Talking With Dr. Faustman

A few weeks ago I was able to meet Dr. Denise Faustman in person. We had previously exchanged emails, but this was our first face to face meeting. She was in town (together with Russel, her business development guy) to give a presentation on her research to interested parents. A local family was hosting her presentation, including providing wonderful food and wine for a large number of families to come and hear her. A member of brave buddies worked with the host who was kind enough to invite me. The Initial plan was for me to just attend. However, they realized that I would have different questions than the other people at the talk, and her answers to my questions would not be of interest to the others. Therefore, they suggested that I come early, and we have a conversation ahead of the regular talk. This sounded like a great idea to me. I asked Dave Forer, another Brave Buddy, to attend as well. Dave is a statistician who has worked on clinical trials for 20 years (although not for type-1 diabetes), so he brought a lot to the table [d1]. (Throughout this posting, marks like [d1] refer to extra discussion at the end of the post.)

This posting is made up of two parts:
    1. A status update on Dr. Faustman's BCG research.
    2. Some thoughts on speaking directly with Dr. Faustman.

Dr. Faustman is a famous and controversial figure in type-1 research.  You can read more about her research in my previous blog postings:
http://cureresearch4type1diabetes.blogspot.com/2008/10/faustmans-research-part-1-history.html 

http://cureresearch4type1diabetes.blogspot.com/2011/08/dr-faustmans-phase-i-results.html 

but the bottom line is that in November of 2007 she started a 7 month phase-I clinical trial with BCG which she hoped would cure type-1 diabetes, or at least be part of the cure.  Data from that study has not been published.  

Status Update and New Information

• The paper with the results from phase-I has been submitted for publication, but has not been accepted for publication, as yet.  So no peer-reviewed results (or detailed results of any kind) on the results of her phase-I clinical trial of BCG have been published.  Nothing has changed there.
• Dr. Faustman is no longer making public the poster that she had presented at the ADA conference last June 2011.  This poster was the most detailed information available on the phase-I clinical trial (including important C-peptide data [d2]) so making it unavailable is a serious step backwards. 
• Because it was still being designed, Dr. Faustman would not share with me any details of the planned phase-II clinical trial.  (One of her slides said it would include 60 people, but she made it very clear that was a goal, but could change for any number of reasons.) 

So my overall summary of movement in the last 8 months is: no visible forward progress, and an important step backward.

Talking to Dr. Faustman

My strongest impression of Dr. Faustman is that she comes across in person just like her advocates come across on the net.  She is incredibly optimistic about her research, and extremely driven to move it forward.  She is very passionate about it, and that passion comes through everywhere and all the time. She has explanations and reasons for all the delays in her research, all the results that don't quite add up, all the previous failures with BCG, and so on.

However, there is a big difference between talking with Dr. Faustman's advocates on the web, and talking with her in person.  When an advocate says something that doesn't mesh with what I know about research, I just assume that person is confused.   However, when Dr. Faustman herself says things like that, the effect for me is much more jarring.

The most important example of this is her answer to the question: why were only three people dosed with BCG in the phase-I trial?  Read [d3] for discussion of why this is a critical question.  Her answer was that the FDA would not allow more people to be dosed.  Because of it's importance we spent quite a while discussing this, and she was very consistent that the 3 person trial size was because of the FDA.

However, I've followed dozens of trials aimed at curing type-1 diabetes during this time, and every one of those other trials had more than three people.  Some of them involved new drugs, and others involved drugs with known side effects much worse than BCG's side effects.   Additionally, I researched all the trials using BCG.  There are dozens of those as well, and (again) every one of them uses more than 3 people.  Some of those trials involved far larger doses than Dr. Faustman is giving. [d4]

So I am supposed to believe that the FDA went to Dr. Faustman and said something like this:  Lots of other people are studying drugs to cure type-1 diabetes.  Some of these drugs have never been used for anything before, and we allow all of these groups to test more than 3 people in their trials.   Also, lots of other groups are studying BCG specifically for other diseases, sometimes in much higher doses than you are using, and we also allow all those groups to test more than 3 people.  However, Dr. Faustman, for you and you alone, we are limiting your phase-I trial to 3 people.

Except I don't believe that.  Having Dr. Faustman tell me that the FDA limited her phase-I trial to 3 people created a real credibility gap for me.

There were a total of three issues where things that Dr. Faustman said were not consistent with what I know about research from other sources.  Another example was the question: why won't you make the poster public, which you previously showed at the ADA poster session 8 months ago?  At first the answer was: ADA won't let me.  Neither Dave nor I had ever heard of such a restriction before.  The poster was made public at the conference, what possible reason would they have to restrict it later?   It's completely unbelievable to me.  Dave also expressed his doubts about this explanation [d6], and when he did, the rationale shifted.   There were ADA restrictions, but also the authors of the poster had a meeting and decided jointly not to present the poster data publicly any more.  So then the question was why?  Several reasons were given, all quickly: maybe the data had been misinterpreted by others, maybe they were afraid it would be misinterpreted, maybe they were afraid people would start using BCG off label, maybe the research was limited.  But again, in all the dozens of research projects that I've followed, the researchers are always making more data available, not less data [d7].

Because her paper with phase-I results had been submitted for publication, but had not been accepted, we could not talk about any of the data in it.

I also tried to find out why her phase-I trial took so long.  When the phase-I study started in Nov-2007, it was supposed to end in July-2008.  It actually ended in late 2010 or early 2011.  So a 9 month trial actually took about 36 (or a few more) months.  I asked specifically about why they stopped recruiting patients for an 8 month period.  Read [d8] for more discussion on why this was important.  However, that discussion led nowhere, because Dr. Faustman said she did not know about the recruiting gap, and did not want to comment on any of the information in the FDA's clinical trials record.

The result of all this is a lot of frustration for me.  I ask about data which should be available.  I get reasons why the data is not available.  I ask about different data, I get different reasons why it is not available.  At the end of the evening I have a large number of reasons [d9] why there is no data, but still there is no data; just requests for funding and support.

After our discussion, I listened to her presentation to the other parents.  It was pretty standard stuff about the history of her research including results from her NOD mouse work, and one slide from her human blood work.  But for me, one of the striking parts of the evening, was left out of the presentation:  There was no information on what had happened to people who had gotten BCG in her phase-I trial!  She's trying to raise money for a phase-II trial, without showing the results from her phase-I trial.  And we know the phase-I study has been completed and analysed many months ago, because abstracts were presented at the ADA meeting 8 months ago.

Summary

My wife read a draft of this post, and turned to me, and said:  "It sounds like she didn't have any new data and you were frustrated."   It's a great summary.

I was hoping that speaking directly to Dr. Faustman would give me some understanding on why her phase-I study took so long, was so small, why the results still have not been published, and why she was collecting money for a phase-II study before publication of her phase-I results.  All of these actions can be viewed as signs of possible research failure in her phase-I trial.  However, none of my questions were answered in a way which allayed my worries.

Thanks!

I want to particularly thank the members of Brave Buddies who went out of their way and put a lot of work into making this meeting possible.  I'd also like to thank Dave, who drove a long way, and contributed a lot of knowledge and expertise to the discussion.

Extra Discussion and References


Note that in a couple of cases below, I've quoted Dave from email that he sent me.  He gave permission for each quote and reviewed this posting.  (All mistakes are my own.)

[d1] The company that Dave works for is a small one, and does not do research, sell, or develop any products for the type-1 diabetes market.

[d2] C-peptides were a secondary outcome of the study.  However, they are what the FDA uses to evaluate potential cures for type-1 diabetes, which is why I describe them as an important outcome of the study.  The most important outcome, however, is the primary outcome: the measurement of autoantibodies.  That data is still a complete mystery.

[d3] Except in a few very rare situations (such as complete cures in all cases), a study that only treats three people is very unlikely to provide strong results. When you are looking for slight improvements, or even medium improvements, three people just isn't enough to rule out random chance. All the people who work with statistics, who gave me opinions on this research, commented on this point. This study is the smallest phase-I clinical trial that I have ever seen in all my coverage of type-1 diabetes research.

[d4] For comparison, phase-I trials of already approved drugs (similar to BCG) include: Anakinra which dosed 15, Etanercept dosed 18, AAT dosed 15, etc. So a 3 person study really stands out as being much smaller than the others. 


[d6] In later email, Dave repeated that point: "any poster presented at a scientific meeting is henceforth 'public' and should be disseminated on request. This is a basic convention of science in America and in clinical trials."

[d7] Not showing us the data from the poster did not sit well with Dave, either.  Days later he sent me these two quotes: 

If she had commercial interest in the drug, there would be more of an argument for confidentiality of the results. But she is very vocal at saying that she wants this drug to be available to all. Therefore she should feel free to show any and all data.

Also, she says that the treatment approach she is pursuing here is one for which the rest of the experts in the field are bearish [negative] on. In all history of science, if a scientist is in disagreement with the rest of their peers, it has always been the case that they show their data to any and all who would spend their time looking at it. They need to convince the rest that they are correct and should jump on any chance they get to show they’re data. That’s science! [emphasis in original]

[d8] Obviously, long delays in a research project are a bad sign.  Research is fundamentally uncertain, and while  it is common for trials to last a little longer than expected, it is very rare for a type-1 diabetes trial to last more than twice as long as expected, and this trial lasted more than four times as long as expected.  The only objective information available to the public on this trial is the clinical trial record, and the record shows that there was an 8 month time period when they officially stopped recruiting patients for the trial, and then started again afterwards.   This is very unusual for the type-1 trials that I follow.  Only one other study had something similar to this, and it was such a big deal, that they issued a press release to announce it.  So asking Dr. Faustman directly about this 8 month hiatus seemed like a good idea.


[d9] I'm deliberately not using the term "excuses" here, because of the negative connotations.  But when you are sitting across the table, and asking for data that was publicly shown 8 months ago, and you get this song-and-dance about why it's not available now.  Boy, does it sound like an excuse.

The Clinical Trials record, complete with a history of every change made to it, can be seen here:
http://www.clinicaltrials.gov/ct2/show/NCT00607230

Scott King's blog on this research which describes what he saw on the poster: 
http://www.hanumanmedicalfoundation.org/blog/2011/07/04/highlights-of-ada-scientific-sessions-i-bgc-trial/

Dr. Faustman's ADA abstract from 2011 is no longer available at the conference web site, but you can see the body here:  http://forums.childrenwithdiabetes.com/showpost.php?p=740311&postcount=2

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

More Information on Zhao's Stem Cell Educator

Zhao's Stem Cell Educator phase-I trial, which I blogged about here:
http://cureresearch4type1diabetes.blogspot.com/2012/01/zhao-et-al-tianhe-publish-successful.html
has generated a lot of interest, so I've done some extra research on it, and this blog contains what I've learned.

Good News First

The best news that I gathered about this work, is that the published paper is not the final report on a 15 person clinical trial.  Is is the initial report on the first 15 people treated in a clinical trial which is on-going and continuing to enroll more people.  This is great news, for two reasons.  First, because it means that they are continuing to follow those 15 people.  With a little luck we can look forward to follow up reports describing what happens to these people in another year, two more years, and so on. Also (again, with some luck) we can expect reports on 50 people, 80 people, maybe even more people.  All this data is already being gathered as part of the current clinical trial.

The next good news is that the researchers very much want to start a clinical trial in the US.  That will take some time, due to regulatory approvals.   If they do start a trial in the US, it is likely to be similar to the one in China [d1].

Several people have asked me how this treatment works, and this is how it was explained to me:
First, there are proteins which train the body's immune system not to attack itself [d2].  These proteins are found on stem cells, so exposing immune system cells to the stem cells has the effect of training the immune cells not to self attack.  Second, these researchers believe that there are cells in the pancreas which are ready to become beta cells[d3], and also that there are stem cells circulating in the blood stream [d4] which can turn into beta cells.  They don't know which of these two routes are creating the new beta cells, but they believe some combination of them is creating enough beta cells to cause the large decrease in injected insulin and increase in C-peptide.

One question that I had was basically this: "Do you really think that the body can regrow so many beta cells that it can generate 25 to 38% of it's own insulin in just a few weeks?  No one else has seen anything like that when using other techniques to stop the autoimmune attack."  The answer was that was exactly what they thought was happening.  First, it was the theory that explained the results the best, and second, it was what they saw in their animal studies, so they were not surprised to see it in people.  We can only hope this is correct.  Future trials will tell.

I did ask if there was anything special about stem cells from the umbilical cord, which made that particular type of stem cell important to the research.  The response was no.  They expected that many types of stem cells would work, but they choose to use umbilical cord cells because they were convenient to use and  easy to get, as compared to other types of stem cells.

The researchers have professional connections to researchers in Amman, Jordan and Hue, Viet Nam, and that is why they might start clinical trials in those places.  Because there will be fewer regulatory hurdles, those studies could start more quickly than the one in the USA.  My feeling was that if they did studies in those place, the studies would be similar to the Chinese one, but they would try to improve ("optimize") the procedure.

Finally, I want to say that I have heard from several different sources (all private communications) that the researchers are in touch JDRF to discuss the funding of future studies.   They may well be in contact with other organizations, I hope that they are, but I've gotten specific information about JDRF.

Not-So-Good News Second

It does not look like this is the kind of treatment that the FDA is likely to allow under the "surgical exception" that I discussed in the previous discussion of this research.  So therefore, it is likely that a full FDA approval cycle will be needed, so about 4 clinical trials (and I'm not sure if this first one would count [d1]).

I do not think that any of the patients were ever free of injected insulin.  So I don't think they cured anyone, even temporarily.  On the other hand, I got the feeling everyone was helped to some degree.  In some research, there are some people where it just doesn't work.  Those people are sometimes called 'non-responders" and I think there were few to none "non-responders" in this trial.

More Reading

The research below was all done in mice so I have not read it in detail, but it is listed, for people who want a lot more details.

http://www.omicsonline.org/2161-1025/2161-1025-1-104e.pdf (2011)
http://www.sciencedirect.com/science/article/pii/S1568997210001795 (Cord Blood Background 2010)
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004226 (Mice Cure 2009)
http://www.springerlink.com/content/0640621007560k70/ (2009?)
http://www.sciencedirect.com/science/article/pii/S0006291X07012715 (Beta Cells from Blood 2007)
http://www.sciencedirect.com/science/article/pii/S0165247806002379  (2007)
http://www.sciencedirect.com/science/article/pii/S0014482706001558 (Why Stem Cells 2006)

Discussion and References

[d1] Unfortunately, the FDA doesn't give much weight to data from foreign trials, so things learned in other countries need to be relearned in the US, so the FDA will fully consider it.  I'm quite worried that even once the study starts in the US, they might be limited to a very small phase-I study, because the FDA will not consider the Chinese study as proof of safety, even it if involves more people than an American phase-I study.

One of the researchers involved told me a story -- equal parts funny and shocking -- about trying to get approval for a medical device that had been tested in Australia.   The FDA would not accept data from Australia.   They wanted studies re-done in the US, so they could review that data, as though Australia was some corruption ridden, third world country, without a quality regulatory system!

[d2] Although I'm not sure exactly which proteins they are referring to, the general idea that a protein could re-educate the immune system is not controversial.  Drugs like DiaPep277 and other antigen specific treatments are based on this idea.   Haller's work in Florida is based on similar ideas, although his effectiveness was no where near what Zhao and crew see.

[d3] Although this idea was controversial a few years ago, I think that consensus is shifting.  There is now some research that shows that stem cells already in the pancreas may be able to grow into beta cells.  Even stronger was a paper published last year (sorry don't have the reference handy) which showed very specifically that in mice, alpha cells in the pancreas could turn into beta cells that produced insulin in response to sugar. Plus there is the Joslin "Medalist" study (more than one) and  Dr. Faustman's paper just published last week which adds support to this same idea.

[d4] This was based on their own previous work in mice.  But I know that other researchers have been looking into this area.  Although the research in mice is not conclusive, there is some supporting evidence for this, in addition to the Zhao group.


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (Feburary-2012)

Diamyd Publishes Their GAD Failure in Phase-III

Diamyd published a full, peer reviewed article on their phase-III clinical trial.  I don't think there is any new information there, but there are a lot of details to read.  However, I do think there are two lessons to be learned here.  One relates to spin.  Take a look at these headlines:

No Improvement in C-Peptide Levels With GAD-Alum‎
Autoantigen Tx Benefits Some Type 1 Diabetics
Type 1 Diabetes Treatment Disappoints in Trial‎
GAD-alum Antigen Therapy Fails to Halt Progression of Type 1 Diabetes‎ 

They are all actual headlines on different web sites for this same news.  That second one gives the news a different spin, than the rest. In this case, most of the headlines are accurate, but if you happen to see that one "outlier" headline, you will get a very different view of the results.

The second relates to timing.  The timeline for these results are as follows:

May 2011: Diamyd announces that the phase-III trial had failed it's primary end point (press release)
June 2011: Data on this failure presented at ADA 71 (non-peer reviewed scientific presentation)
Feb 2012: Publication in the New England Journal of Medicine (top-flight, peer reviewed publication)

The take home point for me, is that this study went from completion to publication in about 10 months.  Furthermore, this study was (a) very large, (b) negative, and (c) published in one of the most important peer viewed medical publications in North America.  All of these factors would usually make the publication slower.  So I think it is a particularly bad sign when trials are completed but have not published in a year or two or more!

Press Release: http://www.marketwatch.com/story/diamyd-medicals-phase-iii-study-published-in-the-new-england-journal-of-medicine-2012-02-02

Gardasil Vaccine does not Trigger Type-1 Diabetes

Obviously, this is not cure research, but I know some people continue to be nervous about vaccinations, and the Gardasil vaccine is given during the time when type-1 diabetes is often diagnosed, so this study should provide a lot of confidence that the two are not related.

Basically, a large health maintenance company (which runs both insurance and hospitals) compared their records for people who got Gardasil and people who were diagnosed with type-1 diabetes within 6 months. These records were then double checked "by hand" and compared to similar people who did not get the vaccine.  They looked for many different autoimmune diseases, including type-1 diabetes, and were able to cover a huge number of patient records (about 190,000).  This was a huge study, so it could generate good data even for relatively rare diseases like type-1.

I don't believe that any one study can prove something with absolute certainty, but I do think that this is very well done study, and should carry a lot of weight.

News Coverage: http://medicalxpress.com/news/2012-01-gardasil-trigger-autoimmune-conditions-vaccination.html

Personal note: I was reading something about Gardasil, and found a great quote by a cancer researcher.  I didn't save it, so this is a paraphrase from memory:  "For decades, people have been clamoring for a vaccine to prevent cancer.  We finally developed one, but some people don't like it, because it has something to do with sex!"

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/