Lou Gehrig's Disease - Motor Neuron Disease - Amyotrophic Lateral Sclerosis
Thought it had been cured by now? Still no known cause. Still no cure. Still quickly fatal. Still outrageous.

Monday, May 30, 2016

Comments On Draft FDA ALS Draft Guidance

Following are the comments that I submitted to regarding their draft of the FDA ALS Draft Guidance document:

I tried to look at this document with two standards in mind:
1. Would it be helpful to someone developing an ALS therapy?
2. Would it change anything from what the FDA is doing today?

I worry that it achieves neither.


The commentary on the ice bucket challenge isn't valuable to drug developers or the FDA (but since you brought it up as the enabler of this document, how much was spent on this document and what was it spent on?).

The reference to the ALS Registry adds no value.

The explanations of the difference between the ALS "guidance" and "guidelines" are just silly.  The guidelines meeting was fare more specific and focused than this document.  I would hope that you could have simply dropped some of the advice from the guidelines group directly into this document.

"The goal of clinical trial guidelines is to lead to more effective and efficient trials but they do not directly impact the FDA regulatory process."  What in this guidance draft will directly impact the FDA regulatory process?  I would love for that to be the case, but I just don't see it in what is presented in this draft.


I think that the references to statistics are not needed and the numbers presented are not helpful.  Any drug developer seeking guidance from the FDA probably already knows more about the ALS market than those statistics reflect.  The "1 of 800" citation is in a paper that uses it with citations to two other papers. Did the references to the demographics come from the CDC's Registry?  In that case there are questions as to the completeness and validity of the data.   On page 17 there is a reference to 25,000 Americans living with ALS with a citation to a paper that just says it without any further background.

At the bottom of page 14 it boasts of guidance that will produce a "clinical development strategy that will provide the best opportunity to demonstrate a treatment's effectiveness and safety..."  I think that isn't the main goal.  The main goal here is to save some lives.

Benefit Risk

Words matter.  On page 15 we see that people with ALS are "vulnerable" to investigational new treatments supported by only minimal evidence of tolerability, safety, and efficacy.  Vulnerable?  The whole idea of risk-tolerance is the ability and right to make informed choices.  Vulnerable?  And then we read about the "rigorous" standards that must remain in place... so that informed decisions can be made that do not unnecessarily "compromise the health and safety of people with ALS."  Oh, please.  These people are dying a difficult death and don't need such paternalistic attitudes.  If we put those words in the FDA's mouth, we're crazy.

On page 16 there are references to oncology patients versus ALS patients attitudes.  Does the fact that many cancers have available therapies make this an apples-to-oranges comparison

There is a reference to perhaps having an influence on lower percentages of people with ALS taking riluzole.  Perhaps a more basic reason is the same underlying reason that people stop using drugs in general -- the cost-benefit proposition.  Why blame social media?

At the bottom of page 16 there are comments on exclusion criteria that indicate that patients want them "less strict."  Again, words matter.  "Less strict" gives an impression that changing exclusion criteria would diminish the science.  I don't think that is the case.

The subsequent comments about the difficulty of some with ALS to get to clinical trial sites was a wonderful opportunity to introduce guidance that would permit more telemedicine and remote monitoring of participants in clinical trials.  Will the FDA guidance encourage that they will accept more remote data from participants?

The first guidance on page 18 left me scratching my head.  What difference does that guidance make from the status quo?

There is a reference to DiPALS vs DPS to question the use of historical controls.  My understanding is that there were procedural differences between DiPALS and the original DPS participants and that this isn't resolved science.  It's probably not a great example to cite.

On page 19 there is a passing reference to Type II errors.  This needs much more attention in my opinion.  This is the crux of much of angst over the eteplirsen situation for DMD.  If a drug has a reasonable safety profile and the disease is quickly fatal without an effective treatment, the risk of making a Type II error is a problem that needs to be addressed.  The FDA should be willing to accept some uncertainty regarding efficacy rather than dismiss drugs that may work on some patients.  If we don't discuss this in this guidance document, we will have missed a major opportunity to actually "impact the regulatory process."

Expanded Access and Accelerated Approval

Why in the world were those two things glumped together?  The are vastly different.  They need to be clarified.

Expanded Access programs have a mechanism that may or may not be attractive to a drug developer.

Accelerated Approval gets products to market faster, and that is very different from EAPS and is far superior from many aspects.  Drug developers need to know that the FDA is willing and able to use the Accelerated Approval path aggressively, and that should be spelled out very clearly in this guidance document.


There is a lot of description of standard interventions affecting ALS prognosis, but are these interventions ever considered to be standard-of-care issues for clinical trials?  Some trials exclude people on NIV or feeding tubes.  Should FDA guidance be standing up for these standard interventions to be a patient right as standard-of-care?

On page 71 you actually used the "gold standard" term.  Last year I got the message from a gentleman with ALS that the gold standard isn't even the "gold standard" any longer.  Words matter.  Let's drop the baggage that makes us think that there is only one way to do clinical trials well.

Things I Didn't See That I Wish Were Included

There was discussion at the guidelines meeting that perhaps biomarker trials should be separated from efficacy trials.  Are we slowing down efficacy trials by adding companion biomarker components?  Are we putting trial participants at risk by tracking biomarkers during washout periods as was done in the NP001 Ph 2 trial?

Is there any mention in this document on rejecting placebo procedures that pose risks to patients?  Many people find placebo surgeries draconian.  It would be refreshing for the FDA to say that they expect alternatives to placebo surgeries or other procedures that would put placebo participants at risk.

Is there anything in this document that would have changed the big dexpramipexole trial design?

Many ALS trials start measuring volunteers from the day they enter the trial -- as if their ALS started on that day.  Others have short lead-in periods to gather some "history," and that lead-in actually delays access to the investigational drug.   It seems to me that historical medical data from clinical trial participants could be very helpful in determining whether an investigational drug is actually doing something in certain patients.  It would be helpful if the FDA guidance could specify acceptance of some lead-in data from trial participants medical histories.

I think that trial data using ALSFRS-R should always include the components of the score.  Perhaps the more granular data might yield some insights that the summary score does not reflect.

The Last Word

There were 38 references to "subjects" in this document.

"Subjects" is a disrespectful word for the most important people in clinical research.  It objectifies them.  It conjures up images of royal underlings.

Many pharmaceutical companies eliminated the word from their vocabularies long ago.

We need to eliminate the word from ALS research, and it has no place in an FDA Guidance document.  If anything, the FDA should tell drug developers that it expects that they will not use the offensive term "subjects" for people who volunteer for clinical studies.

Thank you for the opportunity to submit comments.

Friday, May 13, 2016

"That Wasn't Patient-Centric"

I thought that after a couple of nights' sleep that my ire would have passed.  It has not.  So I write my conference report.

I arrived for the ALS Association Public Policy Conference on Sunday afternoon.  We got a short presentation of the "ask" for Capitol Hill visits on Tuesday.  It had a surprise.  Hmmm.  No questions were to be asked on Sunday.  "Bring all your questions to be answered tomorrow."  Fine.

I wrote some of my questions down.  ALSA social media said to send your questions with hashtag #ALSadvocacyday . Perfect.  I posted some questions in this blog before I left my hotel for the conference. 

When I arrived at the conference hotel, our state was assigned to a table in the big room, front and center.  A few minutes before the presentation was to begin, I fired up the iPad and tried to connect to the wifi.  It wanted a password, so I went to the social media conference staff in the back of the room who were sitting at their connected computers, and I asked for the password.  Ah.  There was no conference wifi supplied for attendees, but we could use the free wifi for the Marriott lobby.  So I left my nice table front and center and found a spot on the perimeter of the room where I could catch the lobby signal.  Hmmm.  But I was connected.   Way too far away to get pics of the screens, but fine.   Connectedness was obviously a priority for ALSA's social media staff but not for the patients, caregivers, and individual advocates in the room.  Ironic when one of the legislative priorities revolves around technology.  Oh, well.

Then the conference began.  Two ALSA executives and and CDC Registry employee sitting on the stage.  The format was like a late-night television infomercial.  It was scripted chit-chat.

It was not informative.  It was patronizing.  When the "moderator" asked what percentage of people with ALS were in the Registry, we didn't hear an answer. We heard that the largest percentage was from the government files. The "moderator" wasn't exactly Mike Wallace with followups.  When the "moderator" mentioned the ALSA contract, the CDC representative talked of spikes in enrollment but gave us no numbers.  I'm not sure what kind of measure a "spike" is -- a dozen, a gross, a spike?

And we watched as they kept chit-chatting to the bitter end of the time period. Three suits on a stage.

There was no Q and A period.  None.  Questions were to be taken up at the later individual opportunities to meet the scientists 1:1.  That certainly stifled any public discourse and wasn't helpful for those of us who had appointments on Monday.

After the session, a man with ALS said to me, "That wasn't patient-centric."


Thursday, May 12, 2016

Transparent Public Discussion -- Lift The Lid

There were no public questions accepted at the ALS Association's #ALSadvocacyday conference presentation this week on the CDC's ALS Registry.  The lid was on.

The answers to questions on a publicly-funded project are important to everyone with any stake in the project.  They should be discussed openly in the spirit of sunshine and transparency.

The answer to one of the questions in my list (posted in this blog before the presentation) may affect research and those with ALS profoundly.

The research notification feature is being touted by the ALS Association (remember, a project contractor) and the CDC's ATSDR as a big success feature in the project.  It is used to help justify yet another $10 million annual taxpayer investment in the Registry project.

This research notification is an emailer that notifies people who have enrolled in the Registry of clinical research opportunities on ATSDR's list.  People with ALS (as well as legislators who allocate the funds) are told that via this tool, trials can find you.  It is sold by ALSA and ATSDR as being widely successful and so much easier than

Take a look at what studies have been included in the notification emailings --

That's a relatively short list of mostly observational studies.

On Monday night, I searched the big list at for ALS trials.
  • There were 83 open, enrolling trials for ALS listed at
  • 47 were interventional trials (you might get a drug)
  • 36 were observational trials (nformational studies but not drug trials)
  • 3 (or just 6%) of the 47 interventional trials were on the Registry notification list and
  • 3 (or just 8%) of the 36 observational trials were on the Registry notification list.

So you might be notified of 6% of the currently enrolling drug trials.

This is  2016.  Welcome back to 1990s-style emailing.  The CDC's ALS Registry has a limited emailing system for researchers.  It simply isn't patient-centric.  Blasting out emails based on crude criteria and a small subset of trials isn't "matching."

This notification tool could actually be doing great harm if the success claims are making people with ALS passive, thinking that they will automatically be notified of their clinical research opportunities.   

People with ALS need to know that they're on their own to find the right clinical research opportunities.  It shouldn't be that way, but it is.  Don't wait for an emailing on 6 percent of interventional trials needing volunteers.

See why it would have been helpful for people with all perspectives to have some open, transparent  discussion at the conference?

Monday, May 9, 2016

It's That Time Of Year For Some #ALSadvocacyday Qs ... And We Hope, As

 Questions kept popping into my mind as I listened to the kickoff comments for ALSA's annual public policy conference yesterday.  I write them here in hopes of hearing answers today.

ALS Registry

  • What is the cumulative taxpayer investment to-date on this project, starting back with the so-called "building block" projects that we were told to pitch even prior to the passage of the ALS Registry Act in 2008?
  • How are you going to spend the next $10 million?  For example, how much is just basic administration and support?  How much is required by the new biorepository project?  How much goes to research grants?  How much is paid to project contractors individually?  What does it cost to administer research notification? etc.
  • Has anyone actually tested the ALS Service Locator?
  • How many unique people with ALS were seen by ALSA clinics in 2015?  Of those, how many have self-enrolled in the Registry?
  • How many unique new patients were seen by ALSA clinics in 2015?  Of those, how many self-enrolled in the Registry?
  • Does anyone have data on whether people with ALS choose Medicare Advantage plans at a greater rate or lesser rate than the general public?  We learned several years ago in the Registry annual meeting notes that Medicare HMO records are missing from the government files that are mined as part of the Registry algorithm. Those are people on Advantage plans, right?  According to a recent study from, the national average to opt for Advantage plans is 31% with some states being much higher.  Minnesota is 53%.  Florida and Pennsylvania are 40%.  And there are clusters in some urban areas.  The original ALS Registry pitch was that the CDC could identify 85% of ALS cases via the passive data mining of Medicare, Medicaid, VA files; however, this HMO problem indicates that you are missing some large percentages of people with ALS from the Medicare files. Is this not a problem?
  • When will the resampling study to help ascertain completeness of the Registry be published?
  • What percentage of the enrolling interventional trials for ALS at are included in the research notification Registry feature?
  • Are biosamples available to researchers right away, or do the data from government files have to catch up to a person's biosamples to confirm that person's case of ALS before the biosamples can be released?
  •  Volume of email sent really isn't a great measure of effectiveness. How many people have actually inquired about a trial or study as a result of having received an email from the Registry?

Drug Approval Paths

  • This is an important month for drug approvals for all fatal, unmet-need diseases as the FDA ruminates on eteplirsen.  Why is the ALS Association not standing loud and proud with arms locked with the parents and DMD kids who are awaiting the Accelerated Approval ruling from Dr. Woodcock?
  • What is the ALS Association's position on all three pieces of legislation being promoted at ?  In particular, why is the Regrow Act not one of the "asks" for this #ALSadvocacyday ?
  • Wasn't the timing of the Lance press conference at the exact same time as the MyRightToTryNow legislative briefing an unfortunate coincidence?
  • Could you please repeat the source of the new report that is to be announced at the Lance press conference tomorrow?  It was difficult to understand in the comments yesterday.

Thanks to anyone who can help with the As.

Friday, May 6, 2016

They're Painting Outside the Lines

And they're using a great big brush!

Welcome to ALS Advocacy Day 2016, when some smart people with ALS are pushing the modest edges of past advocacy efforts and making some people pay attention.

See what Matt Bellina is doing and please consider contacting your legislators about the bills that are described at

And read what Stephen Finger has to say about the proposed FDA Draft Guidance on ALS at  Before the end of May, please submit your own comments, too.

These are two smart people with ALS who are painting Washington red with new ideas that ignore the old limits.  Thanks to them both.

In Case You Wonder About The Jacket Or The Sign

If you saw my yellow jacket with the painting on the back or my sign, here are the quick backstories.

The Jacket

The jacket is #300 in Regina Holliday's Walking Gallery project.  Regina is a gifted artist and patient advocate who paints patient narratives on the backs of jackets to bring them into conversations in a very real way.  You can google to find the complete story of how Regina asked to paint The Rolodex of  some of my friends lost to ALS.  She delivered a treasure in the fight against ALS.

The Sign

Gregg Doyel is a talented sports journalist who had a dear friend with ALS.  He wrote several columns about her and ALS, and the one he wrote in April, 2015, spoke eloquently to frustration and urgency as Maureen was dying.  His ending sentence has become a battle cry for many of us fighting for faster ALS drug approvals... and a more effective fight in general.