Duchenne muscular dystrophy: Drug development and regulatory considerations - From the FDA

Duchenne muscular dystrophy: Drug development and regulatory considerations.

http://www.ncbi.nlm.nih.gov/pubmed/20373504

Muscle Nerve. 2010 Apr 5. [Epub ahead of print]

McNeil DE, Davis C, Jillapalli D, Targum S, Durmowicz A, Coté TR.

FDA/Office of Orphan Product Development (OOPD), 5600 Fishers Lane (HF-35), Food and Drug Administration (FDA), US Department of Health and Human Services, Rockville, Maryland 20857, USA.

Abstract
Duchenne muscular dystrophy (DMD) is one of the most commonly recognized dystrophinopathies. There are no approved therapeutic options available for this disease but recent discoveries have led to hope that effective therapies might be forthcoming. With funding from patient advocacy groups, private investors, and governmental bodies such as the Food and Drug Administration Office of Orphan Product Development (FDA/OOPD), gene modification and other molecular therapies are being actively investigated. However, since DMD patients are few in number and disease manifestations vary considerably in early and late stages of disease, obtaining the data needed for full evaluation of putative therapies may prove challenging. Should ambulation remain the focus of Phase 2/3 studies or should consideration be given to the primary causes of late-stage morbidity and mortality, e.g., cardiac and respiratory dysfunction related to reduced or absent dystrophin production? It seems reasonable to argue that clinical trials planned for DMD should consider the entire population.

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Cheers to that..."it seems reasonable to argue that clinical trials planned for DMD should consider the entire population."
Looks like a step in the right direction, and one would assume that the voices of disapproval raised by the PPMD community after PTC's decision to cancel the Ataluren trials are having some impact after all. Good news!.
Damn this is a tough one. The problems become a lot more complex when trials have to take in extra variables and then analyze data and work out if a trial has been successful. Its still probably more efficient to trial a drug on the entire population of DMD patients but split them into clearly defined groups. This will mean the trials would be seperate as they would have different endpoint goals.
I kinda think all DMD trials should have different end points to consider. That way we wouldn't be relying on one thing to pass or fail. Since Duchenne is extremely complicated and science is blazing a new trail for treating this genetic monster, various and multiple endpoints should be under consideration by regulatory agencies. FDA should allow ANY and ALL positive results to count as endpoints, because we have to fight DMD on many levels. Looking for a one size fits all chemestry isn't going to work.

Somehow, FDA has got to get it's head out of medieval medicine and move into the current century.
OK - I'm confused...if the entire population of DMD patients is considered, isn't that an argument against orphan designation?

I have always understood that the primary reason for giving DMD orphan status is that it's actually an infinite number of possible deletions and mutations, each manifesting it self in uniquely nuanced way.

What am I not getting here?
Not sure really. Maybe I'm the one not getting it Steve :) It's such a complicated issue. I was thinking Duchenne met standards for orphan status because the disease is rare and fatal. But, I really am not sure exactically what orphan status can do for us anyway...how much power do they really have with the FDA? FDA has final say and they must have their protocol followed as standard proceedure. But, I think we are at a crossroad... thier protocol must change to fit the needs of Duchenne & upcoming research, science. It must change quickly if we are going to save this generation of boys. Scientists fighting this disease are breaking into "boutique chemestry" (ie personalized medicines) which is foreign to FDA, foreign to their usual way of processing with or without orphan status.

I believe FDA should consider the entire DMD population for clinical trials so no one gets left behind and researchers can work on all exons, all mutations, all aspects of how Duchenne distroys muscle, all muscles. That is not to say FDA should require one chemestry to fill all needs or treat everything about this disease. Because realistically it won't be coming that way. And I think FDA has already gotten the word, but isn't sure exactically how to create new protocol. This is coming as new science creating new regulatory policies. I think that is why there is a major meeting this fall with FDA. But, please correct me if I am wrong, it happens! :)



Steve Dreher said:
OK - I'm confused...if the entire population of DMD patients is considered, isn't that an argument against orphan designation?

I have always understood that the primary reason for giving DMD orphan status is that it's actually an infinite number of possible deletions and mutations, each manifesting it self in uniquely nuanced way.

What am I not getting here?
Steve Dreher said:
OK - I'm confused...if the entire population of DMD patients is considered, isn't that an argument against orphan designation?

I have always understood that the primary reason for giving DMD orphan status is that it's actually an infinite number of possible deletions and mutations, each manifesting it self in uniquely nuanced way.

What am I not getting here?

I don't think this has anything to do with orphan drug status. The criteria is less than 200,000 patients in the US, and every living person in the US with DMD doesn't come to anywhere near that.

It seems that the development of any drug for DMD will take at least 10 years,so I am afraid that the DMD boys who may benefit from any treatment (if any) ARE NOT BORN YET!!!!!!!!!!!!!!!!!!!!

Idebenone is still in a clinical trial!notice that Idebenone is just an antioxidant and it is available as supplement,so immagine how long it is gonna take a drug as ACE 031 or Utrophin (I will not say gene transfer because it is gonna take 200 years!!!!!!

I am very disappointed!!!!

Hey Moein,

I think there are reasons to be hopeful. There are a number of treatments in trial, and more in development. More to your point, though, there are a lot of already-approved FDA compounds being run through zebra-fish and myomics - those will require a much shorter trial process b/c safety is already done. Also,Viagra and lisinopril already are showing great promise in extending our boy's lives until a better treatment is available.

I don't think it's going to be fireworks, but I believe we'll chip away at this little by little - and it will always be too slow -
until one day we realize we made it.

 

I work for a medical device/pharma company. We have devices that are drug coated that have over 70 different combination of sizes. All 70 didn't have to go through the clinical trial process. What happens is companies have to prove equivalancy accross the matrix. So they take say 3 sizes/combinations and show that they work. Then all 70 combinations are approved. I don't have the lingo to develop a protocol for exon skipping in such a manner, but there must be someone out there who can?? Imagine a trial that will have 3 exon skipping patches that say are aimed at exon 10,30 and 50? And then get approval for a multiple of patches? I know what people are going to reply.... well each patch is in effect a different medicine..etc etc... but....the Reg bodies have to change....or ...lets just let generation after generation after generation after generation suffer and die!! 

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