Email to Dr. Janet Woodcock from Abigail Alliance
Posted by: Christine McSherry on November 27, 2013
From: Steven Walker <email@example.com>
Sent: Monday, November 18, 2013 8:24 PM
To: firstname.lastname@example.org; email@example.com
Cc: Frank Burroughs Subject: FDA’s Recent Shift on the Eteplirsen Development Program
We are extremely disappointed with FDA’s recent determination that the existing clinical data are insufficient for filing of an application for approval of Eteplirsen. The reasons provided by your Division of Neurology Products (DNP) represent an extensive redefinition of the FDA’s expectations for demonstrating the efficacy of drugs designed to correct genetic deficiencies that lead to low dystrophin levels, the known cause of Duchennes Muscular Dystrophy (DMD). The logic presented by DNP for redefining its view of the natural course of the disease and the appropriateness of clinical endpoints used in the pivotal study for Eteplirsen, are speculative and based primarily on the results of a trial conducted for another drug that is not sufficiently similar to Eteplirsen to support the conclusions drawn, and actions taken, by the FDA. To be clear, the FDA’s concerns regarding this drug appear to be manufactured by risk‐averse FDA staff using obsolete regulatory logic.
In FDASIA, the FDA was directed to use its expedited approval mechanisms, including Fast Track and the Breakthrough Designation, across all of its divisions. That undeniably includes using those authorities for serious and life‐threatening neurological diseases. FDA’s neurological drugs review office has been especially recalcitrant over the years in using FDA’s expedited development and approval pathways. It is now time for that recalcitrance to end.
In this case, the existing clinical data for Eteplirsen support a finding by FDA that the drug is safe and effective enough, and the unmet need more than great enough, to merit expedited approval under Fast Track. As you also know, FDA has the authority to require a Risk Evaluation and Mitigation Strategy (REMS) which can include requirements to fully inform patients prior to prescribing of the drug, and continued post‐approval clinical studies to address the FDA’s remaining questions and concerns. Finally, if the results of post‐approval monitoring and studies establish that the risks outweigh the benefits of Eteplirsen, FDA can withdraw its approval. The point here is that approving Eteplirsen now would not in any way be an irresponsible action by FDA, and would be entirely consistent with the framework established by Congress to move much needed drugs like Eteplirsen to the patients who need them as quickly as possible.
We do not agree with FDA’s current opinion that too little is known about the utility of dystrophin levels as a biomarker for DMD, and even if that were true, we point out that approval under Fast Track can also be based on recognition of positive outcomes likely to predict clinical benefit that are not based on a biomarker. FDA can approve a drug for a serious or life‐threatening illness with an unmet need under Fast Track based on any evidence, or combination of evidence, that reasonably predicts clinical benefit, and can use judgment in making these determinations.
In this case, that could be, and in fact should be, any reasonably convincing evidence of clinical benefit, or evidence likely to predict clinical benefit, including an endpoint as simple and obvious as performance improvements in a small group of DMD patients. As you also know, DMD is a serious and life‐threatening disease that causes progressively debilitating neurological decline leading to a severely shortened life span, and Eteplirsen is the only treatment that has ever shown evidence of being effective in delaying progression of the disease. Under these circumstances, Eteplirsen is the only option for DMD patients: an option now irresponsibly blocked by FDA. FDA’s concerns regarding the validity of the biomarker are primarily based on an extrapolation from results of a trial conducted with a different, substantially more toxic drug that is designed to increase dystrophin levels by a similar mechanism of action. The FDA seems to have ignored an obvious problem with Drisapersen: it does not effectively exon skip in the majority of patients given the drug. Drisapersen is not capable of achieving its purported mechanism of action, likely because of its dose limiting toxicity .
In comparison to Drisapersen, Eteplirsen is very well tolerated, with no significant dose limiting toxicities and has exon‐ skipped in every patient administered the drug. Achieving an effective dose is at the core of the successful administration of any drug. Because of the toxicity problems with Drisapersen, a measurable clinical effect was not achieved in the majority of patients given the drug in the treatment arm of its trial, and Drisapersen failed to meet its pre‐specified endpoint. The failure of Drisapersen should not be viewed as evidence that increasing dystrophin levels with Eteplirsen does not predict clinical benefit, especially when the clinical data for Eteplirsen indicates that it does predict, and in fact result in, clinical benefit in the form of performance improvements. To be blunt, DNP’s fabricated concerns regarding Eteplirsen are scientifically invalid.
Our concerns regarding FDA’s new position on Eteplirsen are heightened by the fact that over the last year, the Abigail Alliance requested and attended two high‐level meetings with senior FDA staff to discuss the regulatory path of this drug on behalf of the directly affected patient community. We introduced you to three extremely well‐informed members of the DMD patient community (all mothers of children suffering from DMD) at those meetings. In the first we met with you and Robert Temple. In the second, we met with Commissioner Hamburg, you, Robert Temple and several other senior FDA managers likely to be involved in FDA’s handling of Eteplirsen. We and the DMD patient community representatives were clearly informed by Dr. Hamburg, Dr. Temple and you that FDA’s handling of this drug would receive your direct involvement and oversight. Since those meetings, you have facilitated at least six other meetings between FDA staff and the patient community representatives. Our understanding from those patient community members, and from our own participation in the first two meetings, is that there can be no question in the minds of FDA’s senior leadership, the leadership of the Office of New Drugs I, or its DNP review office leadership and staff, that this patient community is expert in the causes, biochemical characteristics, natural course of the disease, and debilitating and ultimately lethal risks of DMD. They are also very well‐informed and in many cases actual experts regarding the potential risks and benefits of Eteplirsen and Drisapersen, with some of these stakeholders having children participating in the clinical trials for these drugs. You know from your personal contact with them that they are extremely well‐informed, and that their expectations of what these drugs may, or may not, do for their children is realistic and rational.
Janet, to be clear, you, Bob Temple and Commissioner Hamburg have been made aware that this patient community fully understands the risks their children face from their disease, and that they also fully and accurately understand the potential for benefits and risks posed by Eteplirsen. They have clearly informed you that FDA should approve this drug as soon as possible based on the available clinical data. It is their children who will be taking Eteplirsen.
FDA’s recently announced position on this drug indicates that FDA is not adequately incorporating the affected patient community’s input into its drug development and approval process, as it was directed to do by Congress, and as you, Bob Temple and Commissioner Hamburg personally assured the DMD patient community would happen. We note with interest that the Director of DNP (Dr. Eric Bastings) is new in his position and reports to Drs. Ellis Unger (Director of the Office of New Drugs I) and Dr. Robert Temple (Acting Deputy Director of the Office of New Drugs I). All three of these critical decision‐makers for this development program are in your direct reporting line. 3 Janet, thismeansthey work for you, and this serious misstep on the part of DNP is your direct responsibility. You, in turn, report directly to the Commissioner, which should raise your handling of this issue to the immediate attention of Dr. Hamburg.
We acknowledge that you have provided members of the directly affected patient community unprecedented access to the leadership and review staff for purposes of bringing the patient viewpoint to the review team in DNP; however the outcome, and information provided to us by the patient community members who attended those meetings, indicates that you left it solely to them to convince the review team to give sufficient weight to their views, and while the review personnel were compelled by you to listen, they did not hear them, nor did they give adequate weight to what the patient community told them. That is unacceptable. There was one simple message delivered to you by the patient community: the benefits outweigh the risks.
We can only conclude that DNP and its new Director, Dr. Eric Bastings, failed to understand the importance of the input and direction provided to them by the directly affected patient community because FDA senior management (meaning you and the Commissioner) did not adequately communicate the importance of patient input to DNP leadership and the review team, nor did you communicate how that input should be incorporated into FDA decision‐making. Instead, it appears that the FDA’s long‐standing cultural failing of arrogantly dismissing patient input remains firmly in place in the DNP.
Perhaps most troubling in this case is the failure on the part of DNP to grasp the now dire need for entirely new approaches to how we develop and approve these new, scientifically‐based treatments. It is apparent that DNP is not moving forward in its understanding and application of new regulatory science to the now well‐established medical promise of personalized and targeted medicine. DNP is instead calling for a trial design consistent with what the FDA was doing in the 1960s; a randomized, placebo‐controlled trial that will take years to design and run, and will at best produce a simplistic statistical result based on a comparison of median outcomes, information that is almost useless in determining the safety, effectiveness and appropriate use of a targeted drug. Of course, obtaining the crude information regarding average outcomes from FDA’s proposed randomized, placebo‐controlled trial will be obtained only of the trial can be enrolled and run to completion. FDA acknowledges in its comments to Sarepta that such a trial may not be feasible.
Janet, we are again at the doorstep of delivering real medical progress against a horrible disease to patients and families who unquestionably need it, with an FDA review office relying on obsolete regulatory science and the FDA’s deeply‐ rooted counter‐productive culture of delay and denial, acting as a road block. This is happening because the agency’s regulatory science, policies and culture remain decades behind the medical science it is struggling to regulate, and senior FDA management is not using its authority within the agency to mitigate these enormous problems. Consider that, after crashing the current drug development program for Eteplirsen and crushing the legitimate expectations of the patient community, DNP does not know and cannot clearly communicate what it will require in the form of new clinical data to support an application for approval. DNP admits that it does not know what the clinical endpoints should be, or how to design and enroll the trial it wants. Because of the DNP’s incompetence and intransigence, there is no reasonable path forward, and there will be no treatment option for children with DMD for years. This situation is a perfect example of everything that is currently wrong with the FDA’s regulation of new medicines, it is entirely unacceptable and it is your direct responsibility to fix.
Based on the information provided by Sarepta regarding the FDA’s position on what a path forward for Eteplirsen might look like, it appears that DNP’s current wish list is too medically and scientifically complex for this drug and disease, and because the existing data clearly indicate that at least some patients benefit substantially from Eteplirsen, a placebo‐ conrolled trial is unethical. It has long been FDA’s position that randomized controlled trials are “ethical” in all cases if the FDA wants such a trial conducted. FDA has no formal process in its regulations, policies or practices that considers the ethics of any clinical trial, nor does it have any established standards its staff can rely on to make such a determination, a problem we have raised with both you and the Commissioner in recent years; and a problem that remains unaddressed at FDA. But in this case, even a loose interpretation of the unofficial standard of “equipoise” would not be met. Administering placebos to children with DMD for two years or more (in all reality it would be 4‐5+ 4 years) cannot be considered ethical given the existing evidence that Eteplirsen doesin fact provide clinical benefitto at least some children with the disease and the appropriate genetic marker.
To summarize, the evidence that Eteplirsen does increase dystorphin levels and improves performance is consistent in the existing data, and cannot be ignored when considering the ethics of any future trial design for this drug. Eteplirsen likely works, which means a placebo control arm is unethical, and because there are no other treatments that have ever been shown to be effective in delaying the progression of DMD, there is no ethical comparator treatment that can be used. Consider that FDA should be protecting patients from unethical trial designs, not requiring them.
This is a repeat of how your OHOP handled the development program for Zelboraf, requiring an entirely unethical, medically and scientifically unnecessary randomized control trial in which the lives of more than 300 patients assigned to the control arm were wasted in FDA’s mindless pursuit of a p‐value from a randomized controlled trial: a trial required solely because it was the policy of the Division Director (Dr. Richard Pazdur) supported by FDA Medical Policy Director (Bob Temple) that if it was possible to run a large randomized controlled trial (whether medically, scientifically and ethically defensible or not) such a trial would be run. You informed me in the first of our meetings in the last year that both you and the FDA learned from that horrendous mistake. We must question the truth of that statement given that your DNP, with your direct involvement and oversight, is repeating the same horrendous mistake. How many kids will lose their ability to walk, to brush their teeth, to feed themselves, or die while the sponsor attempts to run a likely unfeasible trial? This is the reality FDA is creating. To reinforce the points I make above, I direct you to the editorial you co‐authored regarding the Breakthrough and Fast Track pathways, published in the current issue of the NEJM. Eteplirsen clearly meets the standards for designation as both a Fast Track and Breakthrough drug, and is in fact, an example of a drug that should be moved to patients quickly whether it has formally received one of those designations or not. We are not suggesting that you should ask Sarepta to request Breakthrough designation. It is too late for that. You need to direct DNP to accept the application and review it as quickly as possible within the full context of the flexibility provided by Fast Track, and the risk/benefit perceptions of the real affected patient community.
I also caution you not to follow FDA’s (and your) past practices of searching out a “patient” group that supports DNPs position, and then using that group to buttress the agency’s mistake. You are a public servant, and you are fully aware that the real DMD patient community, with whom you have spent considerable time, supports immediate availability of Eteplirsen through approval.
By allowing DNP to make the mistakes it made in its recent meeting with Sarepta, you now face the challenge of admitting that mistake, and correcting it. There can be no doubt given your close involvement in this development program, that you knew where DNP was headed and you failed to act to stop it. Consequently, their mistake is also your mistake.
Janet, the FDA needs to admit that a mistake was made, and you need to use your authority as the Director of the Center for Drug Evaluation and Research, to correct it. The victims of this mistake will be kids with a horrible disease, that will be left untreated for years as a direct result. In this case, FDA must not take its usual course of never admitting, and never correcting its mistakes. For those kids, the clock is ticking,and their disease is progressing.
Janet. This is your problem. You undeniably bear complete responsibility for this, and you will be held responsible for it by the patient community. You need to fix it – quickly.
We are requesting an immediate telephone call with you to discuss this shift in FDA’s position on Eteplirsen. We are in close contact with the directly affected patient community, and they are aware of the information presented in this e‐ mail. I can be reached at this e‐mail, or at the telephone number below. Please contact me at your earliest opportunity to set a date and time for a call. As you well know, this is a time critical issue; thus I strongly suggest that you make the time to speak with us this week.
Steven T. Walker M.S., P.G. Co‐Founder Abigail Alliance for Better Access to Developmental Drugs www.abigail‐alliance.org Mobile: 813‐340‐3193 e‐mail: firstname.lastname@example.org
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