Misconduct: Where are the Consequences?

A story on Bloomberg starts as follows:

James C. Vestal, a Texas urologist, exposed his patients to ``unnecessary risk'' and ``submitted false information in required reports'' during the clinical trial of a prostate cancer drug, according to the U.S. Food and Drug Administration. The agency's drug division ``believes that you repeatedly or deliberately violated regulations governing the proper conduct of clinical studies,'' the FDA said in a letter to Vestal. ``Accordingly, FDA proposes that you be disqualified as a clinical investigator.'' The FDA didn't send the letter starting disciplinary action against Vestal until May 2007, more than three years after his violations of agency rules were detailed in reports by the FDA's own staff investigators. Vestal continued to conduct drug trials as recently as last year, as he was permitted to do. He has stopped voluntarily while negotiating with the FDA on his case. The agency has failed to complete disciplinary action against 12 researchers, including Vestal, after proposing that they be disqualified from trials based on findings that they violated rules designed to protect patients and ensure accurate data, FDA records show. Cases have remained unresolved for as long as a decade.

Read the whole piece. Regular readers will be angered, but not surprised. David Linden has sex with patients along with other transgressions and gets a slap with a limp noodle. And if you think Linden's record is frightening, check out that of Dr. Louis Fabre (1, 2). Whether it is serious scientific misconduct, high-level sexual misconduct, or whatever else, the penalty is the same -- a slap on the wrist at most. So expect more of the same.

P.S. My post on Effexor is developing quite slowly. I hope to have it up next week.

Nominee for Career Achievement Award: Dr. David Linden

Remember him? The guy who gave herpes to two patients and lost his license for three months as a result (pretty stiff penalty, eh?). According to KLAS TV in Las Vegas, he was recently arrested for allegedly passing bad checks at a casino. To quote the news story:

The District Attorney is charging Linden with passing $300,000 worth of bad checks at three local casinos. According to the complaint, $150,000 in bad checks were passed at the Las Vegas Hilton, $100,000 at Caesars Palace and $50,000 at the Hard Rock.

I had wondered previously why only his Oklahoma license was suspended after he had sexual relations with two patients -- why not his Nevada license? Apparently, his Nevada license was put on probation, meaning he could still practice medicine. Apparently, Nevada is serious about defending its reputation as the state where anything goes. His track record of conducting psychiatric clinical trials is impressive for its violations of several FDA regulations. Giving herpes to patients is quite an accomplishment as well; not many physicians can match that claim to fame. As I noted earlier, Linden has run clinical trials for a wide variety of large drug firms. As long as you can recruit patients, who cares what actually happens to them during the clinical trials?

For the above list of accomplishments, I hereby nominate Dr. Linden for a Career Achievement Award. Even if he is not guilty of the present check fraud charges, I still believe he is a worthy nominee based on prior accolades and accomplishments.

Sex, Psychiatric Drugs, and the Honor System

I had briefly alluded to Dr. David Linden in an earlier post. You may recall that he is the psychiatrist who had his license suspended by the State of Oklahoma because, through sexual contact, he gave genital herpes to two patients. I had never known why Oklahoma was called the Sooner State, but now it makes sense. If you have sex with, and give herpes to your patients, you get your license back sooner than anyone would reasonably expect. To be specific, his license was suspended for a grand total of three months for such misconduct. Can you say slap on the wrist with a wet noodle?

So who is this guy? Let's find out.

License. A link to his Oklahoma physician profile can be seen here. Remember, two cases of herpes transmitted to patients = three months suspension of Oklahoma medical license. I find it more than a bit confusing that his Nevada license is still active. It would appear that in the state which houses Sin City, one can have all the sex with patients that one wants and not be subject to disciplinary action. So give herpes to two patients through sex, and the consequences are having a license suspended for three months in one state and no consequences in another state. Very interesting. Perhaps his transgressions occurred in Oklahoma, so Nevada figures it is out of their jurisdiction. But, if a doctor has sex with patients in one state, I'm going to go out on a limb here and say that his license should be suspended (or, maybe, just maybe, permanently rescinded) in all states.

Imprisonment of Study Participants. That's what the FDA found in their investigation of Dr. Linden. One woman wished to participate in a study in Linden's inpatient facility. She agreed to participate in a study and then changed her mind. She was not allowed to discontinue the study for four days, and only after the involvement of an attorney. What part of "you can discontinue the study at any time" did Linden fail to comprehend?

Patients Without Consent. Two patients did not sign informed consent forms to participate in studies. This is a gigantic no-no. Participants absolutely must provide consent to participate in studies, particularly when they involve taking medications. On six additional occasions, participants signed the incorrect consent form.

Unlicensed Hospital Stays. In one study, patients were placed in an unlicensed hospital for at least two weeks. The study protocol called for patients to be placed in a licensed hospital. Oops.

Drug Dosing. Patients were given incorrect doses of study medication on multiple occasions in one study. I'll quote the FDA report regarding drug dosing in another study:

The amount of study drugs dispensed to, and returned by, subjects 002, 005, 008, 015, and 020 cannot be determined.

Adverse Events? What Adverse Events? Two participants who were placed under emergency inpatient detention during their participation in studies -- their extreme mental instability was not reported as a serious adverse event. Seem to me like it would be rather important to report all serious adverse events that occur in a study. Unless, of course, one was either sloppy or wanted to bury negative data.

And there is more, believe it or not. The FDA investigation only examined two trials. All of the above problems and more based on two studies. Impressive. And then he collects data which is the foundation of the "science" that supports various medications.

Who Would Hire This Guy? Well, let's see. According to his research webpage, he has done clinical trial research for the following:

• AstraZeneca
• Bristol-Myers Squibb
• Boehringer Ingelheim
• Eli Lilly
• GlaxoSmithKline
• Janssen
• Johnson & Johnson
• Novartis
• McNeil
• Pfizer
• Shire

And, to quote his site: "The following Contract Research Organizations have greatly contributed to our success"

• I 3 Research
• INC Research
• Parexel
• PPD Development
• Quintiles
• Rho Inc.

Want to sign up for one of his trials? It appears that his research organization is recruiting patients with the following conditions:

• Alzheimer's
• Dementia
• Depression
• Schizophrenia
• Bipolar Disorder
• Insomnia

On the Stump. Given his impeccable research and ethical credentials, it is no wonder that Dr. Linden...

...is also recognized as a leader in his community and he is a member of several Speakers Bureaus including: Wyeth Pharmaceuticals, Pfizer Pharmaceuticals, Bristol Myers Squibb and others.

Time For Bad Jokes. I can't help myself. Here are a couple of quotes from his site.

Our P.I. is Actively Involved in Trials
David E. Linden, M.D., our Principal Investigator, is actively involved in the research we conduct. As a result, you directly benefit from his years of experience and expertise.

Yes, he has a very hand-on approach. Wink-wink. Also feel free to insert your own punchline. One more...

Dr. Linden has an extensive and prestigious portfolio in Clinical Psychiatry.

Again, I'll leave the punchline to you. It would appear that drug companies have rather lax standards regarding their investigators, would it not? It would seem that imprisoning your patients, having sex with them, playing all sorts of sloppy with data, and other misdeeds would disqualify a person from engaging in clinical trial research. I understand that there will be occasional data errors in research; one can never rule out human error and I accept that. But this is well past slight mistakes due to occasionally poor oversight. And is this what we would like our "science" to based on?

I've written about a similar situation (minus the sex/herpes part) in an earlier post. After reading this post and my prior post, as well as the links contained in both posts, does it not make one wonder the extent to which psychiatric drug research is based on sloppy and/or fraudulent data? I'm not throwing out a number here. I really have no idea. Perhaps these are rare occurrences. But given that FDA oversight of research is close to nonexistent, much of what happens in research is essentially done on the honor system. Unfortunately, it appears that there is enough dishonor in the current honor system to strongly suggest that we need a lot more oversight.

JAACAP Strikes Again

Aubrey Blumsohn has detailed how the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) is standing behind its work, despite some huge questions -- See Chapter 2 below.

Chapter 1: Paxil 329. You might recall my hissy-fit over JAACAP editor in chief Mina Duncan's declaration regarding Paxil Study 329:

I don’t have any regrets about publishing [the study] at all – it generated all sorts of useful discussion which is the purpose of a scholarly journal.

This comment was especially interesting given that the published study had the following issues:

• Renamed suicidality as "lability" and overt aggression as "hostility."
• Declared superiority over placebo in treating depression when, in fact, the study data did not support such an assertion
• Determined (by magic?) that a placebo can make you suicidal while Paxil could not. The folks who became suicidal on Paxil -- it was not because of Paxil, but the one patient who became suicidal on placebo became suicidal due to the placebo. How does that work?
• Study was ghostwritten
• Lead author Marty Keller appears not to have read the study data

Read more about all of the above here. Despite the study being somewhat of a joke, which was noted to some extent by reviewers, Dr. Duncan published it anyway and said she had no regrets about it.

Chapter 2: The Gillberg Affair

To make a long story short, another study that was published in JAACAP has come under a pile of scrutiny. The study claimed that a syndrome called DAMP (Deficits in Attention, Motor control and Perception) was quite common. There was concern that the data was fraudulent, as can be seen by following this link. My point is not to discuss whether the data were or were not cooked -- I have not given this enough investigation to weigh in.

The point is that the lead researcher Christopher Gillberg refused to provide the data to defend against charges that the data were fraudulent. Mind you, no identifying information was being requested. Just the numbers. The plot thickens substantially from there, but one key point worthy of mention here is that a Swedish court insisted that the DAMP study data be provided to investigators. The data were then destroyed. That would be a no-no in science. If nobody can see the numbers, how do we know they weren't cooked?

Aubrey Blumsohn has engaged in email correspondence with JAACAP staff that I found illuminating. JAACAP's point seems to be that they don't care if the study data were destroyed -- it's not their problem.

No, journals, which serve as the official scientific record, don't need to hold study authors accountable to making sure their study data are accurate. That would be just too much to ask, apparently.

Are You Faruk-in’ Kidding Me?

Sorry for my delay in jumping on the latest New York Times story (courtesy of Gardiner Harris and Janet Roberts) detailing how drug companies hire doctors to carry out clinical trials despite their questionable backgrounds.

Much discussion of this sordid tale has already occurred at such outlets as:

• Furious Seasons
• Health Care Renewal
• Psych Central
• Pharma Marketing Blog
• AHRP
• Pharmalot

Most of what I wanted to say has already been said by the above writers. However, I have a bit to add.

Quote of the Week: Hell, this might be quote of the year, really. In the out of touch with real people category, I submit, from the New York Times [emphases added]…

Dr. Ronald Hardrict, a psychiatrist from Minneapolis who pleaded guilty to Medicaid fraud. In 2004 and 2005, he collected more than $63,000 in marketing payments from seven drug makers. In an interview, Dr. Hardrict said it was “insulting” and “ridiculous” to suggest that income from drug markers might influence doctors’ prescribing habits. [and on to the quote of the week…]

“I bought the Mercedes because it has air bags, and I use Risperdal because it works,” Dr. Hardrict said, referring to an antipsychotic medicine for schizophrenia. Johnson & Johnson, the maker of Risperdal, paid Dr. Hardrict more than $30,000 in 2003 and 2004.

SNIP

Asked why other drug makers continue to hire him despite a fraud conviction, Dr. Hardrict responded with an email message stating only, “I will pray for you daily.”

I think I speak on behalf of my readers when I say that we’ll likewise be praying for Dr. Hardrict and his Mercedes.

Are You Faruk-in’ Kidding Me? Sometimes a person’s name makes for a catchy headline, so I thank Dr. Faruk Abuzzahab for that. I was reading through the Minnesota Board of Medical Practice’s lengthy document that detailed the alleged misdeeds which resulted in a suspension of Abuzzahab’s medical license. Very interesting document.

We all make mistakes. Occasionally we make large mistakes. That’s okay. But a pattern of making similar mistakes, errors that lead to significant anguish and, in some instances, may contribute to the death of people – that’s not okay. I’ll run a trio of quotes from the report…

In a number of cases (including but not limited to patients #35, #36, and #40, for example), Respondent [Abuzzahab] enrolled psychiatrically disturbed and vulnerable patients into investigational drug studies without ensuring that they met the eligibility criteria to be in the study and then kept them in the study after their conditions deteriorated.

Respondent's documentation regarding patient #36's participation in the sertindole study differed from the staff's documentation. While Respondent documented at more than one point that patient #36 was much improved and mildly ill, staff consistently noted her deterioration throughout the study. It was also documented that patient #36 made several references indicating that she did not want to take the medications. Respondent failed to document his rationale for continuing investigational medication under these circumstances.

The pattern that emerges from Respondent’s treatment of the approximately 46 patients at issue in the contested case proceedings is that he regularly fails to substantiate his diagnoses, monitor whether the combination of drugs is appropriate for the symptoms being treated and is having the desired effect, and evaluate whether the benefit outweighs the adverse effects noted in the chart. This fundamental failure shows a reckless, if not willful, disregard of the patients’ welfare, exposes the patients to an unnecessary risk of harm and contributes to their deterioration while under his care.

A few years back, here’s a couple slices of what Morris Goldman from the University of Chicago’s psychiatry department had to say about the drug trial research field and about Abuzzahab, whom he investigated:

There are ''people drawn into this field because they are interested in dollars,'' Goldman added. ''They are very profit-conscious. And that combination of a lot of money, plus the added ethical dilemma you face in human research, that is a bad combination. And there are particular risks with psychiatric patients, with the whole issue of informed consent. It can really go wrong.''

''He [Abuzzahab] would have the patient's diagnosis called one thing in the regular chart, and then the person would be put on a drug study and the person's diagnosis would be called something else to fit the criteria''

Journalist Robert Whitaker (in the Boston Globe) said the following about Abuzzahab, and the transcript from the Board of Medical Practice (pgs. 21-22) appears to back his reporting.

In another instance, the psychiatrist took a woman off clozapine, a newly approved drug that had led her to make a remarkable recovery, and enrolled her in a drug trial. The woman had previously spent 13 years as an inpatient at a psychiatric institution, but while on clozapine she had been able to go into the community and even hold a job. One day she approached Abuzzahab with questions about clozapine's side effects; he immediately stopped the drug that had helped her so much and put her into an olanzapine trial. She deteriorated until she found her way to another physician, who put her back on clozapine.

The Payout: Two disclaimers first: 1) I cannot verify the accuracy of the following information, though I have no reason to doubt its veracity. 2) I am not disclosing the source of the information, as I believe it could lead to untoward consequences in the wrong hands.

I found that Abuzzahab lives (or recently lived in) a house described in the following manner:

Built in 1931. The structure is a 2 1/2 story, 7569 square foot, eight bedroom, six bathroom, 17 room, single family dwelling, with a partially finished basement.

I found that a home on his street recently sold for about $2.7 million dollars. The other home appears to be significantly smaller than Abuzzahab’s pad – I’m no realtor, but it my relatively uninformed guess is that Abuzzahab is living large in a three to four million dollar crib. Not bad. Who says forging records and prescribing inappropriately does not have its rewards?

My Take: Granted, the NYT report on Abuzzahab paints a very negative picture, as does the Boston Globe article, as does the Minnesota Board of Medical Practice document. Certainly, all of the above selectively examined negative evidence, and did not have a chance to see the patients who had benefited under his care. That being said, there seems to be more than enough evidence to indicate that there is no way Abuzzahab should ever be involved in clinical research again, and it is a bit scary to me that he is practicing medicine, though perhaps he has reformed his ways.

He’s also listed as an instructor for the University of Minnesota as recently as 2005. I’m not sure if he’s still employed at the university, but it seems quite odd that they would select him as an instructor.

For all I know, Dr. Abuzzahab is the nicest guy in the world. I wish him no ill. We all make mistakes, but there are some missteps, especially when they happen repeatedly, that should disqualify people from teaching university students, conducting research on the latest drugs, and caring for patients.

Lilly, Organon, Roche, GlaxoSmithKline, Pfizer, Janssen, Abbot, Merck, Boehringer Ingelheim, Bristol-Myers Squibb – who is going to run your clinical trials?

University of Minnesota – who is going to teach your students?

Fairview Clinic, who is going to treat your patients?

Evidence Biased Medicine (To the Core)

The Last Psychiatrist wrote an excellent comment regarding a post describing how "scientific" data and/or its analysis and interpretation are often cooked by ghostwriters and/or friendly academics. He discussed how the whole process of publishing research is biased, a point that will be discussed in depth throughout this lengthy post. The Last Psychiatrist said:

Sure Pharma puts pressure on doctors, and forces through studies that are helpful to them (and suppresses those that hurt them).

But the real problem in medicine is the academic centers. Their bias is dangerous because it's so subtle and pervasive.

If Astra Zeneca does a Seroquel study, I think we can guess the bias. But when Assistant Professor Jones does a Seroquel study-- funded by the NIH-- is that study magically free of bias? What about Jones's beliefs on medications (he thinks pharmacotherapy is a gold mine, or is he anti-drugs and pro therapy?; maybe he's pro-seizure drugs (Depakote, Lamictal) and anti-antipsychotics (or the other way around?) Maybe his mentor gets AZ money (which is used to pay his salary through the university?) Maybe NIH has a stake in getting expensive drugs like Seroquel to look bad (e.g. CATIE?)

And journals are worse: think that the editors of a journal don't have biases-- even direct pharma ones?

And the three peer reviewers?

Ever wondered what articles don't get accepted for publication, and why (and I say this as someone who has a pretty high rate of publication success).

And why do those journals-- which publish public data-- cost $1000/yr and can't be accessed by the public?

The first and most important step to fixing medicine is abandoning the journal system. All articles, including the raw data that generated them, photos, scientific notebooks, etc, should go online. Let the world vet the data.

I agree with the great majority of what he said. I find it hard to believe that NIH is against expensive medications, since many of the NIH folks have ties with drug companies which are, of course, pushing newer and more expensive meds.

We have to keep in mind that the whole "scientific" peer-review process includes a lot of bias.

Let's review how studies go from a set of numbers into a published manuscript. It may sound like a dull process, but this is the foundation of our so-called evidence base in medicine, so it is actually very important to understand.

How is it biased? Let me count the ways...

Step 1. Analyzing data and writing the paper. Researchers transform a bunch of numbers into a paper.

1) It's anyone's guess as to whether the researchers have actually seen the data upon which they are to base their writings. In some cases, it is unlikely that they have. So the company could have already made some alterations to the data -- it's unclear how often this happens, but it is certainly a possibility in some (hopefully rare?) instances.

2) The company can analyze the data in any way it sees fit. Go to Aubrey Blumsohn's site for an excellent example of why this can be problematic. Company statisticians can cook the books either overtly or in a more subtle manner (like they did with the Seroquel data -- here and here).

3) The company can interpret the numbers in any way it wants. For example, if someone committed suicide while taking a drug, the drug couldn't have caused it, but if the patient committed suicide on a placebo, then the placebo caused it. Even when the data are not favorable, positive conclusions are reached in most instances (here, for example).

4) The company can bury any unfavorable data. Suppose that depression was measured in five different ways. If a couple of those measures yielded unfavorable results, toss them aside and act as if they never existed. Don't even mention that they existed in the article.

5) When all else fails, deep-six the study. If the data still fail to prove favorable, just bury the entire thing -- don't publish it. When lawyers and/or researchers get their hands on unpublished data, it quite often shows unfavorable results which the sponsoring company thought best to bury.

Step 2. Peer Review. The paper is then sent off to "experts" for peer review. As the LP said earlier, these folks (including me) have their biases. Indeed, one of my peers has called the peer review process "a Rorscach test of the reviewers," meaning that you can easily see their biases through the reviews. Most reviewers of psychiatry journals have ties to industry which have likely shaped their beliefs to roughly the following: "Drugs are safe and effective," though biases will vary.

The comments of these expert reviewers are quite important in determining whether the study will get published.

Here's what one former journal editor, Richard Smith (British Medical Journal) had to say about peer review (with my emphasis):

The problem with peer review is that we have good evidence on its deficiencies and poor evidence on its benefits. We know that it is expensive, slow, prone to bias, open to abuse, possibly anti-innovatory, and unable to detect fraud. We also know that the published papers that emerge from the process are often grossly deficient.

Hmmm. No, this is not sour grapes on my part -- I've little to complain about in terms of being published. But myself and many other researchers are often befuddled by the whole process -- it often seems that reviewers are unhelpful.

Does peer review help, at least a little bit? I think so. Does it solve the problem of low-quality papers hitting journals, which are then turned into marketing copy by the drug and device industry? Obviously not.

Step 3. Editoral Decision. The editor chooses whether to accept the paper (usually after some revisions are made).

Journal editors frequently have huge ties to industry. Just google the names of many editors and you'll find that they have received funding from a lot of different sources. We also know that sometimes peer reviewers make good comments, yet the editor chooses to ignore them.

Note that nearly all journals are a for-profit entity. How can they make money? Advertising, subscriptions, and reprints. If a journal runs an article favorable to industry (saying that vagus nerve stimulation is great for depression, for example), then it is likely that the company will buy thousands of reprints for dissemination to physicians. The journal is making good money from each reprint and can make tens of thousands or even up to a million dollars from reprints of a study. A study that is unfavorable or irrelevant to industry is not going to generate revenue for the journal. So from a business standpoint, it makes more sense to print studies (like this or this) that are written from a slant of favoring a product than to run something less industry-friendly.

What to do?

Start by making all trial information publicly available. The Last Psychiatrist said it. Richard Smith said it, and I agree with it. I don't think we should abolish journals altogether -- seems extreme, but making data publicly available -- that's an excellent idea.

Penalize those who engage in misconduct
As Fiona Godlee (editor of the British Medical Journal) stated recently:

So what can we do to change the blind-eye culture of medicine? In the interests of patients and professional integrity I suggest intolerance and exposure.

--SNIP--

And if journals discover authors who are guests on their own papers, they should report them to their institution, admonish them in the journal and probably retract the paper.

Reputations for sale are reputations at risk. We need to make that risk so high it's not worth taking.

Other thoughts?

Update (2-9-07): Quite a few people have been reading this via reddit. To see comments regarding this post at reddit, click the following link.