Comment on FDA Draft Guidance

I submitted the following comments to FDA on its Draft Guidance to Industry on ME/CFS Drug Development. Please note that there is a 5,000 character limit on electronic comments submitted through regulations.gov, so I sent my comments in by mail. Full instructions for submitting comments are at the bottom of this post. Disclaimer: I am a member of the FDA’s Patient Representative Program. However, this post represents my personal opinions and are not comments made in any official or formal capacity.

Thank you for this opportunity to provide comments on the FDA’s Guidance for Industry Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Developing Drug Products for Treatment.

I am very pleased that FDA has issued Draft Guidance for Industry on developing drugs to treat ME/CFS. It’s clear that FDA listened to the patient experiences recounted at the April 25-26, 2013 Patient Focused Drug Development Meeting. I offer the following comments to improve the draft guidance:

Case Definition:

The Guidance states that FDA does not recognize or prefer any specific case definition for ME/CFS. FDA further explained at the April 23, 2014 webinar meeting that drug sponsors will be permitted to select criteria and expected to provide justification for the same. While this flexibility may be preferred by FDA and sponsors, I believe it creates potential problems.

As FDA is aware, there are multiple case definitions in use for ME/CFS. These definitions range from the narrow Canadian Consensus Criteria for ME/CFS to the very broad Oxford case definition. Indeed, the Oxford definition only requires a patient to have six months of fatigue to be diagnosed with CFS, and conditions like depression or anxiety are not exclusionary. As a result, many patients who meet the Oxford definition will not have most of the symptoms described by patients at the PFDD meeting, including the hallmark criteria of post-exertional malaise and cognitive impairment.

By allowing a sponsor to choose a definition as broad as Oxford, FDA runs the risk of a drug being marketed for ME/CFS when in fact it has only been tested on patients with six months of fatigue. There is no equivalence between six months of fatigue under Oxford and any of the other more restrictive criteria for ME/CFS. A drug that treats fatigue may not be safe and/or effective in ME/CFS patients, and vice versa.

As FDA has rightly said, there is a serious unmet need for ME/CFS treatments, and such products may qualify for one or more expedited review programs. This could potentially give unfair advantage to sponsors of anti-fatigue drugs who never test the treatments in actual ME/CFS patients because they use the Oxford criteria.

FDA may not be prepared to endorse a single case definition at this time, but I urge FDA to be very clear on the difference between chronic fatigue (a symptom) and ME/CFS (a disease). These categories cannot be treated as synonymous. FDA should not accept the use of the Oxford criteria for CFS under any circumstances because those patients may only have the symptom of chronic fatigue.

Measuring Effectiveness:

The Guidance states that efficacy must be demonstrated in improving ME/CFS symptoms. At the April 23^rd webinar, FDA clarified that efficacy can be demonstrated in any one or more of ME/CFS symptoms, and that PRO instruments are required while objective measures are optional.

While it is true that no objective measure or biomarker is universally accepted in ME/CFS, I believe that objective measures play a very important role in assessing treatment efficacy. Specifically, there are cheap and effective ways of measuring functional improvement, including actimeters (e.g. Fitbit and similar devices) and objective cognitive testing. Claims of functional improvement based solely on PROs will not be as strong as functional improvement measured with such objective tools.

PRO instruments certainly play a role in measuring symptom changes, and I am glad FDA is willing to accept PROs validated in other conditions. However, I know from my own experience how difficult it can be to recall or perceive changes in symptom severity. I urge FDA to encourage sponsors to use actimeters or cognitive testing to objectively measure functional changes in patients.

I also strongly recommend that FDA require sponsors to measure changes in symptoms and functionality throughout clinical trials. It is well-known that ME/CFS symptoms fluctuate over time, and sometimes the causes of such fluctuations cannot be identified. A clinical trial that only measures symptoms on the trial start date and the trial end date will be unable to control for such changes. This could result in blunted or inflated efficacy data. While measuring multiple time points will add to the cost of trials, it will more accurately capture any treatment effect (and side effects).

Trial Duration:

The draft Guidance states that sponsors should conduct 24-week clinical trials in ME/CFS patients. However, many patients have reported extreme sensitivity to medications. A 24-week trial may not be long enough to allow patients to ramp up to an effective dose if they must begin at very low doses to avoid severe side effects. In addition, ME/CFS patients frequently must wean down medication doses very slowly to prevent withdrawal symptoms, even if patients with other conditions do not need the same time span to stop the medication. FDA should be aware of both of these factors, and be prepared to instruct sponsors that longer trials may be required to avoid high drop out rates and serious side effects.

Placebo Selection:

Many patients, myself included, experiment with intravenous saline to treat orthostatic intolerance and fatigue symptoms. Therefore, saline may not be a true placebo for drugs administered by IV. This is especially true in patients who have not tried IV saline before. Clinical trials of IV drugs should begin with at least 4 weeks of IV saline for all patients, before beginning courses of treatment or placebo. This will enable sponsors to capture any effect of the IV saline alone in all subjects, and thus better measure actual clinical benefit of the treatment.

Again, thank you for the opportunity to comment on this important Guidance to Industry.

• To submit an electronic comment, go to http://www.regulations.gov and use the docket number FDA–2014–D–0264, or try this direct link. Use the “Comment Now” button to open up a screen to enter your comments.
• To submit a written comment, be sure to list the docket number FDA–2014–D–0264 on your letter and send it to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852