Herding Pharma “Cats”

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The Chinese government released a report in September of 2016 by the State Food and Drug Administration (SFDA) that found fraudulent clinical trial practices on a massive scale. The SFDA concluded that over 80% of clinical trial data was fabricated. The scandal was the result of a “breach of duty by supervision departments and malpractice by pharmaceutical companies, intermediary agents and medical staff.” More than 80% of the applications for the mass production of new medications have been cancelled, with warnings by the SFDA that further evidence of malpractice might still emerge.

Radio Free Asia also reported the SFDA indicated much of the clinical trail data was incomplete at best. But it also failed to meet basic analysis requirements or was untraceable. “Some companies were suspected of deliberately hiding or deleting records of adverse effects, and tampering with data that did not meet expectations.” Apparently, this came as no surprise to industry insiders. “Clinical data fabrication was an open secret even before the inspection.”

Many of the new drugs were combinations of existing ones. Clinical trial outcomes were written beforehand, and their data presented so it agreed with the fabricated outcomes. A doctor at a top Chinese hospital said the problem lay with the failure to implement regulations governing clinical trial data. “Guangdong-based rights activist Mai Ke said there is an all-pervasive culture of fakery across all products made in the country.” Reporting for Pharmafile, Ben Hargreaves said:

The root of the issue is then not regulation, with regulation for clinical trials running on similar lines to Western practises, but in the lack of adherence to them. China’s generic drug industry has struggled with quality problems and therefore there is a temptation for companies to manipulate data to meet standards. The report found that many of the new drugs were found to be a combination of existing drugs, with clinical trials outcomes written beforehand and the data tweaked to fit in with the desire outcomes.

Sadly, clinical trial problems are not unique to China. An editorial published in the British journal The Lancet Psychiatry described multiple issues beginning with how subjects are recruited, moving on to determining what the control group should be, and ultimately defining meaningful outcome measures. Sometimes, trial recruits receive “care” they didn’t agree to. “Researchers and ethics review boards need to examine the ethical arguments and practical procedures from other areas of medicine where consent is problematic.” If such trials are done, regular and rigorous monitoring is essential. Patient safety and autonomy needs to be a priority.

In his discussion of the editorial, Justin Carter elaborated on one of the problems with recruiting subjects. An individual was recruited into a study on three antipsychotics while under a forced commitment order from a judge. “The psychiatrist who recruited him was in charge of the study and was his treatment provider and was also empowered to report on the patient’s progress to the judge.” The individual died by suicide during the drug trial.

The work of Irving Kirsch and others has shown the problem with inert placebos (sugar pills). The side effects from medication make it easy for participants to guess which study group they are in.

And when the trial is over and the data in, do the outcome measures really provide something meaningful for people’s lives? If the ultimate goal is for people to fell better and resume their prior level of functioning, should outcome measures by primarily patient self-reports, clinical assessment, or differences shown by imaging or the as-yet-to-be-clearly-identified biomarkers?

Given the problems running and interpreting psychiatry trials, it is essential to learn how even the most successfully tested interventions work in real clinics with the broad patient population. Implementation, uptake, and effectiveness in real-life settings must be analysed, and delivery of new innovations modified accordingly. Future research should be thought of not as a plain linear process from innovation to trial to implementation, but as a virtuous circle where research feeds into the clinic and vice versa.

Another issue pointed to by Carter was the validity and reliability of the diagnosis or classification system used to determine who to include and who to exclude from the trials. The DSM system, now in its fifth edition (DSM-5), is the current “bible” for assessing and diagnosing problems the psychiatric medications in clinical trials are supposed to “treat” in the U.S. Yet there have been questions about the reliability and validity of the DSM dating from an argument raised by Robert Spitzer and others in the 1970s that ushered in changes still embedded in the DSM-5. Rachel Cooper gave a brief history of the reliability questions with the DSM in “How Reliable is the DSM-5?” You can also refer to “Psychiatry Has No Clothes,” “Where There’s Smoke …”, and  “The Quest for Psychiatric Dragons,” Parts 1 and 2.

A few weeks before the release of the DSM-5, Thomas Insel, then the NIMH Director, announced the NIMH would be “reorienting” its research away from DSM categories. The agency’s new approach is called the Research Domain Criteria (RDoC) project. For now, RDoC is a research framework and not a clinical tool. But NIMH has high hopes for it: “RDoC is nothing less than a plan to transform clinical practice by bringing a new generation of research to inform how we diagnose and treat mental disorders.” While Tom Insel has moved on to work for Alphabet (Google), RDoC is alive and well within NIMH. You can keep up with news about RDoC on the “Science News About RDoC.”

The Science Update for February 16, 2106 noted the March 2016 issue of the journal Psychophysiology would be devoted to the RDoC initiative. Dr. Bruce Cuthbert said the special issue was a unique opportunity for researchers to engage with one another and reflect on work being done in various laboratories throughout the country. He thought it was encouraging to see many investigators already engaged in the kind of work RDoC advocates. “What this shows is that while the RDoC acronym may be new, the principles behind RDoC are certainly not new to psychiatric research.”

If the principles behind RDoC are not new to psychiatric research, how can it bring “a new generation of research to inform how we diagnose and treat mental disorders” in order to transform clinical practice? It sounds a lot like using the same deck of cards to just play a new card game. RDoC may not be the transformative framework it’s touted to become.

Added to these issues is the failure of pharmaceutical companies to publically report the results of clinical trials, as they are required by law to do. New reporting rules will take effect on January 18, 2017. But advocates for transparency in clinical research have cautioned the success of the new rules will depend upon the willingness and vigor of government enforcement of those rules. The failure to enforce the existing rules, which went into effect in 2008, led to widespread noncompliance with reporting requirements. If the FDA had fined the violators, they could have collected an estimated $25 billion.

Reporting for STAT News, Charles Piller said studies have indicated only a small fraction of trials will comply with the law. Yet there are no current plans to increase enforcement staffing at the FDA and NIH. That’s a big problem, according to Ben Goldacre, an advocate for full disclosure in clinical research. Francis Collins, the NIH director said they are serious about this and will withhold funds, if needed. “It’s hard to herd cats, but you can move their food, or take their food away.”

The legislation that created ClinicalTrials.gov emerged from numerous cases of drug manufacturers withholding negative trial results, making drugs look more effective and less harmful. Efforts to market the antidepressant Paxil for teenagers more than a decade ago stimulated the push for better reporting. A recent analysis in the journal BMJ found that GlaxoSmithKline, Paxil’s manufacturer, failed to disclose 2001 data showing the drug to be no more effective than a placebo, and was linked to increased suicide attempts by teens.

Writing for Time, Alexandra Sifferlin reported on a new study that suggested many of the medical reviewers for the FDA go to work for the drug companies they oversaw while working for the government. One of the study’s authors said: “I don’t think there is overt collusion going on, but if you know in the back of your mind that a major career opportunity after the FDA is going to work on the other side of the table, I worry it can make you less likely to put your foot down.”

Returning to the Francis Collins metaphor, it seems that the willingness to try and herd Pharma cats is dependent on whether or not you are afraid they will scratch you in the attempt.


The Quest for the Holy Grail of Psychiatry

Our brain: the final frontier. This is the unending quest of research into biomarkers. Its continuing mission: to explore strange new theories, to seek out new mental illnesses and new diagnoses, to boldly go where no psychiatric research has gone before.

The quest for biomarkers (measurable indicators of a biological state or condition) of mental disorders has gone on for decades without success. The recently proposed research strategy of the National Institute of Mental Health (NIMH) know as Research Domain Criteria (RDoC), has proposed to set aside the DSM diagnoses used to frame past mental health research and utilize data from neuroscience, genomics and behavioral science to spell out the etiology of mental illness.

Psychiatrist Giovanni Fava views the RDoC model as “the reflection of an intellectual crisis in psychiatry.” While its “blanket” approach aims to see that all possible biological and behavioral measurements are utilized, Fava thinks it will result in conflicting results that may be difficult to interpret. He said it was “misguided” to assume that nothing will be missed with such a strategy and that “innovative classification systems will ensue automatically.” The complexity of the new approach and the potential for interpretive problems it is illustrated by this recently published article in World Psychiatry, “Biomarkers and clinical staging in psychiatry.”

He pointed out that major clinical challenges were left without independent research. Among these challenges was the problem of the loss of clinical effects during long-term antidepressant treatment. And despite a lack of any evidence to support their superiority, antidepressant drugs are increasingly used as a first-line treatment for anxiety disorders. Studies on psychological treatment were also “scandalously under-supported.”

A major problem in the development of the Research Domain Criteria project has been the fact that its strong ideological endorsement by leading figures of the National Institute of Mental Health has resulted in suppression of an adequate debate. How many investigators who are likely to submit funding applications to that agency may afford disclosing that the emperor has no clothes and that the strategy may be a road to nowhere?

Fava et. al thought the exclusive reliance upon diagnostic criteria had impoverished the clinical process and did not reflect “the complex thinking that underlies decisions in psychiatric practice.” Current diagnostic definitions of psychiatric disorders are based on collections of symptoms from very heterogeneous populations and are likely to yield “spurious results when exploring biological correlates of mental disturbances.”

The large studies of biomarkers across diagnostic categories proposed by RDoC are anticipated to yield improved clinical information. But “such a view is based on the concept of assessment as a collection of symptoms devoid of any clinical judgment and interpretation.” There is no evidence to support the research direction taken by RDoC. Fava et al. noted that although Kapur, Phillips and Insel proposed that new biomarker-defined subtypes be identified, they were not able to “provide exemplifications suggesting that this approach was likely to yield meaningful clinical results in psychiatry.” Incidentally, Thomas Insel is the current director of the NIMH.

Using meta-analyses of biomarkers commonly used in cardiovascular medicine as an example, Fava et al. noted the presence of publication bias and selective reporting. They said biomarkers could end up being the result of various mechanisms and not necessarily the result of a specific disease process.

The complexity of the brain and the spurious nature of measurements that can be recorded constitute a major difficulty for psychiatry. Specifically, the neuroplastic properties make the brain a unique organ that essentially has to be studied and understood in a longitudinal, lifetime and transgenerational perspective.

Biological reductionism was said to have resulted in an approach that is far from the “explanatory pluralism” required by clinical practice. The exclusion of the methodological triad of observation (outer viewing), introspection (inner viewing), and dialogue (inter-viewing) makes this approach unscientific. Either the human realm was excluded from scientific inquiry or the scientific approach was conformed to the reductionistic, mechanistic requirements of the biomedical paradigm.

This restrictive ideology characterizes the Research Domain Criteria. It is time to enrich such criteria with clinically relevant dimensions and add clinical validity to the reliability and reductionism-focused mainstream of psychiatry research.

Elsewhere (“We Are But Thinking Reeds”) I’ve spoken of the necessity to see human nature as a psychosomatic unity of body (soma) and soul (psyche). The human mind is more than just a manifestation of brain activity. Any approach to “mental” illness research that fails to acknowledge this will never entirely succeed in its quest to find the holy grail of psychiatry.


Psychiatry’s Mythical Phoenix

Prominent research psychiatrists are beginning to sound like their “antipsychiatric” critics. They are saying the current DSM diagnostic system isn’t valid; that something new, something scientifically sound and useful for treating patients is needed. One of these research psychiatrists is Thomas Insel, the Director of the Director of the National Institute of Mental Health (NIMH). He dropped a bombshell last year when he announced that the NIMH would be “re-orienting its research away from DSM categories.” The New York Times quoted Insel as saying: “As long as the research community takes the D.S.M. to be a bible, we’ll never make progress. . . . People think that everything has to match D.S.M. criteria, but you know what? Biology never read that book.”

So the NIMH has developed a new research strategy to classify mental disorders based upon “dimensions of observable behavior and neurobiological measures.” This strategic plan is known as: Research Domain Criteria (RDoC). The long-term goal is for RDoC to be “a framework to guide classification of patients for research studies.” It was not meant to be a useful clinical tool. “It is hoped that by creating a framework that interfaces directly with genomics, neuroscience, and behavioral science, progress in explicating etiology and suggesting new treatments will be markedly facilitated.”

RDoC is in search of the holy grail of psychiatry: reliable biomarkers (measurable indicators of a biological state or condition) for mental disorders. This search for biomarkers has been going on for decades. David Kupfer, the chair of the DSM-5 Task Force said: “We’ve been telling patients for several decades that we are waiting for biomarkers. We’re still waiting.” Susan Kamens suggested that the imminent discovery of biomarkers has been “the driving expectation of psychiatry since its birth in the 18th century.” But there are some problems with the RDoC quest.

What RDoC proposes is to replace the DSM diagnoses used currently to frame mental health research with broad categories based upon cognitive, behavioral and neural mechanisms. This means that the NIMH will be supporting research projects that look across or sub-divide existing DSM categories. But this very same DSM is what is used to assess the potential of future NIMH-funded research under RDoC.

In an article found in Nature, “Psychiatry Framework Seeks to Reform Diagnostic Doctrine,” Nassir Ghaemi said: “It is very hard for people who have been following the DSM their entire professional lives to suddenly give it up.” Ghaemi has felt shackled by the DSM. He wanted to do some research that cut across DSM categories. But his colleagues warned him against straying too far from the DSM structure when he applied for funding from the NIMH, because peer reviewers tended to insist on research structured by the DSM. So he held off from applying.

Steven Hyman, a former NIMH director, blames the DSM for hampering research into the biological or genetic basis of psychiatric illness. He said it was “a fool’s errand” to use symptom-based DSM diagnosis with little basis in nature to try and find a biomarker. Hyman urged the NIMH to think about how biomarkers identified by RDoC would be incorporated into mental health practice with the DSM. “It would be very problematic for the research and clinical enterprises to wake up in a decade to a yawning gulf.”

But Susan Kamens sees a deeper problem with blaming the DSM for hampering the search for biomarkers—it takes for granted that the biomarkers exist. In other words, it presumes what it seeks to find. According to Kamens:

“The main difference is belief versus doubt in the hypothesis that what we call mental disorder is primarily a disorder of biology. We treat that hypothesis as unfalsifiable, as if the proof [that mental disorder is biological] arrived before the evidence. We don’t test whether the hypothesis holds; we test whether and how to make the data fit it. When critics raise doubts, they’re often accused of ignoring the very same evidence that psychiatric researchers have recently declared to be utterly insufficient.”

Kamens noted that the RDoC “blueprint” is no less theoretical that the DSM-5. While the RDoC constructs are more measurable than the categories listed in the DSM, they are “essentially no more than basic human emotions and behaviors.”  She asked how RDoC would make clinically meaningful determinations into its “domains” and “constructs”? How would the research reveal anything beyond the coordinates of normal psychological processes? “In other words, how is RDoC anything beyond basic (nonclinical) neuroscience?”

RDoC is developing a new research model that will undoubtedly yield unprecedented data, but it focuses on the biogenetic correlates and normative mapping of basic psychological processes like visual perception, language, fear responses, and circadian rhythms. The idea is to create interventions for psychological and physiological processes that deviate from the norm. For this reason, RDoC is less likely to save psychiatry than it is to resurrect eugenics.

The quest for biomarkers in psychiatry can be likened to the legend of the phoenix, a mythological bird that repeatedly rises out of the ashes of its predecessor. The DSM seems to be near end of its life-cycle. Now psychiatry is building an RDoC “nest” that it will eventually ignite, reducing both the DSM and RDoC to ashes. And from these ashes, it is hoped, a new diagnostic system—a new phoenix—will arise.

Also see my blog post, “Psychiatry Has No Clothes.”


Psychiatry Has No Clothes

On April 29th of 2013, there was an astounding blog post by Thomas Insel, the Director of the National Institute of Mental Health (NIMH). He said that although the DSM-5 was due to be released in a few weeks, the NIMH would be “re-orienting its research away from DSM categories.” He noted that while the DSM has been referred to as a “Bible” for the field of mental health, “It is, at best, a dictionary, creating a set of labels and defining each.” Did you get that? The Director of the NIMH said the DSM was a “dictionary” that created “labels.” It was not, then functioning adequately, in his opinion, as its title suggests: as a Diagnostic and Statistical Manual of Mental Disorders! (emphasis added)

Insel said its strength had been “reliability”, meaning that it provided a way for clinicians to use the same terms in the same way. Its weakness was that it lacked validity. DSM diagnoses are based upon a consensus about clusters of symptoms and not any objective laboratory measure. “In the rest of medicine, that would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever.”

Insel was not using “reliability” in a statistical sense. In “The Myth of the Reliability of DSM,” Stuart Kirk and Herb Kutchins demonstrated conclusively that the DSM-III and DSM-IIIR were not statistically reliable. In fact, using the same statistic that Robert Spitzer used to justify the major changes to the DSM in the 1970s, they demonstrated that:

The reliability problem is much the same as it was 30 years ago [before the DSM-III]. Only now the current developers of the DSM-IV have de-emphasised the reliability problem and claim to be scientifically solving other problems.

Unfortunately, the tables in Figures 1 and 2 have been removed from the online version of their article. But the tables are still available in the original article found in the Journal of Mind and Behavior, 15 (1&2), 1994, p. 71-86. These tables plainly showed how the DSM statistical reliability was not what it was claimed to be. The Selling of the DSM (1992) by Stuart Kirk and Herb Kutchins has the tables. And there is a graphic comparison of the data within Mad Science (2013) by Stuart Kirk, Tomi Gomory, and David Cohen.

Insel went on in his blog to say that the NIMH will be supporting research projects that “look across current categories” or sub-divide them in order to begin to develop a better system. “We are committed to new and better treatments, but we feel this will only happen by developing a more precise diagnostic system.” In order to work towards that goal, the NIMH launched the Research Domain Criteria (RDoC). RDoC is only a research framework for now; a decade-long project that is just beginning. You can learn more about RDoC here (on the NIMH website).

Robert Whitaker, author of Anatomy of an Epidemic, said in a March 2014 interview that Insel stating that the DSM lacked validity was an acknowledgement the “disease model” has failed as a basis for making psychiatric diagnoses.

When Insel states that the disorders haven’t been validated, he is stating that the entire edifice that modern psychiatry is built upon is flawed, and unsupported by science. That is like the King of Psychiatry saying that the discipline has no clothes. If the public loses faith in the DSM and comes to see it as unscientific, then psychiatry has a real credibility problem on its hands.

Two weeks later on May 13, 2013, a joint press release was made by Thomas Insel and Jeffrey Liebermann, the President-elect of the American Psychiatric Association (APA). They said that the NIMH and the APA had a shared interest to ensure that patients and healthcare providers had “the best available tools and information” to identify and treat mental health issues.

Today, the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders. . . . The National Institute of Mental Health (NIMH) has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states: “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

The DSM and RDoC were said to be complementary, not competing frameworks. As research findings emerge from RDoC, they may be incorporated into future DSM revisions. “But this is a long-term undertaking. It will take years to fulfill the promise that this research effort represents for transforming the diagnosis and treatment of mental disorders.”

Saul Levine, the CEO and Medical Director of the APA said on May 5, 2014 that the DSM and the RDoC will “begin to come together” as the research from NIMH is included into the way they diagnose mental illness. They know that mental illness and substance use disorders are a bio-psycho-social illness. “We work very well together with NIMH. And I think that the whole field is looking to the science coming out of NIMH to include it as a way to help get better treatment for patients in this country.”

So the APA and NIMH affirm they are working towards the same goals as complementary research frameworks. Someday the research findings of RDoC may even be included into the DSM. But until then, the NIMH will have to continue to “ooh and aah” at the APA’s DSM and ignore the nay-sayers crying: “Look at the DSM; look at the DSM!”

Does it seem that psychiatry is trying to promote an unreliable, invalid—perhaps invisible—system of diagnosis?

Also see my blog post, “Psychiatry’s Mythical Phoenix.”