Today, I will be speaking with Treat NMD and European Medicines Agency (EMA) in response to their draft guidance on clinical studies in Duchenne muscular dystrophy. Elizabeth Vroom from Duchenne Parent Project in the Netherlands, Filippo Buccella from Parent Project Onlus in Italy, and I will be speaking on topics like clinical trials, inclusion criteria, and extrapolation. This is a critical opportunity for us to share important information with the European Union agency responsible for the protection of public health through the scientific evaluation and supervision of medicines.

I wanted to share with you the presentation I will be giving today. We are proud to represent the Duchenne community and I will keep you posted on any outcome:

We are honored to represent Duchenne families around the world and deeply grateful for this opportunity to discuss how stabilization of muscle degeneration and associated incremental changes affect the quality of life, first of all for the individual with the diagnosis, but also for family members and the community.


Over the last years we have learned that regulatory authorities - EMA, FDA and its members - value the opinion of patients and their parents. These important, pivotal agencies realize that parents provide unique and extensive expertise as well as personal experience when it comes to the clinical meaning of changes resulting from treatment with new drugs.  The awareness and invitations from regulatory agencies to listen to families, to have them share their opinion and experience, to learn about their lives, and to understand the impact and consequences of the condition is indeed very encouraging for us, parents and patients.  For this reason, we are happy to explain how patients (and parents) interpret the definition of a clinically meaningful difference. 


Decisions must necessarily be based on data and not emotion; though I thought I would begin with my own personal experience.

Both of my sons were diagnosed in 1984.  As infants, they were ‘floppy’ babies, without muscle tone.   If my grip was not firm as I picked them up, they would have slipped through my fingers.  They did not walk independently until they were 16 and 18 months respectively and Patrick, my youngest had considerable speech delay.   In 1984, steroids were not recommended.  Both of my sons lost ambulation before 9 years of age.    At that time, clinicians had the view that the onset of heart disease occurred in their 20s and were unwilling to listen to my concern about, what I believed, to be early signs of heart failure.  My sons died at ages 15 and 17 of heart failure.


As you watched the video, you have seen that Duchenne muscular dystrophy is a progressive disorder where patients lose muscle fibers, causing muscle breakdown every single day and at all ages. This muscle breakdown leads to progressive loss of function, one function after another. In general, one could state that slowing down or stopping the progression of the disease is the most meaningful to patients because it preserves their quality of life, delaying by months or years the next loss of function.


While improving or restoring function would be the ultimate objective, recent data from a pilot study, surveying 120 parents about benefit and risk in Duchenne muscular dystrophy, suggests slowing or stopping the progression as clinically meaningful... Within the study, a total of 16 concerns were identified, spanning issues associated with the child’s well-being, disease management, family impact, and parents’ well being. Overall, weakness as it relates to the loss of function was identified as the greatest concern.

For the younger patients, being able to walk, to stand, to be able to get up from the floor after a fall or to fall less; to have enough arm strength to open a door or to lift one’s arms to reach for an object; simple tasks, but activities of daily living that are important to preserve as long as possible. Maintaining  the ability to walk is a priority which seems quite obvious,  but it is important to recognize that when it becomes impossible to walk up or down one or more steps,  the individual will also be unable to step off a curb, walk across the street, and enter buildings with even a small threshold. If unable to get up from the floor, significant independence is lost as it then becomes unsafe for the individual to be alone, without assistance.  The loss of these abilities impacts the school experience, increases the risks as well as the fear of falling as their healthy peers run from classroom to classroom.  It often makes the children stand with their back against the wall watching other children play rather than participating in activities.  It is important to keep in mind; the longer patients are able to walk up and down a few steps, the longer they will be able to walk independently. 


Losing the ability to stand further compromises the quality of life.  It means the loss of the ability to transfer from chair to the toilet, from the bed to the chair, from chair to the car.  The social impact of loss of function is dramatic, negatively impacts the child’s confidence and impairs ability to make friends.  It increases social isolation and typically results in anger and frustration.


With the loss of ambulation, stability of the trunk and arm function becomes very important to maintain. Arm function impacts the ability to maneuver the chair, to eat, to comb hair, to brush one’s teeth, to take care of the simple tasks of everyday life.   As shown in the video, having the ability to put your hands on the table is an important function for the non-ambulant boys.  Keep in mind, the ability to maintain hand function is the individual’s ability to move from place to place in his chair as well as his connection to the world through technology.  Hand function is a bridge to prevent the social isolation that accompanies progressive, debilitating diseases. 


Preserving the ability to reposition while in bed, the simple task of turning from one side to the other is important as this ability has a major impact on the entire family.  Losing the ability to move in bed necessitates a member of  the family  to wake up several times each night, often between 6 and 10 times to reposition the individual which leads to a great deal of lost sleep and increased stress for both the patient and the parent. The ripple effect of the loss of function impacts the well-being and quality of life of the entire family.


In adolescents and adults, coughing is essential to clear the airway and to maintain respiratory function.  The inability to cough indicates increased weakening of the muscles of respiration because patients are unable to expel secretions and as a result, significant complications and deaths result from infection and pulmonary complications.  Finally, muscles become too weak to properly ventilate the lungs; night time ventilation is required and will ultimately be needed around the clock.


In some children and most adult patients, fatigue and pain have a dramatic impact on their overall quality of life and that of their entire family.


The lack of dystrophin has a negative impact on the heart as cardiomyocytes are replaced by fibrous tissue and fat, which leads to rhythm abnormalities and right sided heart failure. Deterioration of the myocardium is the primary cause of death.  Preventing or slowing the development of dilated cardiomyopathy or heart failure is essential for energy, for endurance, for quality of life, for survival.


Smooth muscle is also affected by the loss of dystrophin.  Very young patients may experience constipation as well as bladder frequency or urgency.  Similarly as adults, digestion can be impaired and patients often have significant problems with elimination. 

In progressive debilitating diseases such as Duchenne muscular dystrophy, the loss of function ripples throughout the family as primary caregivers and other family members accommodate for the loss.  The result is social isolation of the family as well as financial distress, as families struggle to cover expenses due to loss of income for the family as a family member will necessarily be needed to provide the required comprehensive care. 

Individuals with Duchenne muscular dystrophy want and need to be productive members of society.  It is important to realize that small changes - stabilization of disease no matter the age or degree of function - would make a meaningful difference in the lives of these patients and their patients, dramatically impacting the way these individuals feel, function and survive.


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Comment by Pat Furlong on July 7, 2013 at 8:41am

Peter, I apologize for the delay in my response.  The EMA meeting was not focused on a particular trial/compound.  Rather it was directed toward natural history data and what we have learned in terms of the 6mwt and its ability to predict 10% decline (30 meter decrease from baseline) and the correlation to Timed Function Testing (TFT) and North Star (NSAA).      Ataluren is currently recruiting their phase 3 confirmatory study.    Currently PTC therapeutics has an extension study that involves 80+/- boys in the US and more in Europe.  

Comment by Peter on June 22, 2013 at 5:42pm

Dear Pat,

Please lest us now more about the meeting, How your points evaluated by EMA members? especially  am interested in Ataluren, is there any progress on commercial availability of that drug?

Additionally I admit that all the points you presented are as my own.

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