We Have A Santa Claus Problem - Part I

 We have a Santa Claus problem.

NIH

We read of an NIH that has expertise and exerts leadership in other areas such as cancer or infectious diseases.

NIH is in the midst of doing a strategic plan for ALS, and so far in the drafts, we have seen a punch list of 15 priorities.  There is a little something for everyone in ALS research. In the plan, NIH (specifically NINDS) will give grants and our researchers will have resources to move their work ahead.  It's like Santa Claus, and who doesn't love Santa!  But Santa doesn't provide a grand vision of where we're going or accountability for how we're getting there.  Santa has something for everyone in the form of fixed grants.  Santa is not providing leadership or expertise for ALS.  This is a problem, but who is going to talk about it because who doesn't love Santa?

CDC ATSDR

For over a decade we have watched a CDC ATSDR Registry disappoint when it comes to deliverables on the incidence and prevalence of ALS in the US.

Somewhere along the way, a generously funded Registry project started giving grants to researchers for epidemiological work related to ALS.  It was like Santa funding important work that seldom if ever was directly related to the basic disappointing Registry work.  But who doesn't love Santa?  ALS researchers loved the CDC ATSDR Registry, not because it was fulfilling its core mission, but rather because it was a source of valuable grants every year.  Who is going to criticize the Registry work because who doesn't love Santa?

We have a Santa Claus problem, and until we admit it and make government agencies be accountable for leadership and results rather than just doling out grants, we will continue to be stuck with a big red bag full of fragmented, expensive research projects.  

But who doesn't love Santa?

Hi, I'm Sandy's Friend, Cathy

 We lost Sandy Morris to the stinking ALS this week.

As many of you know, she was a huge influence for the better in what we called ALS Land.  If you didn't know her, just google "Sandy Morris ALS."

I've been working at ALS advocacy for a quarter century.  I'm just one of many, and I work hard pounding away at the boulder.  Sandy made the boulder crack.

Sandy made everyone involved in the fight against ALS better, from us simple advocates to top researchers and heads of state.  People knew her and admired her and listened to her because she was right and did not cling to anything of the past as good enough.

Keep in mind that people come along in ALS Land and push the envelope all the time, but seldom do they make a significant dent in anything.  I knew Sandy was the real deal on July 12, 2018.  ALSA held a meeting in Washington to talk about the FDA ALS Guidance (again).  Many of us were tired of talk, but a group of esteemed scientists and people living with ALS were assembled and talked some more.  During a Q and A a woman from California called in and asked why we didn't just play the transcript from the February 25, 2013 hearing on ALS because we were just rehashing everything that had been said then.  Boom.  I knew that Sandy Morris from California was the real deal.

Many of us miss her terribly this week, mostly as a friend, but also as a leader.  Sandy knew how to run a meeting.  She had charisma, but she didn't depend on that.  She always had an agenda.  We always started on time and finished on time and every person understood the homework to be completed before the next weekly meeting.  Sandy had vision and the human skills to manage projects to move to that vision.  How we miss her.

The tangible accomplishments Sandy delivered are immense, and nobody paid her a dime to do what organizations and staffs have never been able to deliver.  Expanded Access started to happen in ALS Land because of Sandy.  She studied, always wanting to have her facts straight, then she acted with purpose.   Legislative efforts were effective because of her relentless efforts.  And drug developers started to design more humane trials because Sandy insisted and taught us all how to insist.  And the Morris ALS Principles will set the tone and boundaries that have never been established before for those dealing with ALS.

I'm very happy working behind the scenes and it was a treat to help Sandy. I go to conferences with top ALS researchers, and most are oblivious to me.  I learned a couple of years ago to introduce myself, "Hi, I'm Sandy's friend, Cathy."  Suddenly they pay attention. Sandy and I joked that my name is now officially, "I'm Sandy's friend, Cathy."  

Sandy was also a talent scout for ALS Land.  She had people skills that brought some immense talent into the fight to work along side her.

We have a huge void in ALS Land this week.  One person can't fill it.  I just hope and pray that we can all chip in the talents we have to keep making cracks in that boulder that Sandy started so well for us.

We muddle ahead in a grief fog this week, but we have homework that is due next week.  And we must deliver.

Sign Here

We sign forms.  We agree to things in order to get treatments, both approved and experimental.  It's exactly the same thing as signing forms in order to rent a car.  There is a lot of fine print and there are things in that fine print that we don't particularly like (if we have the time and eyesight to read it), but what can you do?  The form is a barrier between you and what you need.  You sign to get past that barrier.  You have no power in the deal when you are at the car rental counter.

Your health data, especially when aggregated with the data of lots of other people, are of significant value to medical researchers.  Imagine how much Company B would like to have data on people taking Company A's product.  The blood tests and clinical data observations over time could be priceless.

Let's go back to those forms you sign.  People with ALS are encouraged more and more to get genetic
testing and counseling.  You sign forms to do that, and the company provides your data to you.  Great.  But what do those forms say about what happens next to your data?

People with ALS sign forms to receive treatment and to participate in research.  Wonderful. But what do those forms say about what happens next to your data?

Most people with ALS want their data shared broadly, and that certainly happens in some situations.  In other situations, their data become a commodity.  If data are eventually sold to the highest bidder, is that not having the opposite result of what a person with ALS intended?

We need to talk more about this problem now so that we can influence what is on those forms. People with ALS can use their power to make sure that they are not voiceless pawns in someone else's business model.

And we need to talk more about the role of agencies like NIH to help us with solutions to neutralize this problem.  If we had a robust NIH natural history that was a "come one, come all" destination for people with ALS to contribute their data, we could be assured of open and equitable access to data that would advance the science rather than advance a few investors' bank accounts.

Open the @#$%^& Curtain

Today we wait.  We wait for some therapy developers to do whatever they're doing.  We wait for regulators to do whatever they're doing.  We sometimes don't even know for whom we are waiting.  We just wait.  

The work goes on behind a big, heavy, black curtain.

Imagine a big corporation designing and delivering a new car. There are dozens of sub teams on the project and there may be contracted engineers and test drivers.  Government regulators having a role to play, too.  Do you think that any of those project members gets to go hide behind a big black curtain and do whatever they do, only to come out whenever they get finished?  Do you think that the team is hidden from what others are doing?  Do you think that somebody who needs more time just gets to take more time and tell others to wait?

Ha.  

Even airlines figured out that a flight delay without a reason is disaster for their gate agents.  Tell the waiting stakeholders what is going on.

In the often dysfunctional world of ALS, we have therapies being tested, analyzed, and evaluated for approval.  Is anybody really back there today?  We have no idea of what is going on.  We just wait.  And if nobody is actually back there doing something, we don't know if we're waiting for something that will never happen.  We just wait.

I'm not asking for gigantic regulatory or process upheaval.  Simply provide some basic transparency.  What is going on behind that black curtain.  Who are we waiting for and what are they doing.  We realize that some jobs are difficult and take a long time.  Just tell us what's going on.  Are contracted statisticians working on data for the next three weeks?  Are regulators analyzing public comments for three days?  Are executives meeting with investors for a two-day conference?  Are we waiting for an investigator's hernia surgery?  What is going on?  Or what is not going on?

The mystery of the black curtain gives an awful lot of cover and leads to a lot of misunderstandings. 

Just open the $%^&* curtain and tell us what's going on. 

Dear FDA Advisory Committee

Below are my comments submitted to the FDA Advisory Committee that will be meeting to address questions related to the Amylyx AMX0035 approval.

_____

Mom was diagnosed with bulbar-onset ALS 25 years ago at age 78 (after a long delay to diagnosis).  She had a fast case and died in 1997.

One might think that a therapy option that slows the speed of a difficult terminal disease might not be of much use to an elderly person in her situation.  I think that just the opposite is true.

One morning, for the first time ever, she asked me to help her button her blouse.  She had strength in her hands but was losing finger dexterity.  As I buttoned those few buttons, she said, "Do you know what the worst part is?"  I simply said that I did not.  She then said, "Once I lose the  ability to do something, I know I'll never be able to do it again."  

She had buttoned her last button. 

I think we all need to let that soak in.

She took riluzole without any pretense that she was going to beat the grim reaper.  She simply wanted to try to keep the independence and dignity of being able to button a button or take care of her personal hygiene as long as possible.

My understanding is that AMX0035 hit its primary endpoint with statistical significance and has a good safety profile.  It's a combination of substances that the FDA knows well.  We are realistic that not every therapy will work for every person with this wicked, heterogeneous disease. I think AMX0035 belongs in a physician's toolbox to try to help a person with ALS who isn't ready to throw in the towel on buttoning that last button.

Thank you very much for the opportunity to comment at an important regulatory moment.  This is the time to apply both the spirit and the letter of the FDA ALS Guidance.

Mislead or Lead

 Dear. CDC and ATSDR,  

You can lead or you can choose to continue to mislead.  The choice is yours.

ALS Prevalence and Incidence in the US

Option 1: Mislead. 

This is unfortunately the path you have chosen.

We sporadically get prevalence reports based on the people with ALS you find rather than the population of people with ALS in the US.  You do not have a population-based registry, yet you issue reports with demographics as if you do.

There are some important examples of how misleading you have been in the past few months --

Dr. Walter Koroshetz, the head of NINDS at NIH, testified the following to Congress in July, 2021:

https://docs.house.gov/meetings/IF/IF14/20210729/113983/HHRG-117-IF14-Wstate-KoroshetzW-20210729.pdf

"Neurodegenerative disorders also include rare but devastating conditions like ALS, a rapidly progressive, fatal disease that affects the nerve cells controlling voluntary movement. The CDC estimates that 12,000–15,000 Americans have ALS, and approximately 5,000 Americans are newly diagnosed with ALS each year."

You misled one of the top neurologists in the country, and as a result you misled the Congress.

News outlets also turn to the CDC as a trusted source.

https://www.wdtv.com/2021/07/28/morgantown-resident-talks-about-living-with-als/

"Amyotrophic Lateral Sclerosis (ALS) affects between 12,000 to 15,000 people across the U.S., according to the CDC."

https://khn.org/news/article/dying-patients-with-rare-diseases-struggle-to-get-experimental-therapies/

"More than 16,000 people in the United States were estimated in 2015 to have ALS..."

More than 16,000, indeed.  Way more.

And there is the draft scoping document that ICER produced for their study on pricing related to two anticipated FDA product approvals.  ICER is in the numbers business and turned to the CDC for a very basic number.

https://icer.org/wp-content/uploads/2022/02/ICER_ALS_Draft-Scope_020222.pdf

"There are about 16,500 people living with ALS in the United States, with a prevalence of 5 to 6 per 100,000 persons."

ALSA issued comments related to this draft but failed to mention the understatement of prevalence of ALS by the CDC.  ALSA is a "partner" (another misleading word since ALSA is actually a paid contractor on the project) and for some reason decided to be misleading, too, by ignoring the problem.  Thank heavens ICER did correct the data based on an individual pointing out the incompleteness. of the CDC's data.

Option 2: Lead

Stop publishing prevalence (and now incidence) reports as if your data are complete.  Be clear that this is a sample of the people you found and you don't know what you don't know.  The people you didn't find don't necessarily look like the people you found.  And based on a past analysis, you miss almost as many people with ALS as you find.  Be clear.  Give us details that are actually meaningful such as how many people self-enroll, how many are in the Medicare files, etc.  And please publish data. simply and promptly.   Leaders understand the importance of meeting due dates.

Clinical Trial Notification

Option 1: Mislead

Again, this is the path you have chosen.

People are encouraged to sign up for clinical trial notification and they infer that you will let them know of trials.  They do not understand that you will inform them of a tiny fraction of enrolling interventional trials.  They sit back, relax, and wait for the magic email from the CDC  telling them of the right trial while their eligibility windows evaporate.  

And your matching capabilities are limited.  The fact that dead people can receive trial notifications is a testament to that problem.

Option 2: Lead

Stop using 1980 email tactics.  You have access to a list of all enrolling interventional trials via clinicaltrials.gov.  Work with your "partners" to design trial notification that is more effective and less onerous than yours.  The best way may not involve you at all.  That's fine.  We need what is best for those with ALS and sponsors.

Summary

In an attempt to constantly celebrate success of the project, it has been easy for you to mislead.  Please stop. 

The CDC and ATSDR should lead, and that means being honest and. clear about what we have and what we need to do.  

Please lead.

The Landscape Feels Littered

During the past week I have worked on finding the status of multiple ALS research projects.  You know, the ones that were hot topics ten or five or even just three years ago.  What ever happened to them?  What is going on with them today?

I find the grant information.  Then I find scant published results.  

The most troubling part is that it feels like projects morph from their original designs into something very different.  Maybe that drift is fine.  Maybe it's like converting an old shoe factory into a factory making cell phone cases.  But how do we know what is really going on in there?

How are we supposed to make sense of the entire landscape?  What happens to the project
infrastructures?  Are the lights even on in Building 7 in this figurative factory park?  

It feels akin to an industrial complex that was built helter-skelter.  New buildings are built to manufacture new things, but rather than having a cohesive architecture, we have dozens of individual plants with their own styles.  We have leaders who know how to do their work best in their own buildings.

Modern factories use colocation to leverage efforts among small manufacturers to minimize duplication of efforts  ALS researchers work in their own expensive silos.  And their promises of collaboration involve moving data back and forth, much like old factories used to move materials through arcane chutes and rail cars.

What is wrong with this picture?

So much is wrong.

And it is paid for by generous donors and taxpayers.  The litter of past research projects is as real as the litter of old factory buildings, and it is every bit as expensive.

October 20, 2021 -- Remember The Date

On Wednesday, October 20, a group of people with ALS and caregivers who dub themselves "ALS Problem Solvers" met with nine top NIH NINDS leaders to discuss "Five Things That Will Change Everything."

It wasn't just another meeting.

This was a long time coming, and each of the ALS Problem Solvers knew that the stakes were big.

Over a year ago, Gregg Gonsalves had been on a panel at the NYU conference on pre-approval access to therapies.  As I often do, I asked a question of the panel about how ALS can benefit from such things that are so common for other diseases. Expanded Access Programs are like unicorns in ALS. At the break, I heard a voice behind me as I sought a cup of tea in the foyer, "I want to help."  It was Gregg.  And he has since been generous with his help.

Shortly after that conference, a group of people with ALS and a few caregivers started brainstorming on how we can move ALS research out of its ruts. It seems like other diseases move ahead with concepts and tools that are unused for ALS.  We started meeting on alternating Saturdays with Gregg.  We did a lot of homework.  We did everything good workgroups do, including celebrating some ideas and arguing about others, but we moved forward.

We homed in on the fact that the NIH has implemented basic, successful solutions such as a natural history study for other diseases that are not done for ALS.  Why not ALS?  Why not us?  

For decades ALS has been like the orphan disease that has truly been orphaned by some basic aspects of scientific research.  We were determined to change that, and Gregg encouraged us to make our case directly to top leaders of NIH NINDS.  Directly.  Make the case.  We were on it.  We researched.  We wrote.  We rewrote. Assert nothing without citation. We criticized our own work. We researched more.  We knew we needed to be on solid scientific and academic ground. We wrote the document, "Five Things That Will Change Everything," that described the problems and the solution -- Five cogs that working together would change everything in ALS research.

• A Natural History Study
• A Broad Network of Clinical Trials
• A Framework for Broader Insights - A Parallel Track
• NIH Leadership
• Our Relationship

On September 25 our document was presented to Dr. Walter Koroshetz, the head of NINDS, along with a request for a meeting with the ALS Problem Solvers.  He accepted almost immediately and October 20 was the date.

The preparations were intense. Six people with ALS and four caregivers would speak. These words would be short and pithy.  They would reinforce the cogs with life experiences that showed the need. We practiced, we refined the message, we practiced more.  We rehearsed challenges and questions that NINDS might pose.  We were prepared.

We also got the help of others.  Two top ALS neurologists joined us.  Two professionally accomplished friends of one ALS Problem Solver pitched in and made significant contributions to our presentation.  We had a supportive statement from Senator Murkowski who knows NINDS leaders well.  

Along the way we had a few disagreements and a lot of fun. We were prepared.

The meeting was to start at 5 o'clock yesterday.  The ALS Problem Solvers were online fifteen minutes early, all clad in our blue t-shirts with the five cogs.  We were prepared.  At the stroke of five, the waiting room started to fill with NINDS names we knew and a lot of names we didn't know.  It was time to roll.  

Dr. Koroshetz introduced the eight others from NINDS who were there.  He brought the whole a-team.  That was good.  We got some positive feedback on the document.  They had read it.  The reaction that it was a good mix of science and human experience was encouraging.  And the t-shirts even got their attention.

ALS Problem Solver Danielle started the presentation and what we had practiced so many times was 

finally being said to NINDS staff.  They were engaged. Gwen hit it out of the park with her problem statement bolstered with life experiences. Tim spoke to the natural history study as he does so well.  Becky and Glen hit the marks on the need a broad clinical trial network. Sandy's comments on a parallel track were spot on.  It was my turn to deliver the visual on the first three cogs working together. I remembered to unmute. Phew. Caregiver Bob hit the importance of NIH NINDS leadership to make all ALS research more effective, then Phil brought it home with compelling words on teamwork and our direct relationship with NINDS.  The two top ALS neurologists offered supportive comments. The action items were up next.  We were asking for some things that were easier than others, but we knew we had to be specific.  

Now it was NINDS turn to tell us what they thought of our proposal.

We knew that there would likely be concerns just because of government process and bureaucracy, and there were.  We heard that NINDS has a sweet spot with ALS in basic and pre-clinical research.  Yes, and we are grateful for all their work in those areas.  They emphasized that the lack of understanding of ALS makes clinical research risky and prone to failure.  Yes, we understand that.  

We had about 15 minutes left in our one-hour meeting, and I was starting to worry that we were not going to get any specific next steps out of this, but something started to happen.

The concerns about the lack of understanding about ALS that makes clinical research so risky really made the case for a natural history study.  NINDS shared that there was a natural history study with 800 people. I was puzzled.  Then in the chat, we got the thought from one of the neurologists that perhaps CReATe could be expanded.  Ah, CReATe -- I knew that as a study strictly for familial ALS.  Great. People are thinking.  Perhaps we already have an NIH asset that can be leveraged as a large and broad ALS natural history study for everyone with ALS.  Now we're thinking.

NINDS offered us contact points from their meeting participants for each aspect of change we are requesting.

And we have an opportunity to participate in an upcoming strategic planning process.  That will take more time than we want, but we will be there and direct voices and brains of people with ALS will influence those conversations.

And our foot is in the door in a very good way -- NINDS working directly with these people with ALS and caregivers.  ALS Problem Solvers proved that people with ALS belong and can contribute to the science.  This is a new model for co-producing with NIH, and it could not come at a better time.

And as Gregg reminded us last night, the hard work is just starting.

We're ready.

We're grateful.

October 20. Remember the date. It was an important day.

www.ALSproblemsolvers.org

@ALSprobsolvers

Dear Chair DeLauro and Ranking Member Granger

Dear Chair DeLauro and Ranking Member Granger,  

I write you as a concerned advocate for those with ALS (we lost Mom to ALS in 1997), a person who believes in the value of epidemiological data in science, and a taxpayer.

ATSDR has administered a CDC ALS Registry since we worked hard to have the ALS Registry Act  passed into law in 2008. It has disappointed in many respects -- undercounting cases yet publishing reports as if counts were complete, terribly late reporting of data (we just saw 2016 data for the first time), falling into the distracting temptations of scope creep, and entangling itself in financial relationships that prevent objective and candid oversight.

You wisely inserted language into the recent appropriations bill --

https://docs.house.gov/meetings/AP/AP00/20210715/113908/HMKP-117-AP00-20210715-SD003.pdf

Amyotrophic Lateral Sclerosis Registry.—The Committee directs CDC to present a plan to the Committee within 90 days of enactment of this Act to enhance the oversight and advisory process for the National ALS Registry to increase transparency and better reflect the needs of the ALS community. This plan should consider ways to translate Registry findings to human application that can lower the risks and disease burden of ALS, make disease reporting more representative, more accurate, and more inclusive, and include a range of estimates rather than point estimates of ALS prevalence. Equally important are updates to the survey process to ensure the data they collect are impactful and respectful of participant burden. Finally, the plan should ensure that the ALS community can view as much Registry information as possible without compromising the privacy of participants.

Two weeks ago the CDC ATSDR Registry folks held an annual meeting. It has never been a true oversight meeting.  Two weeks ago it was more of a closed, clubby celebration of questionable achievements (from what little I was able to see).  The public could only watch part of the first day.  It takes an invitation to be a full, two-day participant with the ability to unmute and ask questions and make comments.  We're not sure what it takes to get an invitation. A man with ALS, Stephen Finger, PhD, who has participated for several years and asks good questions was not invited back this year.  He seems to have outlived his welcome.  Good for him, but his exclusion was revealing.  

ATSDR refers to its many "partners" at the meeting.  Those are largely paid contractors, including the ALS Association (ALSA), the Muscular Dystrophy Association, and Les Turner ALS Foundation who together get around $1,000,000 per year in no-bid contracts for some vague "education and outreach."  ALSA is also the lead advocacy organization that lobbies you for the $10,000,000 annual budget for the project.

Add to that a number of grant recipients and potential grant recipients at the meeting, and we have a pretty good recipe for a love-fest rather than any kind of objective oversight.

Please insist that they bring to you an oversight plan that is composed of third parties with knowledge of epidemiology and payer data and information systems who have no financial ties to this project.

Thank you very much.

The Ketchup Was Always Worth the Wait

Anticipation.  Those were the great Heinz ketchup ads of the 20th Century.  The glass bottle with the
narrow neck, the thick, quality ketchup, always worth the frustrating wait while we hummed along with Carly Simon.

We've had a lot of anticipation and waiting since we worked hard to have the ALS Registry Act passed in 2008.  Has it been worth the wait?

We're close to the annual CDC ALS Registry meeting on August 31 and September 1, 2021.  It's not an oversight meeting.  The description is more of a celebration -- "Update stakeholders on the progress and achievements of the National ALS Registry."   Please register and tune in if you are able.  You've paid well over $100 million for this Registry.  Has the ketchup been worth the substantial waits?

The primary purpose of the Registry as written into the law is "to better describe the incidence and prevalence of ALS in the United States."  Everything else is mustard or relish.

Back in the 20th Century we were promised a passive data mining technique that would find 85% of ALS cases via this data mining, and then the other 15% could be added by a patient self-enrollment portal.   We would get annual reports after a time lag necessitated by the wait for public payer files.  That was the promise.

The waiting and the ketchup have been particularly troublesome in the last three years. 

The Waits

We have not received any semblance of annual reporting.  The cavalier attitude about due dates really puts the value of the output into question.  The 2016 data were just published this week.

Heinz knew when to completely redesign that ketchup bottle.  We now use 21st Century bottles that eliminate the wait.  Perhaps it's time for a significant 21st Century bottle change for the Registry. 

The Ketchup

The hit-and-miss prevalence reports have questionable value.  The undercount is significant.  The demographics continue to be published.  It is not clear that these are merely the people that the Registry finds, and there may be just as many people with ALS out there whom they missed.  Two top NIH officials at a recent Congressional said that according to the CDC there are 16,583 people with ALS in the United States.  We repeatedly see the CDC number as being the number.  First do no harm.  These prevalence reports are doing harm by misleading the public about the number of people living with ALS.

A recent study by Miller et al used some different data sources to estimate prevalence that was starkly different from the CDC's.  And the authors were able to be much more timely than the CDC.  

If the ketchup coming out of the bottle isn't what the consumer expects, Heinz knows to change the recipe.

The Recipe

The "FAQ" document that came with this week's publication of the 2016 prevalence report causes major concerns about the recipe.

They are cooking in excuses for even more delays.  That's not acceptable, especially with the trail of inconsistent excuses we've had in the past.

They are cooking in excuses for a flawed design.  They knew full well that ALS was not reportable or notifiable back when they made promises and designed the algorithm for passive data mining and the patient portal.  

They suggest buying data from more sources and adding them to the recipe.  Whoa!  It's time to step back and do some test recipes first.  Figure out what gaps new data sources can or cannot fill.  Design before you start buying ingredients.  We've been asking for years for their "partner"/contractors to supply counts on the numbers of unique people with ALS they served in the past year along with counts of how many of those were new.  Every year this has been completely ignored.  Finally, the CDC seems curious.  Look at the numbers first, please, before you enter into more entangling contractual relationships that may not actually be the best solution for the completeness problem!  They've never been in a rush before.  Why rush into implementation without a smart analysis?  Perhaps there are even some prepared products that could replace some of the old infrastructure.

They also are suggesting that the capture/recapture approach will be the magic spice to make the ketchup better.  That's not necessarily true.  A 2013 report challenges the magic for this project if you read it carefully. 

The Other Condiments

The ketchup hasn't been good and certainly hasn't been worth the waits.  

When insights into incidence and prevalence are questioned, the project fathers often change the focus to all of the other things that a generously funded government project has done.  The mustard and relish become more important when the ketchup isn't good.  How do they measure success of every add-on?  Number of emails sent does not make a great trial notification system.  Number of biospecimens collected does not make a great Biorepository unless we have tissue and data representative of the diverse population of people with ALS.  

It's quite possible that the external research grants are the most valuable contribution that this project makes; however, the grant making process is opaque to the public and we can't even find out how much of the $10,000,000 that this project costs taxpayers is used by these grants.

Nobody at the annual meetings seems curious about the expenditure in general, let alone on functions like trial notification or on the Biorepository or the CME or the prevalence reporting.  

The Ketchup Consumer

Some consumers have questions that never seem be asked at the annual meeting.  We pay $10,000,000 per year even if the ketchup isn't delivered and we pay regardless of the quality that finally comes out of the bottle.  We should be asking questions.

1. How many unique people with ALSA, MDA, LTALS serve last year?  How many of those were new cases?

2. CDC has given ALS, MDA, LTALS annual contracts that total around $1,000,000 (10% of the annual appropriation) for "education and outreach."  How does the CDC come up with those contract amounts?  How does CDC measure those contractors and deliverables?  What is the cost/benefit evaluation? 

3. Does ATSDR have any idea how much the Biorepository costs every year?  The trial notification? The grants?  How do they measure the cost versus benefit?

4. Is ATSDR not concerned about the incomplete prevalence count that has been taken out of context in public media?  People, even top NIH professionals, have quoted the 16K number as the number of people in the US with ALS.  Is this not a concern?

5. The Miller paper underwritten by MT Pharma found half of its people with ALS in private payer files.  That's pretty much the smoking gun that the surveillance of public payer files will not be successful. How did that  paper's authors get data in a much more timely manner than ATSDR? They reported data through 2017 in June of this year.

6. Earlier this year ATSDR received a suggestion to just publish tables of data in a regular annual process so that the report and publication process aren't delaying things.  Again, how about simplifying the process and just providing data tables in a regular and more timely manner? 

7. How many people are represented by the Biorepository?  How many of them are living?  What are the demographics of people represented?

8. How often are Registry data matched with the death index data?  There are reports that deceased people continue to get clinical trial notifications.  That is painful and does not speak well to the matching capabilities of this rudimentary emailer.

9. A 2017 report raised concerns about disparities, equity, and inclusion in Registry data.  What tangible actions have been taken to address and measure these?

10. ALS has a cruel way of imposing term limits on the invited people with ALS who are allowed to speak at your annual meeting.  We have lost Ted Harada, Rob Tison, and Becky Kidd among others, all experienced people who thoughtfully prepared and spoke their minds at your meeting before they died from ALS.  Your decision to change the rules in 2021 so that Stephen Finger could no longer participate  smacks of wanting to eliminate a thoughtful, prepared person with ALS who spoke his mind and perhaps outlived his welcome.  This is not a question.

We'll Have What They're Having

My message for the House Energy Committee Health Subcommittee Hearing coming up on Thursday, July 29, 2021.

______________________

Everyone reading this letter already knows the urgency that ALS demands.

 

ALS has become an orphaned orphan disease.  That’s the worst.  

 

Ever since we lost Mom to ALS in 1997 I’ve written letters and testified to the FDA and written more letters and visited legislators.  We’re still an orphaned orphan disease.  

 

FDA

 

We want the same FDA that oncology has.  They have Project Facilitate to help with Expanded Access.  We don’t.  Why not?  

 

You can find 106 enrolling interventional trials for ALS at clinicaltrials.gov.  How many Expanded Access Programs are there?  Two.  And one of them is highly restricted.  Just two.

 

Something is not right here.  Other diseases have this Expanded Access path that also allows rigorous science to proceed while dying people can get access to therapies.  They even have an 800 number to help.  We in the world of ALS seem to get bogged down in opaque processes that move at the speed of concrete.  

 

NIH

 

We want the same NIH that other diseases have, too.

 

Sure, we appreciate the grants that the NIH makes toward a patchwork of ALS research.  But what about the expertise of the NIH that can make trials smarter and more accessible?  What about the knowledge of the NIH on how to do biorepositories better and more cost effectively than anyone else?  We need the NIH to become engaged with ALS for more than passing out grant money.  Please, we need the NIH that is known for the science that goes on at its headquarters for so many other diseases.

 

 

Is there any question as to why those dealing with ALS and their families feel that they have been orphaned?  We need for our federal agencies simply to do for ALS what they have done for other diseases.

 

That’s all.

 

Thank you.

Were They Just Doodling?

 For over a decade I and others (many of whom have died from ALS) have gone to FDA meetings to give  thoughts on the need for change for ALS.  There have been Patient Focused Drug Development meetings.  There has been an all-day FDA hearing on ALS.  There have been public hearings on innovative trial designs.  There was an all-day ALSA workshop  so that the FDA could hear our thoughts.  I was not a paid invitee.  This was a volunteer effort that I and others thought was important and would make a difference.  

For over 10 years we have worked with pharmaceutical and biopharmaceutical companies that have asked for volunteer patient and caregiver voices.  I have spent countless hours in meetings that many of us  thought would make a difference.

Over the same decade, we have talked to ALS researchers about how we can improve clinical research from the patients' and caregivers' perspectives.  Again, we thought we could add a valuable perspective and make a difference.

I and others spend long hours doing our homework so that we can be informed contributors.  We learn regulatory and industry perspectives that need to be considered.  We know that there were once good reasons for rules that we would like to see changed.  We have been driven to make Expanded Access and faster determination of scientific truth realities.

Today I think we've been had.  Was anyone even listening?  While we spoke, were they just doodling in those meetings, humoring us but not really planning to change a thing? 

Events of the past few weeks have shown that absolutely nothing has changed.

We've been had.

This Is The App We Really Need

Suppose the average life-expectancy for an average American adult is 42 years.

Suppose the average life-expectancy for a person with ALS is 3 years.

That's a big difference, and nobody hears the ALS Clock tick as loudly as a person living with it.

Enter the Apple Watch app that runs on the ALS clock.

It would make my watch run 14 times faster than it does today.  Mickey's hands would be flying.  The dates would be changing before my eyes.

If you tell a person with ALS that a project is being delayed a quarter on your healthy calendar, that is like 3.5 years on the ALS Clock.

If you waste a day on pointless meetings, that's like two weeks on the ALS Clock.

How uncomfortable would it be if an hour Zoom call took up 14 hours on your new ALS Clock App?

Pretty uncomfortable, I hope.

And that's what we need.  Turn your watch to the ALS Clock and get to work, faster.  

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:

https://ir.brainstorm-cell.com/press-releases

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. 

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 -- https://www.cdc.gov/als/ALSReportsMMWR.html

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 -- https://www.tandfonline.com/doi/full/10.1080/21678421.2017.1384021

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 clinicaltrials.gov 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.

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.

Just A Little Bit

Respect.

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.

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.

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.

https://www.braun.senate.gov/senator-braun-introduces-conditional-approval-act-patients-fatal-diseases-asks-comments

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.