1 Boring Old Man

After graduating from high school in 1960, we scattered to the winds – at least I did. It would be decades before I caught up with the people from those days and heard the stories of how those friends from my earlier life negotiated the tumultuous years that followed. Howard and I reconnected 40 years later on an email thread someone started in the lead-in to a class reunion. A classmate started sending around those hyper-patriotic emails with animated flags that followed 911. The invasion of Iraq was in the air. Howard and I were among the few who opposed it, hardly the majority opinion, and in the next few years, we reconnected in person.

I don’t need to tell his story because it’s where everything else that matters is – on the Internet [see Howard Moreland on  Wikipedia]. The short version is that he left high school pursuing his dream of being a pilot. After a few years as an Air Force pilot flying transports back and forth to Viet Nam, he cut that career short and by 1979, he was a full time anti-nuclear activist and the independent journalist who wrote the article "The H-Bomb Secret: How We Got It, Why We’re Telling It." There was a big First Amendment court battle as the Department of Energy tried to halt publication. It ultimately failed and the article was published in November 1979.

The article is true to the title – how to get an atomic bomb [fission] to ignite a fusion reaction in the hydrogen fuel in the millionth of a second before everything scatters to the wind – no small feat. The article makes it very clear [it’s a "bank shot"]. Equally interesting is getting the story with no access to classified information [see his slide show]. If it’s not obvious why I’m telling his story, it has to do with the logic used to justify keeping secrets. And I remembered some of the things Howard said when he first told me this story as I was reading Rationale for WHO’s New Position Calling for Prompt Reporting and Public Disclosure of Interventional Clinical Trial Results calling for Data Transparency.

He said that nuclear proliferation was too important to rely on keeping the process of making an H-Bomb a secret. First, others can figure it out if they try hard enough and ask enough questions, and he proved his point by doing just that. But if you really want to deal with nuclear proliferation, you have to do something out front and effective – like control and monitor access to raw materials with international accords and strict surveillance. At first, I wondered why Howard’s story was in my mind as it seemed very different from the point about Data Transparency in Clinical Trials. But then I realized that only reason to keep the H-Bomb secret is that I have it and they don’t, and that gives me an unfair power advantage. It’s an argument in front of a huge conflict of interest. If it’s not a secret, then I also have to engage in and abide by negotiated restraints just like everyone else. But if it’s just my secret, I get to call all the shots.

WHO Joins the Push for Greater Disclosure of Clinical Trial Data

Pharmalot: WSJ

By Ed Silverman

04/15/2015

But some academics were more circumspect. Harlan Krumholz, a Yale University cardiologist who runs the Yale Open Data Access Project, says the WHO statement “is a great addition to the chorus and worthy of note, but not game changing.” An issue, he says, is that the WHO is “articulating an aspiration. But they might suggest a consequence to non-compliance.”

Similarly, Peter Doshi, an assistant professor of pharmaceutical health services at the University of Maryland and an associate editor at BMJ, a medical journal that has pushed for greater disclosure, says the WHO statement does not call for internal documents such as clinical study reports to be made available. And he notes it does not pressure regulators to release trial data in their possession.

“Instead, it calls for researchers to publish in peer-reviewed journals and upload results into trial registries within 24 and 12 months, respectively. While these are important goals, they only move us so far in terms of clinical trial data transparency, as both journals and registries generally only report aggregate and limited amounts and types of clinical trial data.”

In an accompanying essay in PLOS Medicine, Ben Goldacre, who co-founded the AllTrials campaign, writes that audits are needed to ensure that transparency is achieved. “Previous calls for registration were not enough to fix publication bias, and positive statements require practical implementation,” he writes.

^{hat tip to Howard Moreland…}  

WHO calls for increased transparency in medical research

Note for the media

14 April 2015

14 APRIL 2015 | GENEVA | WHO today issued a public statement calling for the disclosure of results from clinical trials for medical products, whatever the result. The move aims to ensure that decisions related to the safety and efficacy of vaccines, drugs and medical devices for use by populations are supported by the best available evidence.

“Our intention is to promote the sharing of scientific knowledge in order to advance public health,” said Dr Marie-Paule Kieny, WHO Assistant Director-General for Health Systems and Innovation. “It underpins the principal goal of medical research: to serve the betterment of humanity.”

“Failure to publicly disclose trial results engenders misinformation, leading to skewed priorities for both R&D and public health interventions,” said Dr Kieny. “It creates indirect costs for public and private entities, including patients themselves, who pay for suboptimal or harmful treatments.”

Unreported trials lead to misinformation

For example, in a study that analysed reporting from large clinical trials (more than 500 participants) registered on ClinicalTrials.gov and completed by 2009, 23% had no results reported. These unreported trials included nearly 300 000 participants. Among clinical trials of vaccines against 5 diseases registered in a variety of databases between 2006-2012, only 29% had been published in a peer-reviewed journal by the WHO recommended deadline of 24 months following study completion.

“We need the collaboration of all these actors to enforce transparency in their jurisdictions in order to increase the benefits and decrease the risks for patients, clinical trial volunteers and the general public,” concluded Dr Kieny.

International Clinical Trials Registry Platform furthers transparency

WHO’s call for disclosure includes older unreported clinical trials, the results of which may still have an important bearing on scientific research today. WHO also reaffirms the need for all clinical trials to be registered on a WHO primary clinical trial registry so that they can be accessible through the International Clinical Trials Registry platform. This will ensure transparency as to which clinical trials have occurred, and allow verification of compliance with public disclosure requirements.

The recent WHO move expands on a 2005 call for all clinical trials to be registered, and the subsequent establishment of the International Clinical Trials Registry Platform. This registry platform regularly imports trial records from ClinicalTrials.gov, ISRCTN registry, EU Clinical Trials Register, Australia New Zealand Clinical Trial Registry, Pan African Clinical Trial Registry and Clinical Trial Registries from China, India, Brazil, Republic of Korea, Cuba, Germany, Iran, Japan, Sri Lanka, The Netherlands and Thailand.

hat tip to pharmagossip… 

• WHO Statement on Public Disclosure of Clinical Trial Results
• Rationale for WHO’s New Position Calling for Prompt Reporting and Public Disclosure of Interventional Clinical Trial Results [PLoS Medicine]

Is science broken?

the psychologist

British Psychological Society

17th March 2015

[see also Is Science Broken? Let’s Ask Karl Popper]

A lively debate was held at London’s Senate House yesterday with panellists from neuroscience and psychology discussing the question: is science broken? If so, how can we fix it? The discussion covered the replication crisis along with areas of concern regarding statistics and larger, more general problems…

Neuroskeptic, a Neuroscience, Psychology and Psychiatry researcher and blogger, gave a personal perspective on problems with science, speaking of the events which led him to lose faith in the research in the field. He said that as undergraduate students people are taught to do statistics in a very particular way, but once a person begins PhD research things change vastly. After gathering some results for his PhD research, Neuroskeptic found he had one significant result out of seven tasks performed by his participants. He said: ‘I thought back to my undergraduate days and thought “what if you do a Bonferroni correction across all the tasks?”. I got the idea that I’d suggest this to my supervisor but don’t think I ever did, I realised that just wasn’t how it was done. I was very surprised by this. I learned as an undergraduate you do a Bonferroni correction if you have multiple tasks. I started to wonder if we aren’t doing this who else isn’t doing it? I began to lose faith in research in the field.’

Neuroskeptic said he wondered whether there was a good reason that multiple comparisons correction was not used. He added: ‘I still don’t think there’s a good reason we can’t do that. We have come to the tacit decision to accept methods which we would never teach undergraduates were a statistically good idea, but we decide that we’re happy to do them ourselves. That’s how I got on the road to blogging about these issues.’

My own biostatistics and research experience was in another medical field over forty years ago, so when I began to look at the math of clinical trials, it was familiar but only just. Besides coursework, my only hands-on experience was using ANOVA to partition the variance of interactions of effects, so there was  much to learn. But I do have a Bonferroni Correction story to tell from those days. During an Immunology fellowship, my clinical work was with a Rheumatology Section. Rheumatology is like Psychiatry in that there are many conditions where the etiology [cause] was and is unknown. In the 1960s, Rheumatologists were collecting large databases on every patient they saw to develop criteria for diagnoses [sound familiar?]. Databases were new, as were the mainframe computers that held the data entered with punch cards and stored on tapes. Statistics were run with home-grown Fortran programs that ran over-night [if you were lucky]. Bill Gates hadn’t yet made it to high school. Excel was something you did in sports. And correcting for multiple variables was something kind of new.

One afternoon, the statistician and clinical staff blocked out a two hour conference to show us the results from the clinical database they were collecting [with great pride]. It was one of those after-lunch conferences where the eyelids are hard to hold open. Towards the end, the statistician showed us a thick stack of computer print outs with all the significant findings – disorders across the top, parameters down the side, cells filled with probabilities. Then he said something like, "Of course we had to correct the statistics for multiple measurements." I don’t remember the term Bonferroni Correction, but I do remember what he did. He divided all those p-values by the number of things measured, and then he showed a slide of what significance remained from that thick stack of printouts. It evaporated, and left a table that fit on one readable slide. I was pretty impressed, but he seemed deflated watching his fine p-values go up in smoke.

I find this next chapter of GSK USA surrealistic. In January 2011, I read Deirdre Connelly’s speech with amazement. She was the new president of GSK USA, and she was going to shut down the program where Drug Rep’s bonuses were based on the number of prescriptions their territory’s doctors wrote [“so what went wrong?”…]…

Glaxo Exec Concedes Drug Industry ‘Lost Its Way’ And Prescribes Changes

NPR

by Scott Hensley

January 24, 2011

The same day the feds said they recovered $4 billion related to health care fraud in the government’s last fiscal year, a leading drug company exec acknowledged the industry had gone off course. In a speech Monday to hundreds of people who make their living keeping drugmakers on the straight and narrow, GlaxoSmithKline’s U.S. President Deirdre Connelly noted the huge fines paid in recent years by drugmakers and the low esteem consumers have for the companies these days. Then she asked the obvious question. “So what went wrong?”

In the speech, whose prepared text we got from the company, Connelly said, “The answer, I believe, is that, in some ways, our industry lost its way.” Nobody I know would argue with that. She faulted a “competitive selling model” that works fine for autos or candy, but just isn’t right for medicines that can save people’s lives… Her prescription for change included focusing on patients’ needs and operating with greater transparency. One specific change worth noting: Glaxo won’t be paying drug reps bonuses based on increases in prescriptions in their territories anymore. Instead, Connelly said, Glaxo will base the compensation on specific scientific and business knowledge, customer feedback and performance of the business unit they’re part of. You can read the full text of Connelly’s speech here…

I may yet be naive and gullible, but I still think Deirdre Connelly was legit. If that’s true, her retirement brings up something fundamental. Can a publicly owned pharmaceutical company survive in a world where a drug isn’t hyped up and sold with aggressive and deceitful marketing? where it’s instead allowed to stand on its actual worth based on efficacy and safety? or will the push for profits, and the dreams of becoming a blockbuster drive the show? Whatever the case, let’s hope that her influence and policies have at least some sticking power.

Glaxo to Change its Compensation Program for U.S. Sales Reps

Pharmalot:WSJ

By Ed Silverman

April 13, 2015

One month after assuming responsibility for running GlaxoSmithKline pharmaceutical operations in North America, Jack Bailey is looking at changing a compensation program for sales reps that has generated complaints and frustration inside the drug maker. A task force is “in the process of looking at more comprehensive options to simplify” what Glaxo calls its Patient First program, which was begun four years ago in a bid to overhaul marketing practices aimed at physicians. The review was disclosed to Glaxo employees in an April 1 memo, which we have obtained and which was first reported by Bloomberg News.

As we have noted previously, the program was seen as ground breaking because reps are not paid bonuses based on the volume of prescriptions written by doctors. Instead, bonuses have been based on product knowledge, business acumen and understanding needs of patients and physicians, which were assessed in written tests and simulations conducted by third parties. The hope has been to remove the pressure reps may feel to persuade doctors to write prescriptions, which federal authorities charged sometimes led to inappropriate marketing practices. One year after Glaxo began the program, the drug maker paid a $3 billion fine to the U.S. government to settle allegations of improper drug marketing to physicians, among other things, and signed a corporate integrity agreement that requires Glaxo to monitor its marketing practices.

Sales reps, however, have complained the program contributed to sales declines, because there was less incentive to promote prescriptions, even though managers sometimes emphasized prescriptions, anyway. Glaxo recently began cutting $1.6 billion in expenses annually through 2017 amid falling sales in its key respiratory franchise and an overall sales drop in the U.S. market. Two months ago, Bailey replaced Deirdre Connelly, who launched the program in 2011. The drug maker said she retired. For now, the program is being tweaked. To appease its reps, Glaxo will no longer base their compensation on so-called simulations in which actual sales calls are simulated and observed as a way to determine bonuses, according to the memo from Bailey. However, a Glaxo spokeswoman writes us that the drug maker remains “resolutely committed to our commercial model.”

Glaxo, she writes, “has led the industry by changing the way we reward our sales representatives.  Our approach is based on the core principle that we will not link the compensation of our individual sales representatives with the number of prescriptions generated. Throughout the program we’ve looked for ways to simplify the process but the fundamentals remain the same. This approach has now been rolled out in 150 countries where we operate.” One Glaxo sales rep viewed the move cautiously. “We remain hopeful about the upcoming changes yet we remain realistic and guarded as well,” says this rep, who asked not to be identified. “We are under our corporate integrity agreement until 2019 and there isn’t a whole lot the company can do to make major changes to incentivize the reps the way they should be measured on performance.”

Under fire, Schulz stepping down

The head of the U’s psychiatry department is leaving his role amid a swarm of criticisms.

The Minnesota Daily

By Christopher Aadland

April 13, 2015

With the controversies around the department, especially the two recent investigations, I felt it was most constructive for me to step down as the chair of the Department of Psychiatry,” Schulz said. Since he came to the University to lead the department in 1999, Schulz has spent his career working with patients, like Markingson, who have schizophrenia or borderline personality disorder. While Schulz said the department has made many accomplishments under his leadership, he said he regrets dismissing some of the concerns that surfaced after Markingson’s death. He said he wishes he would have met with Markingson’s mother, Mary Weiss, to discuss the concerns she raised during and after Markingson’s death. “You can imagine, for years now, that’s been on my mind,” Schulz said…

These proxies were a step forward in that they offered a way to attach an objective value to the symptoms of mental illness. But they also brought a bag-full of new potential errors into the mix. Because they seemed to objectify the subjective, they gave the illusion that mental illnesses were, indeed, objective in the same way physical illnesses are. That may or may not be true in any given instance, but that still needs to be proved rather than just assumed because something can be measured. So many think, or at least talk like they think, that all mental illnesses are physical – caused by some identifiable pathogen. But there are other pitfalls. A Clinician-Rated PANSS Form is obviously not on the same level as a centrifuged blood sample measuring the % of the blood volume taken up by red cells [Hematocrit]. Just look at the PANSS Forms for Dan Markingson. I don’t know who did the rating, but at a time when we know from his mother’s reports, his own personal journal, and the comments from people around him that he was still lost in a psychotic fog – those objective measures [the PANSS ratings] said he was doing fine. That was not true, and those PANSS results were anything but a psychic hematocrit. The rating scales were never intended to be used for diagnosis. They’re for registering changes. And the reason they’re clinician-rated is to have an actual clinician in the mix to recognize when a subject is just telling the raters what he thinks they need to hear get them out of his face – which is likely what happened with Dan.

I’m not questioning the rightness of the many things already declared wrong in the story of what happened to Dan Markingson [and his mother]. CAFE was, as many have said, an un-necessary Clinical Trial – what Dr. Bernard Carroll dubbed an experimercial, the Clinical Trials undertaken to advance the sales of a medication rather than to refine our scientific understanding of the drug. I don’t question that the design of the study was flawed [for example, leaving out criteria to determine a non-response to the assigned study drug]. I was as appalled by the way Dan was recruited into and retained in the study as anyone else. And I agree with the recent investigations that shut down the whole clinical research enterprise pending a lot of needed reform.

But I want to add something else to the list. The notion of objectifying and quantifying mental illness is a laudable goal. I’m as much of a numbers/graphs guy as anybody around. But mental illness, particularly severe mental illness, is a subjective experience – and the subjectivity of the person doing the evaluation is an important part of assessment. You can’t see a case in the proxies – you have to see the case. And the objective measures used in clinical trials like a PANSS score are soft proxies as opposed to the Hematocrit or blood chemistries. The people who saw Dan at the Theo House, at OT, at the Day Hospital, his mother – all knew that Dan was very ill all along, but the people in charge didn’t. The biggest ethical breach in this whole story was that his doctor, Stephen Olson, didn’t respond to the loud noises screaming "somethings wrong!" by stopping by the Theo House on the way home and spending some serious time evaluating Dan Markingson in depth, in person. In the article above, Dr. Schulz, the co-principle investigator, regrets that he hadn’t "met with Markingson’s mother, Mary Weiss, to discuss the concerns she raised during and after Markingson’s death." Instead, I want Dr. Schulz to regret that he didn’t drive over to the Theo House and interview Dan Markingson himself, in depth, in person, to have the kind of direct clinical knowledge he would’ve needed to have to have met with and responded to Mary Weiss [maybe he could’ve met her there].

There’s a story of a Zen Master who comes upon a scholar pointing at the moon and lecturing on and on to his students. The Master comments, "that fellow is confusing his finger with the moon." In this case, I’m suggesting that the KOL brand psychiatrists have confused their soft proxies [clinical trials and rating scales] for the actual patients in many instances. In this case, I’m suspicious that they paid attention to the rating scales and not the patient. In other places, they’ve claimed that minor differences have clinical meaning when they don’t. But we often think that all examples portend bad motives, and in some cases they do. But this is an error one can make even without bad motives – by overvaluing secondary information without investigating further.

On March 15. 2004 I sent via certified mail a letter addressing my concerns regarding the treatment my son, Dan Markingson, is receiving through the CAFE program. I have not had the courtesy of a reply. I have again left messages for Dr. Olson asking him to point out how he feels Dan is doing better than when hospitalized. I have not received a reply. Actually. I believe the most lucidity I’ve seen Dan in the last six months was when he was first hospitalized, and was on an anti-anxiety medication. He said to me, "Mom. Through all of this you never told me everything would be okay" [I. of course, assured him it would, and it will!]. That was also the only time he indicated any awareness of a problem!…

Weiss letter to Schulz April 26, 2004

To the best of my knowledge, we thought Dan was taking his medication and it was being monitored after January and February by the staff at Theo House.  And in terms of the deterioration, there was no evidence that came to light either before his suicide or after that he was suffering a psychotic decompensation.  The only deterioration that we noted was some deterioration in his grooming and other negative symptoms which are manifestations of schizophrenia that do tend to increase over time, but they’re not amenable to treatment with antipsychotic medications, and there was no indication that he had any return of the behavior being influenced by his delusional thinking.

Olson deposition 2007

I’m not aware that there are substantial data – you’re implying from rating scales that we’re performing, no, I’m not aware that there is evidence of substantial deterioration.

Olson deposition 2007

Charles Schulz under scrutiny for Seroquel study suicide

Is U of M department of psychiatry chair in the pocket of AstraZeneca?

Minneapolis City Pages

By Andy Mannix

Feb 2, 2011

Mary Weiss knew something wasn’t right with her son. Only a year before, Dan Markingson had seemed perfectly normal. But his latest letter from Los Angeles suggested a troubled mind. He claimed he was about to become famous. He was at a crossroads in his life, and would soon have more free time. He even had a big movie premiere in the works. "I knew then that something was wrong," says Weiss. "I knew that there wasn’t a premiere, and when he said he was going to have a lot more free time, I thought he was quitting his job."

Weiss immediately jumped in her car and drove to California. When she arrived, she found her son far worse off than she’d feared. He was talking nonsense and couldn’t be reasoned with. Weiss tried to convince Markingson to come back to Minnesota, where she could look after him. But he had a stipulation: He would only return home if his dead grandmother Daisy told him to. Weiss went to an internet cafe down the street and created an email account under the name "GuardianAngelDaisy." Pretending to be her own deceased mother, she urged Markingson to return to Minnesota. Eventually, he agreed.

He was home for only 10 days before he decided to return to California. Weiss pleaded with him to stay, but he refused. She could either drive him to the airport, or never see him again. Weiss followed him to Los Angeles, where she again tried to urge her son to go back to Minnesota. But this time, his grandmother’s emails weren’t enough. Markingson wanted to talk to a higher authority: Michael the Archangel.

Weiss created another fake email account as Archangel Michael. The two exchanged emails for more than a week before Markingson finally agreed to fly home. Once he was back, Weiss called the South St. Paul police. An officer came to her home to evaluate her son. During the interview, Markingson casually mentioned he would soon be attending a devil-worshipping event in Duluth, and might be ordered to kill people.

That triggered a trip to Fairview University Medical Center, where Markingson was diagnosed with psychosis and placed on a 72-hour hold…

In order to be released, Markingson agreed to a stay of commitment, which would allow him to leave the hospital as long as he followed a treatment plan. The plan involved Markingson enrolling in a study called Comparison of Atypicals in First Episode, or CAFE. The research was sponsored by AstraZeneca, maker of Seroquel, one of the anti-psychotic drugs being investigated. When Weiss found out her son was a human guinea pig, she was furious. She called the hospital and tried to pull her son out of the treatment plan, to no avail. Although Markingson was mentally unfit, he was somehow able to consent to the drug trial.

Over the next few months, Markingson’s condition only worsened, Weiss says. His doctor wouldn’t return her calls, so she tried writing a letter to the head of the department, Dr. Charles Schulz. He didn’t reply.

It wasn’t until April 28, after Weiss’s third letter, that she received a cursory response, in which Schulz wrote, "it was not clear to me how you thought the treatment team should deal with this issue." Ten days later, on May 8, Markingson sat in the bathtub of the halfway house where he was staying and stabbed himself to death with a box cutter. "I left this experience smiling!" read the suicide note.

I gave Dr Olson examples of Dan’s behavior that lead mc to believe the drug he is on is not beneficial: He still believes he is "bulletproof’ [Dan had told my on several occasions in Los Angeles that he is "bulletproof’, and that I was also when I was with him]. He still believes both that he is an actor [not true], and that he will make a living by giving walking tours of Hollywood. He believes his finances are fine [he owes more than $6,000]. He takes no interest in his appearance [he has been wearing the same pair of khaki pants and cutoff sweatshirt since last November]. Does this sound to you like someone who is getting well?

Weiss letter to Schulz April 26, 2004

Mar 23, 2004: "world walking, you were at a farm house and we’re getting presents from dogs who had presents fastened in plastic bags to their snouts… in the gloaming and breening, you were thinking of naming it gloaming and greening or gloam-green. That was someone brings a snowslide in summer or midsummer. It has been left behind…" [Olson 2007 p. 467]

And in terms of the deterioration, there was no evidence that came to light either before his suicide or after that he was suffering a psychotic decompensation…

Olson deposition 2007

I’m not aware that there are substantial data – you’re implying from rating scales that we’re performing, no, I’m not aware that there is evidence of substantial deterioration.

Olson deposition 2007

Evolution of Psychopharmacology Trial Design and Analysis: Six Decades in the Making

by Andrew C. Leon, PhD

Journal of Clinical Psychiatry 2011 72[3]:331–340.

[full text on-line]

Objective: The evolution of trial design and analysis during the lifespan of psychopharmacology is examined.

Background: The clinical trial methodology used to evaluate psychopharmacologic agents has evolved considerably over the past 6 decades. The first and most productive decade was characterized by case series, each with a small number of patients. These trials used nonstandardized clinical observation as outcomes and seldom had a comparison group. The crossover design became widely used to examine acute psychiatric treatments in the 1950s and 1960s. Although this strategy provided comparison data, it introduced problems in study implementation and interpretation. In 1962, the US Food and Drug Administration began to require “substantial evidence of effectiveness from adequate and well-controlled studies.” Subsequent decades saw remarkable advances in clinical trial design, assessment, and statistical analyses. Standardized instruments were developed and parallel groups, double-blinding, and placebo controls became the benchmark. Sample sizes increased and data analytic procedures were developed that could accommodate the problems of attrition. Randomized withdrawal designs were introduced in the 1970s to examine maintenance therapies. Ethical principles for research became codified in the United States at that time. A wave of regulatory approvals of novel antipsychotics, antidepressants, and anticonvulsants came in the 1980s and 1990s, each based on data from randomized double-blind, parallel-group, placebo-controlled clinical trials. These trial designs often involved fixed-dose comparisons based, in part, on a greater appreciation that much of the benefit and harm in psychopharmacology was dose related.

Conclusions: Despite the progress in randomized controlled trial [RCT] design, the discovery of new mechanisms of action and blockbuster interventions has slowed during the past decade.

The initial trials in psychopharmacology involved case series, each with a small number of patients. Cade reported the antimanic properties of lithium based on a series of 10 cases in Australia in 1949. In 1952, the initial psychiatric study of chlorpromazine, which was previously used for nausea in surgical patients, involved 20 patients with psychosis and reported symptomatic improvement. Chlorpromazine was approved by the FDA in 1954 for psychosis. Imipramine has a molecular structure similar to that of chlorpromazine and for that reason was initially tested as an antipsychotic in 1957 with several hundred cases. Although that effort did not demonstrate effectiveness for psychosis, observation of about 12 of the cases with depression revealed the antidepressant property of imipramine. Iproniazid, a monoamine oxidase inhibitor (MAOI), was used for tuberculosis and clinical observation on the tuberculosis wards reported that patients expressed joy and optimism, despite their prognosis. In 1957, a case series of patients with depression showed beneficial effects of iproniazid. The decade from 1949 to 1958 is unparalleled in the history of psychopharmacology, with the discovery of the first mood stabilizer, the first antipsychotic, and 2 antidepressants, a tricyclic and an MAOI. Yet, none of these case series involved a control.

In 1955, Beecher described placebo response rates across a wide range of indications including anesthesia for surgery, highlighting the need for trials to include a comparator.8 He stated, “Many a drug has been extolled on the basis of clinical impression when the only power it had was that of a placebo.”

The inclusion criteria in the early studies were often rather broad perhaps, in part, because the diagnostic nosology of the era, DSM-I [1952] and DSM-II [1968], were narrative based. It was not until Feighner criteria in 1972, Research Diagnostic Criteria in 1978, and DSM-III in 1980 that nosology became criterion based.

Standards for the study design and analysis continued to evolve. Max Hamilton, MD, a psychiatrist and namesake of a rating scale for depression, published a text that comprised 12 of his lectures covering a range of areas in clinical research design and analysis including stages of experimentation, design of experiments, measurement of variability, tests of statistical significance, t test, χ2, ANOVA, correlation, selecting cases and treatment, and problems in design and analysis.

As originally conceived, the ECDEU program consisted primarily of grant- supported clinical investigators working in tine common area of psychotropic drug evaluation [both new and established compounds]. One of the problems they encountered, and task they accomplished, was the development of a uniform battery of clinical assessment instruments known as the ECDEU Standard Reporting System, first introduced for utilization in 1967. The rationale behind this effort was twofold. First, it was felt that such a system would enhance both the quality of early clinical drug research and allow greater generalizability of results across studies and investigating units. Second, data collected on common forms could be stored in a data bank for future study and research. Since the implementation of this Standard Reporting System and the Biometric Laboratory Information Processing System [BLIPS], the ECDEU program has evolved into more than an extramural grant support program for psychotropic drug research teams. In collaboration with The George Washington University Biometric Laboratory, the ECDEU Standard Reporting System has been made available to any investigator interested in conducting clinical trials, whether federally grant supported or not. To utilize these services, the investigator is requested to:

1. Submit a Research Plan Report and agree to send the study data to the Biometric Laboratory.
2. Collect sufficient information about the subjects in his study so that the data can be entered into the ECDEU data bank. This means, essentially, that a core of data must be collected for each patient…

In return, he receives a sufficient number of assessment scales to conduct his research. Once the trial is completed, the forms are returned to the Biometric Laboratory for processing and data analyses, the results of which are sent to the investigator in the form of a standard data package. The rating scales and data processing services are provided at no charge – our sole "remuneration" being the opportunity to add the investigator’s data to the data bank. It should be stressed that an investigator’s data and/or results are never published or disseminated to others without his permission.

Markingson case: University of Minnesota can’t regain trust under current leadership

Years of stonewalling have done too much damage.

Minnestota Star Tribune Commentaries

by ARNE H. CARLSON [Governor of Minnesota 1991-1999]

April 10, 2015

^{“The University constructed a defense to deny liability by claiming immunity. I think that defense evolved or you might say devolved into a strategy to simply avoid any accountability or responsibility and to deny that there were any serious ethical issues. And we found that serious ethical issues and conflicts of interest just permeated this case.”}

^{James Nobles, legislative auditor, March 20, 2015}

The University of Minnesota, like many other universities, has a sizable clinical research program that tests experimental drugs for safety and efficacy. The understanding between the companies that develop these drugs and the consuming public is that such drugs are carefully tested on humans and that these clinical trials must comply with strict ethical, scientific and regulatory standards. These research protections were developed after a series of research scandals that involved abusive treatment of vulnerable populations such as economically disadvantaged communities, prisoners, children, and individuals suffering from mental illness.

Ever since the violent suicide of Dan Markingson in 2004, the administration of the University of Minnesota has received repeated calls for the release of more details about the care and protection afforded the victim. These calls have come from faculty members at the university, from local community members and from researchers from around the world. But instead of being transparent and forthright, the administration created a standard response similar to that expressed by the university’s former general counsel, Mark Rotenberg: “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 any of our faculty.”

If correct, that would be a most understandable and appropriate response. However, it falls far short of the truth. Consider this:

During his first year at the university, Kaler had to make a major decision. Prudent management would have involved meeting with Elliott, learning about the specific ethical issues related to Markingson and broader concerns about psychiatric clinical research, and dealing with the growing scandal. But Kaler chose instead to perpetuate the prevailing coverup. He opposed any independent review, never responded to the charges made in the media, ignored or dismissed critics, and stood firm in his belief that it would all blow over.

In so doing, President Kaler tarnished his office and abandoned the principles of truthfulness, openness and integrity. He also frittered away the moral authority that is so essential to governance. His failure to provide ethical leadership permitted the scandal to grow. The result was more stonewalling of requests for information from faculty and media and increased attempts by administration officials to demonize critics, including referring to some scientists as “wackos.” Perhaps most troubling is the culture of intimidation associated with the Department of Psychiatry. The university’s own external review refers to this culture as a “climate of fear.” Extending from that department to the university’s senior management team, the apparent goal was to make certain no one questioned authority.

On June 16, 2014, I met with Kaler and Board of Regents Chairman Richard Beeson, and went over all the materials covering conflicts of interest, the falseness of their claims of endless investigations, as well as the damage being done by news articles highly critical of the university’s handling of the Markingson scandal. Kaler was quiet and rarely asked a question. As a result, I focused more attention on the lack of oversight and leadership provided by the Board of Regents and its failure to examine the circumstances of Markingson’s death. Given the deeply troubled history of research in the Department of Psychiatry over the past 25 years, a history that includes six suicide deaths, untold injuries, the conviction and imprisonment of one professor, the barring of two researchers by the FDA, and a barrage of poor publicity, I was stunned by Beeson’s response that this matter “has not risen to the level of our concern.”

Last week, the university announced that Charles Schulz has decided to resign as chairman of the Department of Psychiatry. He will retain his position as executive medical director, and his faculty appointment. The news release announcing his departure made no mention of the department’s troubled record, or the research controversies in which Schulz has been personally involved. Rather than removing him as department chairman and taking additional disciplinary action, the university has provided Schulz with a soft landing. The very administrators and regents responsible for the current debacle now promote themselves as trustworthy agents of change. We will not see meaningful reform of research on human subjects, nor the restoration of prestige at the university, so long as Kaler, Beeson and other leaders responsible for years of denials and stonewalling remain in charge.

• April 8, 2015: Implementation team formed to advance University of Minnesota human subjects research protection program [UMn Announcement]
  
• April 9, 2015: The Fix is In by Leigh Turner [Commentary on the make-up of the Implementation Team]
• April 9, 2015: Schulz stepping down as head of psychiatry [Comments from the Dean of the Medical School on the occasion of Chairman Charles Schulz’s resignation today]

U of Minnesota psychiatry chief steps down after concerns about research protocols

Star Tribune

by JEREMY OLSON

April 9, 2015

The University of Minnesota is replacing its Psychiatry Department chairman following an external review that identified subpar safety protocols in research involving human subjects and a legislative audit that chastised the department for its recruitment of a troubled man who later died by suicide in a schizophrenia drug trial. While Dr. Charles Schulz will continue clinical care and research in the department he has led since 1999, Thursday’s announcement that he is stepping down reflects a metamorphasis for a university that even a month ago was adamantly defending his department against claims of coercive recruiting of vulnerable patients into research.

“Changing one person — it’s not like switching a light switch” and problems will be fixed, said Leigh Turner, a U bioethicist who has demanded changes in administration due to problems with psychiatric research. “But there is a symbolic dimension to it. A chair is a symbolic face of a department. And this is a department that has been through a long period of controversy and questions about the conduct of its clinical trials.”

Much of the criticism has centered around the recruitment of Dan Markingson, who died by suicide in 2004 while enrolled in the university’s arm of a national study that compared the effectiveness of three antipsychotic drugs. Markingson was recruited at the time by Dr. Stephen Olson, a psychiatrist who was treating him, and running the study, and advising a judge on whether Markingson should be committed to a locked inpatient facility. Legislation following media coverage of this case in 2008 made this type of potentially coercive recruiting situation illegal…

Schulz brought prestige and a track record for amassing research grants and studying the origins of schizophrenia when he took over the department 15 years ago. He had previously been psychiatry chairman at Case Western Reserve University in Cleveland, and chief of the schizophrenia research branch for the U.S. National Institute of Mental Health…

Schulz has, like other doctors in recent years, been scrutinized for the thousands of dollars he has received from drug companies such as AstraZeneca, the sponsor of the study in which Markingson was enrolled. Schulz’ name surfaced in documents submitted in a lawsuit against AstraZeneca, indicating that back in 2000 he made statements about the superiority of the company’s new antipsychotic drug, Seroquel, that were more favorable than research indicated…

What’s happening at this point is anticlimactic. The powers that be felt like they could just wait things out, and the Dan Markingson case would simply fade away. Throughout the whole eleven years, they treated it as a nuisance. Carl Elliot has Schulz’s only public comments on it here [back in 2010] on his blog. And looking back, this piece gives a lot of information about the case and Schulz I haven’t seen before.

Research Misconduct Identified by the US Food and Drug Administration:

Out of Sight, Out of Mind, Out of the Peer-Reviewed Literature

by Charles Seife, MS

JAMA Internal Medicine. 2015 175[4]:567-577.

IMPORTANCE Every year, the US Food and Drug Administration [FDA] inspects several hundred clinical sites performing biomedical research on human participants and occasionally finds evidence of substantial departures from good clinical practice and research misconduct. However, the FDA has no systematic method of communicating these findings to the scientific community, leaving open the possibility that research misconduct detected by a government agency goes unremarked in the peer-reviewed literature.

OBJECTIVES To identify published clinical trials in which an FDA inspection found significant evidence of objectionable conditions or practices, to describe violations, and to determine whether the violations are mentioned in the peer-reviewed literature.

DESIGN AND SETTING Cross-sectional analysis of publicly available documents, dated from January 1, 1998, to September 30, 2013, describing FDA inspections of clinical trial sites in which significant evidence of objectionable conditions or practices was found.

MAIN OUTCOMES AND MEASURES For each inspection document that could be linked to a specific published clinical trial, the main measure was a yes/no determination of whether there was mention in the peer-reviewed literature of problems the FDA had identified.

RESULTS Fifty-seven published clinical trials were identified for which an FDA inspection of a trial site had found significant evidence of 1 or more of the following problems: falsification or submission of false information, 22 trials [39%]; problems with adverse events reporting, 14 trials [25%]; protocol violations, 42 trials [74%]; inadequate or inaccurate recordkeeping, 35 trials [61%]; failure to protect the safety of patients and/or issues with oversight or informed consent, 30 trials [53%]; and violations not otherwise categorized, 20 trials [35%]. Only 3 of the 78 publications [4%] that resulted from trials in which the FDA found significant violations mentioned the objectionable conditions or practices found during the inspection. No corrections, retractions, expressions of concern, or other comments acknowledging the key issues identified by the inspection were subsequently published.

CONCLUSIONS AND RELEVANCE When the FDA finds significant departures from good clinical practice, those findings are seldom reflected in the peer-reviewed literature, even when there is evidence of data fabrication or other forms of research misconduct.

hat·tip to Elia…  

Are Your Medications Safe?

FDA buries evidence of fraud in medical trials. My students and I dug it up.

Slate

by Charles Seife

Feb 9, 2015

… Much of my research has to do with follies, foibles, and fraud in science, and I knew that the FDA wasn’t exactly bending over backward to correct the scientific record when its inspectors found problems during clinical trials. So as part of my investigative reporting class at New York University, my students and I set out to find out just how bad the problem was — and how much important information the FDA was keeping under wraps. We didn’t have to search very hard to find FDA burying evidence of research misconduct. Just look at any document related to an FDA inspection. As part of the new drug application process, or, more rarely, when the agency gets a tipoff of wrongdoing, the FDA sends a bunch of inspectors out to clinical sites to make sure that everything is done by the book. When there are problems, the FDA generates a lot of paperwork — what are called form 483s, Establishment Inspection Reports, and in the worst cases, what are known as Warning Letters. If you manage to get your hands on these documents, you’ll see that, most of the time, key portions are redacted: information that describes what drug the researcher was studying, the name of the study, and precisely how the misconduct affected the quality of the data are all blacked out. These redactions make it all but impossible to figure out which study is tainted. My students and I looked at FDA documents relating to roughly 600 clinical trials in which one of the researchers running the trial failed an FDA inspection. In only roughly 100 cases were we able to figure out which study, which drug, and which pharmaceutical company were involved. [We cracked a bunch of the redactions by cross-referencing the documents with clinical trials data, checking various other databases, and using carefully crafted Google searches.] For the other 500, the FDA was successfully able to shield the drugmaker [and the study sponsor] from public exposure…

Case 3
A researcher was caught falsifying documents in a number of trials, in part because those falsifications led to the death of a patient undergoing treatment in a clinical trial comparing 2 chemotherapy regimens. The researcher had falsified laboratory test results to hide the patient’s impaired kidney and liver function, and the first dose of the treatment proved to be fatal.The researcher pleaded guilty to fraud and criminally negligent homicide and was sentenced to 71 months in prison. Although this episode is described in detail in FDA documents as well as court documents, none of the publications in the peer-reviewed literature associated with the chemotherapy study in which the patient died have any mention of the falsification, fraud, or homicide. The publications associated with 2 of the 3 other studies for which the researcher falsified documents also do not report on the violations.

The FDA does not typically notify journals when a site participating in a published clinical trial receives an OAI inspection, nor does it generally make any announcement intended to alert the public about the research misconduct that it finds. The documents the agency discloses tend to be heavily redacted. As a result, it is usually very difficult, or even impossible, to determine which published clinical trials are implicated by the FDA’s allegations of research misconduct. The FDA has legal as well as ethical responsibilities regarding the scientific misconduct it finds during its inspections. When the agency withholds the identity of a clinical trial affected by scientific misconduct, it does so because it considers the identity to be confidential commercial information, which it feels bound to protect. However, failing to notify the medical or scientific communities about allegations of serious research misconduct in clinical trials is incompatible with the FDA’s mission to protect the public health…

The sworn purpose of the FDA is to protect the public health, to assure us that all the drugs on the market are proven safe and effective by reputable scientific trials. Yet, over and over again, the agency has proven itself willing to keep scientists, doctors, and the public in the dark about incidents when those scientific trials turn out to be less than reputable. It does so not only by passive silence, but by active deception. And despite being called out numerous times over the years for its bad behavior, including from some very pissed-off members of Congress, the agency is stubbornly resistant to change. It’s a sign that the FDA is deeply captured, drawn firmly into the orbit of the pharmaceutical industry that it’s supposed to regulate. We can no longer hope that the situation will get better without firm action from the legislature. The FDA wants you to take it on faith that its officials have the public’s best interest at heart. Justification through faith alone might be just fine as a religious doctrine, but it’s not a good foundation for ensuring the safety and effectiveness of our drugs. After all, the whole point of science-based medicine is to keep us from having to make a leap of faith every time we swallow a pill.