My son was the first subject enrolled in HOPE2. While on placebo and waiting for open label, he lost the ability to walk and lost 5 points on his LVEF. Since starting on treatment four years ago, he has not lost a single ADL, enabling him to live independently in the dorms through his four years in college. His EF has also stayed completely stable for four years. Some responses to your blog:
- Its Duchenne, not Duchenne’s
- The vast majority have cardiac involvement – no ALL of them do – unless they die of something else before they develop it
- Pre-treatment medication has eliminated the hypersensitivity
- Capricor submitted the BLA based on the long term cardiac data (4 years showing stabilization in ejection fraction) in comparison to the extremely high quality natural history study conducted by Dr. Jon Soslow and funded by FDA because FDA TOLD THEM TO SUBMIT IT after seeing the extension study data. Capricor was intending to wait for the phase 3 data until they received this guidance.
- Those with the most severe function were excluded because there is a point in the progression of Duchenne where cardiac function cannot be rescued no matter what you do. Least severe subjects were excluded to demonstrate a treatment effect more quickly.
- Dr. Soslow’s natural history study has demonstrated LVEF to be predictive of mortality in Duchenne. Your suggestion of a survival study will take 10 years to complete, but as you state in your bio, death is natural – I’ll make sure to tell my son that when he’s withdrawn from treatment and he comes home to die in my living room instead of pursuing his masters degree.
- Capricor utilized the performance of upper limb (skeletal measure) as a primary outcome for their phase 2 and phase 3 studies again because FDA TOLD THEM TO. FDA, similar to yourself, did not have enough knowledge of the cardiac progression in Duchenne to understand the link between LVEF and mortality. Now, because of the additional data we’ve collected, we do. And we also understand that the PUL lacks sufficient sensitivity to guard against Type 2 errors, which is why the FDA should agree to read through any PUL data to determine efficacy based on the LVEF results from the phase 3 study.
Well, Vinay Prasad just abruptly left the FDA after making this sound decision. Apparently, he was also targeted by the far right because he had earlier been critical of Donald Trump. I'm losing my confidence that the FDA will be able to withstand the anti-science onslaught.
It’s all going to be fine. We are not gonna be able to fix the world from the top. The pressure is too great. We’re going to have to work at this from the bottom with all of us folks listening to all of you folks on sensible medicine.Grass roots. Grassroots.
Still: even so I - as a German not being too much bothered by FDA decissions - agree with all your arguments, John, it would have been wise to claim your COI with your long lasting friendship with Vinay Prasad. You, as well as Vinay, often asked for it for others and even so this is not a financial COI, it still is one.
I also am offended at the indemnification of the 'drug' companies re vaccines...if we are taking in the wild west approach. One would think safe and effective would negate the need for such blanket protections.
My guess about cardiac function not chosen as the primary outcome is probably it takes much longer to see clinically meaningful change and would need very large sample sizes. So could be a feasibility issues. And usually PO is approved in talks with FDA.
The point of having regulation of pharmaceuticals is to try to ensure that marketed products have demonstrated safety AND efficacy.
This is already in distinction to unregulated “nutra-ceuticals”, which to me appear to fall into the “safe but useless” category almost without exception.
So maybe this company should’ve just marketed this as a “DMD supplement” and gone to town with it.
I guess the issue here is that the company has failed to demonstrate either safety or efficacy with their 20-pt study. So in some ways it’s even worse than your typical “turmeric enhancer”.
On the one hand, I get that you’re not going to have 1000 pt RCT for such rare conditions. OTOH, it would be irresponsible for a regulator to endorse a product that gives nothing more than false hope (based on available data to date).
good God, you're a clinician? That's terrifying. It's a one percent improvement in contrast with the three-point decline annually seen in the natural history. This is a progressive disease. And if you look at the four-year data, you see EV stabilization. You should really familiarize yourself with the dataset before you patronize parents that know much more about it than you do.
I got paywalled by the WSJ but was able to read enough to see the author’s bias. We are all biased to a degree. I have to hope that Vinay’s role will help reduce what I used to say during the opiate epidemic: FDA approval = business deal made.
PS - for some reason I don’t see Vinay as a Fouchi in any way shape or form.
Here’s the problem with trying to hold the same RCT standard for rare diseases. Some of these diseases have fewer than 100 patients annually and demanding large randomized trials is simply not feasible. Demonstrating zero flexibility simply takes investments away and leaves these diseases unaddressed. I don’t have a problem with someone taking a stand on RcT across the board - you set the standard and live with the outcomes - but doing a whole road show about approving on “plausible benefits” and “small steps forward” and then demanding full randomized trials shows lack of basic integrity where actions don’t match words. I would not trust Dr. Prasad to be in any leadership role - let alone leading an agency like CBER. Sorry, I just don’t agree with the author.
An argument could be made that the FDA doesn’t care about these vulnerable patients lives- bc they will die soon anyway (thus give them all the experimental treatments). They need to be protected even more.
Having read the WSJ for 60 years I find Ms Finley's article like something out of the National Enquirer. I suppose there is an extreme libertarian position that would abolish the FDA and all government regulations but as a libertarian myself I would like to see objective scientific evaluation of treatments and drugs before I consume them. Thank you for taking the time to evaluate this article.
Did you not do the basic research to find out that the BLA was based on the OLE study at 3 years and the cMRIs collected during that time? No PUL data was included in the BLA, and the BLA wasn't based on the primary endpoint of HOPE-2. Research Soslow et al 2023 to learn about the natural history they're comparing against, and why the scientists previously in charge of the FDA thought it compelling enough to submit a BLA based on cardiomyopathy and not skeletal muscle.
Sensible Medicine is a media to promote specific doctors/politics or medical practices? I do not know Dr. Prasad and am looking for medicine here—not politics. Thank you TiredMedStudent, for a comment based on medical perspectives and not promoting politics.
Maybe you need a little more context before making a comment. Dr Prasad actually is very thoughtful and nuanced… im a medical provider but by no means an expert in reading studies… I read the WSJ article and I was inclined to side with the WSJ based on the article (even though I like Dr Prasad)… so I’m glad there was a balanced review of the decision that addressed some of the info in the WSJ article. Dr Mandrola is a lot more credible in reviewing this situation than a WSJ reporter. I think the back and forth conversation is super enlightening and I’m continuing to learn. Thanks Dr Mandrola. This isn’t political- it’s the art of debate of ideas.
My son was the first subject enrolled in HOPE2. While on placebo and waiting for open label, he lost the ability to walk and lost 5 points on his LVEF. Since starting on treatment four years ago, he has not lost a single ADL, enabling him to live independently in the dorms through his four years in college. His EF has also stayed completely stable for four years. Some responses to your blog:
- Its Duchenne, not Duchenne’s
- The vast majority have cardiac involvement – no ALL of them do – unless they die of something else before they develop it
- Pre-treatment medication has eliminated the hypersensitivity
- Capricor submitted the BLA based on the long term cardiac data (4 years showing stabilization in ejection fraction) in comparison to the extremely high quality natural history study conducted by Dr. Jon Soslow and funded by FDA because FDA TOLD THEM TO SUBMIT IT after seeing the extension study data. Capricor was intending to wait for the phase 3 data until they received this guidance.
- Those with the most severe function were excluded because there is a point in the progression of Duchenne where cardiac function cannot be rescued no matter what you do. Least severe subjects were excluded to demonstrate a treatment effect more quickly.
- Dr. Soslow’s natural history study has demonstrated LVEF to be predictive of mortality in Duchenne. Your suggestion of a survival study will take 10 years to complete, but as you state in your bio, death is natural – I’ll make sure to tell my son that when he’s withdrawn from treatment and he comes home to die in my living room instead of pursuing his masters degree.
- Capricor utilized the performance of upper limb (skeletal measure) as a primary outcome for their phase 2 and phase 3 studies again because FDA TOLD THEM TO. FDA, similar to yourself, did not have enough knowledge of the cardiac progression in Duchenne to understand the link between LVEF and mortality. Now, because of the additional data we’ve collected, we do. And we also understand that the PUL lacks sufficient sensitivity to guard against Type 2 errors, which is why the FDA should agree to read through any PUL data to determine efficacy based on the LVEF results from the phase 3 study.
Thank you John for this explanation. Hopefully this will be read alongside the WSJ piece.
My rebuttal here. This is complete mischaracterization of Capricor's BLA. I expected more critical thinking from "sensible" medicine readers.
https://x.com/AppleHelix/status/1950689550642151818
Well, Vinay Prasad just abruptly left the FDA after making this sound decision. Apparently, he was also targeted by the far right because he had earlier been critical of Donald Trump. I'm losing my confidence that the FDA will be able to withstand the anti-science onslaught.
It’s all going to be fine. We are not gonna be able to fix the world from the top. The pressure is too great. We’re going to have to work at this from the bottom with all of us folks listening to all of you folks on sensible medicine.Grass roots. Grassroots.
Still: even so I - as a German not being too much bothered by FDA decissions - agree with all your arguments, John, it would have been wise to claim your COI with your long lasting friendship with Vinay Prasad. You, as well as Vinay, often asked for it for others and even so this is not a financial COI, it still is one.
https://open.substack.com/pub/kevinbass/p/trumps-fda-picks-now-under-coordinated?r=kia1s&utm_campaign=post&utm_medium=web&showWelcomeOnShare=false
I also am offended at the indemnification of the 'drug' companies re vaccines...if we are taking in the wild west approach. One would think safe and effective would negate the need for such blanket protections.
My guess about cardiac function not chosen as the primary outcome is probably it takes much longer to see clinically meaningful change and would need very large sample sizes. So could be a feasibility issues. And usually PO is approved in talks with FDA.
The point of having regulation of pharmaceuticals is to try to ensure that marketed products have demonstrated safety AND efficacy.
This is already in distinction to unregulated “nutra-ceuticals”, which to me appear to fall into the “safe but useless” category almost without exception.
So maybe this company should’ve just marketed this as a “DMD supplement” and gone to town with it.
I guess the issue here is that the company has failed to demonstrate either safety or efficacy with their 20-pt study. So in some ways it’s even worse than your typical “turmeric enhancer”.
On the one hand, I get that you’re not going to have 1000 pt RCT for such rare conditions. OTOH, it would be irresponsible for a regulator to endorse a product that gives nothing more than false hope (based on available data to date).
ONE percent improvement in ejection fraction?
A statistician might be impressed. And certainly Capricor investors. No clinician would be. And yes, I am one.
This is pharma financial skullduggery. They’ll trot out a couple of ‘concerned parents’ to cry the blues and write letters and such.
Sorry. The drug is a BUST. The end.
good God, you're a clinician? That's terrifying. It's a one percent improvement in contrast with the three-point decline annually seen in the natural history. This is a progressive disease. And if you look at the four-year data, you see EV stabilization. You should really familiarize yourself with the dataset before you patronize parents that know much more about it than you do.
I got paywalled by the WSJ but was able to read enough to see the author’s bias. We are all biased to a degree. I have to hope that Vinay’s role will help reduce what I used to say during the opiate epidemic: FDA approval = business deal made.
PS - for some reason I don’t see Vinay as a Fouchi in any way shape or form.
Agree. It’s also nice to see a rebuttal of someone I respect… I like having my biases challenged.
Indeed. I try to look at all sides as well. Sometimes I even watch MSM! 😜
Here’s the problem with trying to hold the same RCT standard for rare diseases. Some of these diseases have fewer than 100 patients annually and demanding large randomized trials is simply not feasible. Demonstrating zero flexibility simply takes investments away and leaves these diseases unaddressed. I don’t have a problem with someone taking a stand on RcT across the board - you set the standard and live with the outcomes - but doing a whole road show about approving on “plausible benefits” and “small steps forward” and then demanding full randomized trials shows lack of basic integrity where actions don’t match words. I would not trust Dr. Prasad to be in any leadership role - let alone leading an agency like CBER. Sorry, I just don’t agree with the author.
An argument could be made that the FDA doesn’t care about these vulnerable patients lives- bc they will die soon anyway (thus give them all the experimental treatments). They need to be protected even more.
It’s a cr*p drug. Go back and make it a better one.
1% improved EF. Functionally irrelevant.
Having read the WSJ for 60 years I find Ms Finley's article like something out of the National Enquirer. I suppose there is an extreme libertarian position that would abolish the FDA and all government regulations but as a libertarian myself I would like to see objective scientific evaluation of treatments and drugs before I consume them. Thank you for taking the time to evaluate this article.
Did you not do the basic research to find out that the BLA was based on the OLE study at 3 years and the cMRIs collected during that time? No PUL data was included in the BLA, and the BLA wasn't based on the primary endpoint of HOPE-2. Research Soslow et al 2023 to learn about the natural history they're comparing against, and why the scientists previously in charge of the FDA thought it compelling enough to submit a BLA based on cardiomyopathy and not skeletal muscle.
Sensible Medicine is a media to promote specific doctors/politics or medical practices? I do not know Dr. Prasad and am looking for medicine here—not politics. Thank you TiredMedStudent, for a comment based on medical perspectives and not promoting politics.
Maybe you need a little more context before making a comment. Dr Prasad actually is very thoughtful and nuanced… im a medical provider but by no means an expert in reading studies… I read the WSJ article and I was inclined to side with the WSJ based on the article (even though I like Dr Prasad)… so I’m glad there was a balanced review of the decision that addressed some of the info in the WSJ article. Dr Mandrola is a lot more credible in reviewing this situation than a WSJ reporter. I think the back and forth conversation is super enlightening and I’m continuing to learn. Thanks Dr Mandrola. This isn’t political- it’s the art of debate of ideas.