Precision Is Required

Post updated June 28, 2013. See end of post for additional information from FDA.

Five ME/CFS advocates recently sent a letter to DHHS, FDA and select members of Congress requesting that FDA convene a second meeting with ME/CFS patients “to develop a clear regulatory pathway” for drugs to help us. This letter has been followed by a call for patients to email FDA in support of such a meeting. However, both the letter and the email template contain multiple statements that are inaccurate or imprecise. I am concerned that these errors are significant enough to potentially undermine the effectiveness of the letter with the very people it is meant to influence.

Part of my role as an FDA Patient Representative is to bring the ME/CFS perspective to FDA discussions. But another part of my role is to bring accurate information about FDA to the ME/CFS community. It is in that spirit that I point out a few of the errors in this letter and email campaign. I am not trying to micro-edit or nitpick. Rather, I believe that precision and careful crafting of requests can make us all more effective advocates.

The rules should not apply

The email template includes this statement:

FDA has the power and the authority to waive traditional regulations when healthcare demands, particularly when the disease is serious/life-threatening, as ME/CFS clearly is.

No, FDA cannot do this. FDA is one of the most highly regulated agencies in order to make it very clear what FDA can and cannot do. The products that FDA monitors and regulates account for a huge part of our economy. FDA has an extraordinary amount of power, but the regulations exist to constrain that power. FDA cannot look at a situation, wave a wand and say the traditional regulations do not apply. There are alternatives to “traditional regulations,” but those alternatives are themselves defined by more regulations.

No regulatory pathway

The letter sent to FDA and select Congressmen states, “The FDA must create such a regulatory pathway for ME/CFS.” I’m seeing this phrase – regulatory pathway – pop up in multiple places now. While the letter does not say so, I frequently see the phrase used in comparison to AIDS, tuberculosis and Alzheimer’s. To paraphrase the argument: those diseases have special regulatory pathways so we need one too.

But this is not correct. TB and Alzheimer’s do not have their own regulatory pathways. To my knowledge, there are no disease-specific or individualized pathways. There are special programs to accelerate review, and these were discussed at the FDA meeting by Melissa Robb beginning at page 74 of the meeting transcript. These programs include Accelerated Approval, Fast Track, Priority Review, and Breakthrough Therapy. These programs are all defined by regulations, but they do not lower the standard for safety and effectiveness nor are they specific to a single disease.

Where FDA does get disease-specific is in issuing Guidance to Industry. Guidance documents are intended to give FDA’s perspective on a specific issue or disease. For example, the draft guidance to industry on developing drugs for early-stage Alzheimer’s provides FDA’s thinking on the design of clinical trials for this purpose, including selection of patients, selection of endpoints, and ways to demonstrate disease modification. Guidance documents go through substantial processes of development, including a period of public comment. The documents also do not establish legal or regulatory requirements; the guidance is a non-binding recommendation from FDA to industry.

Guidance to industry on ME/CFS was proposed at the April meeting by several people, including Ms. Jody Roth from Eli Lilly. Dr. Theresa Michele, Clinical Team Leader in FDA’s Division of Pulmonary, Allergy and Rheumatology Products – where all ME/CFS drug applications are reviewed – said:

[G]uidance for industry is definitely, I think, an important next step. It’s something that we here at FDA are already thinking about. . . and we hope to be working on that definitely over the next months to a year or so. It takes a long time for a guidance from FDA, just the logistics of getting it through the system. FDA Drug Development for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Public Workshop Day 2, April 26, 2013, pp. 339-340.

The advocates’ letter was dismissive of the prospect of a report, saying: “A report of any kind, but particularly one that has no specific deadline, is a very poor outcome for the amount of work that was put forth by the FDA, the experts and, most importantly, this debilitated population of patients.” But there is a significant difference between a summary report of the meeting and a Guidance to Industry document. FDA can’t force drug developers to come into the area of ME/CFS. But FDA can encourage it, and can provide industry with the guidance it needs to design good clinical trials. From what I heard on and off the record at the meeting, FDA is ready and willing to do exactly that. A Guidance report would be an outstanding and much needed outcome from the meeting.

Precision is so important, especially in communicating with FDA. Claiming that other diseases have individual regulatory pathways is inaccurate. I think I know what the advocates mean here: that FDA should clearly state what endpoints and outcome measures should be used in clinical trials, and then shepherd review of products through the various pathways for accelerated approval. But that is not what the letter says, and therefore there is a risk that FDA will not understand that this is what they mean.

May I Have Another?

The fundamental request of the call to action is for FDA to hold a “true” stakeholders’ meeting by the end of the year to define a regulatory pathway for ME/CFS treatments. But why would FDA agree to hold another meeting when we’re only sixty days out from the first, especially when the meeting comment docket has not closed yet? While the letter cites numerous criticisms of the April meeting, it seems to ignore that requesting a second meeting so soon after the first and in this fiscal climate is extraordinary, and therefore a compelling case must be made in support of that request. I fear that the errors and imprecision in this letter and email campaign undermine the attempt to make a sufficiently compelling case.

Effective communication requires understanding the context and language of the audience. If we are imprecise or inaccurate, the audience will get distracted by our mistakes and lose sight of what we are actually trying to say. In turn, this can lead to the failure of the overall communication through misunderstanding or even outright dismissal. FDA’s language is based on statute, regulation and science. The errors I discussed are potential signals to FDA that we do not actually understand what the agency can do or the best ways FDA can help us.

ME/CFS advocates require the same of others. How do we react when someone says “chronic fatigue” instead of “chronic fatigue syndrome”? Or “CSF” instead of “CFS”? We expect clinicians, researchers and agency representatives to know our issues and our language. We all know the difference between the Oxford definition and the Canadian Consensus Criteria, and we justifiably react negatively if someone tries to tell us those definitions are basically the same thing. To communicate effectively with us, an agency representative would do well to be precise and accurate. Otherwise, we end up reacting to the mistakes in the message and the actual message gets lost.

To be effective advocates, we must also be precise and accurate and we undercut our own position if we fail to do so – even if the failure is accidental. I know the advocates who have called for this action, and have worked with them in the past on other efforts. Each of them is deeply committed to advancing the cause of ME/CFS patients. But as advocates, we have a responsibility to communicate as clearly and effectively as possible. It is worth the time and energy invested to craft a specific, accurate and strategic request that speaks to the context of the audience. Such a carefully crafted request focuses discussion on the substantive issue, rather than accidentally diverting attention with misstatements.

We owe it to each other and the ME/CFS patient community to get things right. We must speak with precision and clarity about complex topics, while also presenting a strong case for what ME/CFS patients need. It is not an easy thing to do, but it is essential to our collective and ultimate success.

Update June 28, 2013: After some discussion in the comments, I asked FDA whether the April meeting was sufficient to begin the Guidance to Industry process, and whether FDA would be pursuing it. Dr. Theresa Michele replied via email to me, in part:

With regards to the guidance for CFS—yes, we are working on it. The April meeting was an excellent starting point. Please be aware that the guidance process takes many months of internal writing and editing before anything is posted, since multiple groups at FDA have input into all guidances.   During this process, we will continue to take into account any new information that becomes available, such as the CDC study and the NIH Evidence Based Methodology Workshop. Once the guidance posts, it will be considered a “Draft Guidance” and FDA will take into account any comments we receive from the public before publishing a Final Guidance, usually several years later.

In the meantime, industry is not without recourse—the Division of Pulmonary, Allergy, and Rheumatology has made it very clear that we are extremely open to granting development meetings to any sponsor interested in developing products for ME/CFS. (emphasis added)

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20 Responses to Precision Is Required

  1. Suzanne D Vernon says:

    Thank you Jennie – this is excellent. It reminds me of the testimony given by Leigh Reynolds at the CFSAC. Our communities voice is so important in this discovery and regulatory process, but is has to be the best and most unified voice.

  2. Melissa says:

    These are excellent points, Jennie. Thank you for the clarification.

  3. Gabby says:

    Thank you Jennie. I wish the advocates would have consulted with you before sending out this letter. It is to all of our benefits that the voice that represents us is a voice of knowledge and reason.

  4. pat fero says:

    I am not involved in FDA efforts, although I admire the work everyone has put into getting meetings, writing letters and being clear that we have no treatments. I agree that precision is important, However, oftentimes, advocates work in the worst of circumstances and there is a tendency to take short cuts. WELL intentioned, but unfortunate. I saw this over and over with NIH funding. People making assumptions about the grantmaking process, giving inaccurate testimony and making big generalizations about NIH. BECAUSE I spent 10 years working on this, I knew, but I did not say anything. (My choices). SO what do we do with the fog and the work and the understanding that SOMETHING HAS TO HAPPEN? PROGRESS MUST BE MADE. With NIH I checked every teeny “fact” and process, but it was brutal. MY CHOICE. It is hard. Obviously, Jennie has her facts linked to rules, so there is reason to check it out. OTOH, the people who wrote the letter are taking action which is a good thing. I would hope that out of this might come better checking, and more collaboration. I SO hope that people do not attack the message. We always want to get it right and all of these agencies are complex. I believe that I used to know more about the innerworkings of NIH than most anyone else. I DID. Several years have passed. These agencies evolve. We have no inside operatives to tell us that changes have been made.

    Anyway, to say the best and most unified voice might be a contradiction and it sounds like that means one person, one voice, one group. Simply not true. I just want thunder, our collective thunder and I would hope for absolute accuracy, but that is unrealistic. We just go with the flow of it, don’t take it personally and know that together we can make change. Nice work J.

  5. Christine says:

    Agree with Gabby. I would have been a wise move to consult you with your expertise and your function as FDA Patient Representative. It’s unfortunate that they didn’t and we now have to deal with inaccuracies in both letters.

    Excellent post Jennie, I learned a lot. Thanks so much.

  6. Well said Jennie. Great talking points. Before any advocate(s) meets with Congress, Governmental Committees and/or Governmental Agencies; it would be wise to engage legal and political assistance for guidance in dealing with such agencies.

  7. Kristina says:

    I appreciate the advocates who wrote the letter and also Jennie Spolita for her insight. Hopefully in the future, the advocates can work with Jennie on FDA matters and put together a more precise arguement. Thank you to all who are working on our behalf.

  8. Cort Johnson says:

    As one of the signers of the document I’m speaking on my own. Jennie does have some points and I appreciate her rigor in this matter but I feel compelled to address one point, at this point and that’s the desire for urgency.

    Jennie’s right that it takes a long time to get the government to move forward and we were in discussions with the FDA for over a year to get that meeting going. My original understanding was that the meeting was going to focus on creating guidance for drug development. That obviously didn’t even begin to happen in a rigorous way.

    So while Jennie was listening to the meeting that did happen we were frustrated about the meeting that didn’t happen, and I think it was legitimate and fair to voice that frustration. In fact, I think it was warranted.

    What we’re left with it appears to me is a summary report of a meeting, in my personal opinion, which has little chance of achieving anything significant other than acquainting some FDA members with ME/CFS.

    I don’t see how the FDA can produce a Guidance document from that meeting. There was no rigorous examination of the endpoints needed, nor of the subsets present, nor of the confounding problems with definitions, etc. There was no focused examination of the research of any kind.

    Take measuring post-exertional malaise – perhaps the key issue for the FDA. For that topic we got a presentation from Dr. Snell. What we didn’t get was a rigorous examination of different ways post-exertional malaise has been measured, the pro’s and con’s of each, and the beginning of a process to determine how to best validate that issue in ME/CFS.

    That is just one topic of many that should I believe have been covered in any meeting that was designed to produce a ‘guidance document’ to industry.

    What we got were general ad hoc discussions about panel members good ideas and a kind of ‘get to know’ ME/CFS attitude. While it was helpful for the FDA to get to know ME/CFS better, that was not what I hoped for or expected when we started this process.

    So yes, I think it is appropriate to ask the FDA to do more, even in this difficulty regulatory climate and do it as quickly as possible. As far as I’m concerned I still waiting for the meeting the FDA promised us well over a year ago.

    These are my personal observations and may not reflect the others in the group.

    • Jennie Spotila says:

      This is really helpful perspective, Cort. You raise an important question: was this meeting a sufficient basis for a Guidance to Industry document? What is the process FDA follows in drafting Guidance for public comment? I’ll see what I can find out.

  9. Firestormm says:

    Great post Jennie. Thanks.

  10. Bob Miller says:

    As one of the Advocates who worked for nearly 2 years to get the ME/CFS – FDA Stakeholder Workshop arranged, I can assure ME/CFS patients that much work and research has been done to ensure an accurate process. Working directly with the FDA for over one year now has brought their attention to focus on ME/CFS. While I agree with Cort that Jennie does address some key items in this blog, they only appear to be key, if you are unaware of the ground work and the interactions that have been done thus far. Also the Regulatory process at FDA is a ball of twine, so unless you have the assistance of an FDA regulatory expert, it is easy to miss Special and/or Specific pathways for Drug Approvals.

    I will address this Key Statement below tonight and leave the rest for later:

    “The email template includes this statement:

    FDA has the power and the authority to waive traditional regulations when healthcare demands, particularly when the disease is serious/life-threatening, as ME/CFS clearly is.

    No, FDA cannot do this. FDA is one of the most highly regulated agencies in order to make it very clear what FDA can and cannot do. The products that FDA monitors and regulates account for a huge part of our economy. FDA has an extraordinary amount of power, but the regulations exist to constrain that power. FDA cannot look at a situation, wave a wand and say the traditional regulations do not apply.”

    While the below is Not a magic wand, it does allow great lead way and flexibility for the FDA to stray from their “traditional regulations.”
    The FDA has significant discretion at its disposal in determining whether applications have met the bar of “substantial evidence.” The regulations in 21 CFR §314.105(c) state that the “FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards.” Regulations in 21 CFR §312.80 reinforce the need for flexibility, specifically with regard to the review of drugs to treat life-threatening and severely debilitating illnesses, stating that the “FDA has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness.” In fact, the FDA has the ability to waive any or all of the criteria outlined as required for “ADEQUATE and WELL CONTROLLED INVESTIGATIONS .” The regulations in 21 CFR §314.126 paragraph (c) state, “The Director of the Center for Drug Evaluation and Research may, on the Director’s own initiative or on the petition of an interested person, WAIVE IN WHOLE OR IN PART ANY OF THE CRITERIA [for “adequate and well-controlled” investigations].”

    As I stated above, much work and research has been done and it continues, there have been interactions with FDA, Congressional and Senatorial Representatives, expert ME/CFS researchers & clinicians and others for some time. I appreciate all the work done to move forward to access treatments for all ME/CFS patients. I also appreciate Jennie taking an interest in this Action, Jenie if you have concerns about the Action, my email is posted on the Action, just contact me and I will do my best to update you and address your questions.

    Bob Miller

    • Jennie Spotila says:

      Bob, thank you for taking the time to add your perspective. I know I have a lot to learn about FDA. One thing that impresses me about the Patient Representative program is that FDA provides ongoing training to help Reps better understand FDA and drug evaluation.

      The email template includes the statement that FDA has the power to “waive traditional regulations.” You cite, as an example, the regulation that allows the Director of CDER to waive all or any part of the criteria for adequate and well-controlled investigations. But those are two different things! The regulation you cited sets forth how the Director of CDER can do this, including the requirements for the petition for the waiver. It is a waiver of criteria for adequate and well-controlled investigations. It is not a waiver of the regulation itself. Waiving a regulation is NOT the same as waiving criteria.

      Perhaps this seems like a distinction without a difference to most people. There are people who might say that Oxford vs. Fukuda is a distinction without a difference since they both require severe fatigue. But these distinctions matter very very much to the audience. The challenge of communication (in any context) is ensuring that your statements actually say what you mean. This is especially difficult in specialized contexts like research, medicine or regulation. The audience (in this case, the FDA) can only interpret your words. Our job as advocates is to make sure those words are as accurate and specific as we can make them so that the audience understands what we really mean.

  11. Simon McGrath says:

    Great post, Jennie: considered and wise.

    I also agree with Cort about the need for more precision and urgency on those FDA Guidelines, which is the one thing that could do most to speed up drug approval for this illness.

    I wonder if there is an opportunity for a follow-up letter from the original authors, perhaps correcting some of the misapprehensions and focusing on the FDA Guidelines as the key action from the FDA that needs to happen fast. I suspect that will make it harder for the original letter to be dismissed, and increase the chances of a good outcome.

  12. Kristina says:

    I am very glad to see a discussion between the letter-writers and Jennie here. I hope that it continues now and in the future. I am also hopeful that discussions will take place in a public place where possible so that the greater patient community understands our obstacles.

  13. Sasha says:

    I also appreciate the discussion that’s going on here. We’ve just had two actions where groups of advocates have requested the mass support of the community – the FDA petition on the name and definition and now this – where the call to action has been swiftly followed by concerns voiced by other advocates. Inevitably the discussion quickly moves into a closely-argued and technical discussion that’s beyond the capacity of most patients to follow.

    What results is probably confusion and at least some dissipation of support, not only for the action in question but also any future action called for. That’s why I’m so glad to see a constructive discussion opening up here. I don’t think that we can have this pattern repeating without damage to our ability to get the changes we all want to see.

    I know that everyone who has been involved both in proposing actions and questioning them has acted with the best possible motives and I hope that everyone is now discussing how to avoid this kind of problem happening again.

    I can only guess at how much work goes into preparing one of these calls to action and we must do everything we can to make sure that they’re ready to fly when they’re launched.

    Perhaps there needs to be some discussion of process before the next campaign, whoever’s it is. I also hope that the wider patient community can be involved in that.

    Thanks to all of those involved for doing their best in a challenging environment, especially with their own ill-health to contend with.

  14. James says:

    Thanks for clearing up what can be and cant be done, this article is a lot help to us.

  15. LC says:


    Your points are well-taken and I agree with the need for accuracy but Cort makes a good point about timeliness. If people delayed and delayed until every i was dotted and every t was crossed and every party were satisfied, nothing would ever get done.

    I am also concerned with the burden placed on patients and advocates to learn the system thorougly when 1) we are hardly experts on the system 2) patients are sick to begin with 3) some documents, as you know, as citizen we are not privy to and there are delays in getting answers.

    As to comments about why the letter was not run by Jennie, I can guess. Jennie is the FDA patient representative. Like many things, this is a double-edged sword. On the one hand, she understands the illness well, is eloquent/ thoughtful, and can convey information to the community. On the other hand, as a government employee, even part-time or occasional, there may be restrictions on what she can say or do. And how she can interact or not with advocates. Regardless of how she or advocates feel about it.

    (Having worn several hats in other circles in my past life, I had asked my mentors about this years ago and their instructions to me was to always be honest about your role and who you were representing at different points, esp. when your roles might conflict with each other.)

    I’ll let Jennie and other involved in that process comment on any conflicts further since I have never been a government employee although I’ve read up on the restrictions a bit.

    • Jennie Spotila says:

      LC makes a very important point, which I try to be mindful of: always be clear on which hat you are wearing and the role you are playing at all times. I completely agree. The reason I did not comment on this proposed action or on the letter before my post was simple: I was not asked.

      There are confidentiality rules and conflict of interest rules that I must abide by as a Patient Representative (which is classified as a Special Government Employee status). In this case, I don’t think I would be barred from participating, at least in providing background and feedback. But obviously, no advocate is obligated to talk to me about any action, including one aimed at FDA. And I am not generally barred from advocacy activities.

      I will always be clear about what role I am playing, and I am always willing to help my fellow advocates to the best of my abilities and within my limitations.

  16. Kristina says:

    Thanks Jennie, I did not realize that you were an FDA “employee”. I guess I still don’t quite understand your role with the FDA. Are you supposed to represent the patient side of the issues at non-public FDA meetings? I understand that you would not be allowed to speak publicly to the patients about all that you learn. I was thinking of you as a liason between the patient community and the FDA – would that be accurate? Thanks!

    • Jennie Spotila says:

      Members of federal advisory committees, like CFSAC, are called Special Government Employees. It doesn’t mean I work for FDA in the traditional sense. I think the SGE designation is necessary in order for committee members to receive compensation for their time, and so that the government can do extensive background checks for conflicts of interest.

      As a patient representative, I’m eligible to attend non-public meetings but I understand that to be very rare. I’m also not an official liaison, but the role includes elements of that. I receive training to help me understand FDA better, and there’s general encouragment to share that kind of information with the patient community.

      The primary role for a patient rep is to bring the patient perspective to FDA advisory committee meetings. If you watched the committee meeting on Ampligen, then you probably remember Alaine Perry who served as patient rep at that meeting. She asked good questions, and was very articulate in sharing the patient perspective on multiple points. If there is another advisory committee meeting for a drug to treat ME/CFS, then it is possible that I could serve that way (subject to conflict of interest, etc).

      I hope that makes it clearer, Kristina. Let me know if you still have any questions about it and I will try to explain it better.

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