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  4. Dr Sharpless's remarks to the 2019 NORD Conference on Rare Diseases - 10/22/2019
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Event Title
Dr Sharpless's remarks to the 2019 NORD Conference on Rare Diseases
October 22, 2019

Speech by
Norman E. "Ned" Sharpless, MD
Acting Commissioner of Food and Drugs - Food and Drug Administration

Thank you for that kind introduction. I want to thank NORD for again hosting this important conference, and for inviting me to be here. 

It is an honor to speak to you during this important time in rare disease product development.

This organization plays such an essential role, bringing together the rare disease community to represent the needs and interests of patients, and advance the goal of finding new opportunities, treatments, and cures.

All you have to do is look around the hall and see the level of engagement and excitement and energy that’s percolating (along with a lot of coffee) – even at this early hour.

I want to thank all of you who are here today, whether you represent patient and health organizations, drug and product developers, clinicians and researchers, industry, or representatives of government agencies such as FDA and NIH. 

You’re here today to interact, collaborate, learn, and share information in pursuit of a common goal – developing and bringing new and better treatments to patients.

Most importantly, I want to thank the patients and their families who are here and who devote such a major part of your lives every day in the effort to find new treatments and cures. 

As someone who has spent the vast majority of my professional life researching and treating cancer, the challenge of rare diseases is something very familiar and very personal to me.

As you know, many cancers are rare cancers, they are rare diseases.

Appreciating that cancers come in this immense variety, rather than as a one-size-fits-all entity, well this appreciation has been one of the major movements of our field over the last two decades.

This move to precision therapy for cancers has been a key reason for so much of the success in cancer therapeutics of late. And it is a story of learning to consider cancer as not one thing, but a collection of many, many related diseases, many of which are rare diseases .

For example, virtually all pediatric cancers, which I spent a great deal of effort on when I was at NCI, are rare diseases.

So, the framework of rare diseases has informed, and been informed by work in cancer and the understanding that cancer is not one or ten diseases, but hundreds or thousands of diseases,

Each disease with its own cause, epidemiology, treatment and cure. 

Something else I learned from cancer research:  Rare diseases are not rare.

Taken one by one, they are, by definition of course rare, but viewed collectively they are not.

For cancer, the estimate has been about 1 in 5 patients with advanced cancer have what should be considered a rare cancer. 

So if you were an oncologist, you’d have to either be interested and ready to treat patients with rare cancers, or you’ll have to turn a lot of patients away.

A final comment on what cancer research has taught be about rare diseases:  sometimes, the progress in rare diseases can be rapid, and when this happens, it is wonderful.

For example, there are about 5,000 new cases per year of chronic myelogenous leukemia, what used to be a pretty terrible cancer. 

People with CML would quickly spiral into full blown acute leukemia, and then die of refractory cancer.

And then academic and industry researchers invented this marvelous new drug for that condition, imatinib, and the mortality from CML in the US has since plummeted.

It rapidly went from being an awful disease treated unsuccessfully with toxic therapies like bone marrow txplantation, to being a disease we successfully treat with a relatively non-toxic daily pill.

Progress in rare diseases can be wonderful when it happens, and from where I sit, it seems to be happening more and more.

And something I have learned from my time in federal service, be that at NCI or FDA.

Those agencies are not tasked with making life better for some Americans, or most Americans, but for ALL Americans

Therefore, we have the duty to find new and better ways of approaching the challenge of rare diseases.

We cannot leave any patient behind, which means we cannot leave research into any disease behind.  

Today, during my time with you, I think you will note a few recurring themes relating to how FDA is working to achieve this goal.

They first is the centrality of the patient in pursuing new treatments, the second is the value of developing better approaches to research and clinical trials; and the third is the importance of supporting these efforts, supporting through collaborative ventures, supporting from financial perspective, and supporting through use of regulatory flexibility. 


I think that a good place to start is with the recognition that rare disease therapies are being developed at a faster pace than ever before. 

Though we are far from where we want to be, I think it’s important -- as we gather here -- to remind ourselves of the successes we’ve already had. 

Let’s not lose sight of what we’ve already accomplished. 

Because let me tell you, I feel like the hard work of this group has already been paying off in an impressive way.

Since passage of the Orphan Drug Act in 1983, we’ve seen over 800 orphan products approvals. 

Last year alone, in what was another record-breaking year, we had 94 new approvals for orphan drug indications.

This included 35 novel drugs and biologics with orphan drug designation. 

This is the highest number in the history of the Orphan Drug Act! 

As 2019 draws to a close, we are on a pace to maintain these numbers, with 269 orphan designations of drugs and biologics and approvals of 14 novel (New Molecular Entities) orphan drugs and biologics. 

Let me offer a few of examples of the approvals we had last year. (I hate to leave any out, but there are far too many to name them all). 

But I think even a small sampling of the approvals will make clear just how wide-ranging the advances in rare diseases has been. 

For instance, our approvals included a new treatment for pediatric patients under age two with the most severe form of spinal muscular atrophy -- the first gene therapy for a neuromuscular disease. 

We approved a new drug to increase pain-free light exposure in adults who have a form of porphyria, a rare enzymatic deficiency causing disordered heme synthesis.

We approved a new therapy for certain patients with a specific type of non-small cell lung cancer, a new therapy for multiple myeloma, and a new cancer therapy for a very small number of patients whose tumors harbor a specific genetic marker.

This latter approval was remarkable from the FDA point of view because it is “tissue agnostic” meaning a patient would qualify for that therapy if they have a specific molecular event in their tumor, regardless of what tissue type of cancer they have.

This is an example of how FDA is being led by the science toward novel regulatory paradigms.

And we approved the use of a new treatment for the heart disease caused by transthyretin mediated amyloidosis in adults, which causes a rare and severe cardiomyopathy.

And just yesterday, we approved a novel “triple” therapy for Cystic Fibrosis (using priority review, Breakthrough Therapy, Fast Track and Orphan Drug designation); getting this approval done 5 months ahead of the PDUFA date.  That’s a wow!

In addition to these and the dozens of our other novel drug approvals, we also expanded the label to approve many drugs for new uses to treat patients with rare diseases. 

This, as you know, can be really important to patients living with rare diseases.

And I should point out another important benefit from this work on rare diseases, and one that is sometimes overshadowed in this discussion. 

That is that orphan drug research and development has led to important medical breakthroughs and furthered scientific understanding across a wide range of conditions beyond rare diseases. 

So please, keep doing what you’re doing.


But even as we remind ourselves of the successes, we are well aware of the challenges. 

The approval numbers, as good and promising as they are, are not…. good….enough. 

We know that the vast majority of rare diseases do not have an approved treatment. 

While the recent pace of discovery and advancement is impressive (and best of my lifetime), there is still a long way to go to address the unmet needs for patients living with one of the 7,000 rare diseases. 

Developing rare disease treatments still poses enormous scientific challenges with significant costs. 

The underlying challenge we face is very clear – size. 

By their nature, rare diseases have very small numbers of patients. 

This means that creating studies or clinical trials poses a bigger challenge than it does with common diseases and data collection too, can be a greater challenge. 

And it means that there is an even greater need to try to gain a fuller understanding of the underlying biology and natural history of the disease.

We are working to overcome these challenges in a variety of ways. 

First, and most importantly, we’re engaging our strongest asset:  the patient.

We know that we must understand what matters most to patients living with these diseases. 

To most effectively support the development of treatments, patients should be involved in the development process to inform our understanding of any given rare disease.

At the FDA we’ve made patient engagement a centerpiece of our efforts, and we’ve developed a number of effective ways to gain patient input.

I’ll mention three.

First is through our Rare Disease Patient Listening Sessions. 

This is an ongoing collaboration with NORD, which allows FDA to quickly engage with patients, caregivers, and advocates who have rare disease experience. 

The sessions are facilitated by the Patient Affairs Staff in the Office of the Commissioner, and they offer the community an opportunity to share individual experiences through direct conversation with the FDA staff. 

It enables patient voices to be heard, but also helps the FDA better understand the perspective of patients and advocates related to specific rare disease.

I want to encourage any patients interested in requesting a listening session to contact our patient affairs staff, some of whom are here today. 

Second, The FDA is also developing a series of four methodological patient-focused drug development (PFDD) guidance documents. 

This documents will support the use of systematic approaches to collect robust patient and caregiver input, that can better inform medical product development and our regulatory decision making. 

And third, this year we also held a public meeting titled “Patient Perspectives on the Impact of Rare Diseases: Bridging the Commonalities.”

This meeting offered an opportunity for FDA to hear about commonalities that patients with different types of rare diseases may have, including symptoms like pain, fatigue, sleep disturbances and effects on daily life. 

And we are further hopeful that the discussions from this meeting will support rare disease product development, through the  consideration of endpoints and trial designs that could be useful across multiple rare diseases. 

Funding Opportunities

Now I want to turn one of the other themes I mentioned in the work to find cures for rare diseases, and that is how to support them, specifically the cost.

Everyone here is well-aware of the challenge of finding the resources necessary to fund research on rare diseases. 

I experienced this on a personal level, seeing what a difference a serious commitment, particularly from a government agency can have.

Early in my academic career, I had the opportunity to serve on the board the Adenoid Cystic Carcinoma Research Foundation, a group trying to find a cure for Adenoid Cystic Carcinoma (or ACC), a rare cancer that affects about 1,000 Americans per year.

I became involved with this effort after the wife of a close friend developed the disease. 

The friend was my college roommate, Jeff, who quit his job and started a foundation to try to cure this cancer, and asked me to be on the board.

At the time when we started on this, there was almost zero scientific understanding of the disease, and very few scientists were even studying it, mostly because of a lack of funding for research.

There were no clinical trials, and no hope for the patients.

As you all understand, Jeff did everything one could to raise money to fund research on this disease. 

And I think he did a very good job, raising a few million dollars per year.

But then, through dogged advocacy, we got the NIH interested in this disease. 

And their interest eventually led to a $30 million program funding scientific grants on the topic. 

This drove a lot of new researchers into the field, and had a big scientific impact on our understanding of this cancer.

We still don’t have a cure for ACC, but we know a lot more about its biology, and now there are a number of clinical trials in progress, some showing promising signs. Now I am starting to feel hope for ACC.

Which leads me to another aspect of FDA’s support of rare disease product development – the funding we provide in support of rare disease research.

Our Orphans Products Grants Program provides support for natural history studies and clinical trials for rare diseases.

To date, this program has supported research that led to the marketing and approval of more than 65 treatments for rare diseases.

Recently, we announced 12 new clinical trial research grant awards – totaling more than $15 million over the next 4 years – to enhance the development of medical products for patients with rare diseases. 

More than 100 rare disease experts reviewed the scientific and technical merit of the grant applications, with the awarded grants focused on supporting product development for patients impacted by a variety of rare diseases.  

And something that I find especially pleasing:  three quarters of the of the new awards enroll children. 

And I’m pleased to say that the grant review process has been further enhanced by including patient representatives as reviewers. 

This provides that important patient perspective on whether something is a good grant or not. 

In addition to funding clinical trial research grants, FDA awarded two new research grants of over $4.1 million over the next 4 years for natural history studies in rare diseases (med thyroid cancer and Duchenne Muscular Dystrophy). 

This kind of information is critical to facilitating the design of efficient clinical trials to test future treatments. 

There’s another promising new source of FDA funding I want to mention that goes to one of my areas of focus – better usage of patient data.

The FDA’s Center for Drug Evaluation and Research (CDER) recently provided funding through a cooperative agreement with NORD and the Critical Path Institute (C-Path) for what is called the Rare Disease Cures Accelerator-Data Analytics Platform (RDCA-DAP).

It will house integrated patient-level data from diverse sources, including clinical trials, observational studies, patient registries, and real-world data (for example electronic health records) across a multitude of rare diseases.

Data will be contributed from different organizations and companies around the world.

The platform is an integrated database and analytics hub that will promote the sharing of existing patient-level data and encourage the standardization of new data collection.

The aim will be to receive, from a variety of sources, protected data that can inform disease characterization, clinical trial design and other critical questions in drug development. 

This will provide a resource through which authorized users (I mean disease researchers and drug developers) can access data about rare diseases and how they progress, in order to accelerate development of new therapies.

In so doing, the Rare Disease Cures Accelerator will facilitate a cooperative approach and a common standardized platform for rare diseases,

It will also incorporate the patient’s perspective in designing measures of clinical outcome, and build clinical trial readiness for rare dz in a pre-competitive space.

The Accelerator and the Orphan Products Grant Program strongly complement each other.

Together we believe they will help change the trajectory of rare disease product development.

Let me briefly mention one other FDA grant program. 

As part of our Patient Focused Drug Development (PFDD) efforts, we’ve developed a new pilot grant program to develop standard core sets of Clinical Outcome Assessments and endpoints for specific disease indications. 

Once developed these sets will be made publicly available at no cost or minimal cost.

In September, the FDA made three awards under this program, each of which will provide avenues to advance the use of patient input as an important part of drug development, fostering innovation and for the production of safe and effective drugs.  

The goal of working across diseases is also a goal of another new effort launched by The Orphan Products Grants Program, an interactive webinar called “Orphan Grantees Unite,”

This effort will connect current grantees to advance their shared research goals and further the development of orphan products along the route marketing approval. 

This initiative recognizes that while each rare disease involves specific challenges and considerations, there are plenty of commonalities when it comes to developing new therapies.

Each of the meetings within the webinar series will be an opportunity to discuss these common considerations that foster the successful completion of rare disease studies. 

They will also raise awareness of common research and regulatory issues, and address the most effective ways to handle them. 

So, as I hope you can see from this summary of some of the FDA’s rare disease funding opportunities, that we’re very focused on finding innovative ways to gain patient input, collect and aggregate patient data, and improve clinical studies.

Data Collection

This leads me to the next piece of the rare disease puzzle that I want to focus on today:  the importance of developing great data for our decision making. 

This is through the use of efficient endpoints and innovative study designs to collect robust, rigorous and interconnected data.

I’ve already stressed the role of patient input to provide therapeutic context for regulatory review. 

But patient input is also important regarding data collection too. 

It should inform the selection of the most valid clinical outcomes—what do patient care about.

It should ensure the appropriateness of instruments used to collect these data—are we using the right tool?

And it should ensure that investigations of the effect of treatments are effects that are meaningful to patients—is this therapy treating something the patient cares about or just treating the doctor?

Importantly, if sound data collection tools are used within clinical trials of an investigational agent, patient input itself can provide a direct source of evidence for the benefits and risks of a drug.

Data modernization is a priority to FDA, and we are looking at how we can continue to advance data modernization and integration to support rare disease product development.

We have a wealth of available data, but we are not necessarily able to use all the data. 

If we want to maximize the scientific potential, we must be able to free the data from cumbersome structures in which they may be trapped (think Electronic Health Records)…

And then combine and integrate these data in ways that can be used for regulatory decision-making.

We must turn big data into big smart data. 

Data that allows us to connect cutting-edge scientific discoveries to real-world products and solutions that make a difference in people’s lives.

So that’s why we’re supporting and building approaches that are helping establish new linkages between complex, multimodal data sets…

That can harness these real world data, through the use of novel analytical approaches.

This is important for lots of reasons, but one reason it is important for rare disease is that putting together a traditional clinical trial in a rare disease can be a major challenge.

Patient accrual can be difficult. 

But if we have the right data structure, we can learn from every patient, including those patients that happen to have rare diseases. 

Using trial designs informed by RWE will make trials of rare diseases more efficient, lowering costs and speeding accrual.

In the face of conducting trials for rare disease populations, I’m pleased to say innovation and appropriate regulatory flexibility for rare conditions has led to some success.

For example, our Center for Biologics approved in late 2017 Luxturna, a gene therapy treatment for patients with RPE65 mutation-associated retinal dystrophy.

Importantly, the approval used an innovative clinical trial design.

It was supported by safety and efficacy data from a randomized, open-label phase 3 study with a control arm that was crossed over to treatment at a one-year time point

This approval also relied on the use of a novel primary endpoint specifically developed for this product program.

I think this example shows that “Regulatory flexibility” is not just something we talk about at FDA, it is something we implement daily.

Regulatory Nimbleness

I’d now like to discuss a key way FDA promotes innovation in the rare disease space: by increasing use of expedited review pathways: Fast Track, Breakthrough Therapy, Regenerative Medicine Advanced Therapy, Priority Review, and Accelerated Approval.

These are pathways that Congress established to help speed the development of products to address unmet medical needs.

As someone who has been involved in drug discovery for a long time, I really like these pathways, and I aim to make sure FDA uses them. 

The number of orphan drug approvals qualifying for priority review or breakthrough designation suggest that these are having a positive impact on the rare diseases they treat.

Of the 49 novel orphan drugs and biologics FDA approved from the beginning of 2018 through October 15, 2019, we used at least one expedited review tool --- Fast Track, Breakthrough, Priority Review, or Accelerated Approval for 86% of these approvals – thereby supporting prompt access to patients in need.

And of the 115 Regenerative Medicine Advanced Therapy requests to date, 44 of those have been granted, and 27 of the 44 granted have Orphan Designation, involving mostly cellular therapy products and cell-based gene therapies.

These expedited reviews have moved forward a broad range of medical products.

I already mentioned the CF approval yesterday, but as another example, CDER recently approved a new treatment for tenosynovial giant cell tumor, a rare painful condition in which non-cancerous tumors grow around joint areas and cause damage.

The approval was based on the results of a multi-center international clinical trial of 120 patients, 59 of whom received placebo.

FDA had granted this application a Breakthrough Therapy designation, a Priority Review designation and an Orphan Drug designation. 

It illustrates how our expedited regulatory pathways and incentives can help address some of the challenges faced by small populations and still allow sponsors to obtain highly significant results.

Speed is certainly important, but what FDA does exceedingly well, I think, is to strike a balance between speedy approval of new products and the integrity of both the data and the process –

Approving newer, better, safer, more effective medical products while maintaining FDA’s gold standard for safety and effectiveness.  

This balance is particularly applicable to the world of rare diseases.


I have highlighted some of FDA’s work for rare dz’s; including record numbers of orphan approvals, use of innovative regulatory pathways, and funding of research grants,

But let me finish by now talking about our work to communicate our current thinking on a variety of rare disease topics through the publication of draft and final guidance documents. 

During the last year, we published a number of guidances, indicating our continuing commitment in the area of rare diseases. 

These include a guidance on the Rare Pediatric Disease Priority Review Voucher program, bringing additional clarity and transparency to the voucher review process for rare pediatric disease.

CBER last year issued a group of six draft guidance documents on gene therapy, including documents on gene therapy for rare diseases, hemophilia, and retinal disorders. 

CBER plans to finalize these guidance documents this year, along with guidance on long-term follow up, CMC, and testing for gene therapy products for replication competent retrovirus.

And, among other topics, CBER also plans to issue guidance on sameness of gene therapies for the purposes of the Orphan Drug Act

And CDRH recently finalized a guidance document on the FDA’s Humanitarian Device Exemption Program,

This program encourages the discovery of medical devices for use in diseases or conditions with limited patient populations, such as rare diseases.

This guidance should bring additional clarity and transparency to the Humanitarian Device Exemption review process. 

These are just a few of many areas where we are delineating current FDA thinking with regard to rare disease.

An Exciting Time

It is an exciting time for rare disease product development, one driven by so many scientific innovations. 

We are energized by the advances and opportunities as we work together to support rare disease product development.  

Finding new treatments and cures for rare diseases is an area of highest priority for the Agency, and we will continue to advance the agenda in this area. 

We are proud to be partners with NORD, as well as other rare disease organizations.

I’ll close with one last thought. 

I mentioned earlier that federal agencies like FDA and NIH are tasked to make progress not just in some diseases, but in all diseases. 

We can’t leave any patient behind, even or especially not patients with rare diseases.

Toward that end, it is sometimes very helpful to put patient names and faces on these diseases, it makes them harder to ignore, it makes them something we will face together.

To this end, I would like to invite all of you who are patients or caregivers to stop by Booth number 210 and have your portrait taken by our FDA photographer. 

We would like to use some of these in a future FDA publication in support of rare disease patients and advocacy.

It will help us keep the whole patient, not just the disease, in the forefront of our work to find safe and effective therapies for rare diseases.

I look forward to our continued work together

Thank you.

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