Trial By Error: A Commercial Deal for King’s College London’s IBS-CBT Digital Program

By David Tuller, DrPH

On January 10th, the following information was announced in a press release:

Mahana Therapeutics, a digital therapeutics company reimagining the treatment of chronic diseases, today announced that the Company has entered into a licensing and collaboration agreement with King’s College London, a leading research university and one of the oldest and most prestigious universities in England. Mahana has acquired a worldwide exclusive license to an innovative digital therapeutic for the treatment of irritable bowel syndrome (IBS).

This exciting development in Mahana’s efforts to reimagine the treatment of chronic diseases is related to the IBS study I wrote about last week. In the study, two versions of CBT performed somewhat better than treatment-as-usual (TAU) at 12 and, to a lesser extent, at 24 months.* [*I initially wrote “weeks” rather than “months” in this sentence, although subsequent references to the time frame were correct. I am correcting this shortly after having posted the blog. The effects do diminish but not that quickly!] One group received a course of telephone CBT from a therapist. The second received a web-based course of CBT called “Regul8: A Self-Management Programme for IBS,” supplemented by a minimal amount of therapist contact. After the study ended, those in the TAU arm were offered online access to the Regul8 program [American spelling], but without therapist support.

As it turns out, one of the lead investigators on the study, Professor Rona Ross-Morris of King’s College London, has entered into a financial arrangement with Mahana. According to Professor Ross-Morris’ conflicts-of-interest disclosure in the most recent paper arising from the study: “Since this study was completed, she has received payment for consultancy to Mahana Therapeutics and a private company has signed a licence agreement with King’s College London with the view to bringing the Regul8 website product to the NHS and other international markets.”

I have requested information about this licensing agreement from King’s College London, so perhaps more details about these financial arrangements will be forthcoming.

Conflicts of interest are not disqualifying, of course. But they raise legitimate questions about whether personal concerns might influence investigators’ judgements and actions, consciously or not. (I should mention that I have been accused of my own conflicts of interest–most loudly by Professor Michael Sharpe, an Oxford psychiatrist and a lead PACE investigator–because I have raised support for my academic position at UC Berkeley though the university’s in-house crowdfunding platform. Virology Blog has addressed Professor Sharpe’s accusation here and here.)

Here’s more from the Mahana press release, including a statement from Professor Moss-Morris, who is head of health psychology at KCL’s Institute of Psychiatry, Psychology and Neuroscience:

“We spent over 18 years developing and clinically testing a personalized digital CBT program for adult IBS patients,” said Rona Moss Morris. [The name on KCL’s website is Moss-Morris, not Moss Morris.] “We believe our multi-center, randomized controlled trial (RCT) of 558 patients is the largest clinical trial ever conducted demonstrating the clinical safety and efficacy of a digital CBT product for IBS.” The trial, with results published in 2019 prestigious medical journal, demonstrated that web-based CBT showed substantial and durable IBS symptom severity improvements versus treatment as usual (i.e. doctors visits alone) and also led to reductions in anxiety and depression in patients over three, six and twelve-month time periods. 

“The digital era has allowed us the opportunity to explore new ways to reach patients and provide them with access to psychological-based therapies that help control symptoms in a more convenient way. We are thrilled to partner with Mahana Therapeutics. Mahana shares our vision to provide patients in the U.K. and abroad with clinically and cost-effective treatments for gastrointestinal diseases and they have been an amazing collaborative partner,” said Professor Moss-Morris. [They got it right this time.]

First, to declare that the results for the web-based program indicated “substantial” improvements in symptoms, as the Mahana press release does, seems to be engaging in hyperbole. In fact, the improvements could be described as modest at best, judging from the IBS Symptom Severity Scale–the study’s only outcome that directly relates to the illness. Additional instruments measuring other domains, including anxiety/depression, were not designed specifically to assess IBS. It is possible that CBT could lead to reported improvements in such domains, whatever the underlying medical complaint.

For an individual, a reduction in score of at least 50 points in the IBS-SSS is required for the change to be considered clinically significant. In the study’s web-based arm, the mean score on the scale at 12 months was just 35.2 points lower than the mean score for TAU participants–in other words, quite a bit less than 50 points. At 24 months, those in this arm scored 12.9 points lower than those in the TAU arm—and that finding was not even statistically significant. These are the results being touted by Mahana as not only “substantial” but “durable.”

The telephone-delivered CBT program, which included a manual for at-home activities and featured similar content as the web-based program, generated somewhat better results. But since Mahana licensed the “innovative digital therapeutic” and not a telephone-delivered CBT service, the results of those in the web-based arm are the relevant findings in assessing the deal.

In critiquing the study last week, I noted some reasons to be cautious even about the relatively small reported benefits for CBT. One concern was that the study was unblinded and relied solely on subjective outcomes—a combination of traits that generates a high possibility of bias. While a new study in The BMJ has raised questions about whether blinding is as critical as long believed, it goes without saying that—whatever a study’s design—responsible researchers should seek to minimize the chance that bias could impact their results.

So it would be unwise, in an unblinded trial with solely subjective outcomes, to inform participants that the intervention being investigated had already been shown to work for the condition in question. That means if you’re running a trial testing CBT interventions for IBS that include a self-management program and/or therapy sessions, it would be best to avoid telling participants the following on page three of the trial manual:

“There are a number of clinical trials showing that Cognitive Behavioural Therapy (CBT) to help people with IBS manage their lifestyles and symptoms better, leads to a significant reduction in IBS symptoms and the impact the symptoms have on people’s lives…

This self-management programme is based on an approach that has been shown to work in a smaller research trial with people with early onset IBS…We now want to test the intervention in a larger trial with people who have had IBS for longer, with some telephone support from a therapist.”

When the introduction in a manual for an intervention includes this kind of messaging, it is reasonable to assume that the therapists themselves might reinforce these claims during their conversations with participants. In this study, those in the TAU arm were presumably not being told that the kind of care they were getting had already been shown to reduce symptoms.

Of course, people receiving an intervention in a clinical trial might hope for improvements whatever or not they’re told, and no one can prevent them from seeking additional information on their own. However, it is inappropriate for a study itself to create conditions that could generate such expectations when doing so is avoidable. That the investigators chose to highlight the purported success of their therapeutic approach in the patient manual for a trial designed to test the efficacy of that therapeutic approach is perplexing. The possibility or likelihood that these statements could bias participants receiving that intervention is self-evident, or at least should be.

The press release does not mention whether the web-based program will be offered as it was road-tested in this study—that is, in conjunction with external therapeutic support. It is possible or perhaps likely that reported improvements in symptoms would be even smaller for the web-based program alone, without any therapist contact. For whatever reason, the investigators decided not to include an arm to test how the web-based program would perform on its own–although that fact is not clear from the press release.

[Feb 11, 2020: In the following sentence, I initially wrote “prolonged” rather than “durable.” I apologize for the error.]

So let’s recap: Mahana Therapeutics has licensed from King’s College London a web-based program said to produce “substantial and durable”* reductions in IBS symptoms. But the study cited in the press release shows that, at 12 months, the mean difference between the web-based group and the treatment-as-usual group was less than the 50-point drop that would represent a clinically significant change for an individual. By 24 months, there was no statistically significant benefit on the symptom scale for the web-based program.

Perhaps Mahana executives view this weak evidence through their own idiosyncratic lens or have access to additional information that convinces them the reported symptom changes are “substantial and prolonged.” As it is, the whole deal seems like a lot of hoopla and hype. I’m skeptical it will bring much benefit to IBS patients in the National Health Service, although you never know. It does seem like the arrangement will at least benefit King’s College London.

 

{ 17 comments… add one }
  • Alicia Butcher Ehrhardt 27 January 2020, 4:37 am

    But they will get money for this fake and ineffective ‘treatment’ and that’s all they care about. IBS is a physical disease.

  • Scott Simpson 27 January 2020, 5:15 am

    Galileo, often considered the Father of Science, must be rolling in his grave.

    While Father Charlatan must be proud.

    (He pretended to be a priest of any number of churches in order to swindle gullible worshippers out of money through false miracles and healing.)

  • Lady Shambles 27 January 2020, 6:33 am

    What I find most interesting is the link to the BMJ paper that is attempting to dilute the importance of ‘blinding’ https://bmjopen.bmj.com/content/1/2/e000252 . Given one of its authors is Jonathan Sterne who is co-author with Esther Crawley of the now infamous School Absence study (a study which is so full of holes it could stand in for a colander http://www.virology.ws/2017/08/28/trial-by-error-no-ethical-review-of-crawley-school-absence-study/) my response to the publication of that BMJ paper is ‘Mandy Rice Davies Applies’ or ‘well they would wouldn’t they?’

    Simultaneously trying to undermine good practice ( and ‘well they would wouldn’t they’ applies to both the BMJ and the rest of the BPS school) whilst flogging dubious online CBT programmes (yes I am throwing the whole lot of them into one homogeneous glob because they all act as one.. like a shoal of fish or synchronised swimming at Olympic level) is all rather murky isn’t it?

    Oh why did I have to have this disease and have to endure it during the same time that these imbeciles drive policy-based medicine? There is such little hope out there. Doesn’t matter what disease any of us have now, BMJ and The Lancet and the IOP are running the show and pity help us all.. You can see their cogs turning but stopping the mechanism is proving difficult because those who could change the terrain are as equally invested as the BPS crew. Power corrupts etc and so on…..but the patient’s value is ‘zero’.

  • GK Quiz 27 January 2020, 9:22 am

    Mahana Therapeutics Enters Into Licensing Agreement With King’s College London for Innovative Digital Therapeutic to Treat Gastrointestinal Condition

  • jimells 27 January 2020, 9:38 am

    Imagine the worst possible fraud and corruption in the medical industry. Now multiply that by ten. The result would still be far short of reality.

    Patients will be directly harmed by this “treatment”. When they inevitably fail to improve, they will be labeled “treatment resistant”, blamed for their illness, denied access to real treatments, and of course denied social benefits.

    What is hard for me to understand is that so many people allow this to continue. Are KCL’s students, administrators, professors, and regulators all OK with this? Is it possible they have no idea what is happening at their own institution?

    “Good Germans” are everywhere…

  • Noreen 27 January 2020, 9:53 am

    #FollowTheMoney is the usual adage. #TooMuchDamageBeingCaused is another.

    Our niece always had tummy/bowel problems. Despite bringing her to all types of doctors, nothing was done. Eventually she was diagnosed with IBS. There were times when people thought that she had anorexia, the poor girl.
    Fast forward: because of her “IBS”, weight loss, etc., she stopped menstruating. She was unable to have children 🙁
    At 39 years of age, she was diagnosed as having coeliac disease. She’s like a different person. But she’ll never have children. Her life has been ruined in that respect.

    No amount of CBT was ever going to cure that!!

    These psychs should have enough to do with the amount of ‘mental health issues’ there seems to be around, especially considering the outcry at the lack of care available. Why cross over? I wonder hmm

  • Cheri 27 January 2020, 12:17 pm

    What a lovely fairy tale they are selling. If only treating a real physical illness were that easy. It is not a cost effective treatment if it does not work.

  • Caron Ryalls 27 January 2020, 1:01 pm

    I find the move to psychological and ‘lifestyle’ treatments frightening, having seen the impact of the PACE study in patient care and well being and the difficulties trying to have concerns acknowledged and investigated.

    My daughter was diagnosed first with ME/CFS and then with POTS at the age of 13/14. We had a very difficult few years trying to dodge referrals to psychiatrists, and because of this, I feel we escaped a child protection investigation by the skin of our teeth.

    We have subsequently had antibody tests done at CellTrend in Germany and my daughter has tested positive to adrenergic and muscarinic autoantibodies identified in papers by Scheibenbogen (relating to ME/CFS) and US researchers (relating to POTS).

    With this in mind, and with the acknowledgement from several of her doctors that her illness is likely to be autoimmune driven (although immunotherapies have been refused), I have been dismayed to see that the only U.K. charity and advocacy group for patients with POTS is involved with a study looking at exercise rehabilitation, which looks remarkably similar to the PACE study.

    The website for the PULSE study states:

    “We aim to assess the feasibility of a supervised exercise rehabilitation intervention with behavioural and motivational support, compared to best practice usual care, for people with POTS.”

    I don’t know if POTS patients with comorbid ME/CFS will be screen out of this study.

    I’ve voiced (always politely!) my concerns about this study and POTS UKs reluctance to make their patient population aware of the latest autoimmune research, and their apparent obsession with EDS and exercise/lifestyle treatments, and their response has been to block me from all their social media and parent/patient support groups!

    I fear POTS in the U.K. is on the cusp of going down the same route that PACE took ME.

    http://pulse-project.coventry.ac.uk/what-are-the-aims-and-objectives-of-the-pulse-study/

  • Lucie Webb 27 January 2020, 2:22 pm

    Stool samples not CBT. I think everybody needs their jaws examining.

  • Colleen Steckel 27 January 2020, 4:23 pm

    Caron Ryalls, you make some really important points about how dangerous this approach is, especially for children.

    In my experience talking with a lot of patients in the POTS community there are patients who respond well to exercise and then there are those who do not. It is really important patients have proper screening for myalgic encephalomyelitis before treatments begin.

    The same goes for those who are diagnosed with IBS. NO treatments should be pursued until the patients have been screened for ME using the ME ICPrimer.

    If POTS or IBS is a downstream effect of the known issues seen in ME (low blood volume, lack of homeostasis, elevated blood lactate, NK cell function allowing for opportunistic infections, etc.) then the treatments MUST be adapted with recognition of ME as the driving force behind symptoms.

    This, again, comes back to patients getting properly screened for ME and properly ruling out other conditions that can be mistaken for ME.

  • Richard Vallee 27 January 2020, 4:33 pm

    It’s looking more and more that British medicine and its various official bodies and institutions have turned into a rubber-stamp factory that gives false legitimacy to blatant pseudoscience, up to and including commercialization of those products in blatant personal and institutional conflicts of interests.

    Looking at the papers that Mahana presents as its evidence base, we see The Lancet and several BMJ publications, who know all too well about Chalder’s, uh, conflicts with reality. Even in this case the return of Peter White, who somehow knows enough about IBS to steer a research committee but was utterly puzzled by the inclusion of very common IBS-like symptoms and management in the NICE CFS guideline, in his unearned capacity as an expert on the topic.

    Given the current political pressure among many British politicos and financiers to dismantle the NHS and sell it for parts, it’s hard not to see some alignment of interests in the destruction of the very credibility of British science, especially in medicine, and the very public intent of selling the system off to a profit-driven system.

    Maybe it is some happy coincidence but it would not look any different if this were the explicit intent. I’m also sure this will not have any impact on the credibility of science and expertise. There is simply no possibility of this happening, especially not with such august institutions as The Lancet and KCL, currently mired in the Eysenck debacle, and the overbearing presence of some regius professor knight of some kind in this and other affairs.

    After all, what’s the worst that could happen from a massive crisis of credibility in the value of expertise in medical science? I certainly cannot think of a single example and definitely not one involving any of those institutions. Nope. Making stuff up never ends up blowing in anyone’s faces. Well, as long as no one considers a blown up face to be an adverse reaction anyway.

  • Wendy Boutilier 27 January 2020, 6:45 pm

    DSM-III and DSM-IV have been praised for making a seminal contribution to patient care and to the scientific study of psychiatric disorders by providing rigorous and reliable diagnostic criteria for conditions such as major depressive disorder and social phobia. At the same time, DSM-III and DSM-IV have been criticized for creating too many diagnostic categories and for allowing the distinction between psychopathology and normal psychological phenomena (e.g., sadness after a major stressful event, shyness in social situations) to be eroded.

  • jimells 28 January 2020, 12:44 pm

    Psychobabblers claim that thinking the wrong thoughts causes a wide variety of illness, and they further claim that about a quarter of the population can do this, all without even trying. We must be pretty smart.

    And yet not one psychobabbler has ever claimed to have thought the wrong thoughts and thereby given themselves an illness which they subsequently cured by thinking the right thoughts. Perhaps they are not the smartest ones in the room after all…

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