Good morning.  I’m delighted to be with you again.

As this remarkable and diverse gathering convenes to help shape and support the search for new treatments and cures for rare diseases, I think it’s helpful to recall the historical background of this important collaborative effort, which began more than 40 years ago.

It was a time of extraordinary developments in scientific research leading to many therapeutic advances.  Accompanying this scientific ferment, however, was a growing realization that due to the economic hurdles for developers, sponsors were focused on common, rather than rare diseases.

What this meant, as one prominent geneticist, George Brewer, said at the time, was that millions were being “disenfranchised by American medicine.”

This awareness led to efforts to change the paradigm and spur the development of products specifically focused on meeting the needs of patients with rare diseases. 

At the FDA, for instance, we created the Office of Orphan Products Development, to focus on these patients and the development of products needed to treat them. 

Even more significant was the development of a grass roots movement comprised of patients, advocates, and others. This would lead to the creation of NORD, and, ultimately, the passage of the Orphan Drug Act, (or ODA).

That groundbreaking law was designed specifically to provide incentives for the development of drugs for patients with rare diseases, and to help ensure that everyone with an illness would one day have the safe and effective diagnostics and therapies they need.  

The ODA  has changed the face of drug research. Since it was enacted, we have approved over 500 unique drugs for the treatment, diagnosis, or prevention of more than 1000 orphan indications.  And the trend, both for designation requests and approvals for orphan drugs, continues upward.

This last fiscal year, the FDA approved approximately 90 drugs to treat orphan indications for a wide range of conditions and diseases. 

For example, our Center for Drug Evaluation and Research approved Lonafarnib or Zokinvy to reduce the risk of mortality in patients with Hutchinson-Gilford Progeria Syndrome, a rare condition caused by a genetic mutation that leads to premature aging, and fosdenopterin (or Nulibry), to reduce the risk of mortality in patients with Molybdenum Cofactor Deficiency Type A. 

And approvals by our Center for Biologics Evaluation and Research orCBER included two new products for rare cancers in adults, Breyanzi (or lisocabtagene maraleucel) and Abecema (or idecabtagene vicleucel). 

Both of these products involved the use of CAR-T cells, a promising treatment created using a patient’s own immune system to help fight cancer. The patient’s T-cells, a type of white blood cell, are collected and genetically modified to include a new gene that targets and kills the cancer cells.

Additionally, in June, CBER approved Ryplazim, or plasminogen, for treatment of patients with hypoplasminogenemia.  This is the first FDA-approved treatment for this rare disease, which has an estimated prevalence of 1.6/1,000,000 in the general population, with the majority of severe manifestations occurring in the pediatric population. 

These are important developments which, it’s worth noting, each involved the use of successful FDA review pathways designed to allow for expedited consideration that help get more drugs to more patients more quickly.

Of course, we have a long way to go.  Despite significant advances, most rare diseases continue to lack an FDA-approved treatment and there remain numerous obstacles for investment in research and development of these drugs.

One way we’re working to overcome these hurdles is by providing important funding for clinical trials and natural history studies to advance rare disease medical product development.  In the most recent grant cycle, the FDA awarded 11 new clinical trial research grants to principal investigators from academia and industry totaling over $25 million, including a number of studies enrolling children, newborns and others for the study of rare brain cancers.

We also continue to build on our 2020 reorganization that included the creation of an Office of New Drugs rare diseases hub in the Division of Rare Diseases and Medical Genetics.

And we continue to apply a number of changes Congress has made to help strengthen the law.   

In 2016, for example, the 21 Century Cures Act created the Regenerative Medicine Advanced Therapy (or RMAT) designation, which offers a new expedited option for certain eligible biologics products.

As of last month, CBER has granted 64 RMAT designation requests, half of which are for investigational regenerative medicine products that also have orphan product designation.

This year CBER approved the first two products with RMAT designation, one of which was BREYANZI, one of the CAR-T cell product approvals I mentioned previously.

The challenges involved with rare disease are significant and unique.  To meet the needs of a community forced to operate under a different paradigm, and spur development of new drugs while helping to ensure that those products get to the patients who need them, we have to do things differently … try new approaches, and use new and modern technologies to enhance innovation.

One area where this plays out in the rapidly evolving world of biologic products.  Our goal is to expand the availability of these potential treatments by carefully evaluating the criteria for determining whether a new product is impacted by a currently approved product’s exclusivity and when a product can be made available as a biosimilar.

Gene therapy offers great promise for a growing number of devastating rare diseases caused by a single genetic mutation.  Because the number of individuals diagnosed with a genetic rare disease is extremely small, development of a gene therapy product for the disease is likely to be avoided by most developers, because it would not be considered economically viable.

We recently issued final guidance on how we determine exclusivity and sameness relating to gene therapy.

The FDA also is working to encourage investment and innovation in this area.  For instance, CBER’s Individualized Therapeutics Program is designed to support the development and availability of gene therapy products for devastating rare diseases that affect very few or even one individual.

Another example involves Bacteriophages therapy, which uses viruses that kill bacteria.  Research is being conducted to apply these viruses to treat drug-resistant bacterial infections in patients including Cystic Fibrosis patients with lung infections.

One of the most important aspects of our work, that cuts across all of these areas, is our continued focus on the role of the patient in the evaluation of drug development and treatment. Patient engagement is necessary from the earliest stages of development, including, for instance, the design of clinical trials and the frequency of study visits.

The FDA has a number of programs designed specifically to support patient engagement in the rare disease community. 

Our Patient Listening Sessions program, run in collaboration with NORD and the Reagan-Udall Foundation for the FDA, allows for small, informal meetings between patients and FDA staff.

Since late 2018, when the program began, our Patient Affairs office has organized over 45 Patient Listening Sessions.  This past fiscal year alone, we held 20 Patient Listening Sessions on topics addressing a variety of diseases, including Gorlin Syndrome, Glycogen Storage Disease, Limb Girdle Muscular Dystrophies, Juvenile dermatomyositis, and Ichothyosis.

These allow us to hear directly from patients and their loved ones about the most significant symptoms of their condition, the impact of the condition on daily life, and their current approaches to treatment. 

To support innovation and quality in the drug development pipeline for rare diseases, the FDA established a “Rare Disease Cures Accelerator” in partnership with NORD and C-Path. Through this program, coordinated by CDER, FDA is working to facilitate a cooperative approach and common standardized platforms to better characterize rare diseases, inform drug development, incorporate the patient’s perspective in clinical outcome assessment measures, and build clinical trial readiness in the pre-competitive space, across multiple therapeutic areas.

Sometimes, necessity forces us to try new approaches.  For instance, as part of our response to the COVID-19 pandemic, we saw advances in a number of areas that could also have benefits for rare diseases. 

For example, we saw a large move toward telemedicine and remote study visits which represents a big step forward for rare disease patients.  More widespread use of remote study visits can reduce the burden for rare disease patients to participate in certain trials, including global trials, and thereby increase the number of patients enrolling in these trials. The faster these trials enroll, and the more complete they are, the sooner we can find answers and get treatments to patients.

Another development growing out of the pandemic of potential benefit in the context of rare diseases is our increased use of different types of clinical trials, such as umbrella and platform trials.  These trials include the scientific benefits of a randomized trial but can reduce the number of patients needed in the control arm because they can allow patients to rapidly be reassigned from ineffective treatments to potentially more effective treatments.

These developments have important implications for the challenges posed by rare diseases because they share some of the same special benefit-risk considerations.

As a recent guidance we issued explained, when a drug is developed to treat serious diseases for which there are few or no approved therapies, greater uncertainty or greater risks may be acceptable, provided the substantial evidence standard has been met. 

For this reason, in these cases, the FDA often exercises greater regulatory flexibility, in particular by accepting clinical trials that have lower sample sizes.  It allows for patient contribution to be optimized in small sample size studies while minimizing bias and maximizing precision with trial design features such as randomization, blinding, enrichment procedures, and adequate trial duration.

COVID-19 has taken a particularly hard toll on the rare disease community, and I’m hopeful that the success of platform trials, as well as some of the other efforts undertaken during the pandemic, will help shift how drug developers think about these approaches, and provide some important support for our work in rare diseases.

During my remarks today, I’ve discussed a number of different areas of the FDA’s work in rare diseases.  And I know you’ve heard from a number of other FDA leaders in greater detail on some of these and other topics. 

But what I hope you gather from all of this is just how committed we are to doing what is necessary to deliver on the promise of science in order to protect the health of all patients, and to support you in the work to develop new or better treatments for rare diseases. 

The challenges are great.  But thanks to your efforts in response, we’ve made enormous progress.

As Abbey Meyers, NORD’s first leader once explained, this group would probably not be as effective and cohesive as it is, if it had not faced opposition at every turn.

So, keep up the great work.  We’ll be there working alongside you. 

Thank you for attention. I hope you have an excellent and productive meeting.