin and Lisa Schwartz, from Dartmouth, where they teach and write about their “healthy skepticism” initiative. This program includes documenting exaggeration, overdiagnosis, and studies of effective risk communication.

While it will take me some time to absorb all the material presented in this intense immersion course, they have on-line aids outlining their approach to understanding studies, available online via the Journal of the National Cancer Institute’s web site and Dartmouth’s Healthy Skepticism program site.

I particularly like their systematic, standardized approach, illustrated by their summary of the value of CAT scans for lung cancer screening. It would be extraordinarily helpful to have this sort of uniform reporting of results. Of course, that would lead to a more literate, skeptical public, which is why it will probably never be adopted…way too costly to industries. (Their common sense, pragmatic approach reminds me of Elizabeth Warren’s plain speaking and efforts to have a strong Consumer Protection Agency). For example, they provide a clear glossary of numbers with examples of how to calculate risk, and much of the course had us go through worksheets using these calculations. They similarly provide guidance as to how to report the findings.

Similarly, critically analyzing reports was stressed by Gary Schwitzer. I like his systematic approach as well, though was a bit surprised at the extent of his negativity about cancer screening tests. More for me to review…His HealthNewsReview.org provides handy questions to ask and tips for understanding studies from the fine “Covering Medical Research.”

In addition to these sessions about understanding the numbers and interpreting what the results mean, a couple of the other sessions particularly stood out for me. Hilda Bastian, editor of PubMed Health, provided an important overview of systematic reviews of literature.

Scott Hensley, of NPR’s health blog, Shots, presented valuable suggestions on writing and blogging. He was kind enough to post many of his recommendations here.

Dr. Barry Kramer, originator of this course and now Director of the Division of Cancer Prevention at the National Cancer Institute (NCI), gave an important talk on the hazards of cancer screening, well summarized by Hilda Bastian on Scientific American guest blogs.

A panel discussion, “Inside the kitchen with medical journal editors,” gave an enlightening perspective about what editors are looking for in submissions for publication and how they communicate with journalists.

Panelists were Drs. Barry Kramer, Trish Groves, deputy editor of the BMJ and editor-in-chief of BMJ-Open, and Phil Fontanarosa, of JAMA. It was amusing and impressive watching Scott Hensley both moderate and tweet the panel discussion.

To my surprise, the course was not only quite informative but was often entertaining. We were regaled with tales of travel by T.R. Reid, anecdotes from USA Today’s Liz Szabo, and dramatic readings from participants.

I hope to enlighten you further as I incorporate this week’s messages into my writing.

Credits:

Molecules to Medicine banner © Michelle Banks