At yesterday’s Duchenne Policy Forum, Vice President of Research Sharon Hesterlee, PhD, tweeted throughout the day, reporting to the community what transpired during this historic meeting. We have compiled these tweets and fit them into the agenda to give you a recap. (Please note that these notes may not be verbatim and/or grammatically correct – Twitter limits the number of characters per post.)

For those of you who were streaming the Policy Forum live, we apologize for the periodic disruptions to the broadcast. We were dealing with major internet issues at the hotel the FDA had requested for the meeting.

Unfortunately we were not allowed to record yesterday’s meeting but we hope that this blog will provide you with the day’s most important highlights.



Objectives & Expectations

Comments from Pat Furlong, PPMD President & CEO

  • Responsible drug development is very difficult and we must not falter in our commitment
  • We are disappointed that the FDA has not shown more flexibility in their decision making

CDER Perspective on Duchenne Drug Development
Comments from Janet Woodcock, FDA/CDER

  • We recognize in Duchenne that there is critical unmet need
  • The benefit risk data we heard from PPMD in June very important
  • We need to find out the truth -- the effects of these drugs in muscular dystrophy
  • Data in hand from drisapersen now--starting analysis

Logistics / Ground rules Facilitator: Mark Krueger, MPH

Session 1: Unmet Medical Need
Moderator: Pat Furlong

Opening comment from Pat

  • Each functional loss is a "little death"

Consistency in the global approach
Elizabeth Vroom, UPPMD (Netherlands):

  • Will be important to harmonize regulatory guidelines in US and Europe

Unmet needs: A patient & family perspective across the spectrum of illness

This discussion’s panel consisted of people with Duchenne and parents of people with Duchenne. Each presentation was accompanied by video footage of themselves (or their child) trying to accomplish typical daily tasks. Sharon noted that throughout these presentations, FDA participants were taking notes during testimony from parents and those affected by Duchenne.

Todd Morrow (father of a young son with Duchenne)

  • We were not ready or prepared to have a son with Duchenne

Marissa Penrod (mother of a young son with Duchenne)

  • There's a train racing toward my little boy...I'm acutely aware that I may not stop it in time
  • The risk of having Duchenne far outweighs the risk of most potential treatments

DeeAnn Friar (mother of two sons with Duchenne)

  • How do I explain to my sons why one boy is allowed to be in a clinical trial when they are not?

Mohammed Haider (college student with Duchenne)

  • We have to consider anything and everything that may improve our longevity and quality of life
  • We are willing to take more risk than the average person just to maintain what we already have

Ansel Lurio (29 years old with Duchenne) said he was very frustrated by requirement to be ambulatory to participate in clinical trials.

Jeff Watkins (father of young man with Duchenne)

  • If Noah could be here he would encourage you to "soldier on"


What are important benefit/risk considerations in Duchenne?
John Bridges, PhD presented on data collected from results of a family survey. He reported:

  • Benefit-Risk survey shows that slowing progression compensates for risks of treatment


The session was then opened to the registered speakers’ session. These were two minute comments from families in the Duchenne community chosen from a lottery earlier in the morning. All those chosen were parents of people with Duchenne. Highlights from these comments are below:


  • Parents are willing to take a risk on an experimental drug -- Terri Ellisworth
  • You have things in front of you that are safe...they need to be approved as quickly as possible --Suzanne Gaglione
  • I hug him one day and I hope we can hug him tomorrow. We cannot accept them dying -- Suzanne Gaglione (parent)
  • My heart is broken--my son is already struggling -- Dana Edwards
  • What would you do if it were one of your children? When you go to bed at night, think of us. -- Dana Edwards
  • I never thought 10 years ago that we would have nothing now in terms of new treatment -- Mindy Cameron
  • The price of inaction is huge and too many families have paid that price -- Gurpreet Singh
  • It brings me to tears when I think about so many promising drugs--believe in the magic of more time -- Sarah Burgess
  • Luxury of a large patient cohort does not exist--must change mindsets for trials -- Brian Denger
  • Dystrophin is uniquely positioned to be an obvious and ideal biomarker for Duchenne -- Debra Miller
  • Not approving a safe drug is a greater risk and a greater error -- Debra Miller
  • My greatest fear is entering my son into a trial and being placed into the placebo arm -- Maria Schultz
  • We all in here have the power to make history--I ask you to do what is right and moral--Maria Schultz
  • (referencing the movie "Private Ryan") Our sons are stuck on the beach and it's not a safe place to be -- Bob Getler
  • Imagine 12 children are rescued from the Titanic and the rest are being lost as time passes --Alison Willis
  • Would you want your children left on that sinking ship as research looks for a better lifeboat? --Alison Willis
  • What risk do we find acceptable? The answer is "quite a lot" -- David Jorgensen
  • All of us in this room are at the forefront of personalized medicine -- Jenn Mcnary
  • Let's get the answers in a feasible way without causing our sons to decline in the process -- Jenn McNary
  • "Give me anything I can get--bring it on, I'm taking it!" Christine Piacentino reading for her son Jonathan who was unable to attend
  • We could barely say the words "Duchenne muscular dystrophy"...we live in terror --Alexandra Johnson
  • We need a new flexible regulatory pathway for the approval of exon skipping -- Alexandra Johnson


Session 2: Natural History of Duchenne & Clinical Trial Endpoints
Moderator: Lee Sweeney, PhD

Natural History in Duchenne: What is clinically meaningful?
Comments from Craig McDonald, MD (UC Davis)

  • There has been a changing natural history of Duchenne over last 4 decades
  • Ventilation has had the greatest impact on survival in Duchenne
  • Recent data shows deflazacort more effective than prednisone--boys walk longer
  • Natural history data: loss of one function very predictive of loss of other functions over time
  • Higher baseline function = slower long term decline
  • Dr. McDonald then showed FDA a "decision framework" for inclusion of outcomes in clinical trials

Infant and toddler endpoints
Comments from Anne Connolly, MD

  • Bayley scale looks promising as endpoint in younger boys

Ambulatory endpoints
Comments from Craig McDonald, MD

  • Craig McDonald tells FDA that 6 minute walk test in Duchenne is clinically important
  • We now know a 30 meter change in 6MWT is clinically meaningful for clinical trials
  • If 6MWT greater than 350M at baseline, will have to show improvement or do longer trials

Non–ambulatory endpoints
Comments from Tina Duong, PT

  • We need an upper extremity endpoint that can measure change over time
  • "PUL" scale developed by international clinical outcomes group--measures upper body strength
  • On endpoints: We have to reduce the psychological burden of asking patients to try to do things that they can no longer do
  • Microsoft Kinnect system looks promising to measure upper body reach--PPMD funding Gregorij Kurillo to test in Duchenne

Mutation–specific natural history
Comments from Kevin Flanigan, MD

  • Modifier "LTB" in Duchenne has same protective effect as steroids
  • Difference in function based on mutation type small enough that all mutations could be used for controls

Strength and function relationships
Comments from Craig McDonald, MD

  • Strength and function not related linearly over time--small strength changes = large function changes later in disease
  • Craig McDonald explains why not a good idea to require strength as co-primary endpoint in European trials

Discussion & submitted questions period
Facilitator: Mark Krueger, MPH

Mark presented questions that were submitted from the community to the FDA. Their comments are below:

  • We are open to considering the balance between the risk and the benefit for Duchenne patients
  • We welcome trials with endpoints individually tailored to patients based on the stage of the disease of the patient
  • We are looking at the natural history data very carefully and we are really trying to understand it
  • The variability among patients is a challenge – Eric Bastings, FDA
  • We recognize that parents want their sons to be on drug and not placebo --Ellis Unger, FDA
  • If you have a treatment that has a big effect you can use a historical control -- Ellis Unger, FDA
  • We have seen a lot of variability in placebo group from one trial to the next--it creates problems. --Ellis Unger, FDA
  • FDA agrees with Ansel Lurio (affected by Duchenne) that there must be some scientific gain from a clinical trial
  • It's a scientific judgment to say whether an effect extends to the whole indication--it's a possibility.-- Ellis Unger, FDA
  • Staff trying to understand how to match individual patients to placebo controls--hard to match mean data.-- John Jenkins, FDA
  • There's a lot of data--we will need to mine it very carefully to see if we can avoid placebo controls. --John Jenkins
  • We all understand why parents don't want their boys exposed to placebo if we can help it. --John Jenkins, FDA
  • As a general rule we try to write indications very broadly when we can. --John Jenkins, FDA
  • FDA--important concept that a change in one endpoint is predictive of changes in other endpoints in the future
  • FDA suggests that a "time to event" design could minimize duration of trial, could be powerful (Eric Bastings, FDA)
  • (on new endpoints) You don't need extensive validation for simple endpoints like "ability to feed" --Eric Bastings, FDA
  • (on new endpoints) Could base scale on activities that are "at risk" over next year -- Ellis Unger, FDA
  • We are as flexible as we can be in trying to come up with new endpoints--shouldn't be rocket science. Ellis Unger, FDA
  • (on new endpoints) Size of benefit needs to be clinically meaningful--might be small. --Ron Farkas, FDA
  • (on new endpoints) Must take into account effect of variability on endpoint --Eric Bastings, FDA

The discussion was then open to attendees who had comments or questions for the FDA:

  • Dystrophin clearly being made by Eteplirsen --we need an effective drug on the market. --Steve Wilton (Murdoch University)
  • To me, once we have a plateau we are not as worried about improvements. --Brian Denger (parent) --FDA agrees
  • Suggestion to FDA from audience (Abigail Alliance) that a model be used that does not require a placebo

Session 3: Biomarkers & Surrogate Endpoints in Duchenne
Moderator: Craig McDonald, MD

FDA’s perspective on biomarkers and surrogate endpoints
Comments from Ellis Unger, MD (FDA)

  • We hear the community's frustration, desperation and some anger--have received over 2000 emails.
  • Some of you may think we are bone-headed bureaucrats who don't care-I went to medical school to help people
  • Perception that we are overly protective, but we would accept something that slowed progression
  • Will consider any kind of toxicity. We would put it in the label and go from there. We are not paternalistic.
  • We don't generally stand in the way for a treatment for a serious disease like this.
  • Biomarkers may mislead you if they are not predictive and lead to a failed trial for a good drug. 
  • (surrogate markers) Dystrophin has all the biologic plausibility you might ever want
  • Studies can be designed so that only a subset are evaluated for primary endpoint-no need to be exclusive
  • FDA says not wedded to 6MTW- not as important as more obvious examples of improvements in daily living like ability to feed
  • There are ways to construct endpoints that would be relevant to a much broader segment of patients
  • Categorical endpoints may have more power (time to event analysis)
  • We will probably not be very picky about the safety of a drug for Duchenne that works
  • Accelerated approval does not mean accepting data that is marginal--data must meet high standards
  • FDA--different things: 1. biomarker is reasonably likely to predict function and 2. evidence that the biomarker changes

International benchmarking of methods for dystrophin expression
Comments from Kevin Flanigan, MD

  • Kevin Flanigan argues that parallel techniques should be used for dystrophin quantification, but immunohistochemistry good

Dystrophin SILAM in the qualification process and the status of other non–dystrophin biomarkers
Comments from Eric Hoffman, PhD (CNMC)

  • Accelerated approval = faster/cheaper sustainable rare drug development.
  • How much dystrophin is enough is still a concern. Probably about 5% or more.
  • Can use isotopes to label dystrophin for better quantification using ratios
  • (dystrophin quantification) Mass spec more reliable than blots or immunofluorescence
  • In stage four of FDA process to qualify mass spec for dystrophin quantification
  • Eric Hoffman talks about effect of microRNAs on dystrophin expression -- PPMD funding this work
  • FOR-DMD trial may help get data for surrogate markers

MR Imaging as a surrogate endpoint in Duchenne
Comments from Lee Sweeney, PhD (UPenn)

  • Dr. Sweeney presented PPMD funded pilot data for imaging study to FDA
  • MRI gets around variability of severity in different muscles/parts of muscles--can see whole muscle.
  • In individual patients MRI shows that all muscles progressing over time but not all at same rate
  • MRI shows changes in muscle quality 3 mos. after starting steroids--may see changes in drugs that affect inflammation quickly
  • MRI shows that disease is progressing even when 6MWT is stable
  • Need consensus from FDA on how to use MRI as pharmacodynamics marker and maybe some day a surrogate marker

Discussion & submitted questions period 
Mark presented questions that were submitted from the community to the FDA. Their comments are below:

  • We actively engage in discussions with sponsors of drugs for Duchenne about biomarkers outside of the validation process—FDA
  • Need to understand how much dystrophin is made and how functional that dystrophin is –FDA
  • Pharmacodynamic marker can help support clinical findings even if it can't stand alone --Ron Farkas, FDA
  • Multiple biomarkers that move in the right direction might provide evidence for effect where a single biomarker does not –FDA
  • FDA: Help us understand what is most important to understand about dystrophin--localization? amount? -John Jenkins, FDA
  • Have seen many different methodologies for quantifying dystrophin--Need to fit pieces together. --John Jenkins, FDA
  • Can look at evidence across different diseases to support use of biomarker in a single disease –FDA
  • FDA agrees that Becker situation should be relevant to establishing significance of truncated dystrophin as a surrogate.
  • We have to wrestle with this phrase "reasonably likely" (on surrogates) -- Ellis Unger, FDA
  • We need to understand what happened with Drisapersen --John Jenkins, FDA
  • If dystrophin is such a reasonable biomarker why did drisapersen fail? Maybe some patients did better-FDA
  • Eric Hoffman (CNMC) cautions FDA not to use Drisapersen as basis of understanding dystrophin. Suggests phase II data weak
  • FDA questions baseline levels of dystrophin in Duchenne patients. Gives HDL situation as a biomarker that didn't work –FDA
  • The second the drisapersen data hit our servers we started looking at it --Ellis Unger, FDA
  • Craig McDonald (answering FDA question) tells FDA that exon 51 skippable patients comparable to whole cohort of patients

The discussion was then open to attendees who had comments or questions for the FDA:

  • Giles Campion of Prosensa suggests identifying right muscle to sample important, difficulty doing multi-center biopsies.
  • Allow subsets of patients doing well to continue to have access to drug--Debra Miller (parent)
  • What is time frame to review data for decision about using dystrophin as surrogate? --Tracy Seckler (parent)
  • FDA on time frame to review Drisapersen data--has a high priority--highest ever on anything--Eric Bastings, FDA


Session 4: Next Steps — Development of a draft guidance for optimizing clinical trials in Duchenne
Moderator: Pat Furlong

Draft European Medicines Agency guidelines
Comments from Annemieke Aartsma-Rus, PhD

  • Concerns about EMA guidelines--didn't use new data
  • Stakeholder meeting on EMA guidelines hosted by TREAT-NMD in June provided feedback to EMA
  • Feedback to EMA: slow down disease in older patients, high impact on patient and family, risk-benefit issues
  • Feedback to EMA: strength as co-primary endpoint not appropriate

A framework for the FDA Guidance for optimizing clinical trials in Duchenne
Comments from Tim Franson, MD

  • There is clearly a lot of energy here--we need to channel that into action now.
  • There are P values that go beyond statistics: predictability, and patient perspective for example.
  • On developing guidance: we need to understand ground rules, resources required, time line.
  • Alzheimer's Disease Guidance may provide template (for process, not because diseases are alike)
  • February 2014 around PPMD Advocacy days -- forum for further development of the Duchenne guidance

A Parent’s Perspective
Comments by Joanna Johnson, parent of Elliott & Henry

  • The truth is we are fighters
  • Worried about variability, may need longer trials but with no placebo, must consider burden
  • I am willing to take on the burden (of a trial) just to give my sons a shot.
  • Tomorrow will not be soon enough.

Closing Comments and Next Steps

Comments from Pat Furlong

  • I want to thank the FDA - I can't thank you enough for being here.
  • MD-CARE Act had a significant impact on this disease and we need to reauthorize it.
  • Would like to continue the discussion in February--invites all interested in helping with guidance to do so.
  • In between now and February we are going to be working hard and we invite you to work with us.
  • I hope that we will find a way to work together--a community divided will fall and I'm not interested in falling.


When the community was asked for final thoughts, Bob Gettler (parent) spoke:

  • I was worried you would pretend to listen and we would pretend we matter. But this was good. Thank you.

Related links

Read Pat's blog reflecting on yesterday's Duchenne Policy Forum

Share your story with the FDA

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Comment by Patti Frank on December 15, 2013 at 12:49am

So glad this is here to be able to read and feel what was going on in that room.  I look forward to seeing my NJ fellow parents at a NJ FACES holiday get together tomorrow and get more updates on all this. Also looking forward to having some good time with them as well and our kids.


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