Parent Project Muscular Dystrophy (PPMD) and a broad coalition of stakeholders have submitted the first-ever patient advocacy-initiated draft guidance for a rare disease to the FDA to help accelerate development and review of potential therapies for Duchenne muscular dystrophy.

"This landmark guidance represents a major milestone for the Duchenne community and may open the way for other rare disease groups to incorporate the patient perspective in a well-documented and quantifiable way, moving beyond any one family's experience," said Pat Furlong, PPMD president. "By working closely with the FDA to provide industry and other clinical trial sponsors with clearer guidance from the patient perspective, we will increase the likelihood that clinical trials will be designed to better match the unique needs of Duchenne patients. It is our profound hope that this, in turn, will lead to the approval of much needed treatments for all people living with Duchenne muscular dystrophy."

Duchene, a lethal genetic disorder diagnosed in childhood, is a progressive and degenerative condition with no cure or disease-modifying treatments available in the U.S.

Clinical trials for rare diseases such as Duchenne are difficult to design and implement because of challenges, such as small study populations; incomplete and evolving understanding of rare diseases; and effective ways to measure clinical impact of therapies being studied. Last year, the FDA collaborated with PPMD and its scientific advisors to convene a policy forum that informed the process for developing the Duchenne community's suggested guidance.

"The FDA is appreciative of the input of Duchenne patients and patient advocates. Their input will enhance the essential data-driven process and evaluation of new therapies," said Janet Woodcock, M.D., director of the Center for Drug Evaluation and Research at the FDA.

More than 80 representatives of the Duchenne community—including parents and patients, medical experts, academics and biopharmaceutical industry representatives—participated in seven working groups that met over the past six months to draft the guidance.

The cornerstone of the guidance encourages the FDA and sponsors to engage patients and their families at all stages of trial development and to take into account what they consider acceptable risk in clinical trials. A recent PPMD study published in the journal Clinical Therapeutics shows that parents of children with Duchenne will accept substantial risk when balanced with noncurative slowing or stopping of the progression of muscle weakness, even with no improvement in life expectancy. The results came from the first-ever scientific survey of benefit/risk perspectives that PPMD conducted last year involving 120 Duchenne parents.

"As the FDA evaluates New Drug Applications for Duchenne therapies, it is imperative to take into consideration the value that parent decision makers place on even moderate benefits to function and mobility, and their tolerance for considerable risk and uncertainty," said Furlong. "Parents and caregivers of Duchenne children know firsthand that every day without treatment is another day closer to their child losing essential activities of daily living such as walking, feeding oneself and, eventually, breathing. When your child is living with Duchenne, you find yourself willing to take significant risk for even the hope of modest benefit. Parents can make these decisions thoughtfully and the FDA must recognize that. They cannot protect us from what we think is important in the drugs we need now."

Each section of the guidance includes extensive published or in-press peer-reviewed articles and focuses on six areas aimed at overcoming the challenges in trial design and implementation:

• Benefit/risk assessment provides a community-centered approach for the benefit-risk framework fundamental to the regulatory process and reflecting the community's tolerance of potential risks or uncertainty of benefit associated with new treatment options.
• Diagnosis: referring sponsors to guidance produced by the American Academy of Pediatrics (AAP) on a diagnostic algorithm, as well as providing context on diagnostic delay and importance of genetic analysis using modern technologies, including access to genetic testing.
• Natural history accurately characterizes the clinical course of Duchenne to reflect the timing of the loss of certain abilities based on current medical management practices, including how Duchenne affects cardiac and pulmonary function.
• Clinical trial designs, outcome measures and considerations ensure that trials—to the degree possible—are inclusive of Duchenne patients of all ages and disease stages.
• Muscle biopsy-based biomarkers addressing key considerations when performing muscle biopsies, including the ethical imperative to perform them only when needed and precautions to assure usable specimens; sponsors also are referred to an international effort to standardize methodologies and emerging technologies.
• Non-muscle biopsy-based biomarkers explore the ability to bring non-invasive imaging techniques to replace biopsy (e.g., MRI/MRS skeletal muscle imaging) and eventually reach the goal of being a surrogate endpoint for treatment trials.

The suggested FDA guidance represents the culmination of PPMD's 20-year history of improving care and developing urgently needed therapies for Duchenne. PPMD led the effort to pass the MD-CARE Act, which created the Senator Paul Wellstone Muscular Dystrophy Cooperative Research Centers. The draft guidance builds on PPMD's effort to shape federal policy that reflects the needs of families living with Duchenne, including the release of "Putting Patients First," which calls on the FDA to act more flexibly when reviewing applications for Duchenne therapies.

PPMD also ensured the FDA Safety & Innovation Act of 2012 (FDASIA) responded to the needs of the community, recently published a groundbreaking benefit/risk study that documented the willingness of families to live with risk and held a national PPMD-FDA Duchenne Policy Forum at which the community made its needs and preferences in drug development known to the agency.