The Prescription Pain Pill Epidemic: A Conversation with Dr. Anna Lembke

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My colleague, Dr. Anna Lembke is the Program Director for the Stanford University Addiction Medicine Fellowship, and Chief of the Stanford Addiction Medicine Dual Diagnosis Clinic. She is the author of a newly released book on the prescription pain pill epidemic: “Drug Dealer, MD: How Doctors Were Duped, Patients Got Hooked, and Why It’s So Hard to Stop” (Johns Hopkins University Press, October 2016).

I spoke with her recently about the scope of this public health tragedy, how we got here and what we need to do about it.

Dr. Jain: About 15-20 years ago American medicine underwent a radical cultural shift in its attitude towards pain, a shift that ultimately culminated in a public health tragedy. Can you comment on factors that contributed to that shift occurring in the first place?
Dr. Lembke: Sure. So the first thing that happened (and it was really more like the early 1980’s when this shift occurred) was that there were more people with daily pain. Overall, our population is getting healthier, but we also have more people with more pain conditions. No one really knows exactly the reason for that, but it probably involves people living longer with chronic illnesses, and more people getting surgical interventions for all types of condition. Any time you cut into the body, you cut across the nerves and you create the potential for some kind of neuropathic pain problem.
The other thing that happened in the 1980’s was the beginning of the hospice movement. This movement helped people at the very end of life (the last month to weeks to days of their lives) to transition to death in a more humane and peaceful way. There was growing recognition that we weren’t doing enough for people at the end of life. As part of this movement, many doctors began advocating for using opioids more liberally at the end of life.
There was also a broader cultural shift regarding the meaning of pain. Prior to 1900 people viewed pain as having positive value: “what does not kill you makes you stronger” or “after darkness comes the dawn”. There were spiritual and biblical connotations and positive meaning in enduring suffering. What arose, through the 20th century, was this idea that pain is actually something that you need to avoid because pain itself can lead to a psychic scar that contributes to future pain. Today, not only is pain painful, but pain begets future pain. By the 1990’s, pain was viewed as a very bad thing and something that had to be eliminated at all cost.
Growing numbers of people experiencing chronic pain, the influence of the hospice movement, and a shifting paradigm about the meaning and consequences of experiencing pain, led to increased pressures within medicine for doctors to prescribe more opioids. This shift was a departure from prior practice, when doctors were loathe to prescribe opioids, for fear of creating addiction, except in cases of severe trauma, cases involving surgery, or cases of the very end of life.
Dr. Jain: The American Pain Society had introduced “pain as the 5th vital sign,” a term which suggested physicians, who were not taking their patients’ pain seriously, were being neglectful. What are your thoughts about this term?
Dr. Lembke: “Pain is the 5th vital sign” is a slogan. It’s kind of an advertising campaign. We use slogans all the time in medicine, many times to good effect, to raise awareness both inside and outside the profession about a variety of medical issues. The reason that “pain is the 5th vital sign” went awry, however, has to do with the ways in which professional medical societies, like the American Pain Society, and so-called “academic thought leaders”, began to collaborate and cooperate with the pharmaceutical industry. That’s where “pain is the 5th vital sign” went from being an awareness campaign to being a brand for a product, namely prescription opioids.
So the good intentions in the early 1980’s turned into something really quite nefarious when it came to the way that we started treating patients. To really understand what happened, you have to understand the ways in which the pharmaceutical industry, particularly the makers of opioid analgesics, covertly collaborated with various institutions within what I’ll call Big Medicine, in order to promote opioid prescribing.
Dr. Jain: So by Big Medicine what do you mean?
Dr. Lembke: I mean the Federation of State Medical Boards, The Joint Commission (JACHO), pain societies, academic thought leaders, and the Food and Drug Administration (FDA). These are the leading organizations within medicine whose job it is to guide and regulate medicine. None of these are pharmaceutical companies per se, but what happened around opioid pain pills was that Big Pharma infiltrated these various organizations in order to use false evidence to encourage physicians to prescribe more opioids. They used a Trojan Horse approach.. They didn’t come out and say we want you to prescribe more opioids because we’re Big Pharma and we want to make more money, instead what they said was we want you to prescribe more opioids because that’s what the scientific evidence supports.
The story of how they did that is really fascinating. Let’s take The Joint Commission (JACHO) as an example. In 1996, when oxycontin was introduced to the market, JACHO launched a nationwide pain management educational program where they sold educational materials to hospitals, which they acquired for free from Purdue Pharma. These materials included statements which we now know to be patently false. JACHO sold the Purdue Pharma videos and literature on pain to hospitals.
These educational materials perpetuated four myths about opioid prescribing. The first myth was that opioids work for chronic pain. We have no evidence to support that. The second was that no dose is too high. So if your patient responds to opioids initially and then develops tolerance, just keep going up. And that’s how we got patients on astronomical amounts of opioids. The third myth was about pseudo addiction. If you have a patient who appears to be demonstrating drug seeking behavior, they’re not addicted. They just need more pain meds. The fourth and most insidious myth was that there is a halo effect when opioids are prescribed by a doctor, that is, they’re not addictive as long as they’re being used to treat pain.
So getting back to JACHO, not only did they use material propagating myths about the use of opioids to treat pain, but they also did something that was very insidious and, ultimately, very bad for patients. They made pain a “quality measure”. By The Joint Commission’s own definition of a quality measure, it must be something that you can count. So what they did was they created this visual analog scale, also known as the “pain scale”. The scale consists of numbers from one to ten describing pain, with sad and happy faces to match. JAHCO told doctors they needed to use this pain scale in order to assess a patients’ pain. What we know today is that this pain scale has not led to improved treatment or functional outcomes for patients with pain. The only thing that it has been correlated with is increased opioid prescribing.
This sort of stealth maneuver by Big Pharma to use false evidence or pseudo-science to infiltrate academic medicine, regulatory agencies, and academic societies in order to promote more opioid prescribing: that’s an enduring theme throughout any analysis of this epidemic.
Dr. Jain: Can you comment specifically on the breadth and depth of the opioid epidemic in the US? What were the key factors involved?
Dr. Lembke: Drug overdose is now the leading cause of accidental death in this country, exceeding death due to motor vehicle accidents or firearms. Driving this statistic is opioid deaths and driving opioid deaths is opioid pain prescription deaths, which in turn correlates with excessive opioid prescribing. There are more than 16,000 deaths per year due to prescription opioid overdoses.
What’s really important to understand is that an opioid overdose is not a suicide attempt. The vast majority of these people are not trying to kill themselves, and many of them are not even taking the medication in excess. They’re often taking it as prescribed, but over time are developing a low grade hypoxia. They may get a minor cold, let’s say a pneumonia, then they’ll take the pills and they’ll fall asleep and won’t wake up again because their tolerance to the euphorigenic and pain effects of the opioids is very robust, but their tolerance to the respiratory suppressant effect doesn’t keep pace with that. You can feel like you need to take more in order to eliminate the pain, but at the same time the opioid is suppressing your respiratory drive, so you eventually become hypoxemic and can’t breathe anymore and just fall into a gradual sleep that way.
There are more than two million people today who are addicted to prescription opioids. So not only is there this horrible risk of accidental death, but there’s obviously the risk of addiction. We also have heroin overdose deaths and heroin addiction on the rise, most likely on the coattails of the prescription opioids epidemic, driven largely by young people who don’t have reservations about switching from pills to heroin..
Dr. Jain: I was curious about meds like oxycontin, vicodin, and percocet. Are they somehow more addictive than other opioid pills?
Dr. Lembke: All opioids are addictive, especially if you’re dealing with an opioid naive person. But it is certainly true that some of the opioids are more addictive than others because of pharmacology. Let’s consider oxycontin. The major ingredient in oxycontin is oxycodone. Oxycodone is a very potent synthetic opioid. When Purdue formulated it into oxycontin, what they wanted to create was a twice daily pain medication for cancer patients. So they put this hard shell on a huge 12 hours worth of oxycodone. That hard shell was intended to release oxycodone slowly over the course of the day. But what people discovered is that if they chewed the oxycontin and broke that hard shell, then they got a whole day’s worth of very potent oxycodone at once. With that came the typical rush that people who are addicted to opioids describe, as well as this long and powerful and sustained high. So that is why oxycontin was really at the center of the prescription opioid epidemic. It basically was more addictive because of the quantity and potency once that hard shell was cracked.
Dr. Jain: So has the epidemic plateaued? And if so, why?
Dr. Lembke: The last year for which we have CDC data is 2014, when there were more prescription opioid-related deaths, and more opioid prescriptions written by doctors, than in any year prior. This is remarkable when you think that by 2014, there was already wide-spread awareness of the problem. Yet doctors were not changing their prescribing habits, and patients were dying in record numbers.
I’m really looking forward to the next round of CDC data to come out and tell us what 2015 looked like. I do not believe we have reached the end or even the waning days of this epidemic. Doctors continue to write over 250 million opioid prescriptions annually, a mere fraction of what was written three decades ago.
Also, the millions of people who have been taking opioids for years are not easily weaned from opioids.. They now have neuroadaptive changes in their brains which are very hard to undo. I can tell you from clinical experience that even when I see patients motivated to get off of their prescription opioids, it can take weeks, months, and even years to make that happen.
So I don’t think that the epidemic has plateaued, and this is one of the major points that I try to make in my book. The prescription drug epidemic is the canary in the coal mine. It speaks to deeper problems within medicine. Doctors get reimbursed for prescribing a pill or doing a procedure, but not for talking to our patients and educating them. That’s a problem. The turmoil in the insurance system we can’t even establish long term relationships with our patients. So as a proxy for real healing and attachment, we prescribe opioids. ! Those kinds of endemic issues within medicine have not changed, and until they do, I believe this prescription drug problem will continue unabated.

Before you enroll your child in the MAGENTA chronic fatigue syndrome study: Issues to be considered

[October 3 8:23 AM Update: I have now inserted Article 21 of the Declaration of Helsinki below, which is particularly relevant to discussions of the ethical problems of Dr. Esther Crawley’s previous SMILE trial.]

Petitions are calling for shutting down the MAGENTA trial. Those who organized the effort and signed the petition are commendably brave, given past vilification of any effort by patients and their allies to have a say about such trials.

Below I identify a number of issues that parents should consider in deciding whether to enroll their children in the MAGENTA trial or to withdraw them if they have already been enrolled. I take a strong stand, but I believe I have adequately justified and documented my points. I welcome discussion to the contrary.

This is a long read but to summarize the key points:

  • The MAGENTA trial does not promise any health benefits for the children participating in the trial. The information sheet for the trial was recently modified to suggest they might benefit. However, earlier versions clearly stated that no benefit was anticipated.
  • There is inadequate disclosure of likely harms to children participating in the trial.
  • An estimate of a health benefit can be evaluated from the existing literature concerning the effectiveness of the graded exercise therapy intervention with adults. Obtaining funding for the MAGENTA trial depended on a misrepresentation of the strength of evidence that it works in adult populations.  I am talking about the PACE trial.
  • Beyond any direct benefit to their children, parents might be motivated by the hope of contributing to science and the availability of effective treatments. However, these possible benefits depend on publication of results of a trial after undergoing peer review. The Principal Investigator for the MAGENTA trial, Dr. Esther Crawley, has a history of obtaining parents’ consent for participation of their children in the SMILE trial, but then not publishing the results in a timely fashion. Years later, we are still waiting.
  • Dr. Esther Crawley exposed children to unnecessary risk without likely benefit in her conduct of the SMILE trial. This clinical trial involved inflicting a quack treatment on children. Parents were not adequately informed of the nature of the treatment and the absence of evidence for any mechanism by which the intervention could conceivably be effective. This reflects on the due diligence that Dr. Crawley can be expected to exercise in the MAGENTA trial.
  • The consent form for the MAGENTA trial involves parents granting permission for the investigator to use children and parents’ comments concerning effects of the treatment for its promotion. Insufficient restrictions are placed on how the comments can be used. There is the clear precedent of comments made in the context of the SMILE trial being used to promote the quack Lightning Process treatment in the absence of evidence that treatment was actually effective in the trial. There is no guarantee that any comments collected from children and parents in the MAGENTA trial would not similarly be misused.
  • Dr. Esther Crawley participated in a smear campaign against parents having legitimate concerns about the SMILE trial. Parents making legitimate use of tools provided by the government such as Freedom of Information Act requests, appeals of decisions of ethical review boards and complaints to the General Medical Council were vilified and shamed.
  • Dr. Esther Crawley has provided direct, self-incriminating quotes in the newsletter of the Science Media Centre about how she was coached and directed by their staff to slam the patient community.  She played a key role in a concerted and orchestrated attack on the credibility of not only parents of participants in the MAGENTA trial, but of all patients having chronic fatigue syndrome/ myalgic encephalomyelitis , as well as their advocates and allies.

I am not a parent of a child eligible for recruitment to the MAGENTA trial. I am not even a citizen or resident of the UK. Nonetheless, I have considered the issues and lay out some of my considerations below. On this basis, I signed the global support version  of the UK petition to suspend all trials of graded exercise therapy in children and adults with ME/CFS. I encourage readers who are similarly in my situation outside the UK to join me in signing the global support petition.

If I were a parent of an eligible child or a resident of the UK, I would not enroll my child in MAGENTA. I would immediately withdraw my child if he or she were currently participating in the trial. I would request all the child’s data be given back or evidence that it had been destroyed.

I recommend my PLOS Mind the Brain post, What patients should require before consenting to participate in research…  as either a prelude or epilogue to the following blog post.

What you will find here is a discussion of matters that parents should consider before enrolling their children in the MAGENTA trial of graded exercise for chronic fatigue syndrome. The previous blog post [http://blogs.plos.org/mindthebrain/2015/12/09/what-patients-should-require-before-consenting-to-participate-in-research/ ]  is rich in links to an ongoing initiative from The BMJ to promote broader involvement of patients (and implicitly, parents of patients) in the design, implementation, and interpretation of clinical trials. The views put forth by The BMJ are quite progressive, even if there is a gap between their expression of views and their actual implementation. Overall, that blog post presents a good set of standards for patients (and parents) making informed decisions concerning enrollment in clinical trials.

Simon McGrathLate-breaking update: See also

Simon McGrath: PACE trial shows why medicine needs patients to scrutinise studies about their health

Basic considerations.

Patients are under no obligation to participate in clinical trials. It should be recognized that any participation typically involves burden and possibly risk over what is involved in receiving medical care outside of a clinical trial.

It is a deprivation of their human rights and a violation of the Declaration of Helsinki to coerce patients to participate in medical research without freely given, fully informed consent.

Patients cannot be denied any medical treatment or attention to which they would otherwise be entitled if they fail to enroll in a clinical trial.

Issues are compounded when consent from parents is sought for participation of vulnerable children and adolescents for whom they have legal responsibility. Although assent to participate in clinical trials is sought from children and adolescents, it remains for their parents to consent to their participation.

Parents can at any time withdraw their consent for their children and adolescents participating in trials and have their data removed, without requiring the approval of any authorities of their reason for doing so.

Declaration of Helsinki

The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.

It includes:

In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information.

[October 3 8:23 AM Update]: I have now inserted Article 21 of the Declaration of Helsinki which really nails the ethical problems of the SMILE trial:

21. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.

There is clearly in adequate scientific justification for testing the quack Lightning Process Treatment.

What Is the Magenta Trial?

The published MAGENTA study protocol states

This study aims to investigate the acceptability and feasibility of carrying out a multicentre randomised controlled trial investigating the effectiveness of graded exercise therapy compared with activity management for children/teenagers who are mildly or moderately affected with CFS/ME.

Methods and analysis 100 paediatric patients (8–17 years) with CFS/ME will be recruited from 3 specialist UK National Health Service (NHS) CFS/ME services (Bath, Cambridge and Newcastle). Patients will be randomised (1:1) to receive either graded exercise therapy or activity management. Feasibility analysis will include the number of young people eligible, approached and consented to the trial; attrition rate and treatment adherence; questionnaire and accelerometer completion rates. Integrated qualitative methods will ascertain perceptions of feasibility and acceptability of recruitment, randomisation and the interventions. All adverse events will be monitored to assess the safety of the trial.

The first of two treatments being compared is:

Arm 1: activity management

This arm will be delivered by CFS/ME specialists. As activity management is currently being delivered in all three services, clinicians will not require further training; however, they will receive guidance on the mandatory, prohibited and flexible components (see online supplementary appendix 1). Clinicians therefore have flexibility in delivering the intervention within their National Health Service (NHS) setting. Activity management aims to convert a ‘boom–bust’ pattern of activity (lots 1 day and little the next) to a baseline with the same daily amount before increasing the daily amount by 10–20% each week. For children and adolescents with CFS/ME, these are mostly cognitive activities: school, schoolwork, reading, socialising and screen time (phone, laptop, TV, games). Those allocated to this arm will receive advice about the total amount of daily activity, including physical activity, but will not receive specific advice about their use of exercise, increasing exercise or timed physical exercise.

So, the first arm of the trial is a comparison condition consisting of standard care delivered without further training of providers. The treatment is flexibly delivered, expected to vary between settings, and thus largely uncontrolled. The treatment represents a methodologically weak condition that does not adequately control for attention and positive expectations. Control conditions should be equivalent to the intervention being evaluated in these dimensions.

The second arm of the study:

Arm 2: graded exercise therapy (GET)

This arm will be delivered by referral to a GET-trained CFS/ME specialist who will receive guidance on the mandatory, prohibited and flexible components (see online supplementary appendix 1). They will be encouraged to deliver GET as they would in their NHS setting.20 Those allocated to this arm will be offered advice that is focused on exercise with detailed assessment of current physical activity, advice about exercise and a programme including timed daily exercise. The intervention will encourage children and adolescents to find a baseline level of exercise which will be increased slowly (by 10–20% a week, as per NICE guidance5 and the Pacing, graded Activity and Cognitive behaviour therapy – a randomised Evaluation (PACE)12 ,21). This will be the median amount of daily exercise done during the week. Children and adolescents will also be taught to use a heart rate monitor to avoid overexertion. Participants will be advised to stay within the target heart rate zones of 50–70% of their maximum heart rate.5 ,7

The outcome of the trial will be evaluated in terms of

Quantitative analysis

The percentage recruited of those eligible will be calculated …Retention will be estimated as the percentage of recruited children and adolescents reaching the primary 6-month follow-up point, who provide key outcome measures (the Chalder Fatigue Scale and the 36-Item Short-Form Physical Functioning Scale (SF-36 PFS)) at that assessment point.

actigraphObjective data will be collected in the form of physical activity measured by Accelerometers. These are

Small, matchbox-sized devices that measure physical activity. They have been shown to provide reliable indicators of physical activity among children and adults.

However, actual evaluation of the outcome of the trial will focus on recruitment and retention and subjective, self-report measures of fatigue and physical functioning. These subjective measures have been shown to be less valid than objective measures. Scores are  vulnerable  to participants knowing what condition they are assigned to (called ‘being unblinded’) and their perception of which intervention the investigators prefer.

It is notable that in the PACE trial of CBT and GET for chronic fatigue syndrome in adults, the investigators manipulated participants’ self-reports with praise in newsletters sent out during the trial . The investigators also switched their scoring of the self-report measures and produced results that they later conceded to have been exaggerated by their changing in scoring of the self-report measures [http://www.wolfson.qmul.ac.uk/current-projects/pace-trial#news ].

Irish ME/CFS Association Officer & Tom Kindlon
Tom Kindlon, Irish ME/CFS Association Officer

See an excellent commentary by Tom Kindlon at PubMed Commons [What’s that? ]

The validity of using subjective outcome measures as primary outcomes is questionable in such a trial

The bottom line is that the investigators have a poorly designed study with inadequate control condition. They have chosen subjective self-reports that are prone to invalidity and manipulation over objective measures like actual changes in activity or practical real-world measures like school attendance. Not very good science here. But they are asking parents to sign their children up.

What is promised to parents consenting to have the children enrolled in the trial?

The published protocol to which the investigators supposedly committed themselves stated

What are the possible benefits and risks of participating?
Participants will not benefit directly from taking part in the study although it may prove enjoyable contributing to the research. There are no risks of participating in the study.

Version 7 of the information sheet provided to parents, states

Your child may benefit from the treatment they receive, but we cannot guarantee this. Some children with CFS/ME like to know that they are helping other children in the future. Your child may also learn about research.

Survey assessments conducted by the patient community strongly contradict the suggestion that there is no risk of harm with GET.

alemAlem Matthees, the patient activist who obtained release of the PACE data and participated in reanalysis has commented:

“Given that post-exertional symptomatology is a hallmark of ME/CFS, it is premature to do trials of graded exercise on children when safety has not first been properly established in adults. The assertion that graded exercise is safe in adults is generally based on trials where harms are poorly reported or where the evidence of objectively measured increases in total activity levels is lacking. Adult patients commonly report that their health was substantially worsened after trying to increase their activity levels, sometimes severely and permanently, therefore this serious issue cannot be ignored when recruiting children for research.”

See also

Kindlon T. Reporting of harms associated with graded exercise therapy and cognitive behavioural therapy in myalgic encephalomyelitis/chronic fatigue syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111.

This thorough systematic review reports inadequacy in harm reporting in clinical trials, but:

Exercise-related physiological abnormalities have been documented in recent studies and high rates of adverse  reactions  to exercise have been  recorded in  a number of  patient surveys. Fifty-one percent of  survey respondents (range 28-82%, n=4338, 8 surveys) reported that GET worsened their health while 20% of respondents (range 7-38%, n=1808, 5 surveys) reported similar results for CBT.

The unpublished results of Dr. Esther Crawley’s SMILE trial

 A Bristol University website indicates that recruitment of the SMILE trial was completed in 2013. The published protocol for the SMILE trial

[Note the ® in the title below, indicating a test of trademarked commercial product. The significance of that is worthy of a whole other blog post. ]

Crawley E, Mills N, Hollingworth W, Deans Z, Sterne JA, Donovan JL, Beasant L, Montgomery A. Comparing specialist medical care with specialist medical care plus the Lightning Process® for chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME): study protocol for a randomised controlled trial (SMILE Trial). Trials. 2013 Dec 26;14(1):1.

States

The data monitoring group will receive notice of serious adverse events (SAEs) for the sample as whole. If the incidence of SAEs of a similar type is greater than would be expected in this population, it will be possible for the data monitoring group to receive data according to trial arm to determine any evidence of excess in either arm.

Primary outcome data at six months will be examined once data are available from 50 patients, to ensure that neither arm is having a detrimental effect on the majority of patients. An independent statistician with no other involvement in the study will investigate whether more than 20 participants in the study sample as a whole have experienced a reduction of ≥ 30 points on the SF-36 at six months. In this case, the data will then be summarised separately by trial arm, and sent to the data monitoring group for review. This process will ensure that the trial team will not have access to the outcome data separated by treatment arm.

A Bristol University website indicates that recruitment of the SMILE trial was completed in 2013. The trial was thus completed a number of years ago, but these valuable data have never been published.

The only publication from the trial so far uses selective quotes from child participants that cannot be independently evaluated. Readers are not told how representative these quotes, the outcomes for the children being quoted or the overall outcomes of the trial.

Parslow R, Patel A, Beasant L, Haywood K, Johnson D, Crawley E. What matters to children with CFS/ME? A conceptual model as the first stage in developing a PROM. Archives of Disease in Childhood. 2015 Dec 1;100(12):1141-7.

The “evaluation” of the quack Lightning Treatment in the SMILE trial and quotes from patients have also been used to promote Parker’s products as being used in NHS clinics.

How can I say the Lightning Process is quackery?

 Dr. Crawley describes the Lightning Process in the Research Ethics Application Form for the SMILE study as   ombining the principles of neurolinguistic programming, osteopathy, and clinical hypnotherapy.

That is an amazing array of three different frameworks from different disciplines. You would be hard pressed to find an example other than the Lightning Process that claimed to integrate them. Yet, any mechanisms for explaining therapeutic interventions cannot be a creative stir fry of whatever is on hand being thrown together. For a treatment to be considered science-based, there has to be a solid basis of evidence that these presumably complex processes fit together as assumed and work as assumed. I challenge Dr. Crawley or anyone else to produce a shred of credible, peer-reviewed evidence for the basic mechanism of the Lightning Process.

The entry for Neuro-linguistic programming (NLP) in Wikipedia states

There is no scientific evidence supporting the claims made by NLP advocates and it has been discredited as a pseudoscience by experts.[1][12] Scientific reviews state that NLP is based on outdated metaphors of how the brain works that are inconsistent with current neurological theory and contain numerous factual errors.[13][14

The respected Skeptics Dictionary offers a scathing critique of Phil Parker’s Lightning Process. The critique specifically cites concerns that Crawley’s SMILE trial switched outcomes to increase the likelihood of obtaining evidence of effectiveness.

 The Hampshire (UK) County Council Trading Standards Office filed a formal complaint against Phil Parker for claims made on the Lightning Process website concerning effects on CFS/ME:

The “CFS/ME” page of the website included the statements “Our survey found that 81.3 %* of clients report that they no longer have the issues they came with by day three of the LP course” and “The Lightning Process is working with the NHS on a feasibility study, please click here for further details, and for other research information click here”.

parker nhs advert
Seeming endorsements on Parker’s website. Two of them –Northern Ireland and NHS Suffolk subsequently complained that use of their insignias was unauthorized and they were quickly removed.

The “working with the NHS” refers to the collaboration with Dr. Easter Crawley.

The UK Advertising Standards Authority upheld this complaint, as well as about Parker’s claims about effectiveness with other conditions, including  multiple sclerosis, irritable bowel syndrome and fibromyalgia

 Another complaint in 2013 about claims on Phil Parker’s website was similarly upheld:

 The claims must not appear again in their current form. We welcomed the decision to remove the claims. We told Phil Parker Group not to make claims on websites within their control that were directly connected with the supply of their goods and services if those claims could not be supported with robust evidence. We also told them not to refer to conditions for which advice should be sought from suitably qualified health professionals.

 As we will see, these upheld charges of quackery occurred when parents of children participating in the SMILE trial were being vilified in the BMJ and elsewhere. Dr. Crawley was prominently featured in this vilification and was quoted in a celebration of its success by the Science Media Centre, which had orchestrated the vilification.

Captured cfs praker ad

The Research Ethics Committee approval of the SMILE trial and the aftermath

 I was not very aware of the CFS/ME literature, and certainly not all its controversies when the South West Research Ethics Committee (REC) reviewed the application for the SMILE trial and ultimately approved it on September 8, 2010.

I would have had strong opinions about it. I only first started blogging a little afterwards.  But I was very concerned about any patients being exposed to alternative and unproven medical treatments in other contexts that were not evidence-based – even more so to treatments for which promoters claimed implausible mechanisms by which they worked. I would not have felt it appropriate to inflict the Lightning Process on unsuspecting children. It is insufficient justification to put them a clinical trial simply because a particular treatment has not been evaluated.

 Prince Charles once advocated organic coffee enemas to treat advanced cancer. His endorsement generated a lot of curiosity from cancer patients. But that would not justify a randomized trial of coffee enemas. By analogy, I don’t think Dr. Esther Crawley had sufficient justification to conduct her trial, especially without warnings that that there was no scientific basis to expect the Lightning Process to work or that it would not hurt the children.

 I am concerned about clinical trials that have little likelihood of producing evidence that a treatment is effective, but that seemed designed to get these treatments into routine clinical care. it is now appreciated that some clinical trials have little scientific value but serve as experimercials or means of placing products in clinical settings. Pharmaceutical companies notoriously do this.

As it turned out, the SMILE trial succeeded admirably as a promotion for the Lightning Process, earning Phil Parker unknown but substantial fees through its use in the SMILE trial, but also in successful marketing throughout the NHS afterwards.

In short, I would been concerned about the judgment of Dr. Esther Crawley in organizing the SMILE trial. I would been quite curious about conflicts of interest and whether patients were adequately informed of how Phil Parker was benefiting.

The ethics review of the SMILE trial gave short shrift to these important concerns.

When the patient community and its advocate, Dr. Charles Shepherd, became aware of the SMILE trial’s approval, there were protests leading to re-evaluations all the way up to the National Patient Safety Agency. Examining an Extract of Minutes from South West 2 REC meeting held on 2 December 2010, I see many objections to the approval being raised and I am unsatisfied by the way in which they were discounted.

Patient, parent, and advocate protests escalated. If some acted inappropriate, this did not undermine the righteousness of others legitimate protest. By analogy, I feel strongly about police violence aimed against African-Americans and racist policies that disproportionately target African-Americans for police scrutiny and stoppng. I’m upset when agitators and provocateurs become violent at protests, but that does not delegitimize my concerns about the way black people are treated in America.

Dr. Esther Crawley undoubtedly experienced considerable stress and unfair treatment, but I don’t understand why she was not responsive to patient concerns nor  why she failed to honor her responsibility to protect child patients from exposure to unproven and likely harmful treatments.

Dr. Crawley is extensively quoted in a British Medical Journal opinion piece authored by a freelance journalist,  Nigel Hawkes:

Hawkes N. Dangers of research into chronic fatigue syndrome. BMJ. 2011 Jun 22;342:d3780.

If I had been on the scene, Dr. Crawley might well have been describing me in terms of how I would react, including my exercising of appropriate, legally-provided means of protest and complaint:

Critics of the method opposed the trial, first, Dr Crawley says, by claiming it was a terrible treatment and then by calling for two ethical reviews. Dr Shepherd backed the ethical challenge, which included the claim that it was unethical to carry out the trial in children, made by the ME Association and the Young ME Sufferers Trust. After re-opening its ethical review and reconsidering the evidence in the light of the challenge, the regional ethical committee of the NHS reiterated its support for the trial.

There was arguably some smearing of Dr. Shepherd, even in some distancing of him from the action of others:

This point of view, if not the actions it inspires, is defended by Charles Shepherd, medical adviser to and trustee of the ME Association. “The anger and frustration patients have that funding has been almost totally focused on the psychiatric side is very justifiable,” he says. “But the way a very tiny element goes about protesting about it is not acceptable.

This article escalated with unfair comparisons to animal rights activists, with condemnation of appropriate use of channels of complaint – reporting physicians to the General Medical Council.

The personalised nature of the campaign has much in common with that of animal rights activists, who subjected many scientists to abuse and intimidation in the 1990s. The attitude at the time was that the less said about the threats the better. Giving them publicity would only encourage more. Scientists for the most part kept silent and journalists desisted from writing about the subject, partly because they feared anything they wrote would make the situation worse. Some journalists have also been discouraged from writing about CFS/ME, such is the unpleasant atmosphere it engenders.

While the campaigners have stopped short of the violent activities of the animal rights groups, they have another weapon in their armoury—reporting doctors to the GMC. Willie Hamilton, an academic general practitioner and professor of primary care diagnostics at Peninsula Medical School in Exeter, served on the panel assembled by the National Institute for Health and Clinical Excellence (NICE) to formulate treatment advice for CFS/ME.

Simon Wessely and the Principal Investigator of the PACE trial, Peter White, were given free rein to dramatize their predicament posed by the protest. Much later, in the 2016 Lower Tribunal Hearing, testimony would be given by PACE

Co-Investigator Trudie Chalder would much later (2016) cast doubt on whether the harassment was as severe or violent as it was portrayed. Before that, the financial conflicts of interest of Peter White that were denied in the article would be exposed.

In response to her testimony, the UK Information Officer stated:

Professor Chalder’s evidence when she accepts that unpleasant things have been said to and about PACE researchers only, but that no threats have been made either to researchers or participants.

But in 2012, a pamphlet celebrating the success of The Science Media Centre started by Wessely would be rich in indiscreet quotes from Esther Crawley. The article in BMJ was revealed to be part of a much larger orchestrated campaign to smear, discredit and silence patients, parents, advocates and their allies.

Dr. Esther Crawley’s participation in a campaign organized by the Science Media Center to discredit patients, parents, advocates and supporters.

 The SMC would later organize a letter writing campaign to Parliament in support of Peter White and his refusal to release the PACE data to Alem Mattheees who had made a requestunder the Freedom of Information Act. The letter writing campaign was an effort to get scientific data excluded from the provisions of the freedom of information act. The effort failed and the data were subsequently released.

But here is how Esther Crawley described her assistance:

The SMC organised a meeting so we could discuss what to do to protect researchers. Those who had been subject to abuse met with press officers, representatives from the GMC and, importantly, police who had dealt with the  animal rights campaign. This transformed my view of  what had been going on. I had thought those attacking us were “activists”; the police explained they were “extremists”.

And

We were told that we needed to make better use of the law and consider using the press in our favour – as had researchers harried by animal rights extremists. “Let the public know what you are trying to do and what is happening to you,” we were told. “Let the public decide.”

And

I took part in quite a few interviews that day, and have done since. I was also inundated with letters, emails and phone calls from patients with CFS/ME all over the world asking me to continue and not “give up”. The malicious, they pointed out, are in a minority. The abuse has stopped completely. I never read the activists’ blogs, but friends who did told me that they claimed to be “confused” and “upset” – possibly because their role had been switched from victim to abuser. “We never thought we were doing any harm…”

 The patient community and its allies are still burdened by the damage of this effort and are rebuilding its credibility only slowly. Only now are they beginning to get an audience as suffering human beings with significant, legitimate unmet needs. Only now are they escaping the stigmatization that occurred at this time with Esther Crawley playing a key role.

Where does this leave us?

stop posterParents are being asked to enroll in a clinical trial without clear benefit to the children but with the possibility of considerable risk from the graded exercise. They are being asked by Esther Crawley, a physician, who has previously inflicted a quack treatment on their children with CFS/ME in the guise of a clinical trial, for which he is never published the resulting data. She has played an effective role in damaging the legitimacy and capacity of patients and parents to complain.

Given this history and these factors, why would a parent possibly want to enroll their children in the MAGENTA trial? Somebody please tell me.

Special thanks to all the patient citizen-scientists who contributed to this blog post. Any inaccuracies or excesses are entirely my own, but these persons gave me substantial help. Some are named in the blog, but others prefer anonymity.

 All opinions expressed are solely those of James C Coyne. The blog post in no way conveys any official position of Mind the Brain, PLOS blogs or the larger PLOS community. I appreciate the free expression of  personal opinion that I am allowed.

 

 

 

 

 

 

Hans Eysenck’s contribution to cognitive behavioral therapy for physical health problems: fraudulent data

  • The centenary of the birth of Hans Eysenck is being marked by honoring his role in bringing clinical psychology to the UK and pioneering cognitive behavior therapy (CBT).
  • There is largely silence about his publishing fraudulent data, editorial misconduct, and substantial undeclared conflicts of interest.
  • The articles in which Eysenck used fraudulent data are no longer cited much, but the influence of his claims which depended on these data remains profound.
  • Eysenck used fraudulent data to argue that CBT could prevent cancer and cardiovascular disease and extend the lives of persons with advanced cancer.
  • He similarly used fraudulent data to advance the claim that psychoanalysis is, unlike smoking, carcinogenic and has other adverse effects on health.
  • Ironically, Eysenck incorporated into his explanations for how CBT works elements of the psychoanalytic thinking that he seemingly detested.

If there is sufficient interest, a follow-up blog post will discuss:

  • Because of Eysenck’s influence, CBT in the UK exaggerates the role of early childhood adversity and much less to functional behavioral analysis than the American behavior therapy and cognitive behavior therapy.
  • Both CBT in the UK and some quack therapy approaches make assumptions about mechanism tied to Eysenck’s use of fraudulent data.
  • Consistent with Eysenck’s influence, CBT for physical problems in the UK largely focuses on self-report questionnaire assessments of mechanism of change and of outcome, rather than functional behavioral and objective physical health outcome variables.

8th-chocolate-happy-birthday-cake-for-HansHappy Birthday, Hans Eysenck

March 12, 2016 was the centenary of the birth of psychologist Hans Eysenck. The British Psychological Society’s  The Psychologist marked the occasion with release of a free app by which BPS members can access a collection of articles about Hans Eysenck from the archives.  Nonmembers can access the articles here.

The introduction to the collection, Philip Corr’s The centenary of a maverick states

Eysenck’s contributions were many, varied and significant, including: the professional development of clinical psychology; the slaying of the psychoanalytical dragon; pioneering behaviour therapy and, thus, helping to usher in the era of cognitive behavioural therapy…

Corr also wrote in the March 30 2016 Times Higher Education:

in defence corr

hans ensenck portraitThe articles collected in The Psychologist were written over many years. Together they present an unflattering picture of a controversial man who was shunned by his colleagues, blocked from getting awards, and who would humiliate those with whom he disagreed rather than acknowledge any contradictory evidence. Particularly revealing are Roderick Buchanan’s   Looking back: The controversial Hans Eysenck and a review of Buchanan’s book by Eysenck’s son Michael, Playing with fire: The controversial career of Hans J. Eysenck.

However, the collection stops short of acknowledging what was revealed in the early 90s in The BMJ: Eysenck knowingly published fraudulent data to back outrageous claims that CBT prevented cancer and extended the lives of patients with terminal cancer, whereas psychoanalysis was carcinogenic. He published his claims in journals he had founded, liberally self-plagiarizing and duplicate publishing with undeclared conflicts of interest. Eysenck received salary supplements and cash awards from German tobacco companies and from lawyers for the American tobacco companies for these activities.

slide 2 r smith should editors slide1 R Smith EysenckThe BMJ gave psychiatrists Anthony Pelosi and Louis Appleby a forum in the early nineties for criticizing Eysenck, even though the articles they attacked had been published elsewhere. The BMJ Editor Richard Smith followed up,  citing Eysenck as an example in raising the question whether editors should publish research articles in their own journal. Pelosi filed formal charges against Eysenck with the British Psychological Society. But, according to Buchanan’s book:

The BPS investigatory committee deemed it “inappropriate” to set up an investigatory panel to look into the material Pelosi had sent them, and henceforth considered the matter closed. Pelosi disagreed, of course, but was left with little recourse.

In an editorial in The Times Simon Wessely acknowledged Pelosi and Appleby’s criticism of Eysenck, but said “It would take more than a couple of psychiatrists to ruffle Eysenck.”

Simon on EysenckWessely suggested that the matter be dropped: the controversy was distracting everyone from the real progress being made in psychological approaches to cancer, like showing a fighting spirit extends the lives of cancer patients.  There was apparently no further mention in the UK press. Read more here.

Eysenck’s articles involving fraudulent data are seldom cited in the contemporary literature, but the claims the data were used to back remain quite influential. For instance, Eysenck claimed psychological factors presented more risk for cancer than many well-established biological factors. Including Eysenck’s data probably allowed one of the most cited meta-analyses of psychological factors in cancer to pass the threshold of hazard ratios strong enough for publication in the prestigious journal, Nature Clinical Practice: Oncology. Without the inclusion of Eysenck’s data, hazard ratios from methodologically weak studies cluster slightly higher than 1.0, suggesting little association that cannot be explained by confounds. A later blog post will document the broader influence of the Eysenck fraud on psychoneuroimmunology.

Eysenck’s claims concerning effects of CBT on physical health conditions now similarly go uncited.  However, the idiosyncratic definition he gave to CBT and his claims about the presumed mechanism by which it improved physical health pervade both CBT as defined in the UK and a number of quack treatments in the UK and elsewhere.

It is important to establish the connection between fraudulent data, distinctive features of CBT in the UK, and presumed mechanisms of action in order to open for re-examination the forms that CBT for physical health problems take in the UK and the way in which claims of efficacy are evaluated.

Fraudulent Data

Eysenck repeated tables and text in a number of places, but I will mainly draw on data as he presented them in the journal he founded, Behaviour Research and Therapy [1,   2], which correspond with what he presents elsewhere.

Eysenck’s Croatian collaborator Grossarth-Maticek conducted the therapy and collected the predictor and outcome data. A personality inventory  was used to classify participants receiving therapy into four types , a cancer-prone type (Type 1), a coronary heart disease (CHD)-prone type (Type 2), and 2 healthy types (Type 3 and Type 4). The typology was derived from quadrants in a 2×2 dichotomization of high versus low and rationality versus anti-emotionality, quite different from the dimensions and item content of the Eysenck Personality Questionnaire. Indeed, Roderick Buchanan noted in his biography that “Eysenck had struggled to banish typological concepts in favour of continuous dimensions for most of his career.” Grossarth-Maticekis questionnaire and typology has been sharply criticized later by Eysenck son Michael, among many others.

Eysenck and Grossarth-Maticek reported results of individually delivered “creative novation behaviour therapy”:

… Effects of prophylactic behaviour therapy on the cancer-prone and the CHD-prone probands respectively after 13 yr. It will be clear that treatment by means of creative novation behaviour therapy has had a highly significant prophylactic effect, preventing deaths from cancer in probands of Type 1, and death from coronary heart disease in probands of Type 2.

table 3 prophylactic effectsFor creative novation behaviour therapy delivered in a group format:

It will be seen that both cancer and CHD mortality are very significantly higher in the control group, as is death from other causes. Incidence rates are also very significantly higher in the control group for cancer, but with a difference below our selected P = 0.01 level of significance for CHD. Most telling is the difference regarding those ‘still living’-79.9% in the therapy group, 23.9% in the control group. The results of the group therapy study support those of the individual therapy group in demonstrating the value of behaviour therapy in preventing death from cancer and CHD, and in lowering the incidence from cancer and possibly from CHD.

table 4 group therapyStrong effects were reported even when the treatment was delivered as a discussion of a brief pamphlet. The companion paper  described this bibliotherapy and provided the pamphlet as an appendix,  which is reproduced here.

This statement is given to the proband, who also receives an introductory 1-hr treatment in which the meaning of the statement is explained, application considered, and likely advantages discussed. After the patient has been given time to consider the statement, and apply it to his/her own problems, the therapist spends a further 3-5 hr with the patient, suggesting specific applications of the principles in the statement to the needs of the patient, and his/her particular circumstances.

Six hundred probands received the bibliotherapy and a control group of 500 matched for personality type, smoking, age and sex received no treatment. Another 100 matched patients received a placebo condition in which they met with interviewers to discuss a pamphlet with “psychoanalytic explanation and suggestions.”

I encourage readers to take a look at the pamphlet, which is less than a page long. It ends with:

The most important aims of autonomous self-activation: your aim should always be to produce conditions would make it possible for you to lead a happy and contented life.

The results were:

There are no statistically significant differences between the control group and the placebo group, which may therefore be combined and considered a single control group. Compared with this control group, the treatment group fared significantly better. In the control group, 128 died of cancer, 176 of CHD; in the treatment group only 27 died of cancer, and 47 of CHD. For ‘death from other causes’, the figures are 192 and 115. Clearly the bibliographic method had a very strong prophylactic effect.

table 5 group and biblioEysenck and Grossarth-Maticek reported numerous other studies, including one in which 24 matched pairs of patients with inoperable cancer were assigned to either creative novation behaviour therapy or a control group. The patients receiving the behaviour therapy lived five years versus the three years of those in the control group, a difference which was highly significant.

Keep in mind that in these studies that all of the creative novation behaviour therapy sessions were solely provided by Grossarth-Maticek.

But let’s jump to a final in a series of tables constructed to make the argument that psychoanalysis was harmful to physical health.

We are here dealing with three groups. Group I is constituted of patients who terminated their  psychoanalytical treatment after 2 yr or less, and were then treated with behaviour therapy.

Group 2 is a control group matched with the members of group I on age, sex, smoking and personality type. Group 3 is a control group which discontinued psychoanalysis, like Group I, but did not receive behaviour therapy. Members of Group I and 2 do not differ significantly in mortality, but Group 3 has significantly greater mortality than either. Looking again at the percentage of patients still living, we find for Group 1 92, 95 and 95%, for Group 2 96, 89 and 95%, for Group 3 the figures are: 72, 63 and 61%. Clearly behaviour therapy can reverse the negative impact psychoanalysis has on survival.

table 15 psychoanalysisIn a number of places, this is explained in identical words:

Theoretically, this conclusion is not unreasonable. We have shown that stress is a powerful factor in causing cancer and CRD, and it is widely agreed, even among psychoanalysts, that their treatment imposes a considerable strain on patients. The hope is often expressed that finally the treatment will resolve these strains, but there is no evidence to suggest that this is true (Rachman & Wilson, 1980; Eysenk & Martin, 1987). Indeed, there is good evidence that even in cases of mental disorder psychoanalysis often does considerable harm (Mays & Franks, 1985). A theoretical model to account for these negative outcomes of psychoanalysis and psychotherapy generally has been presented elsewhere (Eysenck, 1985); it would apply equally well in the psychosomatic as in the purely psychiatric field.

dog breakfastCBT for physical health problems: a dog’s breakfast approach

Grossarth-Maticek had already formulated his approach and delivered all psychotherapy before Eysenck began co-authored papers and promoting him. In a 1982 article without Eysenck as an author, Grossarth-Maticek is quite explicit about the psychoanalytic theory behind his approach:

A central proposition of our research program is that cancer patients are either preoccupied with traumatic events of early childhood or with excessive expectations of the parents during their whole life. They are characterized by intensive internal inhibitions toward expressing feelings and desires. Therefore, we speak of a chronic blockade of expression of feelings and desires. We assume that parents of cancer patients did not respond adequately to the child’s cries for help and these children were obliged very early to do non-conforming daily task. Cancer patients have never learned to express persistent cries for help…

The specific family dynamics in the special educational pattern which block hysterical reactions determine the behavior, which in turn is characterized by excessive persistence of performance of the daily task, disregard of symptoms and lack of aggressiveness in behavior. Through the currents of negative life events (i.e., death of closely connected persons) expressions of loneliness and reactive depression can appear intensively and chronically.

If this is not clear enough:

In our approach we try not to deny the psycho analytic propositions but to integrate the psychoanalytic research program with social psychological and sociological factors, hereby assuming that they have interactive effects on carcinogenesis.

Strangely, Grossarth-Maticek suggests in this article, that the psychoanalytic factors interact with “organic risk factors such as cigarette smoking in the case of lung cancer.” Grossarth-Maticek and Eysenck would soon be receiving tens of thousands of dollars in support from the German tobacco companies and lawyers from the American tobacco companies to promote the idea that personality caused smoking and lung cancer, but any connection between smoking and lung cancer was spurious. Product liability suits against tobacco companies should therefore be dismissed.

In the articles co-authored by Grossarth-Maticek and Eysenck, these roots of what Eysenck repackaged as creative novation behaviour therapy are only hinted at, but are noticeable to the observant reader in references to the role of dependency and autonomy. Fraudulent data are mustered to show the powerful positive effects of this behaviour therapy versus the toxicity of psychoanalysis.

On page 8 of this article, ten  explicitly labeled behavioural techniques are identified as occurring across individual, group, and bibliotherapy:

  • Training for reduction of the planned behaviors initiation of autonomous behavior.
  • Training for cognitive alteration under conditions of relaxation
  • Training for alternative reactions.
  • Training for the integration of cognition, emotionality and intuition.
  • Training to achieve stable expression of feelings.
  • Training for potentiating social behavioral control
  • Training to suppress stress-creating ideas
  • Training to achieve a behavior-directing hierarchic value structure
  • Training in the suppression of stress-creating thought.
  • Abolition of dependence reactions.

This approach has only superficial resemblance to American behavioral therapy and CBT. The emphasis on expression of emotional feelings and abolition of dependent reactions is incomprehensible when it is detached from its psychoanalytic roots. The paper refers to behavioral analysis, but interviews about the past, including childhood experiences are emphasized, rather than applied behavioral analysis. The hierarchies of behavior do not correspond to operant approaches, but to a value structure of autonomy versus dependence.

There is also considerable reference to the use of hypnosis to achieve these goals.

In short, neither the goals nor the methods have much relationship to learning theory at the time that Eysenck was writing nor to contemporary developments in operant conditioning. His approach is a tortured extension of classical conditioning. Outside of the fraudulent data that Grossarth-Maticek developed and that he published with Eysenck, there is little basis for assuming that psychological factors were related to physical health in the way the treatment approach postulated.

It should be kept in mind that Eysenck was not a psychotherapist. He actually detested psychotherapy and generated considerable controversy earlier by arguing that any apparent effects of psychotherapy were due to natural remission. It should also be noted that Eysenck was claiming creation novation behaviour therapy modified personality traits, even when delivered in a brief pamphlet, in ways that could not be anticipated by his other writings about personality. Finally, the particular personality characteristics that Eysenck was talking about modifying were very different than what he assessed with the Eysenck Personality Inventory.

Only “controversial” and “too good to be true” or fraud?

 Before Eysenck began collaborating with Grossarth-Maticek, there was widespread doubts about the validity of Grossarth-Maticek’s work.  In 1973, Grossarth-Maticek’s work had been submitted to the University of Heidelberg as a Habilitation, a second doctoral degree required for a full professorship. It was rejected. One member of the committee, Manfred Amelung, declared the results “too good to be true.” He retained a copy and would later put his knowledge of its details into a devastating critique. According to Buchanan’s biography, Eysenck demanded of Grossarth-Maticek “you must let me check your data, for if you deceive me I will never forgive you.”

Eysenck gained access to the data set, sometimes directing reanalyses by Grossarth-Maticek and his statistician. Other analyses were done by Eysenck’s statisticians in London. Eysenck’s biographer Buchanan noted “there were ample opportunities to select, tease out, or redirect attention – given a data set that was apparently sprawling chaotic but rich and ambitious….From the mid-1980s, Eysenck did virtually all of the writing for publication in English and presumably exerted a strong editorial control.” Buchanan also notes that tobacco companies became skeptical of the strength of findings that were reported, but also their inconsistency. They refused to continue to support Eysenck unless an independent team was set up to check analyses and the conclusions that Eysenck was drawing from them.

Eysenck single-authored a target article for Psychological Inquiry that reproduced many of the tables that we have been discussing. More than a dozen commentators included the members of the independent team, but also others who did not have access to the data, but who examined the tables with forensic attention. The commentary started off with Manfred Manfred Amelung who made use of what he had learned from Grossarth-Maticek’s doctoral work.

Many of the commentators suggested that the intervention studies presented conclusions that were “too good to be true,” not only in terms of the efficacy claim for the intervention, but for the negative outcomes claimed for the control group. But other commentators pointed to gross inconsistencies across different reports in terms of methods and results, clear evidence of manipulation of data, including some patients being counted a number of times, other patients dying twice, Eysenck and Grossarth-Maticek’s improbable ability to obtain matching of intervention patients and controls, and too perfect predictions. In the end, even Grossarth-Maticek’s Heidelberg statistician expressed concerns that there had been tampering with the data.

Both Grossarth-Maticek and Eysenck got opportunities to respond and were defensive and dismissive of the overwhelming evidence of exaggeration of the results and even fraud.

The exchanges in Psychological Inquiry occurred over two issues. Taken together, the critical commentaries are devastating, but the criticisms became diffuse because commentators focused on different problems. It took a more succinct, pithy critique by Anthony Pelosi and Louis Appleby in The BMJ to bring the crisis of credibility to a head.

Anthony Pelosi and Louis Appleby in The BMJ

 In the first round of their two-part attack, Pelosi and Appleby centered on Eysenck and Grossarth-Maticek’s  two articles in Behaviour Research and Therapy, but referenced the critiques in Psychological Inquiry. The incredible effectiveness of these two psychiatrists depended largely on their pointing  out what was hiding in plain sight in the two Behaviour Research and Therapy articles. For instance:

After 13 years, 16 of 50 untreated type 1 subjects had died of a carcinoma. Not one of the 50 cancer prone subjects receiving the psychotherapy died of cancer. The therapy was a genuine panacea, giving equivalent results for type 2 subjects and heart disease. The all cause mortality was over 60% in untreated and 15% in treated subjects. The death rate in the untreated subjects was truly alarming as they began the trial healthy and most were between 40 and 60 years of age.

I encourage readers to compare the Pelosi and Appleby paper to the tables I presented here and see what they missed.

Pelosi and Appleby calculated the effort required by Grossarth-Maticek if he had – as Eysenck insisted- single-handedly carried out all of the treatment.

It is striking that all the individual and group therapy was given by Professor Grossarth-Maticek. The trials were undertaken between 1972 and 1974 and involved 96 subjects (or perhaps 192 subjects, see below) in at least 20 hours of individual work, and at least 10 groups (245 subjects with 20-25 in each) for six to 15 sessions each. Add to this Grossarth-Maticek’s explanatory introduction to bibliotherapy for 600 people, and it can be seen that the amount of time spent by this single senior academic on his experimental psychotherapies is huge and certainly unprecedented.

They summarized inconsistencies and contradictions reported in the Psychological Inquiry, but then added their own observation that a matching of 192 pairs of intervention and control patients had only produced a sample of 192! They suggested that in the two Behaviour Research and Therapy articles there were at least  “10 elaborate misprints or misstatements in the description of the methods” that the editor or reviewers should have caught.

At no point, does the word “fraud” or “fraudulent” appear in Pelosi and Appleby’s first article. Rather, they suggest that  “Eysenck and Grossarth-Maticek… are:

making claims which, if correct, would make creative novation therapy a vital part of public health policy throughout the world.”

They conclude with

For these reasons there should be a total reexamination and proper analysis of the original data from this research in an attempt to answer the questions listed above. The authors give their address as the Institute of Psychiatry in London, which must be concerned about protecting its reputation. Therefore the institute should, in our view, assist in this clarification of the meaning of the various studies. There should also be some stern questions asked of the editors of the various journals involved, especially those concerned among the editorial staff of Behaviour Research and Therapy who, in our opinion, have done a disservice to their scientific disciplines, and indeed to Professors Eysenck and Grossarth-Maticek, in allowing this ill considered presentation of research on such a serious topic.

Eysenck’s reply and Pelosi and Appleby’s response

 Readers can consult Eysenck’s reply  for themselves, but it strikes me as evasive and dismissive. Specific criticisms are not directly answered, but Eysenck points to consistency between his results and those of David Spiegel, who had claimed to get even stronger effects in his small study of supportive expressive therapy for women with metastatic breast cancer. Rather than demolishing the credibility of his work with Grossarth-Maticek, Eysenck argues that Pelosi and Appleby only point to the need for funding of a replication. Eysenck closes with:

Their critical review, however incorrect, full of errors and misunderstandings, and lacking in objectivity, may have been useful in drawing attention to a large body of work, of both scientific and social relevance, that has been overlooked for too long.

Pelosi and Appleby took Eysenck’s reply as an opportunity to get even more specific in the criticisms:

We are accused of being vague in mentioning many errors, inappropriate analyses, and missing details in the publications on this research programme. We value this opportunity to be more specific, to clarify just a few of the questions raised by ourselves and others, which Eysenck has failed to answer, and to outline additional findings from these authors’ investigations.

After a detailed reply, they wrap up with references to the criticisms that Eysenck received in Psychological Inquiry, in an ironic note, turning Eysenck’s attacks on proponents of the link between smoking and lung cancer on to Eysenck himself:

Our concern has been to clarify the methods and analyses of a body of research which, if accurate, would profoundly influence public health policies on cancer and heart disease. Other critics have been more challenging in what they have alleged, and in our opinion the controversy which now surrounds one of academic psychology’s most influential figures constitutes a crisis for the subject itself. The seriousness of the detailed allegations by van der Ploeg, although refuted by Eysenck and Grossarth-Maticek, should in themselves prompt these authors to reexamine their own findings after appropriate further training in the methodology of medical research. Perhaps the most skilfully worded criticism on this subject was made not about Eysenck but by him in a debate on the relation between smoking and cancer. In disputing the findings of Doll and Hill’s epidemiological studies on this association he comments: “What we have found are serious methodological weaknesses in the design of the studies quoted in favour of these theories, statistical errors, and unsubstantiated extrapolations from dubious data to unconfirmed conclusions.” Eysenck owes it to himself and to his discipline to reconsider critically his own work on this subject.

In the over 20 years since this exchange, Pelosi and Appleby and their ally editor Richard Smith of The BMJ failed to get an appropriate response from the British Psychological Society, King’s College London or the Institute of Psychiatry, the journal Behaviour Research and Therapy, or the Committee on Publication Ethics (COPE). This situation demonstrates the inability of British academia to correct bad and even fraudulent science. It stands as a cautionary note to those of us now attempting to correct what we perceive as bad science. Efforts are likely to be futile. On the other hand, the editorship of Behaviour Research and Therapy has passed to an American, Michelle Craske, a professor at UCLA. Perhaps she can be persuaded to make a long overdue correction to the scientific record and remove a serious blemish on the credibility of that Journal.

If there is sufficient interest, I will survey the profound influence of the fraudulent work of Eysenck and Grossarth-Maticek in a future blog post.

  • Because of their influence, CBT in the UK gives an exaggerated emphasis to early childhood adversity and much less to functional behavioural analysis than the American behavior therapy and CBT.
  • Consistent with Eysenck’s influence, CBT for physical problems in the UK largely focuses on self-report questionnaire assessments of mechanism of change and of outcome, rather than functional behavioral and objective physical health outcome variables.

Influences can also be seen in:

Contemporary CBT for physical conditions as practiced in UK, including CBT for irritable bowel syndrome (IBS), fibromyalgia, and other “all in the head” conditions that are deemed Medically Unexplained Symptoms (MUS) in the UK, as in PRINCE trial of Trudie Chalder and Simon Wessely.

The “psychosomatic” approach as seen in neurologist Suzanne O’Sullivan’s  recent editorial in The Lancet and her “It’s All in Your Head”, which won the 2016 Wellcome Book Award and her.

Quack treatments, such as Phil Parker’s Lightning Process, which the UK’s Advertising Standards Authority (ASA) ruled against advertising its effectiveness in treatment of chronic fatigue syndrome/ myalgic Encephalopathy,  multiple sclerosis, and irritable bowel syndrome/digestive issues. The Lightning Process is nonetheless implemented in the UK NHS under the direction of University of Bristol Professor Esther Crawley 

Quack cancer treatments such as Simonton visualization method.

More mainstream, but unproven psychological treatments for cancer including David Spiegel’s supportive expressive therapy. Neither Spiegel –nor anyone else– has ever been able to replicate the finding praised by Eysenck, but repeats his claims in a recent non-peer reviewed article in the UK-based Psycho-Oncology and with a closely related article in BPS’ British Journal of Health Psychology.

More mainstream, but unproven psychological approaches to cancer that claim to improve immune functioning by reducing stress.

Some Scottish readers will understand this message concerning Eysenck’s fraud: The ice cream man cometh.

My usual disclaimer: All views that I express are my own and do not necessarily reflect those of PLOS or other institutional affiliations.

What patients should require before consenting to participate in research…

A bold BMJ editorial  calls for more patient involvement in the design, implementation, and interpretation of research – but ends on a sobering note: The BMJ has so little such involvement to report.

In this edition of Mind the Brain, I suggest how patients, individually and collectively, can take responsibility for advancing this important initiative themselves.

I write in a context defined by recent events.

  • Government-funded researchers offered inaccurate interpretations of their results [1, 2].
  • An unprecedented number of patients have judged the researchers’ interpretation of their results as harmful to their well-being.
  • The researchers then violated government-supported data sharing policies in refusing to release their data for independent analysis.
  • Patients were vilified in the investigators’ efforts to justify their refusal to release the data.

These events underscore the need for patients to require certain documentation before deciding whether to participate in research.

Declining to participate in clinical research is a patient’s inalienable right that must not jeopardize the receipt of routine treatment or lead to retaliation.

A simple step: in deciding whether to participate in research, patients can insist that any consent form they sign contains documentation of patient involvement at all phases of the research. If there is no detailing of how patients were involved in the design of this study and how they will be involved in the interpretation, patients should consider not consenting.

Similarly, patients should consider refusing to sign consent forms that do not expressly indicate that the data will be readily available for further analyses, preferably by placing the data in a publicly accessible depository.

Patients exercising their rights in these ways will make for better and more useful biomedical research, as well as research that is more patient-oriented

The BMJ editorial

bmj-logo-ogThe editorial Research Is the Future, Get Involved declares:

More than three million NHS patients took part in research over the past five years. Bravo. Now let’s make sure that patients are properly involved, not just as participants but in trial conception, design, and conduct and the analysis, reporting, and dissemination of results.

But in the next sentences, the editorial describes how The BMJ’s laudable efforts to get researchers to demonstrate how patients were involved have not produced impressive results:

man with empty pocketsYou may have noticed the new “patient involvement” box in The BMJ’s research articles. Sadly, all too often the text reads something like, “No patients were involved in setting the research question or the outcome measures; nor were they involved in the design and implementation of the study. There are no plans to involve patients in the dissemination of results.” We hope that the shock of such statements will stimulate change. Examples of good patient involvement will also help: see the multicentre randomised trial on stepped care for depression and anxiety (doi:10.1136/bmj.h6127).

Our plan is to shine a light on the current state of affairs and then gradually raise the bar. Working with other journals, research funders, and ethics committees, we hope that at some time in the future only research in which patients have been fully involved will be considered acceptable.

In their instructions to authors, The BMJ includes a section Reporting patients’ involvement in research which states:

As part of its patient partnership strategy, The BMJ is encouraging active patient involvement in setting the research agenda.

We appreciate that not all authors of research papers will have done this, and we will still consider your paper if you did not involve patients at an early stage. We do, however, request that all authors provide a statement in the methods section under the subheading Patient involvement.

This should provide a brief response to the following questions:

How was the development of the research question and outcome measures informed by patients’ priorities, experience, and preferences?

How did you involve patients in the design of this study?

Were patients involved in the recruitment to and conduct of the study?

How will the results be disseminated to study participants?

For randomised controlled trials, was the burden of the intervention assessed by patients themselves?

Patient advisers should also be thanked in the contributorship statement/acknowledgements.

If patients were not involved please state this.

If this information is not in the submitted manuscript we will ask you to provide it during the peer review process.

Please also note also note that The BMJ now sends randomised controlled trials and other relevant studies for peer review by patients.

Recent events suggest that these instructions should be amended with the following question:

How were patients involved in the interpretation of results?

The instructions to authors should also elaborate that the intent is require description of how results were shared with patients before publication and dissemination to the news media. This process should be interactive with the possibility of corrective feedback, rather than a simple presentation of the results to the patients without opportunity for comment or for suggesting qualification of the interpretations that will be made. This process should be described in the article.

partnering with patientsMaterial offered by The BMJ in support of their initiative include an editorial, Patient Partnership, which explains:

The strategy brings landmark changes to The BMJ’s internal processes, and seeks to place the journal at the forefront of the international debate on the science, art, and implementation of meaningful, productive partnership with patients. It was “co –produced” with the members of our new international patient advisory panel, which was set up in January 2014. It’s members continue to inform our thinking and help us with implementation of our strategy.

patient includedFor its efforts, The BMJ has been the first medical journal to receive the “Patients Included” Certificate from Lucien Engelen’s Radboud REshape Academy. For his part, Lucien had previously announced:

I will ‘NO-SHOW’ at healthcare conferences that do not add patients TO or IN their programme or invite them to be IN the audience. Also I will no longer give lectures/keynotes at ‘NO-SHOW’ conferences.

But strong words need an action plan to become more than mere words. Although laudable exceptions can be noted, they are few and far between.

In Beyond rhetoric: we need a strategy for patient involvement in the health service, NHS user Sarah Thornton has called the UK government to task for being heavy on the hyperbole of empowering patients but lacking a robust strategy for implementing it. The same could be said for the floundering effort of The BMJ to support patient empowerment in research.

So, should patients just remain patient, keep signing up for clinical trials and hope that funders eventually get more patient oriented in the decisions about grants and that researchers eventually become more patient-oriented?

Recent events suggest that is unwise.

The BMJ patient-oriented initiative versus the PACE investigators’ refusal to share data and the vilification of patients who object to their interpretation of the data

As previously detailed here  the PACE investigators have steadfastly refused to provide the data for independent evaluation of claims. In doing so, they are defying numerous published standards from governmental and funding agencies that dictate sharing of data. Ironically, in justifying this refusal, the investigators cite possible repercussions of releasing the data for the ability to conduct future research.

Fortunately, in a decision against the PACE investigators, the UK Information Commissioner’s Office (ICO) rejected this argument because

He is also not convinced that there is sufficient evidence for him to determine that disclosure would be likely to deter significant numbers of other potential participants from volunteering to take part in future studies so as to affect the University’s ability to undertake such research. As a result, the Commissioner is reluctant to accept that disclosure of the withheld information would be likely to have an adverse effect on the University’s future ability to attract necessary funding and to carry out research in this area, with a consequent effect on its reputation and ability to recruit staff and students.

But the PACE investigators have appealed this decision and continue to withhold their data. Moreover in their initial refusal to share the data, they characterized patients who objected to the possible harm of their interpretations as a small vocal minority.

“The PACE trial has been subject to extreme scrutiny and opponents have been against it for several years. There has been a concerted effort by a vocal minority whose views as to the causes and treatment of CFS/ME do not comport with the PACE trial and who, it is QMUL’s belief, are trying to discredit the trial. Indeed, as noted by the editor of the Lancet, after the 2011 paper’s publication, the nature of this comprised not a ‘scientific debate’ but an “orchestrated response trying to undermine the credibility of the study from patient groups [and]… also the credibility of the investigators and that’s what I think is one of the other alarming aspects of this. This isn’t a purely scientific debate; this is going to the heart of the integrity of the scientists who conducted this study.”

Physician Charles Shepherd, himself a sufferer of myalgic encephalomyelitis (ME) notes:

  • Over 10,000 people signed a petition calling for claims of the PACE investigators relating to so-called recovery to be retracted.
  • In a survey of 1,428 people with ME, 73 per cent reported that CBT had no effect on symptoms while 74 per cent reported that GET had made their condition worse.

The BMJ’s position on data sharing

A May 15, 2015 editorial spelled out a new policy at The BMJ concerning data sharing, The BMJ requires data sharing on request for all trials:

Heeding calls from the Institute of Medicine, WHO, and the Nordic Trial Alliance, we are extending our policy

The movement to make data from clinical trials widely accessible has achieved enormous success, and it is now time for medical journals to play their part. From 1 July The BMJ will extend its requirements for data sharing to apply to all submitted clinical trials, not just those that test drugs or devices.1 The data transparency revolution is gathering pace.2 Last month, the World Health Organization (WHO) and the Nordic Trial Alliance released important declarations about clinical trial transparency.3 4

Note that The BMJ was making the data sharing requirement to all trials, not just medical and medical device trials.

But The BMJ was simply following the lead of the family of PLOS journals that made an earlier, broader, and simpler commitment to data from clinical trials being available to others.

plosThe PLOS journals’ policy on data sharing

On December 12, 2013, the PLOS journals scooped other major publishers with:

PLOS journals require authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception.

When submitting a manuscript online, authors must provide a Data Availability Statement describing compliance with PLOS’s policy. The data availability statement will be published with the article if accepted.

Refusal to share data and related metadata and methods in accordance with this policy will be grounds for rejection. PLOS journal editors encourage researchers to contact them if they encounter difficulties in obtaining data from articles published in PLOS journals. If restrictions on access to data come to light after publication, we reserve the right to post a correction, to contact the authors’ institutions and funders, or in extreme cases to retract the publication

This requirement took effect on March 1, 2014. However, one of the most stringent of data sharing policies in the industry was already in effect.

Publication is conditional upon the agreement of the authors to make freely available any materials and information described in their publication that may be reasonably requested by others for the purpose of academic, non-commercial research.

Even the earlier requirement for publication in PLOS journals would have forestalled the delays, struggles, and complicated quasi-legal maneuvering to characterized the PACE investigators’ refusing to release their data.

Why medically ill people agree to be in clinical research

Patients are not obligated to participate in research, but should freely choose whether to participate based on a weighing of the benefits and risk. Consent to treatment in clinical research needs to be voluntary and fully informed.

Medically ill patients often cannot expect direct personal benefit from participating in a research trial. This is particularly true when trials involve comparison of a treatment that they want that is not otherwise available, but they risk getting randomized to a poorly defined and inadequate routine care. Their needs continue to be neglected, but now burdened by multiple and sometimes intrusive assessments. This is also the case with descriptive observational research and particularly phase 1 clinical studies that provide no direct benefit to participating patients, only the prospect of improving the care of future patients.

In recognition that many research projects do not directly benefit individual patients, consent forms identify possible benefits to other current and future patients and to society at large.

Protecting the rights of participants in research

The World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects spells out a set of principles protecting the rights of human subjects, it includes:

In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information.

Can patients pick up the challenge of realizing the promise of The BMJ editorial, Research Is the Future, Get Involved ?

One patient to whom I showed an earlier draft objected that this is just another burden being thrust on medical patients who already have their condition and difficult treatment decisions with which to contend. She pointed out so often patient empowerment strategies ended up leaving patients with responsibilities they could not shoulder and that the medical system should have met for them.

I agree that not every patient can take up this burden of promoting  both more patient involvement in research and data sharing, but groups of patients can. And when individual patients are willing to take on the sacrifice of insisting on these conditions for their consent, they should be recognized and supported by others. This is not a matter for patients with particular illnesses or members of patient organizations organized around a particular illness. Rather, this is a contribution to the well-being of society should be applauded and supported across the artificial boundaries drawn around particular conditions or race or class.

The mere possibility that patients are going to refuse to participate in research that does not have plans for patient involvement or data sharing can have a powerful effect. It is difficult enough for researchers to accrue sufficient numbers of patients for their studies. If the threat is that they will run into problems because they don’t adequately involve patients, they will be proactive in redesigning the research strategies and reflecting it in their consent forms, if they are serious about getting their research done.

just-say-noPatients are looking after the broader society in participating in medical research. However, if researchers do not take steps to ensure that society gets the greatest possible benefit, patients can just say no, we won’t consent to participation.

Acknowledgments: I benefited from discussions with numerous patients and some professionals in writing and revising this blog. Because some of the patients desired anonymity, I will simply give credit to the group. However, I am responsible for any excesses or inaccuracies that may have escaped their scrutiny.

 

Why the scientific community needs the PACE trial data to be released

To_deposit_or_not_to_deposit,_that_is_the_question_-_journal.pbio.1001779.g001University and clinical trial investigators must release data to a citizen-scientist patient, according to a landmark decision in the UK. But the decision could still be overturned if the University and investigators appeal. The scientific community needs the decision to be upheld. I’ll argue that it’s unwise for any appeal to be made. The reasons for withholding the data in the first place were archaic. Overturning of the decision would set a bad precedent and would remove another tooth from almost toothless requirements for data sharing.

We didn’t need Francis Collins, Director of National Institutes of Health to tell us what we already knew, the scientific and biomedical literature is untrustworthy.

And there is the new report from the UK Academy of Medical Sciences, Reproducibility and reliability of biomedical research: improving research practice.

There has been a growing unease about the reproducibility of much biomedical research, with failures to replicate findings noted in high-profile scientific journals, as well as in the general and scientific media. Lack of reproducibility hinders scientific progress and translation, and threatens the reputation of biomedical science.

Among the report’s recommendations:

  • Journals mandating that the data underlying findings are made available in a timely manner. This is already required by certain publishers such as the Public Library of Science (PLOS) and it was agreed by many participants that it should become more common practice.
  • Funders requiring that data be released in a timely fashion. Many funding agencies require that data generated with their funding be made available to the scientific community in a timely and responsible manner

A consensus has been reached: The crisis in the trustworthiness of science can be only overcome only if scientific data are routinely available for reanalysis. Independent replication of socially significant findings is often unfeasible, and unnecessary if original data are fully available for inspection.

Numerous governmental funding agencies and regulatory bodies are endorsing routine data sharing.

The UK Medical Research Council (MRC) 2011 policy on data sharing and preservation  has endorsed principles laid out by the Research Councils UK including

Publicly funded research data are a public good, produced in the public interest, which should be made openly available with as few restrictions as possible in a timely and responsible manner.

To enable research data to be discoverable and effectively re-used by others, sufficient metadata should be recorded and made openly available to enable other researchers to understand the research and re-use potential of the data. Published results should always include information on how to access the supporting data.

The Wellcome Trust Policy On Data Management and Sharing opens with

The Wellcome Trust is committed to ensuring that the outputs of the research it funds, including research data, are managed and used in ways that maximise public benefit. Making research data widely available to the research community in a timely and responsible manner ensures that these data can be verified, built upon and used to advance knowledge and its application to generate improvements in health.

The Cochrane Collaboration has weighed in that there should be ready access to all clinical trial data

Summary results for all protocol-specified outcomes, with analyses based on all participants, to become publicly available free of charge and in easily accessible electronic formats within 12 months after completion of planned collection of trial data;

Raw, anonymised, individual participant data to be made available free of charge; with appropriate safeguards to ensure ethical and scientific integrity and standards, and to protect participant privacy (for example through a central repository, and accompanied by suitably detailed explanation).

Many similar statements can be found on the web. I’m unaware of credible counterarguments gaining wide acceptance.

toothless manYet, endorsements of routine sharing of data are only a promissory reform and depend on enforcement that has been spotty, at best. Those of us who request data from previously published clinical trials quickly realize that requirements for sharing data have no teeth. In light of that, scientists need to watch closely whether a landmark decision concerning sharing of data from a publicly funded trial is appealed and overturned.

The Decision requiring release of the PACE data

The UK’s Information Commissioner’s Office (ICO) ordered Queen Mary University of London (QMUL) on October 27, 2015 to release anonymized from the PACE chronic fatigue syndrome trial data to an unnamed complainant. QMUL has 28 days to appeal.

Even if scientists don’t know enough to care about Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, they should be concerned about the reasons that were given in a previous refusal to release the data.

I took a critical look at the long-term follow up results for the PACE trial in a previous Mind the Brain blog post  and found fatal flaws in the authors’ self-congratulatory interpretation of results. Despite authors’ claims to the contrary and their extraordinary efforts to encourage patients to report the intervention was helpful, there were simply no differences between groups at follow-up

Background on the request for release of PACE data

  • A complainant requested release of specific PACE data from QMUL under the Freedom of Information Act.
  • QMUL refused the request.
  • The complainant requested an internal review but QMUL maintained its decision to withhold the data.
  • The complainant contacted the ICO with concerns about how the request had been handled.
  • On October 27, 2015, the ICO sided with the complainant and order the release of the data.

A report outlines Queen Mary’s arguments for refusing to release the data and the Commissioner’s justification for siding with the patient requesting the data be released.

Reasons the request release of data was initially refused

The QMU PACE investigators claimed

  • They were entitled to withhold data prior to publication of planned papers.
  • An exemption to having to share data because data contained sensitive medical information from which it was possible to identify the trial participants.
  • Release of the data might harm their ability to recruit patients for research studies in the future.

The QMU PACE researchers specifically raised concerns about a motivated intruder being able to facilitate re-identification of participants:

In relation to a motivated intruder being able facilitate re-identification of participants, the University argued that:

“The PACE trial has been subject to extreme scrutiny and opponents have been against it for several years. There has been a concerted effort by a vocal minority whose views as to the causes and treatment of CFS/ME do not comport with the PACE trial and who, it is QMUL’s belief, are trying to discredit the trial. Indeed, as noted by the editor of the Lancet, after the 2011 paper’s publication, the nature of this comprised not a ‘scientific debate’ but an “orchestrated response trying to undermine the credibility of the study from patient groups [and]… also the credibility of the investigators and that’s what I think is one of the other alarming aspects of this. This isn’t a purely scientific debate; this is going to the heart of the integrity of the scientists who conducted this study.”

Magneto_430Bizarre. This is obviously a talented masked motivated intruder. Do they have evidence that Magneto is at it again? Mostly he now is working with the good guys, as seen in the help he gave Neurocritic and me.

Let’s think about this novel argument. I checked with University of Pennsylvania bioethicist Jon Merz, an expert who has worked internationally to train researchers and establish committees for the protection of human subjects. His opinion was clear:

The litany of excuses – not reasons – offered by the researchers and Queen Mary University is a bald attempt to avoid transparency and accountability, hiding behind legal walls instead of meeting their critics on a level playing field.  They should be willing to provide the data for independent analyses in pursuit of the truth.  They of course could do this willingly, in a way that would let them contractually ensure that data would be protected and that no attempts to identify individual subjects would be made (and it is completely unclear why anyone would care to undertake such an effort), or they can lose this case and essentially lose any hope for controlling distribution.

The ‘orchestrated response to undermine the credibility of the study’ claimed by QMU and the PACE investigators, as well as issue being raised of the “integrity of the scientists who conducted the study” sounds all too familiar. It’s the kind of defense that is heard from scientists under scrutiny of the likes of Open Science Collaborations, as in psychology and cancer. Reactionaries resisting post-publication peer review say we must be worried about harassment from

“replication police” “shameless little bullies,” “self-righteous, self-appointed sheriffs” engaged in a process “clearly not designed to find truth,” “second stringers” who were incapable of making novel contributions of their own to the literature, and—most succinctly—“assholes.”

Far fetched? Compare this to a QMU quote drawn from the National Radio, Australian Broadcast Company April 18, 2011 interview of Richard Horton and PACE investigator Michael Sharpe in which former Lancet Editor Richard Horton condemned:

A fairly small, but highly organised, very vocal and very damaging group of individuals who have…hijacked this agenda and distorted the debate…

dost thou feel‘Distorted the debate’? Was someone so impertinent as to challenge investigators’ claims about their findings? Sounds like Pubpeer  We have seen what they can do.

Alas, all scientific findings should be scrutinized, all data relevant to the claims that are made should be available for reanalysis. Investigators just need to live with the possibility that their claims will be proven wrong or exaggerated. This is all the more true for claims that have substantial impact on public policy and clinical services, and ultimately, patient welfare.

[It is fascinating to note that Richard Horton spoke at the meeting that produced the UK Academy of Medical Sciences report to which I provided a link above. Horton covered the meaning in a Lancet editorial  in which he amplified the sentiment of the meeting: “The apparent endemicity of bad research behaviour is alarming. In their quest for telling a compelling story, scientists too often sculpt data to fit their preferred theory of the world.” His editorial echoed a number of recommendations of the meeting report, but curiously omitted mentioning of data sharing.]

jacob-bronowski-scientist-that-is-the-essence-of-science-ask-anFortunately the ICO has rejected the arguments of QMUL and the PACE investigators. The Commissioner found that QMUL and the PACE investigators incorrectly interpreted regulations in their withholding of the data and should provide the complaint with the data or risk being viewed as in contempt of court.

The 30-page decision is a fascinating read, but here’s an accurate summary from elsewhere:

In his decision, the Commissioner found that QMUL failed to provide any plausible mechanism through which patients could be identified, even in the case of a “motivated intruder.” He was also not convinced that there is sufficient evidence to determine that releasing the data would result in the mass exodus of a significant number of the trial’s 640 participants nor that it would deter significant numbers of participants from volunteering to take part in future research.

Requirements for data sharing in the United States have no teeth and situation would be worsened by reversal of ICO decision

Like the UK, the United States supposedly has requirements for sharing of data from publicly funded trials. But good luck in getting support from regulatory agencies associated with funding sources for obtaining data. Here’s my recent story, still unfolding – or maybe, sadly, over, at least for now.

For a long time I’ve fought my own battles about researchers making unwarranted claims that psychotherapy extend the lives of cancer patients. Research simply does not support the claim. The belief that psychological factors have such influence on the course and outcome of cancer sets up cancer patients to be blamed and to blame themselves when they don’t overcome their disease by some sort of mind control. Our systematic review concluded

“No randomized trial designed with survival as a primary endpoint and in which psychotherapy was not confounded with medical care has yielded a positive effect.”

Investigators who conducted some of the best ambitious, well-designed trials to test the efficacy of psychological interventions on cancer but obtained null results echoed our assessment. The commentaries were entitled “Letting Go of Hope” and “Time to Move on.”

I provided an extensive review of the literature concerning whether psychotherapy and support groups increased survival time in an earlier blog post. Hasn’t the issue of mind-over-cancer been laid to rest? I was recently contacted by a science journalist interested in writing an article about this controversy. After a long discussion, he concluded that the issue was settled — no effect had been found — and he could not succeed in pitching his idea for an article to a quality magazine.

But as detailed here one investigator has persisted in claims that a combination of relaxation exercises, stress reduction, and nutritional counseling increases survival time. My colleagues and I gave this 2008 study a careful look.  We ran chi-square analyses of basic data presented in the paper’s tables. But none of our analyses of group assignment on mortality more disease recurrence was significant. The investigators’ claim of an effect depended on dubious multivariate analyses with covariates that could not be independently evaluated without a look at the data.

The investigator group initially attempted to block publication of a letter to the editor, citing a policy of the journal Cancer that critical letters could not be published unless investigators agreed to respond and they were refusing to respond. We appealed and the journal changed its policy and allowed us additional length to our letter.

We then requested from the investigator’s University Research Integrity Officer the specific data needed to replicate the multivariate analyses in which the investigators claimed an effect on survival. The request was denied:

The data, if disclosed, would reveal pending research ideas and techniques. Consequently, the release of such information would put those using such data for research purposes in a substantial competitive disadvantage as competitors and researchers would have access to the unpublished intellectual property of the University and its faculty and students.

Recall that we were requesting in 2014 specific data needed to evaluate analyses published in 2008.

I checked with statistician Andrew Gelman whether my objections to the multivariate analyses were well-founded and he agreed they were.

Since then, another eminent statistician Helena Kraemer has published an incisive critique of reliance in a randomized controlled trial on multivariate analyses and simple bivariate analyses do not support the efficacy of interventions. She labeled adjustments with covariates as a “source of false-positive findings.”

We appealed to the US Health and Human Services Office of Research Integrity  (ORI) but they indicated no ability to enforce data sharing.

Meanwhile, the principal investigator who claimed an effect on survival accompanied National Cancer Institute program officers to conferences in Europe and the United States where she promoted her intervention as effective. I complained to Robert Croyle, Director, NCI Division of Cancer Control and Population Sciences who twice has been one of the program officer’s co-presenting with her. Ironically, in his capacity as director he is supposedly facilitating data sharing for the division. Professionals were being misled to believe that this intervention would extend the lives of cancer patients, and the claim seemingly had the endorsement NCI.

I told Robert Croyle  that if only the data for the specific analyses were released, it could be demonstrated that the claims were false. Croyle did not disagree, but indicated that there was no way to compel release of the data.

The National Cancer Institute recently offered to pay the conference fees to the International Psycho-Oncology Congress in Washington DC of any professionals willing to sign up for free training in this intervention.

I don’t think I could get any qualified professional including  Croyle to debate me publicly as to whether psychotherapy increases the survival of cancer patients. Yet the promotion of the idea persists because it is consistent with the power of mind over body and disease, an attractive talking point

I have not given up in my efforts to get the data to demonstrate that this trial did not show that psychotherapy extends the survival of cancer patients, but I am blocked by the unwillingness of authorities to enforce data sharing rules that they espouse.

There are obvious parallels between the politics behind persistence of the claim in the US for psychotherapy increasing survival time for cancer patients and those in the UK about cognitive behavior therapy being sufficient treatment for schizophrenia in the absence of medication or producing recovery from the debilitating medical condition, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. There are also parallels to investigators making controversial claims based on multivariate analyses, but not allowing access to data to independently evaluate the analyses. In both cases, patient well-being suffers.

If the ICO upholds the release of data for the PACE trial in the UK, it will pressure the US NIH to stop hypocritically endorsing data sharing and rewarding investigators whose credibility depends on not sharing their data.

As seen in a PLOS One study, unwillingness to share data in response to formal requests is

associated with weaker evidence (against the null hypothesis of no effect) and a higher prevalence of apparent errors in the reporting of statistical results. The unwillingness to share data was particularly clear when reporting errors had a bearing on statistical significance.

Why the PACE investigators should not appeal

In the past, PACE investigators have been quite dismissive of criticism, appearing to have assumed that being afflicted with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis precludes a critic being taken seriously, even when the criticism is otherwise valid. However, with publication of the long-term follow-up data in Lancet Psychiatry, they are now contending with accomplished academics whose criticisms cannot be so easily brushed aside. Yes, the credibility of the investigators’ interpretations of their data are being challenged. And even if they do not believe they need to be responsive to patients, they need to be responsive to colleagues. Releasing the data is the only acceptable response and not doing so risks damage to their reputations.

QMUL, Professors White and Sharpe, let the People’s data go.