It's Not Too Late to Make Your Voice Heard

The following is a special announcement from the Mass CFIDS Association. Please do take advantage of this unprecedented opportunity to make your voice heard.

The FDA will still accept comments from patients, even though the deadline has passed.
In the recent newsletter (July 27) we noted that Friday, August 2 was the deadline for submitting comments to the FDA’s Drug Development for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis; Public Workshop.

However on Friday the FDA’s server was unavailable for most of the day, and several of you notified us that you were unable to submit your comments.  Thanks to great research detective work by one of you, we have reached the person at FDA responsible for dockets, and he has agreed that they will continue to accept comments for the docket by mail or fax.  He assured me that all comments are read, so this is not a useless exercise!  If you have something to say, please say it.  Comments can be brief, and should address any of the points below.  Be sure to include the docket # with your comments.

The mailing address is:

Division of Dockets Management
FDA
5630 Fishers Lane, Room 1061
HFA-305
Rockville, MD 20852
FAX:
Docket #:  FDA-2012-N-0962-0004

Patients and advocates unfortunately have good reason to be disappointed in the lack of government action on this illness, but the FDA is an exception and is working actively to help.  Now we need to HELP THE FDA HELP US.

How you can help - tell the FDA your story 

The first day of the meeting "focused exclusively on gathering patients’ perspective. FDA heard directly from patients about their experiences with this debilitating condition. Discussion focused on two key topics: 1) disease symptoms and daily impacts that matter most to patients, and 2) the patient perspective on treatment of this condition." This portion of the meeting "provided a particularly valuable opportunity for FDA to hear in patients’ own words about how they experience their disease." Hearing the stories directly from patients was apparently eye-opening to the FDA.

Please add your voice - the FDA is listening!!  Even if you think your experience is common to many patients, and you are bored with re-telling it, it will be very valuable to share in this forum. Giving specific, seemingly mundane details is especially helpful to the FDA. Talk about the symptoms you experience and how they affect your life. Describe what helps you get from day to day, and how much (or little) it helps. What is your life like when you feel "better"?  How can you tell if a treatment is working?
Thank you for taking a few minutes to do this.  You will be helping all patients.

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.

Send a YouTube Video to the FDA!

On April 25-26, 2013, the United States Food and Drug Administration (FDA) held a public workshop in Bethesda, MD to discuss the development of safe and effective drug therapies for CFS and ME. The panel heard presentations and comments from CFS/ME physicians, researchers, and patients. Jennie Spotila, founder of Occupy CFS, and Robert Miller, a long-time patient advocate for Ampligen, attended, as did Drs. Klimas, Bateman, Montoya, Peterson, Enlander and many others.

Given the fact that so many patients with CFS/ME are too ill to travel, the comment docket is just as important as live testimony. The information submitted through comments will also help inform FDA's internal review processes. For example, if they hear from patients that VO2max exercise testing is the best way to measure activity intolerance, they are more likely to consider such testing as a good progress measurement in a clinical trial. (Dr. Snell gave an excellent presentation on the VO2max test on the second day of the workshop.) If they hear that cognitive problems are our biggest difficulty, they may be more likely to focus on that as a good endpoint in a clinical trial. So, the docket – whether written or video comments – will be an essential part of their preparation of their report. FDA is keeping the docket open until August 2nd to allow people to comment on issues that either arise in the meeting or were not covered on April 25th and 26th.

Video testimony is especially important because without it, the FDA will not have the opportunity to see the sickest patients. It's very powerful to see a pediatric patient confined to bed, or a patient who cannot sit up because of orthostatic intolerance. Those patients need to have a chance to be seen by FDA, and to make their voices heard. The only way to do that is video.

FDA will accept video comment through the docket in the form of links to YouTube videos. The docket will remain open until August 2nd, and FDA is asking people to file comments answering the questions posed in the meeting notice.  You can submit written comment (2,000 character limit), attach a Word or PDF document, or include a link to a YouTube video.

It is not difficult to upload a video onto YouTube. Click HERE to watch a short, informative video of instructions. Written comments can be submitted HERE.

This is a great opportunity for patients to speak directly to FDA and to influence federal funding for research on treatments! Let's make our voices heard!

(For a summary of the first day of the workshop (April 25), go HERE.)

FDA Holds Public Workshop on Drug Development for ME/CFS: Day One

On April 25, 2013, the FDA held its first day of public workshops to discuss the impact of CFS/ME
symptoms on patients and their caregivers. The purpose of the workshop was to gain insight into developing safe and effective treatments. The first day of the workshop consisted of two panels, the first of which was devoted to hearing from patients and patient representatives about symptoms, and the second to treatments and therapies used by patients.

The workshop was broadcast live over the internet, and questions could be emailed during the presentations, allowing those who could not be there in person a chance to participate. This meeting was an unprecedented opportunity for patients to speak directly to the FDA, the CDC, and even pharmaceutical company representatives about their concerns. After listening to these presentations you may feel inspired to contribute your own comment. It is not too late. Comments can still be added to the docket until August 2nd, 2013.

The full agenda of the two-day workshop can be viewed HERE.

You can read a summary of the second day (April 26th) morning presentations HERE.

You can read a summary of the second day (April 26th) afternoon presentations HERE.

Additional coverage of the April 25 workshops can be found on Phoenix Rising Part I HERE, and Part II HERE.

Sandra Kweder

Video 1: Welcome - Overview of FDA’s Patient-Focused Drug Development Initiative [33 min:16 sec]

The first segment of the workshop outlined the purpose of the meeting, and stressed the FDA’s commitment to developing safe and effective treatments. Sandra Kweder, Deputy Director in the Office of Planning and Informatics at FDA introduced Theresa Mullin, Director, office of Planning and Informatics, Center for Drug Evaluation and Research and Sara Eggers, PHD, Office of Planning and Informatics, FDA. Each gave presentations about what the meetings would cover, how to define CFS/ME, and stressed the importance of patient input. One of the most noteworthy aspects of this discussion was the acknowledgement of CFS/ME as an organic disease, rather than as a psychiatric condition. This marks a major milestone in the federal government’s thinking towards CFS/ME. (VIDEO)  (Transcript)

Video 2: Topic: Disease Symptoms and Daily Impacts That Matter Most to Patients [68:32]

Discussion questions: What are the most significant symptoms that you experience resulting from your condition? What are the most negative impacts on your daily life that result from your condition and its symptoms? 

In this segment, the panelists gave short, and often moving, presentations about the symptoms and effects of CFS/ME on their lives. (VIDEO) (Transcript)

Patient Dr. Jon Kaiser, a medical doctor in the San Francisco area who fell ill with CFS/ME in 1987, discussed how the illness has affected his ability to work. He also spoke about the limitations that CFS/ME has placed on his social and family life. His presentation specifically addressed the impact of CFS/ME on working patients. [timestamp 00:57 – 05:40]

Patient Joseph Landson, a former military linguist and grad student in the DC area who has been ill for eight years, described how cognitive impairment and post-exertional malaise (PEM) have affected his ability to complete his degree and to maintain a career. [timestamp 06:00 – 09:28]

Representative Denise Lopez-Majano described how the illness has affected her sons, Alexander and [timestamp 09:40 – 14:05]

Alexander and Matthew

Matthew, who are both housebound and require 24/7 care. She described a gamut of symptoms affecting her sons: impaired executive function, slowed processing speed, inability to focus, or engage in physical activity. She addressed PEM (post-exertional malaise), which, from her observations, can be triggered by minimal mental exertion (only 20 minutes). In her sons’ cases “malaise” is typified by a collapse that can last for weeks, and may not have an identifiable trigger. Most pharmaceuticals have not helped. From her sons’ perspective cognitive function is the symptom they would most like to improve. In the words of one of her sons, “What’s made with the mind lasts longer.”

Kim McCleary

Representative Kim McCleary, CEO of the CFIDS Association of America, based her comments on responses to a survey conducted by the association. The average age of onset of respondents was between 19 and 35, and the average duration of the illness was 18 years. Of 1300 responses, the five main concerns expressed by patients were, 1) impact on daily life, and fear of increased risk of death and disease, 2) loss of friends and career, 3) lack of effective treatments, 4) not being able to work because of symptoms, and 5) social isolation. [timestamp 14:20 to 19:36]

Patient Charlotte Von Salis, a lawyer who has been ill 23 years, and whose only remission was due to antiviral treatments, talked about neurocognitive impairment, difficulty reading and writing, and sensitivity to light and overstimulation. She also talked about PEM, the loss of her career as a lawyer, the profound limitations of activity, and the experience of being housebound. [timestamp 19:53 – 23:57]

Question from FDA Member Dr. Kweder: “Mr. Landson, is your confusion a cognitive confusion or a fog?”

Answer from Mr. Landson: Lack of recognition of written words.

Question from FDA member Dr. Michele concerning PEM. “Secondary to cognitive and physical exertion, is one a greater trigger than the other, and are symptoms different?”

Answer from various panel members: Cognitive exertion causes a crash that "makes me feel as if my head is going to explode." A physical crash is an exacerbation of everything. A physical exertion crash produces sore throat, in what is essentially an inflammatory response. Interestingly, Dr. Kaiser reported that anti-inflammatories can help to stave off a crash.

The conversation then moved to the floor. Matina Nicholson talked about cognitive function limitations. Dr. Janet Smith talked about difficulty in decision making. Mary gave examples of a CFS crash, and pointed out how much speaking in public costs the people who were giving presentations (applause). Chris Williams talked about the inability to multi-task. Tasha talked about the difference in crashes caused by mental and physical exertion.

Video 3: Discussion Topic: Patients’ Perspective on Treatment Approaches [127:58]

Discussion questions: What treatments are you currently using to help treat your condition or its symptoms? How well does your current treatment regimen treat the most significant symptoms of your disease?

The panelists were Mary Dimmock, Tasha Kelemen, Matina Nicholson, Mary Schweitzer, and Amanda Simpson. (VIDEO)

Representative Mary Dimmock’s son has had CFS/ME since contracting giardia in Asia. He is currently bedbound. Antibiotics had some effect, but it was temporary. Kineret has produced a slight improvement in cognitive function. His doctor has prescribed Rituximab.

Patient Tasha Kelemen fell ill after a tropical illness in Africa, and has been treated in Belgium, the UK, and the US. She reported having taken “everything.” As a patient in the PACE trials, Tasha stressed the importance of not adopting the UK treatment protocol. Specifically, she stated that GET was not a cure. Antiviral treatment has helped, but pacing is her most effective therapy. She was emphatic that the UK approach is “harmful, ridiculous and offensive” and exhorted the US not to follow its example.

Patient Matina Nicholson was in senior management at a top pharmaceutical company. She takes Adderall but still sleeps excessively. She is administered Meyer’s cocktails, takes supplements, and takes Ambien to sleep.

Mary Schweitzer

Patient Mary Schweitzer, a tenured history professor, reported on Ampligen, and what her life was like without it: “Without Ampligen I don’t have a life.”

Patient Amanda Simpson came down with the “flu” in Texas. After many months she was finally diagnosed with CFS/ME. She has taken an aggressive approach. Amanda takes 16 pills a day. She takes Savella for pain management, which, she reported, is the only reason she was not bedridden, as well as Tylenol. GcMAF has led to an increase in functionality, and acupuncture has helped sleep and pain.

OPEN COMMENTS [timestamp 71:35]

Patient Anita Patton commented on subgroups and asked for another Ampligen trial. Anita is an Ampligen responder. [timestamp 75:12 - 77:09]

Representative Dr. Janet Smith, of the Simmaron Foundation, spoke for patient Courtney Alexander. She made a plea for looser FDA approval rules (such as those applied to Alzheimer's disease) for CFS/ME drugs. [timestamp 77:35 - 78: 31]

Researcher Dr. Judy Mikovits stressed that identifying a cause is not necessary for developing [timestamp 78:46-81:40]

Judy Mikovits

treatments. She drew parallels with MS, Parkinson's and lupus, none of which have a known cause, and all of which share similar immunological abnormalities with CFS/ME. Dr. Mikovits stated that immune-modulating treatments such as dimethyl fumarate and Rituxan [rituximab] have already been approved by the FDA, and could be used for CFS/ME. "The absence of a causative agent should not leave this field floundering any longer. It's a new era for CFS/ME treatment."

Dr. Derek Enlander

Physician Derek Enlander founded the ME/CFS Center at Mt. Sinai Hospital in New York. Their first project is to prove whether GET [graded exercise therapy] is an appropriate treatment for this disease. "We will actually prove or disprove the PACE idea." The ME/CFS center has ongoing research on PEM and is looking at all cytokines and immune markers. Dr. Eric Schadt, chair of Genetics and Genomic Sciences at Mt. Sinai, is currently working with Dr. Enlander on assembling genome studies on ME/CFS patients. They already have 39 pages of genome studies. [timestamp 82:08 – 84:05]

Caregiver Gisela Morales Barreto, psychologist, spoke about the emotionally draining experience of watching a loved one suffer with CFS/ME. As a cancer survivor, she pointed out that many treatments were available to her, but this is not the case with ME/CFS. She made a direct plea to the FDA: "If you approve any drug - Ampligen would be nice - it will open the door for pharmaceutical companies." [timestamp 84:25 – 87:35]

Executive Vice Chairman of Hemispherx BioPharma Thomas Equels offered some interesting history[timestamp 88:02 – 92:00]

Thomas Equels

about the company's involvement with CFS. Thirty years ago FDA asked Hemispherx to team up with Dr. Peterson and Dr. Lapp to treat the "Tahoe flu." They conducted a trial of Ampligen on a woman who made a remarkable recovery, and then treated twelve more patients with success. He remarked that it has been a long difficult journey for a company as small as his. Mr. Equels concluded with: “Now we’ve expended a great deal of time and money to get where we are today and I just want to say we’re prepared to enter into a real partnership with the FDA, with the clinicians, and with the patients to bring relief for these people who so desperately need it.”

Dr. Dan Peterson

Caregiver Dr. Dan Peterson spoke as the representative of 9,000 patients over the past thirty years. He began with a direct plea to the FDA on behalf of the patients, their families, and their physicians: "I implore this esteemed gathering and committee to not only devise but to execute a therapeutic strategy, which is much needed." He stated that the CDC has identified one million people in this country suffering from the disorder, with an estimated cost to our country of nine billion dollars a year. A diagnostic marker would yield a company 250 million a year - a therapy probably in the billions of dollars. Yet, twenty-five years later, we have no FDA-approved drug or therapy. Over this twenty-five-year period of therapeutic stagnation there have been thousands of peer-reviewed articles addressing pathogenesis. Worldwide, the number one immunological finding is low NK function. Abnormal brain MRI and SPECT scans are common, and low VO2 on stress tests is universal. Regarding treatment, Dr. Peterson said: “Symptomatic therapy, I think, is useful in quality of life, but I have not seen it return patients to full functional conditions, physical or cognitive. I think targeted immunological therapy has the possibility to do that.” There are worldwide consortia and collaborations with multiple primary care clinics that are ready and willing to do pilot projects, Phase I, II and III clinical trials, and more... "So I implore again this committee to take some action [...] to develop safe and effective therapies."  [timestamp 92:25 – 95:45]

Advocate Eileen Holderman questioned the use of the term CFS in this conference, as opposed to ME. She stated that in 1988, the CDC renamed this disease Chronic Fatigue Syndrome, which is unscientific and dismissive, because it includes an empirical definition which requires just one symptom: fatigue. The results of this faulty definition have been muddy research, the inability to replicate findings, no universal biomarkers, no drug development, bad media and press, skewed public perception, and neglect and harm inflicted on patients who truly have ME. “The solution is that all the government agencies, the scientific medical, academic, legal advocate and patient communities must come together and adopt the Canadian Consensus Criteria and to dismantle the use of CFS and move research and treatment forward to help the over one million Americans with this disease.” [timestamp 96:20 – 98:33]

Researcher Dr. James Baraniuk of Georgetown University Hospital began by saying, "It's not all doom and gloom." His research group has started publishing the results of their studies from Gulf War Illness patients who also meet the criteria of Chronic Fatigue Syndrome. They have identified three separate dimensions of exercise-induced FMRI changes that they believe can be applied to CFS.The simple message is that all of the subjective criteria used in CFS/ME can be abandoned in favor of objective measurements. “We are going to have objective diseases that will end up in the Harrison textbook of medicine.” Baraniuk's group has identified a problem in a white matter tract of the brain that deals with fatigue and the valuation of pain. This tract also connects with the insula, which maintains homeostasis, as well as connecting to areas that deal with working memory, and to dorsal and ventral networks that deal with attention and focus. Given the distinct nature of the brain abnormalities found in CFS/ME patients, Dr. Baraniuk does not feel that the heterogeneity of CFS/ME poses an insolvable problem. [timestamp 98:40 – 101:45]

Physician Charles Lapp has treated patients with CFS since 1985, and has used Ampligen since 1988.  [timestamp 102:14 – 104:12]

Dr. Charles Lapp

He reported using Ampligen with great success - 50% of his patients have responded very well to Ampligen and roughly 30% have had significant improvement. In all the time he has used Ampligen. he has not seen any serious side effects. He compared Ampligen to other new drugs that have been brought into the field, like AZT for AIDS and interferon for MS. Once they were approved, many other players and pharmaceutical companies came into the field and opened up treatment for these two diseases.  “We hope that Ampligen will do that for Chronic Fatigue Syndrome.”

Dr. Steven Lempert gave compelling evidence for the effectiveness of Ampligen in treating a subgroup of CFS/ME patients with active HHV-6 infections. He cited research by Dr. Ablashi regarding Ampligen's in vitro ability to inhibit HHV-6 by 46% to 98%. He stated that the in vitro activity of Ampligen translates clinically into in vivo effectiveness. Mary Schweitzer, who was positive for HHV-6A before Ampligen, was negative when tested on three occasions while on Ampligen. Dr. Lempert suggested that Ampligen be transferred to the FDA antiviral division and re-evaluated now, rather than wait another ten to twenty years. [timestamp 104:20 – 106:15]

Patient Dr. Joan Grobstein has had ME for fourteen years. She brought up several important issues for the FDA to keep in mind. In terms of defining patient population, she strongly suggested the adoption of the Canadian Consensus Criteria for all studies. The validation of biomarkers is a priority as there are already measurable abnormalities. She stated that it is important to treat symptoms as well as the underlying cause of ME. It is also possible to treat associated infections, even if the infection is not the sole cause of the disease. “It’s very likely that multiple agents will have to be used concomitantly to treat this multi-system disease.” Outcome measures must reflect the impact of ME on patients' lives. "The FDA should demonstrate a sense of great urgency to evaluate therapies for ME." [timestamp 106:38 – 108:40]

Patient Jeannette Burmeister urged the FDA to play a more proactive role in working with Hemispherx to put Ampligen on an accelerated track for approval. "At the Ampligen FDA Advisory Committee meeting, the FDA stated that there is no path for Ampligen’s approval under any fast-track program. No explanation was given. In contrast, the FDA has recently developed new guidelines for an accelerated-approval process for Alzheimer’s drugs for patients who are not even sick yet! Why the drastically different standard, I wonder? Looking back at the approval of AZT as the first drug to treat HIV and AIDS, it becomes clear that the FDA does indeed have discretion to adopt looser rules if the circumstances warrant it. At the end of last year, the FDA approved—under an accelerated approval program—Sirturo, a drug to treat tuberculosis that is five times more likely to kill patients than the standard drug treatment for the disease without proof of increased efficacy. I am not convinced that the FDA’s hands are indeed bound when it comes to an accelerated approval of Ampligen. Instead, it seems that an unfortunate double standard applied by the FDA to ME and Ampligen compared to other diseases and drugs has Ampligen headed straight towards the cliff, as Hemispherx is running out of money and the drug is going away, potentially forever." [timestamp 108:52 – 110:46] 

Mindy Kitei

Patient Mindy Kitei is a science reporter and blogger at CFS Central. In 1994, she wrote an investigative piece for Philadelphia Magazine called “The AIDS Drug No One Can Have,” about the experimental drug Ampligen. She stated that much of the data on this disease is based on studying patients using the wrong criteria. She stated categorically that the CDC and NIH are not studying patients with CFS/ME. They are not studying patients who meet the Canadian or International Consensus Criteria, but are rather studying patients based on the Fukuda or Empirical criteria. The Fukuda and revised Fukuda as well as the Oxford criteria are not accurate, yet CDC continues to use these definitions. Dr. Leonard Jason has shown in published studies that CDC, in employing the Fukuda definition, is studying people with major depressive disorder. "That's like doing an HIV trial and none of the people are HIV positive." As a result of studying the wrong cohort, doctors are misinformed. She recalled that Dr. Lisa Corbin tells her patients, “Monday is for mending, Tuesday is for ironing…  Imagine giving this hokey advice to patients with HIV. ME patients need treatment not patronizing bromide." Five of the patients Mindy interviewed in 1994 have since died. One was a close friend of hers; three were in their forties and fifties. “Do you really think that that these patients would be alive if only they had done their mending on Monday?” [timestamp 111:16 – 113:52]

Owner of Hyperion Biotechnology, Inc. Dr. John Kalns is working on an application to measure fatigue using saliva. The US army has been interested in their work because fatigue is a major problem with US soldiers. They recently did a small study with archived saliva from CFS patients. "Why I'm here is to pose a question: I need spit. I want to get that saliva." He believes their technology may have a lot of application in drug development.  [timestamp 114:00 – 116:40]

Patient Dianne Lewis is a licensed certified social worker and clinical therapist who suffers from ME. She attended the workshop to say, as a professional, that this disease does not benefit from CBT. The stigma and discrimination of this disease is uncalled for. "Not having medical parity means we are nonexistent." She says the doctors in her hospital don’t understand ME, and respond to her queries with, "We don’t treat that disease here.” She described her medical interventions as a "mockery." It was only when she brought the results of studies with Dr. Peterson and Dr. Lapp that they took her seriously and prescribed medications to deal with her symptoms.  [timestamp 116:52 – 120:55]

This article first appeared on ProHealth as "FDA's CFS/ME Drug Development Workshop: Day One."