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A Pivotal Moment for the Treatment of Rare Diseases

Speech by Margaret A. Hamburg, MD

Commissioner of Food and Drugs
NORD Rare Diseases and Orphan Products Breakthrough Summit
Alexandria, VA

Address by Dr. Margaret A. Hamburg to the NORD Rare Diseases and Orphan Products Breakthrough Summit


October 22, 2014

Thank you Peter (Saltonstall) for that kind introduction.  I am delighted to join you for NORD’s Breakthrough Summit. I want to thank this organization for so effectively representing the rare disease community and for collaborating on many issues of common interest.

I also want to acknowledge the work of Wayne Pines of APCO, who has helped organize this meeting and who has long played an important role in this field. He has also advised and guided the work of some five different FDA commissioners, including myself (and for which I am grateful).

It is a pleasure to be part of this impressive conference, which brings together experts on orphan product innovation from across government, industry, the research community, patient organizations, health organizations and more. The synergy created by having all these different participants talking and working together is extraordinary. You should all be congratulated.

Meeting the needs of patients with rare diseases is such an important issue, and one that I have cared about throughout my career. Time and again, in working with patients and families struggling with a rare disease, I have been touched by their struggle and struck by their persistence to gain information — whether about the disease itself, about finding the right physician or health care center, or getting the right treatments. It is truly inspiring to see, in the midst of deep heartache, and often confusion and frustration, the determination to find answers and the best possible care. The stories move me today as FDA commissioner just as much if not more as they did when I was a young medical resident in training.

At FDA, we certainly see ourselves as a committed partner in this effort. And we’re proud of what we’ve accomplished and what all of you have accomplished, though we know there is much more to be done.

I know yesterday you heard from top officials within our center for Drug Evaluation and Research, including CDER’s distinguished director, Dr. Janet Woodcock.

And shortly after I conclude my remarks this morning you will hear from a full panel of FDA officials, led by the head of our Office of Orphan Product Development, Dr. Gayatri Rao, who does such a remarkable job leading a very talented group of scientists.

The extraordinary quality of the FDA representatives at this meeting underscores both the agency’s scientific and medical expertise, and our commitment and focus in the area of rare diseases.

And, I want to thank NORD for its continuing support of FDA, particularly for helping to ensure that we have the resources necessary to maintain and strengthen the work we do. Your understanding of FDA’s unique and essential role and the backing you’ve provided for our efforts–whether to incentivize the development of products for rare diseases, enhance the scientific resources of our work, or increase the flexibility in how we take on our public health and regulatory responsibilities–is extremely important. This is especially true at a time of increasing demands and decreasing budgets.

And the world seems more complicated than ever. As we meet here this morning, headlines scream of a ravaging disease, Ebola, which is, in fact, a rare disease. The toll of this epidemic in West Africa is heartbreaking and tragic, and is further complicated because there are no treatments or vaccines shown to be safe or effective for the virus, though there are some products in the early stages of study.

Working closely with colleagues in government as well as the scientific community, industry, and a range of other organizations, the FDA has a critical role in the response, including to help facilitate the development, testing, manufacture, and availability of investigational products for use in diagnosing and treating and preventing Ebola.

FDA is doing all it can to facilitate access to these products as clinical circumstances warrant, working with sponsors and health care providers. We are responding as flexibly as we can, using mechanisms to enable access to investigational medical products when appropriate, after the risks and benefits have been weighed. We are also helping to develop more formal studies to assess safety, efficacy and overall benefit of products as quickly and efficiently as possible.

In August, FDA designated the drug Z-Mapp as an orphan drug for Ebola, with the hope that this would incentivize further development and study of that drug. But while other treatments might qualify for orphan status, it is unlikely that a vaccine would, since it is intended to be protective and therefore, by its very nature, would have to be administered to a much larger population in infected areas to evaluate its safety and effectiveness.

As you know, numbers play a very important role in the world of rare diseases. It is the nature of a “rare” disease – both by the common and legal understanding of that word — that it affects only a tiny fraction of the population. Indeed, even the moniker of a disease as an “orphan” reflects the challenge faced in spurring development of medical products to address conditions for these relatively small populations.

This categorization can also be a bit misleading. When we discuss a rare disease, we refer to the number of those people who have an individual disease. That number, in medical terms, is relatively small.

But as you understand, there are about 7,000 different rare diseases. And so when you “do the math,” as the saying goes, you know well that while each disease may be rare, taken together there are 30 million people in the United States with some form of rare disease — or almost one out of every ten people in this country.

In addition to the danger of understating the impact of rare diseases there is also a risk — as with any disease — that we will lose sight of the individual patients who comprise these statistics. It is essential that we maintain a focus on those whose lives are directly affected by these diseases and who, together with their families and caregivers are desperately searching for the breakthroughs and advancements that can offer a treatment option where none previously existed to at least slow their disease progression or actually result in a cure.

We face enormous challenges in the battle against rare diseases. Far too many of these illnesses still have significant unmet medical needs. And yet, even recognizing the gaps, we have made great progress in the development of new drugs and other treatment options.

Indeed, thanks to several interrelated factors — including our expanding understanding of the biology of many of these diseases and the molecular mechanisms that drive them, the increased development of targeted therapies, the growing number of incentives and expedited programs for serious conditions and other tools available to FDA that are helping to spur investment and innovation in new medical products for rare diseases — I believe this is a pivotal moment for the treatment of rare diseases.

Consider that since the enactment of the Orphan Drug Act, more than 3,000 products have received orphan drug designation and been eligible to benefit from the associated financial incentives for development. And more than 460 drugs for rare diseases have been developed and approved for marketing.

In addition, over 530 clinical trials have been supported through more than $330 million in grants from FDA’s OPD Grants program, which supports the clinical development of drugs, biological products, devices, and medical foods for rare diseases. This has resulted in more than 50 medical product approvals.

Another, much newer program, the Pediatric Device Consortium Grants program, provides grants to advance the development of pediatric medical devices. Nearly $15 million has been awarded since 2009, providing support on about 450 pediatric medical devices.

And the pace is increasing. Last year alone we received more than 100 grant applications through these two programs. Even more significantly, last year we reviewed a record number of requests for orphan drug designations. We have already broken that record this year and are still facing most of the fourth quarter, traditionally the busiest time for designation requests.

Today I want to talk about some of these exciting developments and what FDA is doing to build on progress made. We’ve worked hard in recent years to reposition the FDA to be a stronger, more effective agency for the 21st century, responding to the opportunities of the science before us to modernize, streamline and strengthen the regulatory process along the entire development, review and product oversight continuum. We’ve added flexibility and innovative new approaches by rethinking and even reinventing the way we do business.

Our goal is to reduce medical product development times to ensure that patients receive promising products as quickly as possible, while adhering, of course, to our high standards for safety and efficacy.

For rare diseases, providing orphan drug incentives to industry to develop products where none exist or to create better products where they do exist is enormously beneficial; but so is enhanced guidance to help shape the R and D agenda, early input on clinical study needs and design, expedited regulatory pathways, and targeted assistance for important products and unmet needs.

And these approaches are working. While we will be analyzing recent trends more closely in the coming months, it is clear that drug developers are taking good advantage of the various incentives and programs provided by our orphan drug designation program. And I should point out that even as the activity and responsibilities of the Office of Orphan Products Development continues to grow by leaps and bounds, there has been no comparable growth in staff to meet increased demand–a gap that does need to be addressed.

But NORD should be incredibly proud of your instrumental role in getting the Orphan Drug law in place. You should take great satisfaction in seeing how well many of the incentives included in it are working.

And in a related realm, we are establishing new policies to encourage industry to invest in and develop new products for pediatric rare diseases. While about half of all rare diseases affect children, for many reasons, the development of drugs, biological products and devices for pediatric rare diseases has been more challenging than for rare diseases more generally.

Just this year, we issued a strategic plan outlining how the agency will continue to encourage the development of therapies for pediatric rare diseases. This effort builds on a number of laws focused on the needs of the pediatric population that have been enacted over the past decade or so, from the Best Pharmaceuticals for Children Act (BPCA) to the Pediatric Research Equity ACT (PREA), to the Pediatric Medical Device Safety and Improvement Act (PMDSIA), which have provided various incentives to develop products for children with rare diseases.

The most recent of these, included two years ago in FDASIA, was the Rare Pediatric Disease Priority Review Voucher (PRV) program, designed to encourage the development of drugs for pediatric rare disease.

Under this program, which patient advocates helped create, the sponsor of a drug for a rare pediatric disease may be eligible to receive a voucher upon approval of the drug, which can then be redeemed for priority review of another drug application. The goal is to provide new incentive to industry to pursue investments and take risks needed to make a difference in the lives of the children with these rare diseases.

Earlier this year we approved a drug that received the first voucher under this program. Vimizin (elosulfase alfa), the first FDA-approved treatment for Morquio A syndrome, a rare, autosomal recessive lysosomal storage disease.

After receiving the voucher, the recipient then sold it, in keeping with the program’s intent. The proceeds from that sale will allow the company to make additional investments in research and development that will, hopefully, help seriously ill children.

The incentives we provide for product developers are just part of what we have been doing to facilitate and expedite availability of new drugs that address unmet medical need, drugs that are often aimed at treating rare diseases.

Over the years we’ve developed four expedited drug review programs: fast track, priority review, accelerated approval and most recently, the breakthrough therapy designation. And drugs for rare diseases have been able to take advantage of them all.

Our Center for Devices has also been pursuing various strategies to streamline and modernize review processes and has proposed an expedited program. A draft guidance issued earlier this year calls for a voluntary program that would speed to market products that meet unmet needs for life-threatening or irreversibly debilitating diseases or conditions.

I know some of these programs are addressed in greater detail during some of your sessions, but I want to underscore that our goal is not just to speed product review times once applications come through the door, but to provide meaningful help and direction early in the development process.

It is increasingly clear that everyone benefits from early and continuing engagement of FDA with researchers and product developers. Not surprisingly, one of the most important features of our new breakthrough designation is the intensive guidance developers receive, potentially as early as when the IND is first submitted, offering timely advice and interactive communications to help the sponsor design and conduct a drug development program as efficiently as possible.

We’ve already seen positive results from the Breakthrough Therapy Designation. As of the beginning of this month, we had received some 211 requests for breakthrough designation, and granted 63.  And since Congress established this program in 2012, FDA has approved 9 new drugs for breakthrough designation and 4 new indications.  Of those, 11 have been for rare diseases.

This is indicative of our broader success in approvals of cutting-edge, innovative therapies for rare and pediatric diseases, as well as common disease therapies that are repurposed for rare diseases. Last year, for instance, FDA approved 33 orphan drugs. Of the 27 new molecular entities approved, one third – nine – were for orphan drugs.  And this year we’ve already approved more new molecular entities for rare diseases than we did all last year — 11 out of 29. As I suggested, this is clearly an area of considerable and growing activity.

It is also an area where we have tried to be as creative, though scientifically rigorous, as possible. Two years ago, a study commissioned by NORD analyzed all of FDA’s orphan drug approvals since the beginning of the program, and found that FDA historically exercised regulatory flexibility in approving therapies for Americans with rare diseases.

Yesterday, an updated analysis was released and I was pleased, though not surprised, to learn that FDA continues to be flexible and responsive to needs.

We understand that allowing the use of a wide range of flexible study designs including single-arm studies when patient populations are extremely small, as with some orphan diseases, and when the natural history of the disease is well-characterized, can lead to enormous beneficial effects.

When appropriate, for example, we encourage the use of “adaptive” trial designs that allow design modifications as information about drug response accumulates. This can lead to more efficient studies or “enrichment” strategies to enroll patients more likely to respond to drugs under study, thereby reducing trial size and helping to direct drugs to patients who will benefit the most from them.

Now there will always be naysayers who find fault with the actions we take. And certainly some have criticized our flexibility as a loosening of standards. That is simply not so, but it reminds me of what I was told when I took this job: that there are two ways FDA approves products – too fast, and too slow.

We recognize that we must balance the eagerness to find ways to get promising treatments to patients as quickly as possible—especially for those with limited or no options–with the need to provide assurance that the benefits of these treatments outweigh the risks.

That’s why – as we adapt and improve models and timetables to help patients get earlier access to promising new drugs or to speed up clinical trials through innovative approaches – we ensure that these approaches meet our usual rigorous and high standards for the demonstration of safety and effectiveness.

One area of medical science that offers extraordinary potential to drive new opportunities and discoveries for the treatment of rare diseases is the development of Personalized or Precision Medicine. This potential is due both to the smaller populations affected by these diseases and the high percentage of rare diseases that are genetic in origin.

Personalized Medicine approaches can generate the kind of specialized data necessary to identify genetic differences, and encourage the development of therapies targeted and tailored to the specific characteristics, needs, and preferences of individual patients and their diseases, helping to transform their prevention, diagnosis and treatment.

It’s why we’ve been placing greater emphasis on such approaches, working to develop the scientific expertise and to adapt our regulatory infrastructure to respond to – and anticipate – scientific and medical advances.

Since 2011, one-third of the drugs FDA has approved have included genetic or biomarker data. And because we made this area a priority a number of years ago, we are far better prepared for the growing number of submissions for personalized therapeutics and diagnostics that we receive for review. This is making a real difference for rare diseases.

Generally when we talk about personalized medicine, we’re speaking about the unique genetic makeup of individual patients and their disease. But when we think about rare diseases, there’s another aspect of individual focus that is important. This involves our efforts to strengthen the patient’s role in our understanding of disease, its treatments and what more is needed.

The satirist and playwright Moliere wrote that “Doctors pour drugs of which they know little, to cure diseases of which they know less, into patients of whom they know nothing.” Now that’s not the way it is.

We are certainly learning more every day about the nature and biology of disease, and we are clearly developing new and better treatments for many diseases. But no matter how successful we are in these areas, our responses to these diseases will be incomplete – and indeed weakened — if we do not fully engage the patient’s view and knowledge.

NORD has long advocated such an approach. And I’m pleased that FDA is increasingly making this a priority as well, particularly as it relates to the patient’s role in the medical product development and approval process.

Initiatives like the Patient-Focused Drug Development (PFDD) program, for example, are designed to allow us to more systematically obtain the perspective of real patients on certain diseases and their treatments.

Through this program we hear directly from patients, patient advocates, and caretakers about the symptoms that matter most to them, the impact these diseases have on patients’ daily lives, and actual patient experience with currently available treatments. And this is more than just stories… this information is critical to FDA’s decision-making, especially how we think about unmet needs, outcome measures and, importantly, risks and benefits.

We’re also working to expand patient input on the development of devices. For example, we are working on creating a Patient Engagement Panel as part of the Medical Device Advisory Committee to serve as a body of experts to provide feedback, advice, and recommendations to the agency on a number of cross-cutting issues. We are currently working with NIH, NORD and other groups to conduct an assessment of device needs for rare disease patients, including diagnostics, and we look forward to completion of this review.

I want to mention one other project focusing on patients that FDA is supporting. It is a database being developed by NORD and the Von Hippel Lindau Alliance, which will help researchers searching for potential new treatments to learn more about the “natural history” of the disease.

Having such a resource can yield vital information about biomarkers, demographic, genetic, and environmental factors that correlate with the disease, as well as helping to identify patient subpopulations with different characteristics and effects.

We hope that this database will better serve the needs of patients with Von Hippel Lindau disease and help foster the development and testing of new treatments, but it can also serve as a model for partnership, collaboration, and science in other areas of rare disease.

So as I close my comments today, I hope that I have made it clear that we are working hard at FDA to prioritize the study of rare disease and develop the necessary knowledge, tools and approaches that will offer new and more effective treatments and cures…and we are prioritizing the importance of partnership.

That’s where all of you come in.  Because no matter how much FDA streamlines and modernizes our regulatory pathways to encourage industry … No matter how much we leverage the opportunities in science today … we cannot do it alone.

To effectively address the serious and unmet needs before us will require a collaborative effort that involves real partnerships, innovative strategies, and a joint commitment to understanding and advancing the field.

All of you in this room represent a potent force for finding solutions to the medical challenges before us. So I urge you — as patients, advocates regulators, health care professionals, scientists, members of industry, and policy makers – to work together find the answers we need to provide better treatments and care to these patients – the 30 million people who have rare diseases … and the single patients who are courageously battling their illnesses.

I look forward to working with you to achieve these goals.

Thank you.

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