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.

Wednesday, November 18, 2020

Home Run. Left Field Fence.

Yesterday news broke.  Hearts broke.  

There were statistics.  There was spin.  There were excuses.  There were reasons. 

But there wasn't a home run over the left field fence. 

The news:

There is no doubt to those of us with friends in the Brainstorm clinical trials that the therapy was helpful to some, yet the trial did not deliver statistics to back that up.  We've seen this before in ALS trials.  Unless we stop this madness, we'll see it again. 

In clinical trials, you have to call your home run shot before you take a swing.  Left field fence?  Ok. You have to stand in the batter's box and point to your home run.  Left field fence.  That's your endpoint.  If you swing and it goes into right field (or even clears the right field fence), that's nice but it's not the home run you called.  You said left field fence.  Otherwise it doesn't count.

You also get to call the pitch you want. That should make it easier, right?  Those are your inclusion criteria.  Low in the strike zone with a fast ball.  You get the pitch you want and you have to hit your home run where you say it will clear the fence.  If you call the wrong pitch, you miss your shot.  Unfortunately with ALS, we're not very good at having a pitching machine that puts the ball precisely where you want it. 

In baseball where lives aren't at stake, we analyze swings and pitches and statistics.  Coaches and players work tirelessly to refine their games and improve.  In ALS research where lives are indeed at stake, we make a lot of mistakes over and over. We settle for excuses.  We accept reasons.  It is madness.

The NurOwn trials from Brainstorm have been painfully long and cruel to watch.  The last thing we expected was a right-field double when they said the trial had to be designed with 50:50 placebo and exclusion criteria to give them their statistical left-field-fence home run.  

There were also humane features that were missing.  They couldn't afford them, Brainstorm said.  Perhaps we'll figure out that sponsors can't afford not to include features that give trial participants continuing access to the real therapy if the participants feel it was helpful.  Think of the compelling data (albeit non-trial data) that they would have generated by this time.

A trial participant made an interesting and informed observation yesterday.  He felt that the neuroprotective properties of the therapy helped his still-viable motor neurons but not motor neurons that were too far gone.  That makes a lot of sense in light of the data we saw.  That also makes it all the more cruel to let people who had been in the trial and felt improvement to be abandoned after trial participation.  More motor neurons died as they lost access to their neuroprotection.  And many of them died.

Again in this trial, we have the challenge of the overachieving placebo group.  The disease is heterogeneous.  The random placebo group can help you or hurt you.  Get a bunch of fast progressors on placebo and even a mediocre therapy will look good.  Get a bunch of slow progressors in the placebo group and your therapy is statistical toast.  Hey, it's random. right?  We have this problem over and over and over.  It is madness.

We have somebody stranded on second base as a result of the Brainstorm trial.  Do we call the game over?  

I hope not.

As much as I don't want to reward inhumane trial designers, can we use the trial data and the tools that the FDA will have available to keep advancing the runner?  We can be creative and still deliver good science.  We need to do the same things that good coaches do.  Analyze and react quickly and make the most of what we have.

And we need to make sure that the next batter up does better -- better called shot, better swing, better pitch, better result. 

Wednesday, October 28, 2020

But It Gets Such Good Reviews

Suppose you belong to a service that autoships products to you occasionally. 

You seldom open the boxes.  They accumulate on your doorstep and then you move them to the garage.

You have paid $108,000,000 over the years for these boxes.

Still, you seldom open them to examine the contents.  Sometimes you peek and are disappointed, but you don't get upset.  You assume that's just a bad box. After all, so many people give them five stars.

You assume all these boxes are a good value because of the reviews.  Five stars every time.  People you trust rave.  

Who are these people? 

The manufacturer?  Sure it gives itself five stars.

The manufacturer's contractors?  Sure they give themselves five stars.

The manufacturer's business partners?  Sure.

People who want to do business with the manufacturer?  Sure.  Don't burn bridges.

See what's going on here with all these stellar reviews?


When we worked hard and got the ALS Registry Act passed in 2008, the primary purpose spelled out in the legislation was "better describe the incidence and prevalence of ALS in the United States."

There should be a box in our front porch labeled "Incidence."  Can't find it.  You see, the CDC ALS Registry that we got can't determine incidence from the data it gathers.

Let's look for the "Prevalence" box.  Found one.  This is what is inside --

We were supposed to get Prevalence reports every year.  You can see how well that is going.  They auto ship sporadically, and don't come close to being complete.  Those rave reviewers who love the CDC ALS Registry seldom use its prevalence data themselves because the data are so incomplete.  Five stars?  Really?

Here's a tidbit for you to read that is a real indictment of the quality of what we are getting (and what is being published) regarding Prevalence --

Five stars?  Not even close.


The array of boxes has grown.  The core Prevalence product is poor (and the incidence box never arrived),  so the CDC has pivoted the attention to many other gifts we receive.  Let's look at that added bonus box labeled "Research Notification for Clinical Trials and Studies."  Don't just read the great reviews.  Look inside and see what we actually got.

Today we see that notification has been issued for 11 active studies, all of which are observational only.  In fact, one is itself a "registry" and several others seem to duplicate what we thought was the original intent of the CDC Registry itself.  Egads, this gets confusing.

In real life (using as our source), there are 36 interventional trials actively recruiting people with ALS in the US today.  Not one of these is included in the CDC Registry notification system.  Not one.

Five stars for clinical trial notification?  Really?

But wait, there's more.

A friend's husband died from ALS in early 2019.  She has notified the CDC Registry multiple times of his passing.  He still gets notices for studies that want him.

This does not speak well for
a. The CDC Registry's basic execution.  Even my vet says that you never send a reminder card for shots for a dog who has died.
b. Any targeting that the clinical research notification may do.  This gentleman would not be a good candidate for any study at the moment.
c. The Registry's ability to mark the deceased as deceased.  We thought that there was a routine scanning of death data to make sure that the dead were excluded from the prevalence counts.
d. All of the above.

Five stars?  I don't think so.


Please open up a few boxes and see for yourself if you are getting your money's worth.  Read some reports.  And stop the autopay if it simply isn't worth it.  It's not.  We're just creating foolish, expensive  clutter that is not valuable.

And don't believe every good review until you've examined some of the goods yourself.

Friday, August 28, 2020

Answer The @#$%^& Phone

 Return the %^&*() email.

Answer the *&())(*&^ question.

Own the $%^& problem.

Everything is harder than it needs to be for people with ALS and caregivers.  Sometimes the barriers are the very organizations and people who are supposed to be helping them.  Do they even know?  Do they even care?  

In the last two days I heard multiple examples from people with ALS and caregivers.  One needing help told of five failed attempts to reach a clinical research site coordinator.  Another told of an email to a major ALS research organization inquiring about a study.  The email got no response after two weeks.  Yet another issued a social media plea for help when all other avenues had failed to help find options for long-term care.

These things happen all the time, and they make dealing with ALS more difficult and frustrating and sometimes, maddening.  

Do organizations even know that they are dropping the ball constantly on the people they are supposed to be helping?  Do clinical research staff accept that they owe people with ALS prompt responses to their questions?  Does anyone measure customer service?  

Many years ago I emailed a vp of a major ALS organization suggesting that they might want to try a secret shopper to do some inquiries that a patient or caregiver would do, just to measure the speed (or lack thereof) and quality of their responses.  My email never got a reply.  I rest my case.

I encourage every organization that gets inquiries from people with ALS and caregivers to take customer service seriously.  It will make life significantly easier for those dealing with ALS.

  1. Answer phones and messages promptly (that means on the ALS clock and not your clock).
  2. Answer the questions asked, and if you don't know answers, find them so that you can answer those questions next time.
  3. Never punt.  Steve Gleason taught us that.  If you get messages from people with ALS and caregivers. you need to take them seriously and personally.  Referring a caregiver or person with ALS to someone else without helping with the handoff and insuring that there are no fumbles is simply wrong.
  4. Test your own organizations.  Maybe an incognito board member might like to make some inquiries to see how you do.  Maybe you can hire a secret shopper.  Maybe a volunteer will help you with that.  You need to measure!  And don't save it for a post-experience customer satisfaction survey that will just make more work for a caregiver or person with ALS.
  5. Make sure that poor customer service has consequences that will help fix your problem. Do you value employees who deliver bad customer as much as those who take the time and effort to deliver good customer service?
It's not hard.

But if you don't do it, you are making the lives of people with ALS and caregivers much harder.

Think about that, please.

Thursday, June 18, 2020

Just A Little Bit


In the past two years I have been fortunate to meet and work with some remarkable people with ALS and caregivers.  They are smart.  They work hard.  They study hard.  They listen and they speak up.  They have found an important way to contribute more than their money and their friends' money.  They contribute their creativity and their time and their thoughtful talents within I AM ALS.  I sit in on Zoom with them almost every day. Their books aren't on a shelf behind them.  They open them and read a lot.  I, a healthy person, accomplish a small fraction of what they are able to do to move public policy and industry.  They are a refreshing bunch who seem to be moving gigantic barriers that have deep footings in the fight against ALS.

Yesterday the ALS Association issued an official statement regarding H.R. 7071, a bill to provide some funding for small biopharms for Expanded Access Programs and in addition would establish an FDA Center of Excellence for Neurodegenerative Diseases, modeled after what was done for oncology several years ago.

The ALSA statement got off to a condescending start by calling H.R. 7071 "well-intentioned" before providing a short litany of what I consider to be off-target objections.

Respect my I AM ALS friends, please.

They have studied and worked hard to make Expanded Access Programs an expectation for all clinical trials.  One barrier has been a lack of planning by small biopharms that raised their capital four or five years ago.  The funding in H.R. 7071 is intended to help bridge that gap.  It's not forever.  By 2025 small biopharms will plan for EAPs as they raise capital because they will have figured out that they can't afford not to.

You see, EAPs can actually help speed up their paths to approval.  It gives them a chance to gather informative data on a broader population of people with ALS (beyond the narrow groups they pick  with best chances to be statistically successful).  The data they can gather are priceless.

There seems to be misunderstanding among some about the purpose of the legislation's funds.  They are not intended to spread unproven treatments to as many people as possible like expensive experimental peanut butter.  They are intended to provide a lifeline to small biopharms so that they can provide responsible EAPs.

And lest we all become hung up on arithmetic exercises, remember that in an EAP the sponsor is allowed to recover at most the cost of product, and typically the products are provided gratis for good business reasons.

Open Label Extensions were mentioned in the ALSA retort as being preferable.  It's not either-or, folks.  OLE should be demanded of every clinical trial design, and it is being demanded by my friends at I AM ALS. I'm glad that ALSA has finally decided that OLEs are important, too.

At More Than Our Stories in February, we had a long, and spirited discussion on such public funding for EAPs.  There was legislative, policy, and research expertise involved in the discussion, including some who authored H.R. 7071.  We talked about the importance of not doing whack-a-mole with other important NIH funding.  We talked about new sources of funding raising the tides. We wrestled with supporting small biopharms versus all sponsors.  Honestly, in my opinion, the ALSA concern that the EAP funding might detract from other research funding is specious.  We need to stop acting like we'll eat each other's lunch.

For years it has been clear that "the oncology FDA" has been more forward-thinking about using all available tools to speed development, approval. and access to therapies than "the neurology FDA."   It's like two different FDAs.  If you search for the use of Expanded Access Programs, you'll find plenty in oncology.  You're lucky to find one or two in ALS.  To ask for a FDA Center of Excellence to get things done for neurodegenerative diseases they way they get things done for oncology is hardly the bureaucratic threat that ALSA, an organization that itself is intimately familiar with bureaucracy, describes.

I ask you to pay attention to the people with ALS and caregivers of I AM ALS who are getting things done.  I ask you to respect them for the smart and hard-working and thoughtful people they are.  And I ask you to help them to move public policy forward.

Thank you.

Monday, April 6, 2020

How to Get Nowhere

Ask us.  We know.

Consider an experimental drug for a quickly fatal disease.  One person says it's the greatest hope ever.  Another person says we shouldn't accept it without sufficient data.  Meanwhile, back at the ranch, people are dying while forces row like crazy in exact opposite directions.

Yesterday I saw the President again tout one experimental treatment for Covid-19.

On the same newscast. I saw the head of the American Medical Association say that she would not prescribe it off-label for her patients.

That's it.  Hatfields versus McCoys.  Right versus wrong.  Rowing like crazy in opposite directions.

Neither mentioned joining a clinical trial.  

That's a way to access a therapy that provides exactly the evidence that we all need to figure out whether the stuff works (and for whom).

Rather than rowing in opposite directions, how about promoting the clinical research that can can both provide the experimental therapy to people and help us reach the scientific truth?

And what if the trial isn't near enough people?  There are easy ways to fix that.
And what if the placebo is an issue for some people?  There are easy ways to fix that.
And what if people are too old or too ill to qualify for the trial?  There are easy ways to fix that.

If people would stop arguing and start promoting clinical research that is humane and informative and nimble, we would start getting somewhere.

Ask those in the fight against ALS.  The constant tension between well-meaning forces has gotten us nowhere.

There are ways to do clinical research that will fulfill the goals of both parties who today are rowing in opposite directions.  Both sides need to smarten up if we want to get somewhere.  It applies to Covid-19.  It applies to ALS.

Sunday, February 2, 2020

There Ought To Be A Law

Or should there?

The lack of access to investigational treatments for people with ALS is unconscionable.  The problem isn't new.  We need to fix it now.

What's the best way to fix it?

A law?  More laws?  Fewer laws?  Fewer regulations? More regulations? Public pressure?  Smarter business strategies? Calls to conscience?  Public funding? Private funding? A toolkit of  some of these?

There is a flurry of new legislation currently being proposed to fix various aspects of the problem.

A lesson I learned from the last law intended to fix the problem is that the devil is in the details.  We need to know a lot more than the good intentions and a great name on proposed legislation.

Do we really need a law?  Exactly how would it work?  Examples, please. And details.

Conditional Approval

A proposal that is most interesting to me at the moment is the one on Conditional Approval.

Senator Braun has provided both the full text as well as an opportunity to comment.  I am grateful for that since we need to polish these proposals as much as possible before moving them forward as legislation.

I have more questions than comments, but I hope that they will be helpful and I know discussion of the answers will enlighten me.

Suppose a therapy is in a Phase 3 trial and the sponsor had intended all along to file for full approval. When the trial is complete and the sponsor sees the data, the sponsor isn't sure that the FDA will be enthusiastic about a broad, full approval.

  • Can the sponsor then ask for Conditional Approval when filing trial results with the FDA? 
  • Can the sponsor suggest the confirmatory studies and data that will be supplied in the future as part of the conditions?  Or is that all up to the FDA?
  • If a sponsor had decided to go ahead and ask for full approval, could the FDA respond with a suggestion that Conditional Approval would be more appropriate?  Or must the sponsor always initiate the request without any prompting from the FDA?
  • Could the FDA suggest confirmatory studies today (without this legislation) after viewing an application for full approval?  Do we need a law?
  • Does the FDA have the resources and teeth to enforce conditions on a Conditional Approval?
  • Are there any precedents for the FDA to accept RWE as part of a full approval?
  • Are there FDA guidances for quality-assurance of RWE?
  • Do we know how government payers might approach covering a Conditionally Approved therapy?

Suppose a therapy is a repurposed drug with full approval in another country.

  • Could Conditional Approval give the FDA a tool to force some confirmatory studies with a US population? 
  • Might Conditional Approval help us find the scientific truth on responder subgroups, making the drug a lot more useful and affordable for people in the US with ALS?

Conditional Approval has worked in Europe.  That's encouraging, but the payer situation is very different there.

Conditional Approval has worked for veterinary products.  That's encouraging, but again, the payer situation is very different.

Can we make this concept work?  I hope we can if it can bring therapies to people with ALS sooner.

And as important, it seems to me that this could give us a way to get to scientific truth without giving broad approval to therapies that work only for subsets of responders.

Thanks to anyone who can advance the discussion.  It's important that we don't stop at the title of the legislation.