Although they haven't announced it as 90 days, 3 months past prior PDUFA date would put it
around Aug 24, but who knows if a different procedural path (this claimed DPO BS) would alter
the 90 day timeline. But they have to know 100+ members of Congress and Senate are
watching and waiting for an explanation of any result, plus several thousand DMD patients
and their families.
read about the Myozyme 2008 AdCom where just before the meeting FDA proposed a sensitivity analysis of 6 mwt which Genzyme said was not appropriate. On primary 6 mwt they had 28m benefit v placebo. Eteplirsen has a 120-140 m benefit and pulmonary benefit
(one good question asked at Sarepta adcom was do you (FDA) have a mathematical analysis rather than just your overlapping line drawings to support claim Eteplirsen treated boys having same disease course as DMD natural history)-which FDA staff did not have, because Eteplirsen recipients dominated. overall, the results of untreated patients. Dominated in a game theory sense, ie if you had to choose a strategy, which would you choose go on untreated, or have Eteplirsen and get likely beneft- aboutvwhat Wagner, Connolly and Bryne testified to at AdCom
FDA Advisory Panel to Discuss Genzyme's Myozyme BLA on Tuesday
but it got approved after delays, including in one case a 90 day PDUFA extension.
It is entirely possible that "submission" is a multi-step process involving, among other things, a summary of the data in text form, a write up of procedures used (remember, there was a detailed discussion at the Mar 15 2015 workshop, an a review/audit/questions on the data and procedures. So when do you disclose-the initial sendin of data, the steps along the way, ??? There are good reasons for not disclosing anything if the process is more than one step, until the final approval and results are released.
for large, complex Phase I-IV trials. Phase IV clinical trials are post FDA approval, ie confirmatory after Accelerated Approval
During FDA AdCom, Craig McDonald, the pre-eminent expert on 6 Mwt tried to explain the importance of the Loss of Ambulation four year data, as a hard end point not affected by placebo effect, and then showed a Kaplan Meier comparison of eteplirsen treated patients v CINRG NH. Dr Bastings of FDA then claimed slide was misleading because most eteplirsen boys had not yet reached 15 (despite testimony of multiple DMD clinicians that boys often lost walking at 11-12). Now a mom has posted a video of her son Billy walking steadily at 15 1/2. Perhaps the FDA should stop looking for zebras and start seeing the horses. Eteplirsen has kept its participants walking in large fractional numbers when declines otherwise would have occurred, but delay is impacting others to whom this drug is delayed by denial. The FDA should be trying to make all Exon 51 amenable patients outliers in continuing to walk by granting approval "promptly"
Look at the post marketing commitments for Myozyme, approved on the basis of 39 patients, which then had multiple post marketing studies, now described as post marketing requirements. Here we have the Promovi, and Essence, and monitoring for adverse events (even though we KNOW Etep is safe because of its
charge neutral molecular biochemistry v. the charged 2 O'me) so all these dots and t's have to be crossed before Accelerated Approval based on the latest WB, clinical trial status, and monitoring desires of FDA. When you read the approval letter, if and when issued, it will have all the PMR's laid out ie Sarepta is required to..... and submit annual reports on........ and such clinical trial reporting requirements take time to write up.
FDA noted panel members uncertain about dystrophin level necessary, but level for benefit may be low but some felt de novo dystrophin produced; were moved by patient testimony and felt question on clinical benefit was leading
Contract Award Date:
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Development and implementation of pathogen reduction technology (PRT) for platelet (PC), plasma (P), and red blood cells (RBC).
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It is very important to be aware that the data produced with a western blot is typically considered to be semi-quantitative. This is because it provides a relative comparison of protein levels, but not an absolute measure of quantity. There are two reasons for this; first, there are variations in loading and transfer rates between the samples in separate lanes which are different on separate blots. These differences will need to be standardized before a more precise comparison can be made. Second, the signal generated by detection is not linear across the concentration range of samples. Thus, since the signal produced is not linear, it should not be used to model the concentration.
All reasons, as the March 2015 discussion concluded, to use multiple measures/indications rtPCR and PDPF
Which is why, apparently, the clinical trial secondary endpoints no longer say PDPF or WB, but "dystrophin
protein expression" a broad term which could encompass several measures. Nevertheless, WB is probably
a faith based indicator for FDA which will give them comfort if comparable .9-2% WB results are shown in
a significant fraction of patients.
The dystrophin data may not be disclosable because Sarepta doesn't know the level of dystrophin production that will trigger FDA approval .9% 1.5%, 3% etc. However it is a little odd that Sarepta notified the DMD community of the role of the Essence 45/53 changes and their role as confirmatory for eteplirsen, and then added safe harbor statements (uncertainty, unknown results, possible changes) without making a Regulation FD disclosure (general market dissemination) of its communications to the DMD people about the clinical trial changes. Of course, all of this is subject to the extreme volatility, so less disclosure until an actual FDA action is probably prudent. Because FDA has said they are moving as quickly past PDUFA date as possible, likely that FDA action is before end of July, maybe before a month-6weeks after announcement of dystrophin data request.
Postmarket requirement and commitment studies and clinical trials occur after a drug or biological product has been approved by FDA. For more information, please read: "Report to Congress: Reports on Postmarketing Studies [FDAMA 130]" and the Guidance for Industry (PDF - 456KB)
Percentage of dystrophin-positive fibers
Dystrophin protein expression
(which is not western blot exclusively, so it probably means submission of both PDPF and WB data
or even all of them rt-PCR as well, because the original workshop in Mar 2015 recommended
using multiple means to identify and measure dystrophin induction
This is probably a negotiated point for the PMR/PMC)
FDA has two types of post marketing information collection and submission categories: Post marketing requirments (which is what FDA can require) and post marketing commitments, which co agrees to. One type of post marketing "requirement" is for confirmatory studies, called Phase IV, after accelerated approval. This seems to be what is going on, tying the shoelaces before letting eteplirsen take the boys amenable to Exon 51 out for a walk, which hopefully will last several years. See the FDA website on post marketing requirements (PMR) and commitments
"Morpholinos are also effective to modify pre-mRNA splicing and to inhibit miRNA (Morcos, 2007). These oligonucleotides offer the prospect of a safe and effective therapeutic for a broad range of previously 'undruggable' diseases that include Duchenne muscular dystrophy (Moulton et al., 2009), Huntington disease (Sun et al., 2014), cancer and cardiovascular diseases (Templeton, 2015), Ebola (Heald et al., 2014), etc. Many of the morpholino-based treatments are currently undergoing clinical trials and are showing impressive safety and pharmacokinetics results (Sanghvi, 2011). "
Once platform validated with Exon 51 approval, other disease pipeline will be valued
What is the expected form of the transaction that maximizes shareholder value? Not just a sale, but a reverse spin that minimizes tax liability by providing a business purpose for the new shares to be distributed tax free with new bases determined based on relative value of assets represented??
Captain Mary Kremzner: Now Cat, exactly how does the FDA determine when an expedited approval is warranted?
Commander Catherine Chew: Generally drugs are approved under Accelerated Approval if they have the potential to impact factors, things like survival, day‑to‑day function or the likelihood of stopping a disease from progressing and becoming an even more serious condition.
Captain Mary Kremzner: Now Cat earlier you mentioned filling an unmet medical need. How would you define that?
Commander Catherine Chew: An unmet medical need simply means providing a therapy when none exists or providing a new therapy that may be superior to or less toxic than an existing one.
Captain Mary Kremzner: So without the standard clinical outcomes how does FDA determine if a treatment is potentially effective?
Commander Catherine Chew: Great question Mary. Accelerated Approvals use what we call a surrogate end point in clinical trials. These are markers or a physical sign of sorts used as an indirect measurement to predict a clinically meaningful outcome like survival or symptom improvement.
Captain Mary Kremzner: So exactly how does the surrogate end point save time in the drug approval process?
Commander Catherine Chew: Well for example, instead of having to wait to learn if a drug prolonged survival in cancer patients the FDA has approved drugs based on evidence that they shrink tumors. As a surrogate end point, tumor shrinkage is reasonably linked to real clinical benefit.
Captain Mary Kremzner: Okay, so let me make sure I have this. Let’s say a drug goes through Accelerated Approval and gets to market, how do we know if it really provides that clinical benefit?
Commander Catherine Chew: Any approvals given based on surrogate end points are on the condition that the sponsor will conduct post-marketing clinical trials to verify the anticipated benefit. If these trials, called Phase 4 Confirmatory Trials, shows the drug does in fact provide a clinical benefit then
Sites are currently being initiated into the study. Initiation of approximately 39 planned sites in the United States is expected to be completed by June 2016. The initiated sites can be found in the "Contacts and Locations" section of this posting in addition to a listing of the city and states of sites the investigators are working to initiate. T
FDA needs to post the transcript - now about 7 weeks, even for an extended day, should be available.
I want to see the text where one of the AdCom members says I don't want to have a standoff between the Committee and the FDA and the Chair, Caleb A. says, I think you meant between the committee and the applicant, when what the member accurately really meant was, we don't like the FDA's approach and questions.