Trial By Error: Mary Dimmock on CDC’s New Evidence Review

By David Tuller, DrPH

I have lately been focusing more time and posts on developments in the UK than in the US. I guess that’s not too surprising. After all, this whole project began as an investigation of the PACE trial, conducted by British experts in British health care centers and published in British journals. And there’s so much crap besides PACE to pursue, given the strength of the CBT/GET ideological brigades.

I’m glad that Mary Dimmock and others are keeping up the pressure here. Mary got involved in the issue after her son fell ill several years ago. She has been especially active in prodding US health agencies, and in particular the Centers for Disease Control and Prevention, to do their jobs. The article below, about the agency’s new systematic review of the evidence base for ME/CFS treatments, appeared in last month’s issue of the ME Global Chronicle. I am re-posting it in full here with Mary’s permission.

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CDC Systematic Evidence Review of Treatments for ME/CFS
Mary Dimmock
June 19, 2019

You may remember that in September 2018, the US Centers for Disease Control and Prevention (CDC) solicited bids to conduct a systematic evidence review of ME/CFS treatments as an update to the 2014-2016 systematic evidence review commissioned by the Agency for Healthcare Research and Quality (AHRQ). This new review, currently underway, could have a significant impact on treatment recommendations in clinical guidance for ME. I am a member of the key informants panel providing input on review questions and have agreed to hold those discussions and the names of the other members in confidence. In the meantime, the following summarizes what is known publicly about this important review, based on information provided by CDC and in the documentation for the bid solicitation.

The Key Takeaways:

• CDC is conducting this systematic evidence review as the first step in longer-term plans to develop treatment guidelines for ME/CFS

• The timeline for completion has not yet been stated publicly but is estimated to be the first half of 2020

• The handling of the disparate case definitions has not yet been specified. The 2016 Addendum to the 2014 AHRQ Evidence Review excluded Oxford studies from analysis

• This review may consider other peer-reviewed literature that provides context for treatment of symptoms seen in ME/CFS (e.g. orthostatic intolerance, pain, etc)

• The process for the review of the draft report has not yet been announced. During the 2014 evidence review, the public was given the opportunity to provide input

Details on the Project From CDC

At its March 2019 stakeholder call (1), CDC provided the following information on this project:

“CDC is committed to working with our partners to achieve the goal of improved healthcare access and quality for patients with ME/CFS. Treatment guidelines for ME/CFS could contribute to this goal, and the first step towards guidelines is an updated systematic review of the literature. We have contracted with the Pacific Northwest Evidence-based Practice Center at Oregon Health Sciences University to conduct this review. As you may be aware, systematic reviews start by framing the question(s) to be answered as well as the particular population, interventions, comparators, outcomes, settings, timings. These key questions are extremely important to assure the [usefulness] of the review. This week OHSU conducted interviews with key informants representing advocates and ME/CFS clinicians to refine questions. The discussion was very helpful and OHSU will finalize the key questions prior to initiating the evidence review.”

The Pacific Northwest Evidence-based Practice Center (EPC) contracted by CDC for this new review is the same group that conducted the 2014 diagnosis and treatment evidence review and the 2016 Addendum on behalf of the Agency for Healthcare Review and Quality (AHRQ) (2). The 2014 review concluded that CBT and GET were moderately effective based in large part on Oxford studies and rated PACE as a “good” trial. But it also noted evidence of harms from GET and called for the retirement of the Oxford definition because it included other fatiguing conditions. As a result of community requests to reassess the evidence, the EPC issued the 2016 Addendum, which concluded that there was insufficient evidence for GET and barely any for CBT once Oxford studies were excluded. The 2016 Addendum did not reassess the quality of studies, including PACE. The 2014 review was published in the peer-reviewed literature but the 2016 Addendum was only posted on the AHRQ website.

Information from the September 2018 Solicitation for Contractor Bids
While not the final contract, the September 2018 solicitation provides additional insight (3). The solicitation stated this new review would include studies of treatments in “ME/CFS” but did not specify what case definitions would be included or excluded or how Oxford studies would be handled. As noted above, in the 2016 Addendum, positive results for CBT and GET in Oxford case definition studies did not hold up when those studies were excluded. The 2016 Addendum also pointedly stated that studies of CBT and GET using case definitions requiring hallmark criteria of ME such as PEM were “blatantly missing” from the evidence base.

The 2018 solicitation also stated “any peer-reviewed literature that could provide context to inform treatment recommendations for symptoms associated with ME/CFS warrants review and consideration.” While not explicit, this suggests the review might consider evidence for treatment of symptoms such as orthostatic intolerance and sleep impairment from studies done in other conditions. However, the solicitation does not provide specifics on how this would be done.

Neither CDC nor the solicitation documentation has specified the process for the review of the draft evidence review or who will be involved. As noted above, the 2014 review provided a mechanism for public input on the draft review. Regarding the timeline for the review, the September 2018 project solicitation gives a 15-month timeline for the draft review and 18 months for the final report. Assuming the contract was awarded in October 2018 and these timelines were not changed, this suggests the draft review would be done by about January 2020 and the final review by about April 2020.

Next Steps

CDC staff told me that the Pacific Northwest Evidence-based Practice Center will publish the project description in PROSPERO when ready and CDC will then provide a link to that from its website. PROSPERO is an international database that prospectively registers information about the design and conduct of planned systematic evidence reviews (4). This includes information such as the body of literature to be searched, the population and interventions being studied, the outcomes evaluated and other aspects of how the assessment will be conducted. Prospective registration of the review description is intended to increase transparency and reduce reporting bias and duplication. Hopefully, the information provided in PROSPERO will answer some of the open questions.

References

1) Transcript of the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Stakeholder and Communication Conference Call. Centers for Disease Control and Prevention. March 11, 2019. https://www.cdc.gov/me-cfs/pdfs/orthostatic-intolerance-508.pdf

2) Diagnosis and Treatment Evidence Review. Agency for Healthcare Review and Quality. 2014, updated 2016. https://effectivehealthcare.ahrq.gov/topics/chronic-fatigue/research

3) Centers for Disease Control and Prevention. Evidence-based treatment guidelines for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Solicitation Number: 75D301-18-Q-69445 FedBizOps. September 8, 2018
• Summary: https://www.fbo.gov/?s=opportunity&mode=form&id=30dd6fa6af05215774b9d11d01f9f6c2&tab=core&_cview=0
• Details: https://www.fbo.gov/utils/view?id=051bae33d4ba7a1086c61e6d2f50b651

4) PROSPERO https://www.crd.york.ac.uk/prospero/#aboutpage

{ 10 comments… add one }
  • Lady Shambles 11 July 2019, 5:48 am

    As I understand it, and please correct me if I’m wrong, Mary Dimmock is fully supportive of the IOM definition of ‘CFS/ME’ as ‘SEID’. SEID has many problems associated with it not least that it captures large populations who do not have what those of us in the UK might describe as the discrete disease ‘ME’ using early ‘Ramsay’ criteria or the more recent ICC. Given we have sensible researchers such as the Griffiths team and Maureen Hanson using the tightest definition we have atm, ie ‘ICC’, wouldn’t it be prudent for those who have the ear of the CDC (many who have long travails with advocacy in the US have been excluded from this.. which is a real worry) demand the use of ICC in order to ensure the right people are being diagnosed with the right disease?

    Clearly a descriptive criteria, in advance of bio-markers, can never be wholly accurate but the ICC is more able to capture the population in question (without drawing in significant percentages of people who do not have ME) than SEID, or any other criteria proposed to this point in time. Mixed cohorts due to muddy criteria (and we have to ponder why the CDC have always seemed to prefer the muddier option..not unlike the Wessely School in the UK) lead to missed-diagnoses, mis-diagnoses and uninterpretable research. ICC has been operationalised by dint of the aforementioned researchers and is also designed for clinical interpretation.

    Given the wealth of experience of those who created the ICC, it seems very silly to yet again limit one’s advocacy to an all-encompassing criteria such as SEID and I’d urge Mary Dimmock to sign up to demanding better diagnosis, leading to better care and better research, ie: sign up to ICC. Over six and a half thousand people have requested this be so via a petition which has never had the thrust of the major charities behind it. It seems grass roots patients suffering at the pointiest end of this disease (and some of us know how utterly intolerable that end of the spectrum can be), and whose needs are not being reflected by current representation either in the UK or US (though thankfully the UK now has a brand new ethically-minded, patient-oriented charity which does endorse ICC as criteria of choice), have tried to make their opposition to SEID and other diagnostic criteria known by signing this petition. It would be nice if those sufferers could be heard..just for once, not least because their approach is driven purely by a need for help and for the implementation of the scientific method. Yes their voice is weak..because they are weak.. but they speak truth to power..if only they are given the opportunity.

  • Couch Turnip 11 July 2019, 9:13 am

    Thank you for posting this update about what’s going on in the US. It’s important for us to know what’s happening around the world because it’s all closely intertwined. We’re so fortunate to have someone on the case who is happy to globe trot both physically and cerebrally!

  • Wendy Boutilier 11 July 2019, 2:50 pm

    In 1978 the Royal Society of Medicine accepted ME as a nosological organic entity. The current version of the International Classification of Diseases—ICD‐10, lists myalgic encephalomyelitis under G.93.3—neurological conditions. It cannot be emphasised too strongly that this recognition emerged from meticulous clinical observation and examination.

    None of the participants in creating the 1988 CFS case definition and name ever expressed any concern that it might TRIVIALISE the illness. We were insensitive to that possibility and WE WERE WRONG.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994528/

  • Colleen Steckel 11 July 2019, 9:09 pm

    With any issue related to myalgic encephalomyelitis (ME) it helps to have a grasp of the history as well as the people involved.

    Historically the US health agencies have misrepresented the reality of ME. (See Osler’s Web book). Changing the criteria in 1994 and using the label CFS buried the information we had about ME stemming from outbreaks in various locations around the world. The CDC continues to ignore the disease ME by using criteria and labels that do not properly reflect what someone with ME experiences. By doing this, the narrative about ME has been turned into something based on fatigue of more than 6 months. Their recommendations include avoiding extensive testing as well as treatments based on changing a patient’s behavior (pacing/diet).

    Because information about this review is clouded in secrecy, the history we know about the CDC and EPC (the company contracted by CDC for the review) is all we have to go on. The CDC have made clear they will not recognize ME as per the International Consensus Criteria (ICC) as a distinct patient group. The EPC previous report showed a lack of understanding about ME as described by experts with a focus on therapy and graded exercise. This could indicate there will be no recommendations based on the ICC studies showing immune, neurological or cardiac issues stemming from ME. Mary Dimmock told me personally and has stated publicly she does not agree with using the ICC. (Twitter July 4, 2019)
    CDC has made clear that the focus will continue to be based on the IOM report’s vague criteria that excludes those issues seen in ME. A comparison of the CDC’s ME/CFS criteria and the ICC clarifies the danger ME patients face from any review that refuses to acknowledge the specific issues seen in the ICC.

    Comparison chart between ICC and SEID (ME/CFS on the CDC website)
    https://d3n8a8pro7vhmx.cloudfront.net/meadvocacy/pages/22/attachments/original/1531592663/ICC_compared_to_IOM.pdf?1531592663

    Any conversation about ME/CFS should include the patients who fit the ICC. Otherwise the status quo of ignoring this estimated 1 million US patients will continue.

    In the end, what we all want is for every patient to get proper recognition, proper diagnosis, and proper care. The ICC and the IC Primer gives medical professionals a solid understanding of the depth and breadth of ME. When medical professionals understand ME they can diagnosis properly and those who don’t fit the criteria can pursue proper diagnosis and treatment. By excluding ICC from the review process those patients who have ME will continue to be neglected and abused.

    It is imperative that the ICC patient group is properly represented at every level and in every venue that ME is being discussed. Without knowing who else is involved, I’m concerned the report will be issued without any recognition of ME.

    Very few of us who understand ME have the kind of access (or health) required to stay on top of this situation or participate. Patients with ME are much too ill to maintain pressure needed to make sure ME is not ignored. We constantly hear that we need to “Act Up” like they did with the AIDS movement. We are much too ill to mount that kind of response. Too many who might have been our allies have been gaslighted into silence. Without a significant change in the status quo, ME patients will continue to suffer and die without proper medical support.

  • Mary E Dimmock 11 July 2019, 11:40 pm

    To clarify – This is an evidence review of *already published* treatment trials. As of the 2014 evidence review, only Fukuda and Oxford had been used in treatment trials. Since then, in addition to those two definitions, at least one treatment trial reported using NICE. But as far as I know, few if any treatment trials used the ME-ICC and none have used the IOM.

    As noted in the article, the 2014 AHRQ review concluded that CBT and GET were moderately effective but that conclusion relied heavily on Oxford studies (and the conclusion that PACE was a good quality study). But that conclusion about effectiveness virtually disappeared once Oxford studies were excluded in the 2016 Addendum. Just as importantly, the 2016 Addendum also concluded that studies using definitions requiring hallmark symptoms like PEM/PENE were “blatantly missing” from the evidence base and warned that conclusions in the published studies “may not be generalizable to all patients” meeting more specific ME definitions.

    Clearly, the question of the case definition used and how it’s generalized to people meeting other case definitions is an important issue as are questions of study conduct and quality. I do not know how these issues will be addressed and recommend reviewing the PROSPERO description of this evidence review when it is published.

  • Mary E Dimmock 12 July 2019, 12:22 am

    Correction to the above – a few treatment studies used the 1988 Holmes CFS definition, most often in conjunction with the 1994 Fukuda.

  • jimells 12 July 2019, 10:51 am

    All initiatives of the CDC must be viewed with extreme cynicism. The goal of burying the illness has not changed in thirty years. And how do we know what is the policy of NIH and CDC? By reading their own words written on official letterhead:

    “I predict that fatigue itself will remain the subject of considerable interest but the notion of a discrete form of fatiguing illness will evaporate. We would, then, be left with Chronic Fatigue that can be distinguished as Idiopathic or Secondary to an identifiable medical or psychiatric disorder.

    I consider this a desirable outcome.”
    ———–

    This letter, written by Stephen E. Straus on NIH letterhead, was addressed to CDC’s Keiji Fukuda. Yes, *that* Fukuda…

    http://www.cfidsreport.com/News/14_Chronic_Fatigue_Syndrome_Definition_IOM_Straus.html

  • Colleen Steckel 13 July 2019, 12:46 pm

    Mary Dimmock, thank you for clarifying and for the information provided. It is important everyone in the community have this kind of information as it becomes available. I will definitely be watching for the PROSPERO description of the evidence review.

    I realize I may not have been as clear in my original comment as I had hoped. Let me rephrase the points I was trying to get across.

    The International Consensus Primer (IC Primer) belongs in any conversation about treatment for ME/CFS, since that is currently the best vehicle ME patients have to be part of the conversation.

    From the article: “This review may consider other peer-reviewed literature that provides context for treatment of symptoms seen in ME/CFS (e.g. orthostatic intolerance, pain, etc)”.

    To me that means the review could include the IC Primer as it is “peer-reviewed literature”. But it will only be part of the process if someone is bringing that information to the table.

    As a patient, I think the treatment information in the IC Primer should be included because those clinicians collectively had more than 500 years of clinical experience and the primer cites sources for this information.

    For example: Pages 13 – 19 of the IC Primer give treatment guidance. One study cited is “Nutritional Strategies for Treating Chronic Fatigue Syndrome” which explains nutritional deficiencies clinicians should watch for in patients. This basic, simple information could be life changing for many patients whose doctors have not been educated to look for even the basic vitamin D3 deficiency so many of us have. This paper cited in the IC Primer gives information and lists many studies that could be used in the review. http://archive.foundationalmedicinereview.com/publications/5/2/93.pdf.

    I urge anyone looking for treatment guidance for ME to look at the information in the IC Primer: https://d3n8a8pro7vhmx.cloudfront.net/meadvocacy/pages/2292/attachments/original/1554817421/Myalgic_Encephalomyelitis_International_Consensus_Primer_2012.pdf?1554817421

    Some further clarification about my comment – As I stated it is helpful to understand the people involved. Hopefully my point of view on this topic will clarify my original comment.

    I’ve had ME (as described in the International Consensus Criteria – ICC) since August of 1989. I’ve fluctuated between severe and moderate. My advocacy is specifically aimed at the patient group who, like me, fits the ICC. (See interview I did in April discussing the importance of adopting the ICC: https://www.youtube.com/watch?v=VqM_OUf0fBk )

    Those who follow me, know that my comments are aimed at clarifying how any research, report etc. applies to the #MEICC patient group. As presented in the original article, what is being done at EPC is unlikely to include information from the IC Primer.

    The point I was attempting to make is that from what we know, it is unlikely the IC Primer will be represented in this venue. I would love to learn that the IC Primer is being used in the review process.

    What those advocating for the ICC would like to see is that ANY discussion involving ME includes the IC Primer information. Unfortunately, that is seldom the situation.

    On a more hopeful note, the #PwME4ICC petition asking HHS to adopt the ICC and educate using the IC Primer was presented on July 8 to U.S. Health and Human Services (with over 6,500 signatures).

    Adoption of the recommendations in this petition would ensure this patient group is finally properly recognized and future studies and meetings about ME will ensure ICC patients are part of the conversation. See announcement of Eileen Holderman and Gabby Klein presenting petition to HHS here: https://twitter.com/TurnItUp4ME/status/1149816292716818432

  • Mary Dimmock 16 July 2019, 10:11 am

    Regarding Colleen Steckel’s comment calling for the ME-ICC Primer to be reviewed in the systematic evidence review being conducted by CDC….
    This is a review of peer-reviewed publications reporting directly on the results of studies examining the effectiveness of treatments – e.g. the publication on an Ampligen trial, an antiviral trial, PACE, etc. The AHRQ evidence review also required that the trials be randomized, in adults, last for 12 weeks, and be published in peer-reviewed journals. When published, the PROSPERO information will provide further details on other requirements for this trial.

    But the ME-ICC primer is not a publication reporting directly on the results of randomized trial into a specific treatment(s). And while it may include references to specific published, peer-reviewed treatment trials that could be helpful, I don’t believe the ME-ICC primer itself was peer-reviewed.

    Further, as I noted above and as far as I know, no randomized treatment trials have been conducted that used the ME-ICC for the selection criteria. Perhaps some of the newer trials are but it appeared to me at recent conferences that the Canadian Consensus Criteria was more commonly mentioned. Because this is a systematic review of existing published, peer-reviewed treatment trials, it can only evaluate what is actually in the published literature. While I can’t say for sure, I expect that even the part looking at treatments for ME symptoms will still be focused on published, peer-reviewed treatment studies.

    Regarding questions raised about my position on adopting ME-ICC … In my opinion, the situation people with ME face is much broader and more complicated – as can be seen with this issue – than is going to be solved by simply calling for the ME-ICC and ME-ICC Primer to be adopted.

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