I think we all agree that the best case scenario is to get trials started in the US asap.
How do we do that?
I think providing pharma with easy access to the number and type of patients they need to run a trial is key. That's something we as parents can take action on. Make sure you're registered at duchenneconnect.org, and keep it updated. That's how they're going to find patients in the US.
I also think making sure they see a united duchenne community, with advocacy efforts in place at NIH, CDC, FDA, and members ready to push them to action is important.
And as Ofelia mentioned before - this is not the only game in town. Other stuff's in the pipeline.
Couldn't agree more that the best case would be seeing trials begin now here in usa. But that's not happening and nobody knows for sure when it will. And while we wait - shouldn't we be pursuing other means to obtain meds in just case things continue to drag out?
Although I'm not sure if this type of international collaboration has been done before but GSK and all other pharma's can seek FDA permission for drug use in the USA, prior to approval. That's been done before. The issue here is getting the pharma to want to do this. For that they must be presented with the gains they will obtain by doing so.
I wonder if GSK can obtain FDA permission since FDA doesn't allow start of trials based on safety I'm assuming... If FDA would not have safety concerns I assume the trial would recruit US boys by now. Remember that they filled the IND and FDA requested additional data. So under these circumstances would FDA allow them to sell this drug in the US?
I think Acceleron said that they have FDA approval for thier trial, so FDA is not slowing that one down.
Leeandra, I believe the answer to your question is "no," and I don't know which exon needs to be skipped to put your son's dystrophin back into frame. I recommend you look at the Leiden University site for there exon skipping calculator. Even if you're in one of the rare categories, I don't believe that the game is over. This is because the FDA has a comprehensive set of rules to address "expanded access to investigational drugs for treatment use."
These rules include general eligibility requirements:
1. Serious or life threatening condition with no adequate alternative treatment (Check)
2. Potential benefit justifies potential risks (based on recent NEJM article, double check)
3. Providing the drug for use outside of a clinical trial "will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use." For bypassing the FDA process for the more common categories of mutation, this certainly means that making the drug broadly available will be impossible unless the promoters have decided that they won't seek US approval, a clinical trial program is before the FDA, or the FDA has made a binding decision that it will accept the European data.
Who ever wants to administer a drug not approved by the FDA and outside of a clinical trial has to fill out a really detailed form, FDA Form 1572. It's available at the FDA website if you're curious.
There are rules for individual access. 21 CFR 312.310, and (emphasis on the "and") for "intermediate-size patient populations" 21 CFR 312.315.
For individuals, the application can be made by either the drug sponsor or a treating physician, though the treating physician has to have the permission of the drug sponsor. If multiple individual applications are made, the FDA will require the sponsor to make a application for a intermediate size poplulation or a "treatment IND."
For "intermediate-size patient populations" it appears that only the sponsor can be the one to make the submission. It's available if "the drug is not being developed, for example, because the disease or condition is so rare that the sponsor is unable to recruit patients for a clinical trial." 21 CFR 312.315(a). This is obviously very good news for the rarer mutation categories. However, the FDA must determine that:
"(1) There is enough evidence that the drug is safe at the dose and duration proposed for expanded access use to justify a clinical trial of the drug in the approximate number of patients expected to receive the drug under expanded access; and
(2) There is at least preliminary clinical evidence of effectiveness of the drug, or of a plausible pharmacologic effect of the drug to make expanded access use a reasonable therapeutic option in the anticipated patient population." 21 CFR 321.315 This means that the FDA not only will, but MUST, approve exon skpping for the rarer mutation categories where there is theoretical benefit and evidence that the toxicity is similar between the various categories.
Since ProSensa is pursuing drug development ("development" is a defined term meaning that the drug is part of an FDA IND application), the small group exemption is only available for those patients who are "unable to participate in the trial. For example, patients may not be able to participate in the trial because they have a different disease or stage of disease than the one being studied or otherwise do not meet the enrollment criteria, because enrollment in the trial is closed, or because the trial site is not geographically accessible." 21 CFR 312.305(a)(3).
There are some significant paperwork burdens on the drug sponsor, and it would be a really good idea, if this has not been done already, to try to convince grant recipients from PPMD to agree to undertake those burdens.
|Exon skipped||Potentially Repairable Deletions|
|51||45-50, 47-50, 48-50, 49-50, 50, 52|
|50||51, 51-53, 51-55|
|45||12-44, 18-44, 44, 46-47, 46-48, 46-49, 46-51, 46-53, 46-55|
|53||10-52, 45-52, 46-52, 47-52, 48-52, 49-52, 50-52, 52|
|44||10-43, 19-43, 30-43, 35-43, 36-43, 40-43, 42-43, 45, 45-54|
|8||4-7, 5-7, 6-7, 3-7|
|55||47-54, 48-54, 49-54, 50-54, 52-54, 54, 56, 56-62|
|7||2-6,8-11, 8-17, 8-43, 8-45|
|52||53, 53-55, 53-57, 53-59, 53-60|
|17||12-16, 18, 18-20, 18-22, 18-25, 18-27, 18-29, 18-33, 18-36, 18-38, 18-41, 18-44|
Djamel, deletion of 45 needs exon 44 skipped. Prosensa is working on this one, phase 1 trial in Europe.
Thank you Paul...that's great!
Now, all we need to do is figure out how to pay for the expanded access. Obviously, health insurance companies can legally exclude experimental treatments and generally prefer to do so, but I imagine that they also have a pretty good handle on the costs of a DMD patient over the late teens and early twenties where they are legally obligated to provide coverage. I suspect they'd be pretty interested in anything that would reduce or delay that cost.
Would Prosensa help our son who is 5 yrs old and recently been diagnosed with DMD he has no deletion/duplication but a stop codon -Glutamic acid> OCH- Codon position 1066- Nucleotide position 3196- DNA Variant 1 Transversion G>T we been told this is a sequence alteration can someone please explain this to us.where is the mutation we can't seem to get a answer. We see Dr wong next week for the first time and I'm sure she will have the answer but I don;t know if I can wait any longer.
Would Prosensa help our son who is 5 yrs old and recently been diagnosed with DMD he has no deletion/duplication but a stop codon -Glutamic acid> OCH- Codon position 1066- Nucleotide position 3196- DNA Variant 1 Transversion G>T we been told this is a sequence alteration can someone please explain this to us. where is the mutation we can't seem to get a stright answer
Most often you hear stop codons associated with the PTC 124 / Ataluren strategy. I don't know enough about stop codons to comment beyond that. Dr Wong can definitely answer that question for you.