The news that GSK is not pursuing a phase III study for skipping exon 51 here in the US has certainly come as a blow. It seems that the FDA would like to see longer term toxicology data before approving the 48 week human study. Meanwhile, almost every European family with DMD will have access to the phase III study. It seems obvious that the FDA is being blindly obstructionist and GSK is showing its true stripes as money-sucking big pharma company that is going to choose the path of least resistance for drug approval after leading parents in the US on a merry-go-round of broken promises and shattered expectations. Or is it?
In the 1950’s and 1960’s between 10,000 and 20,000 babies around the world were born with severe birth defects and many didn’t survive due to the use of the drug thalidomide for morning sickness. The drug has been called one of the “biggest medical tragedies of modern times.” In the US the drug had minimal impact because a pharmacologist at the FDA refused to approve it for marketing because she felt that the drug needed “further tests.”
And then there are the FDA regulators who made the decision to leave on the market Vioxx—a prescription anti-inflammatory drug for arthritis—despite some indications that it might be linked to an increased risk of heart attack and stroke. It’s now estimated that the drug may have been responsible for between 88,000 and 139,000 heart attacks worldwide. The drug has been withdrawn, FDA officials have been hauled in front of congress, jobs have been lost, lives have been lost and millions of dollars of law suits are still progressing through the system. Although the general consensus is that Merck’s advertising team was responsible for some misleading information about the drug, congress still pointed fingers at the FDA and Merck jointly in public hearings.
Now imagine that you are an FDA official reviewing an application for a phase III study of exon-skipping in the US that will involve weekly subcutaneous injections of little chemically modified pieces of DNA into children for close to a year. This is a new class of drug with no approved applications anywhere in the world. On the one hand, if there is some cumulative toxic effect of this drug that can only be seen after it’s given over a longer period of time you might be responsible for another great and preventable “modern medical tragedy.” On the other hand, by not approving the studies, you may be delaying access in the US to this drug that could potentially slow the progression of a fatal disease and buy these boys many years—also a great modern medical tragedy (keeping in mind that the drug is experimental because we don’t know if it will work or not). The rock and the hard place.
I guess the point is that most of the FDA staff I’ve met over the years take their jobs extremely seriously—they feel a crushing weight of responsibility knowing that their decisions can impact so many lives for better or worse. Of course there is always some CYA (“Cover Your Rear”) behavior and bureaucratic nonsense going on because a certain amount of that happens everywhere, and we should fight that behavior vigorously when it’s clear that that’s the case. But I think we don’t really know what’s going on behind the scenes at the FDA on exon-skipping. Is the FDA reacting to the unknown with an overabundance of caution despite the EMEA’s approval in Europe of the same data? Have they asked GSK for data that GSK decided not to provide because of the expense? Or have they asked for new data that GSK doesn’t yet have and so can’t provide immediately? Because of the confidential nature of these discussions, we really can’t know the cause of the latest delay.
And what about the profit-motivated companies involved? Those of you who were able to attend the PPMD conference got to meet at a breakfast session Dr. John Kraus, who is a senior Medical Science Director at GSK and Dr. Steve Shrewsbury, who is AVI’s Chief Medical Officer. Companies, like any other organization, are actually groups of people who have come together in some sort of formal way to achieve an end. In the case of a for-profit organization, the goal is to make money (it’s the American way—all you Republicans out there give a big “head nod”). But a for-profit goal doesn’t make the people who work for a company bad people. In fact, like John and Steve, many of them seem to be quite caring—many are medical doctors who went into the field with a desire to help people. I’ve gotten to spend some time with Steve Shrewsbury, both at AVI headquarters in Bothell and in Tucson, and he shared with me how upset he used to get when he volunteered at camps for children with asthma and saw so many whose symptoms hadn’t been treated properly. These are the people behind those black-box facades. Now to be fair, there are people behind those people, and even more people who have invested in the company to make money—the further removed the investors are from the company’s mission the more likely they are to make decisions based purely on profit motives. But it’s not fair to tar the whole company with the same brush or perhaps even to complain in the first place about their reason for being.
Are all of the agencies, companies and organizations out there doing everything perfectly? Of course not. There is always room for improvement until we have an effective therapy and more in some cases than in others—at PPMD we are constantly evaluating what we are doing and whether or not it’s having the impact we’d like. But anger can be a very blunt weapon—today I demonstrated this perfectly when I took a hammer to the latch on the back gate because it tends to stick. Now it doesn’t open at all (and in fact my husband is going to be most displeased). Not to make this analogy too drawn out and painful, but what I should have done was figured out which part of the mechanism was sticking and put some WD-40 on it. To advocate for your child effectively it’s important to direct your energy toward the real bottlenecks in the process and these aren’t always the obvious culprits.
In other words, after the announcement on Monday from GSK that phase III studies will not go forward in the US (at this point in time) it may look obvious that the FDA is being obstructionist and/or that GSK just doesn’t care about the kids in the US and is moving on…but neither is necessarily true. I guarantee you that at the FDA there are officials who have agonized over this decision because they don’t want to be responsible for the preventable deaths of children taking part in a clinical study—children that may have a disease that reduces lifespan, but who are right now regular kids who just walk a bit slower. And GSK has some internal strategy for getting these drugs approved as widely as possible, including in the US, because that’s the best way to maximize the market size. It may mean stepping back now to do the extra studies that the FDA wants, but they are going to jump through all the hoops they need to test the drug in the US if they are ever going to see profits. The true breakthrough is that a big pharma like GSK is involved in developing a small-market drug in the first place.
Here’s where I think the true bottlenecks are – where we need to add a little lubricant:
1. Lack of harmonization between the FDA and the EMEA. We shouldn’t have to do clinical trials in multiple countries to get drugs approved in multiple countries unless there is some demonstrable difference or reason to think there would be a difference in the way the populations in those countries react to the drug (which is rarely the case). The EMEA is not always faster than the FDA, it’s just different. The FDA is not always “safer” than the EMEA, it’s just different. We need to push for harmonization of regulatory requirements between these two agencies—this was on the PPMD advocacy agenda this year and it’s going to be one of our major priorities going forward. The barriers to FDA/EMEA harmonization are largely political and therefore something we can and should take on as a community.
2. Splintering of resources. The DMD community is too small to build clinical infrastructure—registries, clinical networks, databases—over and over again. In the US we need a single, far-reaching clinical research network with a single patient registry so that every child diagnosed with DMD can participate in a clinical study. Read about the Children’s Oncology Network if you want to see the system I think we should emulate: .
3. The requirement that every institution participating in a clinical study reviews and approves the study protocol through its own Institutional Review Board (IRB). This means that a multi-center study with 12 participating sites must have 12 different IRB approvals and every change that’s made to the protocol must go through an IRB approval—a process that can take weeks, and more commonly months. The institutions themselves have put these IRBs in place to protect patients from dangerous or unethical studies, but it’s not clear to me that reviewing the same protocol 12 different times makes it any safer. So called “centralized” IRBs exist, but most institutions won’t use them because they are in CYA (“Cover Your Rear”) mode. The use of a single centralized IRB could dramatically reduce the time and therefore the cost of the multi-center phase II and III trials that are required to get a new drug on the market. This is another issue that I think this community can help tackle (along with all the other disease associations out there) that would have an immediate and beneficial effect in how quickly we can test and approve new drugs.
4. Lack of a “voice” at government agencies. Both the FDA and the National Institutes of Health provide numerous opportunities for people from the general public to get involved in the development of policy, but this community hasn’t taken advantage of these opportunities as thoroughly as it should. Although Pat and I between us are on committees for almost every government agency that touches DMD, it’s important that you out there who are not professional advocates also be represented directly, either through sitting on committees, attending congressional hearings, or submitting comments to the FDA and NIH when they are requested. The FDA Office of Orphan Products is currently looking for families from the DMD community in the Washington DC area to participate in a committee—please let me know if you are interested and I can pass on your name. We will post other opportunities for commenting or participating as they are available, starting with the planned FDA meeting on exon-skipping this Fall (info should be available soon—it will be posted simultaneously by multiple organizations when it is).
None of this is black and white and none of this is easy, but beating on the FDA and/or GSK with a hammer probably won’t help (although it might feel good at the time). We need to pull together and focus on changing the things that we know for sure are a problem.

Note added from Pat:

FDA is holding a Webinar? And PPMD/Cure Duchenne are hosting? And the webinar will not be specific to DMD issues? So what?

All of the above is correct, but this is about building a foundation. This is about understanding FDA requirements and have the opportunity to ask important questions. Given the recent news from GSK, there are loads of questions and not many answers (at least not the ones we were hoping for). This webinar becomes even more important to build a solid foundation of information and utilize the opportunity to ask basic questions. Questions such as :

What is the requirement in terms of toxicology studies

Are there instances when the requirement is different – less? Or more?

Under what circumstances could this happen?

What is the time frame for review?

Are there circumstances when a review process is expedited?

Describe and Individual IND. If the company is unwilling to participate, do patients have any



The planned webinar will serve as a basis for information, a primer of sorts about FDA. It will serve as a platform and an opportunity to prepare for the DMD specific workshop on AON planned for Fall, 2010. It will familiarize you with some of the individuals working within FDA. It will help you better understand Advocacy efforts and rationale for the advocacy strategy. It is FDA 101 for sure and may feel a bit frustrating as for some, it may repeat what you already know, but in there, you may find a tidbit of information that you will tuck away for later. (details on front page of PPMD site).

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Comment by Paul Cliff on July 10, 2010 at 11:42am

This approach is going to take a few years to reach fruition, but it is nonetheless worth pursuing. If you look at the exponential increase in the pace of translational research starting with the original MD Care Act in '01, it's apparent that the effect in adjusting priorities from basic research to translational research took a few years to play out. Because that impact is way further up the drug development pipeline than this regulatory chokepoint, which is right at the tap, so to speak, I believe that a cultural change at the FDA could be accomplished in a matter of a couple of years which would benefit EVERY DMD patient alive today. There are a half dozen compounds in some form of clinical development in civilized countries right now, with a number of others in preclinical development. We, and the advocacy groups for all other life threatening diseases, could with a coordinated effort convince Congress to require mandatory reporting from the FDA on the status of addressing these roadblocks to drug availability. Right now we need to make it so that getting chewed out at a Congressional hearing for lack of progress is certain while getting chewed out for prematurely approving a drug for clinical trials which turn out to be unexpectedly dangerous is a mere possibility. A lot of the statutory structures like the Orphan Drug Act and MD Care Act are already in place and may only need to be modified slightly to impose this type of formal accountability on the FDA. In the meantime, people, especially teen aged DMD patients and their siblings should prepare brief video testimonials about their lives, dreams and lack of good current options. Collect those on a DVD and deliver it at the upcoming meeting.
Comment by Ofelia Marin on July 9, 2010 at 8:40pm
Good luck! It will be great if that happens. I don't believe it will be soon enough for this generation of boys but hopefully for the next. And I love your confidence! :)
Comment by cheryl cliff on July 9, 2010 at 11:05am
I too believe this battle with FDA is doable and certainly worth the fight...pitchfork at the ready Sharon for when we storm the bastille. Not sure if we'll make headway soon enough for Alexander tho.
Comment by Sharon Hesterlee on July 8, 2010 at 8:24pm
Absolutely! We can and will do these things and not to the exclusion of trying to help in the short term. We are definitely going to fix the IRB problem and will make improvements in the FDA/EMEA problem. You'll see...
Comment by Ofelia Marin on July 8, 2010 at 8:01pm
Living with DMD, I learnt that you have to pick your battles wisely. It is hard for me to believe in winning this fight with the FDA & EMEA and IRB approval in my son's lifetime. It's not even about exon skipping or other potential therapy, it's about choosing a winnable battle. It is great what you want to do in theory, but I do not believe that you have a chance to change #1 or #3 anytime soon. I cannot even believe that you want to take this on. The parents supporting this organization have boys who need help now or in the near future and you plan to fight to synchronize FDA and EMEA and eliminate individual IRB approval? Do you really think you have a good chance changing them anytime soon?
Comment by Sharon Hesterlee on July 8, 2010 at 9:44am
Here's the link to the information on the FDA Hearing on Drug Evaluation for Rare Disease--the comment period has been left open until August.
Comment by Sharon Hesterlee on July 8, 2010 at 9:41am
We are meeting in August to refine our advocacy strategy for next year and points number 1 and 3 are right at the top of the list. It will likely require a coalition of organizations to accomplish both of these objectives, but PPMD is a member of the Health Research Alliance and affiliated with the Genetic Alliance, as well as the Biotechnology Industry Organization, so we could likely put together these coalitions pretty quickly. I have good working relationships with the staff at many other large non-profit organizations. This is going to take a village and it might take as long as two years, because these are major regulatory and legal changes to the system. But it would be so worthwhile. We have already discussed this with John Keast at Cornerstone and we are gearing up to make a hard push on these issues.

So how does this get your son into the exon skipping trial? It doesn't immediately, but these things will have the greates impact for the largest number of boys in the long term. In the short term we are using every available opportunity and public forum to comment on the exon-skipping situation (we registered two public comments this Summer in response to the agencies for feedback, one to the FDA and one to the NIH, describing the exon-skipping situation and laying out concrete suggestions for change). BTW, I posted the FDA comment information along with the deadline so that all of you could post comments as well s--I hope you all did. Your voice can make a difference but the FDA has to hear it. The FDA isn't monitoring comments on the DMD Community site. In fact, I think you can still comment until the end of August--I'll post the link to that information. You are right that as parents you should be able to weigh all the available evidence and make informed decisions and you need to tell the FDA that. PPMD did, but it's more meaningful coming from a large number of individuals.
Comment by Ruchika Batra on July 7, 2010 at 10:40pm
Sharon, I go with Ofilia one hundred percent and more..... The conditions of our boys is critical... we are talking of long term accumulated side effects... there may not be those side effects at all... or there might not be 'long term' at all. Our boys are moving towards a life of invalidity, dependency and untimely fatality. Though i buy almost every argument which FDA or PPMD puts forwards... this does not go down my throat at all. Sorry.... but what ever the reason FDA has for its action..... it is simply not fair at all!
Comment by Ofelia Marin on July 7, 2010 at 7:55pm
Sharon, how do you plan to accomplish #1 or #3? When is this going to happen? Did I understand this correctly, do you have a plan to accomplish these points or is this a "need to have" list in order to reduce the time to test/approval?
Comment by Sharon Hesterlee on July 7, 2010 at 11:17am
Ofelia, I think you have to focus on being the best advocate you can be for your son--absolutely. At PPMD we have to focus on moving the bar for everyone--the things I listed in my blog are things that I believe will dramatically reduce the time it takes to test new drugs for DMD. They may not help your son specifically get into a specific clinical trial, but they will help a lot of people's sons in the future. But you have to do what you need to do right now for your own son-- no argument there.

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