Guidance to Industry

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 In this post, I will simply summarize the draft guidance.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.


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13 Responses to Guidance to Industry

  1. Robert Morley says:

    While I know we’d all like for there to be concrete criteria applied to ME/CFS, I like how they’ve handled this topic here. Yes, it can still leave the door open for some very broad definitions, but with the requirement that efficacy be demonstrated and any subgroups noted, I think it works. If a treatment happens to be effective on all of us, great! If it only seems to affect certain subgroups, they’re required to note that. Seems like a good approach to me.

    While I realize this is intended to apply to drugs, looking at some of their requirements—like diagnostic criteria, PEM, qualify of life, and duration—I have to wonder how the PACE trial would have faired if this had been applied there.

    • Jennie Spotila says:

      Given what we know of the PACE methodology, not well at all! Changing your analysis plan post hoc is a very bad thing.

  2. Rebecca says:

    What are PROs?

    • Jennie Spotila says:

      Patient Reported Outcomes. It refers to questionnaires and other ways of measuring the patient’s experience of symptoms and quality of life.

  3. Tina says:

    I note they want to use measurement tools for other diseases. I can see positive and negative for this. Positive is that it legitimizes our illness in that it isn’t that weird disease that isn’t like anything else. Negative because we really do have symptom fluctuation unlike any other disease, at least to that extreme.

    CDC is big on the PROMISE tool, saying it exists and is used in other diseases, and they think it will work for our disease too.

  4. Robert Morley says:

    @Robert Morley
    One of the things I hate about CFS is how often I make homonym typos without realizing it now. 🙂

    “faired” = “fared”

  5. rivka says:

    thanks for this! what sort of comments do folks think we need to offer the FDA about this?

  6. Billie Moore says:

    Thanks, Jennie. This will be a very useful overview in reviewing the document, for a guidance long needed. Next what we need is a meeting of the FDA, stakeholders, and INVITED pharmaceutical companies (not just a notice in the Federal Register) – companies that are already producing drugs that are used off label successfully for some patients – anti-virals, rituximab, etc., to discuss how to get a drug or drugs for the disease approved in the near future. And to have the FDA do this in 2014.

    I have to say, I think the FDA has made much more of an effort to be more responsive to the ME/CFS community than the NIH and the CDC. Although I also have to say – the FDA would NOT have done it without the push from the patients in 2012 and 2013. Still, the NIH is not budging on the IOM study regardless of the patient and expert outcry against it, and the CDC is only making superficial changes to its education efforts (toolkit, CME course, etc.) in face of great pressure from the community to do so. So, kudos to the FDA for moving farthest fastest.


  7. Mike Walzer says:

    Thank you.
    I understand the FDA has no single case definition or set of criteria that is uniformly recognized as the standard for diagnosing patients with the disease. 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.
    This may be off topic, but I remember at the most recent FDA Ampligen approval process there were drugs to be considered that were already approved and considered for fast track to market. Unfortunately the medications were antidepressants and I believe Provigil, etc. These medications that were suggested by the FDA are for secondary symptoms. Cidofovir IV which is an already approved FDA medication (safety and efficacy to reduce viral load for CMV-herpes family..with diagnostic tests).
    I have to ask that if off label use of Cidofovir IV for patients with EBV, HHV6, CMV are being used sucessfully by Dr Martin Lerner and Dr Daniel Peterson why is there no diagnostic criteria approved test for viral, immune, and auto-immune dsyfunction in a similar subset of CFS not HIV patients? On the ground lab test that show activation of of these viral antigens with depressed immune function have sufficed for the FDA w CMV- a herpes virus. I dont believe our population or partial population should suffer one more minute. If Cidofovir IV is safe and efficacious for reducing CMV load by the FDA why cant they approve this drug immediately for other viruses that all lump into the herpes family? I am a huge proponent of drug development, but I see no reason why this medication is not at the top of the list for fast track and would love to know why not from the FDA (unless it is?). In addition governing agencies should require lab tests for viral load and immune deficiency to paid for by all insurers. Is it not so with CMV? I am scratching my head why fellow ME patients properly tested arent getting the same test and treatments that the FDA approved and covered for CMV HIV. This medication has already shown more effective than Provigil and AD’s for Viral and immune issues by our clinicians. Not to discount antidepressants for secondary depression and Provigil for fatigue. Cidofovir IV has its risks and must be administered in and by the proper physician/setting. These venues already exist and at least with CMV are demeaned safe/risk/benefits,insurance approved by the FDA,et al. Why isnt the FDA starting here?
    Thank you for your blog. I realize this might be off track but should be stated.

    • Jennie Spotila says:

      I don’t know anything about the status of Cidofovir IV at FDA for ME/CFS or any other indication. It’s important to note that FDA can only act on applications that have been submitted and accepted for review. If the manufacturer of Cidofovir is not pursuing approval of the drug to treat ME/CFS (or a subset) than there’s nothing FDA can do. Do you know if there are any active clinical trials (double-blind, placebo controlled)? If so, the new Guidance would provide some info about what FDA will be looking for in evaluating such trials.

  8. Nancy Blake says:

    It certainly sounds like the FDA have a pretty open mind, and seem to think that ME etc is a physiological illness for which research to find useful drug treatments makes as much sense as for any other illness. Which, as I live in the Wessely-dominated UK, is a very refreshing attitude. Having looked into the background, it seems clear to me that the IOM are taking their advice from some of the Wessely-school psychiatrists and that they have already decided to put ME/CFS into the ‘Complex multisystem illness’ bracket – but also, as has already been stated in their Gulf War Syndrome report, regard these as ‘functional’ disorders, and of course CBT and GET will be coming down the line, as we all already know. What I find interesting is that the ‘Complex multisystem illness’ category includes ME and lupus, both of which were considered to be psychosomatic, or hysterical, or conversion disorders – until they became better understood medically, as autoimmune disorders. Have they not noticed? In the meantime, cheers to the FDA!!
    Postscript re PACE – they used an actometer in the pilot, which I understand does actually measure activity levels (which are known to be exaggerated in self-reports), and they dropped its use in the trial itself. I think it should be suggested that research into improvement should include a way of independently measuring increases in activity, rather than relying only on self-reports. And Tom Kindlon has written an impressive paper about the reporting of harms in any medical research – that should be part of it as well. If half the subjects drop out because the treatments are making them worse, they should not drop out of the final statistics.

  9. Nancy Blake says:

    Dear me – please correct: ‘Complex multisystem illness category includes MS and lupus! Should have edited…

  10. Anonymous says:


    Not to put too fine a point on it but:

    1) ME/CFS is not the only illness with severe fluctuations. Other diseases have this characteristic too.

    2) It’s not “pormise” if anyone wants to look it up. It’s “PROMIS.”

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