Undisclosed conflicts of interest in a systematic review protocol of interventions for medically unexplained symptoms

Update March 19, 2016: The protocol has now been corrected with this declaration:

medically unexplained update

Hey, PROSPERO, we’ve got a problem.

Prince Prospero

Vincent Price as Prince Prospero

A protocol for a systematic review of the treatment of medically unexplained symptoms (MUS) that is posted and downloadable at York University’s PROSPERO site has blatant but undeclared conflicts of interest. Yet, the review has the potential to change health policies in the UK and elsewhere.

 Joanna Leaviss, Glenys Parry, Matt Stevenson, Andrew Booth, Alison Scope, Sarah Davis, Shije Ren, Anthea Sutton, Peter White, Rona Moss-Morris, Marta Buszewicz. Medically unexplained symptoms(MUS): primary care intervention. PROSPERO 2015:CRD42015025520 Available here.

The review is funded by £206,000 (US$304,087 ) from the UK National Institute for Health Research.

  • A key purpose of systematic reviews is to evaluate the relevance of the scientific literature for health policy with a buffer against the agenda and self-interests of the researchers who conducted the original individual studies.
  • There is strong evidence of an undeclared agenda in these authors conducting this systematic review, based on the authors’ disclosures of conflicts of interest elsewhere and their strong public and professional advocacy of a particular viewpoint.
  • The circumstances of this systematic review highlight a serious blurring of lines between advocacy and what should be independent assessment of the claims of investigators in systematic reviews, as well as the media.


The PROSPERO website describes it as

…An international database of prospectively registered systematic reviews in health and social care. Key features from the review protocol are recorded and maintained as a permanent record. PROSPERO aims to provide a comprehensive listing of systematic reviews registered at inception to help avoid unplanned duplication and enable comparison of reported review methods with what was planned in the protocol.

The development and ongoing management of PROSPERO is supported by CRD’s [Centre for Reviews and Dissemination] core work programme which is funded by the National Institute for Health Research, England; the Department of Health, Public Health Agency, Northern Ireland and the National Institute for Social Care and Health Research, Welsh Government.

I have used PROSPERO to register the hypotheses and methods of my group’s Stress as a risk factor for cancer: a systematic review and meta-analysis.

But registration in PROSPERO of a protocol with undeclared conflicts of interest poses a problem. It discourages someone else from undertaking a systematic review who does not have such a bias. The goal of avoiding duplication of efforts gets compromised when it leads to a lack of unbiased reviews in a particular area of research.

PROSPERO does not police protocols for undeclared conflict of interest.

The named contact for each registered review is entirely responsible for the content of their registration record.  CRD accepts the information provided in good faith and bears no responsibility or liability for the content of any registration record.

What is the purpose of this review?

A scientific summary of the protocol is available here.

The summary provides a sweeping definition of medically unexplained conditions:

The term ‘MUS’ is used to cover a wide range of symptoms which cannot be clearly explained by a general medical condition, even after a thorough examination and any relevant investigations. Henningsen et al (2005) describe three main types of MUS: pain in different locations, for example headache, back pain, non-cardiac chest pain (NCCP); functional disturbance of organ systems; and complaints of fatigue or exhaustion. The term MUS may be applied to patients presenting with single symptoms, multiple symptoms, or clusters of symptoms that are related to one another and are specific to a certain organ system or medical specialty, for example chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), or fibromyalgia. The latter are usually referred to as functional somatic syndromes (FSS) (Wessely et al., 1999). Patients presenting with MUS may vary in terms of reported severity i.e. number of symptoms, functional disability or quality of life, and duration of symptoms.

Consistent with a broad definition of the conditions, a broad range of intervention studies will be included:

Intervention interventions that aim to modify behaviour will be included. These include CBT, GET, behaviour therapies. Where the intervention is not explicitly behaviour modification, we will adopt a broad inclusion criteria, with studies included if i) at least one primary outcome is a functional or behavioural change measure, or ii) the stated explicit aim of the intervention is to change behavior.

Conflicts of interest in systematic reviews

According to one view, persons with significant conflicts of interest, particularly investments in a particular treatment approach, should simply not conduct systematic reviews. The problem is not resolved by disclosing interests, they shouldn’t be involved in the review because of the high risk of bias.

Handoll H, Hanchard N. From observation to evidence of effectiveness: the haphazard route to finding out if a new intervention works. Cochrane Database of Systematic Reviews. 2014 Jan 1.

…This illustrates what we feel should become a cardinal rule: the need to separate the clinical evaluation of innovations from their innovators, who irrespective of any of their endeavours to be ‘neutral’ have a substantial investment, whether emotional, perhaps financial, or in terms of professional or international status, in the successful implementation of their idea.


The reporting of financial conflicts of interest in systematic reviews may not be sufficient to mitigate the effects of industry affiliations, and further measures may be necessary to ensure that industry collaborations do not compromise the scientific evidence.

There are notorious examples of promoters of psychological therapies and psychosocial interventions producing biased systematic reviews to promote their products. Along with Phil Wilson and Manuel Eisner, I exposed a group of Australian academic entrepreneurs who make millions dollars from their “evidence-based” Triple P Parenting program.

The main evidence that promoters of Triple P cited came from trials in which they been involved. They then in turn reviewed these studies in meta-analyses and systematic reviews. None of this work had disclosed conflicts of interest. The evidence from subsequent independently conducted trials and independently conducted meta-analyses that controlled for bias was markedly weaker for their program.

In the ensuing controversy, over 50 articles by this group had to post errata or correction notices belatedly declaring conflict of interest. Based on new evidence of a lack of effectiveness, commitments to Triple P Parenting programs were reevaluated in a number of regions and defunded. In a retrospective account, I noted:

Meta-analyses of psychotherapies are strongly biased toward concluding that treatments work, especially when conducted by those who have undeclared conflicts of interest and investigator allegiances, including developers and promoters of treatments that stand to gain financially from their branding as “evidence-supported” (see e.g., Hayes, Luoma, Bond, Masuda, & Lillis, 2006; Johnson, Hunsley, Greenberg, & Schindler, 2006; Nowak & Heinrichs, 2008; Sanders, Kirby, Tellegen, & Day, 2014) .


Disclosure of conflicts of interest should be enforced and nondisclosure identified in correction statements and further penalized. Apart from reporting of conflicts of interest, reviewers and meta-analysts should consider investigator allegiance when assessing risk of bias.

Developers of treatments and persons with significant financial gain from a treatment being declared “evidence-supported” should be discouraged from conducting meta-analyses of their own treatments (for a striking example, see Sanders et al., 2014.

Evidence concerning effects of reviewers’ conflict of interest on conclusions of systematic reviews

Dunn and colleagues examined the association between financial conflicts of interest and characteristics of systematic reviews of the effectiveness of the drug neuraminidase inhibitor drugs in preventing and treating influenza. Reviewers with financial conflicts of interest may be more likely to present evidence about neuraminidase inhibitors in a favorable manner and recommend the use of these drugs than reviewers without financial conflicts of interest.

They concluded

 The reporting of financial conflicts of interest in systematic reviews may not be sufficient to mitigate the effects of industry affiliations, and further measures may be necessary to ensure that industry collaborations do not compromise the scientific evidence.

Yet, ignoring of conflicts of interest in reviews of psychotherapeutic interventions is much higher than when industry is involved in evaluation of a drug or medical device.

Even when journals do allow such conflicts of interest, it becomes particularly important that they be declared. If adequately informed, skeptical readers might not settle for a declaration, but view the review with considerable skepticism, if not simply dismissing it.

Non-financial conflicts of interest

In an editorial in British Journal of Psychiatry, Mario Maj has argued for the importance of non-financial conflicts of interests in psychiatric research and practice:

Not all conflicts of interests affecting psychiatry are financial in nature. Our field is vulnerable to some varieties of nonfinancial conflicts of interests. Examples include the possible conflict between a researcher’s allegiance to a school of thought and the integrity of psychotherapy research, or between a psychiatrist’s political commitment and patients’ welfare

The serious conflicts of interest of Peter White

 goods to declare2pgOne of the authors listed on the PROSPERO protocol with no conflicts of interest declared is Peter White.

Yet, in other quite recent articles, he discloses conflict of interests. PLOS One  requires that authors not simply tick a box indicating that they do not have a conflict of interest, but provide an overall answer based on a detailed set of questions. Peter White declared conflicts of interest for a PLOS One article and:

PDW has done voluntary and paid consultancy work for the United Kingdom Departments of Health and Work and Pensions and Swiss Re (a reinsurance company), and led a randomised controlled trial about graded exercise therapy funded by the Linbury Trust.

 If we look up Peter White’s consultation with Swiss Re’s UK Life & Health Claims  we see him making unrealistic claims about the efficacy of cognitive behavior therapy in the PACE trial.

The key message is that pushing the limits in a therapeutic setting using well described treatment modalities is more effective in alleviating fatigue and dysfunction than staying within the limits imposed by the illness traditionally advocated by “pacing”. If a CFS patient does not gradually increase their activity, supported by an appropriate therapist, then their recovery will be slower. This seems a simple message but it is an important one as many believe that “pacing” is the most beneficial treatment.

Peter White serves as a paid and unpaid consultant in the adjudication of disability claims would get a boost in the value of his services from a systematic review in which he controlled the conclusions to be consistent with the position he advocates.

Is Peter White the man you would want to be involved in evaluating the literature concerning treatments for MUS?

Dr. Peter White2Peter White has been remiss in declaring conflicts of interests in situations where they are required. For instance, in the recruitment and consenting of patients for participation in the PACE trial, there was no mention of White’s conflicts of interest. Because knowledge of potential conflicts of interest of investigators is essential to patients’ decision-making whether to participate in a trial, this nondisclosure is a violation of the internationally accepted Declaration of Helsinki.

Moreover, during conduct of the PACE trial, the primary outcomes specified in the original protocol were altered in a way that increased the likelihood of getting spurious results favoring the intervention.

Despite the universal acceptance of the value of investigators sharing data so that others can independently evaluate their work, Peter White and his colleagues have refused to share data from the PACE trial, even after he was ordered to do so by the UK Information Commissioner’s Office.

Despite agreeing to share data as a condition for publishing in PLOS One, Peter White and colleagues refused my request for data from a PLOS article and attacked my character and motives for making the request.

Despite international policies about sharing data, Peter White has testified that universities in the UK should not have to provide data in response to requests, and he cites the possible damage to the careers of researchers by independent scrutiny of their work by those skeptical of their original conclusions.

So, Peter White

  • Has interests that would be furthered by arriving at particular conclusions in this review.
  • Has a history of not declaring conflicts of interest in situations in which such information is quite relevant and expected.
  • Has a record of not adhering to registered protocols for clinical trials.
  • Does not believe in sharing data and aggressively defends against legitimate requests for independent evaluation of his work.

Does Rona Moss-Morris have a conflict of interest to report?

RonaMoss-MorrisAlthough one of the authors of the protocol, Rona Moss-Morris doesn’t report a conflict of interest, she declared a relevant conflict of interest in a gushy press-release endorsement of Peter White’s work.

Expert reaction to long-term follow-up study from the PACE trial on rehabilitative treatments for CFS/ME, and accompanying commentary.

Declared interests

Prof. Rona Moss-Morris: “Two authors of this study, Trudie Chalder and Kimberley Goldsmith, are colleagues of mine at King’s College London. I work with Trudie on other CFS work and with Kimberley on different work.  I published a small study on GET in 2005. I am a National Advisor for NHS England for improving access to psychological therapies for long-term conditions and medically unexplained symptoms. Peter White (another author of the present study) is Chair of trial steering committee for an HTA NIHR-funded RCT I am working on with people with irritable bowel syndrome.”

I challenge readers to find other instances of a formal declaration of a potential conflict of interest in a press release. Why did Rona Moss-Morris feel the need for such an unusual disclosure? The context was the press release was coming from the Science Media Centre an organization, which explicitly indicates that its endorsement of biomedical and scientific findings is fair and unbiased:

Our Mission

To provide, for the benefit of the public and policymakers, accurate and evidence-based information about science and engineering through the media, particularly on controversial and headline news stories when most confusion and misinformation occurs.


Our Independence

The independence of the Science Media Centre is critical to the work we carry out. We do not have any specific agenda other than to promote the reporting of evidence-based science, and are completely independent in both our governance and funding.

Prof. Sir Simon Wessely is listed as a member of the Board of Trustees. Wessely is an outspoken defender of the PACE trial.

So, Moss-Morris felt the need for disclaimer because otherwise her review would seem like an inside job. But we need to ask whether declaring potential conflict of interest eliminated the threat of her not providing an independent evaluation. Why didn’t she simply decline? And if she felt the need to disclose a conflict of interest here, why not declare one for the PROSPERO protocol?

Rona Moss-Morris’ review of the CFS/ME: PACE trial follow-up study

Prof. Rona Moss-Morris, Professor of Psychology as Applied to Medicine, King’s College London, said:

“I think this is a robust study with some limitations that the authors have been clear about. The original PACE trial published in 2011 showed that at one year people with CFS/ME who received either graded exercise therapy (GET) or cognitive behavioural therapy (CBT) in addition to standard medical care were significantly less fatigued than those who received standard care alone or those who received adapted pacing therapy. The authors concluded GET and CBT were moderately effective treatments for CFS. Now, moderately effective may not sound all that impressive until you consider that many of our commonly used pharmaceuticals for medical conditions have similar moderate treatment effects. When using pharmaceuticals as treatment, maintaining these effects may mean taking ongoing medicines. This study shows that even two years or more after treatment has completed, patients receiving GET and CBT sustain their clinical benefits. A small percentage of these patients accessed some further treatment, but even so, these sustained effects are impressive.

Despite these impressive results, this isn’t time for complacency. Some patients do not benefit from the treatment. We need to do more to understand why. We also need to develop and tailor existing treatment to get larger effects. It is also important to note that the CBT and GET protocols used in PACE were developed specifically for CFS. They are not the same as CBT for depression and anxiety or the exercise training you may receive at a local gym. The therapies are based on a biopsychosocial understanding of CFS and the health care professionals in PACE received specific training and supervision in these approaches. This is an important note for commissioners as not all CBT and exercise therapies are equal. Specialist knowledge and competence in these therapies is needed to obtain these sustained treatment effects.

Moss-Morris is parroting the critical evaluation by Peter White and her other friends among the PACE investigators of their own trial and is specifically recommending their treatment. My own assessment of the same evidence is captured in the blog post’s title: Uninterpretable: Fatal flaws in PACE Chronic Fatigue Syndrome follow-up study.

In contrast to Moss-Morris’ evaluation, I showed that there were no differences between treatment groups at the end of the follow-up. Furthermore, the follow-up data was analyzed in terms of the initial treatment assignment of patients at randomization. However, at the time of follow-up, a considerable proportion were receiving other treatments, making it impossible to obtain an assessment of independent effect of initial assignment. See Keith Laws’ Dystopia blog for additional criticisms.


 In an earlier blog post, I noted the extraordinary number of authors on articles reporting results of the PACE study as well as members of various advisory boards that were acknowledged. I questioned the difficulty in obtaining independent evaluation of the results of the trial. Investigator allegiance effects are known to be strong in psychotherapy trials. It is important that there be checks and balance on subsequent evaluations both in the media and in systematic reviews. Yet, once again we encounter a mutual admiration society of “friends and family” as well as the original investigators themselves in the interpretation of the trial in the media for consumers and professional audiences, and now in a costly systematic review in which results of the trial will figure heavily.

Consumers and taxpayers are put at risk from biased evaluations of interventions which will undoubtedly affect health policy decisions.