Study 329: By the Standards of the Time

Getting Real about Clinical Research

The controversy over “Study 329” on the effects of Paxil in teen depression has raised questions about the state of ALL medical research.  What looked like a study conducted by leading psychiatrists from top medical schools turned out to have been controlled by the company. Individual patient data was hidden or distorted, statistical tests were massaged, and a company ghostwriter spun a narrative that turned an ineffective, risky drug into a safe and effective treatment.

Study 329 was performed in the 1990’s, and the resulting journal article was published in 2001. To this day no one has retracted that article. Top medical journals continue to publish drug-company directed research. When you search “the literature” for the best way to treat depressed teens, you will  still find that 2001 paper and others like it (about which we know even less).

The Ghost of Research Past

Study 329 was done at 12 research sites: two in Canada and ten in the U.S.  For each site, there was a named author from a major university or teaching hospital actually involved in the research. However, while each of them knew more-or-less what went on at their own site, only the drugmaker knew the whole picture. SK had paid for the study. It ran the analysis, and it produced the draft paper that made the drug look much better than it really was.

The record shows the named authors worried that the results were being distorted, and that SK might leave them to take the blame if the facts came out. In the end, they signed on for whatever reason.

The paper mentions “treating clinicians” made the decisions about raising or lowering doses of paroxetine.  Today GSK reassures us that the subjects’ treating doctors were responsible for following up on any problems they had during the study. The investigators apparently decided that none of the truly serious problems were due to paroxetine. Which means that they couldn’t explain to the Paxil Kids what had happened to them, or how to stay safe in the future.  Neither, of course, could their colleagues – your doctor and mine.

The Ghost of Research Present: Vraylar

The picture painted by Study 329 is scary, but what if there were fifty study sites instead of twelve, or 150 in several different countries? What if the academic “authors” of an article hadn’t laid eyes on any of those sites, much less been a Site Investigator?

What if the real Site Investigators were professional researchers-for-hire?  What if they’d taken part in a hundred studies, but seldom if ever been named as authors? They wouldn’t have to worry if the study design was seen as biased, or the results too good to be true. Their reputations would not be on the line; they’d made their money, and the official “authors” could deal with the fallout.

What if the subjects had no doctors of their own, and were signing up for the study simply to get some medical care? What if their doctor was a professional researcher-for-hire? Either way, the subjects would be dependent on care from a doctor with an economic stake in the success of the study. This could affect their personal welfare, and the reliability of the study results as well.

What happens when a doctor under pressure to recruit subjects with “bipolar depression” is the same one diagnosing you with “bipolar depression”? What if you need, for your health’s sake, to drop out of the study, but “your” doctor needs to maximize the number of subjects who finish?  What if you’re a patient with, say, a thyroid disorder or a drinking problem, who figures this will likely disqualify you from the study but you really need the free medical care, and the travel money will come in handy too.  Will you be tempted to say Yes, when the integrity of the depends on your saying No?

One Drug, Twenty Countries

I decided to look at the research for the most recent psychiatric drug approved by the FDA, a new antipsychotic called cariprazine or Vraylar.  I located twenty studies of Vraylar on www.ClinicalTrials.gov, the U.S. government-sponsored registry for clinical trials.  Three were still in process, and seventeen were completed.  Not one had shared its results on the government website, a supposedly mandatory step.

I found at least a half-dozen published papers directly based on these studies, although only two were posted on CT.gov. The average number of authors?  Six to eight. The typical paper had a lone academic as “lead” author, the rest being drug company employees. Some had only employee-authors.

The average number of trial sites per study?  Fifty-one.  The “median” Vraylar study would involve 403 subjects at 65 different study sites in four countries!  Together, the twenty studies spanned twenty countries, from Colombia to Bulgaria and from India to Finland. Unlike those U.S. academics on Study 329, I doubted these people would ever get together, in person or via e-mail, to compare notes and debate what the finished paper should say.

Unlike some sponsors, Forest did not share the site names with CT.gov – only locations and ZIP codes.  However, a few of the papers thanked various “investigators” by name. With some patient searching of PubMed, CT.gov and Google, it was possible to identify many of the U.S. sites.

Overwhelmingly they were contract researchers.  Some were freestanding clinical trial businesses.  Others were busy medical practices with a thriving research business “on the side.” The first recruited subjects largely by TV, newspaper and online advertising which emphasized free treatment. The second combined some advertising with recruitment among their own patients.

A Study Like Many Others

I picked one study to focus on:  “Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, Phase III trial.”  It was published, available for free online, and it had a manageable number of study sites.

The lead author, Gary Sachs, is from Massachusetts General Hospital.  His seven co-authors include four employees of Forest Pharmaceuticals in New Jersey and one medical writer from a Chicago agency hired by Forest.   The last two, Istvan Laszlovszky and Gyorgy Nemeth, work for the drug’s original developer, Gedeon Richter in Hungary.  They also hold patents on Vraylar, and are co-authors on most of the published studies.

The paper confirmed the study was carried out at ten sites in the US and 18 in India between February 2010 and July 2011.  The authors acknowledged just 14 clinical investigators by name: six Americans and eight Indians.  I was able to match all six named Americans with their research sites, whose numbers are listed in bold on the table below, and to figure out the identities of three of the four unnamed investigators using CT.gov.

None of the sites were anywhere near Mass General, or Forest’s Jersey City headquarters either; the closest was in Cleveland, Ohio, some 800 miles from Boston.   It appears safe to conclude that Dr. Sachs did not give Vraylar to manic patients or observe the results himself.

#	Location	PI & hospital affiliation	Organization	Funding in 2014
001	Flowood, MS 39232	Joseph Kwentus, M.D.Brentwood Behavioral	Precise Research Centers	$897,985.70$51,813.42
002	Houston, TX77008	Carlos Herrera, M.D. 7 nursing homes	Heights Doctors Clinic	$176,032.57$6,498.01
003	Creve Coeur, MO 63141	Franco Sicuro, MDAdvanced Geriatric Mgt	Millennium P.A.	$1,188,324.92$9,065.84
004	Long Beach, CA  90813	Stephen J. Volk MDDel Amo Hospital	Apostle Clinical Trials	$393,715.86—
005	Riverside, CA 92506	Sadashiv Rajadhyaksha, MD	Clinical Innovations, Inc.	None; license revoked 2012
006	Lake Charles, LA 70601	Kashinath Yadalam MDLake Charles Memorial	Lake Charles Clinical Trials	$1,038,407.13$910.69
007	San Diego, CA 92123	Michael Plopper, MDSharp Behavioral	Sharp Behavioral Health Mesa Vista	$304,782.89$568.91
008	Cleveland, OH 44109	[Unknown]	[Metro Health Medical Center]	Unknown
009	Chicago, IL60640	John Sonnenberg PhD[Michael Reinstein MD]	Uptown ResearchLakeshore Hospital	*SEE BELOW*
010	Oklahoma City, OK 73116	Willis Holloway Jr., MDSt. Anthony Hospital	Cutting Edge Research	$600,995.75$83,005.44

The funding figures are posted online thanks to the Sunshine Act. The first number is the amount of research funding each doctor received in 2014, while the second tallies “personal” payments for consulting, speaking, and traveling or dining at company expense.

Two physicians had no figures for 2014.  Dr. Rajadhyaksha surrendered his medical license in 2012, a year after our study ended, having been found guilty of sexually molesting two women patients.  Clinical Innovations, Inc. is still in business but has lost its Riverside “campus” for now.  Dr. Reinstein lost his license in August 2014, and is headed for federal prison.  But more about him later.

Our lead author, Dr. Gary Sachs, reported no drug-company research funding in 2014, and a mere $4,713.20 in personal payments!   With over 100 published articles and a seat on the Harvard Med School faculty, he’s clearly a bigger name in his field than Joseph Kwentus or Kashinath Yadalam.  I’m sure there are rewards for such eminence.  However, they don’t come from clinical trials these days, at least not directly.

Start Your Journey to Mental Health Treatment

At Precise Research Centers, just outside Jackson, Mississippi, they don’t make picky distinctions between research and treatment. “Precise is one of the top depression clinics in Mississippi.  Dr. Joseph Kwentus is one of the nation’s leading bipolar doctors,” their website declares. Their ads on local TV help you figure out if you are depressed, and tell you where to go for free help.

At Lake Charles Clinical Trials, “A Place Where Change Is Possible,” Dr. Yadalam will even put you in touch with the local chapter of NAMI, the National Alliance for the Mentally Ill.  He’s been a board member since 2002.  At the Heights Doctors’ Clinic in Houston, a banner outside the clinic in Spanish and English promises “Experimental Medications, Free.”

Dr. Holloway takes another approach. His Oklahoma clinic is actually three facilities in one:  Cutting Edge Clinical Trials; Holloway & Associates, his own psychiatry practice; and Optimal Health Weight & Wellness, which treats obesity, chronic fatigue and sexual dysfunction.  (If you wonder why a psychiatrist is running a weight-loss clinic, consider the number of new drugs recently tested in this area.)   Dr. Herrera at the Heights Doctors’ Clinic also combines a busy internal medicine practice with a clinical-trials business.

Sponsors: Click Here for Our Metrics!

These doctors do have reputations to protect.  The sponsors, mainly drug companies, want volume, reliability and speed.  While experience and efficiency count, often the first one to recruit ten patients with Condition X wins the contract. Apostle Clinical Trials, like many sites, posts its recruitment statistics online to impress sponsors.

These centers are located outside the major cities, or in low-income areas. Black and Latino Americans may be more likely than whites to find one in their neighborhoods. Some patients, especially immigrants, may be uninsured. Many are on disability, with low-paying public medical plans that aren’t accepted by many doctors.  Others have insurance that requires large out-of-pocket payments.  For ambitious trialists, a “patient base” like this can be an asset. They get access to lots of people with serious conditions like schizophrenia or multiple sclerosis.  Rates of hypertension and diabetes are well above average.  And as one of my local trial sites explains, “managing retention” can be easier with a “diverse” population and a clinician-trialist who knows how to talk to them.

Clinical Research: An offer You Can’t Refuse?

Most of this was nothing new.  What I didn’t expect was that eight of our ten sites would have close links to (mostly for-profit) inpatient psych units or nursing homes. Dr. Volk is on the staff of Del Amo Hospital, part of the huge Universal Health Services (UHC) chain. Dr. Kwentus is medical director at Brentwood Behavioral Health, the UHC hospital down the road, and his trials are promoted on Brentwood’s website. Lake Charles Memorial does the same for Dr. Yadalam, its former chief of psychiatry and still on its medical staff.

Dr. Plopper is both chief of staff and chief of research at Sharp Mesa Vista, and Dr. Holloway directs the special program for “resistant” youth ages 12-17 at St. Anthony’s in Oklahoma City.  Uptown Research offers sponsors an “affiliated inpatient hospital” – Chicago Lakeshore.  Dr. Herrera is on staff at seven Houston-area nursing home.  Dr. Sicuro, our top doc in research funding, heads a geriatric psych practice which is likely nursing-home based.  (In many states, long-term care and housing for people with serious mental illnesses is left to the private nursing-home industry.)

When you hear “private psych hospital” you may think wealth and privilege. Think again. Today’s successful player in the U.S. market is usually investor-owned, often part of a national chain, and may qualify for federal aid due to its “disproportionate share” of poor patients.  It also has a keen interest in “non-voluntary” patient groups: troubled teens, people with psychotic disorders, elderly folks with dementia.  UHS has opened special units for active-duty soldiers as the military hospitals overflow, and a few companies have won state contracts to treat prison inmates.

In most U.S. states, you can be held involuntarily for brief but renewable periods if you are judged an immediate threat to self or others. Online patient reviews for these hospitals are striking, not for their general negativity (expected), but for the number of people claiming they or their loved ones were kept against their will.  Many allege that “suicidal statements” were coaxed from them or fabricated outright.  In California, they talk of “5150’s,” while in Florida it’s the “Baker Act.”  In Illinois, the good old 72-hour hold seems to have magically grown to five days at Chicago Lakeshore.  In all cases, padding the bill seems the obvious motive.  Could research be another?

From Dan Markingson to Michael Reinstein

All of this has echoes of a recent, infamous human-research scandal: the death of Dan Markingson in a clinical trial of antipsychotic medication at the University of Minnesota. The hospital made Dan an offer he couldn’t refuse: Sign up for the trial, and they’d agree not to have him forcibly committed. How he could be ill enough to warrant commitment, but not too ill to “consent,” was never explained.  In any event, Dan was kept in that trial, despite evidence that he was getting worse on the new medication, until his death by suicide in 2004.  It took another ten years for Dan’s mother and a few tireless faculty activists to defeat the University’s coverup campaign.

Which brings us back to Uptown Research Institute and its founder Dr. Michael Reinstein.  Chicago’s Uptown neighborhood was for years a hub for rescue missions, flophouses and large nursing homes where thousands of people with serious mental illnesses were (and still are) warehoused. Reinstein amassed a small fortune there, providing psychiatric “care” to as many as 4,000 patients in 13 nursing homes, and parlaying his clout as a mass prescriber into a second career as a paid Pharma researcher and lecturer.  Astra-Zeneca, makers of Seroquel, were his first clients, followed by various makers of clozapine, one of the riskiest drugs in psychiatry.

The results, as reported in a 2009 expose by ProPublica, were horrific: Patients “trembled, hallucinated, lost control of their bladders … Staffers said Reinstein had induced some patients to take powerful psychotropic drugs with the promise of passes to leave the home.” Reinstein’s role as the “Clozapine King” of Uptown also resulted in at least three wrongful-death lawsuits.

In 2014 Reinstein lost his license and was charged with felony fraud. Following the 2009 expose, however, control of Uptown Research passed to cofounder John Sonnenberg, a psychologist, who disavowed any further connection to Reinstein. However, Sonnenberg was not a physician. An M.D. was needed to give and monitor medications.   Reinstein was still practicing out of a storefront next door to the Institute.  If he wasn’t the physician, who was?

All indications are that Reinstein was active in the research at Uptown through at least 2012 – including the period of our Vraylar trial. We don’t know how many Dan Markingson-type tragedies Reinstein was responsible for. But a look at this single study is enough to convince me that other Dr. Reinsteins must be out there – and the system has no way to stop them.

What Does it all Mean?

Why was the “Sachs study” of Vraylar for mania limited to three weeks?  Why were the subjects offered so many extra medications to relieve side effects, from benzos and chloral hydrate to Ambien?   If a 4-7 day “medication washout” period was needed at the beginning, what meds were people taking, and how did stopping affect them?

I can’t answer those questions, but I have one of my own:  Given what we know about the study’s structure and the system it took place in, how will we ever arrive at any reliable answers?

First, in many cases it may do no good to put pressure on medical-school faculty (or their schools) to share the data, when they themselves know so little.  Med Schools now have more in common with celebrities lending their names to a new cologne or athletic shoe than with scientists actually testing a new treatment. The drug companies may be the only source of information.

Second, when investigators have an economic stake in both the trial and the patient’s treatment, patients’ rights and safety are up for grabs.   In addition, any diagnoses and treatment records coming out of this system may be valid – or may be fictions created for one billing purpose or another.  In other words, the integrity of the research is also up for grabs.

Third, the popular idea of a patient research boycott may simply not work, at least in countries where healthcare is not a right.  It’s often said that people volunteer for trials for two reasons:  Their conditions haven’t responded well to standard treatments, and they also want to help others by contributing to medical knowledge.  If patients just refused to participate in trials, the reasoning goes, they could force study sponsors to agree to open data sharing.

The assumption is that the boycotters can simply go back to “standard care.”  In the U.S. and  other countries, many don’t have that choice.   When patients are dependent on the researcher for medical care, how many will just say no?  The problems multiply when psych patients are treated against their will – which may be on the rise in national health systems as well as privatized ones.

The Ghost of Research Future

The focus of reform movements so far, including the landmark expose of Study 329, has been on fighting for open data. Conflicts of interest, and even pharma sponsorship of the research, some say, would not be insurmountable problems if we just had access to the raw data.

In the course of this research, however, I bumped into some emerging trends that might lead to a system where raw data no longer exists, at least as we think of it today.  But that’s for the next article.

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This article appeared first on
David Healy’s website, DavidHealy.org