FDA Perspective on Rare Diseases

Rich Moscicki, M.D., Deputy Center Director for Science Operations, FDA spoke to an audience of 75 senior physician executives from the Boston CMO Network on April 7, 2014.  The event was hosted by Sarepta Therapeutics at the company’s new headquarters in Cambridge, MA.

Dr. Moscicki focused his prepared remarks on  current CDER priorities, with particular emphasis on:

  • Rare Diseases
  • Paths for expedited review
  • Drug Shortages & Pharmaceutical Quality
  • Patient focused drug development

  • Rare Diseases

    Rare Diseases continue to be a major focus for FDA.  More than one-third of novel drugs approved in 2013 were for rare diseases. This continues a trend in recent years.  From 2008-2013, one-third of NMEs and original biologics product approvals have been for rare diseases.   This trend is expected to increase.

    A therapy is considered a targeted therapy if the inclusion/exclusion criteria in pivotal trials or the label indications are based on a genetic test, biomarker or susceptibility test.  An increasing percentage of new approvals are for targeted therapies, particularly with rare diseases.  In 2013, 80% of rare disease approvals were for targeted therapies.

    The growth in targeted therapies is creating orphan subsets within more common diseases, such as BRAF V600 mutation subsets of melanoma.  Drugs developed for these smaller subsets of populations will have smaller clinical development programs and are expected to have improved risk-benefit profiles.  They create a need for flexibility, novel trial designs, translational science development.

    Dr. Moscicki noted that every FDA reviewer goes through rare disease training and senior leadership meets frequently to share views. The Rare Disease Program in CDER is a small group that provides education, training, input and advice to divisions and reviewers.  This group tends to be more involved with smaller companies, helping them do the right thing.

    Paths for Expedited Review

    FDA has a number of paths for expedited programs including priority review, Fast Track, Breakthrough designation and Accelerated Approval. Rare Disease drugs are the majority in each category.  Of the 14 Accelerated Approvals in 2013, 13 were for rare diseases.

    Breakthrough Therapy is a new designation, established by FDASIA for expediting development and review for serious and life threatening diseases.  Breakthrough Therapies receive more attention, with senior leadership updated and involved on a regular basis.

    The industry has responded enthusiastically to this new program:

  • 138 requests for breakthrough designation have been received
  • 40 have been granted
  • 3 have already been approved, 2 of which were for rare diseases

  • Dr. Moscicki outlined some of the lessons that have been learned to date:

  • Some drugs have been late in development.  However, the intent and focus of the program is for drugs that are early in development
  • Manufacturing development & scale-up, not clinical development, is often the rate-limiting step for these drugs
  • It is a very resource intensive program at FDA. The number of requests and designations exceeded expectations
  • When breakthrough therapy designation is denied, the most common reasons have been:

  • Lack of clinical data or evidence is too preliminary to be reliable
  • Failure to demonstrate substantial improvement over available therapy
  • Reliance on a biomarker or surrogate endpoint without sufficient evidence of patient benefit
  • Post-hoc analyses of failed studies that identify a subset that may benefit, “the triumph of hope over evidence”

  • Drug Shortages

    FDA has been devoting a lot of effort to improving drug shortages.  Dr. Moscicki noted that 66% of drug shortages were due to quality issues.  FDA’s plan has focused extensively on early notification as the key to resolving drug shortages.  The agency is conducting risk-based analyses to determine ways of addressing shortages, including:

  • Determining if other manufacturers can increase production
  • Expediting inspections and reviews of submissions
  • Exercise of temporary enforcement discretion for new sources of medically necessary drugs
  • Working with manufacture to investigate root causes of shortages
  • Reviewing possible risk mitigation measures for remaining inventory.
  • These measures are beginning to prevent and reduce the number of shortages.  However, the industry needs to devote more effort and focus to improving manufacturing quality.  There is a proposal to initiate a new Office of Pharmaceutical Quality with the following principles:

  • Put patients first by balancing risk and availability.
  • Have one quality voice by integrating review and inspection across product lifecycle.
  • Safeguard clinical performance by establishing scientifically-sound and clinically relevant quality standards.
  • Maximize focus and efficiency by applying risk-based approaches.
  • Encourage innovation by advancing new technology and manufacturing science.
  • Put Quality over Compliance
  • Attention on how well drugs are manufactured
  • Metrics, ie lot failure
  • Create an ability to examine Quality across the industry

  • Patient-Focused Drug Development

    Patient-focused drug development is part of FDA commitments under PDUFA V.  The agency is particularly interested in hearing from patients to help understand severity of condition, degree of unmet need and risk tolerance.

    The agency is convening at least 20 meetings on specific disease areas to gain patient perspectives.  The 2013 meetings included narcolepsy and muscular dystrophy.

    The agencies focus for meetings in FY 2014-2015 will be:

  • Alpha-1 antitrypsin deficiency
  • Breast cancer
  • Chronic Chagas disease
  • Female sexual dysfunction
  • Fibromyalgia
  • Hemophilia A, Hemophilia B, von Willebrand disease, and other heritable bleeding disorders
  • Idiopathic pulmonary fibrosis
  • Irritable bowel syndrome, gastroparesis, and gastroesophageal reflux disease with persistent regurgitation symptoms on proton-pump inhibitors
  • Neurological manifestations of inborn errors of metabolism
  • Parkinson’s disease and Huntington’s disease
  • Pulmonary arterial hypertension
  • Sickle cell disease

  • Summary Q&A Session

    Dr. Moscicki summarized his prepared remarks noting that CDER initiatives in drug shortages, pharmaceutical quality, expedited reviews, pediatric rare disease vouchers, and patient informed decision making should have a significant impact on rare disease drug development.  Rare Diseases have always been a leader in innovation and will continue to do so.

    During a lively Q&A session, Dr. Moscicki touched on some additional topics:

  • Sponsors developing drugs for rare diseases sometimes encounter difficulties with the reviewing division. Dr. Moscicki suggested that it is a good idea to get the Rare Disease Program involved, along with the review division.  You can also request senior management attendance at meetings.
  • The Sentinel Initiative – This new program will be looking at safety signals via claims databases for over 150 million lives.  The results will be made public.
  • Unlike pilot programs in Europe, Dr. Moscicki does not expect FDA to collaborate on decision making with payers unless mandated by Congress.


  • About the Boston CMO Network

    The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.



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