Last year, the FDA said it would be preparing Guidance to Industry on drug development for ME/CFS and now they have delivered. Guidance for Industry Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Developing Drug Products For Treatment* has been published in draft form, and the public has 60 days to submit comments. In this post, I will simply summarize the draft guidance. I hope to post more detailed analysis later this week.
FDA’s Guidance for Industry documents are intended to capture FDA’s thinking on a topic, including drug development for specific diseases. The need for such guidance was put on display last year in the FDA’s denial of approval for Ampligen and in discussions at the April PFDD and Drug Development meeting on ME/CFS. While Guidance documents are not legally binding, they do convey a sense of FDA’s preferences and how it might approach the drug review process for ME/CFS treatments. Here’s what stood out to me in my review of the document:
Unmet need: FDA says “CFS/ME is a serious disease and there is unmet medical need in the treatment of CFS/ME.” This represents “a public health concern.” (page 3) This means that drugs for ME/CFS may qualify for one or more of the expedited review programs.
What is it: Consistent with earlier statements, FDA is using CFS/ME to refer “to a disease or set of diseases.” (page 2) FDA is not taking a position on exactly what disease or diseases is covered by this Guidance, so it can include CFS, ME, or ME/CFS. The document includes a list of symptoms, and notes that post-exertional malaise and cognitive impairment are particularly severe for patients.
Defined as: FDA is also not taking a position on the suitability of one or more case definitions, also consistent with earlier statements:
At this time, the FDA does not recognize any particular disease definition, nomenclature, or diagnostic criteria for CFS/ME as the most appropriate for use in clinical trials of new drug products. Consequently, any case definition or criteria for CFS/ME can be used to define the patient population. (page 3)
Patients with confounding conditions that cause fatigue and related symptoms should be excluded, and sponsors should define whether the target population is a “general CFS/ME population or a subset.”
Endpoints: Efficacy endpoints should include patient-reported symptoms, and may include objective measures. A single primary endpoint with supportive secondary endpoints will be sufficient. Biomarkers can be used as “exploratory endpoints,” but primary endpoints must reflect benefit in how the patient feels and functions. In other words, patients have to feel better; change in a biomarker is not sufficient on its own. (page 4)
Other treatments: A placebo group does not need to preclude usual care treatments, and “patients enrolled in the trial should be permitted to use concomitant treatments as needed to manage disease symptoms.” (pages 4, 6) The treatment design must take this into account.
What is effective: The sponsor must demonstrate substantial evidence of efficacy in CFS/ME symptoms. Since no PRO instruments are optimal for measuring fatigue or other symptoms of CFS/ME, FDA will consider using instruments validated in other conditions. This is good news, because it means developers do not need to wait for FDA to validate PRO instruments specifically for ME/CFS. (page 5)
Post-exertional malaise: FDA recognizes that post-exertional malaise and exercise capacity are two different potential areas of treatment benefit. Either exercise testing or PROs measuring post-exertional symptoms can be used to measure efficacy of treatment, recognizing that some tools would not be appropriate for severely impaired patients. (page 5)
Quality of life: As for general measures of effectiveness, FDA will consider health-related quality of life measures validated in other conditions. Direct evidence of improvement in a patient’s performance of work, household, and personal tasks can demonstrate treatment benefit. (page 6)
How long: Given the chronic nature of CFS/ME, treatment trials must last at least 24 weeks, and possibly longer. Two definitive trials showing efficacy should be sufficient. Long-term safety trials must be conducted, given that treatment is likely to be prolonged. (page 6, 7)
Combos: A new drug product can include a combination form of two or more individual drugs. This is important because several clinical trials of combination therapies are in the works. In addition, a drug product that requires a specific accessory (like an injector) must ensure the device is approved as well. (page 7)
*Credit to @mrkipping on Twitter for putting out the first notice I saw about the document. 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.