FDA Workshop on Drug Development for CFS and ME

[Sasha]

Cort has just posted on his blog about Day 2 of the meeting - I've just skimmed the beginning but it starts with some interesting stuff about Dr Bernard Munos, worth reading for that alone:

http://www.cortjohnson.org/blog/201...rome-ii-barriers-breakthroughs-possibilities/

 

[JT1024]

Nielk .... where are you getting those great slides?? I'm particularly interesting in the Panel Two slide that included Dr. Montoya, Klimas and a few others.

On some site the last few days, there was a synopsis of what drugs these doctors use or need now.... the first ones were antivirals and I think the second was an immunomodulators. Now I can't find the blog post that summarized this information.

 

[JT1024]

Re Patientlikeme (aka PLM)

I've been on PLM since 2009, right around the time of the XMRV publication. The tools on the site are great for tracking but the forum lacked the depth that PR had.

I wrote one of the founders of PLM and I spoke with Cort, hoping their could be some synergy. People started working on creating something like PLM here on PR. I've actually suggested using PLM to a few researchers I'm in direct contact with but it seems most are too busy in existing projects.

Since then, I have also looked into a few crowdsourcing clinical trial sites. Here is info on one crowdsourcing company: http://www.transparencyls.com/ They actually have the first FDA Crowdsourceed Protocol (copied below). Another company I was following was Curetogether.com. They were acquired by 23andme so that is an intersting twist. Not sure what they're going to do with it!

http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=803108

The First FDA-Approved Crowdsourced Protocol: An Interview with Tomasz Sablinski, MD, PhD

Publish Date: Jan 22, 2013
By: Lisa Henderson​

​

Go to the Transparency Life Sciences web site and take yourself on a tour of drug development in the future. A future where the 80-80-80 paradigm becomes the 20-20-20 paradigm, and as TLS Founder and CEO Tomasz Sablinski, MD, PhD says, will become a reality by 2020.
Sablinski, who freely admits he operates in triplet, says that clinical trials are 80% too expensive; 80% are trials that no one wants; and they all use technology from the 80s. Sablinski envisions by 2020, trials will be 20% of current legacy costs; only 20% will be trials no one wants; and all will be using technology of the 20s…that is 2013 and onward.

And the key to achieving that is through the triple pillars of TLS: transparency, open crowdsourcing and telemonitoring. All three of which would not, say, come up in the top three keyword search for the clinical research enterprise. But what the three do address is what Sablinski knows is his single largest personal pet peeve, and sees as the biggest detriment to clinical trials…waste.

“Some industries are wasteful, like healthcare, but clinical trials are wasteful and they start with tremendously inefficient processes,” says Sablinski. “It is criminal that we have huge discoveries in research, and new medication, in the past 25 years, but we have the same systems, processes and cultures that persist from 25 to 40 years ago.”

Four years ago, Sablinski left Novartis after fits and starts in clinical study innovation. He moved to Celtic Therapeutics, an innovative and entrepreneurial drug development firm in its own right, and launched TLS January 31, 2012. Less than one year later, the company founded on open innovation had its IND for a Phase II trial of lisinopril as an adjunctive therapy in multiple sclerosis approved.

Crowdsourcing

You can link here to go to a blog my colleague wrote and features a rich background on crowdsourcing. What TLS specifically has created is a way for both the patient community and the research and medical community to come together to provide answers to survey questions, assembling aggregated data and opinion on draft protocols using its Protocol Builder on-line tool. Users must be registered, but as I mentioned, anyone can tour the site and look at the data. It is so very interesting to go into the lisinopril protocol and see the patient input directly on the screen and know that this represents a person. One who has the most complete and intimate knowledge of their disease.

Sablinski says there was no active marketing outreach from the company, save for the impact of media stories from various outlets, to spur participation in this first protocol. On the professional side, Sablinski said the team relied on its own Rolodex of business contacts and researchers who thought it was a great idea and spread the word. Regarding the patient community, said Sablinski: “When they see something where they can help make a difference, they spread the word.” The company is planning proactive outreach to relevant patient and professional communities going forward.

TLS started with four protocols, of which the approved one and two others in Crohn’s and Parkinson’s are still active. The company made the decision, as a start-up initially with limited funds and manpower, to focus on the MS protocol and not spread themselves too thin through the FDA submission and fundraising processes. A feature of the Protocol Builder process is designating a patient expert and a research expert for the specified indication to help provide guidance for the survey and the input, and these experts are called Curators. The company, with its first FDA win, is confident it will soon be able to move forward on one of the other protocols.

During the MS protocol process, TLS discovered a few things. One is that telemonitoring, a key component of the TLS business model, is very attractive to the MS community. The protocol stipulates a first visit on day zero, and a second site visit at 12 months. “We learned a lot about the patients’ comfort zone regarding participating in trials,” said Sablinski. “It’s very difficult for patients to see the value in the office visits needed in conventional trials. It’s frustrating to wait in the doctor’s office, and there is not any value added in that wait time.” Now while telemonitoring is an ideal solution for many chronic conditions, and avoids that office wait scenario, Sablinski notes that there remains a key quality for the study-patient relationship, and that is direct contact. “There needs to be a link between the site and person, whether it’s a doctor or study nurse, a reference point for a patient. Someone they can always call or push a button on a computer to be able to chat online.”

Through crowdsourcing, they were also able to identify a qualitative scale that has been identified for years by MS experts as a more accurate and effective measure, but that was not logistically achievable. Turns out this superior scale, which provides a more holistic status of the MS patient, is ideal for the telemonitoring environment. TLS’s telemonitoring partner is Advanced Monitored Caregiving (AMC) Health, which provides at-home patient monitoring for healthcare, and which is, by virtue of that environment, more related to the day-to-day clinical care of a patient. AMC Health executives noted in a release that it is looking forward to working with TLS to ensure the success of this patient-centric approach to clinical research.
I’ll be writing more soon about the TLS approach to clinical trials in regard to other efficiency initiatives in clinical development, patient centricity, and a key three pillar--transparency.

 

[ballard]

Thank you Jennie!

I am so glad that you recorded what a crash looks like. You looked great at the FDA workshop, and the contrast today, during a crash, is stunning. It is too bad that there isn't a day left in the workshop to show your video to the participants.

A crash is a totally familiar situation to me, since I have been through the same thing countless times as I try to push myself to do normal things.

You have told the story of a crash with grace and clarity. You are very strong and courageous. Thank you for representing us at the workshop.

 

[Gemini]

Nielk .... where are you getting those great slides?? I'm particularly interesting in the Panel Two slide that included Dr. Montoya, Klimas and a few others.

On some site the last few days, there was a synopsis of what drugs these doctors use or need now.... the first ones were antivirals and I think the second was an immunomodulators. Now I can't find the blog post that summarized this information.

JT1024,

Perhaps you saw list posted on PR thread "ME/CFS Clinician Panel Lists Top Drugs to Explore at FDA Workshop?

Dr. Bateman answered with her priority list (below) & other panel members concurred:

1. Antivirals
2. Immune modulating agents
For symptom relief:
3. Pain medications
4. Stimulants for cognition
5. Sleep medications
6. Orthostatic intolerance medications

Audience members added:
7. Large-scale Rituxan clinical trial
8. VO2 max agents

 

[JT1024]

Thanks Gemini! I knew I had read that information somewhere but I couldn't find it.

I don't know about anyone else but there should be more on the list that those listed.

It would be preferable to understand the root cause rather than finding meds to treat clinically documented symptoms indefinitely. Personally, I'm tired of all the meds and supplements. It is bad enough to have a chronic illness with many systems effected resulting in difficulty in the very basics of "living" if you can even call this living. To add many supplements/drugs without identifying the cause places an additional burden on patients who are physically and economically at whit's end.

I can't see big Pharma running to develop effective treatments when the patient population includes those with insurance that struggle to pay for care and those without insurance that are at the mercy of governments and Pharma programs.

While there is a HUGE market.. and I suspect an even larger one down the line, I don't think any US government agency wants to acknowledge the problem(s) and/or their so-called "ignorance" aka their deliberate obfuscation of valid clinical data.

My gut is telling me that many years of experimentation without sufficient knowledge has resulted in products (food, chemicals, vaccines, medicine, etc) that have harmed. While the harm may not have been deliberate, Those with susceptible genetics have suffered.

I'm now wondering what genetic profiles are susceptible and where have they originated. Given the technology of today, I believe the answer has already been found. Truly scary stuff.

 

[David Egan]

"And that's my attitude to raising money for research."​

I have had correspondence with a family who have a child who has ME. As there is no ME/CFS clinic in Ireland, I recommended Dr. Austin Darragh and Dr. Kenny De Meirleir. They saw the child and they did several diagnostic tests. They found a number of infections, thyroid problems and immune system deficits. It cost a lot of money. The child is now getting treatment and is recovering from ME. Isn't that a wonderful development Tom ? The parents and child didn't wait around for research. Tom would you prefer to wait several more years / decades for research or get down to the business of diagnostics, treatment and a plan for recovery for yourself and others with ME?​

 

[David Egan]

The FDA officials kept saying "there are no biomarkers", "there are no biomarkers", "there are no biomarkers", etc. etc.. Nancy Klimas said there were biomarkers, but they didn't listen to her. If the FDA and some ME/CFS advocates took the time to actually analyse the research findings and clinical findings over many years, they would see that there are biomarkers. Why are they lying about (i) biomarkers (ii) effective diagnostics and treatments of biological abnormalities in ME/CFS ?? why do people want to remain trapped in lies and hopelessness ?

Why is it so difficult for some people to see the truth and facts staring them in the face - there are biomarkers and there are diagnostics and treatments for the biological abnormalities in ME/CFS ! some are listed here www.cfs-ireland.com/structure.htm#7

 

[Gemini]

The FDA workshop closed with the awkward statement, “I want to thank you again for your inquisitiveness, commitment, your willingness to ask questions, your willingness to challenge each other and wish you a safe travels and a wonderful rejuvenating weekend.” (Ouch!)

We all knew that it would take the patient representatives more than a weekend to recover and that the experience wouldn't be wonderful. Jennie Spotila has now posted a video of herself: “Crash Day 3 After FDA Meeting:”

Thank you, Jennie, for going to the Workshop,making this important video. A picture is worth 1000 words! And your description of the physical impact is excellent!

Any way to get the video into the FDA Docket which is still open or at least a link to it?

Patients attending looked & sounded well countering a sense of urgency.

On the other hand the first speaker Dr. Kaiser referred to the homebound/bedbound too sick to attend: "Now there are a lot of people who are totally disabled from this condition, bedbound or can't leave their homes. And there are a lot worse off than I am, but I'm not here to speak for them..."

How do we get a picture of the homebound/bedbound into these public meetings?

How do we get someone to speak for them?

And how do we get patient data & specimens (blood, saliva, DNA, etc) from them into the biobanks & studies. Dr. Chu had some ideas about this...

 

[Ember]

The FDA officials kept saying "there are no biomarkers", "there are no biomarkers", "there are no biomarkers", etc. etc..

The FDA pretended to side-step (as promised) the critical issue of case definitions, despite acknowledging that these are “the nuts and bolts” of drug development:

FDA doesn't endorse any particular definition; however, what we expect is that parties who are engaged in drug development who are submitting clinical trials for our review or new drugs where clinical trials have been conducted will articulate details about what definition they used for entering patients in the clinical trial so we can all understand who it is that we're studying. Okay. That's an important aspect that will probably come up more tomorrow and sort of the nuts and bolts of studying, testing drugs.

They had invited Dr. Unger to present interim findings in her attempt to replace CFS Fukuda: "Measures of CFS in a Multi-site Clinical Study."

Dr. Unger's message must have been discouraging to any drug company hoping to identify a homogeneous patient population. Some 18 months into her study, she reported:

I would like to emphasize that I think that this interim analysis so far has shown us that there is a heterogeneity in the CFS population as a whole. There is a little bit between clinics but more in the patients than between clinics. This is also giving us a hint that phenotypic measures themselves may be limited in their ability to distinguish robust phenotypes and/or robust subgroups, and that's why we're proposing to expand this study to some other measures. And it could very well be that other biologic correlates will be needed in order to better define subgroups.

Did the FDA mention that there are viable alternatives?

 

[Ember]

Any way to get the video into the FDA Docket which is still open or at least a link to it?

May 2nd, 2013 Jennie Spotila

I originally recorded the video in order to submit it to the FDA comment docket. But after I did that, I thought maybe it was worth sharing with you because it might be similar to what other patients experience....

Wow. Just . . . Wow! Your response has been incredible, and far greater than I anticipated....You reminded me I am not alone, and you used my video to help teach others about this disease.

 

[beaker]

It's ok for us to disagree.

I think a lot of patients don't have money even for speculative therapies.
And those that do can spend quite a bit, but then some people do get some health back from that, so it's no surprise that people spend their money there rather than on research efforts, which wont bring results for them for maybe a decade.

Though I do think many people do donate quite a bit to research. When you look at research that does get done in ME/CFS there are almost always charities backing them and they get a lot of their funds from ME/CFS patients, and their families, who donate money.

I so think there is a big problem that the majority of the public are not interested in donating to our disease to anywhere like the same levels as say MS, even though it affects less people. Thats down to perception and it cant just be down to patients to fix that, though many are working very hard there, and have been for years.

I totally agree with us doing the maximum we can for fundraising by the way, I'm heavily involved with fundraising at the moment, as many people are now (more than there used to be I think) and it does speed things up and we are getting better at it, but research costs are astronomical, especially on sizable studies that have the most chance to change things for us.

I think governments have to do a lot more, not just push it back on the sick.

I think a big problem with fundraising ( at least for me and those I know and would ask to contribute) is that there has been no one trusted ME/CFS organizations to donate to. Oh I send money when I can off to individual groups -- like Enlander Cedar Sinai. But the CAA has been very divisive in the community, I did not feel money sent there in the past would be well used. ( I do not mention them to bring up any CAA bashing. Kim is gone. Hoping for change)
That said, there are more unified groups for other illnesses. Oh breast cancer -- I'll donate to Susan G. Komen Foundation. CAncer -- American Cancer society ( or your local chapter) and on and on.
I don't know how to do some marketing for research donations with the splintering of the ME/CFS groups .
I only know to try and rally round a particular study. But it's hard to get that w/o the funds to lift it off the ground.
sorry rambling and my hadns in splints so my typing gettin gworse and I was going back and correcting but now notw and it slow. so I end here.

 

[beaker]

Thanks.

I'm not sure I will recover, but I feel there should be a reasonable chance something can help me improve.

I remember Dr. Weir saying he did a small trial (n=10) of alpha-interferon (I think it was) around two decades ago . One person recovered but the statistician said that wasn't significant. This sort of thing both frustrates me and shows to me that developing basic understanding of the condition is important (i.e. if it could be isolated what sort of person responds and who doesn't respond). There are lots of elements to making this happen of course.

I knw your point. you are using that med as ex. and it is agood point.
as a side note fyi. the alpa Interferon has been done other tiem as well.
back over 20 years ago wth chen y and bell.
i got horribly ill. as in 2 additional immune illnesses that I have been stuck with.-- well one eventually dissipated. ( not to mention the side effects after injecting.
and a stay in the hospital. They didn't use after taht to my knowledge.

I think the long time cfids docs have tried a lot of things that never made it to official studies b/c they didn't pan out and yes also $$$. But I am sad to say more from them not working . and if you haven't been sick a long time or at some of the bigger name docs( or any doc who is willing to use you to experiment with), you might not realize what has been tried.
I know I've tried a lot of things. I have friends who have tried a lot of things.

 

[Ember]

We need a movement towards progress. It will never be "perfect". We can keep on harping on all the problems..ie. the name, the definition, which biomarkers to use etc.

I don't think that we're harping, Nielk. At the CFSAC October, 2012 meeting, Admiral Kweder was unequivocal: “A research definition is needed so that we can begin to study things.... Clinical therapeutics are not going to be developed until this is done.”

In their joint letter to the FDA, advocates advised:

CDC has inappropriately lumped this disease into an umbrella of fatiguing illnesses called chronic fatigue syndrome and has said that CFS is defined by any of five disparate definitions. Three of these definitions describe the essential and hallmark of ME; the Canadian Consensus Criteria, the ME International Consensus Criteria and the 2006 IACFS/ME Pediatric Case Definition.

The FDA ignored our input. We heard, “If you build it, they will come.” Tell that to the International Consensus Panel, two of whom were sitting in the room.

Nothing personal, but I was reminded of a comment from How to Survive a Plague. “It sort of felt like reaching the Wizard of Oz. You got to the centre of the whole system, and there's just this schmuck behind a curtain.”

 

[Ember]

According to Bernard Munos, "The good news is that, 'if you build it, they will come,' and we know that because (by 'they' I mean the scientists)...because they do it every time.” But I don't think that any mention was made of Dr. Lipkin's samples, ready and waiting. Dr. Maier wrote to Jennie Spotila last September:

We are very pleased that Dr. Lipkin has offered to make remaining specimens available to any ME/CFS investigator who successfully competes for NIH funding. Dr. Lipkin and NIH program staff agreed that the NIH peer review process would offer the fairest means to decide who should have access to these samples. Consequently, interested investigators will be advised to consider currently available and relevant NIH funding opportunities in order to pursue these samples. NIH will be issuing a notice in the NIH Guide to Grants and Contracts very soon that will elaborate upon these points. However, it is important to note that there are no set-aside funds associated with these samples. In addition, Dr. Lipkin’s laboratory will maintain these samples, which is standard NIH protocol. They will not be stored at NIH.

The FDA turned the tables on the patients and physicians with Mr. Mudos' do-it-yourself drug development on a shoe-string:

There has been very interesting research at MIT done to suggest that actually scientists or physicians, I'm sorry, physicians working with patients for whom no treatments are available have been historically very powerful source of innovation, possibly the most powerful source of innovation in the pharmaceutical industry over the decades because they know the disease, they know the patients, they know a little bit about pharmacology, and they were trying to customize treatments for those patients using drugs that were approved for something else. It's kind of Darwinian (?) experimentation that's repeated millions of times every day across the land, and when you have that sort of thing going on, by luck or by design, some of that thing is going to work, and we see it in every disease. So if you have patients that are alert, and if you network them and allow them to share the clinical insight, especially the clinical observations that are unexpected, I don't think it will be long before someone notices, “Gee, you know, I had this patient and she had disease XYZ and I gave her that drug and the CFS got better or disappeared.” There have been instances of that happening already, so we need to harvest that sort of creativity.

How will the Rituximab creativity be harvested?

 

[Nielk]

I don't think that we're harping, Neilk. At the CFSAC October, 2012 meeting, Admiral Kweder was unequivocal: “A research definition is needed so that we can begin to study things.... Clinical therapeutics are not going to be developed until this is done.”

In their joint letter to the FDA, advocates advised:

The FDA ignored our input. We heard, “If you build it, they will come.” Tell that to the International Consensus Panel, two of whom were sitting in the room.

Nothing personal, but I was reminded of a comment from How to Survive a Plague. “It sort of felt like reaching the Wizard of Oz. You got to the centre of the whole system, and there's just this schmuck behind a curtain.”

I share your frustrations, Ember, but I am really not sure what the expectations were for this FDA meeting. I thought that it was an initial "fact finding" mission. Regarding this, I thought that it was relatively successful. I felt like we were heard. The FDA being a government agency will not act swiftly. They will probably have more meetings and progress, if any, will be very slow.

In the meantime:

1- We had a place/platform where our patients and patient advocates can be heard. I , personally, felt that there was a genuine interest from the FDA panel to hear about our experience whether it was about symptoms, impact on life, crashes or potential treatments. Hopefully, there were many others, including representatives of pharmaceutical companies listening to the webcasts.

2- We had a chance to hear from professionals and specialists and gain from their knowledge.

When Munos stated "if you build it they will come", I think he meant us - patients. I thought he was advising us to find a patient representative leader to organize this and put i into action. I thought that he was genuine in his advice to us as to how to make this happen. I think that if we want to affect real change, we have to be willing to do part of the work ourselves.

It is true that we are plagued by the CDC's ill-definition of the illness. This is a huge problem. I know that for me, personally, this has been very damaging. My own GP, ten years ago when I first became ill, looked at the CDC for advice and put me on anti-depressants which caused me to cascade downward for a couple of years. This is a major obstacle to progress and we need to fight this every chance we can.

You state "the FDA ignored our input". How do we know this, only two weeks later?

 

[Ember]

You state "the FDA ignored our input". How do we know this, only two weeks later?

I was referring to our input in the joint letter to the FDA.

I wouldn't call the meeting relatively successful if the expectation now is that "progress, if any, will be very slow." Dr. Unger's message must have been discouraging to representatives of pharmaceutical companies listening to the webcasts.

 

[Nielk]

I was referring to our input in the joint letter to the FDA.

Thanks. I didn't realize this is what you meant. I get it now.

 

[jspotila]

I posted my video in the comment docket, and also sent it directly to a few of my contacts at FDA.

In terms of Munos' presentation - there are some real opportunities right NOW to build the data and the tools, but this entire community is going to have to work together. It won't be easy for all sides to do that, but we have to or we will fail.

And on the definition, don't forget that NIH has awarded money to work on a definition through the Consensus Development Program. Here is what we know about it: http://www.occupycfs.com/2013/03/21/evidence-based-at-nih/

I'm hoping we hear more at the CFSAC meeting . . . .

 

[Ember]

In terms of Munos' presentation - there are some real opportunities right NOW to build the data and the tools, but this entire community is going to have to work together. It won't be easy for all sides to do that, but we have to or we will fail.

Sasha has already posted suggestions here and here. Has anyone been able to locate the National Advocacy Alliance for ME mentioned by Lily Chu?