Keeping PACE: Patients Denied Access to Full Data from PACE Trial

This article appeared on June 12, 2013 on the UK Human Rights Blog. Mr. Courtney's unsuccessful attempt to gain access to the complete results of the PACE trial raises two important points: 1) While the write-up in the Lancet claimed that there was an improvement in patients with ME/CFS after treatment with GET and CBT, it intentionally failed to mention the number of patients who got significantly worse on each treatment during the trial, and 2) When full results from a medical trial are withheld from the public, how does that affect the right of patients to know if a therapy might potentially harm them?

Freedom of information and unpublished data from a randomised controlled trial on ME/CFS 

By David Hart, QC

"Between 2005 and 2010 Queen Mary ran a trial into the efficacy and safety of the current treatments for Chronic Fatigue Syndrome/Myalgic Encephalopathy, namely Adaptive Pacing Therapy , Cognitive Behaviour Therapy and Graded Exercise Therapy. £5m of public money was spent, and the perceived benefits (and some of the detriments) were written up into a major article published in the Lancet in March 2011. The upshot, said this article, was that CBT and GET could be safely added to current medical care with a moderate improvement in outcomes. This recommendation has already fed into an interim review of the NICE guidelines on CFS/ME.

However, the data on deterioration within the trial had not been fully published. You could not see how many patients deteriorated in response to each therapy, just the net deterioration over the whole cohort. Our appellant, Mr Courtney, is evidently a bit sceptical about the results of this trial. As he pointed out, the deterioration data had a 20 point difference, whereas the improvement had only to be modest – an 8 point difference. And, he said, how can patients sensibly form a view on treatment without knowing how much deterioration that specific treatment might cause?

So Mr Courtney asked for a full set of the deterioration data for each therapy. Queen Mary sought to withhold it on the basis of section 22 of the Freedom of Information Act 2000 – information intended for future publication. And, after a hiccup before the Information Commissioner, they succeeded before the FTT."

Like most of the exemptions in Part II of FOIA,  withholding the requested information must be shown to be in the public interest. So, given that (a) the data existed and (b) the main trial results had already been published, what on earth was the public interest in withholding it, however temporarily?

QM said that, because they had undertaken the work which generated the raw data, they should have the opportunity to present in the context of a full scientific commentary tested by peer review. Conversely, premature publication of provisional research results “particularly if made in a lower ranking journal” might undermine the credibility of the final conclusions. (Here we are very much in the territory of the UEA climate change scientists not wanting the sceptics to get the raw data before UEA has said its piece). Without peer review, QM would be “casting clinicians and patients adrift” – “the data could be manipulated”‘; there is a need for “sufficiently robust scientific contextualisation.”

There is something in all of this, but it is also a little bit over the top. It is quite understandable that the researchers might want a short priority period for publication of their research.  But their wishes should not be driven by the desire of private top-ranking journals to have an exclusive on the data – as Mr Courtney rightly argued, that is a matter of private interest, not public interest.

The FTT found for the University. The additional time sought by it was necessary to finalise the analysis, commentary and peer review process. Hence, the withholding of this data fell within section 22 and was in the public interest.

This sort of issue does not seem to have come before the FTT or the courts before. There is an Information Commissioner’s decision on section 22 (see here) where, one infers, a rival academic wished to get hold of a PhD student’s thesis deposited with Liverpool University – the application was refused. The PhD student wished to publish the thesis in book form, and wanted a period in which to see if she could do so. The public interest was rather limited; the student had privately paid to do the PhD, so unlike the QM case, public money was not involved. The IC decision is also very coy about the nature of the thesis, so one cannot tell whether it is of wider public or narrowly academic interest. On the other hand, one cannot be too sorry that the applicant lost, given the more general interest in wider academic publication of scholarly work – better that it be in a published book rather than in a university archive.

One final observation. QM nearly got itself into trouble in this case because of its curious publication strategy. It is odd to publish research about the merits of a given set of treatments, without having finalised one’s analytical work on the therapy-specific demerits. From a medical ethics perspective, I wonder to what extent the clinicians and patients appreciated that to some extent the 2011 Lancet publication was work-in-progress – because that is the implication of QM’s arguments on this appeal."

FDA's CFS/ME Drug Development Workshop: Day Two, Afternoon Panels

The focus of the first afternoon session was on designing clinical trials for drugs to treat CFS/ME, drawing on the experience of CFS/ME researchers and physicians.

You can read a summary of Day One, April 25th, HERE.

You can read a summary of Day Two: Morning Panels HERE.

You can read a transcript of the April 26 sessions HERE.

Panel 3: CFS and ME Clinical Trial Endpoints and Design (158:05) (VIDEO)

Moderators: Jordan Dimitrakoff, M.D., Ph.D., Assistant Professor, Tufts University, Boston, MA and Edward M. Cox, M.D., M.P.H., Director, Office of Antimicrobial Products, OND, CDER, FDA 

Speakers: Dr. Peter Rowe, M.D., Professor of Pediatrics, Johns Hopkins University School of Medicine, Director, Chronic Fatigue Clinic, Johns Hopkins Children’s Center

Christopher R. Snell, Ph.D., Professor, Health, Exercise and Sport Sciences, University of the Pacific

Elizabeth R. Unger, Ph.D., M.D., Chief, Chronic Viral Diseases Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention 

Ashley F. Slagle, MS, PhD, Oak Ridge Institute for Science and Education (ORISE) Fellow, Study Endpoints and Labeling Development Staff, ONDIO, CDER, FDA (contractor)

First Speaker: Dr. Peter Rowe, “Clinical Trial Design in CFS.” [timestamp 7:10 – 48:09]

Peter Rowe

Dr. Rowe drew upon his experience over the past 20 years as a CFS researcher and clinician. He addressed several important issues pertaining to clinical methodology: what has and has not worked in clinical trial design, ideal patient populations, ideal endpoint, and potential study designs that might decrease the confounding effects of the heterogeneity of the illness, and which might help identify an effective therapy against the background noise of other comorbid conditions.

Main themes of Dr. Rowe's talk: 

• Heterogeneity: Because CFS is so heterogeneous with variable onsets, and types of symptoms, as well as different combinations of comorbid conditions, heterogeneity needs to be taken into account when designing a trial for effective therapies. Design problems are the following: Careful selection of groups and subgroups, including those who recently have contracted CFS versus those with established symptoms, how to include patients with different levels of severity. And as with any illness with a lot of heterogeneity, small studies are almost certainly doomed to failure from the outset. We will need large studies to identify clinically significant but modest differences between patients.
• Outcome measures that are currently in use are fairly serviceable. Imperfections in measurement tools are not the biggest impediment, but outcome measures need to remain simple.
• Trial design: If trials are designed properly, they can yield clinically useful data.

Success and failure of previous clinical trials: Some historical lessons

The first of the modern trials was Strauss’ acyclovir study in 1988 (“Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial.”). It had been hypothesized that CFS was due to a persistent Epstein-Barr viral (EBV) infection. In this study each patient received either acyclovir or placebo. Outcomes included measures of daily energy, how people felt, temperature, and mood. Of the 24 who completed the study, 21 rated themselves as improved, but improvement was evenly distributed among the placebo and acyclovir. (As an aside, Dr. Rowe noted that this was one of the few CFS studies in which there was a high placebo response. Usually CFS patients exhibit a low placebo response.) 

In spite of its failure to prove that acyclovir was an effective treatment, Dr. Rowe noted certain design features in the acyclovir study that should be used in current trials, namely crossover design (patients acted as their own controls by taking both the drug and the placebo), culling the study population to increase the likelihood of enrolling those who would most benefit from the intervention, insisting on a clinical evaluation to confirm diagnosis, and simple outcome measures. Although this trial was not a success, it revealed that while a small study could not determine what was effective, it could reveal the negative effects of medications. (Some measurements were actually worse during the acyclovir phase of the trial. i.e. mood and wellness). This is valuable information for future studies.

By 2006 there were 56 randomized trials and 14 non-randomized clinical trials for CFS. These included behavioral interventions (e.g. GET and CBT), immunological treatments (e.g. acyclovir, IVIG, imunovir), corticosteroids (e.g. Florinef, hydrocortisone), various pharmaceuticals (e.g. galantamine, NADH) and complementary therapies (e.g. massage, carnitine, liver extract). The outcome of nearly all these studies has been that pharmaceutical interventions are not helpful.

Why haven’t these trials shown that drugs can be effective therapies for CFS? Dr. Rowe pointed out that the main problem with these studies is methodology. Unless the patients share the same type of onset (sudden or gradual) and similar comorbidities (such migraines, IBS, allergies, orthostatic intolerance, to name a few), the studies run the risk of comparing apples to oranges. 

How can heterogeneity be reduced?

• Careful subject selection. Clear case definition and clear eligibility criteria need to be established for subsets under study. If subsets are not identified, a predominant comorbidity, for example, can skew the results.
• Identifying comorbid conditions. Flares in comorbid illness have the potential of obscuring treatment effects, especially in small samples. These fluctuations can overwhelm the effect of the treatment under study.
• Large sample sizes. Given the heterogeneity of CFS and OI, large sample sizes are required, unless there is a powerful medication that applies across all subgroups.

Dr. Rowe stressed the advantage of large sample size by pointing out that while many CFS/ME studies were done using between 12 and 35 patients, the fibromyalgia study of pregabalin enrolled 529 patients. The outcome was simple: pain. Using a daily pain scale, they were able to show that 21% had more than 30% improvement in pain. This study shows that a large sample allows researchers to find results that are clinically significant for a small population.

Dr. Rowe also discussed the PACE trial in terms of its methodological success (with the quip that anyone who ventures into a discussion of the PACE trial probably needs an armed guard). Because the size of the trial was so large – 641 participants – the study showed a small but statistically significant difference (3 points). To put this in perspective, Dr. Rowe said that as physicians, a three-point difference in the Chalder Fatigue Scale (33 points) over a year would be enough to make them hang up their licenses and quit. But, he added, whatever our views are on CBT, it is important to focus on the methods lesson: the study was positive based on the sample size.

Dr. Rowe went on to discuss the Florinef trial conducted in 2001 (“Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial.”). The study was based on Dr. Rowe’s clinical observations of several patients who had made startling improvements while on Florinef.

The study concluded that there were no significant differences between placebo and Florinef. However, when Dr. Rowe re-examined the results, he found that younger patients and those with a shorter duration of illness had responded to the drug, while patients who had been sick longer than three years had not. The failure of the Florinef study was due to lack of selectivity in patient selection. Additionally, Dr. Rowe pointed out that the success of the PACE trial may have been in part due to selecting for a patient group which had not had a long duration of the illness (2.7 years average). He compared this to the rituximab study which used patients who had been ill for a much longer period of time (5.8 years average).

What is the ideal endpoint?

In his discussion of the rituximab study, Dr. Rowe pointed out that results need to be measured within the context of specific outcomes: cognitive improvement, activity, and functional measures. Simply asking patients how they feel compared two weeks ago is not an accurate measure of improvement, because patients will increase their level of activity as they get better, generating the same level of fatigue. “We’ve got to watch that we don’t use fatigue as the only outcome measure.”

What are the best trial designs for CFS/ME?

Dr. Rowe’s recommendations for improving CFS/ME trial designs were as follows:

• Larger study groups
• Stratification for subsets
• Run-in periods prior to the beginning of the study in which co-morbid conditions are treated and stabilized
• Randomized trials in which ostensibly effective treatments are withdrawn (Ampligen)
• Crossover designs, in which the patients take both the drug and placebo with a wash-out period (off the drug) to limit prolonged effects
• Trials using a single patient

Christopher Snell

Second speaker: Christopher Snell, “Repeated CPET Results as Clinical Endpoints for ME/CFS Research.” [timestamp 48:36 – 85:42]

Dr. Snell reported on the value of cardiopulmonary exercise testing (CPET) to establish endpoints in CFS/ME studies. The beauty of exercise testing is that it measures function. Before CPET, nobody had an objective measure of fatigue. Simply asking people how tired they are is not real science. Dr. Snell believes the exercise test is a biomarker for CFS/ME because it provides both diagnostic and prognostic data.

The definition of fatigue is reduced efficiency as a result of doing work.

People are energy-producing machines with a built-in ability to stretch that energy when needed through the fight or flight response. Disease states reduce this capacity. But, even in disease states, in the absence of stress, reduction in functional capacity isn’t always seen. Exercise is an effective way to induce stress. Once stress is created, the true functional capacity of an individual can be objectively measured.

The goal of exercise testing is to assess the function of the cardio-respiratory system.

The way we produce energy is through the cardio-respiratory system, so we need to look at how efficiently that system operates. The cardio-respiratory system determines your functional capacity – or how much work you can do. This system functions on aerobic capacity – that is, how efficiently is the body able to use oxygen?

There are two main energy liberation systems: aerobic and anaerobic.

• Aerobic metabolism – dependent on oxygen, is very efficient, can be used for extended periods of time, predominates at lower workloads, produces CO2
• Anaerobic metabolism – no oxygen needed, predominates at higher workloads, 2ATP per glucose (as opposed to 36), produces lactic acid. Lactic acid is associated with pain, reduced muscle function, altered enzyme activity, cessation or reduction of activity.

Quantifying aerobic capacity 

• VO2 Max is peak oxygen consumption. This is the maximum amount of oxygen a person’s system can deliver in order to produce energy.
• Anaerobic threshold: the point at which a person switches from aerobic to anaerobic metabolism.

Both VO2Max and anaerobic threshold can be measured directly using gas exchange techniques and measuring blood lactate levels. Indirect measurements include heart rate and fatigue onset. Indirect measurements are not reliable. They don’t apply in disease states. Indirect measurements, such as field tests (e.g. the 6-minute walk) are also highly subject to bias. They can be influenced by motivation, the attitudes of the testers, and other factors.

As a case in point, Dr. Snell offered an interesting analysis of PACE trial. In the PACE study the 6-minute walk field test went from 341 at the beginning of the study to 414 yards a year later. Dr. Snell calculated the mph (miles per hour) as 1.9 at the beginning to 2.3 mph at the end. According to tables used to measure cardiac capacity, walking 6 minutes at 2 mph translates as severely disabled. Dr. Snell does not consider “severely disabled” to be an adequate endpoint for a trial, especially after 52 weeks of graded exercise. Because the improvement was so small, he attributes it to an increase in motivation.

How VO2max is calculated

Aerobic metabolism burns oxygen (O2) and releases carbon dioxide (CO2). Once CO2 exceeds O2, the person is approaching his or her maximum capacity. Aerobic metabolism is strongly dependent on the heath of the circulatory system. Anaerobic threshold is measured using gas exchange. If the ratio exceeds more than 1.1, the person’s CO2 is exceeding O2, which means that person is getting close to his or her limit. 

Because breathing is involuntary, this result cannot be faked. Gas exchange is therefore a much more accurate measurement than field tests.

Workwell test results for CFS/ME patients

Dr. Snell’s group was not able to distinguish CFS patients from controls until they looked at the results of the exercise. People with CFS were sick after the test. Strikingly, their ability to utilize oxygen decreased on the second day of testing. Controls were able to utilize oxygen better on the second day. Later, this study was replicated using 56 patients. While the results were not as dramatic, the second larger study showed that there was a big drop-off in efficiency. CFS patients produced less work for more effort and had a greater buildup in lactate.

Summing up

Post exercise morbidity distinguishes deconditioning from CFS.  CPET is a valid and accepted form of testing - there are just over 400 clinical trials around the world that currently include CPET (clinicaltrials.gov) - and should be used as an endpoint to evaluate the efficacy of any drug treatment in clinical trials.

Elizabeth Unger

Third speaker: Dr. Elizabeth Unger, “Measures of CFS in a Multi-site Clinical Study.” [timestamp 86:04 – 107:43]

[For additional coverage of Dr. Unger's talk, see the HealthRising article by Simon McGrath.]

Dr. Unger talked about a new CDC study that is currently gathering data to help define subgroups in CFS/ME. The study utilizes patient data from seven participating clinics: Drs. Natelson, Lapp, Bateman, Peterson, Klimas, Kogelnik, and Podell. Specifically, the CDC study addresses the main characteristics of heterogeneity: duration of illness, severity, comorbid conditions, medications and demographics. This study differs from previous CDC studies in two respects 1) it was designed to capitalize on the experience of the clinicians who treat CFS/ME, and 2) it collects standardized data to evaluate the heterogeneity of CFS patients across practices in order to revise the case definition and define subgroups.

The data gathered from the CDC study were generated via a physical exam, patient questionnaires – pain, sleep, depression and anxiety scales, CDC symptom inventory, and the DePaul symptom inventory (DSQ) – data extraction from medical records, patient illness history, tests, family history, and infection/immunization history.

First analysis of data from 393 patients in seven clinics (with variation between clinics):

Overall demographics:

• Mean age 48.6 yrs
• 71% female
• 95.4% white 
• Mean BMI 27.2 (overweight) [Calculate your body mass index HERE]
• 58.1% married (16.1% previously married, 25.7% never married)
• 78.3% college educated
• 97.8% insured
• 75.4 % not working (15.4% with unemployment benefits)(this was the only statistic that did not vary between clinics)
• Illness onset
• Mean age at diagnosis 38.2 years
• Sudden onset 66.7% (with variation between clinics)
• Mean duration of illness 15 years

Dr. Unger stressed that the patient population in this study is not necessarily representative of the CFS/ME population as a whole. For example, the vast majority of patients were white and insured, which does not correlate with demographic findings of Jason et al., in which CFS/ME was shown to have a high prevalence in non-white populations. Dr. Unger pointed out that this is an indication of lack of access to care that needs to be addressed.

Symptoms results

Fatigue scores varied not only between clinics, but between various instruments used to measure types of fatigue. Of note was the fact that using the general fatigue scale, 37% of the participants scored at the maximum range.

The SF-36 questionnaire was used to measure function. [Note: The SF-36 is a health survey with only 36 questions. It measures functional health and well-being as well as physical and mental health. It is a generic measure, used to compare the relative burden of diseases, and to compare the benefits produced by a wide range of different treatments.]

• Interestingly, the highest scores on the SF-36 were mental health and emotional role (activity limitations due to emotional problems). [Note: This calls into question the frequent assertion that depression is a common comorbid condition of CFS/ME. It also reveals one of the flaws of using a case definition for CFS/ME that does not exclude clinical depression.]
• The lowest scores were vitality and physical role (activity limitations due to physical health)
• In this group of patients, daily vertical activities (upright or sitting with feet on the floor) averaged 7.2 hrs and the exercise average was 3.4 times a week, which means this was not a severely ill population.
• Measures of pain: 80% had pain last week

Symptom scores were very illuminating [timestamp 101.50]

• The symptoms that were most often reported as most severe were fatigue after exertion, and unrefreshing sleep 
• The least: joint pain, sore throat, tender lymph nodes, fever, depression.  
• Cognitive problems varied between those who had severe problems or none.

[Note: The distribution of symptoms is reflective of a patient population that is 1) older, and 2) has already passed the initial stage of the illness, in which flu-like symptoms predominate.]

Finally, Dr. Unger showed a chart that compared findings of the PROMIS scores for symptoms of CFS/ME against five other conditions: chronic pelvic pain, spinal cord injury, muscular dystrophy, post-polio syndrome, and MS. While sleep and pain that influences what you can do is about the same in chronic pelvic pain, in all the other measures: fatigue, sleep disturbance, pain, CFS/ME scored higher than the other conditions.

Conclusions: There is heterogeneity in the CFS population as a whole and measures based on symptoms alone are limited in their ability to determine subgroups. The CDC data will, however, allow the CDC to evaluate how well these instruments work.

Fourth speaker: Dr. Ashley Slagle, “Clinical Outcome Assessments to Evaluate Treatment Benefit in Clinical Trials for CFS and ME.” [timestamp 108:24 – 138:39]

Dr. Ashley’s main point was that in order to find effective therapies we must be able to assess those therapies in a reliable fashion. The FDA requires that drug developers provide documentation of “substantial evidence from adequate and well-controlled clinical trials” and that the methods of assessment of the subjects’ response be “well defined and reliable.” Well defined and reliable are the key criteria by which the FDA judges outcome assessments.

How the FDA measures treatment benefit

Benefits are determined by how patients feel, function or survive. Clinical studies use biomarkers to determine the effectiveness of a medication, however, biomarkers do not tell us how a patient feels, functions or survives.

Biomarkers may, however, provide indirect evidence of treatment benefit, by showing a biologic treatment response to a drug. Because there are currently no agreed-upon biomarkers to use as outcome assessments for CFS/ME, it is critically important to find assessments that can tell us how patients are feeling or functioning.

To determine how patients feel and function, clinical outcome assessments (COA) may be provided by patients, clinicians or caregivers. Unlike biomarkers, COAs are influenced by patient choices, because they depend on reporting. They require rigorous development and evaluation. Assessments reported by patients can also be used for epidemiology, prognosis, and other contexts. COAs do not need to be used in conjunction with a biomarker – FDA says that any assessment can be defined as well reliable.

Another important consideration when measuring treatment benefit is the context of use. Context of use includes disease definition (which must be explicit and specific) as well as characteristics (severity of disease). What is important is that the assessment match the population in which it is being used, taking into consideration age, severity, comorbidities, etc.

Challenges to developing outcome assessments: Subpopulations

One of the biggest challenges in CFS/ME is that the disease definition is not entirely clear. Therefore, it is important to identify a rational set of clinical trial entry criteria which permit the exclusion of other comorbidities as much as possible.

Another challenge is that subpopulations need to be defined. Some of these are:

• Acute and gradual onset
• Patients with OI and those without
• Adults and children
• Those with abnormal neurological findings and those without
• Recent onset and those with long-time suffering
• Severe forms and less severe forms
• Patients with varying symptom experience
• Others?
• Defining subpopulations for clinical trials

There are already a number of existing instruments that can be used to measure the symptoms and domains of subpopulations of CFS and ME. But they have not been specifically developed for CFS and ME, so they may need to be modified to use for CFS and ME. (slide)

Some concerns are that some instruments have been developed for diagnosis, or epidemiology, so they are not useful for clinical trials. Generic measures are not specific enough, and include items that are not relevant to the CFS/ME population. There are conceptual framework concerns, for example how is “fatigue” defined? Sometimes the measures do not include activity level, which is very important in CFS and ME.

In spite of all the hurdles of complying with FDA regulations for determining the efficacy of a treatment, Dr. Slagle closed on an optimistic note. While none of the assessment instruments have been appropriate for CFS and ME overall, there are other options: assessment instruments can be used for specific subgroups, modified, and new instruments can be developed. To ease this process and ensure their conformity to FDA regulations, modifications can be made by independent groups (including those other than drug companies) and submitted to the FDA for use in future trials through the Drug Development Tool (DDT) qualification program.

Question and Answer Period: [timestamp 138:52]

Question: It’s clear that we need large clinical trials, because of the heterogeneity in the patient population, but those trials are usually paid for by pharma, which is not interested in funding large trials for CFS and ME. Patients do not have the resources to bridge this gap. Comments?

Answer: Dr. Rowe: This is a big problem. If studies don’t come from pharma, I don’t know who would fund them. Dr. Snell: This is a major economic problem. Yes, we need something to drive it. Dr. Slagle: If you develop good outcome assessments for pharma to use and lower the risk, and if they have well-established measures they can use, in consultation with the FDA, they are more likely to engage in clinical studies. Ms. Unger: Once we get a critical mass of data, and infrastructure, pharma will come. CDC is making a start on the data. Dr. Kogelnik: One of the promising funding avenues is a shared grant mechanism through a partnership with the NIH.

Question: Only 18% of patients with ME/CFS have those diagnoses exclusively, with no comorbidities. The high rate of comorbidity may be an additional challenge for clinical trials. Comments?

Answer: Dr. Rowe: Fibromyalgia has a high rate of comorbidities, yet it has a number of approved drugs. A large enough sample size will randomize comorbidities. Another option is that while any two people have a lot of differences, each person can act as his or her own control.

Question: Dr. Unger, infection/immunization is in your database. Have you made any connection between immunization and onset or relapse, and are the data maintained in such a way that such an analysis could be done?

Answer: Dr. Unger: We don’t have onset correlated with infection or immunization. We will have that information when the data are analyzed. We think this will be an important data point.

Question: Does the FDA assist with the development of trials and with developing outcome measures?

Answer: Dr. Slagle: There are two processes for outcome assessments. During the course of normal meetings with drug developers, the FDA will respond. The other option is the independent qualification process (DDT program) in which the FDA will provide specific consultation. The FDA welcomes the opportunity to talk with those who are designing trials and endpoints; the earlier the better.

Question: What does substantial improvement in VO2 max – and in steps walked – consist of (as per the Ampligen trial)?

Answer: Dr. Snell: We don’t have a lot of data related to treatments, because we don’t know what is causing the deficit. If the immune system is causing the problem, then treating the immune deficit will show improvement. There are no criteria for steps. Counting steps is not necessarily helpful unless you decide to relate it to something else.

Question: Is there insurance coverage for exercise testing?

Answer: Usually, insurance reimburses.

Question from Dr. Grobstein to Dr. Unger: The FDA says the patient population must be well defined for clinical trials, yet the CDC study does not ask participant clinics to use any particular definition. How do you reconcile these two views of how to do trials?

Answer: Dr. Unger: Ours is not a treatment trial. We are collecting data on what ME/CFS looks like in the clinic. That objective data can be used to develop a case definition. There are times when you want a broad case definition, and times when you want a narrow one.

Question from Dr. Grobstein to Dr. Slagle : You briefly pointed out problems with outcome measures – the instruments are not ideal. Does this mean we can’t do trials until we modify existing instruments or develop new ones.

Answer: Dr. Slagle: Not having great instruments shouldn’t hold up progress on trials. The problem is that although there may be a treatment benefit that’s there, it may not be picked up by the instruments being used. On the other hand, if there is a huge treatment effect, then existing instruments will show it. Until existing instruments can be modified, mapping the instrument to the population, even if it isn’t ideal, is what is important.

Question: What knowledge may be obtained by brain mapping, and what impact will that have on general research?

Answer: Dr. Unger: A lot of data will be coming from brain studies, eventually.

Question: What is the prevalence of CFS in different racial and ethnic groups? 

Answer: Dr. Unger: CFS is very common in racial and ethnic minorities.

Panel 4: Roundtable Discussion -- Summary and Path Forward (95:57) (VIDEO)

Moderators: Dennis Mangan, Ph.D. and Badrul Chowdhury, M.D., Director, Division of Pulmonary,

Badrul Chowdhury

Allergy, andRheumatologyProducts, ODE II, OND, CDER, FDA

Panelists:

• Lily Chu, M.D., M.S.P.H. 
• Jordan Dimitrakoff, MD, PhD 
• Nancy Klimas, M.D. FACP, FIDSA 
• Nancy Lee, M.D., Deputy Assistant Secretary for Health;Director, Office of Women’s Health, Department of Health and Human Services (HHS) 
• Susan Maier, Ph.D., Deputy Director, Office of Research of Women’s Health, National Institutes of Health (NIH) 
• Theresa Michele, M.D. 
• Robert Miller, Patient 
• Jody L. Roth, MS, RAC, Director Regulatory Affairs, Biomedicines Eli Lilly and Company

Question 1: What were the key messages on drug development you heard in this meeting?

Dr. Lily Chu: Data is necessary to do research. But not enough money is being spent on CFS research. Severely ill patients need to be studied.
Dr. Dimitrakoff : The key message is that it is actually possible to have a drug for CFS. The second message is that there is a great deal of support from the FDA supporting the development for medications for CFS/ME. This meeting validates how important it is to get young people involved in CFS research in the early stages of their careers.
Dr. Klimas: We are much further along than we think. Investigators are already linked together, and we have many years of experience using the instruments we’ve been talking about.
Dr. Nancy Lee: Partnerships with academia, patients, clinicians, pharma, and foundations are necessary to bring these efforts to fruition.
Dr. Susan Maier: Measurement is the key to making sure we have accurate representation of what happens in clinical trials and research.
Robert Miller: There is a crisis in the ME/CFS community and that crisis is lack of treatment. Measurements already exist that can be used to evaluate CFS symptoms. The government needs to take action now to clarify a very clear special pathway to approval for drugs for ME/CFS. This will make it clear to pharma that FDA will support drug development. Fund it and they will come. Treatments must not be withheld because of the heterogeneous population. FDA should move within the next two months to create a set of criteria and outcome measurements. CDC and NIH should study the responders to Ampligen to find out for whom it works and why. This is a crisis, this is an emergency, this is a time for everyone to work together and try to move forward.
Dr. Theresa Michele: Patients were articulate and clear.
Jody L. Roth: It is essential for pharmaceutical companies to understand endpoints. We have the correct framework to continue forward.

Question 2: What do you think are the most important factors in facilitating drug development in CFS and ME? [timestamp 29:21]

Jody L. Roth: What are the criteria we need to have in place for clinical trials? What is the framework, how are we going to implement the trials to get the endpoints in place? How can we leverage other fatigue instruments we have used in order to find out if our drug will work in this syndrome?
Dr. Theresa Michele: We have a need for data. We already have a lot of data, but we need more longitudinal data. There are a number of different databases already out there. We need to establish networks to bring those databases together.
Robert Miller: Willingness from all the federal health agencies to work together and figure out the pathway to do clinical trials. A plan needs to be in place in order to move forward.
Dr. Susan Maier: Be willing to accept researchers working on other diseases to broaden how we do research.
Dr. Nancy Lee: Developing data infrastructure is very important. Drug repurposing has promise in the shorter term in order to find useful therapies that have already been approved
Dr. Klimas: The most important facilitating factors have to do with organizational infrastructure. We have the platforms, and things are cheaper than they used to be. It is very reasonable to think about putting together a series of clinical trials. Subgroups of patients can be a strength, because it helps us target specific drugs and therapies. There is no reason, at this point, in delaying any further. We have good reliable, validated, well-published variables already. We’re ready to go.
Dr. Dimitrakoff: The key word is collaboration. It is important to work together with people in similar and related fields.
Dr. Lily Chu: A big piece of research is educating researchers and physicians about CFS/ME. 85% of physicians think that the illness is psychiatric. There are biomarkers for CFS/ME. [applause] What’s more CFS is not the only disease with a lot of heterogeneity or comorbidities. It is not a unique disease.   

Question 3: Based on the discussion from Panel 3, what clinical trial design elements are most important to ensure success of drug development programs for CFS and ME? [timestamp 43:42]

Dr. Nancy Klimas: Important design elements are: sample size, symptoms that have to ability to improve and which you can measure, and the length of the trial itself. Little 10-week and 4-week trials may not be enough. You need at least four months to get even a hint of efficacy. Our group is using an exercise challenge to induce relapse, intervening with the targeted drug, and then challenging the system again. This not only demonstrates the efficacy of the drug, but it teaches us more about the dynamic of the illness.
Dr. Michele: It is critical that we not forget measures of safety. Efficacy is only half the equation. So we need to understand clearly what the risks are, even for drugs that are being repurposed.
Dr. Lily Chu: There are two papers which might be interesting to pharmaceutical companies. One is by Haywood, “Quality and acceptability of patient-reported outcome measures used in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review.” [Read the abstract HERE.] The other paper is by Cockshell, “Test effort in persons with Chronic Fatigue Syndrome when assessed using the Validity Indicator Profile.” [Read the abstract HERE.] 

Question 4: What do you think are the most important barriers to conducting research for CFS and ME, and what can be done to overcome them? [timestamp 47:36]

Dr. Michele: From the FDA ‘s perspective, we don’t perceive any barriers. We have outcome measures, we have definitions, we have symptoms that can be used. Regulatory-wise we are ready to go.
Dr. Chowdhury: The time has already arrived to enroll patients in trials.
Dr. Dimitrakoff: There are two barriers that have been consistently pointed out: lack of new investigators coming into the field, and limited availability of funds. All the clinical centers should come together and do a large clinical trial. The NIH has something called the U34 grant, which allows teams of investigators to come together to design a clinical trial over a period of one or two years. Following that period, there is an additional funding period of five years when you actually do the trial.
Dr. Maier: Money is the primary obstacle. What drives funding from the NIH is well-conceived ideas, good science and well-written proposals. We can’t fund research, even requests for applications, without a proposal. [Submit them and they will come.]

Question 5: How can we best leverage your individual experiences in order to facilitate drug development in CFS and ME? Please respond for your group (Health and Human Services, FDA, pharma, academia, patient/advocacy).

Dr. Michele: FDA can express its willingness to work with companies and investigators on drugs for CFS. If FDA considers CFS to be a serious disease, this sends a message to pharma that this may be a good opportunity to make some money. Money makes the world go round. When people come in with clinical trials, we can help them with trial design, and with lessons learned from other diseases. Our division has its doors wide open for applications for CFS.
Dr. Maier: Call me. [This was a direct personal invitation to researchers to seek advice and recommendations on proposals from Dr. Maier.]
Jody L. Roth: Pharma needs to get together with these consortia to establish endpoints and measurements that we can use.
Dr. Lee: We need data infrastructure, and the CDC is doing that.
Bob Miller asks Dr. Klimas to talk about her applications.
Dr. Klimas: We write eight applications for every grant that we get. From the point of view of academia, we need philanthropic support. You want us to be quicker, so that you can have your drugs, but I am struggling to get Phase I work done. It’s not that we don’t have good ideas, or good science. What we don’t have is your time to waste. Dr. Klimas stated that she has nine grants on the board right now.
Dr. Chu: IACFS can help disseminate information. Patient groups are enthusiastic to work with anyone. NAAME is a patient organization that will help facilitate this. http://naame.org/
Question 6: What are possible next steps following this meeting? (Please respond as per your group.)
Dr. Klimas: We need to have a small meeting with the experts in the FDA to talk about outcome variables, and really nail them. Dr. Klimas volunteered to come back to Washington DC to do that. (Dr. Dimitrakoff did as well.)
Jody Roth: we need regulatory effort for trials to move this forward.
Dr. Michele: Guidance for industry is the next step. This will not happen quickly, but we are very well aware that it needs to happen.
Dr. Dimitrakoff suggested that a peer-reviewed paper should come out about the FDA meetings, so that the larger medical community has some idea that the field is moving forward. [applause]
Dr. Chu: Publishing in a peer-reviewed journal is also a way to engage new researchers.

Bob Miller

Question and Answer Session [timestamp 74:10]

Questions: Are there clinical FDA trials approved for CFS? Why was Ampligen not approved? Does FDA have a working group to write industry guidelines?

Answers: First question: There are approved clinical trials, but not too many. Second question: FDA sends a response letter to the drug company and that is confidential. [Third question not answered.]

Question: Bob Miller: What are the approved clinical trials?

Answer: Dr. Michele: Just google CFSAC.

Question: How can repurposing of drugs be financially worthwhile for a pharmaceutical company?

Answer: Jody Roth: We are look for line extensions, or new uses, to add to existing drugs.

Question: Is anybody lobbying Congress to set aside money for CFS research?

Answer: Lily Chu and Bob Miller said they were both lobbying, but they did not have sufficient energy to do so.

Question: How are serious adverse events taken into account, especially in light of the fact that any hospitalization is considered a serious adverse event, whether it is drug-related or not.

Answer: Dr. Michele: This is why we need large groups for clinical trials. Serious adverse events can then be measured in both treated and non-treated groups.

Question: We have biomarkers, so why does the FDA continue to insist that we have none? What needs to be done to validate NK cell function, immune markers, and viral titers as biomarkers?

Answer: Dr. Chowdhury: Biomarkers are not needed for clinical trials. There is no up-front need to develop a biomarker. Dr. Klimas: The primary outcome needs to be function. What we need is something to predict function, and, yes, I do think we have the data to support that we have biomarkers that predict function. Both Dr. Chu and Jody Roth pointed out that biomarkers are indeed necessary for establishing subgroups and outcomes.

FDA's Drug Development Workshop for CFS and ME: Day Two: Morning Sessions

Day Two (April 26, 2013) of the FDA’s Drug development workshop for ME/CFS focused on clinical trial design, outcome measures, regulatory issues and possible pathways to expedite drug development for CFS and ME. The purpose was not to discuss individual products, but to discuss how to get effective drugs through the pipeline quickly.

Note: For additional coverage of the second day read Cort Johnson’s article on HealthRising. 

You can read a summary of the presentations made on April 25, the first day of the workshop, HERE.

You can read a transcript of the April 26th sessions HERE.

You can read a summary of the afternoon April 26th sessions HERE.

Welcome by Dr. Michele: Objectives of Day 2: To examine common issues in drug development, and consider scientific and regulatory tools that might be brought to bear to move drug development forward in this area.(15:29) (VIDEO)

Panel 1: Drug Development, Innovation, Expedited Pathways, Regulatory Considerations (96:21) (VIDEO)

Panelists: Dr. Bernard Munos, founder of InnoThink Center for Research and Biomedical Innovation, Dr. Suzanne Vernon, scientific director of the CFIDS Association of America, Melissa Robb, associate director for Regulatory Affairs at the Office of Medical Policy.

I. Presentations

Bernard Munos

First speaker: Dr. Bernard Munos [timestamp 4:59 - 31:26]

Dr. Bernard Munos spoke on “Drug Innovation and Derisking Drug Discovery.” [Note: “Derisking” in this context does not mean lowering the risk to patients taking drugs, but making drug discovery attractive to pharmaceutical companies.] The question Munos asked was, “How do we get innovation in CFS and why don’t we have innovation like we do in HIV and a number of other fields.”

Summary: The traditional model for drug innovation is not suited to a complex illness like CFS. Drug hunters generally look for established illness that new products can be developed for. There is a dearth of discoveries that could be turned into novel drugs for CFS. There is also lack of infrastructure, namely, data and tools. The disease shares symptoms with many other illnesses, therefore treatments address symptoms, not the underlying cause. The lack of a single etiology, and the shared symptoms makes for an ill-defined situation, which makes it hard for regulators to do their job.  What is needed is an innovation supply chain. Patients have to make it worthwhile for scientists to investigate the illness.

How do we make it worthwhile?

1) We need data. There cannot be science without data. Data drives innovation. The data challenge in CFS/ME is magnified by its heterogeneity, which means we need more patient data. We also need international data to understand how CFS/ME affects people who come from different backgrounds. The natural history of the disease needs to be better documented, and genomic data must also be collected. Patients are the only ones who are qualified to speak on this.

2) We also need tools – tissue banks, animal models, biomarkers, and networking tools. The ability of scientists to “cross pollinate” across international boundaries is essential. Although patents are competitive, data are not, which means we should collaborate on the science. If you create the tools, the scientists will come.

3) Partners are essential for drug innovation. Partners include established scientific leaders, physicians, and young investigators. CFS/ME is a virgin field, which means it is important to attract young, enthusiastic researchers. Because they are on the front line, physicians should also be involved. Historically, physicians have been the most powerful source of innovation, because they know about the illness, and they customize and experiment with drugs that are used for other conditions.

4) Passion raises quality and success. Parents who have children who are ill, for example, agitate and become specialists in the disease. Scientists are moved by the passion of these parents, who are driven to find cures. Passion also lowers costs and raises the possibility of success. It’s hard to say "no" to people who are driven to a level of passion, and for whom failure is not an option.

5) Money is not as much of an issue as people think. You can run a very audacious program on a shoestring. Waste is prevalent in this industry – but it’s getting cheaper to gather data. The CFS/ME community is larger than other communities, so the ability to raise money is already there. Gathering data can be done cheaply, if it is taken up by the patient community.

When you have all five of those ingredients, you get to the point where you can generate intellectual property. At that point you can get companies interested in developing new drugs for CFS/ME. Munos' message was: “Frankly, for industry, CFS hardly exists … but if you build it, they will come.”

Suzanne Vernon

Second speaker: Dr. Suzanne Vernon [timestamp 31:36 - 60:42]

Dr. Suzanne Vernon, scientific director of the CFIDS Association of America (CAA), gave a presentation entitled, “Knowledge and Intuition to Reposition Drugs for CFS.” The subject of the talk was drug repurposing, or the use of existing drugs to treat CFS/ME. Dr. Vernon also spoke about “derisking science” i.e. making the research on CFS/ME attractive for industry, and for pharma.

Summary: The CFIDS Association of America is currently finding ways to make information that comes from the bedside available, and attractive, to the pharmaceutical industry. The Association is gathering data through their Solve CFS BioBank, which includes a repository and registry. There is already a tremendous amount of information about CFS. There are over 6,000 abstracts and articles in PubMed about CFS/ME. Dr. Vernon stressed that we do, in fact, understand the pathophysiology of the illness. We simply lack validated markers for replication and we have no standardized guidelines or a regulatory framework. Because of that, our doctors are still treating CFS/ME symptomatically, which has both advantages and disadvantages. The advantage of symptomatic treatment is that because its symptoms are so numerous, CFS/ME is ideal for drug repurposing.

The CFIDS Association has partnered with BioVista to mine information in PubMed and other databases through a search engine called a Clinical Outcomes Search Space (COSS). COSS searched through 20 million abstracts on PubMed, combined with a “whole bunch” of databases, which they then queried to extract information about CFS/ME. This technique can be used not only to identify drugs, but to identify biomarkers. The outcome is an extensive amount of data that people can then hone down to a plausible list that correlates symptoms and markers with medications.

[Dr. Vernon showed a number of slides which, unfortunately, were almost impossible to read.]

The most prominent association that COSS found was with serotonin, which was highly correlated with symptoms. From this data, Dr. Vernon drew the conclusion that some of the drugs [antidepressants] being used in this population may be contributing to symptoms. A second database measuring adverse events also indicated that the frequency of exhaustion was very high with antidepressants. These findings validated the central fatigue hypothesis of CFS, i.e. CFS fatigue is generated in the central nervous system.

Using the COSS, two drugs were identified which, in combination, might address sleep, pain and fatigue. [Regrettably, Dr. Vernon could not tell us which drugs those were, as they are currently under investigation.] Vitamin B12 injections were identified as effective in treating brain fog.

Dr. Vernon went on to talk about the results of the patient survey conducted by the CAA. Responses from the association’s survey showed symptoms clusters that could group patients into phenotypes. She noted that the pain subgroup was very distinct from the others. In terms of treatment, most patients used supplements and complementary strategies as well as anti-inflammatory drugs. The lesson learned from the survey is that patients have a lot of information that cannot not be discovered except by asking them directly.

Dr. Vernon finished her presentation with three proposed steps to help further research: taking the next steps in drug repurposing by expanding the Biobank, optimizing clinical information from physicians, and operationalizing data collection from patients.

Third speaker: Melissa Robb [timestamp 61:16 - 78:23]

Melissa Robb, Associate Director for Regulatory Affairs at the Office of Medical Policy at FDA gave a talk entitled “Drug Development and Review: FDA’s expedited Programs for Serious Conditions.”

Ms. Robb spoke about the history of the FDA’s expedited programs for serious conditions and explained the FDA’s rules and regulations that pertain to this area. She defined two common terms that are common in expedited programs:

• Serious conditions are associated with morbidity that has a substantial impact on day-to-day activity, including life-threatening conditions. 
• Areas of unmet medical need are illnesses that have no approved therapies, but also those conditions in which new drugs may show an advantage over available therapy, if one exists.

There are four expedited drug approval programs:

1) Fast track designation - is determined by whether there is data (clinical and nonclinical) to address an unmet need. It allows sponsors to complete portions of applications, rather than submit a finished package. This is called a “rolling review.” The goal is to speed up the development process.

2) Breakthrough therapy designation – addresses the development of drugs for serious conditions. It covers all aspects of development, review and production. Like fast track, this helps developers.

3) Accelerated approval – uses an endpoint that is clinical, and can be measured earlier. Allows FDA to take into account a lack of availability of appropriate therapies. The endpoint is likely to show a benefit, but there is safety and efficacy to consider as well. These clinical endpoints shorten the approval process. The accelerated approval program has been used extensively with cancer and HIV. Post-market validation is required.

4) Priority Review – a program that is intended to shorten review time (by the FDA). Typically the review time is 10 months. For a priority review, the period is 6 months. The drugs that qualify must have the potential to provide a significant improvement in safety or effectiveness.

Go here for information about the four programs.

Question and Answer Period: [timestamp 81:35]

Question: From Dr. Vernon to Bernard Munos: As far as drug development in concerned, what kind of time frame would you put us on?

Answer: Under normal circumstances, it could take 10 to 15 years to get a new drug on the market. But this period can be shortened by half, if patients get involved. Dr. Munos stressed the point that with a million people with CFS, patient involvement is key, and could contribute significantly to getting new treatments developed and approved. We need more networking between physicians, scientists and patients to accomplish this goal. There must be a rich network of ideas and hypothesis for physicians to draw upon.

Question: Dr. Vernon, you searched only for fatigue and exhaustion in adverse event database, so it’s not surprising that you came up with neurotransmitters. Have you looked at multiple infections, orthostatic intolerance, and abnormal immune functions? It seems to me you are biasing your results by your choice of search terms. 

Answer: [Dr. Vernon could not answer the question, facing the panel instead and asking, “Can you guys help me out on that?”] Yes, there probably is some bias. But the result was clear that fatigue was associated with the mechanism of these drugs.

Question: Dr. Vernon, are the results of the survey available online? 

Answer: Yes. Well, not yet. We are still collecting data.

Question: Dr. Vernon, it is known that the “CFS” literature includes studies based on overall broad and non-specific definitions. As a result, these studies don’t have the disease that patients described yesterday. Did you eliminate those studies from the Biovista analysis, and, if not, how has that influenced your results? 

Answer: The 20 million PubMed articles were not culled. The search was based on terms used to describe CFS. It’s an agnostic approach. We tried to be as inclusive as possible. Dr. Kweder: This is a heterogeneous group.

Question: Ms. Robb, is low-grade fever a surrogate marker?

Answer: [Ms. Robb was not comfortable answering the question.] Dr. Kweder interjected with, “That depends.” What is low-grade fever a surrogate marker for? In AIDS it predicts mortality. But the companies were required to show that low-grade fever actually led to mortality once they were further down the road. The key is that you have to show that the marker is predictive after approval.

II. Panel 2: Symptoms and Treatments: A View from Clinicians and Patients (71:37) (VIDEO)

Nancy Klimas

Moderators: Nancy Klimas, M.D., FACP, FIDSA, Chair, Department of Clinical Immunology, Director, Institute for Neuro-Immune Medicine, Nova Southeastern University and Theresa Michele, M.D., Clinical Team Leader, Division of Pulmonary, Allergy, and Rheumatology Products (DPARP), Office of Drug Evaluation II (ODE II), Office of New Drugs, CDER, FDA

Panelists: Lucinda Bateman, M.D., Fatigue Consultation Clinic, Salt Lake City, Utah, Lisa W. Corbin, M.D., FACP, Associate Professor, Division of General Internal Medicine University of Colorado Denver School of Medicine, Lily Chu, M.D., MSPH, International Association for CFS/ME and Patient, Jose G. Montoya, M.D., FACP, FIDSA, Professor of Medicine, Division of Infectious Diseases and Geographic Medicine Stanford University School of Medicine. Jennifer Spotila, JD, Patient and Christine Williams, MEd, Patient.

Questions: What were your key take-away messages from the discussion yesterday on the most significant symptoms experienced by patients with CFS and ME? Please describe any significant differences in your experience as clinicians and patients compared to yesterday’s discussion. [timestamp 8:44 – 24:00]

Dr. Bateman said that she concurred with what she heard yesterday. She would add the psychological suffering that comes along with the illness. Top of the list are cognitive limitations and fear.

Dr. Lily Chu talked about the results of the survey she conducted. Fatigue, PEM (post-exertional malaise), pain, and cognitive impairments came first. Multiple chemical sensitivities, gastro-intestinal symptoms, and orthostatic intolerance appeared in over 50% of respondents. The impact of the illness was substantial: respondents were more than 95% impaired and 89% needed assistance for daily chores.

Dr. Montoya stated that the two most salient clinical features were cognitive dysfunction and unpredictable crashes. The ability to drive is significantly impaired in his patients. This makes sense, because driving is the perfect example of multi-tasking. When patients get better they start to come to their visits alone. Herpes simplex is a trigger in a cohort of patients. The third thing to consider is that there are several triggers for patients. We should keep in mind how the effect of a drug is undermined when there are several triggers.

Christine Williams, who became ill at the age of 56, brought up the “double whammy.” These are the effects of this illness on an aging population. For her, the flu-like symptoms are the worst, because they make her feel very sick.

Jennie Spotila: We need to remember that the working ill, who struggle to maintain jobs and raise families, are a significant part of the patient community. For her, the words “fatigue” and “tired” are placeholders to avoid the long description of a crash. She stressed the need to include multiple aspects of cognitive function in order to measure improvement in drug trials. Ms. Spotila noted that gut disturbances had not been addressed. She also pointed out that prevalent symptoms, like orthostatic intolerance, can be masked. In addition, many symptoms could be measured and identified, but people are not looking at them. There is a lot of suffering that is going under the radar.

Question 2: Based on your expertise as clinicians and your experience as patients, which symptoms of CFS and ME could be identified as valid, quantifiable and reliable outcome measures or endpoints in clinical trials to evaluate potential drugs to treat CFS and ME? [timestamp 24:01 - 39:10]

Dr. Lily Chu: Any symptom of ME could be used as a valid and quantifiable outcome measure, it depends on which scales you want to use and which drug you want to test. She also mentioned that because the disease is heterogeneous, studying subgroups would yield better results. Her second point is that it is very important to come up with a good outcome measure for post-exertional malaise. Post-exertional malaise (PEM) is not that same as post-exertional fatigue. Malaise can have a flu-like component, and involves collapse and confusion. There is not enough basic research on PEM. The difference between fatigue and fatigability is important, because it not only takes into account the subjective feeling of feeling tired, but puts it in relation to activities. The real test is whether a drug improves function, rather than measuring a subjective state.

Dr. Montoya

Dr. Montoya talked about the importance of separating out symptoms. He mentioned a double-blind study he did in whicha smallgroup of patients were given antivirals. Their cognitive symptoms improved before their physical symptoms, but this improvement was only discovered when they compared a subscore on their initial questionnaire. Otherwise, it may have been missed. Separating cognitive fatigue from physical fatigue could be helpful for clinical trials. Because of the fluctuating nature of the disease he recommended using linear regression statistical models in order to measure various points, rather than simply comparing a beginning and endpoint. Type of onset is also extremely important. Do patients have viral onset, abrupt onset? What is the duration of the illness? “It’s very hard to believe that a patient with CFS of two years’ duration would have the same pathogenesis as a patient with 20 years’ duration”.

Dr. Lisa Corbin brought up the point that while it is important to look at function as an endpoint, there may be different parameters for function in the CFS/ME population. For example, being able to read a book for two hours (or at all) will not appear on any functional scale. The way we measure function needs to be more specific for this population. It’s important to follow the symptoms that are most distressing for patients.

Dr. Bateman mentioned that there are already objective measures in place to measure orthostatic intolerance,

Dr. Bateman

sleep disorder, as well as other symptoms. One problem in clinical testing is that as a patient’s ability to function increases they do more, which produces symptoms. So, unless patients maintain the same level of activity throughout the trial, measuring symptoms is unreliable.

III. Question 3: What are the key factors you take into account when making decisions to prescribe (as clinicians) or use (as patients) therapies to treat symptoms associated with CFS and ME? [timestamp 40:00 - 56:15]

Dr. Lisa Corbin: The first factor is patient input. I treat the most disabling symptom first. I do treatments one at a time. Start low and go slow.

Dr. Bateman talked about individualizing treatments as well as managing and coping strategies.

Dr. Montoya talked about preventing the wild fluctuations of the illness. He also addressed treating infectious triggers. He does PCR tests for HHV6 and measures viral loads. Those patients are treated separately. Other patients undergo testing to identify other viral triggers, risk factors for Q fever, and other pathogens. But, Dr. Montoya stressed, the pathogens must be correctly identified.

Question 4: If you had a drug to explore what would be your top one or two choices? [timestamp 56:26 – 58:56]

Dr. Bateman: On top would be antiviral and immune-modulating drugs. Next would be symptom management drugs for pain, stimulants for cognition, and sleep meds and meds for OI (orthostatic intolerance).

Dr. Lily Chu: Same plus Rifaxamin

Dr. Montoya: Antivirals, immune modulators. He believes that the immune response to the infectious agent is what drives CFS/ME symptoms, but for some patients it may be too late.

Jennie Spotila added Rituximab, as well as drugs that can increase VO2 max. These could potentially make a huge difference in the functionality of patients.

Question and Answer Period [timestamp 58: 56]

Question: How do we deal with the fact that so many patients are not located close to clinical trials?

Answer: Dr. Klimas mentioned that there is a spouse CBT protocol that involves long-distance CBT via a video group session. (Dr. Klimas noted that CBT is not a treatment.) Dr. Klimas added that there is a disconnect between 20-year-old guidelines and how doctors actually treat their patients.

[Questions about viral makers and immune markers were referred to, but the questions were not read.]

Question for Dr. Montoya:  “Do you subgroup out to foreign diseases, and what is the prevalence of HSV and CMV in your practice, and do you use cidofovir (Vistide) for HSV positive patients?

Answer: Dr. Montoya: We have a small group of patients with positive test results, but it is hard to come up with treatments for tick-borne illnesses. For herpes simplex we use acyclovir. We reserve cidofovir for patients who are severely ill, because it is very toxic. Doctors need to remember to “do no harm.”

Question: How can we better break down the barriers of data sharing?

Answer: Lily Chu: There are problems with privacy when it comes to freely disseminating medical data from individual patients. Dr. Montoya: Something similar needs to be done as was done for AIDS. Within 15 years they had highly effective treatments. We need a “bailout” for CFS/ME, a huge infusion of money and infrastructure. Dr. Vernon mentioned that CAA requires that anyone they give a grant to must share their data. Dr. Klimas stated that NOVA shares its data with other CFS/ME institutions, and there are other multi-institutional initiatives underway. Dr. Montoya mentioned that Stanford also has a biobank of several hundred CFS/ME patients. There is, in fact, a large amount of data already gathered and accessible for pharmaceutical companies.

Originally posted on ProHealth.

CFS: THE DIAGNOSIS THAT KILLS

Sophie Coldwell

On May12th - International CFS/ME and FM Awareness Day - members of the ME/CFS community sent a letter to the Department of Health and Human Services asking for a change. They wanted the vague, out-of-date definition of CFS to be changed to the more accurate Canadian Consensus Criteria for ME (myalgic encephalomyelitis). Theirs was a reasonable, well-argued letter, with all the facts, and with all the logic that a long-suffering population could bring to bear.

The current definition is simply too broad, the letter said, and confuses CFS/ME with “fatigue,” thus lumping people with ME together with people with depression and simple deconditioning. The consequence is that, left untreated year after year, comorbidities develop, and people with ME may end up dying from premature heart failure, cancer, and suicide. They also die of ME. In 2005 Sophie Mirza became the first person in Great Britain to officially die of chronic fatigue syndrome.

The DHHS ignored the request. They ignored Sophie Mirza.

They also ignored Sophie Coldwell.

In March 2013, 17-year-old Sophie Coldwell was diagnosed with CFS. Ten days later she was dead. The cause of her death was leukemia. But she hadn’t been diagnosed with leukemia, she’d been diagnosed with CFS, because she was tired. Is Sophie an aberration, someone who somehow “slipped between the cracks”?

She is not.

In the U.S. over 30% of existing MS patients – that’s 1,584 people - were diagnosed with CFS before being correctly diagnosed with MS. These are people who, had they been properly diagnosed in the early stages of the illness, would have had access to treatments that might have slowed or even halted the progression of the disease. Instead, they were told they had “chronic fatigue syndrome,” an illness for which there is no treatment. Those 1,584 people have now had their diagnoses corrected to MS. Just imagine how many people with MS are currently being diagnosed with CFS.

But it doesn't end with hard-to-diagnose illnesses.

More than 10% of people coming to “fatigue centers” in Belgium have been found to have physiological injuries to their pituitary glands – cysts, tumors, and a shrunken pituitary (empty sella). They had been diagnosed with CFS because they were tired. And because they had CFS, nobody bothered to do an MRI of their brains. Is this gross oversight limited to Belgium? It is not. I personally know one man here in the U.S. who, in fact, had no pituitary due to empty sella. It was years before a doctor thought of doing an MRI, because this man had been diagnosed with CFS.

How many more people have to suffer –  those of us with ME, those of us with cancer, Hashimoto’s disease, leukemia, MS – simply because the ridiculous diagnosis of “chronic fatigue syndrome” exists?

This needs to stop. Now.

Sign this petition. Tweet it. Facebook it. Reddit it. Send it to your family, friends, neighbors, co-workers. Let's put an end to this medical malarkey. We have 30 days to gather 25,000 signatures. And with everybody's help, we can do it.

Do it for yourself. Do it for me.

Do it for Sophie.

How Will a Name Change Affect People Diagnosed With CFS? FAQs

The CFS/ME community has posed a number of questions concerning the petition to replace the CDC ("Fukuda") criteria with the Canadian Consensus Criteria for ME. The petition calls for dropping the name CFS entirely, replacing it with ME (myalgic encephalomyelitis), the term currently in use in the rest of the world. In this Q&A, Mary Dimmock, President of the newly formed organization, National Advocacy Alliance for ME (NAAME) answers frequently asked questions.

You can read the letter to the DHHS HERE.

You can read and sign the petition HERE.

FAQs

Question: What will happen to the patients who have been diagnosed with CFS? We cannot abandon the patients who have been given a “CFS” diagnosis incorrectly.

Answer: Patients with “CFS” will not be abandoned. It is critical that implementation of this change be carefully managed so that these patients are re-evaluated and given a correct diagnosis. If unexplained conditions remain, it will be necessary to perform the studies needed to understand these conditions and establish more appropriate names and definitions.

Question: How will this affect disability or insurance? We cannot afford to lose either one. 

Answer: It will be important to have a carefully thought out implementation plan that manages this change to ensure that patients do not lose disability or insurance benefits simply as a result of changing the diagnosis.

Question: The vast majority of the 6000 articles in the literature use the name “CFS,” not “ME. If we stop using the name “CFS,” will we lose all that literature?

Answer: Researchers and professionals routinely learn about the history of names and definitions associated with any disease. They also need to understand what criteria were used in the past for any study under review.

This is especially critical with the “CFS” literature, because while it contains good research studying the essential features of ME, it also contains studies that used patients who met other conditions (i.e. depression and deconditioning) falling under the Oxford and Fukuda (CDC) case definitions. As a result, much of the “CFS” data does not represent one illness or even one illness with subsets, but rather a variety of “fatiguing conditions,” which have been thrown into the CFS diagnosis-of-exclusion wastebasket.

Continuing to use the “CFS” label will only exacerbate a very confusing situation, doing a disservice to ME patients and to all patients who deserve to be properly diagnosed and treated.

Question: We have more important issues to deal with such as funding, and attracting new doctors and researchers. Isn’t this just a side issue?

Answer: It is critical that we have more funding, but if we don’t fix the definition first, we will continue to study the wrong disease and have progress impeded by poor cohorts. The resulting confusion will make it difficult to attract young researchers and doctors who will not see a career opportunity in “CFS.”

Question: Research centers for CFS have recently been established. If we stop using the name “CFS” won’t that confuse the donors?

Answer: It is true that a number of research institutes have recently been opened and some of them use the term “”CFS” or even “CF.” But the donors to these institutes have a personal connection to the disease. They will continue to fund the centers no matter what the illness is called. However, attracting additional funders will be hindered by the confusion generated by the definition of the disease. The sooner we can resolve this problem, the better off we’ll be.

Question: CFS biobanks have been established using the Fukuda criteria. Will we lose those samples if the definition is changed? 

Answer: The biobanks using the Fukuda definition could contain a mix of patients with ME and those who don’t. Using these mixed samples will continue to confound research. It is important that we have a well-characterized set of samples in the biobank and know which samples are from ME patients.

Question: ME may not be the right name. Shouldn’t we wait for science to figure out what the right name is?

Answer: It is possible that with further study we will eventually determine a better name. But because ME was adopted by the World Health Organization in 1969, it is the best placeholder until that time and avoids the serious problems caused by the use of the term “CFS”.

Question: Wouldn’t the best course be to tighten up the “CFS” definition, not get rid of it? Then we can keep the literature base, the biobanks, and so on.

Answer: There are two problems with this approach. First is the long history of the term “CFS,” which is non-specific and now widely associated with diverse conditions, especially psychiatric illnesses. This has tainted the term and made it clinically meaningless. Second, the term “CFS” is used for those studying patients who meet the Oxford criteria (which is essentially fatigue). As long as we keep the term “CFS” the Oxford criteria will remain in effect.

Question: Dr. Leonard Jason recently published a paper that reports that the ME-ICC and the Canadian Consensus Criteria include more psychiatric co-morbidities than the Fukuda definition, and recommended that more study be done. Does that mean we should wait to recommend any criteria until then?

Answer: Dr. Jason acknowledged that his study was limited due to the use of a questionnaire designed for the Fukuda definition. Additionally, the study was unable to assess one of the key ME-ICC symptoms because the data were not available. Finally, the study did not look at homebound or bedbound patients.

What is also significant in Dr. Jason’s study is that ME-ICC identified a much tighter group of patients (39 compared to 113 for Fukuda) with more functional impairments and physical, mental and cognitive problems than those meeting the Fukuda criteria.

Clearly, additional study is needed to operationalize the definition and to improve how it characterizes the disease, especially subtypes. But continuing to use the 19-year-old Fukuda definition - which is also not operationalized and does not describe subtypes - is not going to advance scientific knowledge and will only continue to hurt patients.

The Canadian Consensus Criteria (CCC) has been used clinically and in research for over ten years. There is no doubt that it better represents the disease. Using the CCC now will allow us to begin to make progress in research and to address the widespread dismissive attitude held by the medical community.

Question: We still don’t know for sure that post-exertional malaise (PEM) is real and we don’t have agreement on how to measure it. How can PEM be used by researchers as a primary symptom?

Answer: The work of Dr. Christopher Snell as well as the work of the Lights have not only demonstrated the reality of PEM but have provided the objective test to demonstrate it using the two- day cardiopulmonary exercise test (CPET). This test is the gold standard for functional capacity evaluations and is approved by a number of major American medical societies and organizations.

Question: Why were the Canadian Consensus Criteria and not the ME-International Consensus Criteria used as the initial baseline?

Answer: The Canadian Consensus Criteria has been used clinically and in a number of studies, providing the experiential foundation for its use. It is expected that as additional data is obtained, this definition will evolve. This must be done in partnership with the experts who developed the ME-International Consensus Criteria and the Canadian Consensus Criteria.

Question: Isn’t the Canadian Consensus Criteria is too complicated for doctors to use?

Answer: At the May, 2013 CFS Advisory Committee meeting (CFSAC), Dr. Unger raised a concern that the Canadian Consensus Criteria is too complicated for doctors. But we must not lose sight of the fact that this is a complicated disease and simple criteria, especially those like Fukuda and Oxford, that fail to require the hallmark symptoms of the disease are misleading doctors and hurting patients every day. Any doctor capable of treating the complexity of this disease will be able to understand the Canadian Consensus Criteria.