I find the FDA's characterization of SRPT's addendum as a "major addendum"to NDA as a change in direction from their previously released briefing docs. "Major" can be defined 2 uniquely different ways. "Major" as in voluminous submission or "major" as in an addendum that changes the FDA's briefing docs narrative. The narrative has changed .
Sarepta's briefing docs addendum [rebuttal] has rattled Farkas. 2 fundamentally different interpretations of data and the criticism by DMD experts on the FDA's misunderstanding of the DMD pathogenesis and the methodologies used to analyze submitted data is increasing. Factor in the insider trading allegations of scientists inside the FDA [Forbes] and DMD families have a reason for optimism. Sunlight is the best disinfectant.
Irdrk13, I believe there is a decent chance of a positive vote by the panel. Closer then it should be. There is a disconnect between the briefing docs and Sarepta's data. Sarepta did a great job with their rebuttal via addendum. One obvious contradiction is the use of a matched historical control and the FDA suggesting SRPT not only use one but helped with the matched criteria. Comments on increased care during trial and the confusing conclusion that Farkas came too regarding stated steroid use. Today I read a professional analysis of the FDA's report on the eteplirsen data set and they concluded that the FDA regulators confused several of the fundamental issues regarding DMD progression, historical controls and dystrophin quantification, including the ridiculous comparisons to Becker's patients. If the panel members have read the addendum and go about their business in an objective way and with intensive knowledge of the DMD pathogenesis then we should have a good vote.
FDA Subpart H Accelerated /Conditional Approval...Sec. 314.510 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.
Here's Sarepta's interpretation of AA/Conditional approval found in their briefing docs…"The AA pathway means that there will be an acceptable degree of uncertainty about whether the therapy will actually result in the anticipated clinical benefit. This uncertainty is addressed by the requirement that “appropriate post-approval studies to verify and describe the predicted effect” would usually be underway at the time of approval.
This uncertainty about whether the ultimate clinical benefit will be achieved is accounted for in the AA statute"
IMF can be manipulated??? Look at Biomarin's dystrophin Western Blot quantification submitted in their NDA. Western Blot can't be manipu;lated? Biomarin pack the wells and got caught. You have to be kidding.
I and most of us have read the entire FDA briefing docs for eteplirsen and Sarepta's addendum to the FDA's report but I have just finished reading Sarepta's own briefing documents derived from their NDA application and it is worth reading. It's presentation of data and the application of the AA statute by the FDA is clear and precise. It is convincing and everyone should read it. I can't post link but it can be found at the FDA's website located on the same page as SRPT's addendum.
A section of my post that was truncated by Yahoo dealt with the glaring contradiction of the FDA's political document known as the eteplirsen briefing documents and analysis. Fargas inserts the statutory Accelerated and Conditional Approval language but then quotes the Full approval standard of "significant proof of efficacy". This is a slap in the face of every DMD parent who has a child who suffers and will suffer from this fatal disease. I really hope some aggressive journalist has the nerve to print the names of every Adcom panel member, where they practice, their individual votes and the boys who will become wheelchair bound and/or will die because they refused to follow statutory requirements and guidelines of the AA law. The PhaseIII trial data will confirm efficacy via the statistically significant threshold that has been the gold standard and I want them on the record as stating this threshold is not "significant proof" of efficacy. Shame on them.
It took me a couple of days to get over my anger over the FDA's briefing doc report on their putative biostatistical analysis of Sarepta's eteplirsen Phase II data. The small group of bureaucratic, last in their medschool graduate, psuedoscientists have been let down by their education, by not understanding the basic scientific method that objectivity drives this process. This group began with a result and ended with a hypothesis. Let me explain. The emphasis of this report that the 3.5 year PhaseII study was an "exploratory Study" and that we will focus on the first 24-48 week cohorts and if these results appear supportive of approval that is because of improved health care, steroid therapy and physical therapy. So if one interprets these results positively then we can explain this away but if you are part of the bureaucracy you can determine that these results are in-line with historical placebo controls groups even though they misrepresented the historical controls. "Increased Health care and physical therapy"???None of the patients in the PhaseII trial had regular PT. The historical control data was conducted by health care centers that had equal or superior "health care" as compared to the IV administered eteplirsen clinical trial sites that only administered trial drug, is bizarre. This is a bias. Not knowing that the eteplirsen trial boys were on a "low-dose" steroid regimen is another bias. Dystrophin, respiratory Fx. and 6MWT versus matched historical controls in eteplirsen treated boys was statistically significant. This is the gold standard of FDA acknowledgement but not in this case. The placebo control dogma of FDA studies does not apply in DMD studies. Not only is it unethical but a matched cohort iS a better cohort then randomly chosen group that differs significantly in age, baseline 6MWT scores, weight, and steroid use as a matched cohort. Dogma is a tough thing to overcome when it comes to a bureaucracy.
Ru, If I was wrong in my analysis I would apologize. I have no problem with that but my comments regarding quantification have been correct. You side with bureaucrats with old dogma analysis regarding protein translational changes that do not address the short comings of Western Blot. If i wanted to measure albumen I would use WB but to measure newly formed, drug induced, phenotypical proteins and qualify said protein IMF is superior to WB. Your lab tech education limits your ability to understand this . I feel sorry for you. I'm sure there is an internet degree program that can help you u understand these complex issues. Good luck in your educational endeavors.
Besides the preposterous comparisons to Beckers, Farkas's analysis concentrates on the 24-48 week data set. Very little on the 3+ years of eteplirsen therapy. Also discounts signs of efficacy by declaring that due to significant site care including physical therapy that this could explain these benefits. This is demonstrably false. Very few of the boys had regular PT throughout the 3+ years. The 2 boys which lost ambulation