Association Offers its Feedback on the FDA Draft Guidance

FDAOn May 12, 2014, the Solve ME/CFS Initiative submitted a thorough review of the FDA Draft Guidance for Industry concerning ME/CFS. While there is still much work to be done, we are greatly encouraged that ME/CFS is receiving this kind of attention on a federal level and we hope the draft guidance can be further improved by our and other feedback received. We hope that the issuance of it will encourage more research into treatments and a cure for ME/CFS.

The draft guidance is intended to assist sponsors in the development of drug products for the treatment of myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The guidance focuses on specific drug development and trial design issues that are unique to the study of ME/CFS and on the FDA’s current thinking on how effective treatments can be developed for ME/CFS. The document offers industry input on trial design and duration, potential efficacy endpoints, the need for patient reported outcomes (PRO’s) and safety considerations.FDA_DraftGuidance

Below is the full text of our feedback, as submitted on the FDA docket:

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The Solve ME/CFS Initiative, our Research Advisory Council and Dr. Larry Baldwin, ME/CFS patient, reviewed the draft guidance “Guidance for Industry Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Developing Drug Products for Treatment”.  Our Research Advisory Council is a volunteer group with expertise in clinical research, pharmacology, medical devices and regulatory science.  Specific contributors and corresponding expertise are listed at the end. Comments are organized into the three categories, 1) general comments, 2) strengths and 3) limitations.  Where relevant, we have highlighted questions or gaps in the guidance document.

General Comments:

  1. Throughout the guidance document, change CFS/ME to ME/CFS.  This would make this guidance document consistent with the terminology used by other federal agencies including HHS, NIH and AHRQ.
  2. Line 76-77 of Background uses “public health concern”.  We suggest that the end of this sentence be changed to “… public health crisis for those with the disease and adversely impacts society.”
  3. In Development Program Section III. A. 1., the Institute of Medicine consensus study, “Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” should be acknowledged, as this will have a positive impact on drug development.

Strengths:

  1. The guidance sets an important precedent as a statement from the FDA that ME/CFS is an important object of study for treatment development.
  2. The statement that the absence of approved treatment represents a significant public health concern is also an equally important point of recognition and legitimacy for the disease and a welcome statement from this federal agency.
  3. The recognition of the existence of several consensus case definition criteria and that any of these may be acceptable to define a patient population for clinical trial investigation of a therapeutic is notable.
  4. The mention that sponsors should define the targeted patient population, e.g., general ME/CFS population or a subset (e.g., ME/CFS plus POTS) is important because some subsets have an evidence base that supports the identification of objective signs accompanying the specific subset population.
    1. We believe therefore that there is an opportunity to utilize such objective measures as primary outcomes measures in clinical trials.
    2. Noting that biomarkers can be used legitimate object of study of exploratory endpoints to assist in clarifying potential disease mechanisms is welcomed and important.

Limitations:

  1. This draft guidance document is very general. The background could highlight the opportunities that exist for ME/CFS drug development (e.g., sleep disturbance, cognitive impairment and pain are symptoms of many chronic diseases where drugs have been developed and therefore are potential valid opportunities for study in ME/CFS as they are in other illnesses).
  2. The draft guidance should include medical devices given that may be of therapeutic benefit for this population.
  3. There are a number of issues in section III.B.2. Efficacy Endpoints. The statement that the FDA is unaware of any specific measures for core functions that are disrupted in ME/CFS is puzzling as there are clearly well validated measures of fatigue, pain, cognitive function, sleep, and psychiatric symptoms that are likely to be perfectly valid to use in the setting of a study on ME/CFS.  In fact, some studies have already used these measures. Validation of their use in a specific ME/CFS sample can certainly be a part of the overall study design if a methodological question remains.
    1. The FDAs publication “The Voice of the Patient” documents the impact of ME/CFS on cognitive and physical function (functional capacity).  We suggest functional capacity be considered as a key ME/CFS domain.
    2. Post-exertional malaise can result from cognitive or physical exertion.  However, under “other domains” having both exercise capacity and post-exertional malaise listed implies these are related.  In fact little is known about the relationship of exercise capacity to post-exertional malaise.  This section should be revised considerably to remove the implied relationship and to be more cognizant of the other domains affected in ME/CFS patients.
    3. The HRQL section reads like there is HRQL measures specific to ME/CFS.  This section should be edited to note several validated HRQL measures could be used to assess the effect of therapeutic measures on HRQL.
    4. There is no mention of psychiatric symptoms (i.e., mood, anxiety, or cognitive impairment) as important symptom domains for outcome assessment.
    5. A brief and limited consideration of how to address the question of confounding illness comorbidities is provided as well as how these should be identified and excluded.  It is unrealistic to expect to recruit a large, generalizable sample of patients who meet one of the existing case definitions and where no such illness comorbidities are present.  Most complex chronic diseases address this issue by allowing certain illness comorbidities to be permitted when the secondary condition is medically stable at the time of study.  Whether comorbid illness is a modifying factor in disease progression should be addressed in the statistical analysis plan for the study.
    6. There is no consideration of the importance of disease staging.  This is a critical issue in a chronic illness such as ME/CFS, where recruitment of a significant portion of the sample from the refractory patient pool is likely to result in clinical trials with an enormous risk of being either statistically underpowered, producing an uninterpretable result due to a false negative result.  This should be among the more important methodologic features to be considered in ME/CFS study design.
    7. The requirement for 24 weeks as a standard outcome interval duration for a study design may not be justified as an across the board universal recommendation.  Indeed, if this is seen as a requirement of approval it is likely to deter sponsors of otherwise valid short-term interventions.  The duration of study should be tailored to the claim being requested.  For example, a short term study might be very appropriate to an intervention that would be expected to have a rapid benefit on improvement of non-restorative sleep.
    8. The recommendation of as needed use of concomitant treatment should be tempered, as this is highly likely to confound interpretation of outcome on some of the symptoms that are core to the illness itself (and on safety assessments).  Furthermore, permitting this strategy may also inadvertently create more population heterogeneity, or permit the enrollment of subjects who are more refractory to any treatment intervention (because of their urgent clinical requirement of concomitant medication use), thereby reducing the likelihood of identifying important treatment benefits from the intervention under study.  If perceived as necessary, an alternative approach would be to use the need for access to rescue treatment or early termination as a secondary efficacy endpoint in a study design, or to limit access and require study discontinuation if a participant cannot maintain in the study without such support.

In conclusion, the creation of this draft guidance is important because it documents ME/CFS as a genuine object of regulatory study.  The major drawbacks to the document are that it lacks a level of specificity that is up to date with the current research activity that has already occurred, or with emerging evidence of standard outcome measures that already can be plausibly considered as appropriate study endpoints or at least be considered as model starting points for future development.  As written, it points out more of the gaps that exist in the research arena and does not serve as a very inviting guidance that would inspire an industry sponsor to step up to the research plate.  We hope that these comments serve to strengthen this guidance document and to highlight the opportunities for drug development and to help this population of patients.

Carol E. Head | President & CEO | Solve ME/CFS Initiative

Suzanne D. Vernon, Ph.D. | Scientific Director | Solve ME/CFS Initiative

R. Larry Baldwin, M.D. | General Surgeon | ME/CFS since 1993

Italo Biaggioni, M.D. | Professor of Medicine and Pharmacology | Vanderbilt University

Mark A. Demitrack, M.D. Vice President and Chief Medical Officer Neuronetics, Inc.

Peter Rowe, M.D. | Professor of Pediatrics | Johns Hopkins Children’s Center

Terry Tyler, M.D. | Diagnostic Radiologist | Father of ME/CFS patient

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Read our prior blog posts on the draft guidance

On April 24th, FDA held a webinar to discuss the guidance. If you are interested in hearing the webinar in its entirety, it was recorded and is available on the FDA website HERE.
http://www.fda.gov/Training/GuidanceWebinars/ucm392577.htm

To review the draft guidance document in its entirety, you can access it HERE:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM388568.pdf