Highest Priority, Part One

Posted on January 28, 2013 by Jennie Spotila

Over the years, the CFS Advisory Committee has made dozens and dozens of recommendations to the Secretary for Health and Human Services. This month, the Committee posted a document entitled “High Priority Recommendations from CFSAC, January 2012” (pdf link) which narrows down all those recommendation to just seven. In this part one of two articles, I examine the document itself and share some information I received from Dr. Nancy Lee. In part two, I’ll share what I learned from some additional digging (and it’s not pretty).

The Background

The idea of identifying the highest priority recommendations arose at the November 2011 CFSAC meeting. On November 8, 2011, Dr. Marshall said:

By my quick count, there are 58 recommendations, 27 of which are as yet unresolved. What about CFSAC parsing those into rough categories and make them the object of subcommittee meetings tomorrow where we cut some of them down and come up with two or three strong recommendations? The trees are getting lost because of the forest. So cut most of the forest down. CFSAC Minutes, November 8, 2011, p. 43.

The next day, discussion returned to the idea. Dr. Lee suggested, “We could do some work on these in the next month or two with subcommittee calls. When presenting material to high‐level people, you have got one page and if you cannot say what you want them to learn in about in one page, you are saying too much.” CFSAC Minutes, November 9, 2011, p. 49.

Committee members made a variety of suggestions on how to go about reducing the number of recommendations, but the minutes do not reflect any final decision for how the process would occur. Dr. Nancy Lee told me in an email on January 24, 2013 that “CFSAC members worked via the subcommittees to identify the top priority recommendations which are now on the website.” Dr. Lee provided no additional information about how the process worked or when it was completed.

The Recommendations

Whatever process the CFSAC may have followed to produce this document, the end result is seven recommendations out of the 76 made between 2004 and 2012. The document lists the selections in reverse chronological order, although Dr. Lee told me that “The priority recommendations are listed in no particular order.” Here is what the CFSAC has chosen as its high priority recommendations:

Clarify the Department’s process for considering the CFSAC recommendations. This recommendation was made in November 2011, and was answered in Dr. Koh’s letter of August 3, 2012, in which he explained the mechanics for transmittal of recommendations and responses.

Classify CFS in the ICD-10-CM in section G93.3 along with myalgic encephalomyelitis. The CFSAC has made recommendations on the code classification of CFS six times (9/04, 8/05, 5/10, 5/11, 11/11, 6/12) although the selected wording in this document is from November 2011. Dr. Koh’s August 3, 2012 letter noted that roll out of the ICD-10-CM will be delayed, but makes no further commitment or response to the CFSAC’s recommendation.

The Interagency Working Group should pool resources to enact the Centers of Excellence concept repeatedly recommended by the CFSAC. Centers of Excellence has been a recurring theme for the CFSAC, with recommendations for the idea made seven times (9/04, 8/05, 5/07, 5/09, 10/09, 10/10, 11/11). This specific recommendation was made in November 2011 and partially addressed in Dr. Koh’s August 3, 2012 letter, in which he described the Ad Hoc Working Group. He did not address the Centers of Excellence concept in any way.

Fund more research. CFSAC has recommended increasing research funding for ME/CFS through NIH or CDC at ten different meetings, frequently in multiple ways at a single meeting (9/04, 8/05, 11/06, 5/07, 11/07, 5/09, 10/09, 5/11, 11/11, 10/12). In the High Priority document, the CFSAC used a modified version of its recommendation from May 2011, and combined it with two other recommendations. I will examine this more closely in part two.

Adopt the term “ME/CFS” across HHS programs. This recommendation was made in October 2010. Despite NIH’s and FDA’s at least partial adoption of the term, there has been no HHS-wide decision made or progress reported on this recommendation.

Create a task force to focus on coordinating support for children and young adults with CFS. The specific wording used in the High Priority document dates from October 2008, but the CFSAC has made recommendations on pediatric issues at six different meetings (9/04, 8/05, 10/08, 5/09, 10/09, 6/12). These recommendations have included the creation of pediatric management guidelines and research into the diagnosis, epidemiology and treatment of pediatric CFS.

Public awareness and education. The CFSAC has made recommendations on public awareness and public education campaigns seven times (9/04, 8/05, 11/06, 11/07, 10/08, 5/09, 10/09). The CFSAC selected a recommendation made in September 2004 and August 2005 for the High Priority document, but this recommendation was marked as “complete” by HHS after the CDC’s public awareness campaign of 2006.

The Missing

The High Priority document was apparently compiled some time around January 2012, which means that none of the recommendations from the June and October 2012 meetings were included. Among the missing recommendations are the removal of the CDC Toolkit, distribution of the IACFS/ME Primer, education of educators and school nurses about ME/CFS, a standing review committee at NIH, a meeting of ME/CFS experts to discuss the case definition, and research funding for cluster outbreaks, epidemiology of severely ill patients, and biomarker discovery.

Another category of recommendations missing from the document is provider education. Over the years, the CFSAC has recommended a number of efforts to educate healthcare providers, and this area remains one of critical need. But the topic was largely ignored by the Committee in selecting the high priority recommendations, with the exception of a mention within the recommendation on Centers of Excellence.

Going Forward

I asked Dr. Lee if this High Priority list had been shared with Assistant Secretary Dr. Howard Koh, and how he had responded. She said “CFSAC leadership discussed this priority list with Dr. Koh last year; he was very supportive.” That’s all well and good, but it does not appear that this list has been used or will be used going forward.

Although the list appears to have been finalized in January 2012, there has been no public mention of it until now. Dr. Koh made a nonspecific comment at the June 13, 2012 CFSAC meeting when he said, “We want to thank [the subcommittees] for pushing those efforts forward and continuing to prioritize the recommendations that are coming out of CFSAC.” CFSAC Minutes, June 13, 2012, p. 5 (emphasis added). Apart from that, not a single member of the CFSAC referred to this document in public at any point in the year since it was completed.

This begs the question of what use the document can be if no one is using or referring to it. Furthermore, what is the status of the Committee’s other 69 recommendations not included in this document? Will this document be updated as new recommendations are made by the Committee? And finally, if this document was finalized a year ago, why was it not posted until now? Dr. Lee told me that “CFSAC staff continue to strive for transparency and frequent communication, so the list was posted when we realized it was not on the website.”

 

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Comparing Exercise Advice

Posted on January 18, 2013 by Jennie Spotila

Exercise is an issue for every CFS patient, and there is no shortage of advice on whether and how to do it. On January 14th, the CDC hosted a conference call as part of its Patient Centered Outreach and Communication Activity (PCOCA) efforts. Dr. Nancy Klimas and Dr. Connie Sol presented their exercise advice for people with ME/CFS. I’ve seen some sharp criticism of the presentation, so I thought it would be helpful to compare their advice to the recommendations from Dr. Christopher Snell’s group at the Pacific Fatigue Lab. Dr. Snell and his collaborators (Staci Stevens, Todd Davenport, Mark Van Ness) have done the most work on exercise capacity in CFS, and published a conceptual model for safe exercise in 2010. You can learn more about their work in this webinar they gave last year.

Why Do It?

It’s common knowledge that exercise is an important part of preventing heart disease, diabetes, and osteoporosis. And I think most CFS patients would be eager to exercise if it did not make us sick. On Monday, Dr. Klimas said that deconditioning explains much of the dysautonomia seen in CFS. I think she may have overstated it because there are physically fit people who develop POTS, NMH or other orthostatic conditions, but deconditioning certainly wouldn’t help. Dr. Klimas described herself as the “perfect advocate to talk about exercise” because of her decades of research and clinical experience focused on biomarkers and immune function. She does not believe exercise is the only possible treatment for the disease (unlike proponents of the psychosocial model), but she also does not think it should be ignored.

I should note that while Drs. Klimas and Sol use exercise to provoke PEM so they can measure the gene expression cascade that follows, they have published no papers on exercise physiology in CFS. Snell and his group have published multiple papers on the topic, including a study that shows deconditioning is not the cause of PEM. Despite showing that there is metabolic dysfunction unique to CFS, Snell and many other experts recommend being as active as is safely tolerated. Stronger muscles will lead to less pain. Being as physical fit as possible will improve our chances with heart disease and other long-term consequences. If we can safely tolerate a certain kind or level of activity, we should do it. The emphasis must be on the word SAFE, and activity should be tailored to each individual patient’s capacity.

Identifying a Target Heart Rate

My articles on PEM and exercise explain the body’s energy systems and the importance of heart rate in detail. For purposes of this post, I can say that both Klimas and Snell agree that heart rate at the anaerobic threshold is the limit for safe activity in CFS. So how do we identify the correct heart rate?

Dr. Sol uses a single test in which the patient exercises to exhaustion. Multiple measurements help identify the heart rate at the anaerobic threshold, and then that heart rate is used to design an individualized exercise protocol. Dr. Snell and Staci Stevens use a two day maximum exercise test to do the same thing. That second test is critical because CFS patients’ metabolic function declines significantly after the first test. In my own case, my heart rate at the anaerobic threshold went from 105 on day one to 95 on day two. Under Sol’s system, 105 beats per minute would be my maximum heart rate, but that would be too high on any day that I was not well rested. My personal view is that by skipping the second test, Sol and Klimas are at risk for setting the safety limits too high for most patients.

Not everyone can take a two-day exercise test (for a variety of reasons), so there is a simple calculation for guessing at your heart rate at the AT. Klimas and Sol recommended: 220 minus your age times 60%. In my case, (220 – 44) x 60% = 105.6 bpm (matching my AT on day one).  Stevens recommends 50%, or (220 – 44) x 50% = 88bpm (lower than my AT on day two). Here’s the problem with the calculation: a bedridden patient would not have the same limit as me (housebound) or a friend of mine (who can leave the house every day). We’re all sick with CFS; we all have metabolic dysfunction. But it’s unlikely that our heart rate limits are identical.  Patients must be cautioned that the calculation is a guess only; careful experimentation is necessary to establish your safe level.

Defining Safe Activity

Both Sol and Stevens agree that the safe level of activity is the level that does not produce symptoms. Dr. Sol said that she knows she has prescribed the right level of activity when the patient reports that he/she feels no difference. Stevens has said that any symptom flare that lasts more than a few hours is too much and that activity must be scaled back.

What qualifies as exercise? Both Sol and Stevens agree that activities of daily living should be seen as exercise. The effort required to cook a meal or shower can raise your heart rate too high, and may need to by modified to stay in the safe zone. They both agree patients should examine the activities that make them tired, and try to adapt and pace those activities. Dr. Klimas said that these methods will lead to a more even, reliable supply of energy; Dr. Snell has said the same thing.

Beyond activities of daily living, Sol suggested yoga or non-weight bearing activities such as water exercises. She recommended starting with a minute or two of activity followed by a few minutes of rest, repeated five times once a week to start. In contrast, Stevens recommends a more modest starting point of stretching and range of motion exercises. Patients should advance to low intensity, short duration activity only if the stretching is well tolerated. For Snell and Stevens, heart rate is not the only indicator of capacity. Patients must pay attention to their perceived level of effort, and avoid activities (or activity duration) that feels “somewhat hard.”

Severely Ill

There is no question that there are CFS patients who are too sick to come to a lab and pedal a bike for eight minutes. Accordingly, these patients have not been studied for metabolic dysfunction and exercise capacity. Drs. Klimas and Sol made no comment on Monday about what these patients could or should do. I interviewed Staci Stevens as part of the research for my article on exercise, and based on her advice I wrote:

A bed bound patient may need assistance to turn in bed or complete basic activities such as showering, but heart rate biofeedback can help identify the appropriate pace and duration of these activities. Bed bound patients can also try deep diaphragmatic breathing, perhaps six deep breaths at a time. Deep breathing will lower heart rate, and also work the large muscles of the diaphragm. Severely ill patients might begin with passive stretching, where a physical therapist or caregiver moves the patient’s limbs slowly and carefully to gently stretch muscles and try to improve flexibility.

This must be done very cautiously. There is simply no published data that investigates the metabolic dysfunction in bedridden CFS patients or that explains what they can do safely. The cost of trial and error can be high, so patients should be very careful.

Expectations

Reasonable and realistic expectations are an important part of any rehabilitation effort. Snell and his group describe the goal as being as active as possible within toleration, and hopefully this will lead to a more predictable energy supply (eliminating the push-crash cycle). In contrast, Dr. Klimas said on Monday that patients will show improvement if they follow the program, and that when they stay below the AT they feel “much better.” Then Dr. Klimas claimed that some patients have been able to return to work or athletics. This is an extraordinary claim, especially in the absence of published data. How impaired were these patients to start with? How long did they follow the program, and was the program standardized across patients? Did these patients show objective improvement on subsequent exercise testing? How long did their improvement last?

Personally, I was very surprised to hear Dr. Klimas make this claim. She is quite familiar with the severity of the disease, the dearth of treatments, and the danger of false hope. In my opinion, claiming that pacing with a heart rate monitor and slowly progressing exercise is curative in the absence of published data is misleading, at best. The notion that exercise will make us all better is pervasive and potentially harmful to patients. Show me the data.

The Comparison

There are many similarities between the advice of Klimas and Sol on the one hand and Snell and Stevens on the other. Both sides agree that patients should be as active as they can safely tolerate. They agree that activities of daily living should be seen as exercise. Both recommend using a heart rate monitor to pace activity by staying under the anaerobic threshold. Both recommend starting very slow with exercise, and avoiding exercise that increases symptoms.

There are also some differences. The two groups calculate the safe zone differently, with Klimas and Sol potentially setting limits higher than patients’ anaerobic thresholds. Klimas and Sol offered no advice to bedridden or other severely incapacitated patients, while Snell and Stevens offer at least a little guidance. Finally, Snell and Stevens do not suggest that their program is curative in any way. They suggest a cautious but realistic goal of eliminating the push-crash cycle. In contrast, Dr. Klimas was quite expansive in her claim that her program had helped some patients return to work.

Despite their differences, both groups give the same basic advice to CFS patients: use a heart rate monitor to help you recognize when you are doing too much; ensure adequate rest; be as active as you can without triggering symptom flares or post-exertional malaise. This is a good starting point, but I hope that one day we will have access to physical therapists and others trained to help us navigate these limits. From my own experience, trying to apply this expert advice on my own has been unnecessarily frustrating.

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Best Laid Plans

Posted on January 15, 2013 by Jennie Spotila

This is not the day I planned to come back from my holiday hiatus, nor is this the post I planned for the beginning of a new year. But as they say: “The best laid plans of mice and men often go astray.”

I made it through the holidays pretty well. One final family event was beyond my capacity, and my husband proceeded to come down with a sinus infection during his time off, but compared to previous years I was doing alright in early January. I gave myself extra days of rest, and I made some fabulous lists of things that either need doing or that I want to accomplish. I felt like I had a handle on things. Which, of course, is the signal in my personal universe for the wheels to come off the cart.

I got a norovirus.

Or something like a norovirus. Stomach bug, food poisoning, stomach flu, whatever. The acute symptoms lasted about 24 hours, and my gut took another four days to normalize. But it’s the fatigue to the point of prostration that kicked my butt. For about a week, I was sleeping ten hours at night and another three to five hours during the day. And the time I was awake, I spent staring out the window or watching tv. The first sign of improvement was when I started to stress about everything on those lovely lists I had made the week before. I’m sleeping a little less now, and writing this post, so I guess things are looking up.

It amazes me that even after more than 18 years of this disease, “fatigue” can still take me by surprise. Fatigue is such an inadequate word to describe the experience. And as most patients know, even the small systemic disruption caused by a common virus has an enormous negative impact on our body systems. I seem to be strongly resistant to upper respiratory viruses, almost never catching my husband’s colds. But we are the reverse when it comes to gastroenteritis – he never gets it and I do.

If the severe fatigue cleared up after a few days, it wouldn’t be so bad. But as it stretches into week two, I get more anxious. Will I get back to baseline? Will this acute illness cause a permanent worsening of my activity? How will we cope if I become more disabled? How will I endure day after day of sleep and misery? So far, I’ve been lucky. I always return to baseline, even though it can take weeks. And I have learned (the hard way) to listen to my body when it screams “SLEEP!”

So Happy Freaking New Year. I hope this is not an omen for how the year will go. And I hope I’ll be back to baseline and resuming my planned activities and blog posts very soon.

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Hiatus

Posted on December 18, 2012 by Jennie Spotila

Sing with it with me: It’s the most challenging time of the year!

Some CFS patients I know feel like summer is the most challenging time, between the heat and kids being off school. For me, it’s the holidays. Every year, I try to adjust my expectations and scale back on what I try to do. And every year, there is at least one day that has me on the verge of sitting in a corner, rocking back and forth and muttering about glitter.

The queue of blog posts I want to write currently stands at seventeen, and some are more time-sensitive than others. There is also the FDA meeting on Ampligen this week. But in service to my efforts to pace my activities and be realistic about my capacity, I’ve decided those posts will have to wait.  I want to keep writing for you, and some of the upcoming posts are important. But I need to spend time with my family, too. And I would really like to get to New Year’s Day and not need the entire month of January to recover from the holidays.

So I hope you will be patient with me, and that you’ll come back in a few weeks when I start posting again. I wish you a joyous holiday season, and a Happy and HEALTHY New Year for us all!

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NIH Collaboration

Posted on December 17, 2012 by Jennie Spotila

The news didn’t make much of a splash, but NIH recently issued a funding opportunity announcement that could benefit people with CFS. This purpose of this funding opportunity is to support “collaborative translational research projects” aimed at turning basic discoveries into “clinical applications that improve health.”

Unlike other NIH program announcements for ME/CFS, this one is focused on collaborations between NIH investigators at the NIH Clinical Center and researchers at labs outside NIH. The NIH Clinical Center has pioneered many treatments, including the first trial of AZT in AIDS patients and many new chemotherapy treatments. Dr. Harvey Alter, known to many CFS patients because of his involvement in the XMRV saga, is Associate Director of Research in the Department of Transfusion Medicine at the Clinical Center and a member of the Trans-NIH ME/CFS Working Group.

The NIH Clinical Center has an extraordinary set of resources for translational research, including banked specimens, high grade equipment, healthy volunteers, and experience in clinical trials. How could this be relevant for ME/CFS? Imagine bringing patients into the clinic for a pathogen study or complete neurological workups. Imagine accessing the best equipment and researchers to analyze spinal fluid from patients and controls. Most projects into the causes, diagnosis, and treatment of CFS could be done in partnership with the Clinical Center.

Fourteen institutes at NIH joined together on this program announcement, including the Office of Research on Women’s Health which chose to highlight ME/CFS as an area of interest for this funding:

One of the goals of the WG is to increase focus on collaborative ME/CFS research by identifying NIH resources that may be useful to advance the translational research within this field. ORWH encourages applications from investigators to address research questions focused on the etiology, diagnosis, underlying mechanism, or treatment of ME/CFS.

Note that this announcement is not an RFA with dedicated money set aside, and many areas of interest are highlighted. However, this represents an extraordinary opportunity for CFS researchers. NIH is offering a pre-application webinar on January 11th for interested applicants. I hope we will see applications from institutions and researchers in the CFS world to collaborate with the Clinical Center.

 

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Coffee

Posted on December 13, 2012 by Jennie Spotila

I graduated with honors from an Ivy League law school, and it was largely made possible by coffee. There was a Cinnabon right around the corner, so most mornings I picked up a ginormous vat large cup to get the day going. I mean, how else do you fuel an 11-hour study session? Coffee got me through the bar exam, and then carried me through a six week road trip. One of the best memories I have of that trip is laughing with a best friend over The Worst Cup of Coffee In The World. No, really. The coffee at the Conoco in Sandpoint, Idaho was the worst, and we gave it the official designation it deserved. Buying the first cup of coffee of the day on my way to work was my treat for being in the office by 7am, and on the weekends it was an integral part of pretending to be a writer.

Then I got sick. Still loved coffee but it stopped loving me. First I gave up regular for decaf. Then I gave it up altogether, except for occasional indulgences, because it had such a vicious effect on my gut. My coffee pot was pushed farther and farther back in the cabinet. I drank tea, but even that became touch and go after awhile. Giving up tea or coffee sounds like such a small thing. Compared to losing my career or the ability to drive, being unable to drink coffee sounds so insignificant. But to me, losing coffee was one of a thousand paper cuts. On its own, it means very little but along with everything else I’ve lost or been forced to give up? It was insulting. I know I can’t work, but I can’t even drink coffee? Come on!

I found some treatments that dramatically improved my gut symptoms. As my gut improved, I started to wonder if any of my dietary restrictions were now obsolete. First, I added back tea. Then a cup of coffee, just as a test. No problems. So in a fit of optimistic insanity, I had coffee three days in a row. I know, right? And it was fine. FINE!

And just like that, I got coffee back. I know many people recommend that CFS patients avoid caffeine (and a host of other things). I also know at least one CFS patient who is able to take care of her teenaged sons only through the power of coffee. For me, it’s about being able to drink the beverage I associate with productivity, long road trips, friendship, and writing. It’s about having that piece of my normal back in my life.

This morning, I made half a pot of coffee. I filled my cup and went to carry it upstairs to bed so I could work on this post. And it bothered me that there was coffee left in the pot that I was 50% likely to leave unconsumed because I would not want to use the energy to go back to the kitchen, refill my cup, and carry it back up the stairs. Sometimes I make it back for that second cup, sometimes I don’t. What a waste.

And then it hit me in a flash of clarity that made me feel brilliant and stupid at the same time. We have insulated travel mugs in this house. DUH! So I fished one out of the cabinet, and poured the second cup in there. Thus armed, I carried both cups upstairs to bed. No wasted coffee, and my second cup would stay warm until I was ready for it.

It’s only taken me 18 years to figure this out.

 

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Speeding Things Up

Posted on December 10, 2012 by Jennie Spotila

In my previous post, I explained the definitions FDA used to determine that CFS is a serious or life-threatening condition. But the true significance of FDA’s decision is that it makes CFS treatments eligible for programs that speed up the process of getting those treatments to patients. To understand these programs, you first have to understand the drug approval process.

The Pipeline: A Hypothetical

Let’s say that XYZ drug company has created a drug called PemX to treat CFS, and has tested that drug in animals to show that it is not toxic. XYZ then files an Investigative New Drug (IND) application with FDA and includes information on the drug and the plans for clinical trials in humans. XYZ conducts a Phase 1 clinical trial in 75 patients to test the safety of PemX. The results show PemX is safe, so XYZ conducts a Phase 2 clinical trial in 300 patients. The Phase 2 trial is designed to test whether PemX is effective in treating CFS, so half of the patients get PemX and half receive placebo. Since Phase 2 was a success, XYZ and the FDA discuss the design of Phase 3 trials. Phase 3 trials typically involve thousands of patients, and are designed to test appropriate dosages, side effects and drug interactions.

XYZ believes that the Phase 3 trials are a success, and files a New Drug Application (NDA). This is a request to FDA to approve PemX for sale in the United States, and the application includes all the data from all the studies. FDA has 60 days to decide whether to file the NDA for review. If the NDA is filed for review, then an FDA review team is appointed to examine all the data, the proposed labeling, and the manufacturing facility. FDA may also ask an advisory committee to examine the data. After all the reviews, FDA decides whether to approve PemX, including what dosages should be available.

Fast Track

Fast Track is an expedited process for drugs that treat serious diseases and fill an unmet medical need. Serious diseases include cancer, heart disease, AIDS, and now includes CFS as well. An unmet medical need is a condition for which there are no approved treatments (like CFS) or when the proposed drug is potentially superior to existing drugs.

Fast Track designation must be requested by the drug company, and the request can be made at any point in the drug review process. In our hypothetical, XYZ requests Fast Track status after the Phase 2 trials, and FDA has 60 days to make that determination. FDA approves Fast Track for PemX, and so now XYZ will have more meetings and more correspondence with FDA about the clinical trials. PemX is now eligible for rolling review, meaning that XYZ can submit portions of the NDA as they are completed rather than waiting to the end and submitting all at once. PemX is also now eligible for Accelerated Approval.

Accelerated Approval

There are many potential treatments that can take years to show true effectiveness. For example, a chemotherapy drug may be intended to extend the lives of cancer patients but it could take a decade or more to prove that the drug does in fact do so. To address these situations, FDA uses Accelerated Approval to base review on a surrogate endpoint. For cancer, that endpoint might be tumor shrinkage. The chemotherapy drug could be approved because it successfully shrinks tumors, and FDA would require post-approval studies to verify that the drug does in fact extend the lives of the cancer patients.

In my example, PemX is intended to treat CFS, but it could take years to be certain that patients experience long-lasting benefits that make it possible to return to work or normal life. In the Accelerated Approval process, XYZ proposes that exercise testing be used as a surrogate endpoint. Patients are put through two-day exercise challenges before treatment and then at six and twelve months post-treatment. Improvement in exercise capacity and reduction in recovery time are used as surrogate endpoints, and longer term studies would be needed to prove that PemX really did enable patients to return to work. If PemX is approved in the accelerated process, then FDA can require post-approval studies and restrictions on use of the drug.

Priority Review

Normally, FDA has a goal of ten months to review an NDA for approval. But a drug company can request Priority Review for a treatment that offers a major advance over existing therapies or where no treatment exists. If FDA assigns Priority Review for a drug, the goal timeline for review is six months. Priority Review does not change the requirements for clinical trials or drug safety and effectiveness. In our hypothetical, XYZ requests Priority Review for PemX because there are no existing therapies for CFS. FDA grants the request and the review process for the PemX NDA is now six months.

On Speed

Because FDA has determined that CFS is a serious or life-threatening condition, my hypothetical drug PemX gets to market faster. First, XYZ requests Fast Track status and this means that FDA has more contact with XYZ during the trials process, and XYZ can submit sections of its final NDA as they are completed. PemX also becomes eligible for Accelerated Approval, meaning that exercise testing is used as a surrogate endpoint for treatment success. As a result, clinical trial data can be collected for 12 months instead of many years. XYZ also requests and is granted Priority Review for PemX, and the final NDA review process takes only six months instead of ten. These three programs shorten the time it takes for PemX to move from “bench to bedside,” and it all happens because FDA determined CFS is a serious or life-threatening condition.

Note: PemX is a drug invented in my imagination, and all the examples in this post are purely hypothetical. The FDA website has an incredible amount of information on the drug approval process, and I relied heavily on the FDA’s descriptions of these programs in writing this post.

 

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Serious Or Life-Threatening

Posted on December 6, 2012 by Jennie Spotila

During the stakeholder teleconference with FDA on September 13, 2012, Dr. Sandra Kweder said that FDA considers ME/CFS to be a serious or life-threatening condition. In the world of FDA regulations, this is a very important designation. Here’s the full quote from Dr. Kweder:

We consider your condition to be in the category of serious or life threatening diseases. Okay, so all of the measures to move things through rapidly, all of the tools that we have here at FDA to try and expedite reviews or expedite development and work with companies to try and encourage them along that would apply to, you know, immediately life threatening cancer, as far as we’re concerned they apply to this condition. This is a serious condition and I just want to make that clear. We consider it in the same category because there are no approved treatments for this condition and we understand how seriously and severely peoples’ lives are impacted by this disease – by this condition. (FDA Stakeholder Teleconference Transcript, pp. 13-14)

But what does this actually mean? How did FDA make this determination? Richard Klein, FDA Office of Special Health Issues, provided me with some background information.

FDA’s definitions of serious and life-threatening come from the Federal Regulations governing FDA. According to the regulations, a serious disease or condition “has substantial impact on day-to-day functioning.  . . . Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.” (21 CFR 312.300) It is patently obvious that CFS meets this definition because of its devastating impact on day-to-day functioning.

The definition of life-threatening is found in several regulations. In the section on investigational new drugs, “life-threatening” means “(1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and (2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival.” (21 CFR 312.81) Another section of the regulations says “Immediately life-threatening disease or condition means a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.” (21 CFR 312.300)

So is FDA saying that CFS is a life-threatening condition? I know many patients believe that it is a life-threatening condition, and Dr. Lily Chu had made a strong case for why research should examine the issue. But I suspect FDA has not drawn this conclusion. Note that Dr. Kweder said “serious OR life-threatening,” according to the transcript. Several patients discussed the possibility that CFS is life-threatening, but no one from FDA said that it was. It is unclear to me whether FDA believes CFS is life-threatening.

Having said that, it is very clear that FDA believes CFS is a serious condition. This is a very important designation because serious (or life-threatening) conditions are eligible for several drug review programs intended to speed drugs to market. In my next post, I will attempt to explain what these programs are and how they might help those of us waiting for treatment.

 

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Insufficient Data

Posted on December 4, 2012 by Jennie Spotila

One of the most frustrating aspects of coping with CFS is the lack of definitive data. A PubMed search for “chronic fatigue syndrome” yields 4,877 results (as of today), but as a patient on the front lines I have to make treatment decisions based on theory, supposition, and anecdotal evidence.

Case in point: I’m wearing a heart rate monitor and reducing my activity to stay below my anaerobic threshold based on a few studies that show CFS patients have disruptions in their energy metabolism. There is even a published case study showing that following this pacing method and short duration exercise leads to improvement in functional capacity and activity recovery. But because my anaerobic threshold is so low, I exceed my heart rate limit just by climbing 12 steps. An expert advised me to reduce my activity to stay below the heart rate limit, even if it meant stopping halfway up the steps to rest or using a shower chair. Another expert endorsed the use of beta blockers to lower my heart rate. That topic is worthy of a separate post, but there are patients who have benefited from this approach. Sue Jackson has written excellent posts about her experience doing just that, and she credits beta blockers with drastically improving her functional capacity. When I asked the first expert about beta blockers, the expert responded that beta blockers would not change my actual anaerobic threshold but would mask when I was exceeding my limit by lowering my heart rate.

So how do I decide what to do? Expert One advises significantly reducing my activity to obey the heart rate limit, and not using medication to lower the heart rate. Expert Two advises using the medication to lower heart rate in order to increase my activity levels. There is no research that definitively answers this question. There have been no case control studies or systematic long-term follow up. Both experts can support their theories with anecdotal patient data. Both experts can support their theories with sound reasoning. There is simply no data that answers the question: which method is better for my health?

Large treatment trials, longitudinal studies, and sophisticated research into etiology and disease course drive treatment decisions for many diseases and conditions. If I had breast cancer, detailed analysis of the tumor would tell my doctor which chemotherapy regimen to use and for how long. If I had a broken hip and a heart condition, a physical therapist would be able to prescribe a rehab program suitable for both conditions. If I was HIV positive, triple therapy would be prescribed and tightly monitored to make frequent adjustments.

But those of us with CFS are left flapping in the wind. I think even the best CFS expert doctors in the country would acknowledge that treating people with CFS involves a lot of trial and error, educated guesses, and fine-tuning. The CFIDS Association recently stated that CFS patients on Patients Like Me report trying over 800 different treatments. This is insane! It’s like throwing spaghetti at the wall to see how much will stick.

Making CFS treatment decisions should be like playing sudoku – there might be some trial and error, but there is inherent logic to the puzzle. Instead, making these decisions feels like the Sunday New York Times crossword on steroids, with incomprehensible clues and multiple right answers. No one can get all the right answers based on insufficient data. Should I take the beta-blockers, or should I buy a shower chair? Your guess is as good as mine. Literally.

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Rest Medicine

Posted on November 28, 2012 by Jennie Spotila

I have been working really hard at resting. That probably doesn’t make sense, but I have been struggling to incorporate preemptive rest into my routine and it feels like a lot of work. The rationale for preemptive rest is that scheduled breaks help your body restore its energy capacity because you are not pushing to the point of exhaustion. Bruce Campbell explains preemptive rest very well, and credits it as a key component of his own recovery.

I was very resistant to trying it. My functional window of opportunity is so small and fleeting. Why should I interrupt an activity to rest, especially when I feel like I can keep going? I’ve always been a power-through-it kind of person, and I’ve approached CFS the same way. Taking two scheduled breaks a day to lie down and rest, regardless of how I feel, has been a huge emotional disruption. I hate this daily reminder that I am weak. I hate feeling like a sick person who has to lie down after an hour on the computer. I don’t want to need this rest. I shouldn’t have to need it. I should be able to overcome these limitations, not feed them or cater to them. When I started taking these rest breaks, I hated it so much I would lie on my bed and fume about it (and yes, that defeats part of the purpose of resting).

But I wanted to give this method a fair trial. I knew I had to change the way I think about the rest breaks in order to get any benefit from it. I thought about treatments for other diseases and how those patients probably don’t enjoy the process either. If I had cancer, I would hate chemotherapy but I would do it. In fact, I think I would attack chemotherapy with a “let’s do this!” attitude. Cancer? Screw cancer, give me the chemo – I’ll take it and kick cancer’s ass. Rather than seeing preemptive rest as a burdensome imposition, would it help me to treat it as a daily medicine?

I don’t get pissy about taking my medications; I need them, so I take them on schedule every day. But I am still struggling to feel that way about preemptive rest. For example, I should lie down right now but I want to finish this blog post before lunch. I’m at war with myself every day because my expectations and desires are always bigger than my energy capacity. No matter how short my list is, no matter how much I have reduced my expectations, I never accomplish everything on my list. Taking rest breaks feels like a disruption and waste of time.

Would I resent chemo like this? All the horrible side effects and agony of chemo have a purpose: to rid you of cancer. I see my medications the same way: I take pain medication and it helps my pain. I am trying to bring the same attitude to preemptive rest. The rest breaks are necessary, just like my pain medication, and I should embrace it as another part of my arsenal. I realize that it might take months to see benefits from any treatment, whether it’s chemo or a new pain medication or rest breaks. I know I have to stick with it, and part of that process is adopting a positive attitude towards a method designed to help me. I am working hard, every day, to give rest breaks a fair chance.

Update (11/30/12): After I published this post, ME/CFS Self-Help Guru posted about reframing challenges in a positive way.

 

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