- TREATING RARE AND NEGLECTED PEDIATRIC DISEASES: PROMOTING THE DEVELOPMENT OF NEW TREATMENTS AND CURES

[Senate Hearing 111-1147]
[From the U.S. Government Publishing Office]

S. Hrg. 111-1147

TREATING RARE AND NEGLECTED PEDIATRIC
DISEASES: PROMOTING THE DEVELOPMENT
OF NEW TREATMENTS AND CURES

=======================================================================

HEARING

OF THE

COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS

UNITED STATES SENATE

ONE HUNDRED ELEVENTH CONGRESS

SECOND SESSION

EXAMINING TREATING RARE AND NEGLECTED PEDIATRIC DISEASES, FOCUSING ON
PROMOTING THE DEVELOPMENT OF NEW TREATMENTS AND CURES

__________

JULY 21, 2010

__________

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Pensions

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COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

TOM HARKIN, Iowa, Chairman
CHRISTOPHER J. DODD, Connecticut MICHAEL B. ENZI, Wyoming
BARBARA A. MIKULSKI, Maryland JUDD GREGG, New Hampshire
JEFF BINGAMAN, New Mexico LAMAR ALEXANDER, Tennessee
PATTY MURRAY, Washington RICHARD BURR, North Carolina
JACK REED, Rhode Island JOHNNY ISAKSON, Georgia
BERNARD SANDERS (I), Vermont JOHN McCAIN, Arizona
SHERROD BROWN, Ohio ORRIN G. HATCH, Utah
ROBERT P. CASEY, JR., Pennsylvania LISA MURKOWSKI, Alaska
KAY R. HAGAN, North Carolina TOM COBURN, M.D., Oklahoma
JEFF MERKLEY, Oregon PAT ROBERTS, Kansas
AL FRANKEN, Minnesota
MICHAEL F. BENNET, Colorado

Daniel Smith, Staff Director
Pamela Smith, Deputy Staff Director
Frank Macchiarola, Republican Staff Director and Chief Counsel

(ii)

C O N T E N T S

----------

STATEMENTS

WEDNESDAY, JULY 21, 2010

Page
Harkin, Hon. Tom, Chairman, Committee on Health, Education,
Labor, and Pensions, opening statement......................... 1
Enzi, Hon. Michael B., a U.S. Senator from the State of Wyoming.. 2
Dodd, Hon. Christopher J., a U.S. Senator from the State of
Connecticut.................................................... 4
Brown, Hon. Sherrod, a U.S. Senator from the State of Ohio....... 7
Prepared statement........................................... 9
Franken, Hon. Al, a U.S. Senator from the State of Minnesota..... 11
Goodman, Jesse, M.D., M.P.H., Chief Scientist, U.S. Food and Drug
Administration, Silver Spring, MD.............................. 13
Prepared statement........................................... 17
Guttmacher, Alan E., M.D., Acting Director, National Institute of
Child Health and Human Development, Bethesda, MD............... 21
Prepared statement........................................... 24
Casey, Hon. Robert P., Jr., a U.S. Senator from the State of
Pennsylvania................................................... 34
Prepared statement........................................... 35
Sanders, Hon. Bernard, a U.S. Senator from the State of Vermont.. 38
Silver, Alexander J., Founder, Jackson Gabriel Silver Foundation,
New York, NY................................................... 38
Prepared statement........................................... 40
Dorman, Diane Edquist, Vice President for Public Policy, National
Organization for Rare Disorders, Washington, DC................ 47
Prepared statement........................................... 50
Crowley, John F., President and CEO, Amicus Therapeutics,
Cranberry, NJ.................................................. 54
Prepared statement........................................... 56
Moon, Suerie, Board Member, Doctors Without Borders USA, New
York, NY....................................................... 62
Prepared statement........................................... 66
Frattarelli, Daniel A.C., M.D., FAAP, Chair, Committee on Drugs,
American Academy of Pediatrics, Dearborn, MI................... 73
Prepared statement........................................... 75

ADDITIONAL MATERIAL

Statements, articles, publications, letters, etc.:
Senator Murray............................................... 83
Advanced Medical Technology Association (AdvaMed)............ 83
Peter J. Hotez, M.D., Ph.D., President, Sabin Vaccine
Institute.................................................. 91
Huntington's Disease Society of America (HDSA)............... 92
National Venture Capital Association (NVCA).................. 93
Response to questions of Senators Harkin, Enzi, Casey, Hagan,
and Franken by the Department of Health and Human Services,
Food and Drug Administration............................... 96
Response to questions of Senators Enzi, Brown, Casey, and
Hagan by Alan E. Guttmacher, M.D........................... 100

(iii)

Response to questions of Senator Enzi by Alexander J. Silver. 107
National Organization for Rare Disorders (NORD).............. 110
Response to questions of Senators Enzi, Casey, and Franken by
Diane Edquist Dorman....................................... 111
Response to questions of Senator Enzi by John F. Crowley..... 121
Response to questions of Senators Enzi and Casey by Suerie
Moon....................................................... 123
Response to questions of Senators Enzi and Franken by Daniel
A.C. Frattarelli, M.D., FAAP............................... 128

TREATING RARE AND NEGLECTED PEDIATRIC DISEASES: PROMOTING THE
DEVELOPMENT OF NEW TREATMENTS AND CURES

----------

WEDNESDAY, JULY 21, 2010

U.S. Senate,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 10:03 a.m. in
room SD-430, Dirksen Senate Office Building, Hon. Tom Harkin,
chairman of the committee, presiding.
Present: Senators Harkin, Dodd, Sanders, Brown, Casey,
Franken, and Enzi.

Opening Statement of Senator Harkin

The Chairman. The Committee on Health, Education, Labor,
and Pensions will come to order.
Good morning, everyone. We meet today to discuss a
profoundly important issue: the lack of effective treatments
for rare and neglected diseases. Over the years, Congress has
devoted extraordinary sums for research into major diseases
that afflict millions of Americans. Mostly this goes through
the National Institutes of Health. Some, not an insignificant
amount, goes through the Department of Defense. But, we've been
less generous, and less successful, in mobilizing the research
community to come up with therapies and cures for rare and
neglected diseases.
In the United States, rare diseases are defined as those
that affect fewer than 200,000 people. According to the
National Institutes of Health, there are nearly 7,000 rare
diseases, affecting more than 25 million Americans. Yet, there
are FDA-approved treatments for only as few as 200 of these
diseases. And many of them afflict the most vulnerable members
of our population, including children, and their effects can be
profound.
I know that there are several people, who are in the
audience today, living with different diseases. I thank you for
being here today to bear witness to what we need to do here, in
terms of getting better, and more, research into this area.
In addition to the rare diseases, the World Health
Organization estimates that, beyond our borders, over a billion
people suffer from one or more neglected tropical diseases.
These are a group of parasitic and bacterial infections. They
ravage the poorest populations in the world, and they
disproportionately affect children.
The conventional wisdom is that these diseases are ignored
by drug and device companies because there are inadequate
market incentives for engaging in the costly process of
developing products for FDA approval. Our discussion this
morning will explore the accuracy of that belief and what can
be done to improve the current situation.
Of course, in 1983, we passed the Orphan Drug Act, which
provides certain tax benefits and market exclusivity for
developing medicines to treat rare diseases. And in 2007,
Congress added a tropical disease provision to the Federal
Food, Drug, and Cosmetic Act.
Most recently, Congress directed the FDA to convene a
working group to recommend appropriate trial design and
regulatory paradigms to optimize prevention and treatment of
rare and tropical diseases. That working group convened in
March, and we're supposed to have a report from them by March
2011.
And I'm also heartened that the Department of Health and
Human Services is taking steps on its own to try to address
this challenge. The Center for Disease Control and Prevention
is working with the World Health Organization on combating
certain neglected tropical diseases. In addition, the FDA
recently created an Office of Rare Diseases, in its Center for
Drugs, to assist sponsors in navigating the Agency's clinical
trial and approvement requirements.
All of these steps seem to be moving in the right
direction. But, today we'll hear from witnesses, inside and
outside government, who are confronting this crisis on the
front lines.
We'll have two panels. The first, from the Department of
Health and Human Services, the second will be from our
nongovernment witnesses. Each has a different perspective to
share.
Regrettably--I think I can speak for Senator Dodd--both of
us will have to leave about 10:30 to go down to the White House
for a signing ceremony. Senator Brown, who has been one of the
great champions in the Senate, and certainly on this committee,
of focusing on rare and neglected diseases, will take over the
chairmanship at that time. He has been an outspoken voice, an
advocate, for these rare diseases.
And with that, I want to thank our former chair and Ranking
Member, Senator Enzi, for his interest over a long time in this
area, and will recognize him for an opening statement.

Statement of Senator Enzi

Senator Enzi. Thank you, Mr. Chairman. I want to thank you
for calling the hearing on this important issue of rare and
neglected diseases, focusing on rare pediatric diseases.
The Food and Drug Administration defines a ``rare disease''
as one that affects fewer than 200,000 Americans. Nearly half
of rare diseases affect fewer than 25,000 people. According to
the National Institutes of Health, there are about 6,800 rare
diseases affecting 25 to 30 million people, total. Most of
these conditions have no treatment or cure, and companies are
unlikely to undertake the expensive, lengthy, and difficult
research to develop a drug if they can't recoup their
investment in such a small market.
In 1983, Congress enacted the Orphan Drug Act to overcome
these obstacles and encourage the discovery and development of
treatments for rare diseases. The Orphan Drug Act includes: tax
credits for up to 50 percent of the costs of research to
develop the product; grants to assist with the costs of
clinical testing expenses; a 7-year period of market
exclusivity for the orphan indication, after approval of the
orphan product; and waivers of FDA application fees and annual
product fees. Since its enactment, there have been over 300
orphan products approved by the FDA.
The Orphan Drug Act is not the only mechanism to address
rare diseases and conditions. Many diseases that occur in
children are less common than in adults. Pediatric diseases
face the same market disincentives that apply to other rare
diseases. Treating children also creates unique issues because
of their size, their metabolic rate, and their growth.
Over the past decade, Congress has provided a number of
incentives to overcome these obstacles and develop better
treatments for children. Because of these incentives, we know
how kids respond to drugs like ADHD, asthma, arthritis,
depression, diabetes, epilepsy, hepatitis, HIV/AIDS,
hypertension, influenza, kidney transplants, leukemia and other
cancers, malaria, obesity, OCD, pain, seizures, and many other
conditions.
Three years ago, Congress passed the Food and Drug
Administration Amendments Act, which included a number of
important measures to encourage the development of treatments
for rare, neglected, and pediatric diseases. We're beginning to
see the effects of that work, and I hope we can continue to
build on those achievements so that we can have a similarly
successful reauthorization in 2012. This hearing will help us
understand where there may still be barriers to success, and
how we might lower those barriers.
The 2007 FDA overhaul also established an innovative
incentive system for the development of treatments for certain
diseases that affect global populations that otherwise might
not have sufficient market incentives. These products can be
rewarded with a voucher for priority review of a drug. The
voucher can be used for another product, or even sold to
another company. This sort of creative thinking is very helpful
to the debate. We must continue our commitments to the
continued development of these products.
We've also made investments in research in the area of rare
and neglected diseases through the National Institutes of
Health. The Office of Rare Disease Research, established in
1993, has the mission of coordinating NIH activities to ensure
our Nation's biomedical research investments do not overlook
the importance of investments in rare and neglected diseases.
In 2009, Congress mandated the office establish the
Therapeutics for Rare and Neglected Diseases, or TRNDs, to
encourage and spend the development of new drugs--speed the
development of new drugs for rare and neglected diseases.
Congress appropriated $24 million for the initiative. The goal
of the program is to reduce the risk associated with developing
drugs for rare and neglected diseases to meet FDA requirements
for an investigational new drug application. Once the drug is
ready to be licensed, the NIH will work with industry to find a
partner to continue clinical development.
I hope to hear from Dr. Guttmacher today about the Agency's
activities through the TRND program, and about other innovative
approaches to increasing investments in rare and neglected
diseases, like the Bench-to-Bedside Program.
I would also note that this topic brings up an important
point about how we allocate funding for the NIH. We worked
tirelessly to pass the NIH Reform Act to end a funding
structure that targeted specific diseases in response to
political, rather than scientific, reasons. The funding should
be directed toward research grants that are based on scientific
merit, not popularity. If it was based on popularity, probably
the Senate would put all the money into prostate cancer.
[Laugher.]
A strategy for determining how NIH funding should be
allocated is certainly necessary, but tying funds to specific
diseases will only tie the hands of the Agency and prevent the
scientists from innovating and conducting research in areas
that could benefit a multitude of diseases and conditions. This
is directly related to the topic of our hearing today. If a
``rare disease'' is defined as impacting less than 200,000
individuals, then we're talking about groups that have
significantly smaller lobbying force to request increases in
funding, which is not a fair or scientific process for
determining funding allocations. We should continue in our
practice of providing funding to the Institutes and allowing
the scientists to determine which grants have scientific merit
to receive funding, and not impose strict funding requirements
that are based on successful lobbying by advocates for a
specific disease.
I'd like to thank Senators Alexander, Dodd, and Brown for
their tireless work on pediatric and rare and neglected disease
issues.
I have some statements here from outside groups, and I ask
unanimous consent that they be entered in the record. One of
them is from venture capitalists, which was kind of a surprise.
But, I look forward to the testimony today.
[The information referred to may be found in Additional
Material.]
The Chairman. Thank you very much, Senator Enzi.
Senator Dodd.

Statement of Senator Dodd

Senator Dodd. Thank you very much, Mr. Chairman. And, like
Senator Harkin, we'll have to be leaving a little early today.
I'm sorry to do this. The timing is unfortunate, because this
is an area that my colleagues on the committee know that I
dedicate an awful lot of my time, during the Senate years, on
these subject matters. And I'd be remiss if I didn't point out
that Jeannie Ireland, sitting in the front row up here with my
staff person--we did a lot of this work--and is now with the
FDA.
Jeannie, good to see you. Thank you for your tireless work
over the years on this subject matter, as well.
I just have a brief couple of comments, if I can, Mr.
Chairman, about this.
This is the opening round. We've got some reauthorization
to do, and won't get it done in this Congress. But, I can't
commend you enough for beginning the conversation. There were
very contentious debates, going back some years ago, as we
talked about the subject matter, generally speaking, and went
through a number of rounds dealing with pharmaceuticals, then
medical devices, as well, going back to the orphan drug issue
that both you and Senator Enzi have discussed and talked about.
Obviously, it's an ongoing discussion, debate, how we do a
better job of this, all the way along. So, I think it's really
worthwhile we begin the conversation this early on, and you
couldn't have better witnesses to do that.
Dr. Goodman has done a terrific, terrific job. Dr.
Frattarelli, who'll be coming up later--I won't be here to hear
his testimony, and Dr. Rich Gorman, who testified at our
hearing on pediatric drugs and devices in 2007, and a wonderful
individual, as well.
So, let me just share some thoughts. Today's hearing is an
important topic not just for children's health, but family
health. And I spend a good part of my time in this committee
working on--I'm pleased to see so many friendly faces in the
audience--the reality is, we can't talk about rare diseases
without talking about children, because most of the
approximately 7,000 rare diseases are pediatric diseases.
When Congress first began looking at the issue of safety
and efficacy of pharmaceuticals for children, it was at a time
when children were rarely included in studies of medical
treatments, and therefore, we knew little about how children
responded to these products. The majority of companies invested
little or no resources into pediatric research. For some
companies, the prospect of clinical trials in children posed
problems of finding enough children to comprise a trial, while
grappling with the ethical questions about conducting research
involving children. The good news is that most children are
healthy. And so, the idea is--as an audience, as a
constituency--relatively small numbers of children find these
problems. So, the incentives really weren't there. For the most
part, the economic incentives, in fact, to pursue research in
the smaller market of pediatrics was lacking, and all of those
were realities we were dealing with. As a result, doctors and
nurses had to guess at which treatments were best, at what
dosage, for their pediatric patients. That's not because they
were bad people or they were practicing bad medicine at all.
They did the best they could for their patients with the
limited information that they had.
The situation today is vastly different as the result of an
awful lot of work, primarily in this committee, I might add, by
Democrats and Republicans, alike, working on this issue
together. With the passage of the Better Pharmaceuticals for
Children Act, in 1997, where my partner in that bill was Mike
DeWine of Ohio, we began that process of really looking at
pharmaceuticals for children and how we could engage in better
information.
The subsequent reauthorization, in 2002 and 2007, has led
to more than 385 drug labels that have been revised with new
safety, effectiveness, and dosage information. The studies
completed under this program revealed that, in some cases, our
children were being overdosed and, in some cases, under-dosed.
In others, we discovered that the drug was simply not effective
in children.
The Pediatric Research Equity Act, which was part of that
reauthorization that Senator Clinton, our former colleague, and
I were deeply involved in--she had originally issued a rule,
when she was in the White House--the Executive order, back when
President Clinton was in the office--and that was overturned,
at one point. And so, we began to then incorporate,
legislatively, her language.
One of the things we did, unfortunately, with that bill is
to sunset the requirement of trials to be done with children,
which I regret. We don't do that with adults at all. But, that
sunset provision was written into the legislation, back with
the reauthorization of the bill.
With the Better Pharmaceuticals for Children's Act--it's a
voluntary program. The incentive structure produces benefits
for children, because the FDA can and does set the requirements
for what companies must study. And the FDA has the final say
over whether the 6 months of exclusivity can be granted. But,
with the experience, we learned new things about the program,
and we learned how to make it better.
During the most recent reauthorization of the Better
Pharmaceuticals for Children Act, in 2007, we made improvements
that have resulted in companies conducting studies earlier in
the patent life of their products, meaning more and faster
labeling changes, improved adverse-event reporting, and we
created, as I mentioned, the Pediatric Review Committee, which
has better integrated pediatrics across the review divisions in
a consistent and productive way.
In 2005, the Institutes of Medicine published a report,
entitled, ``Safe Medical Devices for Children.'' In it, the ILM
experts called for systemic attention to children's needs in
medical device design, use, and evaluation, as well as a better
functioning system of postmarket surveillance for medical
devices to safeguard children. As a result, along, again, with
Senator Mike DeWine, my partner in that legislation, we
authored the Pediatric Medical Device Safety and Improvement
Act, which became law in 2007.
The development of pediatric devices shares obstacles
similar to those faced in drugs, but the incentive structures
are different. The law has produced the first pediatric
humanitarian-use device approved as a result of the incentives
under this program. And the FDA is running a robust new grant
program encouraging the development of new pediatric devices,
thanks to the funding from our good friend from Wisconsin,
Senator Herb Kohl, who chairs the Agricultural Appropriations
Subcommittee.
As I head into my final months in all of this service in
the Senate, Mr. Chairman, there's still much to be done in the
area of rare and neglected diseases in children. As we've made
an awful lot of progress with the passage of the Orphan Drug
Act, but only 200 of the nearly 7,000 rare diseases currently
have FDA-approved treatments. We've made headway with
identifying newborns for rare, but debilitating, genetic
conditions, through the expansion of newborn screening. And I
authored that bill along with--Lamar Alexander, of Tennessee,
who was my partner on that, as well--as we did in the premature
birth legislation, as well. I point out, this is the kind of
cooperation we've had on this committee in dealing with these
issues, historically. And hopefully that will be the case
again, as we move forward.
Here we've improved the availability of safe and effective
treatment options for children, but many of these children will
remain and have lifelong problems. There, their parents
struggle with insurance coverage, because, oftentimes,
treatments for children are considered investigational or are,
in fact, off-label. And when I see people like Sherrod Brown
and Al Franken here, as relatively new members of this
committee--even though I'll be leaving in January, I'm very
encouraged that the same kind of effort that's been made in the
past 20 or 30 years, working on these issues, will continue.
And obviously Al Franken, coming from Minnesota, the home
of the medical device industry, for the large part, has a great
familiarity with the subject matter. We would like a little
more cooperation from the device industry in this legislation,
I'd point out to my friend from Minnesota. He might want to
look into that, and talk to us about it, as well, since we
passed the legislation.
But, nonetheless, these are some great starts in this area.
And again, wonderful witnesses today to set the tone, in my
view, as we look forward now to the reauthorizations that will
have to occur.
And I thank you, Mr. Chairman, for the time.
The Chairman. Well, thank you, Senator Dodd. And again,
thank you for all your years of focus and attention on this and
all the various pieces of legislation that you worked with
others on to get through. We're going to miss you on this
committee, but, as you pointed out, we have other champions
here.
Senator Brown has devoted a large part of his service, in
both the House and the Senate, in focusing on this issue. He's
been one of the true champions of rare and neglected diseases.
And so, we'll have a good person to carry on here.
Senator Dodd. Thank you, Mr. Chairman.
The Chairman. Senator Brown, I'll recognize you for an
opening statement.

Statement of Senator Brown

Senator Brown. Thank you, Mr. Chairman.
I appreciate so much your work on this committee on these
issues, Senator Dodd and Senator Enzi, and Senator Dodd's work
on children's issues for his whole career, and what it's meant
to so many young people in our country, and so many families.
There's been a lot of partisanship in the halls of Congress
recently. But, I don't expect partisanship in this room today,
and that's to the credit of this committee's leadership. The
unfortunate reality is that, whether we're talking about
education or poverty or violence or health, the well-being of
our Nation's children is not made a high enough priority. Great
strides are being made, with respect to children's health,
thanks to Medicaid, CHIP program, and the recently passed
health reform legislation, but there are still areas where our
efforts fall substantially and woefully short.
One such area, as we know, is research and development for
pediatric diseases and conditions. Despite the fact that
children and adolescents account for one-fifth of our Nation's
population, pediatric research by NIH accounts for a mere 5 to
10 percent of the total NIH budget. Despite the fact that
children account for some 20 percent of our Nation's
population, most drugs on the market have never been tested in
children.
If we're falling short in our efforts to cure and treat
pediatric diseases and conditions, we're falling woefully and
inadequately short in our efforts to cure and treat rare and
neglected pediatric diseases and conditions.
Seven thousand known rare or orphan diseases afflict nearly
30 million Americans--approximately 50 percent of whom are
children. Even with millions affected by these rare diseases,
research opportunities remain all too scarce; and approved
therapies, even scarcer.
One of these rare diseases is epidermolysis bullosa,
otherwise known as EB. EB is a debilitating, disfiguring,
potentially deadly skin disease directly affecting
approximately 12,000 people in the United States, most of them
children. Because these children are born without the typical
anchors that hold the epidermal and dermal skin layers
together, any form of pressure creates unbearable friction, and
can make the simplest of activities, like hugging and playing,
even sleeping, calamitous. The most common characteristics of
EB are chronic blistering and ulcers and scarring. Though the
genes causing all types of EB have been identified, a cure
continues to elude the medical community, primarily because
funding is insufficient to support full clinical trials, and,
as my predecessors on this committee, said, because market
incentives simply don't exist for this rare pediatric disease.
With no cure and limited treatment options, children and
families struggling with EB continue to suffer as they wait and
hope for cures and treatments that have yet to be developed.
Waiting and hoping for a cure that may or may not
materialize is, all too often, the reality for families
affected by rare and neglected diseases. Because these rare
diseases affect fewer than 200,000 people in the U.S., and
because neglected diseases often affect impoverished or
disenfranchised populations in developing countries, there
exist significant barriers and very limited market incentives
for research and for development. Because the unique set of
circumstances discourage innovation in this field, thinking
outside the box becomes a necessity.
I would like to commend Senator Brownback, from Kansas,
who's been a leader in developing innovative ways to encourage
research in diseases that lack a large market incentive.
Senator Brownback and I were successful, 3-plus years ago,
during the FDA authorization, in authorizing a Priority Review
Voucher Program that awards a voucher for expedited FDA review
to any company that obtains approval for a treatment for a
neglected tropical disease. And we already have begun to see
the impact of that in tuberculosis and other mostly developing-
world diseases. We're working now to expand that program to
include rare childhood diseases like EB.
Another innovative strategy, this one spearheaded by
Senator Specter, is the Cures Action Network. This grant
program, authorized under health reform and housed within the
Office of the Director at NIH, was established for the express
purpose of helping ensure that treatments and cures for rare
diseases make it over the finish line when funding for later-
stage research is holding them back. The next step is to fund
this tremendously promising program so we can realize its
critical goals.
Examining solutions like these, as well as barriers to
research and development, is why we're here today, why I
appreciate so much Chairman Harkin holding this hearing.
Witnesses in our first panel will be able to talk about
current research and development initiatives taking place with
respect to rare and neglected pediatric diseases. Dr. Goodman
and Dr. Guttmacher will discuss ongoing efforts at FDA and NIH
to enhance research and development for rare and neglected
pediatric diseases.
And witnesses in our second panel will discuss barriers
that hamper our efforts to cure and treat these diseases, and
provide suggestions about how we move forward.
For instance, I know the National Organization for Rare
Disorders, NORD, has long advocated for more transparency in
the regulatory system so that investigators and drug and device
manufacturers have a better handle on expectations for the
approval of new products. I know the American Academy of
Pediatrics has long fought, and continues to fight, to ensure
that drugs and devices are studied and labeled for pediatric
purposes. I know the biotech industry is developing some of the
most effective and innovative treatments for rare pediatric
diseases, but that attracting sufficient capital for these
efforts is always a challenge.
And finally, I'm pleased that Alex and Jamie Silver are
here today with us. The father of the son with EB, Mr. Silvers,
fought tirelessly, along with his wife Jamie, to raise
awareness about this rare pediatric disease. He will be
offering a number of suggestions to improve private and public
efforts. I thank him personally for work he's done with my
staff. I know there's no better advocate than a parent, and I
appreciate him and the parents here who are working not just on
behalf of their own children, but for children whom they don't
even know, and thank them for that.
Thank you, Mr. Chairman.
[The prepared statement of Senator Brown follows:]

Prepared Statement of Senator Brown

Thank you, Chairman Harkin. I would like to begin by
thanking both you and Senator Enzi for working with me to put
together this important bipartisan hearing.
There has been a lot of partisanship in the halls of
Congress recently, but I do not expect partisanship in this
room today--and that is to the credit of this committee's
leadership.
The unfortunate reality is that--whether we're talking
education, poverty, violence, or health--the well-being of our
Nation's children is not made a high enough priority.
While great strides are being made with respect to
children's health--thanks to Medicaid, the Children's Health
Insurance Program, and the recently passed health reform
legislation--there are still areas where our efforts fall
short.
One such area is research and development for pediatric
diseases and conditions.
Despite the fact that children and adolescents account for
more than 20 percent of our Nation's population, pediatric
research by the National Institutes of Health (NIH) accounts
for a mere 5-10 percent of the total NIH budget.
Despite the fact that children account for more than 20
percent of our Nation's population, most drugs on the market
today have never been tested in children.
If we are falling short in our efforts to cure and treat
pediatric diseases and conditions--we are falling woefully and
inadequately short in our efforts to cure and treat rare and
neglected pediatric diseases and conditions.
Seven thousand known rare or orphan diseases afflict nearly
30 million Americans--approximately 50 percent of whom are
children.
Even with millions affected by rare diseases, research
opportunities remain scarce, approved therapies even scarcer.
One of these rare diseases is Epidermolysis (ep-uh-derma-
lo-sis) Bullosa (otherwise known as ``EB'').
EB is a debilitating, disfiguring, and potentially deadly
skin disease directly affecting approximately 12,000 people in
the United States, most of them children.
Because these children are born without the typical anchors
that hold the epidermal and dermal skin layers together, any
form of pressure creates unbearable friction and can make the
simplest of activities--like hugging, playing, or even
sleeping--calamitous.
The most common characteristics of EB are chronic
blistering, ulcers, and scarring.
Though the genes causing all types of EB have been
identified, a cure continues to elude the medical community--
primarily because funding is insufficient to support full
clinical trials and because market incentives simply do not
exist for this rare pediatric disease.
With no cure and limited treatment options, children and
families struggling with EB continue to suffer as they wait--
and hope--for cures or treatments that have yet to be
developed.
Waiting and hoping for a cure that may or may not
materialize is, unfortunately, all too often the reality for
families affected by rare or neglected diseases.
Because rare diseases each affect fewer than 200,000 people
in the United States--and because neglected diseases often
affect impoverished or disenfranchised populations in
developing countries--there exist significant barriers and
limited market incentives for research and development.
Because of the unique set of circumstances that discourage
innovation in this field, thinking outside the box becomes a
necessity.
I would like to commend Senator Brownback--who has been a
leader in developing innovative ways to encourage research on
diseases that lack a large market incentive.
Senator Brownback and I were successful in authorizing a
``priority review voucher program'' that awards a voucher for
expedited FDA review to any company that obtains approval for a
treatment for a neglected tropical disease.
We are working now to expand that program to include rare
childhood diseases--like EB--in that program.
Another innovative strategy--this one spearheaded by
Senator Specter--is the Cures Action Network.
This grant program authorized under health reform and
housed within the Office of Director at NIH, was established
for the express purpose of helping ensure that treatments and
cures for rare diseases make it over the finish line when
funding for later stage research is holding them back.
The next step is to fund this tremendously promising
program so we can realize its critical goals.
Examining solutions like these, as well as barriers to
research and development, is why we are here today.
Witnesses on our first panel will be able to talk about
current research and development initiatives taking place with
respect to rare and neglected pediatric diseases.
Dr. Jesse Goodman and Dr. Alan Guttmacher will discuss
ongoing efforts at FDA and NIH to enhance research and
development for rare and neglected pediatric diseases.
And witnesses on our second panel will discuss barriers
that hamper our efforts to cure and treat these rare diseases
and will provide suggestions about how we can move forward.
For instance, I know the National Organization for Rare
Disorders (NORD) has long advocated for more transparency in
the regulatory system so that investigators and drug and device
manufacturers have a better handle on expectations for the
approval of new products.
I know that the American Academy of Pediatrics (AAP) has
long fought--and continues to fight--to ensure that drugs and
devices are studied, and labeled, for pediatric populations.
I know that the biotech industry is developing some of the
most effective and innovative treatments for rare pediatric
diseases, but that attracting sufficient capital for these
efforts is an ongoing struggle.
And, finally, I am so pleased that Mr. Alex Silver is here
today.
As the father of a son with EB, Mr. Silver has fought
tirelessly to raise awareness about this rare pediatric disease
and he will be offering a number of suggestions to improve
private and public efforts.
I'd like to thank Chairman Harkin and Senator Enzi again
for their commitment to rare and neglected pediatric diseases
and I'd like to thank all of our witnesses for taking the time
today to discuss these issues, which are so close to all of our
hearts.

The Chairman. Senator Brown, thank you very much.
Senator Franken.

Statement of Senator Franken

Senator Franken. Mr. Chairman, thank you for holding this
hearing on rare and neglected pediatric diseases.
This is an issue that touches the lives of thousands of
Minnesotans. I'm looking forward to hearing from our witnesses,
one of whom has worked at the University of Minnesota.
Every day, I receive letters from Minnesotans of all ages
who suffer from rare or under-studied conditions, and that have
little or no prospect for care. The most heartbreaking stories
are about kids, children with little-known diseases that have
been frozen in time. Decades have gone by, and there's still
been no progress on new treatments. And I also hear the stories
of kids with conditions that we do have treatments for, but the
therapies or devices they need aren't covered yet by insurance.
We need to do more for all of these cases. I'm heartened by
the progress brought by laws like the Orphan Drug Act and the
Pediatric Medical Device Safety Act. And I want to thank my
senior colleagues on the committee who have championed these
bills.
Today I'm interested in learning what the next steps are,
so we can develop treatments more quickly and make sure that
they reach kids who need them the most. For example, many of
the humanitarian-use devices now available have come from
companies with Minnesota ties, a fact that all Minnesotans are
proud of. But, I'm concerned that we still don't have
equivalent incentives for devices as we have for drugs. I think
we can do more, and I look forward to exploring this issue with
the panel.
The fact is that, here in Congress, we have lots of
disease-specific bills that try to bring resources to these
rare and neglected diseases. These bills are worthwhile, but
it's a real challenge, because there are thousands of these
diseases. I believe there has to be a better way to make sure
our scientific infrastructure and financial incentives produce
treatments for both prevalent and rare diseases. And I look
forward to hearing from the panel.
Thank you, Mr. Chairman.
The Chairman. Thanks, Senator Franken.
As I said, we have two panels. The first would be the Food
and Drug Administration and the National Institute of Child
Health and Human Development, at NIH. And then, another second
panel.
As I mentioned earlier, both Senator Dodd and I have to
leave, like right now, because of the presidential signing of
the bill, downtown. And so, I apologize for that. But, I want
to reassure everyone that your testimonies have been read--I do
those the night before--and that all of your testimonies will
be made a part of the record in their entirety.
I leave you in the good hands of both Senator Enzi and
Senator Brown and Senator Franken--as you can tell, all great
champions of this issue, and have a great deal of interest in
it.
So, I'm going to have to excuse myself. And I will yield
the gavel to Senator Brown for the remainder of the hearing.
[Pause.]
Senator Brown [presiding]. For the first panel, I would
like to introduce Jesse Goodman and Alan Guttmacher. I have a
couple of words in introduction, and then I'd like you to
proceed for 5 minutes or so, and then, of course, we'll ask you
questions.
I'd like to welcome Jesse Goodman from the Food and Drug
Administration. He's a chief scientist, deputy commissioner for
science and public health at the FDA, formerly served as the
director for the Center for Biologics at the Food and Drug
Administration; and continues to be an active clinician and
teacher who's board-certified in internal medicine, oncology,
and infectious diseases. Dr. Goodman's a staff physician and
infectious diseases consultant at the National Naval and Walter
Reed Army Medical Centers.
Alan Guttmacher is our second panelist, acting director of
the National Institute of Child Health and Human Development.
He's a pediatrician and medical geneticist. He's also served in
a number of roles at the National Human Genome Research
Institutes at the National Institutes of Health, where he
oversaw the Institute's effort to advance genome research and
integration of that research into healthcare, an extraordinary
effort. Dr. Guttmacher is a member of the Institute of Medicine
and a fellow of the American Academy of Pediatrics.
Dr. Goodman, if you would proceed.

STATEMENT OF JESSE GOODMAN, M.D., M.P.H., CHIEF SCIENTIST, U.S.
FOOD AND DRUG ADMINISTRATION, SILVER SPRING, MD

Dr. Goodman. Thank you very much, Senator Brown, and good
morning. And thank you, Senator Enzi and Senator Franken. I'm
very pleased to be here with you.
I'm also with members of my team that I'll introduce a
little later. And I'm happy to be here to talk about FDA's
efforts to encourage development of medical products for
children with rare and neglected diseases.
I do want to send a very--I hope I'll convey a very strong
message that we're engaged on every front. And I'd like to sort
of start out with the key message being, I think there are two
critical ways we can help. One is in a very highly interactive
science-based review process with sponsors and investigators.
And the other is through our regulatory science efforts, which
really are to bring science to bear that can move things across
this gap, from promising ideas in basic science to products
that really help people.
Just to start, as a practicing physician I see, frequently,
the impacts of these diseases. We've heard some about the
suffering they cause in children and their families. I like to
always take the opportunity to remind folks that it's not just
that these neglected diseases that affect others around the
world cause tremendous impacts and there are humanitarian
reasons to face them, but our country, too, is at risk for
these diseases, as we see with the spread of influenza,
tuberculosis, etc. So, I would argue that there's both pressing
humanitarian reasons to act, but also national public health
and security reasons that we should be on top of infectious
diseases.
Now, for both these rare diseases and neglected diseases,
as has been identified, there's really two big barriers to
getting products. First is the market incentives that are not
always clear, as we've heard about. But, second, and not always
recognized, is, there are some serious scientific challenges in
translating basic science and getting enough basic science to
translate ideas and concepts into products.
For the neglected diseases--and excellent examples are TB,
malaria, and HIV. Actually, in those areas, despite a lot of
basic science investment, we still don't have clear answers.
And part of what makes these diseases so good at infecting
people is also what makes them so hard to develop vaccines and
drugs against, which is how they evade the normal host defenses
and immune response. So, there are scientific needs.
Now, I want to emphasize FDA's particular role here in
assuring that products are safe and effective. And I also want
to say that people with rare and neglected diseases are
particularly vulnerable, due to either their illness, their
poverty, etc. So, it's very important that we do our job, and
be sure these products are safe and effective. People around
the world, in fact, look to FDA to make the best risk-based
decisions about medical products.
Also, I want to really clearly emphasize that if a product
is promising, FDA wants to work with product developers to help
that product succeed in the development process. And then if a
product works, we're going to approve it.
The essential problem here is that there are simply not
enough effective products being developed. And so, we want to
join with you, our colleagues at NIH and elsewhere, and
industry, to do everything we can to facilitate the development
of these products. This is a huge task, but we're very
committed to it.
Now, as you've heard--and rightfully credited Senator Dodd,
particularly, with--Congress has helped, in a bipartisan way,
in this fight against rare and neglected disease. And we thank
you. And we're pleased to be part of that effort.
As you've heard, the Orphan Drug Act accomplished a lot.
Before it, there were very few products for rare diseases.
Since it, there are 358 approved products. And many of these
actually do address some of the rarest diseases. But,
obviously, looking at that, we have a long way to go.
And I wanted to recognize and introduce to you Dr. Tim
Cote, who is here and directs our Orphan Product Program. And I
want to point out that they have a number of activities: a
large grants program to help people develop products;
personalized assistance to people in the development process;
working with patient groups who we think are extremely
important and can help inform us. They've helped identify drugs
that could be promising in rare diseases, and put those out
there for industry and academic interest. We do a huge amount
of outreach and training, including courses in how to develop
products for rare diseases in small clinical trials, etc, one
recently attended, online and in person, by 1,500 people,
including both FDA reviewers and outside investigators. And Dr.
Guttmacher will talk more about it. But, we're working very
closely with NIH, including working with them up front in this
very exciting TRND program that you'll hear about.
Now, as Senator Enzi noted, children are not just small
adults, and we need a lot of data about their diseases. And
again, thanks to your leadership, we have the Best
Pharmaceuticals for Children Act and the Pediatric Research and
Equity Act that work together to help achieve this goal. Before
these acts were present, 80 percent of products approved had no
information about pediatric uses, forcing clinicians,
essentially, to do their best and guess.
Today, we still have a lot more work to do, but pediatric
information, as a result, is routinely included in the product
labeling. And again, part of our team, Dianne Murphy--Where are
you, Dianne?--is here, and she leads our Pediatric Therapeutic
Office that coordinates this effort.
You've mentioned the Humanitarian Device Exemption Program.
We think this is a creative program. It, again, has allowed
people--device-makers to target devices to small populations
and allow their approval based on a probable-benefit standard,
which provides flexibility to help get these products to
people.
And Dr. Barbara Buch, from CDRH, our Device Center, Is she
here somewhere? Barbara? Hi, Barbara.--is also here, and an
important part of that team.
Also, just in February, FDA created a new position,
associate director for rare diseases in the Drug Center, where
much of the review activity is located. Anne Pariser is running
this activity. She's here. I see Anne. This program is to
really promote best practices and innovation throughout the FDA
and in collaboration with outside stakeholders.
Now, I want to also point out that we are fully committed
to applying flexibility in the development and review of these
products. That doesn't mean we will necessarily always agree
with every proposal that every sponsor makes, but we really
want to be open to those proposals, and be flexible.
It's really important to point out--and I have details in
my written testimony--that we've approved quite a number of
products based on very small clinical trials--10, 20 people--
and often on one trial, where all the information can be
reasonably applied, and where the product has worked.
The issue of surrogates, biomarkers, things that can allow
us to predict effectiveness more quickly, and not have to wait
for years, in a long-term clinical trial, that's an area
where--we also are very open to, and I agree with several of
the other people testifying today, that we can develop the
science there. I'll come back to that a little.
Again, as a result of your and Senator Brownback's
leadership, we have a review going on--new review groups for
both rare and neglected diseases. And we do look forward to
gathering all that input and providing Commissioner Hamburg
with our best ideas and coming back to you with a report.
Now, on neglected diseases, I want to say, we have seen
tremendous increase in interest, both from Congress, from the
American people, from the Administration, from nongovernment
organizations, from--even from industry on this--in developing
products that can meet this incredible humanitarian and public
health need. And we are very excited about that, very engaged
in it. This was a very high priority for me, when I directed
the Biologic Center at FDA with all our relationships with WHO,
and it remains one for me and Dr. Hamburg.
I'd like to mention a few things we've done in the
neglected disease area. We've issued a guidance on development
of vaccines for global infectious diseases. We provide a huge
amount of technical support and expertise to WHO in their
efforts to set high standards for the world. We serve as a
reference national regulatory agency, for WHO, that can approve
products for their programs, that distribute them throughout
the world. We're involved with them in trying to build
capacity, throughout the world, for other regulatory agencies
so that places like Africa--where there are other developing
countries--can exercise appropriately their autonomy in looking
at products, but also can be partners that help those products
get effectively developed and evaluated. And then we do a lot
of training for foreign regulators.
I want to finish up by mentioning our regulatory science
work. In the area of neglected diseases, we have a very large
program to develop better measures of safety and effectiveness
and quality, for example, of vaccines for diseases like HIV,
TB, malaria, meningitis, Leishmania.
Now, I want to talk a little bit about our highly applied
and targeted regulatory science efforts, because most of the
problems that we find we're dealing with--and the difference
between success and failure in product development is often
based on, What is the science we have, and how can we apply it?
As you know, researchers have defined the genetic basis of
thousands of diseases. We have all the information from the
human genome. But, there still is this very persistent and
troubling gap between all that basic science knowledge and
product development and products that can benefit people. And
this is part of the reason we have that gap in getting to those
products. We believe that, through our regulatory science
efforts and the kind of interactive review I talked about, we
can help bridge that.
This is particularly important for rare and neglected
diseases. For example, we do want to see more accelerated
approvals and markers for effectiveness and safety that can
help us approve products and develop them more quickly. But, to
do this, you need the science. You have to have endpoints that
are sound, or we end up with products that are approved and
then later found not to work, as we've seen occasionally in the
drug world.
We're very actively engaged with other partners, through
consortia, through our own research efforts, in trying to
develop better surrogate markers for effectiveness. And we
recently had a TB workshop, just focused on this, that involved
our colleagues at NIH and CDC, as well as industry.
Some examples of the success of some of our fairly limited
but, I think, robust and focused regulatory science program
includes the work of FDA biochemists that solved a
manufacturing problem for a meningitis vaccine that is then
allowing a major NGO to produce meningitis vaccine for much of
the world, where it's a huge problem. Another thing is work
that FDA chemists are doing now to better understand how dosing
forms, like tablets, of drugs are handled by children, and how
we can improve that. And those are just a couple of examples.
We thank Congress, and our 2011 budget of the
Administration includes the first dedicated funding, in fact,
for FDA to rebuild its scientific infrastructure, and develop
these kinds of tools that can help turn ideas into products.
We're also very excited about our new collaboration, led by Dr.
Hamburg and Collins, our Leadership Council between FDA and
NIH, and our grant program on applied regulatory science that
we're doing together.
And then, to close, I'd like to say that strong science is
critical in an intensely interactive review process that we
know improves the chances of the outcome of success. That
success is good for patients, but also for our economy, where
our leadership in product development is critical.
FDA science can and should meet with scientists from
companies and sponsors early in development, and help identify
issues and problems, and help to solve them, to increase the
odds of success. And these interactions are very labor-
intensive for FDA, but we've seen, for example, in our medical
countermeasure review, a very different subject, but with some
similarities, that the more we can work with sponsors early on,
and identify and solve problems, the higher the likelihood of
success.
And perhaps my most important suggestion--I make it every
day to people who call me--is that sponsors seek and engage in
this kind of approach, meeting with us early, including with my
colleagues that I identified here.
Finally, I want to reemphasize that we are really committed
to this, our leadership and so much of our staff. And we really
welcome your engagement and ideas.
Thank you very much.
[The prepared statement of Dr. Goodman follows:]

Prepared Statement of Jesse L. Goodman, M.D., M.P.H.

INTRODUCTION

Good afternoon, Chairman Harkin and members of the committee. I am
Dr. Jesse L. Goodman, Chief Scientist and Deputy Commissioner for
Science and Public Health at the Food and Drug Administration (FDA), an
agency of the Department of Health and Human Services. I appreciate the
opportunity to be here today to describe the role of FDA in encouraging
and speeding the development of drugs, vaccines, devices, and
diagnostic tests to improve the lives of children affected by rare
diseases.
There are more than 7,000 rare diseases, defined by the Orphan Drug
Act (ODA) as diseases affecting fewer than 200,000 people in the United
States, and many of these affect children. Some diseases, such as
severe genetic diseases, predominantly or exclusively affect children.
As a practicing physician and a researcher specializing in infectious
diseases and trained in oncology, I have personally witnessed the
devastating human face of diseases like these.
While we have made great progress in addressing this challenge,
there are still an estimated 20 million Americans suffering from rare
diseases for which there are no approved therapies available. Factors
responsible for this are only magnified for children. In many cases,
and even when the basic scientific problem is understood, the applied
scientific knowledge is still not there to identify or develop good
candidates. In addition, market incentives may be insufficient to drive
the sustained commercial interest and investment necessary to develop
new medical products for pediatric rare diseases. Furthermore,
conducting clinical trials to treat this population presents real
challenges. As with all rare diseases, the number of patients available
for clinical trials is small, and our knowledge about the history and
best management of these diseases is often limited. Small populations
are made even smaller when we consider that diseases and therapies may
affect children differently at different ages--and not all children are
the same. A product that is effective in an infant may not work for an
older child or a teen. In addition, with limited information about rare
diseases, we may have difficulty determining whether a child's response
to therapy in a clinical study is related to intervention with a
medical product or is a result of the natural course of the disease
over his or her lifetime. Other factors that impact all clinical trials
in children, such as limitations on the amount of blood that can be
drawn from a child, also come into play. All of these issues complicate
progress in this area.
In the face of these challenges, FDA believes it can contribute
collaboratively to achieve progress, and we are taking a multifaceted
approach to supporting the development of medical products for
pediatric rare diseases. I welcome your shared interest and commitment
to this issue, and I am pleased to be here today to provide you with an
overview of our major efforts to enhance the development and
availability of products that can improve the lives of those affected
by pediatric rare diseases.
Congress has empowered FDA with many innovative tools to help
address pediatric rare diseases. I will begin by providing a summary of
the statutory authorities under which we are currently conducting these
efforts, followed by a discussion of other related activities at FDA.

FDA STATUTORY AUTHORITIES TO ADDRESS PEDIATRIC RARE DISEASES

The Orphan Drug Act
The 1983 Orphan Drug Act (ODA) created financial incentives,
including grants, to support the development of new drugs for people
with rare diseases. Under this system, developers of promising drugs or
biologics can, prior to submitting applications for approval of those
products, apply to receive ``orphan drug status'' designation. If
products so designated are subsequently shown to be safe and effective
and receive marketing approval, their developers receive market
exclusivity for 7 years.
FDA's Office of Orphan Products Development (OOPD) serves as a
focal point for FDA's efforts to address rare diseases, and can provide
significant assistance to scientists who may lack product development
and regulatory experience. OOPD also fosters new approaches throughout
FDA to advance development of therapies for rare diseases. For example,
last month OOPD announced the availability of a new tool, the Rare
Disease Repurposing Database, which identifies drugs that are deemed
promising for rare illnesses and are already approved by FDA for
another disease. A novel feature and major advantage of this database
is that it focuses on drugs that have already gone through the FDA
approval process. Thus, repurposing of these drugs for a new rare
disease indication might be attainable quickly, relatively
inexpensively, and at great benefit to the patients involved.
ODA has been extremely successful in changing the landscape and
success rate of orphan drugs and improving the lives of many patients.
Prior to the existence of ODA, there were few new products for people
with rare diseases, but, since 1983, more than 2,150 medical therapies
have been officially designated as ``orphans,'' and 358 of these
therapies have gone on to full marketing approval. Of these products,
approximately 67 (19 percent) are for diseases that occur exclusively
among children and 201 (57 percent) of these are for diseases that
occur among both children and adults. ODA also established FDA's
largest grants program, $15.2 million for fiscal year 2010, managed by
OOPD. Forty-seven products have been found to be safe and effective as
a result of data generated in part by those grant monies. Of these
products, approximately 11 (24 percent) are for diseases that occur
exclusively among children and 28 (62 percent) of these are for
diseases that occur among both children and adults.
The approved products now on the market that qualified for orphan
product designation are a testament to the important accomplishments
and successes of the program. Success stories include:

Carbaglu (carglumic acid) for the treatment of NAGS
deficiency, the rarest of the Urea Cycle Disorders, which are diseases
that lead to elevated ammonia levels in the blood and cause seizures,
poor muscle tone, respiratory distress, coma, and even death. NAGS
deficiency affects fewer than 10 patients in the United States at any
given time. This drug was approved in March 2010, based on a case
series in 23 patients.
Myozyme (alglucosidase alfa) for the treatment of Pompe
Disease, which is a rare genetic disease resulting in progressive
skeletal and respiratory muscle weakness caused by an accumulation of
glycogen (a carbohydrate). About 1,000-2,000 patients in the United
States suffer from Pompe Disease, of which only a few hundred are
infants. In infants, the disease can be rapidly fatal due to
respiratory failure. This drug was approved in April 2006, based on the
results of a single, pivotal study in 18 patients.
Ceprotin (Protein C Concentrate) for treatment of severe
congenital Protein C deficiency, the prevention and treatment of venous
thrombosis (blood clots in the vein), and purpura fulminans (life-
threatening bleeding and tissue death). The life-threatening form of
the disease affects about 1 in 500,000 to 1 in 750,000 newborns. This
drug was approved in March 2007, based on a clinical study involving 18
patients.
Kogenate FS (Antihemophilic Factor (Recombinant)) to
prevent bleeding episodes and the risk of joint damage in children with
hemophilia A. The disease affects about 15,000 individuals in the
United States, nearly all of whom are male. This drug was approved for
this indication in October 2008, based on a clinical development
program of 65 boys under 30 months of age.

Best Pharmaceuticals for Children Act and Pediatric Research Equity Act
Under the leadership of Senator Dodd and the members of this
committee, over the past decade, Congress created and reauthorized two
critical programs that have dramatically improved the practice of
medicine for children: the Best Pharmaceuticals for Children Act
(BPCA), first enacted in 1997 as part of the Food and Drug
Administration Modernization Act, and the Pediatric Research Equity Act
(PREA), first enacted in 2003. Together, BPCA and PREA create a
``carrot and stick'' approach to the development of important new
safety, effectiveness, and dosing information for medical products used
in children. BPCA is an incentive program that grants market
exclusivity to sponsors that elect to study their product in children
according to protocols set by FDA. PREA gives FDA the authority to
require pediatric studies under certain conditions. Before these laws
were enacted, an estimated 80 percent of medication labels did not
include information about use in children. Without pediatric studies,
doctors treating children most often have to use medical products
without important information about correct dosage or safety and
effectiveness. Today, using the tools that Congress provided with BPCA
and PREA, we have worked with industry to add new pediatric information
to the labels of 385 products.
The Food and Drug Administration Amendments Act of 2007 (FDAAA)
established the Office of Pediatric Therapeutics (OPT) within FDA's
Office of the Commissioner. Its primary mission is to ensure access for
children to innovative, safe, and effective medical products. OPT
includes four distinct yet interrelated programs to support FDA efforts
to improve pediatric access to medical products:

The OPT Ethics Program supports FDA efforts to ensure that
children are only enrolled in clinical studies which are both
scientifically necessary and ethically appropriate.
The OPT Safety Program coordinates the mandated review by
the Pediatric Advisory Committee of the safety of drug and biologic
products 1 year after labeling changes, in response to voluntary and
required pediatric studies.
The OPT Scientific Activities Program works with FDA
scientists and reviewers to ensure that pediatric studies are
rigorously designed and conducted in accord with current scientific
understanding of such issues as exposure-response and extrapolation.
The OPT International Program facilitates communication
and collaboration between FDA and partner regulatory agencies around
the world as well as other regions, such as Europe.
The Priority Review Voucher Program
FDA has long had in place a review system to ensure that the most
critical medical products are reviewed on a priority basis. Priority
review applications for products that treat life-threatening and
serious diseases are reviewed in a 6-month period, compared to the 10-
month period for other products. Most products to treat pediatric rare
diseases are entitled to get this quicker review cycle, which does
assist in getting needed products to market more quickly
Thanks to the leadership of Senator Brown and others, the FDAAA
granted FDA the authority, beginning in 2009, to award priority review
vouchers to a company that submits and, after review, receives
marketing approval for a product for 1 of 16 neglected ``tropical''
diseases listed in the legislation. While these diseases are not rare
in the global context, they often affect fewer than 200,000 individuals
in the United States and are therefore eligible for orphan drug status
designation. If transferred to apply to a blockbuster drug, the 4
months of earlier market access available when a priority review
voucher is redeemed could translate into an incentive worth hundreds of
millions of dollars. Already, one such voucher has been issued to
Novartis, for its anti-malarial drug Coartem (artemether,
lumefantrine). FDA has informed major human pharmaceutical companies
that also own veterinary medicines that appear promising for neglected
human diseases that they could qualify for a priority review voucher if
evaluation for human disease indications supported marketing approval
for 1 of 16 neglected diseases listed in the legislation.

The Humanitarian Device Exemption Program
Also included in FDAAA is the Pediatric Medical Device Safety and
Improvement Act, which expanded the Humanitarian Device Exemption (HDE)
program. The HDE program provides an exemption from the otherwise
applicable effectiveness requirements for devices that are designed to
treat or diagnose diseases or conditions that affect fewer than 4,000
individuals in the United States per year. To qualify for this
exemption, certain criteria must be met, including a determination by
FDA that the probable benefit outweighs the risk of injury or illness
from use of the device. FDAAA provided an additional incentive for
development of devices intended for treatment or diagnosis of rare
pediatric diseases by lifting certain restrictions on charging for the
device. An example of a device granted an HDE is the adjustable
titanium rib for children with thoracic insufficiency syndrome, a
condition where the child's chest cannot support normal growth of the
lungs or spine. This device prevents the child's body from collapsing
on itself, allowing for growth and maturation of lungs and spine in
patients who otherwise might not survive. The inventor, an orthopedic
surgeon, recognized the need for a device that could be adjusted as a
child grows.
FDAAA also established a grants program to fund pediatric device
consortia that facilitate the development, production, and distribution
of medical devices for children. These consortia serve to connect
pediatric medical device innovators with potential manufacturers and
provide advice and assistance. So far, four consortia have been
established. Since their inception in October 2009, the consortia have
assisted in the evaluation and development of more than 50 pediatric
medical devices, including development of a critical pediatric
ventricular assist device, which (at least on a temporary basis)
partially or completely replaces heart function for children with heart
disease while they await a transplant.

ADDITIONAL FDA EFFORTS TO ADDRESS PEDIATRIC RARE DISEASES

Establishment of Rare Diseases Director Position Within FDA Center
Expanding on its commitment to facilitate the development and
approval of safe and effective drugs for Americans with rare diseases,
in February 2010, FDA created a position of Associate Director for Rare
Diseases in the Center for Drug Evaluation and Research (CDER). In
conjunction with OOPD, the Associate Director for Rare Diseases
supports collaboration among scientists and clinicians throughout FDA,
including with the Office of Pediatric Therapeutics, promoting
scientific and regulatory innovations to help facilitate timely
development and approval of new treatments for patients with rare
diseases.

Training and Collaboration to Support Rare Disease Product Development
Since 2008, FDA has sponsored an annual course designed to teach
FDA reviewers and other interested clinicians the science of conducting
and analyzing small clinical trials, which are especially useful for
testing medical products for pediatric rare diseases. In October 2010,
FDA will co-sponsor a larger and more comprehensive Annual Rare Disease
Investigator Training Course, in collaboration with the National
Institutes of Health (NIH) and the National Organization for Rare
Disorders (NORD). FDA is planning a series of scientific workshops to
address important and difficult rare disease research issues, and is
developing a ``rare disease database'' to establish the natural history
of rare diseases to assist with planning trials to test rare disease
therapies. Lastly, FDA is enhancing collaborations to increase
transparency, share advice, and establish new programs with several
pertinent organizations, including NORD; NIH's Office of Rare Diseases
Research, Therapeutics for Rare and Neglected Diseases Program, and
other NIH Institutes and Centers; patient advocacy groups; academia;
and the Institute of Medicine (IOM).

FDA Rare and Neglected Disease Review Groups
Section 740 of the fiscal year 2010 Appropriation Act (Agriculture,
Rural Development, Food and Drug Administration, and Related Agencies
Appropriation Act, 2010, Public Law 111-80) directed FDA to establish
internal review groups to address rare and neglected diseases, to
report to Congress 1 year after establishing the review groups and to
issue guidance relating to rare and neglected diseases. To implement
section 740, in March 2010, FDA established two new expert working
groups, the Rare Disease Review Group and the Neglected Disease Review
Group.
Last month, a meeting was held on rare diseases, at which 26
speakers provided comments. Those comments will be made available when
FDA finalizes its report to Congress on March 11, 2011. A similar
meeting to discuss neglected diseases is planned for September.
Finally, FDA and NIH are co-sponsoring an IOM study, which began in the
fall of 2009, to review national policy for rare disease research and
related medical product regulation. The results and recommendations of
that study are due at the end of September 2010, and FDA review groups
will consider the IOM study findings in their ongoing work.

Office of Special Health Issues
FDA's Office of Special Health Issues (OSHI) serves as a liaison
between FDA and patients, patient advocates, health professionals, and
their representative organizations. OSHI staff encourages and supports
active participation of these stakeholders in forming FDA regulatory
policy to ensure the Agency's decisions are based upon a full range of
perspectives. OSHI also is responsible for communicating important
safety and regulatory information to health professionals and patients.
This office is a resource to patients with rare diseases who have
questions about FDA-regulated products or seek access to
investigational new products. It is also a resource for parents whose
children are suffering from rare diseases.

The Role of Regulatory Science
Researchers have now defined the genetic basis of more than 2,000
rare diseases and identified potential drug targets for many rare and
neglected diseases. However, a large gap exists between advances in
basic scientific research and needed applied product development and
evaluation research, a gap that contributes to the lack of real
products getting to patients for many such diseases, despite advances
in basic sciences. This gap can be filled in part through enhanced
regulatory science, which is the development of tools, methods, assays,
standards, and models that help speed and improve the development,
review, and approval of innovative products.
The President's fiscal year 2011 budget for FDA includes dedicated
funding for the Agency to strengthen its critical scientific capacity
to leverage the opportunities provided by 21st-century science and to
enhance its scientific collaborations. In February 2010, FDA and NIH
announced a new collaboration on regulatory and translational science
to help speed the translation of research into medical products and
therapies, and we see real opportunities in working together to help
move promising therapies for rare and neglected diseases from concepts
to realities.
Through collaboration, FDA will foster new opportunities for
patients and consumers. Regulatory science at FDA holds great promise
for bridging the gap in our scientific knowledge about how medical
treatments impact children specifically and for unlocking their
potential for children. For example, during the 2009 influenza
pandemic, FDA's regulatory science work on dosing of the antiviral drug
Tamiflu (oseltamivir phosphate) in children under the age of 1 year was
adopted by countries around the world. As another example, FDA
scientists from the Agency's Center for Biologics Evaluation and
Research originated a collaborative effort with the National Toxicology
Program to improve the safety of gene therapies, in order to design
vectors that can deliver needed curative genes to children with genetic
diseases, but without the serious risk of malignancy seen in some
studies.
Enhanced regulatory science at FDA also is intended to inform and
strengthen our review processes and interactions. Strong science,
whether lab-based, clinical, or involving population and statistical
sciences, is critical in supporting the kind of intensely interactive
review processes that we know can improve the odds of success in
product development. This is particularly true for diseases where
experience is limited or to support product developers with more
limited experience. FDA scientists can meet with sponsors early in
product development, even before human studies are planned, to help
identify and resolve critical issues and provide input on proposed
development plans. Such meetings, and continued high quality scientific
interactions, while labor intensive, are particularly critical in
identifying and resolving scientific issues with respect to products
for pediatric rare diseases.

CONCLUSION

FDA's multifaceted and collaborative approach to addressing the
obstacles of product development for pediatric rare diseases has
resulted in many successes and real progress, but much more work
remains to be done to meet the tremendous needs of this population.
Through the statutes already in place, Congress has granted FDA
important authorities that we have found very useful to help address
this challenge. In addition, both new initiatives and enhanced efforts
engaging many FDA components, including in interactive review and
regulatory support for sponsors, collaboration and training, and in
regulatory science, are underway to facilitate development and
evaluation of needed products. We look forward to continuing to work
with you and our colleagues in the public health arena to address the
challenges that we face. Thank you again for this opportunity to
discuss pediatric rare diseases. I welcome your comments and questions.

Senator Brown. Thank you Dr. Goodman.
Dr. Guttmacher.

STATEMENT OF ALAN E. GUTTMACHER, M.D., ACTING DIRECTOR,
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT,
BETHESDA, MD

Dr. Guttmacher. Thank you, Senator Brown and Senators Enzi
and Senator Franken, for your interest in this truly important
topic, and for the opportunity to testify.
We appreciate your interest in a topic which is so
important to the many, many individual children who are
affected by rare diseases, and to their families.
I'd like to begin by illustrating this with one of the
literally millions of stories that really bring home to me, why
this is an important topic. It's a story of one of my former
patients, Kevin Hartmann, whom I've known since the day he was
born, when I became his physician. Kevin is now a young adult
with Marfan syndrome, an inherited rare disorder that affects
the body's connective tissue. Perhaps its most serious
manifestation is that the aorta can become distended and
stretched so thin that it tears, requiring emergency surgery,
or even resulting in sudden death, as was the case with U.S.
Olympic volleyball star Flo Hyman, several decades ago.
Individuals with Marfan syndrome are usually counseled to
avoid physical stress to their hearts, as is caused by many
athletic activities, and must be monitored closely their entire
lives. Having Marfan syndrome affects both the activity and the
personality and lives of individuals who have it, even when
they are children.
The availability of a medication that could slow aortic
growth and prevent its tearing would make an enormous
difference to Kevin and to the many other children with Marfan
syndrome. When Kevin was a young child, the only such drugs we
knew of, so-called beta blockers, were not as effective as we
wished for. However, a few years ago, groundbreaking research
supported by the NIH showed that another drug, already on the
market and approved by the FDA for other indications, Losartan,
dramatically prevented aortic enlargement in a mouse model.
Therefore, we are quite excited about the potential of an
ongoing clinical trial, funded by the National Heart Lung and
Blood Institute at the NIH, comparing Losartan with the beta
blocker Atenolol to see whether Losartan is also better in
humans at slowing the speed of aortic enlargement, which would
make a real difference in the lives of Kevin and other children
and young adults with Marfan syndrome. Kevin hopes that this
kind of approach will enable him to avoid the serious surgical
complications that, for instance, his father had from this same
condition.
Many such examples exist across the NIH. Although the NICHD
supports the bulk of research on child health and development,
most of the NIH's 27 institutes and centers include pediatric
research in their portfolios.
In fiscal year 2009, the last for which we have complete
data, the NIH funded nearly $3 billion in pediatric research
from its annual appropriation, and another $500 million through
the American Recovery and Reinvestment Act. This 2009 funding
included over $86 million in pediatric grants in the orphan
drug category.
Developing and testing drugs in children has long posed a
particular challenge because of children's particular
vulnerabilities. The Best Pharmaceuticals for Children Act, or
BPCA, seeks to address the lack of information on medication
safety, effectiveness, and dosing in children. The NIH is
authorized to identify therapeutic gaps in pediatrics and
support the research necessary to fill them. Led by the NICHD,
all of the NIH institutes and centers that have significant
pediatric portfolios contribute funds and expertise to
implement the BPCA.
Current projects include a number on understanding and
treating rare diseases. For example the National Cancer
Institute's Children Oncology Group is performing five BPCA
pediatric cancer drug studies. And the NICHD is funding a
pharmacokinetic and safety study of baclofen to treat
spasticity in children with cerebral palsy. Our BPCA
implementation efforts also include training to address the
dearth of pediatric pharmacologic researchers. In partnership
with the National Institute of General Medical Sciences, the
NICHD is now co-funding six postdoctoral trainees in pediatric
clinical pharmacology.
Some rare conditions affect individuals systemically, thus
requiring the expertise of the NIH institutes. One way to deal
effectively with such situations is a trans-NIH working group.
For instance, NICHD leads one such effort, the NIH Fragile X
Research Coordinating Group. Nine participating NIH institutes
and centers meet regularly to discuss implementation of the
research plan on Fragile X. Through support from several NIH
institutes and the private foundations Autism Speaks and FRAXA,
scientists are testing a compound in healthy adults as a
potential treatment for Fragile X syndrome. Should the results
from these adult trials prove promising, the compound will then
be assessed for pediatric safety and in clinical trials in
children. Such public/private partnerships can help leverage
investment and other resources for rare disorders.
Individually, the NIH institutes and centers are engaging
in a wide variety of research projects on pediatric rare
diseases, and a sampling of those projects is included in my
written statement.
Established in 1993, the NIH Office of Rare Disease
Research, or ORDR, helps to coordinate and support these
activities across the NIH. The ORDR, in collaboration with six
other NIH institutes, oversees the Rare Disease Clinical
Research Network, which comprises 10 consortia with more than
70 sites across the United States. The goals of these sites are
to make investigational studies and treatments more accessible
to patients with rare diseases, and to facilitate the
recruitment of patients for clinical trials. Researchers
affiliated with the network study more than 40 rare diseases,
many of them pediatric. The network also targets early-stage
investigators, to encourage them to focus their careers on rare
diseases.
Another new NIH program specifically developed therapeutics
for rare diseases, including pediatric condition. Launched in
May 2009, the Therapeutics for Rare and Neglected Diseases, or
TRND, initiative is a trans-NIH collaborative program, which
has already been mentioned today. In most cases, a TRND
investigator will begin with a chemical compound that is known
to have some biological effect in the laboratory for a given
rare disease and progress to a candidate compound suitable for
a new drug application to the Food and Drug Administration.
And, as Dr. Goodman has referenced, this is one of a number of
new endeavors where NIH and FDA are increasingly working
closely together to try to overcome the many obstacles in drug
development for rare diseases.
In terms of TRND, often the candidate compound will be
licensed to pharmaceutical companies for clinical testing,
permitting the TRND program to remain focused on the more
scientifically challenging stages of preclinical development.
Our goal is to derisk development of new drugs for less common
diseases, to make them more attractive to private companies.
Among the projects initiated in 2010 is a re-purposing
project. That is, testing a drug previously developed for
another purpose, this time for the rare pediatric
neurodegenerative disease Niemann-Pick Type C.
Newborn screening is a mainstay for improving the lives of
many children with rare diseases. It permits referral to
medical specialists and treatment for numerous pediatric rare
diseases to occur as soon after birth as possible. The NICHD
leads NIH efforts to increase the number of rare and common
conditions for which newborn tests are available through the
Hunter Kelly Newborn Screening Program, aimed at identifying
new screening technologies and furthering research on managing
and treating conditions that newborn screening can detect.
For families whose children have a rare disorder, obtaining
a diagnosis can be a devastating process requiring years of
frustrating effort. For many conditions, even if there is no
cure, a diagnosis is essential to receive appropriate
treatment. Together, the ORDR, the National Human Genome
Research Institute, and the NIH Clinical Center recently
organized the NIH Undiagnosed Diseases Program. The goals of
this new program, which sees both pediatric and adult patients,
are to provide answers to patients with mysterious conditions
that have long eluded diagnosis, and to advance our basic
understanding of rare diseases.
With this breadth of NIH-funded research, and armed with
new resources such as the Human Genome sequence, we are
entering an historic era of greater understanding of the
biology of many rare diseases, and thus, for the development of
more effective therapies.
Thank you, again, for the opportunity to testify today, and
I would be pleased to answer any questions you might have.
[The prepared statement of Dr. Guttmacher follows:]

Prepared Statement of Alan E. Guttmacher, M.D.

Good morning, Mr. Chairman and members of the committee, my name is
Alan E. Guttmacher, and I am representing the National Institutes of
Health (NIH), an agency of the Department of Health and Human Services
(HHS), at today's hearing on pediatric rare diseases. By background, I
am a pediatrician and medical geneticist and currently serve as Acting
Director of the Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD) at the NIH. We appreciate the
committee's interest in this topic, which is so important to the
individual children who are affected by rare diseases and to their
families. A rare (or orphan) disease is generally considered to have a
prevalence of fewer than 200,000 affected individuals in the United
States.
Let me begin by offering a specific example: one of my former
patients, Kevin Hartmann, has Marfan syndrome. This is a genetically
inherited disorder which affects the body's connective tissue.
Individuals with this condition tend to grow extremely tall and thin,
have unusually lax joints and share certain other physical features.
One of the most serious issues associated with this condition is that
the aorta can become stretched so thin that it tears, requiring
emergency replacement of the aortic root or sometimes resulting in
sudden death, as was the case with the U.S. Olympic volleyball star,
Flo Hyman. Individuals with Marfan syndrome are usually counseled to
avoid physical stress to their hearts or other tissues caused by many
sports, and must be monitored closely all their lives. Kevin has made a
terrific video about his life with Marfan syndrome, http://vimeo.com/
12005105.
Clearly, the availability of a medication that could slow aortic
growth and prevent tearing would make an enormous, literally
potentially lifesaving difference to Kevin, his family, and others with
Marfan. In 2007, a clinical trial began, funded by the National Heart,
Lung, and Blood Institute (NHLBI) at the NIH and conducted through its
Pediatric Research Network, comparing two drugs--Atenolol and Losartan,
which are already on the market--to see if one is better than the other
at slowing the speed of aortic enlargement. Both of these drugs are
commonly used to lower high blood pressure, but groundbreaking research
using a mouse model and published in 2006, supported by several NIH
Institutes and Centers (ICs), showed that Losartan prevented aortic
enlargement and other features seen in individuals with Marfan
syndrome.
Many such examples exist across the NIH. Although the NICHD
supports the bulk of research on normal and abnormal child health and
development, most of the NIH's 27 ICs include pediatric research in
their portfolios. In fiscal year 2009, the last year for which we have
complete data, the NIH funded nearly $3 billion in pediatric research,
with another $505 million for pediatric research from funding under the
American Recovery and Reinvestment Act. Although the NIH does not
report specific funding information on rare diseases, it does collect
and report on the category of orphan drugs; in fiscal year 2009, the
portion of grants funded by the NIH in the Orphan Drug category that
was also reported in the Pediatric category was just over $86 million.
Developing and testing drugs in children has long posed a
particular challenge, even for drugs used to treat more common
conditions, because of the vulnerable nature of this population and
because children change substantially as they grow. The Best
Pharmaceuticals for Children Act (BPCA), most recently reauthorized in
2007, sought to redress the lack of information on medication safety,
effectiveness, and dosing in children through several means. Under the
act, the NIH is authorized to identify therapeutic gaps in pediatrics
and support the research necessary to fill those gaps. Led by the
NICHD, all of the NIH ICs that have a significant pediatric portfolio
contribute funds and expertise to implement the BPCA. Current co-funded
projects include many studies on understanding and treating rare
diseases: the National Cancer Institute's (NCI) Children's Oncology
Group is performing five BPCA pediatric cancer drug studies, the NHLBI
is supporting the ``Baby HUG'' trial, aimed at demonstrating whether
the drug hydroxyurea is effective at decreasing painful crises and
preventing chronic organ damage in young children with sickle cell
disease, and the Foundation for the NIH has contributed to NICHD's
pharmacokinetic and safety study of Baclofen to treat spasticity in
children with cerebral palsy.
Some rare conditions affect individuals systemically, thus
requiring the expertise of several of the NIH ICs. One mechanism used
at the NIH to deal effectively with such conditions, is the
establishment of a trans-NIH working group. The NICHD leads one such
group, the NIH Fragile X Research Coordinating Group. Fragile X
syndrome (FXS) is the most common inherited cause of intellectual and
developmental disabilities. Nine participating NIH ICs meet regularly
to discuss implementation of the Research Plan on Fragile X and
Associated Disorders, which the group developed with the input of
outside experts and published in fiscal year 2008. Each goal area of
the plan is being addressed by grants funded across the member
institutes. One excellent example is a Phase I trial of a novel drug
that may effectively compensate for the missing protein in individuals
with Fragile X; through support from several NIH ICs [the NICHD, the
National Institute of Mental Health (NIMH), the National Institute of
Neurological Disorders and Stroke (NINDS)] and the private foundations
Autism Speaks and FRAXA, scientists at Seaside Therapeutics are testing
a leading compound in healthy adults as a potential treatment for FXS.
Results suggest that the medication is safe and tolerable; a Phase II
clinical trial study of dosage and efficacy in adults with FXS is
planned. Should the results from these adult trials prove promising,
the compound will be assessed for pediatric safety and clinical trials
in children. Such public-private partnerships can help leverage
investment and other resources for rare disorders for which no
treatment is currently on the market.
Individually, the NIH ICs are engaging in a wide variety of
research projects on pediatric rare diseases. Established in 1993, the
NIH Office of Rare Diseases Research (ORDR) helps to coordinate and
support these activities across the NIH and to provide information to
the research and patient communities about these conditions, potential
treatments, and ongoing research opportunities. Among other activities,
the ORDR, in collaboration with six other NIH ICs, oversees the Rare
Diseases Clinical Research Network, which comprises 10 consortia with
more than 70 sites across the United States. The goals of these sites
are to make investigational studies and treatments more accessible to
patients with rare diseases, and to facilitate the recruitment of
patients for clinical trials. Researchers affiliated with the Network
study more than 40 rare diseases, many of them pediatric, such as
intellectual and developmental disorders, rare bone marrow failure
conditions, and rare pediatric liver disease. Many Network members are
testing the safety and efficacy of new therapeutic agents, including
pediatric therapeutics. For example, the NINDS supports several of the
research consortia within the Network, including the Inherited
Neuropathies Consortium and the Lysosomal Disease Network, both of
which include research on disorders affecting children. The Network
also is targeting early stage investigators to encourage them to center
their careers in rare diseases; in September 2010, the Network and the
NIH Clinical and Translational Science Awards (CTSAs) are cosponsoring
a conference to teach new researchers and junior faculty about rare
disease research methodology.
Another new NIH program is aimed specifically at the issue of
development of therapeutics for rare and neglected diseases, including
pediatric conditions. Announced in May 2009, the Therapeutics for Rare
and Neglected Diseases (TRND) initiative is a trans-NIH, collaborative
program overseen by ORDR and administered by the National Human Genome
Research Institute (NHGRI). TRND investigators will begin with a
chemical compound that is known to have some biological effect in the
laboratory on a given disease, and progress to a candidate compound for
a new drug application to the Food and Drug Administration. Often, the
candidate compounds will be licensed to pharmaceutical companies for
clinical testing, permitting the TRND program to remain focused on the
most scientifically challenging stages of preclinical development. The
goal is to ``de-risk'' development of new drugs for less common
diseases to make them more attractive to private companies. At the same
time, this innovative program will advance the entire research
enterprise by allowing open dissemination of the information learned
during the initial testing phases, expanding the overall research base
and potentially shortening the time period for the development of new
drugs. Among the new projects initiated in 2010 is a mid-stage ``re-
purposing'' (testing a drug developed for another purpose) project for
the rare pediatric condition, Nieman-Pick Type C (NPC), a neurodegen-
erative disease. As will be true of many of TRND's efforts, this
project is a collaboration of government, academic scientists, and
patient advocacy groups.
In addition to the research activities already mentioned, a
sampling of the types of research across the NIH illustrates the range
of basic to clinical research activities underway and also provides a
sense of why therapeutics for some pediatric rare conditions remains so
elusive.

The NCI's Childhood Cancer TARGET Initiative is a public-
private partnership developed to harness the power of cutting-edge
genomics technologies to identify valid therapies for childhood cancers
rapidly. The program's initial focus was on neuroblastoma and acute
lymphoblastic leukemia (ALL) but was expanded with ARRA funds to
include several other conditions. As a result of TARGET, there will be
a virtually complete catalogue of gene mutations and other gene
alterations that occur in these childhood cancers.
The Children's Oncology Group (COG) develops and
coordinates cancer clinical trials at over 200 member institutions
throughout the United States and around the world. Through the COG
network, children with cancer can access state-of-the-art therapies
regardless of where they live. One of the many consortia of
investigators within COG, the Pediatric Brain Tumor Consortium, aims to
rapidly conduct phase I and II clinical evaluations of new therapeutic
drugs, biological therapies, and radiation treatment strategies for
children.
The National Eye Institute has sponsored research that
provides health care professionals with improved prognostic indicators
and treatments options for retinopathy of prematurity, a blinding
disease that affects premature infants. The Early Treatment for
Retinopathy of Prematurity study demonstrated that therapy administered
in the early stages produced far better outcomes than traditional
timing of treatment. The study also resulted in an improved risk
assessment model to identify those infants at highest risk for
developing severe vision loss.
In addition to its research on rare pediatric genetic
diseases, such as cystic fibrosis, sickle cell disease, thalassemia and
hemophilia, which has resulted in many individuals with these
conditions living into adulthood, the NHLBI also supports research on
rare acquired pediatric diseases. For instance, the NHLBI funded the
development of recombinant surfactant to improve the lung function of
the children with bronchopulmonary dysplasia, a serious lung condition
that primarily affects children who received oxygen therapy when they
were premature neonates.
Medulloblastoma, the most common form of pediatric brain
tumor, is relatively responsive to traditional cancer treatments
(surgery, chemotherapy, and radiation), but long-term survivors often
suffer from life-long developmental, behavioral and cognitive
disturbances. Investigators supported by the National Institute on
Aging are working to understand the basic mechanisms underlying
medulloblastoma, so novel treatments can be developed to target tumor
cells specifically, without damaging the developing brain.
The National Institute of Allergy and Infectious Diseases
(NIAID) conducts and supports a broad portfolio of basic,
translational, and clinical research on primary immune deficiency (PID)
diseases. PID diseases, such as DiGeorge syndrome, Hyper-Immunoglobulin
E syndrome, and Severe Combined Immunodeficiency (SCID), are rare
genetic diseases that lead to recurring, often life-threatening
infections in affected individuals. Among other research-related
activities, the NIAID-supported Primary Immune Deficiency Treatment
Consortium is a multi-center collaborative network focused on studying
children with PID diseases and the treatment, with hematopoietic stem
cell transplantation, of these diseases.
Epidermolysis bullosa (EB) is a group of rare, inherited
blistering conditions. Recessive dystrophic EB (RDEB) is a particularly
severe form of the disease, with debilitating, chronic wounds of the
skin, mouth, and esophagus. Researchers supported by the National
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
have succeeded in healing wounds in a mouse model of this disease by
injecting the mice with RDEB patient cells in which the gene defect has
been corrected. This approach may be useful in developing therapies for
RDEB. On another front, the NIAMS helped to establish the Childhood
Arthritis and Rheumatology Research Alliance, a nationwide network of
pediatric rheumatologists. The group is completing a clinical study of
the effects of statins (drugs used to lower ``bad'' cholesterol)
against fat buildup in the blood vessels of children with lupus, which
could lead to preventive treatments for these pediatric patients.
Recurrent respiratory papillomatosis (RRP) is a disease in
which non-cancerous tumors grow in the air passages leading from the
mouth and throat into the lungs. The tumors may grow quickly, requiring
surgical removal to prevent blockage of the respiratory tract and
suffocation. Caused by a virus possibly contracted during childbirth,
the tumors often recur, requiring additional surgeries. Researchers
funded by the National Institute on Deafness and Other Communication
Disorders are exploring whether the use of a common anti-inflammatory
drug may delay or prevent the recurrence of these tumors, as well as
examining the genetic makeup of individuals of those who are exposed to
the virus but do or do not develop RRP.
In the early 1960s, the life expectancy of a child born
with cystic fibrosis (CF) was just 10 years; current life expectancy
for individuals with CF has almost quadrupled to 37 years. The 1989
discovery of the CF gene by now-NIH Director Francis Collins opened
important windows into understanding the CF disease process, and
suggested potential therapeutic approaches. While there is, as yet, no
cure for CF, ongoing research provides hope for continued improvement
of medical care for CF. Scientists supported by the National Institute
for Diabetes and Digestive and Kidney Diseases recently developed a pig
model of the disease, which provides an important tool for testing
therapeutic strategies. New medications are currently in development,
including one which may provide a protein for patients with some
versions of the gene, and others to improve the salt-water balance in
people with CF to enable them to clear mucus from their lungs.
Understanding environmental exposures that can lead to
clinical disease is critical to the prevention of those diseases or
development of therapies to treat them. For example, investigators
funded by the National Institute of Environmental Health Sciences are
studying cognitive and motor development related to prenatal exposure
to organophosphate pesticides in 3- to 9-year-olds. The study is
evaluating the effects of these exposures on brain structure,
metabolism, and connectivity among regions of the brain, and assessing
attention deficit hyperactivity disorder, pervasive developmental
problems and sleep disorders in these children.
To build on new opportunities made possible through gene
discoveries and other basic science advances, the NINDS supports
translational research programs to develop therapies for spinal
muscular atrophy, muscular dystrophies, and other rare pediatric
neurological diseases. Some of these therapies are now entering early
clinical trials, and a new clinical trials network that will help
expedite such research for these disorders is underway. In May 2010,
the NINDS and the NIAMS launched a 5-year natural history study of
Duchenne muscular dystrophy, which aims to validate non-invasive
approaches to monitor the progression and treatment of this disease,
with the potential to facilitate the development of promising new
therapies.

For many parents whose children have just been diagnosed with a
rare condition, it is difficult to find reliable information about that
condition. The Genetic and Rare Diseases Information Center (GARD) was
created in 2002 by the NHGRI and the ORDR to help people find useful
information about these diseases by providing timely access to
experienced information specialists who can offer information on what
research is being conducted, what genetic testing services are
available, and which patient advocacy groups to contact for a specific
rare or genetic disease (see http://rarediseases.info.nih.gov/GARD).
Genetics Home Reference is a free online health resource from the
National Library of Medicine (NLM). It is designed to give patients,
families, and caregivers basic information about genetic conditions and
the genes or chromosomes related to these conditions. This Web site
includes summaries of more than 500 rare genetic disorders, many of
which directly affect the health of infants and children. The site also
provides background materials to help the public understand the
significance of genetic disorders and newborn screening. Genetics Home
Reference is available at http://ghr.nlm.nih.gov.
For many families whose children have a rare disorder, even
obtaining a diagnosis can be a devastating process taking years of
frustrated effort. For many conditions, a diagnosis can be essential in
allowing the patient to receive appropriate treatment, even if there is
no cure. Early treatment or other intervention can often ameliorate the
full impact of the disease. The NIH is taking steps to expand
scientific knowledge around rare diseases and diagnoses.
Together, the ORDR, the NHGRI, and the NIH Clinical Center recently
organized the NIH Undiagnosed Diseases Program. Using a combination of
the extensive scientific and medical expertise available at the NIH,
the twin goals of this new program are to provide answers to patients
with mysterious conditions that have long eluded diagnosis, and to
advance medical knowledge about rare diseases. Any patient, whether a
child or adult, with an undiagnosed medical condition can be referred
by his or her physician for possible evaluation in the program.
Genetic screening shortly after birth permits referral to medical
specialists and treatment for pediatric rare diseases to occur as soon
as possible. Starting in the 1960s, with a screening test for a rare
disorder (phenylketonuria, or PKU), a majority of States now screen for
29 conditions. The NICHD is leading research efforts to increase the
number of genetic tests for a wide range of rare and common conditions
through the Hunter Kelly Newborn Screening Program, formally
established in 2009 to honor the son of National Football League Hall
of Fame quarterback Jim Kelly, who died in 2005 of Krabbe disease, a
rare, fatal genetic disorder affecting the nervous system. The NICHD
program is aimed at identifying new screening technologies and research
on managing and treating conditions that newborn screening can detect.
Because most conditions targeted by newborn screening are rare,
large sample sizes are needed for research, and standard coding and
terminology are required so data can be compared and pooled across
State jurisdictions. In collaboration with other HHS agencies, the NLM
created a Newborn Screening Coding and Terminology Guide, a free online
resource that provides guidance to promote efficient electronic
exchange of standardized newborn screening data. The goal is to
encourage widespread use of these national data guidelines for
transmitting newborn screening results to support the creation of
regional and national data registries that will be used for detection,
prevention, and treatment of rare conditions that affect the pediatric
population, and facilitate more timely diagnosis and follow-up in the
medical home.
Research on pediatric rare diseases, and future breakthroughs, are
dependent on the interest and expertise of well-qualified scientists.
In addition to the NIH's ongoing research training and career
development programs, the NIH's Office of Science Education, in
collaboration with ORDR, has developed a science education module for
middle schools focused on medical genetics and rare diseases such as
Marfan syndrome, childhood leukemia, and flesh-eating bacteria. After
taking the lessons, students will have investigated what constitutes
scientific evidence, will understand the fundamentals of inheritance
and learn that this explains why some rare diseases are more prevalent
in some groups than others, and will understand that many people with
rare diseases can lead meaningful lives and should not be stigmatized.
This curriculum will be available in September and free to teachers, in
the hopes that it will engage young people on these topics and catalyze
their thinking about choosing scientific careers.
With this breadth of NIB-funded research, and armed with such new
resources as the human genome sequence and approaches such as the TRND
program, we are poised for an era of greater understanding of the
biology of many rare diseases and thus, more effective therapies. Thank
you for the opportunity to present today, and I would be pleased to
answer any questions you may have.

Senator Brown. Thank you, Dr. Guttmacher.
The testimony from both of you really underscores the
importance of coordination in research. Senator Bond and I
introduced legislation to create a nationally coordinated
research network to pursue new treatments and cures for
childhood diseases, the Pediatric Research Consortia
Establishment Act, based in part and modeled after the highly
successful NCI sort of efforts to coordinate.
And in light of that, I'd like to ask--starting with Dr.
Gutt-
macher--a concern I've heard a number of times is, ``The
current research environment does not include adequate
incentives to encourage better sharing of information among
researchers.'' And I think that's especially a problem on rare
pediatric diseases, where the population base is so small, and
collaborative efforts are that much more important for learning
more about diseases, making that lack of cooperation and
coordination and sharing especially troublesome.
Talk to me about what steps NIH is taking to make sure that
important research into rare pediatric diseases is made more
widely available among researchers in the scientific community.
Dr. Guttmacher. You raise several very important issues.
One of them is this question about cooperation, collaboration
in scientific research. And I think, in some ways, the most
fundamental advance that we've made in scientific research in
the last decade is changing the culture of scientific research.
The Human Genome Project, which has been mentioned previously,
and for which the Congress should be justifiably proud for
funding it and really sparking it, in many ways, many people
make the obvious sort of observation that the reason for doing
this was to sequence the human genome. That was the reason for
doing it, but I would argue that its most fundamental
contribution to science has been helping to change the culture
of science.
A fundamental aspect of that program was that, every 24
hours, all of the research data developed was made publicly
available for anyone who had a computer and paid their
electricity bill, and therefore, could download the data. That
has been instrumental, along with a number of other advances,
in changing the culture to say that data that's derived in
biomedical research, particularly biomedical research that's
funded by the Federal Government, does not belong to the
principal investigator, it belongs to society, and that we need
to come up with ways to encourage collaboration, to make
research data available not just to the person who developed
it, but to the entire research world.
This is particularly important, this cultural change, when
we talk about rare diseases. Because there will be a relatively
small group of researchers involved in these diseases, it's
particularly important that they work collaboratively to tackle
this.
I think it also has caused the NIH to think of new and
creative ways to work across the silos that are the NIH
institutes too often. NIH institutes were founded for various
reasons, but today's science tends to go to looking at the
basic sort of biological causation of disease, and that does
not observe the silos that we happen to have at NIH. So, NIH
has come up with many ways to make sure that we fund creative
research that goes across the traditional boundaries that we've
had, which, again, is particularly important, I think, when we
talk about both pediatric research and rare disease research,
let alone the combination of the two.
Senator Brown. Thank you.
Dr. Goodman, you mentioned, in your opening statement that
conducting clinical trials for rare pediatric diseases,
presents particular challenges. Our second panel's witnesses
will talk about the need to ensure that requirements for
clinical trials are stringent enough to provide reasonable
assurances of safety and efficacy, but also take into account
that patients with rare diseases might be--and, I think, are,
in many cases--willing to accept higher levels of risks than
other patients might be willing to do. So, speak to that issue
for a couple or 3 minutes, if you would.
Dr. Goodman. Yes, I think--this is a very important point--
I think, not just in pediatrics, but, I will say, quite
generally, the clinical trial enterprise and developing the
clinical information we need to develop products in this
country is very threatened. And it's a whole other subject that
I think we could spend a lot of time on.
With respect to clinical trials in general, we do look at,
and we must look at this, in a risk-benefit manner. Obviously,
the equation of what could go on, and at what point in a
product's development, really depends on, What are the
available treatment options for that individual? What do we
know about the product? So, we approach looking at proposed
clinical trials in very much of a risk-based manner. We've
recently made it possible to test compounds, certain compounds,
where appropriate, earlier in individuals. We had a number of
initiatives to increase access to investigational therapies,
where appropriate. So, we're really behind this.
I would also say there's a whole science behind clinical
trials. And I think we need--we are moving, as part of both
personalized medicine and as we incorporate genomic information
into clinical studies, from very--the necessity for very large
trials that might observe a benefit only in a proportion of the
population, to much more targeted trials that can be much more
efficient and effective. And we're developing science around
how to analyze data from much smaller numbers of patients to
reach conclusions.
So, I think there's a lot of promise in this area, but
there's a lot of need. Bottom line: we do look at what patients
need and the specific product and trial in mind when they come
to FDA.
Senator Brown. Thank you, Dr. Goodman.
Senator Enzi.
Senator Enzi. Thank you, Mr. Chairman.
And I do have a number of questions, for both of you, which
I won't have time to be able to do this morning. So, I will
submit a number of the more technical ones in writing, and
would hope that you would respond on them. It will be helpful
as we proceed on this.
But, I'll begin with Dr. Goodman. I like the idea of these
NIH and FDA initiatives linking up to cover the span of product
research, development, and then commercialization. It seems
that the baton is passed well from initiative to initiative,
but are there any gaps?
Dr. Goodman. Yes. I think there are huge gaps. And
essentially, there's been a--the academic and basic science
enterprise has been a very distinct one with a distinct culture
and in distinct locations, and it's very different from the
product evaluation and development and manufacturing
enterprise, where industry and FDA are major players. And I
think one of the things we really want to look at in our new
NIH/FDA partnership--and frankly, we've been doing, in targeted
areas--is how we can identify the biggest opportunities to fill
that gap and increase the success of the enterprise.
So, I would say, in general, there are many gaps there.
And, as I mentioned, there are also scientific gaps. How do we
move an idea for a product, or something in an academic
laboratory, into a product we can safely give people, study and
understand its safety and effectiveness.
What we want to do is not try to do everything--we'd love
to do everything, but obviously there are resource
constraints--but, identify, where we can, where we can bridge
this gap to really meet the needs of our medical system, public
health, and also of these terrible needs of patients with rare
diseases. So, we're very interested in doing that. A lot of it
is about how we do things and how we work together.
Senator Enzi. Thank you.
Dr. Guttmacher, how has the NIH Common Fund improved the
Agency's ability to fund research on rare and neglected
diseases? And what about pediatric research?
Dr. Guttmacher. Sure. I think, Senator Enzi, that's a
wonderful example of this very problem that I was mentioning
before of following the way that's--scientific discovery goes
these days, which is across the traditional divisions that
we've had between and among NIH institutes. The Common Fund
allows us to approach biological issues in a more creative kind
of way, to have funding that can look at the various
manifestations.
What happens with many rare diseases is that they are
multisystem diseases, so that, while one NIH institute,
historically, may have taken the lead in working with that
disease, it's very important that the community of researchers
involved in that disease come from very different perspectives,
very different disciplines. And the Common Fund allows a form
of funding that really is better, often, at bringing these
somewhat large and very broad teams together to look at
diseases.
One of the rare diseases I've had a particular research
interest in, myself, is one called hereditary hemorrhagic
telangiectasia. It's even rarer to find someone who can spell
it. But, it's a rare disease, and that's one that affects the
lungs, the brain, the skin, the GI tract, etc. So, I know full
well, from my own experience, that it's been important to come
up with ways to fund research that goes across many areas. And
the Common Fund has been a very good mechanism for doing that.
Senator Enzi. Good. How many therapies or research projects
will the Agency be able to conduct and complete with the $24
billion? On average, how much is necessary to--and I realize
averages don't work very well--but how much, on average is
necessary to successfully develop a candidate compound that's
ready to be tested in patients and licensed to the private
sector?
Dr. Guttmacher. To some degree, we don't yet know the
answer to that question. And that's because both--that the
costs do vary significantly, depending upon exactly what
compound you're looking at and what disease you're looking at.
But also, part of what the TRND program is trying to do is to
come up with some new processes for going through these steps
in developing new medications. And so, it's both an experiment,
in terms of finding some new therapies, but also an experiment
in seeing if we can't do the process somewhat more efficiently
than has been done historically.
We're hoping that--to get to that stage in drug
development, it will cost somewhere, we would suspect, between
$5 million and $8 million per compound. But, we don't really
know until we have enough of them out of the pipeline.
Senator Enzi. OK. Thank you.
And my time is expired.
Senator Brown. Thank you, Senator Enzi.
Senator Franken.
Senator Franken. Thank you, Mr. Chairman.
Thank both of you gentlemen, for your testimony.
And this is to both of you. There seems to be significant
differences between the incentives for developing orphan drugs,
on the one hand, and humanitarian-use medical devices, on the
other. Could either, or both, of you please comment on these
differences?
Dr. Goodman. Yes. Well, I think, you know, we do operate
under the laws that we have. And, you know, I would say it's
good that it has been recognized that devices intended for
small populations and rare diseases face some of the same
economic and development challenges that drugs do. This is
recognized in the humanitarian device legislation. I think it's
good that that's recognized. And it is having an effect. We're
seeing--I think there's been about 50 devices approved under
the humanitarian device exemptions. So, that's good.
Drugs and devices are different, so it's understandable
that you have some differences in this legislation. But, I
would say, many of the challenges are the same.
Senator Franken. What are some differences that you see?
For example, I know that a drug developed under this system has
a long life, and so the patent on it is valuable.
Dr. Goodman. Right.
Senator Franken. But, the devices tend to have a shorter
life. So, that's a difference, isn't it?
Dr. Goodman. That's right. One of the very exciting and
interesting things about the device development process is they
tend to be frequently improved. There's a lot of innovation
around engineering and technology.
Senator Franken. So, you don't have quite the same
incentive there.
Dr. Goodman. So, the----
Senator Franken. I'm trying to find----
Dr. Goodman. Right. And the original approval paradigms are
different, so that, for example, the major incentive in the
orphan program, of the additional exclusivity, is not applied
to devices. So, I think that's definitely one difference there.
Senator Franken. I'm proud that many humanitarian-use
devices have been generated by companies with Minnesota ties.
But, I think they could do more, under the right conditions.
I'd like to ask GAO to look into this issue further and do a
thorough analysis of how the incentives in the drug industry
compare to those in the device industry. We need to make sure
that we're doing all we can to get devices to the kids who need
them. I'll be following up with the GAO shortly to pursue this
question. And I look forward to revisiting the issue with the
committee.
Dr. Guttmacher, I'm sorry, I want to ask you a specific
question. I was pleased to work with Senator Brown to request
appropriations for research on epidermolysis bullosa, which is
a terrible genetic--skin disease that affects about 30,000
Americans, mostly children. But, in reality, we can't do a
separate request for each disease.
In Congress, we hear from many groups advocating or
progress on rare disease--parents, family members, and patients
themselves. And there are a lot of disease-specific bills to
advance research on these rare conditions, which is difficult,
because there are really so many of them--really thousands.
Would you agree that we need more of an overarching plan
for rare and neglected diseases, to enable the basic science
and clinical research for these diseases? And, if so, what do
you think that would look like, or should look like?
Dr. Guttmacher. I think we already have some elements of
such a plan, and I think it is the way to approach this.
Because, what one really wants to be able to do is to follow
the scientific opportunities, the ones that are most likely to
be able to make advances. And sometimes, particularly when
one's talking about basic science, you're not even exactly sure
where it's going to lead--what disease it's going to have an
impact on, for instance.
So, I think having both funding and programs in place, it
allows one to look broadly across rare diseases. Many rare
diseases do have relationships to others so that sometime one
can make an advance in one area that also goes to benefit
another. I think that one needs to follow the scientific
opportunities.
I think, also, though, that there, increasingly, have been
partnerships between, for instance, the NIH and various
specific disease advocacy organizations and groups, looking at
creative ways together, and moving forward research in that
area. That can be very important, not simply in terms of
providing resources, though that is helpful, but also often
bringing together communities of researchers who may not be
paying attention to a specific disease. The public advocacy
groups, the patients themselves, in working in concert with the
NIH and the FDA, can often make real progress that neither
could make by themselves. Sometimes these programs, and often,
simply relationships, and having discussions, and making sure
that one is getting the perspectives of multiple groups
involved in doing it.
Senator Franken. Yes.
Dr. Goodman. I'd like to add an example to that, if
possible. One of the things we can do, and we've done with our
colleagues at NIH--it's involved patient groups, product
developers--is where we see an area where the science isn't all
there yet, but there's a lot of interest, there's a lot of
innovation. People have new products.
We will frequently hold workshops that essentially bring
all the developers together, all the scientists--basic and
applied, the clinicians--and say, you know, ``What is the best
approach to moving this field forward?'' For example, we've
done this in a number of areas of stem cells. So, if we want to
investigate stem cells for cancer, for heart disease, for
replacing insulin in diabetes, to get islet cells, for example.
What are the things--build in, up front--What are the things
we're going to need to know at FDA? What are the tools the
scientific community needs and the issues they need to resolve
to say, ``Does this work? Can we make this product in a way
that can be a real product that helps people?''
So, we have quite a number of these workshops that advance
this applied science that really bridges to get the products to
patients. And, you know, I think we need to be much more
strategic, and have that be our normal practice, rather than
the exception.
Senator Franken. Thank you.
Senator Brown. Thank you, Senator Franken.

Statement of Senator Casey

Senator Casey. Thank you very much.
I want to thank Dr. Goodman, Dr. Guttmacher, for your
testimony and for the work you do on so many of these issues.
I also want to thank both Senator Brown, Senator Enzi, and
especially Senator Brown, for calling this hearing and
highlighting all of the challenges that we face when it comes
to these diseases and the strategies that we employ to deal
with so many difficult issues here.
For me and for, I think, a lot of Members of Congress, we
can't go through a week, or sometimes even a day, without being
both informed and inspired by constituents who come to us with
a problem, or sometimes more than one problem, and they give us
ideas about how to solve it or how to deal with a particular
problem. Senator Specter and I had a visit, going back a number
of years ago, from the mother of Nino Todaro. And Nino's mom,
Lori, was what every child should have, a passionate advocate
for her son. And in this case, he had the blessing of a
wonderful mother, who was a fierce advocate on his behalf, and
also the blessing of medical technology and all of the wonders
that come with that.
But, the problem he had was that even though the NIH was
treating him for his illness, a rare disease known as, periodic
fever syndrome--and he was getting that treatment--the problem
was that after his treatment at NIH ended, the treatment was
then denied by his insurance company because it was,
``experimental.''
And so, Senator Specter and I introduced Senate bill 406,
which would deal with that kind of gap that a lot of families
and children have to deal with everyday.
So, I'd ask you about that basic problem, where you have
treatment and progress made for an individual or a group of
individuals--in this case, children--and then you have that gap
because their treatment is considered experimental.
Then I want to ask a second question, in the limited time
that I have, about antibiotics. We have had spectacular success
with infant mortality in the United States going from 20
percent in the 19th century to under 1 percent in the most
recent number I have here, which is 1998. But, you have
antibiotic strategies that are then adversely impacted when you
have resistance built up.
So, can you speak to both of those issues? What's the
strategy for making sure that when resistance is built up, you
have a strategy to deal with that kind of resistance, No. 1?
And No. 2, is the type of investment that has to take place to
deal with that basic problem. I know that's a lot, and you've
got a minute and 40 seconds to do it. But, we'll try to revisit
it if your time gets short. We can do it on the second round.
Dr. Guttmacher. I think, to address the issue of antibiotic
resistance, there are two major steps. One is to make sure the
antibiotics are being used appropriately. One of the real
reasons for antibiotic resistance is through inappropriate
overuse of antibiotics, whether they be in humans or in other
animals. So, one real way to prevent it is to use antibiotics
when indicated, and not at other times, because the more widely
they're used, the more resistant strains you're going to
develop.
The other one, of course, is to try to move more quickly
than the bugs do; that is, to advance, in terms of new drugs,
more quickly than the various bacteria are able to evolve to be
resistant to the old ones. And that's going to be--no matter
what else we do--it's one of the major reasons why we need to
develop new antibiotics, because old ones do tend--not all--
but, they do tend to develop--or, strains develop resistance to
them. So, I think it's both a question of use and in terms of
development of new antibiotics.
Senator Casey. But new investments are needed here?
Dr. Guttmacher. New--I think, clearly, as in the rest of
developing pharmaceuticals, whether it's antibiotics or other
pharmaceuticals, it takes investment, in terms of both basic
research and then also more translational applied research, to
be able to do it.
Senator Casey. Dr. Goodman, any thoughts?
Dr. Goodman. Well, I have a lot of personal interest here,
and passion about it. When I was at the University of
Minnesota, we had a very strong program in how we used
antibiotics in trying to reduce development of resistance. So,
I agree with Alan that how we use antibiotics, in human use and
agriculture, is very important. And that's one target.
I would say that it's interesting you brought this up here,
and very appropriate, because it is another area very similar
to what we've heard about rare diseases or device development
for small populations, where the economic incentives for
development do not always drive the public health outcome we
seek. So, I think it's very reasonable for you to consider that
issue, you know, How do we incentivize development of new
drugs?
The other thing about appropriate use is, as we think about
healthcare reform and having a very good learning and effective
health system, really, How do we develop science about
something very practical? It's not typically done in university
laboratories, which is--What is the best way we use our
therapies, to keep them useful and avoid problems? So, I think
this is a very important and fertile area, and not unrelated,
because of the incentive issue, to the issue of rare and
neglected diseases. In fact, resistant bacteria start out rare.
And for a developer who wants to make a product for that
specific bacteria, the audience or market at that time may be
very small, and the incentives may be unclear, and then,
particularly if we in the medical system want to say, ``Use
that very appropriately, and just for those resistant
organisms.''
Senator Casey. Thank you.
[The prepared statement of Senator Casey follows:]

Prepared Statement of Senator Casey

I would like to start off by thanking my colleague and
friend Senator Brown for calling this hearing today to draw
attention to rare and neglected diseases in children. I would
also like to recognize the leadership of this committee for the
past work that has been done on this important issue--and the
progress that has followed as a result of bipartisan efforts.
Today, we gather to discuss the challenges facing
individuals with rare diseases, their families, friends and
caregivers. While each of the 6,000 or 7,000 rare diseases that
we know of affects only a small number of people, collectively
these diseases affect 25 to 30 million Americans--almost 10
percent of our population. Many of those affected are children.
The diagnosis of a rare disease can be frightening even to
an adult; for a child, it is particularly devastating. I am
glad that progress has been made over the last two decades to
improve children's access to treatments for rare diseases. But
much remains to be done. Among children with the most common
rare diseases, one in four will not live to see their first
birthday. This startling and disturbing fact should evoke not
just concern, but action.
When I consider the challenges of confronting rare diseases
and legislative actions that will protect our children, I am
reminded of my father's work as a public official over many
years in Pennsylvania. As a State senator in the 1960s, he
learned that a simple test for PKU, a birth defect that
prevents an individual from metabolizing certain foods, was not
required in Pennsylvania. Children with undiagnosed PKU often
end up with severe intellectual disabilities. So he introduced
a bill requiring that all children born in Pennsylvania be
tested at birth for PKU; the bill passed, and many children's
lives were immeasurably improved by one simple law. Thirty
years later, after serving as Governor, he remembered the bill
as one of the best things he ever did as a public official.
I, too, believe that helping every American child reach
their full potential is one of the most important things that
we, as public officials, can hope to do. This committee has
shown great leadership on this issue in the past, and I am
committed to seeing it continue to ensure progress continues
for children with rare and neglected diseases. Too often, there
is no effective therapy for a rare or neglected disease, let
alone a cure. The treatments that are available are often
experimental, ``off-label,'' meaning that in addition to
battling the disease afflicting their child, parents must
battle with insurance companies to pay for treatment.
I have heard from many of my constituents about the
challenges they face with rare diseases, including some of the
diseases that I believe our witnesses will discuss today. In
2007, I met with a group of mothers who shared their struggles
and frustrations in getting ongoing and consistent treatment
for their children, each of whom suffers from a rare disease.
Many of these parents had been able to enroll their children in
clinical trials at the National Institutes of Health (NIH) and
had found experimental treatments for their children that had
proven extremely successful. The doctors at NIH do miraculous
work in finding treatments for children with rare genetic
diseases. However, when the trial ends, these children and
parents are often left on their own, with no access to the
previously free and effective treatment that their children
were receiving.
If the treatment is a drug that has not been approved by
the Food and Drug Administration or has not been specifically
approved for a child's particular disease, then insurance
companies typically will not cover it because the treatment is
considered ``off-label'' or ``experimental.'' If a family has
enough insurance and there is off-label FDA approval, sometimes
families can get coverage of the drugs. If not, the resulting
cost to families is astronomical--ranging anywhere from $10,000
to $30,000 per month.
This is what happened to Nino Todaro, a young boy from
Carlisle, PA, and that is why Senator Specter and I introduced
Nino's Act, S. 406, which will allow children to transition out
of successful treatment in NIH studies without a gap in
treatment. There are thousands of children like Nino across
this country who desperately need the continuity of ongoing
successful treatment for their rare disorders. These are
children who have been very ill, sometimes incapacitated, and
have been able to resume normal childhoods through successful
drug treatment.
With all our medical technology and advancements, no child
in this country should ever be denied medical treatment that is
available and proven effective. Nino's Act will give these
children and their parents the peace of mind in knowing that
when a study ends, their children's successful ongoing
treatment will not end. To address this, Nino's Act will
require Medicaid to cover the cost of treatment in the event
that a child's health insurance does not.
I hope that today's hearing will help us chart a path
forward. I would like to thank our witnesses for their
testimony today, and for sharing with us their insights as
researchers, parents and advocates for children with rare
diseases.

Dr. Goodman. Sure.
Senator Brown. Thank you, Dr. Goodman.
Senator Casey, if you have further questions, you can
submit them for the record, of course, for them.
Thank you very much, Dr. Guttmacher and Dr. Goodman. You're
dismissed and I'd like to call the second panel.
[Pause.]
Thank you all for joining us.
I will begin the introductions, from left to right. And I
know that Senator Sanders wants to introduce Ms. Moon, which he
will certainly be given an opportunity to.
Alex Silver will start off our second panel. I'd like to
begin by welcoming him and his family, including his wife,
Jamie, his mother, Margaret, his father, David, and his father-
in-law, Edward, and the good family and grandparents they are.
So, thank you for joining us. He's a partner at P2 Capital, a
private investment firm in New York, holds an MBA from Harvard
Business School, a BA in Political Science from Brown
University. Mr. Silver is a trustee of the Dystrophic EB
Research Association of America, an organization dedicated to
finding a cure for EB. He recently founded the Jackson Gabriel
Silver Foundation, a nonprofit dedicated to both increasing
research and finding a cure. The foundation is named after the
Silvers' 2\1/2\-year-old son, Jackson.
Our next witness, Diane Dorman, is vice president for
public policy for the National Organization for Rare Disorders.
She is the primary Washington representative for more than 20
million Americans who have one of the 7,000 known rare
diseases. Since joining NORD in October 2000, Ms. Dorman's
advocacy has been instrumental in the passage of two new public
laws. She's been influential in the adoption of numerous
programs and regulations that touch the lives of patients with
rare disorders.
John Crowley is president and CEO of Amicus Therapeutics.
Mr. Crowley has worked with several top pharmaceutical
companies, and was instrumental in finding a treatment for
Pompe disease, which is a fatal neuromuscular disorder. His
involvement with this disease is personal, rooted in the 1998
diagnosis of two of his children, Megan and Patrick. His
dedication toward finding a treatment was highlighted in
several television shows, was featured in a book entitled ``The
Cure: How a Father Raised $100 Million and Bucked the Medical
Establishment in a Quest to Save His Children.'' His efforts to
develop a treatment for his children were also chronicled in
the movie ``Extraordinary Measures.''
Thank you, Mr. Crowley, for joining us, too.
Senator Sanders.

Statement of Senator Sanders

Senator Sanders. Thank you very much, Mr. Chairman. I am
pleased to welcome our next witness. Ms. Suerie Moon is a
member of the board of directors of Doctors Without Borders
U.S.A., known internationally--forgive my French here--Medecins
Sans Frontieres, or MSF. In 1999, MSF received the Nobel Peace
Prize, ``in recognition of the organization's pioneering
humanitarian work on several continents.'' MSF is an
international independent medical and humanitarian
organization. And I want to applaud MSF for all the wonderful
work they do.
In this country, MSF is most widely known for emergency
response during armed conflict or following cataclysmic natural
disasters. What is not so widely known is that it has been
engaged for decades in providing care and treatment to
impoverished people suffering from diseases so neglected that
most people in developed countries have not even heard of them.
Ms. Moon's own experience spans three continents over more
than a decade, including field work in the Democratic Republic
of Congo and China, and research and analysis on access to
medicines and innovation policy issues.
It is my pleasure to introduce her today.
Senator Brown. Thank you, Senator Sanders.
Our last witness will be Dr. Daniel Frattarelli, who's the
chair of Committee on Drugs at the American Academy of
Pediatrics. He's a practicing pediatrician and an expert in
clinical pediatric pharmacology. Dr. Frattarelli is chair
pediatrics at Oakwood Hospital Medical Center in Dearborn, MI,
not far from my State.
Welcome, to all of you.
Mr. Silver try to keep your testimony close to 5 minutes.
And if that means--we have all your testimony in the record, if
you want to summarize, however you want to do it.
Proceed, Mr. Silver.

STATEMENT OF ALEXANDER J. SILVER, FOUNDER, JACKSON GABRIEL
SILVER FOUNDATION, NEW YORK, NY

Mr. Silver. Thank you. I would like to thank Ranking Member
Enzi, Senator Brown, a real champion in this area, Senators
Casey and Sanders, and the rest of the committee for inviting
me to speak today on behalf off of the children who have
epidermolysis bullosa, also known as EB.
I would like to thank the committee members who supported
Senate Resolution 180, establishing national EB awareness week.
With your continued support, EB can be cured. I would like to
recognize Megan Barron, Joella Murray, Kati Ward, Michelle
Hall, and Wyeth Carpovich, all who are here today, and all who
suffer from EB. Thank you for being with us. Your burden, one
that no one should face, inspires us to do what we must: cure
this disease.
EB is a devastating disorder that affects a child from the
moment of birth. A child suffering from EB lacks the critical
protein which acts as a Velcro between the layers of skin.
Without this, skin slides apart, blisters, and sheers off,
causing severe pain, disfigurement, including fused toes and
fingers, shredded corneas, closed throats, and, in too many
cases, premature death.
To give you a sense of what EB life is like, I'd like to
tell you about my 2\1/2\-year-old son, Jackson, who was born
with a severe form of EB. We learned of his EB when nurses
removed a Bandaid from his newborn heel and it ripped off all
his skin. Every morning, my wife Jamie and I wake up and hope
that Jackson hasn't torn the skin off his neck and face. We
hope his mouth and throat have not blistered, preventing him
from eating. We check his body for blisters, and we lance any,
with large needles. Jackson takes stinging baths with bleach,
every day, to kill the bacteria in his open wounds. He sits
patiently through bandage changes. A fall on the playground can
tear the skin off his palms. Every day, we witness his body
being ravaged by this disease, and it does not have to be this
way.
The Government considers EB to be a catastrophic disease.
Catastrophic only begins to describe what life with EB is like.
Respectfully, Senators, please take a moment and imagine your
son or daughter as one of these innocent and helpless children,
painfully having their bodies transformed into one devastated
by infected wounds, blisters, and scarring. Imagine the simple
act of hugging your child could tear the skin off. This
describes a fraction of what these children experience.
Everything we do in life impacts our skin.
Perhaps the most hopeful aspect of EB today is the quality
of research being performed. EB research is at a stage where
treatments and cures have the potential, with your help, to
become a reality. We are not at the beginning of this journey.
With more funding, a finish line can be in sight.
The solution must be a combined effort between public and
private sectors. To give EB children a chance, they need more
research funding and incentives for private research, a
streamlined approval process, and affordable treatments.
Fewer than 3 percent of rare diseases have treatments
available. Only 0.3 percent of the NIH's 2009 budget was spent
directly on rare diseases. I estimate that only $16 per
affected person per year is spent on searching for cures--$16.
The 2010 Federal budget calls for $3.4 billion for carbon
capture technology. Investing in the future of American energy
is important. Shouldn't investing in the future of the leaders
of America be at least as important? The authorized, but
unfunded, Cures Acceleration Process is a good start, but we
need to do more.
When curing a disease is the mathematics of how many
children are afflicted verse the profit potential of a
treatment, we have gone far astray of our fundamental American
values. Private funding will not cure a disease affecting too
few people. We need you, our government, to provide incentives
to spark private development of therapies. The proposed
Priority Voucher Program is a fantastic example. It encourages
companies to focus on rare drug disease development, providing
commercial benefits without costing the taxpayers anything.
Achieving the balance of safety of treatments and the
devastation of rare diseases is a tremendous challenge. Because
of the horrific symptoms of EB, individuals and their parents
are more willing to accept risks that may be inherent in
emerging therapies. I am not advocating that safety be cast
aside. I am saying that a person with EB defines safety
differently than a healthy person, because simply living is
unsafe. As CureTheProcess suggests, the FDA should consider
issuing new guidelines to give rare diseases an accelerated and
streamlined approval process.
Treatments of rare diseases often lead to discoveries with
wider applications. By devoting the resources to protein, stem
cell, and gene therapies to combat EB, we could be aiding many
other Americans. This potentially includes brave veterans who
suffer burns on the battlefield, and those suffering from
chronic wounds and ulcers that will not heal.
In closing, while there is promising research focused on
helping children with EB, the current system fails them. The
solutions are clear: more public and private funding, an
accelerated review process, and affordable treatment. With this
committee's help Jackson, Joella, Megan, Michelle, Kati, and
Wyeth, and other kids with EB, can grow up to live healthy and
pain-free lives, but only if we give them that chance. Inaction
is not a choice. We can cure this disease. Let's turn that hope
into a reality, and let's do it now.
Thank you for the opportunity to testify today.
[The prepared statement of Mr. Silver follows:]

Prepared Statement of Alexander J. Silver

SUMMARY

My testimony presents a parent's perspective of the painful day-to-
day experience of living with Epidermolysis Bullosa (EB) and conveys
the devastation that this disease has ravaged on my son and other
children who suffer from it. I aim to raise awareness about EB as well
as to provide solutions that are within our grasp to treat and cure EB
and other rare diseases. My testimony describes the current state of EB
research and recommends the following measures be taken as soon as
possible: (i) increase funding for EB and rare disease research; (ii)
create and refine private market incentives to spur development of
treatments and cures; (iii) re-
design and streamline the approval process for rare diseases; and (iv)
ensure treatments are attainable to those who need them.

WHAT IS EPIDERMOLYSIS BULLOSA?

EB is a disorder that impairs a child's layers of skin
from staying together. This child is missing a protein that acts as the
``velcro'' between the layers of skin causing his or her skin to
blister and shear off with movement. There are three major EB
subtypes--Simplex, Junctional and Dystrophic. Only 2 to 4 out of every
100,000 children are born with EB. My son Jackson was born with
Recessive Dystrophic EB (RDEB), one of the most severe subtypes, in
October 2007.

THE DEVASTATION OF EB

EB profoundly impacts every aspect of life. Skin is the
body's largest organ. Children with EB may be unable to walk, eat,
play, sit, write, hug or even sleep without significant risk of skin
shearing off their little bodies. Fingers and toes can become fused
together forming mittens and unusable feet. The esophagus can close due
to injury from eating. Malnutrition, infection, ocular and dental
issues, constant pain and cancer at an early age characterize the lives
of these children.

CURRENT EB RESEARCH AND THE REASONS EB PATIENTS CONTINUE TO
SUFFER NEEDLESSLY

There is high quality research being performed today that
can render this disease livable and curable. Researchers know exactly
what causes this disease and have encouraging knowledge of how to fix
it. We are failing to marshal the resources needed to get there. EB is
at a stage where treatments and cures have the potential, with more
funding, to become a reality.
Major areas of research being conducted include protein
replacement as well as stem cell and gene correction therapies. Many of
these researchers are hoping to commence Phase I trials as soon as
possible.
Children with EB needlessly continue to suffer because the
target market of EB children is not large enough to attract commercial
interest on its own. When curing a disease devolves into the
mathematics of how many children are afflicted versus the profit
potential of developing attainable treatments, we have gone astray from
our fundamental American values.

WHAT IS NEEDED TO BEAT EB, OTHER RARE DISEASES AND SAVE AMERICA'S
CHILDREN

More Funding--Of the 7,000 rare diseases affecting 30
million Americans (10 percent of the population), less than 0.3 percent
of the 2009 NIH budget was spent on finding cures for these diseases
and likely less than $16 annually of Federal funds is spent per person
suffering from a rare disease to find a cure. This is not a question of
additional spending but one of our priorities.
Public/Private Partnerships and Commercial Incentives--For
a disease that affects too few people to spark commercial interest, the
government must provide incentives for private development of drugs and
therapies. The proposed priority voucher program encouraging drug
development for rare pediatric diseases enables a company to focus on
orphan drug development because it can enjoy commercial benefit and
also serve a social good. This would bring additional solutions to the
market quickly, which would help children with EB and other rare
diseases without costing the taxpayers anything.
Streamlined Approval Process--Achieving a balance between
the safety of treatments and the devastation of rare diseases remains a
tremendous challenge for regulators. Because of the horrific symptoms
of EB, individuals with EB and their parents are more willing to accept
risks that may be inherent in emerging therapies. The CureTheProcess
campaign suggests that the FDA create a new review division for rare
biochemical diseases; and for the FDA to issue new guidelines to give
the rarest diseases access to an accelerated approval process. By
working together, CureTheProcess, the NIH TRND Program, Cures
Acceleration Network and others can ensure patients with rare disorders
get earlier access to effective treatments.
Affordability of Treatments--Potential treatments for EB
and other rare diseases must be made affordable to those who need them
most. A cure for EB is useless to the child shut out because he or his
family cannot afford to pay for it.
Wider Application of Treatments Developed for EB--
Treatments for rare diseases often lead to discoveries with much wider
applications. A few examples are Remicade, Rituxan and Epogen. By
devoting resources to protein, stem cell and gene therapies to combat
EB, we may also aide many other Americans. This potentially includes
brave veterans who suffered burns that resulted in blistering and
scarring while serving our country, as well as victims of other burn
injuries and those who suffer from wounds and ulcers that will not
heal. These individuals share many characteristics with severe RDEB
children. EB is worthy of curing in its own right, but many Americans
could benefit as well.
______

I would like to thank Chairman Harkin, Ranking Member Enzi, Senator
Brown and the entire committee for allowing me to speak today on behalf
of the children, and their families, who suffer from Epidermolysis
Bullosa, also known as EB. I would also like to thank the members of
the committee who supported Senate Resolution 180 in 2006, which
established National EB Awareness Week. Specifically, I would like to
thank Senator Hatch, who was a co-sponsor of this resolution. S. Res.
180 passed the Senate by unanimous consent and without amendment. With
your continued support, we can transform EB into a treatable and
curable disease. I would also like to recognize Megan Barron, Joella
Murray and Leandro Santos who are in attendance today. These
individuals all suffer from EB. They endure more pain than one can
imagine. Their burden, one that no child or person should face,
inspires us to do what we must--cure this disease.

WHAT IS EPIDERMOLYSIS BULLOSA (EB)?

EB is a debilitating and devastating genetic disorder that affects
a child from the moment he or she is born. EB is not specific to any
ethnicity or gender. A child who suffers from EB lacks the critical
protein that binds his or her layers of skin together. This protein
acts as the ``velcro'' that attaches one layer of his or her skin to
the other. Without this ``velcro'' when this child moves, his or her
skin slides apart, blisters and shears off leading to severe pain,
disfigurement, and in too many cases, a premature death from an
aggressive form of skin cancer called Squamous Cell Carcinoma. Within
certain subsets of EB, the cumulative chance of developing this cancer
is almost 100 percent. A child with a severe form of EB can have a 60
percent cumulative risk of dying by age 15. There are three major EB
subtypes--Simplex, Junctional and Dystrophic and within each type there
are multiple subsets. The difference among them is the level at which a
blister forms within the skin and which particular protein is missing
or impaired.
My experience with EB began on October 11, 2007. On that day, my
wife Jamie and I were blessed with the birth of our beautiful son
Jackson, who is the light of our lives and a joy to everyone around
him. Yet, our lives were nearly shattered with the diagnosis that
Jackson was born with a form of EB called Recessive Dystrophic EB (or
RDEB for short). Despite being born at a major metropolitan hospital,
the physicians caring for Jackson had never seen a case of RDEB before,
which made his condition difficult to diagnose, an experience most EB
children share. RDEB is considered to be one of the worst forms of EB.
Jackson, like all those with RDEB, is missing the protein Collagen VII.
This became evident on the day after Jackson's birth, when nurses
removed a bandaid from his newborn left heel and the adhesive tore off
his precious skin. Most of my comments will focus on RDEB, although
there are equally horrific forms of EB which share many characteristics
with RDEB.
Like most people, I had never heard of EB and had no awareness that
our son would suffer from this condition until he came into this world.
We did not know about EB because it is an orphan disease, which is
defined as a disease affecting fewer than 200,000 people. Figures from
the National Institutes of Health estimate that between 2 and 4 out of
every 100,000 children are born with EB. Based upon these figures, EB
would be an ``ultra-orphan'' disease defined as a disease that affects
fewer than 20,000 people in the United States. The Government considers
EB a ``catastrophic illness.'' ``Catastrophic'' only begins to describe
life with EB.

THE DEVASTATION OF EB

To say that EB impacts every aspect of a child's life is a gross
understatement. Skin is the body's largest organ. Among its most
important functions, skin is the first line of defense to protect the
body from trauma and infection. Everything we do in life impacts our
skin--walking, eating, playing, sitting, writing, hugging, sleeping--
the list goes on. For children with EB--like our son Jackson--every
aspect of their lives at every moment is overshadowed by this terrible
disorder. These children are often born missing large areas of skin
leaving gaping wounds that never heal; walking and standing are
impaired over time because their toes become fused as the result of
continuous injury; the simple joy of holding a crayon to draw becomes
impossible because their fingers fuse and contract turning their young
hands into mittens; eating is painful and sometimes impossible because
the esophagus closes due to injury and scarring, which is only
temporarily reprieved by a surgical procedure in which the esophagus is
stretched open. When this solution stops working, a gastric feeding
tube is placed in their small bellies in order to enable proper
nutrition and hopefully stave off growth retardation and anemia. Even
the fundamental act of sleeping is extraordinarily difficult because of
the level of pain and discomfort that these children experience 24
hours a day.
Like all kids, children with EB rub their eyes when they are
sleepy. Only in their case, rubbing their eyes can tear their eyelids
and corneas, prohibiting these children from opening their eyes in the
morning without suffering extreme pain. Naturally, children with EB
also want to play alongside their peers. However, falling down on the
playground can remove all the skin from their little palms or produce
blisters on their knees the size of oranges. Respectfully Senators,
please take a moment and imagine yourself, your son or your daughter,
or a relative being one of these innocent and helpless children--slowly
and painfully having your little body transformed into one devastated
by infected open wounds, blisters and scarring. Imagine that the simple
act of hugging your child could tear the skin off his or her body. This
describes just a fraction of what these children experience, as it does
not account for the social scrutiny and the stares they receive by
simply walking or being wheeled down the street. In its entirety, EB
impacts vision, speech, nutrition, mobility and indeed every single
aspect of a child's life. Unfortunately, a recent study determined that
approximately 50 percent of children with RDEB are always in pain.
During a typical day, a child with RDEB undergoes a special bath
and a bandage change. Given the large areas of skin missing from such a
child's body, bathing is an extraordinarily painful experience. Bandage
changes can last anywhere from 30 minutes to several hours and bandages
can cost a family as much as an astounding $14,000 per month. An EB
child's meals consist mostly of soft foods and liquids, assuming he or
she has not been forced to resort to receiving nutrition through a
feeding tube. When skin blisters or tears, it must be treated as soon
as possible, causing parents to carry a costly arsenal of needles and
bandages anytime that they leave the house. For a child with EB, the
joyful act of participating in sports--such as little league or youth
soccer--is often out of the question due to the skin tears, blisters
and scarring that would result. For this reason, even playing with
other children can be impossible. Simply put, this disease prevents a
child from just being a child.
Speaking for a moment as Jackson's dad, every morning Jamie and I
wake up and hope that Jackson hasn't torn the skin off his neck and
face from rubbing during his sleep. We hope he does not have a blister
in his mouth or his throat that prevents him from eating that day.
Throughout the day, we check his body for blisters that have developed
and lance any with large needles when we see them. Sometimes this can
be extremely painful to Jackson but we are forced to physically
restrain our son and do it anyway. We dress him in special shoes and
only soft clothing. We keep bacterial culture kits at home and use them
all too often to check him for infection. Like many EB patients, our
son must avoid crowded places that kids love such as zoos, museums and
birthday parties. And we must stay indoors during the bulk of the
summer because the heat and humidity exacerbates his blistering. Every
day, Jackson takes a bath with vinegar or bleach to help kill the
bacteria on his little body. This bath often causes stinging pain to
Jackson's many open wounds. He sits patiently through his uncomfortable
bandage changes; sadly, our little boy does not know any differently.
He endures physical, occupational and feeding therapies as well as
specialized nursing visits six times per week to keep his body as
mobile and healthy as possible. And yet, through all these painful
challenges that would cause most of us simply to give up, our brave
Jackson's smile lights up a room even though his body is slowly being
ravaged by this disease. Some additional examples: as noted above, our
son lost all of the skin on his heel from the removal of a bandaid the
day after his birth which has never grown back normally; his hands are
severely scarred and the quality of his skin is poor due to the
continuous damage they endure; that damage continues to progress up his
arms everyday. It's critical to note that--despite the pain and
discomfort I have just described--Jackson has a moderate case of RDEB.
Children with more severe cases suffer exponentially more.
With this background, the key questions are: (i) where are we now;
(ii) where can we can go; and (iii) what is needed to succeed at giving
these children the fundamental American right of a chance at living
good lives.

CURRENT EB RESEARCH AND THE REASONS EB PATIENTS CONTINUE TO
SUFFER NEEDLESSLY

Perhaps the most hopeful aspect of EB today for Jackson, and all
children living with EB, is the quality of research being performed in
the United States and internationally that can render this disease
livable and ultimately a disease of the past. Due to research dating as
far back as 1974, which has been funded by NIH grants as well as
private donations; EB is at a stage where treatments and cures have the
potential, with your help, to become a reality. Indeed, researchers
know exactly what causes this disease and have encouraging knowledge of
how to fix it. But where we are failing is in marshalling the resources
needed to get there. To reiterate, we are not at the beginning of this
journey. Technology has caught up to the research and, with more
funding, a finish line can be in sight for the thousands of children,
like our son Jackson, who were born with this disease.
Some of the major areas of research currently being conducted in
the United States include protein therapy by Doctors David Woodley and
Mei Chen of the University of Southern California and Doctor Peter
Marinkovich of Stanford University. The concept of this research is
straightforward. EB researchers estimate that a person needs only 35
percent of the typical level of Collagen VII for the skin to behave
normally. Drs. Woodley and Chens' concept is to replace the protein
that is missing in RDEB kids--Collagen VII--with localized injections.
Drs. Woodley and Chen have proven in a mouse model that this method
works. They are now looking to commence a Phase I trial as soon as
possible. Experts indicate that with the sufficient resources, a
commercialized therapy could be available in 5 to 8 years. Imagine what
that would mean to a child whose skin tears off in her shoes to have a
localized injection that renders the skin on her feet potentially
normal. For years, doctors have administered localized injections of
Collagen I for cosmetic purposes. Collagen VII and Collagen I are
related. In this proposed treatment, the doctors would simply
administer Collagen VII in a similar fashion as Collagen I is
administered in a cosmetic setting. In other words, doctors have the
knowledge to apply this treatment as soon as it is available. While not
a cure, this would be a truly viable ``game changing'' treatment,
allowing a child like my son to live a better life.
Other potential cures are being pioneered both at the University of
Minnesota and at Columbia University by Drs. Wagner, Tolar, Christiano
and Cairo. These are stem cell therapies and the basic concept is to
replace the bone marrow of an individual with EB with a donor who has
the proper Collagen VII production capability. As the body's wounds
heal and the skin regenerates, the theory is that Collagen VII would be
produced, which in turn would keep an EB patient's layers of skin
together. There are currently trials ongoing at both locations, which
have shown promise as a systemic cure.
At Stanford University, Drs. Lane and Khavari have labored over a
form of gene therapy to treat EB. In this approach, a small section of
skin is removed from a person with EB and the gene ``error'' is
corrected to produce Collagen VII. The corrected skin is grown into
larger amounts and then grafted back onto the body. We hope that they
can commence a trial very soon.
In addition to these efforts, internationally, there has been work
by Dr. John McGrath in the United Kingdom in which individuals with EB
received injections of donor cells that produce Collagen VII. Results,
though early, have been promising.
So why hasn't Collagen VII been developed commercially? Given that
its unquestionably important life saving purpose? The answer is that
the target market of EB children is not large enough to attract
commercial interest on its own. Development costs--which can run into
the hundreds of millions of dollars--trump the profit that can be made.
Simply said, the economics do not work in most cases--and children like
our son Jackson are the victims of this unfortunate and unfair fiscal
reality. When curing a disease devolves purely into the mathematics of
how many children are afflicted with EB versus the profit potential of
developing this attainable treatment for these children, we have gone
astray from our fundamental American values. As I described earlier,
there are real therapies and treatments in the works that--with
appropriate funding--can offer these children suffering from EB a
chance at a ``normal'' life. What keeps these children in bandages is
the lack of funds, the difficulty in attaining any funds that may exist
and the cumbersome approval process of potential treatments.

WHAT IS NEEDED TO BEAT EB AND SAVE AMERICA'S CHILDREN

I believe the solution must be one of a combined effort between the
public and private sectors. For EB children to have a chance at a life
free of pain--one where they can ``truly'' be kids--they need more
available funding for researchers, more incentives to fund this
research via a public/private partnership, an approval process that
considers both safety as well as the devastating effects of EB, and
finally a mechanism to ensure the treatments are affordable to those
who need them.
The National Organization for Rare Disorders (NORD) estimates that
there are 7,000 rare diseases affecting 30 million Americans. Of these
disorders, only approximately 200 have FDA-approved treatments. Less
than 3 percent of these diseases have treatments available. According
to figures provided by the NIH, it provided only $118 million in
research funds for orphan drugs out of its $30 billion budget in 2009.
Unfortunately, this amounts to 0.3 percent of the NIH budget. The
Office of Orphan Drug Development provides approximately $15 million
annually in grants. Assuming there is additional funding via other
Federal sources, it may be safe to assume that approximately $500
million in Federal funding per annum is available for orphan diseases.
To put this in context, Genzyme, a biotechnology company, estimates
that it cost over $500 million to develop a treatment for a rare
disorder called Pompe disease. It also means that of the 10 percent of
the U.S. population affected by rare diseases, roughly $16 per person
is spent per year in searching for cures. ONLY $16. The U.S. Federal
budget is $3.5 trillion. Of that amount, the 2010 budget calls for $3.4
billion to support carbon capture and storage technology. Investing in
the future of American energy is very important. But it begs the
question; shouldn't investing in the future leaders of America--
including our son and the many other bright young stars afflicted with
this horrible disease--be at least as important? Given the current
economic environment, I understand as well as anyone that there is
little room for additional spending and we have many pressing issues at
hand. It is a question of what our priorities should be as Americans
who value human life and the right to have a ``normal'' and carefree
childhood.
The Government cannot provide the solution itself, nor should it be
expected to. However, for a disease that--although devastating and
debilitating--affects too few people to spark commercial interest, the
Government must lead and provide incentives for private development of
drugs and therapies. The proposed priority voucher program encouraging
drug development for rare pediatric diseases, which is a refinement of
the tropical disease voucher program, is a fantastic example. If this
program is expanded to cover rare pediatric diseases, then a company
that would not otherwise focus on orphan drug development will do so
because it can enjoy commercial benefit while also serving a social
good. This would bring additional solutions to the market quickly,
which would help every child with EB and indeed any other rare disease.
Corporations will follow the Government's lead. Public interest,
awareness and incentives can shape private behavior. Creative solutions
that provide direct or indirect incentives are effective and
indispensable methods to spur the pace and likelihood of treatment
developments. I--along with all other parents of sons and daughters
suffering from rare diseases--urge you to consider the proposed
priority voucher program. This program can improve and save the lives
of millions without costing the taxpayers anything.
Beyond additional funding and private market incentives, the
process for the approval of rare disease therapies must be streamlined.
Achieving the delicate balance between the safety of treatments
(particularly new or developing treatments) and the devastation of rare
diseases remains a tremendous challenge for regulators. We need a
process which deeply considers the alternative that individuals with EB
or other orphan diseases face in lieu of approved treatments. A child
with RDEB lives each day with tremendous pain, hoping his fingers and
toes do not fuse and his esophagus does not close. With this disease,
every breakdown is one step closer to a terminal cancer. Because of the
horrific symptoms of this disease, individuals with EB and the parents
of children with EB are more willing to accept risks that may be
inherent in emerging therapies because the alternative is a painful and
debilitating life. I am not advocating that safety be cast aside. I am
saying that a person with EB defines safety differently than a healthy
person; to a person with EB, simply living life is inherently unsafe.
The CureTheProcess campaign by the Kakkis Foundation has promising
ideas on how to address this issue. CureTheProcess suggests that the
FDA create a new review division for rare biochemical diseases; and for
the FDA to issue new guidelines to give the rarest diseases access to
the accelerated approval process. We can quickly and dramatically
improve the current regulatory process for rare diseases. The result
should be a surge in development activity for even the rarest
disorders. An improved regulatory path working together with the NIH
TRND Program, Cures Acceleration Network and other new incentive
programs will help ensure more patients with rare disorders will get
earlier access to specific, effective treatments.
These potential treatments for which we seek funding must also be
made affordable to those who need them most. A cure for EB is useless
to the child shut out because he or his family cannot afford to pay for
it.
One additional area that is often overlooked is that treatments for
rare diseases often lead to discoveries with much wider applications.
For example, Remicade--which was developed for the treatment of Crohn's
disease, a population of 500,000 people--has been found to effectively
treat Rheumatoid Arthritis and forms of Psoriasis, a population of over
5 million people. Rituxan, developed for non-Hodgkin's lymphoma--a
group of 70,000 people per year now helps the 1.3 million Americans who
suffer from Rheumatoid Arthritis. Epogen, now used for Anemia, is
another illustration.
As these examples demonstrate, funding of orphan diseases can
frequently have the unintended consequence of benefiting a much broader
population than those suffering from the orphan disease itself. By
devoting the resources to protein, stem cell and gene therapies to
combat EB, we may also indirectly aide many other Americans. This
potentially includes brave veterans who have suffered burns that
resulted in blistering and scarring while serving our country on the
battlefield, as well as victims of other burn injuries. These
individuals share many characteristics with severe RDEB children. EB is
worthy of curing in its own right, but many Americans (including many
of America's Finest; the men and women of our military) could benefit
along the way.

CONCLUSION

In closing, while there is promising research focused on helping
children with EB, the current system fails them. It does not provide
enough funding, sufficient private market incentives or a review
process that is appropriate for the severity of the disease. The
solutions are clear--more public and private funding and partnerships,
a streamlined and accelerated review process and affordable treatments.
We know the solutions and now, with this committee's help and support,
Jackson, Joella, Megan, Leandro and every child with EB can grow up to
live healthy and pain-free lives. But only if we give them that chance.
Inaction is not a choice. This can be done. We can cure this disease.
Let's turn hope into reality, and let's do it now. Thank you for
inviting me to testify today.
______

Appendix

I. FORMS OF EPIDERMOLYSIS BULLOSA\1\

There are three main forms of EB: Eli Simplex. Junctional Eli and
Dystrophic EB. These different subtypes are defined by the depth of
blister location within the skin layers. Blister formation of EB
simplex is within the epidermis. Sometimes EB simplex is called
epidermolytic. Blister formation in Junctional EB is seen at the level
of the lamina lucida within the basement membrane zone. Dystrophic EB
or dermolytic EB is a scarring form of EB which occurs in the deeper
tissue at the level the lamina densa or upper dermis.
---------------------------------------------------------------------------
\1\ Dystrophic Epidermolysis Bullosa Research Association of
America (DebRA).

EB Simplex is caused by faulty proteins in the top layer of skin.
This results in incorrectly formed keratins, deeming them unable to
perform their normal role as a ``scaffolding'' for the top most layer
of skin. The top layer of skin falls apart, resulting in a blister.
Although EB Simplex is considered a non-scarring form of EB, secondary
infection may cause scarring.
Junctional EB is caused by mutations in the genes encoding alpha 6,
beta 4 integrin, collagen XVII or one of the three chains of Laminin 5.
This leads to defects in the formation of hemidesmosomes or anchoring
filaments. Defects within any of those components of the skin allows
for the separation of tissue and blister formation whenever there is
friction or trauma to an area. In many instances blistering can occur
spontaneously.
Dystrophic EB is caused by mutations in the genes that carry the
instructions necessary to produce the proteins in the basement membrane
zone of the skin. This results in incorrectly formed anchoring fibrils,
deeming them unable to perform their normal role as a ``stable
interweave'' between the dermal and epidermal layers of the skin.
Mutation occurs within the Collagen VII gene, which encodes the protein
of the anchoring fibril. Anchoring fibrils hold together the two layers
of skin. As a result, there is a lack of adherence and disruption of
the skin when any friction or trauma occurs to an area. Where the two
layers separate there is a blister. Blistering in the various types of
dystrophic EB causes scarring.
To differing degrees, EB can manifest itself in the following ways:

Generalized blistering.
Growth retardation and malnutrition.
Gastrointestinal tract--may include blisters in mouth,
esophagus and/or anal margins.
Pseudosyndactyly--Fusion of fingers and/or toes.
Problems with the soft tissue inside the mouth leading to
esophageal strictures.
Squamous Cell Carcinoma.
Ocular (eye) involvement.
Atrophic scarring--depressions in skin as a result of
thinning in epidermis or dermis.
Nail dystrophy--presence of rough, thickened or absent
finger or toenails.
Presence of Milia--tiny skin cysts.
Anemia--a reduced amount of red blood cells, volume of red
blood cells and amount of hemoglobin.
Granulation tissue--appearance of red fleshy tissue which
is capillary formation during tissue healing.
Dental caries (cavities).
Enamel hypoplasia--underdeveloped enamel upon the teeth.
Genitourinary tract involvement including scarring and/or
urethral stenosis.
Scalp abnormalities--presence of blisters on scalp and/or
scarring alopecia (areas of scarring with absence of hair growth).
Respiratory tract involvement.

Senator Brown. Thank you very much, Mr. Silver.
Ms. Dorman.

STATEMENT OF DIANE EDQUIST DORMAN, VICE PRESIDENT FOR PUBLIC
POLICY, NATIONAL ORGANIZATION FOR RARE DISORDERS, WASHINGTON,
DC

Ms. Dorman. Thank you, Senator Brown, Ranking Member,
Senator Enzi, and other distinguished members of this
committee, for inviting me to testify today regarding a topic
that is extremely important to NORD.
In the United States, as already been mentioned, there are
nearly 7,000 diseases considered rare or affecting fewer than
200,000 Americans. Some of these diseases affect only a few
hundred people, or even a few dozen. There are certain
challenges and issues that all people with rare diseases share,
no matter where they fall in this spectrum.
Since many rare diseases are genetic, more than two-thirds
of these patients are children. Rare diseases tend to be
serious and lifelong. Many are life-threatening.
A recent editorial in the journal Nature noted that, among
patients afflicted with any of the 350 most common rare
diseases, 27 percent will not live to see their first birthday.
My colleagues and I have a great deal of contact with
patients and their families. Over and over again, we hear about
the difficult issues they face, which include diagnosis delay,
too little research, too few treatments, reimbursement issues,
and a general sense of having been abandoned by our Nation's
healthcare system.
I've organized my comments and subtopics reflecting the
most urgent issues, challenges, and opportunities that we face.
No. 1 are preclinical challenges. Families often contact
NORD just after having received a diagnosis. They are typically
in a very fragile state, desperately seeking information, and
hoping to find resources, medical experts, and clinical trials.
All too often, we have to tell parents that there are no
treatments for their child, and no one doing research.
Part of the problem is a lack of natural history data,
validated animal models, patient registries, and other tools
that form the foundation for clinical research. The rare
disease patient community is highly motivated and resourceful,
but patients can't do it alone. There must be Federal funding
and Federal guidelines to establish these basic tools for
research. With such support, I can guarantee that patients and
patient organizations will be active partners in moving studies
forward.
Then there are clinical challenges. Because patients are
scattered around the globe, clinical research on rare diseases
is more expensive and more challenging than other research.
This must be taken into account in study requirements.
Furthermore, patients with rare diseases are generally willing
to accept higher levels of risk than other patients may be
motivated to do.
Also, rare-disease research today is often funded by the
patient community, through golf tournaments, raffles, even bake
sales and car washes. As a society, it is wrong for us to
expect people with devastating diseases to fund the search for
their treatments. A more significant commitment is needed at
the Federal level.
And there are regulatory challenges. NORD hosted a summit
for 300 participants, in May 2009, to focus on accelerating the
development of orphan products and ensuring patient access to
them. A point made by several speakers was that industry
frequently develops a second product for a disease rather than
addressing a disease that has no treatment. This was
attributed, in part, to a climate of regulatory uncertainty.
A few weeks ago, the chairman of NORD's board of directors
addressed a public hearing hosted by FDA. Noting that only
about 200 of the nearly 7,000 rare diseases have treatments, he
urged FDA to implement a statement of policy on rare diseases
and orphan products. His point was that, while orphan drugs are
reviewed with the same standards of safety and effectiveness as
other drugs, FDA does exercise a certain degree of scientific
judgment in reviewing products for rare diseases.
There are reimbursement challenges, which is really
devastating for families. Certain metabolic diseases, such as
PKU, require specialized infant formulas and medical foods.
Patients who don't get these special foods may suffer very
serious consequences, including severe mental retardation.
However, insurers, including Medicaid, don't always reimburse
for these expenses, since these foods are not prescription
drugs. Only about a third of the States currently mandate
reimbursement for specialized infant formulas and medical
foods. Since these foods are a necessary part of medical
treatment for children with certain diseases, NORD would like
to see a Federal mandate to ensure that no child is denied a
needed medical food.
Another reimbursement issue is the off-label use of drugs
for rare diseases. It has been estimated that 90 percent of
Americans with rare diseases are treated off-label, simply
because there's no FDA-approved treatment for them. But,
increasingly, insurers, both public and private, are denying
coverage for off-label use of drugs, biologic and medical
devices, on the basis that such therapies are experimental. For
people with rare diseases who have no other option, this is a
serious problem.
Then there's the issue of humanitarian-use devices that
Senator Franken has brought up. Pediatric medical devices are,
similarly, very important. Children are not just small adults;
they need both drugs and devices developed specifically for
their unique needs. A member of NORD's medical advisory
committee, Dr. Robert Campbell, who is a pediatric orthopaedic
surgeon at CHOP, in Philadelphia, invented, developed, and
brought to market a pediatric device, known as the ``expandable
titanium rib,'' that has saved the lives of hundreds of
children who have a rare condition known as thoracic
insufficiency syndrome. Prior to his work, there was no
treatment for children with this condition. Dr. Campbell's
research was begun with a small seed-money grant from NORD and
later funded by FDA's Orphan Product Grants Program. The device
he developed was approved by the FDA as humanitarian-use
device. Because no company was interested in manufacturing it,
Dr. Campbell also took it upon himself to find a small company
willing to do so. It took him 14 years to do so.
This story is not unusual, and there are many children
today desperately needing pediatric devices who don't have a
Dr. Campbell looking after their interests. Those children need
our help.
In medical education, NORD worked closely with the medical
community. And we believe that our Nation is blessed with many
caring, dedicated medical people in the field. However, we feel
that medical education in the United States does not adequately
address rare diseases and related challenges at this time. We
urge greater emphasis on rare diseases and on medical education
centers to prepare young clinicians.
Then there are current initiatives that we are working on.
NORD believes significant progress has been made in recent
months that will help to accelerate the development and
treatment for children and adults with rare diseases. We urge
continuation of initiatives, such as a training course for rare
disease investigators, sponsored by FDA, NIH, NORD, and Duke
University, that will result in development of a handbook to
serve as a roadmap; a task force instituted by NORD, with NIH
and FDA, collaborating to identify weaknesses in the system and
ways for the two agencies to work closely together; and also, a
congressional Rare and Neglected Diseases Caucus to focus on
attention on these important issues.
Our recommendations were as follows: continued progress in
innovative initiatives, such as a training course; Federal
funding and guidelines to develop natural history data; patient
registration of their basic tools; recognition that clinical
trials for rare diseases represent a unique set of
circumstances and needs; reduced regulatory uncertainty; and
increased emphasis on rare diseases in our centers of medical
education. We endorse funding measures proposed for orphan
product development in the current Senate appropriations bill.
And we urge this committee to remember that research on rare
diseases often provides fundamental breakthroughs in knowledge.
In closing, I would like to reiterate several points. Among
patients afflicted with any of the 300 most common rare
diseases, 27 percent will not live to see their birthday.
Patients and their families are willing to take on a far
greater degree of risk than those affected by more common
conditions. And finally, in an essay entitled ``The Keys to the
Kingdom,'' by Dr. Fred Kaplan, the expert on one of the most
rare and horrendous bone disorders, fibrodys-
plasia ossificans progressive, or FOP, Dr. Kaplan said,

``Research into the study of rare disorders will
provide the key that unlocks the door to the treatment
of the common disorders that affect the majority.''

We all stand to improve our lives and our health by
promoting the development of new treatments and cures for rare
pediatric disorders.
[The prepared statement of Ms. Dorman follows:]

Prepared Statement of Diane Edquist Dorman

I wish to thank Chairman Harkin, Senator Enzi and other
distinguished members of this committee for inviting me to testify
today regarding a topic that is extremely important to my
organization--the development of safe, effective treatments and cures
for the millions of American children afflicted with rare diseases.
My name is Diane Dorman, and I am the vice president for Public
Policy of the National Organization for Rare Disorders (NORD). NORD is
a non-profit organization with offices in Washington, DC and Danbury,
CT, that provides a voice to the nearly 30 million Americans with rare
diseases. It was established in 1983 by patient organization leaders
who served as the primary consumer advocates responsible for enactment
of the Orphan Drug Act.
In the United States, there are between 6,000 and 7,000 diseases
considered rare, according to the National Institutes of Health. To be
classified as ``rare'', a disease must be believed to affect fewer than
200,000 Americans. This is the definition used by the Food and Drug
Administration and by the National Institutes of Health.
Although each individual rare disease affects no more than 200,000
people, and some affect only a few hundred or even a few dozen, rare
diseases in the aggregate affect approximately 1 in 10 Americans. There
are certain issues and challenges that are common to all people with
rare diseases, no matter where they fall on this spectrum.
Since many of these diseases are genetic, many of the patients are
children. It is believed that more than two-thirds of the individuals
affected by rare diseases in the United States are children.
Furthermore, most rare diseases are serious and chronic or
lifelong. Many are life-threatening. A recent editorial in the journal,
Nature, noted that among patients afflicted with any of the 350 most
common rare diseases, 27 percent will not live to see their first
birthday.
My colleagues and I have a great deal of one-on-one contact with
rare disease patients and their families, as well as with patient
organization leaders. As you might imagine, some of the most difficult
phone conversations we have are with parents of young children who have
rare diseases. These families are faced with very difficult issues such
as diagnosis delay, too little research, too few treatments,
reimbursement or other financial issues, and a general sense of having
been abandoned by our Nation's health care system.
We very much appreciate the invitation to speak to you today. Since
the topic is broad, I would like to organize my comments into the
following sub-topics to reflect what we see as the primary issues and
challenges through our daily contact with the families of children
affected by rare diseases.

PRE-CLINICAL CHALLENGES

Families often contact NORD just after having received a diagnosis
for a child. They are typically still in a very fragile state in which
they are desperately seeking information about the disease and hoping
to find resources, medical experts, and opportunities to participate in
clinical trials.
You can imagine how difficult it is to have to tell families, as we
frequently do, that not only is there no treatment for their child's
disease but there is no research in progress. The sad reality for far
too many people with rare diseases is that no one--at NIH, at a
teaching hospital, on a university campus, or in industry--is doing
research on their disease at this time. And no research means no hope
for the future.
Part of the problem is a lack of natural history data, validated
animal models, patient registries and prevalence/incidence data on rare
diseases. These basic tools form the foundation for clinical research,
and they are a necessary first step.
The rare disease patient community is highly motivated and
resourceful. Many of the few patient registries and other research
resources that exist at this time have been funded or launched by
patient organizations. But patients can't do it alone. There must be
Federal funding and Federal guidelines and encouragement for the
establishment of these basic tools for research. With such support, I
can guarantee that patients and patient organizations will be active
partners in moving studies forward.

CLINICAL CHALLENGES

Because of the small patient populations, and the fact that rare
disease patients are scattered around the globe, clinical research
aimed at developing treatments for the rare disease community is by its
very nature more expensive and more challenging than other research.
The requirements for clinical trials need to be stringent enough to
provide reasonable assurance of safety and efficacy for patients, but
they must also take into account the fact that these diseases present a
unique set of challenges for researchers. In addition, patients with
rare diseases are generally willing to accept higher levels of risk
than other patients may be motivated to do.
At this time, a significant portion of rare-disease research is
funded by the patient community. While NIH and particularly the NIH
Office of Rare Diseases Research have made admirable strides in recent
years in focusing greater attention on the need for research on these
diseases, for many of the very rare diseases it is still too often the
patient community that funds and drives research through golf
tournaments, raffles, even bake sales and car washes. As a society, it
is wrong for us to expect people with devastating diseases to fund the
search for their treatments. We need to make a more significant effort
at the Federal level to fund studies of rare diseases and incentivize
researchers to pursue them.

REGULATORY CHALLENGES

NORD hosted a Summit in May 2009 at which we drew together
approximately 300 participants from NIH, FDA, patient organizations and
industry to focus on how to accelerate the development of treatments
for rare diseases and how to ensure patient access to treatments. A
point made by several speakers was that industry frequently develops a
second product for a disease that already has one or more treatments
rather than addressing a disease that has no treatment at all. This was
attributed, at least in part, to reduced regulatory uncertainty once
the first product is brought to market.
A few weeks ago, the chairman of NORD's board of directors
addressed a public hearing hosted by the FDA. His recommendation, on
behalf of NORD, was for FDA to reduce regulatory uncertainty and
increase consistency by implementing a statement of policy on
regulation of therapies for rare diseases.
Only about 200 of the nearly 7,000 rare diseases currently have
FDA-approved treatments. To NORD and the patient community, it appears
as if the low-hanging fruit have been harvested since enactment of the
Orphan Drug Act in 1983, but much more remains to be done.
While orphan drugs are reviewed with the same standards of safety
and effectiveness as other drugs, FDA publicly acknowledges that it
exercises its scientific judgment in taking into account the special
challenges of developing treatments for very small patient populations.
However, without a statement of policy on rare diseases and orphan
products, it is not possible to ensure consistency in that process.
Other uncertainties in the regulatory arena include the need for
identification and agreement on clinical endpoints and surrogate
markers, the need for greater transparency and understanding of the
regulatory process, and the need to have regulators who understand the
special challenges of developing orphan products. NORD applauds the
recent creation of an Associate Director for Rare Diseases position in
FDA's Center for Drug Evaluation and Research (CDER) and the inclusion
in the current Senate Appropriations bill of funding for staff to
assist the associate director.

REIMBURSEMENT CHALLENGES

Certain metabolic diseases, such as phenylketonuria, require
specialized infant formulas and medical foods as a very important part
of treatment. Patients who don't get these special foods may suffer
very serious consequences, including severe mental retardation.
However, insurers (including Medicaid) don't always reimburse for the
cost of these foods since they are not prescription drugs.
Only about a third of the States currently mandate reimbursement
for the costs of specialized infant formulas and medical foods. Since
these foods have been demonstrated to be an important part of medical
treatment for children with certain diseases, NORD feels strongly that
access should not be hindered as a result of inability to pay. We would
like to see a Federal mandate to ensure that no child is denied a
needed medical food because of failure by insurers to provide coverage.
Another reimbursement issue is the off-label use of drugs for rare
diseases. It has been estimated that 90 percent of the nearly 30
million Americans with rare diseases are treated off-label simply
because there is no FDA-approved therapy for them. As the cost of
healthcare continues to skyrocket, insurers (both public and private)
increasingly are denying coverage for off-label use of drugs,
biologics, and medical devices on the basis that such therapy is
experimental. For people with rare diseases who have no other options,
this is becoming a serious problem.
NORD does not want to discourage pharmaceutical and biotechnology
companies from conducting clinical trials to obtain FDA approval for
these additional uses. However, we feel that legislation might be
employed appropriately to help rare-
disease patients and families obtain reimbursement for off-label
treatment that is medically necessary when no FDA-approved options are
available to them.

HUMANITARIAN USE DEVICES

While we've been speaking primarily of orphan drugs and medical
foods, clearly there is a need for the development of pediatric medical
devices for many children with rare diseases. And NORD feels strongly
that it is important to emphasize that children are not just small
adults. Sick children need medical devices and drugs developed
specifically for their unique needs, taking into account their smaller
size, growing bodies, and active lifestyles.
To illustrate the challenges inherent in development of medical
devices for this particular population, we cite the experience of Dr.
Robert Campbell, a pediatric orthopedic surgeon on NORD's Medical
Advisory Committee, who is affiliated with the Children's Hospital of
Philadelphia.
Dr. Campbell invented, developed and brought to market a pediatric
device known as the expandable titanium rib that has saved the lives of
hundreds of infants and children who have a condition known as thoracic
insufficiency syndrome. Prior to his work, there was no treatment for
children with this condition, and most ultimately died because there
was not enough room for their lungs to expand as the children grew.
(Please see attachment 1)
Dr. Campbell's research was made possible by a small seed-money
grant from NORD, when no other funding was available. Later, he was
able to obtain funding to continue the research through the FDA Orphan
Product Development grant program. Ultimately, the device he
developed--the titanium rib--was approved by FDA as a Humanitarian Use
Device. Because no company was interested in manufacturing it, Dr.
Campbell also took it upon himself to find a small company that would--
essentially for humanitarian reasons--agree to manufacture and market
the titanium rib.
The families helped by this medical device remain tremendously
grateful to Dr. Campbell and his colleagues. But there are many others
with other rare diseases who may not have a Dr. Campbell, and they need
help, too.
A complicating factor is that, while FDA considers HUDs to be
approved, they must still be reviewed by IRBs. As a consequence,
insurers (both public and private) consider them experimental and may
not reimburse for them. In addition, while pediatric HUD developers can
now realize a profit, this is not the case for all humanitarian
devices. The prohibition against developers profiting from these
devices needs to be lifted.

MEDICAL EDUCATION

NORD works very closely with the medical community, and we know
that our Nation is blessed with a caring and dedicated medical
establishment. However, we feel that medical education in the United
States does not adequately address issues and challenges related to
rare diseases, and is not at this time encouraging enough young
scientists to engage in both research and clinical care related to rare
diseases. Given the fact that approximately 1 in 10 Americans are
affected by rare diseases, we believe a greater emphasis on these
diseases is warranted in our centers of medical education.
One of the primary problems encountered by rare-disease patients
and families is delay in obtaining an accurate diagnosis. In 2003, NORD
partnered with Sarah Lawrence College on a study to replicate, on a
smaller scale, an earlier study by the Federal Government of problems
experienced by people with rare diseases. Sadly, our study showed that
the diagnosis problem remained essentially unchanged since the Federal
Government's study done in 1989.

SOME CURRENT INITIATIVES THAT BRING HOPE TO PATIENTS

Currently, NORD is working with FDA, NIH and others to address some
of the problems outlined above and to accelerate the development of
rare disease therapies. These initiatives include:

A three-day training course for investigators from
academia and small biotechnology and pharmaceutical companies involved
in conducting research to develop treatments for rare diseases. This
course will be taught by experienced faculty from academia, industry,
NIH and FDA, and is being sponsored by NORD, FDA, NIH and Duke
University. It will result in the development of a handbook for rare-
disease investigators.
A task force instituted by NORD, in which NIH and FDA have
agreed to work together to examine the interface between the two
agencies, identify weaknesses, and find ways to work together more
effectively to facilitate the development of safe, effective treatments
for patients. This task force has already had several meetings.
A series of orphan designation workshops being hosted by
the FDA Office of Orphan Products Development, in partnership with NORD
and others, to de-mystify the process of getting orphan designation for
a product in development as a rare-disease treatment.
A series of focus groups, hosted and sponsored by NORD, to
gather information from academic researchers, patient advocates, the
investment community, and the biopharmaceutical industry to help NIH
and FDA review current practices and consider possible improvements.
An increasingly global response to the needs of rare
disease patients, as evidenced by the partnership of NORD and its
European counterpart, the European Rare Disease Patient Organization or
EURORDIS.
The launch of a Congressional Rare and Neglected Diseases
Caucus, advocated by NORD and its partners, to help focus attention on
these important issues and how to address them.

OUR RECOMMENDATIONS

In general, our recommendations to this committee, reflecting what
we've learned over the past 27 years as well as our current assessment
of the most critical needs of patients at this time, are as follows:

Continued progress in areas such as the NORD Task Force
through which NIH and FDA are identifying ways to work together more
effectively; the Rare and Neglected Diseases Congressional Caucus; and
the development of a handbook to serve as a roadmap for rare-disease
clinical investigators.
Federal funding and guidelines to develop natural history
data, patient registries, epidemiological data and other basic tools to
support research.
Recognition that clinical trials related to rare diseases
are, by their nature, different from studies of more common diseases
and that they represent a unique set of circumstances and needs.
A renewed Federal commitment to funding research on rare
diseases through offices such as the NIH Office of Rare Diseases
Research.
Reduced regulatory uncertainty through steps such as
greater transparency of FDA practices and creation of an FDA statement
of policy on rare diseases and orphan products.
Incentives to encourage young investigators to study rare
diseases.
Increased emphasis on rare diseases in our centers of
medical education.
Adoption of the funding proposed in the current Senate
Appropriations bill for the FDA Orphan Products Research Grants Program
and to staff the new associate director function in FDA CDER.
Assessment of reimbursement issues related to medical
foods and off-label treatment for children with rare diseases.
Training in rare diseases and orphan product development
for FDA reviewers and staff involved in review of orphan products.

In closing, I would like to reiterate several very important
points:

1. Among patients afflicted with any of the 350 most common rare
diseases, 27 percent will not live to see their first birthday.
2. Patients and their families are willing to take on a far greater
degree of risk than those affected by more common conditions.
3. Understanding the pathogenesis of rare diseases will advance the
scientific and medical understanding of common conditions.

Chairman Harkin and Ranking Member Enzi, thank you once again for
allowing NORD to testify before you today.

Senator Brown. Thank you, Ms. Dorman.
Mr. Crowley.

STATEMENT OF JOHN F. CROWLEY, PRESIDENT AND CEO, AMICUS
THERAPEUTICS, CRANBURY, NJ

Mr. Crowley. Great. Thank you, Senator Brown.
Senator Brown. Thank you.
Mr. Crowley. Thank you, Senator Brown--and thank you for
the leadership in the Rare Disease Caucus--Senator Enzi,
Senator Sanders, Senator Casey.
I come here wearing a number of hats today. I come as the
chairman and chief executive officer of a small biotechnology
company, Amicus Therapeutics, a 100-person company in Cranbury,
NJ, developing novel medicines for human genetic diseases. I
come also as a member of the board of directors of the Biotech
Industry Organization. But, most importantly, I come as the
father of two children with a rare disease, as you alluded to
in your kind introduction, Senator, Megan and Patrick.
My whole involvement in this industry goes back to that
1998 diagnosis. My wife and I were a year out of graduate
school, 31 years old, and we are recessive carriers for a gene
to cause this fatal neuromuscular disease, Pompe, so there's no
history of it in our family. We were told, in March 1998, that
our then 15-month-old daughter, Megan, and our then 7-day-old
son, Patrick, had this rare form of a muscular dystrophy. We
were told that there was very little research, there was no
drug in clinical development, and the doctor said, most
apologetically--he said, ``I'm sorry. There's nothing we can
do. They'll live maybe another year or two.''
What has happened in the last 12 years, I think, could only
happen in the United States. It was a common effort by a lot of
people who worked incredibly hard, tirelessly. And I think it's
representative of what is very unique about drug development in
America, this virtuous circle, where it was years of academic
research; it was researchers at the NIH; it was reviewers at
the FDA; it was philanthropist patient advocates; a small
biotechnology company that I started; more out of frustration
with the pace of development than anything, to just try to move
the ball a little bit; it was venture capitalists; it was
eventually large biotech companies. And from 1998 to 2006, we
helped to develop a drug eventually brought to market by a
large biotechnology company, Genzyme. And with that, it was 8
years of clinical development, almost $500 million of
investment--almost exclusively private industry investment--to
bring the medicine to just a couple thousand people in the
United States and around the world.
With Pompe disease in children, there is a severe
enlargement of the heart. Our kids' hearts were two to three
times normal size when they went into the clinical study.
Within months, their hearts shrunk back down to normal. We saw
significant improvements in their muscle strength.
Years later, they still take that medicine--every other
week, a 6-hour infusion. It maintains their strength. It keeps
their heart healthy. It is still not a cure. It is a first-
generation approach. They're still in wheelchairs. They're
still on ventilators. They are now, I'm happy to report, 13 and
12 years old, going into the eighth and seventh grades--
amazingly smart and vibrant and precocious little kids.
We had the incredible experience of having this movie,
``Extraordinary Measures,'' made about our lives that came out
just earlier this year. And it was a very positive experience
for our family--at times, very surreal. But, in many ways,
Megan and Patrick, in that film, are proxies for millions of
other children, some of whom have received life-saving
medicines, medicines that never would have come about without
the efforts of a lot of people and the Orphan Drug Act, 27
years ago. But, probably even more significantly, I think they
really represent the millions of children who still strive for
therapies, who need cures, who need development, who need that
virtuous cycle of development that we've put in place, in the
last many decades in the United States, to not only continue,
but to grow and to thrive.
And with all those different hats I wear, I can tell you
I'm very concerned that, on one hand, we sit on what I think is
a Golden Age of Medicine, in the next 10 or 20 years, as we
look at all the technologies in development in universities, at
the NIH, in private industry--so much potential to
fundamentally alleviate human suffering, to cure these
diseases, to provide breakthroughs that could ultimately affect
much more broadly prevalent disorders, like Parkinson's and
Alzheimer's, diseases that really are genetic diseases at their
core.
But, as an industry, we look at things like the financial
markets. For small biotechnology companies, venture capital
funding is down 30 percent. Much of that doesn't go into the
risk-taking enterprises that are typically involved in this
development.
IPOs in our industry--there were 35--our company was one of
them, in 2007. In the last 5 years, there have been five. Our
company, in 5\1/2\ years, has raised $300 million, and spent
over $200 million, to develop a handful of drugs for very rare
human genetic diseases, none of which are still approved. Our
lead drug has been in clinical studies now for 5 years, through
phase 1; safety studies through phase 2; proof-of-concept
studies; and now, in what will be a fairly lengthy time to
enroll, hopefully by the end of this year, a phase-3 study to
prove its safety and efficacy. All in, my guess is, it will be
$200 million to develop that drug, and that it will have taken
7 years of clinical studies for a drug that's probably going to
help a couple thousand people with a rare disease called Fabry
disease.
That paradigm can't continue. We can't raise that type of
money. We can't do 7 years of clinical work.
In 1992, the AIDS community was very active, and they got a
drug called AZT approved, the first treatment that started to
check the disease, HIV. In the 20 years since, under the
subpart H regulations of the FDA for accelerated approval,
approval based on a surrogate endpoint, almost 20 drugs for
AIDS have been approved, much, much to the benefit of that
community, and rightfully so.
In those 20 years, just one drug for a human genetic
disease has been approved under those accelerated standards.
I think, with that, some of the proposals that, as a dad,
as an entrepreneur, and as an industry representative, we
support are: urging the FDA to issue new guidance and review
standards for demonstrating the efficacy and safety of rare
diseases; greater use of surrogate endpoints likely to predict
clinical benefit; much faster timelines; ultimately, I think,
the ability to accept higher levels of risk--I think the mantra
should be ``approve fast and follow long.'' We should look at
funding the Cures Acceleration Network. I think that's a good
example of public/private partnership that can play a role for
the most rare of the rare diseases. I think, too, promoting
industry--in the fact that industry is the one that develops
all of these drugs through capital markets incentives,
extending and expanding the Qualifying Therapeutic Discovery
Project Tax Credit, I think will be incredibly important.
I thank all of you for the time. This is obviously an
incredibly important issue to all of us. I think it will be
incredibly important going forward. And I look back to 1984,
when Ronald Reagan signed the Orphan Drug Act into law. It was
a very bold move, and it was with full Democrat and Republican
support. When he signed that bill in the White House, he said,
``I only wish, with the stroke of this pen, that I could also
decree that the pain and suffering of people living with these
diseases would cease, as well.'' It didn't, with the stroke of
that pen, but it set in place a whole new framework, a system
of incentives, the patient advocacy movement, itself, that has
led to a significant number of cures. We need to take it to the
next level. Maybe we need a second Orphan Drug Act to address
these challenges.
But, hopefully we can get to the day where fewer and fewer
parents have to sit in that doctor's office and hear what we
heard 12 years ago, a doctor saying, ``I'm sorry, there's
nothing we can do.'' I think we can do much better.
Thank you.
[The prepared statement of Mr. Crowley follows:]

Prepared Statement of John F. Crowley

INTRODUCTION

Good afternoon Chairman Harkin and members of the committee. My
name is John F. Crowley of Princeton, NJ. I am the chief executive
officer and chairman of Amicus Therapeutics, Inc. and I serve on the
board of directors of the Biotechnology Industry Organization (BIO).
More importantly, I am the father of two children diagnosed in 1998
with Pompe disease--a rare and devastating neuromuscular disorder. I
appreciate the opportunity to be here today to talk about ways in which
the Federal Government can encourage and speed the development of
drugs, vaccines, and diagnostic tests for rare and neglected diseases.
Amicus Therapeutics is a 100-person biopharmaceutical company
developing orally administered, small molecule drugs called
pharmacological chaperones, a novel, first-in-class approach for
treating a broad range of human genetic diseases. Amicus' lead program
is in Phase 3 testing for the treatment of Fabry disease, a rare and
severe lysosomal storage disease affecting an estimated 10,000
individuals worldwide. My involvement with the biotechnology industry
stems from that 1998 diagnosis of our two youngest children, Megan and
Patrick.
BIO represents more than 1,200 biotechnology companies, academic
institutions, State biotechnology centers and related organizations
across the United States and in more than 30 other nations. BlO members
are involved in the research and development of innovative healthcare,
agricultural, industrial and environmental biotechnology products,
thereby expanding the boundaries of science to benefit humanity by
providing better healthcare, enhanced agriculture, and a cleaner and
safer environment.
From my perspectives as both a biotechnology entrepreneur and as a
father, I am most appreciative that the committee is undertaking this
broad inquiry into the state of rare and neglected pediatric diseases.
The time to consider change and to build on past successes could not be
better. We have come a long way but we have much further to go to
address the severe unmet medical needs of people who bravely live with
these rare diseases, especially children. Research and drug development
in this crucial field is at a precarious tipping point.

THE FOUNDATION OF SUCCESS: THE ORPHAN DRUG ACT

The Orphan Drug Act (ODA) of 1983 has brought unprecedented
success. It contained several market-based incentives for biotechnology
and pharmaceutical companies to develop and market products for rare
diseases. To date, in excess of 1,000 orphan product designations have
been granted by the FDA's Office of Orphan Product Development and more
than 250 drugs and biologics have received approval by the FDA with
Orphan designation, collectively helping millions of adults and
children with rare diseases worldwide. We have come a long way, indeed.
In the decade prior to enactment of the ODA fewer than 10 products for
rare diseases came to market. Among these advancements are
accomplishments that I have participated in professionally and, in the
case of my own children, have witnessed most personally. Today, there
are an estimated 7,000 rare diseases, each one affecting 200,000 or
fewer individuals, but collectively affecting nearly 30 million
Americans. Treatments exist for only a fraction of these devastating,
life-threatening diseases leaving so many people of all ages with
significant unmet medical needs. And of those treatments, the majority
of approved orphan drugs are for those rare diseases with higher
prevalence.
BIO believes that the lesson we can learn from the ODA is that
government policies can effectively foster research and development of
products for rare diseases--and create an entirely new marketplace to
meet severe unmet medical needs. The challenges of developing orphan
products are great and they require innovative policy and regulatory
solutions. Further, many rare diseases affect far fewer patients than
the 200,000 threshold in the ODA. For these diseases, the challenges
are even more daunting.

CONTINUED UNMET MEDICAL NEED

The gap in development for pediatric rare diseases is particularly
acute for the most uncommon disorders, which collectively still affect
the majority of children with rare diseases. Most all rare or orphan
diseases with lower prevalence remain without treatment. According to
an Orphan Drug Development Trends report published by BioMedical
Insights in January of this year, 83 percent of rare diseases are
``ultra-rare,'' yet only 11 percent of orphan designations issued
between 1997 and 2009 were for these ultra-rare diseases (144/1,310).
What do these numbers translate to for the average patient family in
the rare disease community? No treatment options and the invariable and
painful words from a physician that are all too common: ``I am sorry.
There is nothing we can do. There are no treatment options for your
child.''
For most of these rare and extremely rare diseases, perhaps as many
as 2/3, medical research is absent--completely. Affected patients,
their families and friends strive to bring attention to their causes.
For other diseases, such as Tay-Sachs, for example, medical research is
just now gaining momentum, despite it being one of the most commonly
known rare, genetic diseases, with one of the oldest advocacy groups in
the country, and the first disease for which a carrier genetic test was
perfected back in 1970. Yet it could be many more years before a safe,
effective treatment is ready for the clinic, and tens of thousands of
children and adults will still die from this deadly neurodegenerative
disease. As a past-president of the National Tay-Sachs & Allied
Diseases Association, I've seen the hope sustained by parents listening
to academic researchers, while they watch Tay-Sachs ravage their young
children physically and mentally. And for those rare diseases fortunate
to have a treatment, not all is perfect. As can be the case with Pompe
disease, for example, many patients cannot tolerate the treatment due
to immunogenicity or other significant issues. For others, the
treatment may be of limited effectiveness but there are no other
options. Much work remains to be done in orphan drug development to
evolve the unmistakably critical work already achieved for rare
diseases.

ABILITY TO MEET THE CHALLENGES

In the year 2010, we have the collective ability to tackle the
challenges of understanding and developing viable treatment options for
rare and ultra-rare diseases with unmet medical need, especially for
children. Basic scientific, biomedical and preclinical research is
taking place with groundbreaking technology in laboratories at colleges
and universities, independent academic medical centers, at the National
Institutes of Health, and in the biotechnology industry. Initiatives
such as the Therapeutics of Rare and Neglected Diseases (TRND) Program
at the National Human Genome Research Institute (NHGRI) have impressive
capabilities and hold great promise for discovery at the level of
public/private collaboration that is necessary to help address many of
these challenges. In particular, this is a new and exciting approach to
moving forward from screening and developing compounds through the
junctures of pre-clinical and clinical work, optimizing resources and
harnessing the varied expertise of collaborators along the way.
Though just getting off the ground, the TRND program has the
potential to help companies bring promising products forward. Many of
these products stall in development because biotech companies lack the
financing to advance them. The TRND program could fill some of these
funding gaps. BIO is encouraged by this effort. We pledge to work with
the NIH on intellectual property concerns, technology transfer rules,
and other matters to make sure the program accomplishes its goals.
Patient advocacy for pediatric rare diseases is increasingly
important. Families and friends of children and adults affected by
these debilitating, horrific, often fatal rare diseases no longer
passively sit around sick rooms and hospital rooms. They--we, because I
am one of them, are well aware of the promising developments taking
place in the research labs of the biotechnology industry and at
academic institutions and are confident that technology can match our
sense of urgency. Patient advocates are proactive agents for changing
how this research can be conducted and how quickly it gets translated
to the clinic, all with the hope that it will positively influence
their loved one's clinical outcome. Today's patient advocacy and
disease organizations are partners in social and venture philanthropy
with industry. They want the exciting and promising technology that
exists for their diseases to see the light of day, and even more they
want treatments and potential cures to be realities in their lifetimes.
Here are just two examples.
The Cystic Fibrosis Foundation is one such health venture
philanthropist. In 2000, there were few potential treatments in the CF
pipeline. Today, there are more than 30 treatments in development, a
few already available to patients, with a pipeline portfolio ranging
from gene therapy, protein rescue, mucus alteration, restoring airway
surface liquid (ion transport), anti-inflammatory, anti-infective,
transplantation and nutrition. In the area of protein rescue alone, the
CF Foundation invested more than $100 million with Vertex
Pharmaceuticals and $25 million with PTC Therapeutics, both fellow BIO
member companies, for two different small molecules in the past few
years.
``Fight Spinal Muscular Atrophy'' (FightSMA) dedicates itself to
research for a cure for this group of diseases which affect the motor
neurons of the spinal cord and brain stem. In its infantile form, SMA
kills more babies than any other genetic disease. With grants up to
$250,000 each, FightSMA is a social philanthropy funding about 20
academic and medical institutions in the United States and
internationally. The organization brings approximately 25 SMA
researchers together for an annual scientific conference to encourage
collaboration at the same time that SMA-
affected families come to meet each other for support and learn from
these researchers.
It is exactly this type of community-driven, cross-fertilization
and financial support of ideas, and sharing of disease experience that
has occurred at advocacy organization conferences for years that the
patient community is more recently asking take place on a broader scale
in clinical research and drug development. Patients are appreciative of
the active role of the Office of Rare Diseases at NIH in supporting
these meetings and of the Office of Orphan Product Development
participation at many programs. Collaborative approaches are in the
United States and abroad, originated by highly respected organizations
such as NORD and now assumed by their counterparts, such as EURORDIS,
CORD and ICORD. The 2010 European Conference on Rare Diseases held last
month in Krakow, Poland, attracted more than 600 participants from 43
countries, with one-third from Eastern Europe: the aim to discuss
public policies and actions that will improve the lives of people with
rare diseases. The rare disease community may be growing, but it
represents a world that is getting smaller all the time. The demands of
the diseases themselves have always been there; however, the presence
of the diseases is augmented by the fast-paced technology available to
researchers, the charged atmosphere of advocacy, immediate access to
information about diseases, research and support groups, and
connectivity through the Internet and social media for all disease
stakeholders.
Collectively, these activities represent a trend toward
acceleration of all aspects of orphan drug development to ultimately,
and most importantly, benefit patients living with rare diseases. The
Federal Government can support new policies and programs that extend,
leverage and enhance these global efforts.
The biotechnology industry has made a significant contribution to
this field over the years. Indeed, the mission of many biotech
companies, such as my own, is to bring hope to the patients who suffer
from rare diseases. Today, I would like to provide you with some
thoughts about policies that will complement and advance the objectives
of the ODA and facilitate the development of the next generation of
orphan products for children.

New Policies for Consideration to Accelerate Treatments for Rare
and Neglected Diseases

CHANGING THE FDA REGULATORY ENVIRONMENT FOR PEDIATRIC RARE DISEASES

The committee must address the current regulatory environment and
the FDA's review process for orphan products. For instance, the sheer
size of patient populations is an important factor for consideration in
clinical study design. Affected individuals are part of such small
individual patient populations; they may represent disease prevalence
of as many as 67:100,000 to as few as 2:100,000. No one rare disease
exceeds an incidence of 200,000 in the United States. Limited
individual disease experience makes it unlikely that there are
organized registries from which to draw information for the majority of
these diseases, and unrealistic to consider conducting natural history
studies as prelude to or in parallel with clinical trials. (The topic
of disease and product registries currently is a controversial one in
the rare disease community and one worth exploring, as well.) Numbers
of subjects for any orphan product study should be carefully considered
based on current disease situations. Given that these trials,
especially registration studies requiring larger numbers of subjects,
typically necessitate global recruitment, protocols should be able to
satisfy institutional review boards and ethics committees
internationally. In the ultra-rare category, consideration also should
be given to combined Phase 1/2 and Phase 2/3 studies with a Phase 4
commitment from sponsor companies making these investments. The
regulatory mantra should be: Approve fast, follow long.
The committee should respectively consider enabling the FDA to
focus on orphan diseases/orphan products beyond the fine work already
being conducted by the Office of Orphan Product Development. The multi-
systemic, complex nature of the majority of rare diseases, as genetic,
metabolic, inborn errors of metabolism, further complicates a simple
route forward for the guidance and development of well-
designed clinical protocols. Therefore, study design guidance and
review for rare diseases should also have an approach
characteristically distinct from that used with common disease guidance
and review. The FDA would benefit from a dedicated team of experts in
the genetic and metabolic disorders that together with regulatory
colleagues can offer guidance to study sponsors that will result in
clinical protocols that account for limited patient numbers, the most
current collective thinking on disease biomarkers, surrogate endpoints
and better use of pharmacogenetics.
I suggest that the establishment of a separate Division of Genetic
and Metabolic Disorders at FDA is essential and long overdue. Along
these same lines, the Agency might consider having reviewers, staff
other than OOPD, spend more time with rare disease patient
organizations to learn from their leadership and members what they
think and know of clinical trials, barriers to participation, etc. This
might be mutually beneficial for educational purposes and understanding
the rare disease patient experience.
Additionally, BIO urges FDA to publish further guidance regarding
orphan drug development that provides interpretation of current
regulations including: what are acceptable subsets of disease to meet
the prevalence requirement; what is a ``major contribution to patient
care'' that allows a drug to be found ``clinically superior'' even if
it has the same active moiety of a previously approved drug; what is
the definition of ``reasonably likely to predict clinical benefit,''
and whether the sponsor of the original drug can also be a ``subsequent
sponsor.''
Other regulatory changes should be pursued as well. For example, we
urge that FDA review use of its standards for demonstrating efficacy of
a rare disease product. The requirement for sponsors to use two
adequate and well-controlled studies is the same standard used by the
Agency for other drugs and biologicals. However, it is significantly
harder to develop those studies for rare disease products because of
the small patient populations available. This is particularly true for
very rare diseases. BlO urges FDA to consider alternatives that
include: approval based on a single adequate and well-controlled trial
at a ps.05, if there have been NIH-conducted studies using the same
populations; use of consortia between government, academia and
industry; and use of patient registries for rare diseases as part of
efficacy considerations.
In addition, we urge FDA to support greater use of surrogate
endpoints for product approval, either for full approval or accelerated
approval purposes. Although they currently can be used during the
accelerated approval process, more guidance from the Agency is needed
on use of surrogate endpoints for registration. Amazingly, in the past
20 years, only one drug for the treatment of a human genetic disease
was approved under the ``accelerated approval'' provision of subpart H
of the FDA regulations.
Moreover, BIO believes FDA can improve communications processes for
rare disease stakeholders. For example, once orphan designation has
been granted, there is no communication policy for sponsors as the
review divisions take over. This often makes interaction with the
Agency difficult. It is important that FDA encourage reviewers to
establish communications processes that allow reviewers and sponsor
researchers to discuss scientific issues based on real-time data more
efficiently. Such real-time scientific dialogue would not take the
place of the required regulatory communications and meetings with FDA
but rather ensure that these required communications and meetings are
utilized more efficiently. Additionally, there is no special priority
given to rare disease products in current FDA practices regarding
protocol assistance, communication with the Agency and other matters.
Given the complexity and special challenges of developing rare disease
products, these communication gaps impede development and approval.
Other regulatory changes should be pursued as well, such as greater
transparency at the Agency including more meeting opportunities, and
greater consistency among FDA's review divisions. The challenges of
developing rare disease products require new regulatory approaches.
Also, in light of the fact that biomedical research and development is
a global enterprise, we urge the FDA to work with foreign regulatory
agencies, particularly in Europe, to harmonize requirements for
pediatric research.
In addition, many patients suffering from rare diseases are treated
by products that are labeled for another indication. Companies looking
to get FDA approval for the rare disease indication are often either
prohibited or severely restricted from performing a placebo-controlled
trial for that indication because the commercially available (off
label) product has become the clinical standard of care. In such
situations, FDA should allow non-placebo controlled trials such as
historical control or open label trials.
Regarding FDA's approval of medical devices for rare diseases, the
use of different threshold numbers for defining rare (``orphan'')
disease for medical device (4,000) versus drugs and biologics (200,000)
is illogical. The device regulations should be changed, as it is the
disease incidence not the therapy that should define the population.
Finally, we note that the dual statutes governing pediatric
research, the Best Pharmaceuticals for Children's Act (BPCA) and the
Pediatric Research Equity Act (PREA), have been remarkably successful
in ensuring that the medications used in children are tested and
labeled appropriately for their use. Together BPCA and PREA have
generated a wealth of pediatric drug information for physicians and
parents. BPCA rewards drug companies with 6 months of additional market
exclusivity after the completion of studies in children as requested by
the Food and Drug Administration (FDA). PREA requires new drugs to be
studied in children and allows FDA to mandate child studies in certain
already marketed drugs. However, despite a proven track record in
encouraging pediatric medical research, both programs are scheduled to
expire in 2012. BIO urges Congress to recognize the success of these
programs, eliminate the sunset provision, and make permanent the
incentives for ongoing pediatric research.

UNDERSTANDING AND ACCEPTING APPROPRIATE RISK TOLERANCE

The required pre-clinical and clinical safety studies and risk
assessments for the development and approval of life-saving pediatric
drugs for rare diseases is virtually the same in all instances as for
antibiotics for common ear infections. We need to better understand the
risk/reward ratios for these rare diseases drugs. Addressing the
tolerance for risk in drug development in the rare disease space is
also essential to advancing newer therapies. Individuals directly
affected by these highly unusual disorders, or their parents, custodial
family members and caregivers are experiencing unusual, almost unique
and unprecedented unmet need. They have a sense of urgency few if any
can understand, but this does not necessarily cloud their judgment or
ability to understand the risks and benefits of clinical trial
participation. There should be no less scrutiny of safety for patients
with ultra-orphan diseases but many of the traditional pre-clinical and
clinical safety studies typically required of most drugs need to be
reevaluated in the context of the cost and time associated and the
severity of the unmet need.
Certainly, the protracted timelines too often impose the ultimate
cost on affected families awaiting treatment for their rare disease--
the loss of their child or other loved one. It behooves the FDA to
reassess the process and the extraordinary financial costs involved in
developing orphan drugs. For example, the last five drugs developed and
approved to treat lysosomal storage diseases have cost more than $200
million each in research and development expenses alone to develop,
while addressing populations in the United States of less than 3,000
patients. Each of these drugs were for use in children as well as
adults. There is no current economic framework that exists to promote
this kind of investment. While the industry is appreciative of the
existing incentives established by the Orphan Drug Act 27 years ago, it
is time to update these to ensure ongoing and future innovation to
benefit rare diseases. Some very practical considerations are:
investment tax credits, permanent R&D credits and tax grants for
companies conducting research for ultra-orphan treatments, accelerated
clinical studies, and special tax treatments for investments in smaller
companies with fewer than 250 employees.
BIO companies believe that FDA has made great strides to make sure
that safe and effective orphan products reach patients as soon as
possible, For example, we applaud the FDA Office of Orphan Products
Development for their sponsorship of the training program for reviewers
on statistical methods for small patient populations. In addition, the
``Build an Orphan''--designed to help companies properly submit the
application for orphan drug designation in a timely fashion--holds
promise. But more must be done.
The ODA created a grant program administered by the FDA to fund
companies for development of orphan products. It's called the Orphan
Drug Grant Program. This program has not had increases in funding
commensurate with inflation for many years. BIO urges increased funding
for the Orphan Drug Grant Program.
Similar to what FDA has done through its Critical Path initiative,
we believe the Agency also needs to take affirmative steps to spur drug
development for rare diseases. The regulatory approval pathway simply
must be more predictable. For example, during the most recent
negotiations surrounding enactment of the Prescription Drug User Fee
Act (PDUFA), the FDA committed to developing a series of guidances
regarding clinical trial design; adaptive clinical trials; and new
methods of statistical analysis. These would be valuable for developers
of rare disease products. We appreciate the publication of the adaptive
clinical trial guidance and the non-inferiority draft guidances
released earlier this year, and we look forward to timely publication
of other pending guidances on clinical trial design.

FUND THE CURES ACCELERATION NETWORK

The recently enacted Patient Protections and Affordable Care Act
(PPACA) includes a provision called the Cures Acceleration Network
(CAN) that is intended to speed the translation and application of
promising new treatments for diseases from the laboratory to the
marketplace. The CAN will be placed under the Office of the Director of
NIH, and is authorized to make grants through the NIH to biotech
companies, universities, and patient advocacy groups to target
applicants that have shown promise at the laboratory level, but have
not been able to advance enough to attract investors that are willing
to commit to a promising discovery.
Specifically, CAN will focus on funding the development of ``high
need cures'', defined as those which the NIH Director determines to be
a priority to ``diagnose, mitigate, prevent or treat harm from any
disease and condition'' and for which commercial incentives are
unlikely to result in timely development. The functions of CAN will be
to not only support research that would accelerate the development of
high need cures, but to reduce barriers of getting discoveries that are
in the lab into clinical trials, as well as facilitate the FDA review
process.
In regards to providing assistance with the FDA review process, CAN
will work to facilitate communications with the FDA on the status of a
high needs cure approval and ensure activities are coordinated in a
manner that would expedite their development approval. Lastly, CAN will
work to connect those developing high need cures with additional
technical assistance.
PPACA authorizes $500 million for fiscal year 2010 for the creation
of two new grant programs. Importantly, these grant awards will be
available to biotech companies, medical centers, universities, disease
advocacy organizations, patient advocacy organizations, pharmaceutical
companies and academic research institutions.

EXTEND AND EXPAND THE QUALIFYING THERAPEUTIC DISCOVERY PROTECT TAX
CREDIT

One provision included in the health reform law that may be of
enormous benefit to small life sciences companies is the Qualifying
Therapeutic Discovery Project Credit program, now section 48D of the
tax code. Modeled after existing tax credits for investments in
advanced renewable energy efforts, this program creates $1 billion of
tax credits or grants to encourage investments in promising new
therapies to prevent, diagnose, and treat acute and chronic diseases.
For qualifying companies with 250 employees or fewer, this program will
provide immediate funding for work on therapies for cancer and other
debilitating conditions, including a number of rare diseases, while
providing small firms the ability to weather the ongoing economic
storm. Without help to these companies, the effects of the financial
crisis and the resultant capital markets contraction threatens to halt
or significantly delay the next generation of promising therapies for
various diseases and afflictions that affect tens of millions of
patients and their loved ones.
Today, July 21, is the deadline for applications for the
therapeutic credit program. While Congress saw fit to fund this program
with $1 billion, the Treasury Department has estimated that more than
1,000 applications could easily be filed. In reality this number could
be closer to 2,000. Whatever the number of applications, it is clear
that there will be many more promising projects than can be funded
under the initial $1 billion.

CONCLUSION

I agree with President Obama's statement that,

``science is more essential for our prosperity, our security,
our health, our environment, and our quality of life than it
has ever been before--including [the] creat[ion of] new
incentives for private innovation [to] promote breakthroughs in
energy and medicine.''

Change does not come easily. It was not an easy process when a
group of parents led by Abbey Meyers, the founder of NORD, spearheaded
the development of the Orphan Drug Act in 1983. In January 1984, when
Ronald Reagan signed the Orphan Drug Act into law, with Democrats and
Republicans at his side, he stated that, ``I only wish that with the
stroke of this pen that I could also decree that the pain and suffering
of people living with these diseases would cease as well.'' It didn't,
but the act did create an environment with a system of special
incentives for industry and certain government-supported programs that
spawned a new era of research and drug development. We have come very
far in that last quarter of a century but we have much further to go.
The change brought about by the Orphan Drug Act improved millions of
lives in this country and abroad, helped launch an industry and
established the global rare disease advocacy movement. It does not come
easily for every family that struggles with illness and then receives a
life-altering diagnosis of a rare disease with no treatment or cure. But
each of us committed to orphan drug development, including the FDA and
those responsible for seeing the Agency is appropriately funded, owe
those families a more-than-fighting chance that their medical needs
will be met and that more and more parents will instead receive a
diagnosis of a rare disease in their child, followed immediately by the
words: ``There are, however, several treatments options for your
child.''

Senator Brown. Thank you, Mr. Crowley, for your story.
Ms. Moon, welcome.

STATEMENT OF SUERIE MOON, BOARD MEMBER, DOCTORS WITHOUT BORDERS
USA, NEW YORK, NY

Ms. Moon. Thank you, Senator Brown, Ranking Member Enzi,
Senator Sanders, and Senator Casey.
My testimony today is based on our decades of experience as
one of the only actors providing treatment and care for
neglected diseases in the developing world. It's also based on
our experience as a founding member of the Drugs for Neglected
Diseases Initiative, or DNDI, which is a public/private product
development partnership. Our support to DNDI makes us the
third-largest philanthropic funder of neglected disease
research in the world.
In a nutshell, we're facing two different types of problems
in addressing neglected diseases in developing countries.
First, there's very limited access to the tools that already
exist to diagnose and treat these diseases. But, at the same
time, the tools that we have are terribly insufficient. We
urgently need innovation and new and better products in order
to address these diseases. We need products that are effective,
that are easier to use, and that are well-adapted to field
conditions in resource-poor settings.
Globally neglected diseases affect what are often called
the ``bottom billion,'' people who live in the most rural
areas, who have little or no access to healthcare, and who are
often living on as little as a dollar or less per day.
Therefore, it was welcome news for us, in 2008, when the
Presidential Initiative on Neglected Tropical Diseases was
established. However, the initiative only focused on 5 of the
14 neglected tropical diseases that were identified by the
World Health Organization. It did not fund diagnosis and
treatment of the deadliest neglected diseases, such as Chagas
disease, sleeping sickness, and kala azar. These have been
identified, in fact, as the most neglected, and are the focus
of a number of MSF programs.
Many of you in this room may never have heard of these
diseases. They often occur in remote areas or in countries that
are undergoing political instability. Because of time
constraints, I won't go through and describe each of them to
you, but perhaps I could tell you a little bit more about one
of them, Chagas disease, because it infects about 300,000
people in the United States today, as well as 15 million people
around the world.
It's the largest parasitic killer in the Americas, and is
responsible for about 14,000 deaths every year. The disease is
caused by a parasite that's transmitted by what's called the
``kissing bug,'' because the bite of the bug is so gentle that
victims often don't even know that they've just been infected.
Chagas disease can also be transmitted from mother to child
during pregnancy, so it infects infants, through blood
transfusions and organ transplantation, as well as through oral
transmission. If left untreated, it eventually infects the
heart and the digestive system, and kills 30 percent of those
who are infected.
Despite its deadly effects, we don't have many tools to
combat Chagas disease. For example, currently we only have two
medicines, nifurtimox and benznidazole. Both were developed 45
years ago, and neither of them were developed specifically in
research aimed at Chagas disease. Neither of these drugs are
currently adopted for use in children, although, in the coming
months, we hope to have a pediatric formulation of benznidazole
made available.
Furthermore, there's no tests for cure for Chagas disease.
So, once a patient has gone through a treatment course, we
still don't know if they've actually been cured of the disease.
We urgently need new diagnostic tests, better medicines, a
vaccine, and a test for cure to help prevent, diagnose, and
treat this disease.
Another area where we urgently need better innovation is
for diagnostics for tuberculosis, or TB. In 2008, there were
12,900 cases of TB here in the United States, and 9.4 million
cases worldwide. TB is one of the world's leading causes of
pediatric and adult mortality, causing nearly 5,000 deaths per
day.
However, the current system that we have for diagnosing TB
in most developing countries is very weak. It detects less than
half of all TB cases, and it detects even fewer among children
and people who are living with HIV.
So, I think the question that comes up is, Why don't we
have better tools available to combat neglected diseases? It's
precisely because the patients that we're talking about are
poor and their needs get neglected. The current system that we
have to incentivize R&D to develop new drugs, diagnostics, and
vaccines is driven by commercial rewards. So, generally
speaking, a company will develop a drug or diagnostic tool,
then they'll receive a patent that allows them to sell the
product at a high price, and the high price is, in turn,
expected to cover R&D costs.
But, the system fails miserably to meet the needs of people
who cannot pay the high prices, either because there are too
few of them, which is the case, of course, for orphan and rare
diseases, or because they're too poor, which is often the case
for neglected tropical diseases that affect millions of people.
This is the reason why, between 1975 and 2004, only 1.3 percent
of all drugs that were developed targeted tropical diseases or
tuberculosis, even though these diseases account for 11.4
percent of the global burden of disease.
It's clear to me, then, that if we want new tools to combat
these diseases, we need new incentive mechanisms. MSF believes
that the key principle in evaluating and designing new
incentive mechanism should be what we call ``delinkage.'' And
what do I mean by this term? I think this term is relatively
new here in Washington, so I'll take a few minutes to explain.
Delinkage refers to the idea that we can separate the
market from R&D from the market for product manufacturing. What
I mean is that, on the one side, we can specify the kind of R&D
that we need, generate competition amongst researchers, and
then reward the best innovator, once they've solved the problem
that we've set out.
On the other hand, we have a market for production of the
tool, whether it's a drug or a diagnostic or a vaccine. Once
the product has been developed by the innovators, there would
be no need to grant monopoly rights. So, what we could do is
encourage a number of different manufacturers to enter the
market, and encourage robust competition, to get the lowest
sustainable prices.
So, when I say ``delinkage,'' the link that we're breaking
is, in fact, the link between high medicines prices and R&D.
Because if high medicines prices are the only incentive we have
for R&D, we're not going to get innovation and access for the
needs of the poorest patients.
Delinkage can stimulate R&D where there's no profitable
market; that is, for the neglected, rare, orphan, or pediatric
diseases that we've been hearing about this morning. But,
because the product development process is long and uncertain,
we need a range of different funding mechanisms that allow
delinkage, either to push R&D at the beginning of the pipeline
or to pull R&D at the end, and make sure that the right
products make it through.
One of the proposals I'd like to put on the table in front
of you today is for prize funds. We believe that prize funds
are an attractive pull mechanism that incorporates the
principle of delinkage. A prize is essentially an award that
would be provided for different stages of the R&D process. It
could be provided for identifying biomarkers, for proof of
concept, for product synthesis, or for the final product. Once
a prize is awarded, as I mentioned before, there would be no
need to give the innovator a monopoly to recoup their R&D
costs, because we would have just paid for it.
A well-designed prize offers a number of benefits,
including: No. 1, the ability to drive R&D based on health
needs; No. 2, allowing competition to determine the path or the
team that's most likely to succeed, rather than relying on
government or donors to do so; No. 3, it would attract a
broader, more diverse base of potential solvers for the problem
that we've identified; and No. 4, it allows us to build a lot
of flexibility into the--I'm sorry--it gives us a lot of
flexibility to build provisions into the prize to serve the
public interest. For example, we can encourage collaboration,
knowledge-sharing, and affordability provisions.
A prize fund, we believe, could quickly be established for
a TB diagnostic test that could be used at the point of care in
resource-poor countries.
In summary, we welcome the increased political attention
being paid to the needs of the most neglected patients.
However, we urge the U.S. Government to include the most
neglected tropical diseases, by which I mean Chagas disease,
sleeping sickness, kala azar, and Buruli ulcer, within the
scope of the new Global Health Initiative. We ask the
initiative to provide support for improved access to existing
health tools, as well as to support the development of new and
improved ones.
In order to develop new and improved tools, what we need is
to explore new innovation mechanisms that address the
shortcomings of the existing system. The key principle to keep
in mind is delinkage; that is, breaking the link between high
medicines prices and the funding of R&D. We believe prize funds
are one promising mechanism for generating innovation that
meets the health needs of the poorest people on the planet. We
ask this committee and the U.S. Government to support
innovative new approaches, such as prizes, that can be
established relatively quickly, such as for TB diagnostics. We
also ask the committee to consider prizes for other areas of
neglected innovation, such as Chagas disease. At the same time,
we urge the United States to support more systematic long-term
changes that are needed to improve sustainable financing for
health-needs-driven R&D that ensures equitable access to the
end products. And important discussions are currently taking
place at the World Health Organization and the Pan American
Health Organization in this regard.
In closing, there's increasingly widespread recognition
that the existing R&D system is failing. I think the previous
speakers on the panel illustrated that very clearly. It's
failing patients with neglected tropical diseases, with orphan
or rare diseases, and children, among others. Now is the time
to begin testing new approaches to generate the innovation that
we need to meet global public health needs.
Thank you very much for this opportunity to share our
experience.
[The prepared statement of Ms. Moon follows:]

Prepared Statement of Suerie Moon

EXECUTIVE SUMMARY

Doctors Without Borders/Medecins Sans Frontieres (MSF) is an
international independent medical humanitarian organization. For
decades, MSF has been one of the only actors providing care and
treatment to impoverished people suffering from neglected diseases,
such as Chagas disease, kala azar, sleeping sickness and Buruli ulcer.
Globally, neglected diseases target the bottom billion--those living in
the most rural locations, with poor or no access to healthcare, and
extraordinarily limited resources. As a founding member of the Drugs
for Neglected Diseases initiative (DNDi), a product development
partnership (PDP), MSF is also the third largest philanthropic funder
of neglected disease research. The problems we face are twofold: there
is limited access to the tools that exist to diagnose and treat these
diseases, but the existing tools are also terribly insufficient--new
products are urgently needed.
However, the current commercially driven system for drug,
diagnostic and vaccine development leaves many urgent health needs
unanswered. New medicines for sleeping sickness were not developed for
50 years despite pressing needs. There is no test to determine whether
patients have been cured of Chagas disease after a course of treatment.
A diagnostic tool for tuberculosis (TB) does not exist in a form
appropriate for resource-poor settings. The populations afflicted by
these diseases are simply too poor to provide adequate commercial
incentives for R&D in a system that relies almost entirely on the
ability to sell products at high prices to incentivize drug and
diagnostic development. New incentive mechanisms are needed.
MSF believes that de-linking the cost of R&D from the price of
health products needs to be the key principle used to evaluate and
develop mechanisms to stimulate R&D and ensure access. De-linkage would
separate the market for R&D from the market for product manufacturing.
The concept of de-linkage fully accepts that R&D costs money, but seeks
alternative ways to fund it. By paying for R&D through financing rather
than through product prices, de-linkage removes the need to incentivize
R&D through high prices. In this way, de-linkage can also stimulate R&D
where there is no profitable market--that is, for neglected, rare,
orphan diseases, or diseases like pediatric HIV/AIDS. From our
experience with DNDi, we know that a range of different funding
mechanisms that allow de-linkage are needed, either to ``push'' R&D via
up front funding (e.g., through PDPs) or to ``pull'' R&D to ensure that
the right products reach the end of the pipeline.
Prizes are one attractive ``pull'' mechanism for de-linking the
markets for R&D and product manufacturing. The key potential benefits
of a well-designed prize include: the ability to drive R&D based on
health needs; allowing competition (rather than governments or donors)
to determine the path or team most likely to succeed; attracting a
broader, more diverse base of potential ``solvers'' to a problem; and
the flexibility to build in provisions for collaboration, knowledge-
sharing, and affordability of end products. Prize designs can vary, and
they can also be given for different stages of the R&D process. Prize
funds would be promising, and could quickly be established, in at least
two areas of urgent need: a point-of-care TB diagnostic test and new
products for Chagas disease.
In 2008, the U.S. Government established the Presidential
Initiative on Neglected Tropical Diseases. However, the initiative only
focused on 5 of the 14 most neglected tropical diseases identified by
the WHO, did not fund diagnosis and treatment of the deadliest
neglected diseases, and did not provide support for the development of
innovative products for these diseases. MSF urges the U.S. Government
to include the most deadly tropical diseases (Chagas disease, sleeping
sickness, kala azar, and Buruli ulcer) within the scope of its new
Global Health Initiative, and to provide support for improved access to
existing health tools, as well as for the development of new and
improved ones.
We also urge the U.S. Government to craft its policies and mobilize
its financial resources to support new incentive mechanisms that
embrace the principle of de-linkage, such as prize funds, in order to
generate the innovation that we need to improve the lives of the
world's poorest children and families.
______

Thank you, Chairperson Harkin, Ranking Member Enzi, and the Senate
Health, Education, Labor, and Pensions Committee for calling for this
important hearing. This is a critical moment of both need and
opportunity for innovation and access for neglected tropical diseases.
My name is Suerie Moon and I am on the U.S. Board of Directors of
Doctors Without Borders, known as MSF, an acronym for our French name,
Medecins Sans Frontieres. MSF is an international independent medical
humanitarian organization. My experience with MSF dates back to 1999
and includes fieldwork in the Democratic Republic of Congo and China,
as well as over a decade of research and analysis on access to
medicines and innovation policy issues.
We are most known for our emergency responses during armed conflict
or following devastating natural disasters, or for our work against
medical disasters like HIV/AIDS.
Less visible is our engagement in providing care and treatment to
impoverished people suffering from diseases so neglected that many in
the world have never heard of them before--Chagas disease, kala azar,
sleeping sickness and Buruli ulcer, to name a few. From our decades of
experience running programs and conducting operational research, we
know that there is limited access to the tools that exist to diagnose
and treat these diseases. But we also know very well that these tools
are terribly insufficient, and new products are needed.
Globally, neglected diseases can best be thought of as the diseases
of the bottom billion--those living in the most rural locations, with
poor or no access to healthcare, and extraordinarily limited resources.
People suffering from these diseases do not represent a profitable
potential market and therefore current market incentives have proven
insufficient to generate the development of better tools for
prevention, diagnosis, treatment, and cure for these diseases. Between
1975 and 2004, only 1.3 percent of all new drugs were specifically
developed for tropical diseases and tuberculosis, even though these
diseases account for 11.4 percent of the global disease burden.\1\ In
addition, even when effective tools do exist, these populations can be
difficult to reach due to geographic or social marginalization.
Political will is often lacking, and healthcare infrastructure can be
weak.
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\1\ Chirac, P., & Torreele, E. (2006). Global Framework on
Essential Health R&D. The Lancet, 367(9522), 1560-1561.
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I would like to take the opportunity to share with you today the
experiences of MSF in both treating and supporting innovation in
treatments and diagnostics for neglected diseases.

MSF EXPERIENCES WITH NEGLECTED DISEASES

Many diseases, such as tuberculosis and tropical diseases, are
neglected because they primarily affect people in poor countries.
Across many of the diseases that disproportionately affect developing
countries, children are particularly neglected: adapted pediatric
medicine formulations are missing for diseases such as tuberculosis,
Chagas disease and HIV/AIDS.
The World Health Organization (WHO) has identified as neglected
tropical diseases (NTDs) 14 major parasitic, bacterial and viral
diseases that are the most common infections in the 2.7 billion people
living on less than $2 a day. Those affected are often marginalized and
forgotten by governments, left to suffer in silence. Other diseases
like tuberculosis and pediatric HIV/AIDS are also neglected but are not
within the WHO list of NTDs.
MSF has for many years provided diagnosis and treatment for
individuals afflicted with NTDs, primarily focusing on visceral
leishmaniasis (VL, or kala azar), human African trypanosomiasis (HAT,
or sleeping sickness), Chagas disease (American trypanosomiasis), and
Buruli ulcer. Three of these NTDs--VL, HAT, and Chagas disease--are
often fatal if left untreated and have the highest rates of death of
all of the NTDs. MSF is one of the only actors in the world involved in
the treatment of these diseases.
Governments and donors have continued to neglect those who suffer
from these diseases. These four diseases are largely left out of
control and treatment programs by health actors and donors because they
are considered too difficult and costly to treat; the available tools
are limited; little investment has been made into research and
development (R&D); and their disease burdens are poorly understood due
to inadequate screening and surveillance systems. Nevertheless, the
diseases are no less devastating for the individuals and countries
affected. These barriers beg greater, not less, attention for effective
responses to these diseases.
In 2008, the U.S. Government established the Presidential
Initiative on Neglected Tropical Diseases. However, the initiative only
focused on 5 of the 14 identified by the WHO.\2\ It did not fund
diagnosis and treatment of the deadliest neglected diseases, and did
not provide support for the development of innovative products for
these diseases. As part of the Global Health Initiative (GHI), the U.S.
Government has now proposed a significant increase in funds for NTDs.
MSF welcomes this increased attention to the NTDs. However, there
remains an ongoing neglect of the most deadly and most forgotten
diseases.
---------------------------------------------------------------------------
\2\ The Presidential Initiative on Neglected Tropical Diseases
disaggregates one WHO identified disease into three, therefore
identifying the Presidential Initiative as responding to seven
neglected diseases.
---------------------------------------------------------------------------
It may be impossible in an illustrious committee room in the U.S.
capital to paint a picture of the diseases that affect the poorest of
the poor, who often live in the most remote areas of the world, but I
will try.

Chagas Disease (American Trypanosomiasis)
Chagas disease is an appropriate place to start if only because
there are currently an estimated 300,000 people living with this
disease in the United States today. There are 15 million people living
with Chagas disease around the world. It is the largest parasitic
killer in the Americas, responsible for about 14,000 deaths per year,
mostly in South and Central America.
This disease is caused by a parasite transmitted by a bug (the
triatome). They call it the ``kissing bug'' because it bites gently,
and victims often do not even know they have been bitten. It also can
be transmitted from mother to child during pregnancy; and through blood
transfusions and organ transplantation, and sometimes through oral
transmission. If untreated, it infects the heart and digestive system
of one-third of those carrying the parasite--with fatal effects in 30
percent of patients over a period of time.
Diagnosis currently requires confirmation through laboratory tests.
In many cases, the endemic countries do not have the necessary
facilities or staff available to carry out these tests.
MSF has provided free diagnosis and treatment for Chagas disease
since 1999 in countries including Honduras, Nicaragua, Guatemala, and
Bolivia, which has the highest prevalence in the world. In Cochabamba,
Bolivia, MSF runs free, urban and rural Chagas programs that are
carried out in collaboration with the Bolivian Ministry of Health in an
integrated way in five primary care centres, where children and adults
up to the age of 50 are treated and diagnosed. Through 2009, MSF has
screened over 60,000 people for Chagas disease and treated more than
4,000. We are also currently exploring the possibility of opening a
project here in the United States to improve detection and access to
treatment for people living with Chagas disease.
The tools we have at hand can be used for treatment, but are
insufficient. Currently, there are only two medicines to combat Chagas
disease: benznidazole and nifurtimox. Both were developed over 45 years
ago through research that was not even specifically targeting Chagas
disease. Presently, neither of these drugs is adapted for use in
children, although a paediatric formulation of benznidazole is
anticipated in the coming months. As the side effects of the treatment
are more common in older patients, doctors have been reluctant to
administer the medicine out of fear of the consequences. Further, there
is no test for cure for Chagas disease.
Millions suffering from Chagas disease, especially in rural areas,
have neither the opportunity to find out that they are infected nor the
possibility of being treated. New diagnostic tests, better medicines, a
vaccine, and a test for cure are urgently needed to help prevent,
diagnose and treat this disease.

Sleeping Sickness
Sleeping sickness, otherwise known as human African trypanosomiasis
(or HAT), is a fatal parasitic disease found in 36 countries in sub-
Saharan Africa, with an estimated 70,000 annual cases and 60 million at
risk. During 2009 less than 10,000 cases were diagnosed and treated,
but many more are affected--the true size of the problem remains
unknown. Sleeping sickness occurs in the poorest rural areas of Africa,
where difficulty of diagnosis, political instability, and lack of
health surveillance make diagnosis and care difficult. Sleeping
sickness rapidly deteriorates into coma and death--and is fatal in 100
percent of patients within approximately 2 years if untreated.
Up to 10 years ago, patients with advanced sleeping sickness would
have received an arsenic-based treatment called melarsoprol.
Melarsoprol is more than 50 years old and highly toxic, with rising
rates of treatment failure. No new treatments had been developed for a
half-century for sleeping sickness even though melarsoprol was killing
the patient in about 5 to 10 percent of cases, and in some affected
areas had only 50 percent effectiveness.
Thanks to the efforts of many partners, including MSF, the WHO,
Epicentre, the Drugs for Neglected Diseases initiative and the Swiss
Tropical Institute (STI), there is now a new treatment for patients
with advanced sleeping sickness. These partners have also supported the
development of research capacity in countries where sleeping sickness
is endemic. Using nifurtimox-eflornithine combination therapy (NECT)
has proven to be safer and more effective compared to the existing
standard of care. Eflornithine is given intravenously twice a day for 7
days alongside orally administered nifurtimox. The treatment is life-
saving and prevents relapse back into the sickness. In May 2009, the
WHO added NECT to the Essential Medicines List (EML) for the treatment
of advanced sleeping sickness.
Despite these improvements, the current treatment for sleeping
sickness remains long and difficult--for both patients and health
workers. Both diagnosis and staging--which requires painful lumbar
punctures--demand significant technical capacities and are therefore
difficult to implement in remote areas where the disease occurs. There
is an immediate need to improve current diagnostic and treatment
options, particularly for patients in the advanced stages of this
disease.

Tuberculosis
Tuberculosis (TB) is a major public health problem, with over 9.4
million new cases and almost 1.8 million deaths in 2008 alone--or
nearly 5,000 people every day. TB is a leading cause of mortality in
children worldwide, with approximately 1 million cases and 400,000
deaths each year in children under 15 years old as of 2006. The most
commonly used TB diagnostic test is Sputum Smear Microscopy (SSM).\3\
It is relatively fast and easy to implement in resource-limited
settings, but it has significant limitations: it detects less than half
of all TB cases \4\ and performs even worse in children and people
living with HIV who either have difficulties producing enough sputum,
or don't have sufficient or any mycobacteria in their sputum to be
detected under the microscope. It also completely misses the
extrapulmonary form of TB.\5\ \6\
---------------------------------------------------------------------------
\3\ Sputum smear microscopy is done by staining a sputum sample
with an acid-fast stain and then examining the sample with a microscope
for acid-fast bacilli.
\4\ In countries characterized by high HIV prevalence, the
challenge of providing timely TB diagnosis and treatment initiation is
even greater. In a study recently conducted in Rwanda, where 62 percent
of the recruited patients were TB/HIV co-infected, only 18 percent of
TB confirmed cases were started on treatment within 1 month and only 56
percent within 2 months.
\5\ Perkins, MD, Roscigno, G, Zumla, A. (2005) Progress towards
improved tuberculosis diagnostics for developing countries. The Lancet
367(9514): 942-943.
\6\ Shingadia, D, Novelli, V. (2003) Diagnosis and treatment of
tuberculosis in children. Lancet Infect. Dis. 3(10): 624-632.
---------------------------------------------------------------------------
A study analyzing the contribution that improving TB diagnostics
could make to reducing the global burden of TB, shows that improving
the performance, speed and accessibility of TB diagnostic tests are key
factors.\7\ The study calculates that 392,000 deaths or 22 percent of
annual deaths due to TB in the four highest-burden WHO regions, could
theoretically be avoided by the introduction of a new TB point-of-care
diagnostic.
---------------------------------------------------------------------------
\7\ Keeler, E., et al., (2006) Reducing the global burden of
tuberculosis: the contribution of improved diagnostics. Nature 444: 49-
57.
---------------------------------------------------------------------------
We desperately need a new point-of-care diagnostic test able to
diagnose active TB in adults and children who may also be co-infected
with HIV; has high sensitivity and specificity; is simple to use and
can be operated without the need for extensive infrastructure. Despite
the valuable work supported by grant programs administered by entities
such as the Foundation for Innovative New Diagnostics (FIND), there is
widespread agreement that there is insufficient progress on the
development of a new test that meets these needs.
MSF Experience in Innovation
A decade ago, MSF created the Campaign for Access to Essential
Medicines because of our concern about barriers for access to medicines
in low- and middle-income countries. People in developing countries are
dying because medicines do not exist due to inadequate incentives for their
development; or because they are unavailable due, in part, to high
costs.
Our work on NTDs convinced us that we wanted not only to advocate
for new tools, but also to engage actively in the development of these
tools. Therefore, MSF became a founding member of the Drugs for
Neglected Diseases initiative, or DNDi, a product development
partnership (PDP). We continue to contribute funding, making MSF the
third largest philanthropic (under of neglected disease research.\8\
From our experience as a founding member of DNDi, we know that a
critical role is played by ``push'' funding--that is, grants invested
into promising candidates for future drugs. While push funding and PDPs
play an important role, our experience also tells us that incentives
are needed throughout the innovation process to ensure that the right
products reach the end of the pipeline. For this reason, we also need
``pull funding''--that is, incentives at the end of the product
development process, such as the promise of a profitable market or
other reward. While donors and governments have invested increased
amounts in push funding, we are just beginning to see serious efforts
to explore how best to put in place pull funding.
---------------------------------------------------------------------------
\8\ Moran, M., Guzman, J., Henderson, K., Ropars, A., McDonald, A.,
McSherry, L., Wu, L., Omune, B., Illmer, A., Sturm, T., & Zmudzki, F.
(2009). Neglected Disease Research and Development: New Times, New
Trends. Sydney, Australia: The George Institute for International
Health, p. 62.
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PRIORITIZATION OF ACCESS CONSIDERATIONS: THE IMPORTANCE OF ``DE-
LINKAGE''

The current system for drug, diagnostic and vaccine development
creates both innovation and access barriers. Driven by commercial
rewards, it is a system that leaves many pressing health needs
unanswered--needs that we identify in our medical programs every day.
New medicines for sleeping sickness were not developed for 50 years
despite pressing needs. The diagnosis of sleeping sickness is
complicated, and often requires a blood sample, lymph node aspiration
and a painful lumbar puncture. There is no test to determine whether
patients have been cured of Chagas disease after a course of treatment.
A diagnostic tool for tuberculosis does not exist in a form appropriate
for resource-poor settings. These populations are simply too poor to
provide adequate commercial incentives for R&D in a system that relies
almost entirely on the ability to sell products at high prices to
incentivize drug and diagnostic development.
But what if we could separate the market for medicines production
from the market for R&D? What if we could encourage robust competition
in both?
MSF believes that de-linking the cost of R&D from the price of
health products needs to be the key principle used to evaluate and
develop mechanisms to stimulate R&D and ensure access. This principle
has gained increasing acceptance worldwide. The concept of de-linkage
fully accepts that R&D costs money, but seeks alternative ways to fund
it. Rather than relying on high prices charged after the innovation has
been developed, de-linkage would seek to stimulate innovation from many
sources and consider access issues in advance. This approach would
broaden incentives for innovation beyond just the profitable diseases,
and remove the access barriers created by high prices.
The concept of de-linkage has been included in the Global Strategy
and Plan of Action on Public Health, Innovation and Intellectual
Property (GSPoA), which was agreed upon in 2008 by all WHO Member
States, including the United States.\9\ In conjunction with this plan,
several governments have proposed the creation of new incentive
mechanisms, including prizes, based on the principle of de-linkage.
Just 2 months ago, the Council of the European Union decided to explore
``models that dissociate the cost of Research and Development and the
prices of medicines,'' as a part of its global health efforts.\10\
---------------------------------------------------------------------------
\9\ The Global Strategy and Plan of Action Section 5.3.a states:

``explore and, where appropriate, promote a range of incentive
schemes for research and development including addressing where
appropriate, the de-linkage of the costs of research and development
and the price of health products, for example through the award of
prizes, with the objective of addressing diseases which
disproportionately affect developing countries.'' World Health
Assembly. (2008). Global Strategy and Plan of Action on public health,
innovation and intellectual property. Resolution 61.21. Geneva.
Available: http://www.who.int/gb/ebwha/pdf_files/A61/A61_R21-en.pdf.
\10\ Council of the European Union. (2010) ``Council conclusions on
the EU role in Global Health.'' 2011th Foreign Affairs Council meeting.
Brussels. 10 May 2010. Section 18.c. Available: http://
www.consilium.europa.eu/uedocs/cms_Data/docs/pressdata/EN/foraff/
114352.pdf.
---------------------------------------------------------------------------
Why the broad interest in ``de-linkage''? De-linkage is important
because the price of the final product is critical for affordability
and access, and because R&D should be driven by health priorities, not
the size of the market. Innovation by itself is of little value if the
tools developed are unavailable or unaffordable to the people who need
them. By paving for R&D through financing rather than through product
prices, and by addressing the price and availability of the product at
the outset, de-linkage removes the need to incentivize R&D through high
prices. De-linkage also stimulates R&D where there is no profitable
market--that is, for neglected, rare, orphan diseases, or diseases like
pediatric HIV/AIDS which has been all but eliminated in rich countries
even as a rich country market continues to exist for adult HIV/AIDS
medicines.
De-linkage is not just about breaking the link to high prices, but
is also about pro-actively designing into any new incentive mechanisms
ways to ensure that the affordability and availability of any new
health tool are incorporated from the outset of the R&D process. A
range of different funding mechanisms that allow de-linkage are needed,
either to ``push'' R&D via up front funding (e.g., through PDPs) or to
``pull'' R&D via incentives that focus investment efforts on products
needed in developing countries (such as prize funds).
Once the market for R&D is de-linked'' from high medicines prices,
we can encourage robust competition among producers of the end product.
Our experience shows that competition is the most effective way to
achieve reliable price reductions and sustainable, affordable prices.
Intellectual property can and should be managed in a way that ensures
that a new health tool can be manufactured by other producers,
fostering competition and access. A recent example is the patent-free
development of the anti-malarial fixed-dose combination of artesunate
and amodiaquine by DNDi, in collaboration with the pharmaceutical
company Sanofi-Aventis. (In cases such as vaccine development where
competition may not be technically feasible in the immediate term, even
when favorable licensing terms exist, a pathway to facilitate access is
needed, including technology transfer.)

BREAKING THE INNOVATION BARRIERS

Prizes are one attractive option for de-linking the markets for R&D
and product manufacturing. Prizes can act as powerful incentives for
innovation, but need to be designed carefully in order to maximize the
sharing of knowledge, access to end products, and overall return on the
public's investment. Prize designs can vary, and they can also be given
for different stages of the R&D process, such as identifying
biomarkers, proof of concept, product synthesis, or developing a
finished product all the way through the registration process. The key
potential benefits of a well-
designed prize include some of the following \11\:
---------------------------------------------------------------------------
\11\ See, e.g., Love, James and Hubbard, Tim (2009). ``Prizes for
Innovation of New Medicines and Vaccines,'' Annals of Health Law, 18
(2): 155-186.

1. It would allow R&D efforts to be driven by health needs.
2. It would establish a bold and important goal without having
donors or governments pick winners by choosing in advance the path or
team that is most likely to succeed in reaching it.
3. Payment would only be made when results are achieved. The prize
is only paid if the challenge has been met, i.e. if donors can see a
direct connection between their funding and the outcomes.
4. With the right backing, a prize can create a ``lighthouse''
effect by highlighting a problem to a whole new range of potential
innovators, who may have previously been unaware of the problem. This
increases the number and diversity of potential ``solvers'' for a
problem, which could include, for example, both commercial enterprises
and academics. An even wider range of participants could be sought
through the award of intermediate prizes for solutions to specific
technical challenges.
5. A prize could include incentives for collaboration and
knowledge-sharing.
6. By including affordability criteria, the prize could promote
both innovation and access.

Two specific examples of urgent needs that we've identified in our
programs--and for which there will be little engagement from the major
R&D players without novel innovation mechanisms--are related to TB and
Chagas disease.
Millions would benefit from the creation of a point-of-care (POC)
test that would allow the diagnosis of TB at local health centers in
resource-poor contexts. The dearth of R&D in TB diagnostics is
demonstrated by the chronic lack of investment in this area,
particularly from the private sector. Only U.S. dollars--41.9 million
was directed towards TB diagnostics R&D--a mere 9 percent of total
resources spent on TB product development, which is already an under-
funded field. Of this amount, only U.S. dollars--2.5 million came from
the private sector. A TB diagnostic test designed for use in resource
poor areas, which necessarily has to be low cost, requires a different
form of incentive that would allow for the cost of the final product to
be de-linked from the cost of R&D. A prize competition would create the
incentives for R&D in this neglected area.
As noted above, a prize fund would allow for many different
approaches to be pursued without deciding at an early stage which is
the most promising. This is particularly important in the field of TB
POC diagnostic development since there are several approaches that
could potentially lead to the delivery of the right test, but it is not
clear which angle will be the most successful. Current R&D in different
areas of the POC diagnostic market, such as bioterrorism, pandemic
influenza, and HIV viral load testing, holds the potential for
breakthroughs in the area of TB diagnosis. The governments of
Bangladesh, Barbados, Bolivia and Suriname have proposed a prize fund
of $100 million or more for a TB POC diagnostic.\12\ By providing a
sizeable incentive, the prize would attract many developers to the
neglected area of TB.
---------------------------------------------------------------------------
\12\ Governments of Bangladesh, Barbados, Bolivia and Suriname.
(2009) Prize Fund for Development of Low-Cost Rapid Diagnostic Test for
Tuberculosis. 15 April. Contributions from Member States. WHO
Secretariat on Public Health, Innovation and Intellectual Property.
Available: http://www.who.int/phi/
Bangladesh_Barbados_Bolivia_Suriname_TBPrize.pdf.
---------------------------------------------------------------------------
Prizes are not a new mechanism, but have successfully been used in
the past to induce innovation. For example, recently the Global
Alliance for TB Drug Development (a PDP) and the Rockefeller Foundation
awarded two prizes for more efficient ways to synthesize a new
tuberculosis drug candidate, PA-824. Prizes are also receiving renewed
attention in policy circles because of their potential to help address
our most pressing public problems. Just this past spring, the White
House issued guidance on the Open Government Directive, supporting the
use of prizes to encourage innovation in a range of areas, including
climate change technology and promoting open government.\13\
---------------------------------------------------------------------------
\13\ Executive Office of the President: Office of Management and
Budget. (2010) ``Memorandum for the Heads of Executive Departments and
Agencies (M-10-11).'' Washington, DC. 8 March. Available: http://
www.whitehouse.gov/omb/assets/memoranda_2010/m10-11.pdf.
---------------------------------------------------------------------------
While individual initiatives that can be established quickly, such
as a TB POC diagnostic prize fund, are important, others are exploring
how prizes could be used as part of longer-term systemic changes that
are needed to provide sustainable financing for health needs-driven R&D
that ensures equitable access.
Similarly, we need innovative tools for the diagnosis, treatment,
and test of cure for Chagas disease. The governments of Bangladesh,
Barbados, Bolivia and Suriname have proposed creating a $250 million
prize fund to reward the development of new products that would
decrease the burden of disease from Chagas.\14\
---------------------------------------------------------------------------
\14\ Governments of Bangladesh, Barbados, Bolivia and Suriname.
(2009) Chagas Disease Prize Fund for the Development of New Treatments,
Diagnostics and Vaccines. 15 April. Contributions from Member States.
WHO Secretariat on Public Health, Innovation and Intellectual Property.
Available: http://www.who.int/phi/
Bangladesh_Barbados_BoliviaSuriname_Chagas
prize.pdf.
---------------------------------------------------------------------------
Prizes are also flexible tools. There is not just one model, and
they can be designed to fit the medical, scientific, and technical
problems that need to be addressed and the specific access issues for a
disease area. In some areas it may be more appropriate to have a prize
that rewards the development of the final product. In others, it might
be more effective to support a prize that can be focused on a critical
milestone that could overcome a key barrier to further development. In
all cases, however, it is critical that methods to ensure affordable
access must be part of the prize design at the start.
DNDi has been considering milestone prizes for Chagas drug
development. Substantial rewards for attaining specified milestones
along the path to a new drug or other health technology could be a
useful supplement to grants for diseases for which market incentives
are deficient and where patents are not an effective incentive.
Milestone prizes promise earlier pay-outs and are likely to attract new
actors such as biotechnology firms, which cannot make major investments
in pursuit of rewards that may be many years away.
Several discussions to explore de-linkage mechanisms for the
technological needs of Chagas are also ongoing at the regional level as
part of the Pan American Health Organization's (PAHO) regional
implementation of the GSPoA. These discussions provide a framework for
agreement on new incentive mechanisms, including appropriate prize
designs to stimulate innovation for Chagas disease.

CONCLUSION

MSF welcomes the growing attention to patients who suffer from
neglected diseases around the world. We ask the U.S. Government to
include the most deadly tropical diseases (Chagas disease, sleeping
sickness, kala azar, and Buruli ulcer) within the scope of its new
Global Health Initiative, and to provide support for improved access to
existing health tools, as well as for the development of new and
improved ones. We also urge the U.S. Government to craft its policies
and mobilize its financial resources to support ambitious, visionary
approaches to generating medical innovation that can improve the lives
of the world's poorest children and families. In particular, the United
States should support relevant discussions at the WHO and PAHO, and the
efforts of the Consultative Expert Working Group that will be formed in
the coming months to analyze new innovation mechanisms in depth.\15\
---------------------------------------------------------------------------
\15\ See the mandate given to WHO by the 2010 World Health
Assembly. (World Health Assembly (2010). ``Establishment of a
consultative expert working group on research and development:
financing and coordination.'' Resolution 63.28. Geneva. Available:
http://apps.whoint/gb/ebwha/pdf_files/WHA63/A63_R28-en.pdf.
---------------------------------------------------------------------------
I have outlined today just two promising possibilities--the
potential of a prize fund for TB diagnostics and for Chagas disease--
but there are many others. We need strong political commitment and
financial support from governments and other donors if we are to make
new incentive mechanisms work. There is increasingly widespread
recognition that the existing R&D system is failing--failing patients
with neglected tropical diseases, with orphan diseases, and children,
among others. Now is the time to begin testing new approaches to
generate the innovation that we need to meet global public health
needs.
Thank you very much for this opportunity to share our experience
with you.

Senator Brown. Thank you, Ms. Moon.
Dr. Frattarelli.

STATEMENT OF DANIEL A.C. FRATTARELLI, M.D., FAAP, CHAIR,
COMMITTEE ON DRUGS, AMERICAN ACADEMY OF PEDIATRICS, DEARBORN,
MI

Dr. Frattarelli. OK. All right.
Senator Brown, Senator Enzi, Senator Sanders, Senator
Casey, on behalf of the AAP, I'd like to thank the committee
for holding this important hearing on treatments for children
with rare and neglected diseases.
I want to let you guys know this testimony is also
supported by the American Pediatric Association, the American
Pediatric Society, the Association of Medical School Pediatric
Department Chairs, and the Society for Pediatric Research.
Pediatricians often say that children are therapeutic
orphans because they lack the breadth of available therapies
that are offered for adults. That's not just for rare diseases,
that's across the board. Lower financial incentives and greater
clinical-trial obstacles have resulted in fewer drugs being
developed specifically for children.
There are significant barriers to the development of
therapeutics for children, in general. These obstacles are
magnified for children with rare diseases.
As we've already heard, most of the rare diseases are
pediatric. And because most of these are genetic, they're
present from birth into adulthood. Pediatricians play an
important role in the care of children with rare diseases, but,
as we've already heard, really, so eloquently from Mr. Silver
and Mr. Crowley, a lot of the time, we're left without proven
therapies to treat them, or with existing therapies that just
aren't sufficient for taking care of children.
The American Academy of Pediatrics have been working for
decades to improve medicines for children by ensuring that the
drugs used in children are studied in children. As we've heard
so many times here, children are not just little adults. I'm so
glad to hear that, so many ways, here, because that used to not
be the case. Many people used to think that, in fact, they
were; and that distinction hadn't been made. Children need
drugs that are safe, effective, and developed just for them,
and drugs which meet the same standards as we have for adults.
Because rare diseases are often so serious and so life-
threatening, physicians must think differently about how they
balance therapeutic risks and benefits in treating them. When
therapeutic gaps exist for children, drugs are frequently used
off-label without the benefit of the same drug labeling
information that we've come to expect for adults. The outcomes
of these off-label treatments, however, all too often stay with
the physician and fail to benefit other patients. We need a
greater capacity to capture and interpret data from what are
essentially a bunch of small studies which are being conducted
independently every time we treat one of these children off-
label.
One possible mechanism for this would be the creation of a
central repository for data generated on these individual
treatment basis, to establish the efficacy and the safety of
medications for rare diseases.
Now, two laws--the Best Pharmaceutical for Children's Act,
BPCA, and the Pediatric Research Equity Act, PREA--have made
historic progress in improving the information available to
pediatricians and families for drugs used in children.
Together, these laws have resulted in 385 drug labels revised
with new safety, new efficacy, and new dosage information. And
we can now say, with confidence, that BPCA and PREA have
changed pediatric practice for the better.
Senator Chris Dodd--I was hoping he was going to be here to
hear this--but, really, in particular, deserves great credit
for his passionate leadership, over the course of his career,
to improve the health of children. BPCA and a more recent
initiative, the Pediatric Medical Devices Safety and
Improvement Act, from 2007, will stand as long-lasting legacies
to his dedication to child health and well-being.
BPCA and PREA have been important for children as a whole,
and also for children with rare diseases. The laws greatly
complement the Orphan Drug Act, which has done a remarkable job
in stimulating new therapies for rare diseases. And of those
385 drug labels resulting from BPC and PREA, 56 have also
received an orphan designation.
BPCA, PREA, and the pediatric devices law must be
authorized in 2012, and the AAP looks forward to working with
this committee on reauthorizing and strengthening these
important programs.
Studying drugs in children is difficult and requires
specialized skills. However, we still lack a number of
qualified experts which are needed to actually do the work.
We're training far too few new pediatric clinical
pharmacologists. And if more is not done to reverse this trend,
children will be left behind.
Finances, as we've already heard, can also be a barrier to
effective therapies. New and novel drugs for children with rare
diseases, which are usually expensive or often deemed
experimental by insurance programs and are not reimbursed, and
paying out-of-pocket for these drugs is simply not possible for
many families. The promise of healthcare reform for children
with rare diseases can only be realized if life-saving and
life-improving therapies are paid for by insurance programs.
Along with drugs, medical and surgical devices are also
important components in the treatment of many pediatric rare
diseases. The development of pediatric devices shares the same
obstacles, or at least similar ones, to pediatric drugs. And
the Pediatric Medical Device Safety and Improvement Act was a
first legislative step to ensuring that children will have
access to devices that are safe, that are effective, and that
are made with their unique characteristics in mind. Children
deserve a continued sense of urgency around medical devices,
though, and we look forward to working with the FDA to fully
implement this law.
Finally, regarding the neglected diseases, it's
unacceptable for any of us, from regulatory agencies to
manufacturers, for the medical community to neglect to treat
diseases for which effective therapies are within reach. And
the AAP encourages ongoing work focused on the identification,
prioritization of clinical conditions which affect a sizable
number of children, but which have, for whatever reason, been
neglected.
Thank you for allowing the Academy of Pediatrics to share
its views on this important issue.
[The prepared statement of Dr. Frattarelli follows:]

Prepared Statement of Daniel A.C. Frattarelli, M.D., FAAP

Mr. Chairman, members of the committee, I am Daniel Frattarelli,
M.D., FAAP, a practicing pediatrician who has taken care of infants,
children and adolescents for 13 years. I am chair of Pediatrics at
Oakwood Hospital and Medical Center in Dearborn, MI and chair of the
American Academy of Pediatrics (AAP) Committee on Drugs. On behalf of
the AAP, I would like to thank the committee for holding this important
hearing on new treatments and cures for children with rare and
neglected diseases.
Pediatricians often say that children are therapeutic orphans
because they lack the breadth of therapies available to adults. Lower
financial incentives and greater clinical trial obstacles have resulted
in fewer drugs developed and studied specifically for children. When a
disease population is small, there is a lower likelihood that
pharmaceutical companies can recoup the costs of developing new drugs.
It is also difficult to recruit sufficient numbers of participants for
a robust clinical trial. Both children and rare disease populations
suffer from these similar small market problems. There are significant
therapeutic obstacles for children in general, and these obstacles are
greatly magnified for children with rare diseases.
Most of the approximately 7,000 rare diseases are pediatric
diseases. Because most rare diseases are genetic, they are present from
birth, through childhood, and into adulthood. Pediatricians play an
important role in the care of children with rare diseases from
diagnosis to treatment and care. For many of these patients, however,
pediatricians are left without proven therapies to treat them or with
existing therapies that are not sufficient.
The American Academy of Pediatrics has been working for decades to
improve therapeutics for children by ensuring that drugs used in
children are studied in children. In 1977, AAP said for the first time
that not only is it not unethical to study drugs in children, but that
it is unethical not to. Children are not little adults. They need drugs
that are developed just for them and they deserve the same level of
safety and effectiveness in drugs that is assured for adults.
Because rare diseases are so often serious and life threatening,
physicians must think differently about how they balance therapeutic
risks and benefits when treating them. When therapeutic gaps exist for
children--and in particular for children with rare diseases--drugs must
frequently be used ``off-label,'' or without the benefit of the same
drug labeling information that we have come to expect for adults.
As doctors we know that better medical evidence is based on trials
with a larger ``N,'' or a larger number of patients. But when this
evidence is not available for children, the standard of care is off-
label treatment. We call this a trial with an ``N of one.'' Physicians
must monitor their young patients and try additional therapies,
combinations, or dosages depending on the results. The outcomes of
these ``N of one'' trials too often stay with the treating physicians.
For other children to benefit from these studies, new tools are needed
to collect and interpret the clinical results of off-label treatments.
One possible mechanism for the collection of these data is the
creation of a central repository for data related to the safety and
efficacy of treatments in rare conditions. Consensus on the specifics
of the data collected can be reached by the combined efforts of
physicians trained in pediatric research and those physicians in the
trenches who care for these children day in and day out. The most
apparent benefit from this approach is the ability to capture and
meaningfully interpret the data from what are essentially a bunch of
small studies being independently conducted across the country. But
another significant benefit to this approach would be a standardization
or leveling of the risks to these children, as by virtue of their being
enrolled in a study there is a greater, more formal, more clearly
defined awareness of and attention to possible risks, which would come
to light more fully through the consensus process than is possible for
an individual physician.
Two laws, the Best Pharmaceuticals for Children Act (BPCA) and the
Pediatric Research Equity Act (PREA), have made historic progress in
improving the information available to pediatricians and families on
drugs used in children. PREA provides FDA the authority to require
pediatric studies of drugs when their use for children would be the
same as in adults. BPCA provides a voluntary incentive to drug
manufacturers of an additional 6 months of marketing exclusivity for
conducting pediatric studies of drugs that the FDA determines may be
useful to children.
Together these laws have resulted in 385 drug labels revised with
new safety, effectiveness, and dosage information. We can now say with
confidence that BPCA and PREA have changed pediatric practice for the
better. They have also changed the way drugs are developed by Industry
and regulated by FDA. Pharmaceutical companies have invested in greater
internal pediatric infrastructure, so that pediatrics can be considered
at each stage of drug development. At FDA, with the help of the new
BPCA-created Pediatric Review Committee (PeRC), pediatrics has been
integrated across the review divisions in a consistent and productive
way for the benefit of children. The pediatric efforts at FDA would not
have been possible without the leadership of Dr. Dianne Murphy and the
Office of Pediatric Therapeutics (OPT).
Senator Chris Dodd in particular deserves great credit for his
passionate leadership over the course of his career to improve the
health of children. BPCA and a more recent initiative, the Pediatric
Medical Devices Safety and Improvement Act of 2007, will stand as
lasting legacies to his dedication to child health and well-being.
BPCA and PREA have been important both for children as a whole and
for children with rare diseases. The laws greatly complement the Orphan
Drug Act, which has done a remarkable job stimulating the development
of new therapies for rare diseases. Of the 385 drug labels resulting
from BPCA and PREA, 56 have been for drugs that have also received an
``orphan'' designation.
BPCA, PREA, and the pediatric devices law must be reauthorized in
2012 along with the Prescription Drug User Fee Act, and the AAP looks
forward to working with this committee on reauthorizing and
strengthening these important programs for children.
As effective as these laws have been, there is still a great need
for more progress. The majority of drugs still lack pediatric
information and many rare and neglected pediatric diseases lack
effective therapies. New creativity in overcoming the obstacles to
small market therapies, coupled with renewed resources for research and
incentives for development, will be needed to continue making progress.
Advances in basic research must be a fundamental part of any
strategy to develop new cures for children with rare diseases. We must
work to find new drug targets for rare diseases and develop appropriate
endpoints to evaluate potential therapies. The National Institutes of
Health (NIH) and the National Institute of Child Health and Human
Development (NICHD) are key partners in this effort and we must
continue to give them the resources necessary to accomplish this
essential work.
Studying drugs in children is difficult and requires specialized
skills. Each stage of the pediatric drug development process comes with
unique challenges. Early phase clinical trials are particularly
difficult in pediatric populations. Recruitment is frequently a problem
throughout the process. Trials must be designed with the
vulnerabilities of children in mind, and these challenges are even
greater for the smallest of children, neonates. FDA approval of drugs
is also challenging, often complicated by vastly different indications
for pediatric and adult use.
All of these difficulties necessitate trained pediatric
investigators, and we still lack the number of qualified experts to
actually do the work. Pediatric pharmacology studies require a very
different level of skill to appropriately conduct and analyze, skills
which are not often needed in adult studies. We are training far too
few new pediatric clinical pharmacologists and if more is not done to
reverse this trend, children will be left behind. BPCA made initial
progress in this effort by expanding access to loan repayment for
physicians who study pediatric pharmacology, but this alone will not be
sufficient.
Barriers to access unfortunately do not stop at the development of
an effective therapy. New and novel drugs for children with rare
diseases are often expensive. Comprehensive insurance coverage is
essential for these children and their families. The Affordable Care
Act has taken great steps forward in ensuring that all children have
access to health insurance regardless of family income, pre-existing
conditions, or exceeded lifetime and annual benefit caps. Therapies for
rare diseases, however, are often deemed experimental by insurance
programs and not reimbursed. Paying out-of-pocket for these drugs is
simply not possible for many families. The promise of health care
reform for children with rare diseases can only be realized if life-
saving and life-improving therapies are paid for by insurance programs.
Most of our discussion so far has focused on rare diseases, but we
also would like to say something about neglected diseases as well.
While development of safe and effective treatments for rare diseases is
constrained by their low prevalence, the same cannot be said for those
conditions which have been neglected. It is unacceptable for any of us,
from regulatory agencies to manufacturers to the medical community, to
neglect to treat diseases for which effective therapies are within
reach. The AAP encourages ongoing work focused on the identification
and prioritization of clinical conditions which affect a sizable number
of children but which have, for whatever reason, been neglected.
Along with drugs, medical and surgical devices are integral
components of the treatment of many rare diseases. The development of
pediatric devices shares obstacles similar to pediatric drugs. The
Pediatric Medical Device Safety and Improvement Act, passed in 2007,
was a first legislative step to ensuring that children have access to
devices that are safe, effective, and made with their unique
characteristics in mind, which include smaller sizes, growing bodies,
and different biology. It is important that FDA proceed quickly to
realize the promise of this legislation for children and take bold
steps to improve representation of pediatric expertise with the Center
for Devices and Radiological Health (CDRH). We are encouraged by the
approach new leaders in CDRH and FDA have taken but children deserve a
continued sense of urgency.
When fully implemented, the pediatric device law will increase the
tracking of pediatric device approvals and the postmarket surveillance
of these devices. It will also help incentivize pediatric device
development. The law modified the humanitarian use device (HUD) program
to remove the profit cap for pediatric HUDs. This year, the first
pediatric HUD was approved under this revised program. FDA's Office of
Orphan Products Development is successfully administering a new grant
program authorized by the law to fund consortia to encourage the
development of new pediatric devices. We look forward to working with
FDA to continue the implementation of this law, including provisions
that require device applicants to submit ``readily available''
information on potentially affected pediatric populations.
Thank you for allowing the American Academy of Pediatrics to share
its views on therapies for children with rare diseases and for raising
awareness of this important issue. We look forward to working with the
committee to improve the health and well-being of all children. I am
happy to answer any questions from the committee.

Senator Brown. Thank you very much, Dr. Frattarelli.
I'll start with Mr. Silver. Tell us about the difficulties,
if any, that you were faced with, with insurance, in paying for
your son's illness. And not just for you, who appear to have a
good-paying, decent job, probably with good insurance. Talk to
me about others that you know from your dealings with EB and
what you've seen with insurance.
Mr. Silver. Absolutely. Starting from my own perspective,
when our son was born, we were told his disease was anywhere
from mild to fatal. And they took him away within 12 hours of
his birth. And the first thing I did, actually, was e-mail
someone who deals with our health insurance, and had him listed
as soon as possible. The reason I bring that up is one of the
people, who's in the audience today, who shared this story with
me just before we started. This is Kati Ward. She doesn't have
her bandages covered, because it was deemed a preexisting
condition.
Now, to give you a sense of what bandage costs for EB are
like, they can be as high as $14,000 a month--$14,000. Our son,
who has a severe form of EB, but a more moderate case, his
bandages run about $6,000 a month. You add, on top of that,
medical bills for doctors' visits, so forth, you easily get
into 2-, 250, as a category.
Another person in this room is limited to the number of
types of bandages she can have per month. So, what does that
mean? That means there are certain bandages which are
relatively high-tech that enable you to manage the disease
better, and you're told, ``Well, we will only give you five.''
And there's no particular reason why five is selected.
This is a long way of saying that it has been a difficult
battle, a very difficult battle. And for someone with fortune
to have resources, we went to battle with our insurance
company, and ultimately they honored that contract, mostly
because we had the contract, and we were fortunate to do so.
For those who are struggling, day-to-day, who may have
insurance, the hoops you have to jump through are unbelievable.
There are a number of other examples we can point to, actually
just in this audience, again. Michelle, who's here, who came
down, she is also limited to the number of bandages she gets.
This has to be an easier process to deal with. What you
deal with when you have a child who has a disorder like this
is, in so many ways, crushing, and changes your life. To add on
top of that having to fight, tooth and nail, just to get your
son or daughter the coverage that is, in many ways and certain
cases, actually already under contract, or that you have to
fight so much just to help get them through the day, needs to
change.
Senator Brown. Thank you.
Dr. Frattarelli, what is the single most significant
barrier to R&D for rare and neglected diseases?
Dr. Frattarelli. I think one of the biggest ones is that
there's often not enough children out there that you can
actually get them together, get them enrolled in a clinical
study, and have this conducted so that you can meet the same
criteria that we would use, let's say, if we were doing a new
antibiotic or something that affects a broader part of the
population.
The other thing that we really don't have right now is a
well-enough-developed pediatric research infrastructure. I was
mentioning, before, that there's just not enough well-trained
general pediatric clinical pharmacologists out there to
actually design and conduct these studies properly.
I think those are probably the two biggest obstacles we're
seeing right now.
Senator Brown. OK.
Ms. Dorman, how do we attract more young scientists to this
field? If we're going to do what pretty much everybody has said
here, the work Mr. Crowley's doing, the work that Ms. Moon and
Mr. Silver advocate, do you have any special thoughts on how we
attract young people into this research?
Ms. Dorman. You know, the NIH has been doing some really
important work--the Office of Rare Disease Research. They've
been going into junior high schools and talking about rare
diseases, and getting them really interested in the science of
rare diseases.
I also think that the medical colleges and schools don't
really focus on rare diseases. It's basically just an
afterthought. And I think there needs to be an increased
interest in the study of rare diseases.
Also in the academic community--a lot of times they're not
willing to do any of these type of studies because, in many
cases, it's publish or die, and to do very limited studies on
rare diseases, it doesn't work for them. So, that's really a
big problem.
I think greater outreach into the medical community and
medical schools are going to be really important.
But, there is an increased interest. We're working with
Duke University. We're working with Notre Dame. We're also
working with the Manton Center, in Boston. So, there's an
increased interest into the study of rare diseases because I
think many of them are beginning to realize that understanding
the pathogenesis of rare diseases is going to advance society's
understanding of diseases that affect far wider populations.
So, we're very excited about that, that there is an increased
focus.
Senator Brown. Senator Sanders.
Senator Sanders. Thank you, Mr. Chairman, for holding this
very important hearing today. And thank you, Senator Brown, for
the leadership role you've played on this critical issue. I
appreciate the committee's holding this hearing today.
It seems to me that the problem that we're having--and I
want to hear responses from the panelists, and perhaps starting
off with Ms. Moon--is the following, Mr. Chairman.
If you have a disease, and if you have the money--no matter
how serious or nonserious that medical problem may be--but, if
you have the money to pay for the medicine or the drug to treat
that problem, the drug companies will provide that medicine to
you. On the other hand, if you or your child is one of a
relatively small number of people who have a disease which
could be fatal or cause a whole lot of suffering, but there's
not a whole lot of money to be made from that, the drug
companies are not going to gravitate toward that issue.
The function of a drug company, as I understand it, is to
make as much money as possible. That's what the market is
about. So, if you have an illness that one can make money from,
you will see that advertisement on television, telling you to
run out to your pharmacy to buy a drug for a disease you may
not even know that you had. But, you're certainly going to run
out and get that drug. On the other hand, if, as Ms. Moon
indicated, you're living on a dollar a day in Africa and your
child may be dying of a disease that, if diagnosed, might be
cured, no one's going to get that medicine to you. Because, how
do you make money from people who are living on a dollar a day?
That's not a very good group of folks from which you can make
money.
So, I think we have a dual problem. No. 1, diseases in
which there are relatively few people who are suffering from
it, and, second of all, diseases where millions may be
suffering, but they don't have the money to pay for the
treatment or the diagnosis.
Ms. Moon, I agree with you. I think we've got to move to a
new concept, in terms of funding, research, and development,
and it shouldn't be simply a market mechanism.
Can you talk a little bit about the concept of the prize,
and how that differs from where we are right now?
Ms. Moon. Thank you very much for the question, Senator
Sanders.
The concept of the prize, and the reason why we think it's
such a promising mechanism, is that we would still reward
innovation. We would still pay for R&D, but we would do it in a
way that would not rely on high prices. As we just heard from
Mr. Silver, and as I think many people in the room have
experienced personally, the high prices of medicines is
something that people all over the world struggle with--in
developing countries, in particular, but, of course, also here
in the United States, with escalating healthcare costs.
So, the idea of the prize is that we could specify, based
on public health concerns, What is the goal that we want? What
is the new product, medicine, diagnostic tool, vaccine,
whatever it may be that we want? And set out a number of
criteria for what types of characteristics of that--What would
be the characteristics of that product? And then put that out
there and basically allow any innovator in the world who might
be able to tackle this problem and come up with a solution, to
propose a solution.
Once a product had been developed and the solution was
brought to the table, a certain amount of money from the prize
fund would then be paid to reward that innovator. And so, the
R&D would be paid for.
What we could do after that is allow a number of different
companies to produce that drug.
Senator Sanders. Well, the point here is, we are rewarding
and incentivizing the research.
Ms. Moon. Absolutely.
Senator Sanders. Once we have a product, we're allowing a
competitive and generic market out there, by definition.
Ms. Moon. That's exactly right.
Senator Sanders. And the price will be affordable to
people.
Ms. Moon. That's exactly right.
Senator Sanders. It will not be controlled by one company,
who can then charge a very, very high price.
Ms. Moon. That's exactly right.
Senator Sanders. Would others like to comment on that
concept? Does that make sense? Fairly radical concept, but what
do you think? People have any familiarity with that?
Sir. Dr. Frattarelli.
Dr. Frattarelli. You know, one other option I'd like to
mention here--it's not always the case that we have to go ahead
and actually develop a whole new drug from scratch. A lot of
what's going on right now is that people are using these drugs
off-label, basically on an individual-case basis. All right?
And, as I was mentioning earlier, we're not doing anything,
collectively, to capture all that information right now. I
think we could get a lot of benefit by taking these children,
who are already being exposed to the risk of this therapy--
right?--they're already taking these drugs off-label, and
they're getting some of the benefit here, but we're getting
that benefit on an individual label, not as a global sort of
understanding of medicine-as-a-whole level. So, if we can go
ahead, take this information, centralize it all in one place.
Another advantage I see of doing something like this would
be that, while we're deciding what information we need to
centralize, instead of having one individual physician doing
this, you may have a group of, you know, 20 or 30 smart people,
here, who can all say, ``Well, you know, if you have this
treatment, these are really the things you want to focus on, in
terms of what a side effect might be.'' And so, I think it's
going to step up everyone's game, in terms of following the
safety for these things.
Senator Sanders. OK, let me just jump in, because my time
is running out.
First of all, I want to really applaud every single one of
you for the outstanding work that you have done in your areas.
And again, we're dealing today with rare diseases, and we're
dealing with neglected diseases. So, some of these diseases are
not necessarily rare--they may be impacting millions of
people--but those folks are not getting the treatment.
Ms. Moon, in general, do you think the industry and
government--and this is not just in the United States, it's
internationally--have the developed countries played the kind
of appropriate role that they should be playing, in terms of
getting the medicines and the diagnosis to people in the Third
World, in developing countries, that they require?
Ms. Moon. If I understand--the question is, Are industry
and government playing the roles that they should be?
Well, of course industry and government can always do more.
And that's why we would ask that the new Global Health
Initiative include some of the deadliest tropical diseases that
I mentioned earlier.
But, I do think that industry responds to the public
policies that government puts in place. And this is why this
hearing, and others like it, are so important. But, if we can
put in place the right new incentive mechanisms, we're quite
confident that industry would respond by delivering the types
of innovation that we need, that would respond to the public
health needs of people with orphan diseases, as well as
neglected diseases.
Senator Sanders. But, my guess is that government is going
to have to play a strong role here, because, left alone,
industry is not going to make a whole lot of money in providing
a product to people who make a dollar a day.
Ms. Moon. In the current system, we would not expect
industry to respond that way. It doesn't make sense, with the
current rules. But, if we can change the rules and put in place
new incentive mechanisms, we do think they would respond. And
that's what we've heard in private conversations with people
from some of the largest drug companies.
Senator Sanders. Which brings us back to the prize concept.
Thank you very much, Mr. Chairman.
Senator Brown. Thank you.
Ms. Moon, we are going to just ask Mr. Crowley a question,
in closing, but in our list for the priority review voucher, we
had 16 rare diseases or neglected diseases, around the world,
as you know. We want to add the rare pediatric diseases in this
country, but we also plan to, in this legislation, do that, add
Chagas. It was an oversight in those 16. I think most of the
other ones you mentioned are included in the 16, I believe.
But, if they're not, certainly come to us, as we work on this.
This is the last question, Mr. Crowley. I asked Dr.
Frattarelli the same question. What do you think the most
significant barrier to research and development for rare and
neglected pediatric diseases is?
Mr. Crowley. I think the most significant barrier, Senator,
is uncertainty. When we go to start new biotechnology
companies--and they're all started virtually the same way--with
the technology, with patents, usually out of a university--and
we meet with a venture capitalist, and they ask us questions
about the technology and the patents, but they want to know,
What's the regulatory path? How long is it going to take?
What's it going to cost? And, once you're on the market, are
insurance companies going to pay for these drugs? What's the
size of the market?
And right now, those answers are so incredibly variable and
increasingly uncertain that a lot of adventure investors, a lot
of other players in the field--although for the last 10 or 15
years, there's been a lot of excitement about rare diseases, I
still think the excitement is there, but the barriers have
actually risen. And I think the more that we can do to reduce
that uncertainty through different pronouncements, better
guidance, more use of surrogate endpoints, the biostatistics,
potentially even the division--and one of our recommendations
is the creation of a review division at FDA focused
specifically on rare genetic metabolic disorders. I think
anything that we can do to take the middle part of that
funnel--you've had a lot of patients on this side, you've got a
lot of technologies in the early stage of development here--
they tend to get squeezed in the middle, through the clinical
development--the more that we can do to reduce that
uncertainty, to drive it forward, partly through different
regulations and pronouncements, and also, too, through
increased capital available to companies like ours, I think
will go a long way to solving the problem.
Senator Brown. Well, thank you.
Thank you all for your commitment, your activism, and your
work that you do for so many around the country whom you don't
know, and around the world. I thank you all for that,
especially this panel.
I thank Bill, with Senator Harkin's staff, and Amy and
Hayden, with Senator Enzi's staff. This is a hearing that shows
a good side of the U.S. Senate, with the kind of bipartisan
cooperation that Senator Enzi is known for around here. And I
appreciate working with him on this. And, Senator Sanders,
thank you for your question, too.
The record will remain open for 10 days for statements to
be submitted. If you have anything that you left out today, if
you want to add, or any requests of us, certainly make those
available to the committee in the next 10 days. As I said, the
record will be open until then.
Thank you, again.
This Committee on Health, Education, Labor, and Pensions
will be adjourned.
Thank you.
[Additional material follows.]

ADDITIONAL MATERIAL

Prepared Statement of Senator Murray

Thank you, Senator Harkin, for holding this hearing.
Rare diseases, particularly rare pediatric diseases, are
very challenging for research funding and drug therapies. They
tend to have less money dedicated to research and treatments,
but there are still patients across the country who desperately
need for cures to be found. So we need to find ways to
encourage investments and find a safe way to streamline the
approval process for life-saving drugs.
I am pleased that through the passage of health care
reform, we authorized the Cures Acceleration Network (CAN).
This initiative seeks to cut the time between discovery and
development of drugs and therapies through new grant-making
mechanisms at the NIH. It will establish CAN within the Office
of the Director of NIH and authorize grants expected to speed
the move from discoveries in the lab to the next generation of
therapies. In addition, CAN will help coordinate the efforts of
all stakeholders in the drug development process in order to
help move discoveries forward.
The biomedical and life science industry has been a leader
in the quest to find cures for rare diseases, and we need their
great work to continue. This industry has the remarkable
ability to create new and breakthrough medicines, allowing us
to treat diseases that were previously untreatable and give
hope back to families that had thought there was none.
That is why I am so proud that my home State of Washington
is a leader in the life science industry, with universities and
biomedical firms doing fantastic work finding innovative cures
and medical therapies for a vast array of diseases.
Not only are Washington State companies on the cutting edge
of biomedical research, they are also a major driver of
economic development in my home State. According to a study
published last fall by the Washington Biotechonology and
Biomedical Association, the life sciences industry in
Washington State directly employs over 22,000 people, and an
additional 55,000 jobs in the State depend on this sector. It
is also important to note that while employment has been
declining in many sectors, the life sciences industry has
continued to add jobs despite the economic downturn.
Once again, I am pleased that the HELP Committee held this
hearing to bring more attention to this critical issue. I look
forward to continuing to work to support this industry and
their important work, and to help families and patients across
the country by supporting the quest for cures to rare and
neglected pediatric diseases.
Prepared Statement of the Advanced Medical Technology Association
(AdvaMed)

Summary

ADVAMED ORPHAN AND PEDIATRIC DEVICE DEVELOPMENT RECOMMENDATIONS

Humanitarian Use Device Program
Provide the Secretary with authority to selectively raise
the annual population cap for specific pediatric conditions when FDA
determines the health of pediatric or orphan patients requires an
increase.
Ensure parity with the orphan drug program by creating a
tax credit for orphan and pediatric device research and to help offset
high R&D costs associated with small populations.
Develop guidance on level of evidence needed to meet the
HUD standard of safety and probable benefit.
Develop guidance to clarify for payors that HUDs are FDA-
approved devices for reimbursement purposes.
Remove HDE limitations placed on diagnostic devices that
limit development of diagnostic tests for rare diseases.
Make Better Use of Existing FDA Regulatory Tools and Valid Scientific
Evidence
While maintaining the existing standard of safety and
effectiveness, where appropriate FDA should:

Use objective performance criteria (OPCs), historical
controls or well-documented case histories as endpoints to show
effectiveness.
Allow the extrapolation of clinical data between different
sizes of the same device based on engineering testing and other non-
clinical data.
Rely on non-clinical data for modifications of devices
specifically approved for pediatric patient populations when such
modifications are unrelated to changes in intended use.
Allow the acceptance of 510(k) devices intended for adult
populations with the same use as a pediatric device as predicates for
the 510(k) pediatric device.
Allow the acceptance--as an appropriate control for
investigational pediatric devices--of devices intended for use in adult
populations when such devices provide the only device-related means for
treating, diagnosing or preventing diseases or conditions in pediatric
patients and have become the standard of care for such patients.
Allow use of general device claims where appropriate
rather than requiring specific device claims for each pediatric age
bracket to respond to the broad definition of pediatric (from neonate
to age 21).

OTHER FDA AND NIH-RELATED RECOMMENDATIONS

Establish Compassionate Use Orphan/Pediatric Device
Program to allow manufacturers to distribute no more than 100
unapproved devices annually to pediatric patients when such patients
are afflicted with diseases or conditions that affect too few patients
annually to justify the expense necessary to achieve an approved device
under the HDE program. Appropriate controls would be specified.
Develop adaptive clinical trial designs and regulatory
models to respond to regulatory barriers and small population sizes.
Create Orphan and Pediatric Ombudsman in CDRH to assist
manufacturers in how to use existing and new regulatory pathways to
achieve on-label indications.
Develop custom device guidance to clarify the number of
custom devices that can be manufactured.
Ensure collection and prioritization of data on unmet
pediatric needs through NIH to identify and assist basic research
needs, offset R&D costs associated with small populations, and spur
technology transfer and commercialization of devices.
Create NIH Office of Orphan and Pediatric Diseases to
conduct and coordinate data collection, establish priorities and
research needs and coordinate with Orphan and Pediatric Ombudsman.
______

On behalf of AdvaMed, thank you for the opportunity to submit
written testimony for the record to the Committee on Health, Education,
Labor, and Pensions. This testimony includes our recommendations on
ways to promote the development of new treatments and cures for
treating rare and neglected pediatric diseases.
AdvaMed represents manufacturers of medical devices, diagnostic
products, and health information systems that are transforming health
care through earlier disease detection, less invasive procedures and
more effective treatments. AdvaMed's members produce nearly 90 percent
of the health care technology purchased annually in the United States
and more than 50 percent of the health care technology purchased
annually around the world. AdvaMed members range from the smallest to
the largest medical technology innovators and companies. Nearly 70
percent of our members have fewer than $30 million in sales annually.

INTRODUCTION

It is important to understand the device regulatory context with
respect to rare diseases. The Orphan Drug Amendments of 1988 created
the orphan products grant program. For this purpose, rare is defined as
a prevalence of fewer than 200,000 patients in the United States. The
related humanitarian use device program, authorized in the Safe Medical
Devices Act of 1990, is a special product approval pathway to market
for devices that treat or diagnose diseases and conditions that affect
fewer than 4,000 patients per year in the United States, including
pediatric populations and subpopulations. Although medical device
companies are authorized to apply for grants under the orphan products
program to support device research and development for rare diseases,
device manufacturers can only use a Humanitarian Use Device (HUD) to
treat rare diseases or conditions of less than 4,000 patients per year.
FDA approval of a Humanitarian Device Exemption (HDE) authorizes a
manufacturer to market a HUD.
In contrast to pre-market approval (PMA) requirements which
necessitate that manufacturers demonstrate their products are both safe
and effective, the review standard for HDEs requires manufacturers to
demonstrate the safety of the device, the likelihood of effectiveness
(termed ``probable benefit''), and to demonstrate that the device will
not expose patients to significant or unreasonable risk. This standard
recognizes the challenges of fully establishing efficacy via clinical
trials in very small populations but strikes an important balance by
requiring demonstration of safety. Device manufacturers are prohibited
from making a profit on the marketing of HUDs although they are
permitted to recoup the costs of research and development,
manufacturing, packaging and distribution.
Importantly, to spur pediatric device development and under the
leadership of Senator Christopher Dodd, the Food and Drug
Administration Amendments Act of 2007 (FDAAA 2007) amended the
humanitarian use device program to permit a device manufacturer to make
a profit for HUD devices designed to meet a pediatric device need.
FDAAA 2007 also created the Pediatric Device Consortia Grant Program
under the FDA Office of Orphan Products Development (OOPD) to develop
nonprofit consortia to facilitate pediatric medical device development.
Much of AdvaMed's testimony will focus on pediatric device
development issues because they are an important orphan ``sub-
population'' and the issues involved in pediatric device development
exemplify many of the challenges associated with orphan diseases and
conditions.

NEED TO COLLECT DATA ON UNMET NEEDS

A key to addressing unmet orphan and pediatric device needs is to
methodically collect data on unmet pediatric device needs including the
number of patients with a particular disease or condition, age ranges,
and current treatment and diagnostic options and health outcomes. At an
October 2009 FDA workshop on pediatric clinical trial design, pediatric
cardiovascular physician panelists pointed out that there are still
many unanswered basic pediatric research questions. As the physicians
noted, failure to answer or address certain basic pediatric research
issues resulted in corresponding challenges in the FDA regulatory
process (e.g., making it difficult for manufacturers and FDA to select
and agree on appropriate surrogate or other clinical trial endpoints).
Thus, attempting to understand the associated basic research questions
related to unmet medical device needs should also be an important part
of any data collection effort. We understand the National Institute of
Child Health and Human Development (NICHD) has recently undertaken an
effort to collect information on a pediatric research agenda that
includes devices. A similar process should be utilized for orphan
diseases although it is our understanding that the National
Organization of Rare Diseases (NORD) has already collected or conducted
a considerable amount of research with respect to many rare diseases.
In addition to directed specialty evaluations, participants in
previous National Institute of Health (NIH) conferences devoted to
pediatric device development issues have suggested that existing
hospital discharge databases could assist in identifying specific
device needs for pediatric patients. Efforts to collect pediatric data
through the establishment of registries [e.g., the American College of
Cardiology IMPACT RegistryTM (IMProving Adult and Congenital
Treatments)] may be another important source of such data.
AdvaMed believes the primary responsibility for data collection
efforts and basic research questions associated with unmet orphan or
pediatric medical device needs should reside with the National
Institutes of Health (NIH). NIH is the only entity with the breadth and
depth of knowledge, funding and resources to conduct such research.
Once such data is collected and prioritized, it should be made public
(e.g., through a public NIH Web site or clearinghouse or for
registries, via the Agency for Healthcare Research and Quality's
proposal to create a registry of patient registries) to enable all
interested stakeholders, including pediatric device consortia and
device manufacturers to understand potential orphan and pediatric
device development opportunities.
It will also be important to prioritize orphan and pediatric needs,
perhaps based on criteria such as size of patient population, public
health need, and recognition that some small markets may not be
commercially viable, or by targeting needs that are cross-cutting in
nature and provide benefits beyond one subpopulation. Prioritization of
needs is important to help determine and assess basic pediatric
research requirements that may be beyond the resources or financial
scope of any one device company and that should be conducted by NIH.
Such activities may for example include assessing existing biomaterials
for their effects in pediatric populations; identifying new
biomaterials that are safe and effective for use in pediatric
populations; or assisting in the basic research and development of key,
priority research questions for devices and their related clinical
trials. The latter activities could significantly reduce the
development costs linked with the small markets associated with many
orphan and pediatric disease device needs--a key barrier to device
development--thus enhancing chances that such devices would get to
market.
There is a significant need to utilize government funding in more
efficient ways to address questions that are faced by all developers of
orphan or pediatric-focused technologies. Although the deficit may make
it challenging to significantly increase funding for orphan and
pediatric research, better coordination of existing or future research
at the National Institute of Child Health and Human Development
(NICHD), the National Heart, Lung, and Blood Institute (NHLBI), the
National Institute for Biomedical Imaging and Bioengineering (NIBIB) or
other relevant Institutes that target specific orphan or pediatric
device needs could:

1. Help spur the basic research needed for areas where breakthrough
devices are desired;
2. Help offset the tremendous expense associated with early orphan
device research and development, thus enhancing commercialization
opportunities for interested stakeholders such as device manufacturers
or pediatric consortia; and
3. An enhanced technology transfer program between the relevant
Institutes and the device industry could help assure the development
and manufacture of the needed breakthrough medical devices.
NIH Office of Orphan and Pediatric Diseases
AdvaMed also recommends that the NIH develop an office of orphan
diseases and conditions including pediatric populations. Such an office
would presumably be aware of ongoing orphan or pediatric research
issues being conducted within each institute and could also serve an
important coordinating function with stakeholders to ensure that
priority needs and research issues are being addressed. An office of
this nature would be an automatic touch point for interested parties
and stakeholders. For example, pediatric stakeholders attending FDA co-
sponsored pediatric stakeholder meetings in 2004 learned--many for the
first time--that the National Heart, Lung and Blood Institute (NHLBI)
was developing a number of left ventricular assist device (LVAD)
prototypes for commercialization, an important pediatric cardiovascular
priority. Such an office would make sure that ongoing NIH research of
this nature received the needed attention by relevant stakeholder
groups. Further, an NIH office that could delineate and prioritize
orphan and pediatric device research and development needs would create
a readily understood roadmap for congressional authorizers and
appropriators and other stakeholder advocates to improve congressional
funding for new orphan device development projects.

RECOMMENDED IMPROVEMENTS IN THE HUD/HDE PROGRAM

Need for Guidance on Level of Evidence Needed to Meet Standard of
Probable Benefit
As outlined at the start of our testimony, Section 520(m)(2)(C) of
the Food Drug and Cosmetic Act (FDCA) establishes the standard for FDA
approval of HDE applications, specifically that ``the device will not
expose patients to an unreasonable or significant risk of illness or
injury'' and that ``the probable benefit to health from the use of the
device outweighs the risk of injury or illness from its use, taking
into account the probable risks and benefits of currently available
devices or alternate forms of treatment.'' This is clearly a different
standard than the pre-market approval (PMA) requirement of reasonable
assurance of safety and effectiveness which typically requires full-
scale prospective randomized clinical trials because you cannot
reasonably conduct such a trial in small populations. However, FDA has
provided no general guidance to manufacturers regarding the type or
level of evidence that must be developed to demonstrate that an HDE
meets the probable benefit standard. This lack of guidance ultimately
hinders the use of the HUD program as a pathway to market for devices
that treat or diagnose diseases and conditions that affect fewer than
4,000 patients, including pediatric populations and subpopulations.
Further, without clear FDA guidance, demands for evidence can continue
to drift upward, until they begin to resemble the expectations for a
PMA filing, as has been reported by some manufacturers.
For this reason, AdvaMed recommends that FDA develop general
guidance on appropriate types and levels of data necessary for HDE
approval. Such guidance should provide examples of what FDA believes
are the appropriate types and levels of data needed to demonstrate
probable benefit. AdvaMed believes that prospective randomized
controlled clinical trials generally should not be necessary to
demonstrate probable benefit to health, and that FDA should consider
non-clinical data, published literature, historical data and patient
records, surrogate endpoints and statistical methods and evidence from
experience with similar devices.

FDA Guidance on HUD as an Approved Device Needed for Reimbursement
Purposes
On a related point, during FDA-sponsored pediatric stakeholder
meetings on pediatric device development in 2004, numerous participants
pointed out that private insurers typically refuse to reimburse for
pediatric HUDs. The statute requires that HUDs can only be administered
in facilities with properly constituted and functioning IRBs. Insurers
thus assume the HDE must therefore be an investigative device that is
not eligible for private insurer reimbursement. As a result, many
times, costs associated with HUDs are out-of-pocket. While payment
issues are not within the normal purview of FDA, in this instance,
inclusion of an additional Question and Answer in FDA's HUD/HDE
guidance that explicitly states that a HUD has FDA approval could be a
useful addition to the guidance, assisting facilities and physicians in
seeking reimbursement, improving patient access to needed HUDs, and
importantly, helping patients avoid unnecessary out-of-pocket costs.
For this reason, AdvaMed recommends that language be added to the
guidance that explains that an HUD constitutes an explicit approval
from FDA. Similarly, the Centers for Medicare and Medicaid Services
(CMS) should have a process to cover and reimburse HUDs. Insurers
frequently follow the lead of CMS with respect to coverage and
reimbursement decisions.

Provide Flexibility on the HDE Cap
AdvaMed also believes that because there continues to be so little
information on the size of certain orphan and pediatric populations
associated with specific conditions (due among other reasons to the
lack of data on unmet pediatric device needs), it is unknown what
affect applying the general HDE population cap of 4,000 to children's
devices may have on the availability of devices to treat pediatric
conditions. AdvaMed recommends that the Secretary be given authority to
selectively raise the cap for specific conditions when FDA determines
the health of orphan or pediatric patients requires an increase in
excess of the annual distribution number--based on medical, demographic
and scientific information provided by a petitioner. As an example, it
is unlikely manufacturers will be incentivized to develop devices for
an orphan disease that affects 4,500 patients annually and is under
full PMA requirements, yet because the population is only 500 patients
over the 4,000 cap, it is ineligible for the HUD program.

Remove HDE Limitations Placed on Diagnostic Devices for Rare Diseases
A significant obstacle to using the HDE process for development of
diagnostic devices for rare diseases is the HDE requirement to
demonstrate the number of patients that would be subject to diagnosis
by the device, rather than the number of individuals affected or
manifesting the rare disease. Unlike other medical devices, where a
demonstration by authoritative references that the disease or condition
affects or is manifested in fewer than 4,000 people in the United
States per year, for a diagnostic device it is necessary to demonstrate
by authoritative references that the number of patients per year who
would be tested by the device is fewer than 4,000. Because such data is
generally unavailable, the identification and presentation of
authoritative references to support this requirement essentially
renders the HDE process unavailable for diagnostic devices. In short,
if a diagnostic test were developed to diagnose patients with a
condition that manifests in 4,000 people or less per year, it is quite
likely that physicians would prescribe the test more than 4,000 times a
year in order to diagnose those with the referenced rare disease. To
address this limitation, we recommend removing this requirement and
requiring the same demonstration of diagnostic devices as is required
for other medical devices.

Proposals to Help Offset Costs of R&D and Commercialization Risks
In addition to the proposals and comments outlined above, AdvaMed
has a number of other recommendations to improve orphan and pediatric
device development. Many of these programs would help offset the costs
of orphan or pediatric device research and development and address
small market size and commercialization risks. These include:

A strong orphan and pediatric device research and
development tax credit program,
A tax credit for orphan and pediatric HDEs similar to the
tax credit that currently exists for orphan drugs,
Minimization of governmental costs associated with
developing products for orphan and pediatric populations such as
restrictions on user fees,
Expedited FDA clearance or approval of orphan or pediatric
device applications, and
Clear pathways for reimbursement once such products are
cleared or approved.

Orphan and Pediatric Ombudsman in the Center for Devices and
Radiological Health
AdvaMed also recommends the creation of an orphan/pediatric
ombudsman in the Center for Devices and Radiological Health (CDRH).
Currently, no one person or entity within CDRH has either the
responsibility or the expertise to assist and counsel manufacturers or
other interested stakeholders in how to utilize existing regulatory
pathways (510(k), PMA or HDE) to achieve on-label indications for
orphan and pediatric diseases and conditions. This individual could
also serve as the liaison with an NIH office of orphan and pediatric
diseases and conditions.

ADVAMED RECOMMENDATIONS TO RESPOND TO CHALLENGES TO ORPHAN AND
PEDIATRIC DEVICE DEVELOPMENT

A key challenge in orphan and pediatric conditions and diseases is
that failure to overcome certain regulatory or other barriers to on-
label use consigns certain devices and the diseases and conditions they
treat to an unending cycle of ``jerry-rigging'' or off-label use. As a
result, data that could be used to improve device research and
development, obtain on-label indications, or improve patient outcomes
is never collected. It is not clear that orphan or pediatric
populations are well-served by this un-ending cycle. While it may not
be feasible for all orphan diseases or conditions and their associated
devices, a concerted effort must be made to find ways to break this
cycle and enable companies and clinicians to begin to obtain and to
collect the data that will allow devices for orphan and pediatric
diseases and conditions to be on-label.

SMALL MARKET SIZES

A related and significant obstacle to pediatric device development
for devices ineligible for HUD is that the annual market associated
with specific diseases and conditions may not be commercially viable
(for either large or small device companies). Secondly, orphan diseases
and conditions are difficult to study because patients with the
affected conditions are widely dispersed making it extremely difficult
to accrue sufficient numbers of clinical trial participants over a
reasonable timeframe and within a manageable number of investigational
sites and to assure an adequately powered clinical trial to meet FDA
requirements. AdvaMed has a number of recommendations below that are
responsive to small market size and failure to overcome regulatory
barriers to on-label use.

General versus Specific Device Claims
FDA requirements for limited and very specific claims and their
associated data can be an important barrier to device development for
small and dispersed orphan and pediatric populations. For example, FDA
may require 100 patients in each pediatric age group to demonstrate
device safety and effectiveness. FDA should consider and allow for more
general claims to enable device approval. Subsequent condition of
approval requirements, such as requirements for a registry, could then
be used to ascertain whether there are particular issues associated
with specific age ranges.

New Regulatory Models and Adaptive Clinical Trial Designs
To address small market issues, FDA must develop regulatory models
and adaptive clinical trial designs that take into consideration the
reduced sample sizes associated with orphan diseases and conditions.
For example, FDA could approve certain devices based on smaller
confirmatory trials in conjunction with a long-term registry
requirement either for an individual device or for certain device
types. This would enable the collection of essential data to better
understand patient outcomes and provide FDA with better data for future
device approval decisions. Related to this, to facilitate pediatric
device development by interested stakeholders (e.g., manufacturers or
pediatric consortia), FDA should post on its Web page, examples of
adaptive clinical trial designs\1\ that have already been successfully
used to obtain on-label orphan or pediatric indications.
---------------------------------------------------------------------------
\1\ FDA must take care not to reveal proprietary or trade secret or
confidential commercial or financial information when sharing trial
designs.
---------------------------------------------------------------------------
Valid Scientific Evidence Other Than Well-Controlled Trials
Section 513(a)(3)(A) of the Federal Food Drug and Cosmetic Act and
21 CFR 860.7 give FDA authority to utilize valid scientific evidence
other than well-controlled trials.
Importantly, the standard of reasonable assurance of safety and
effectiveness is the same no matter what type of scientific evidence is
required. While FDA relies on many types of valid scientific evidence
(other than well-controlled trials) in other areas, it is our sense
that FDA has been reluctant to take advantage of this statutory
authority in the case of pediatric devices.
FDA should be encouraged to make better use of all forms of valid
scientific evidence which could help address the problems associated
with the extremely small numbers of orphan or pediatric patients that
are afflicted with any one condition or disease state. For example,
what may have evolved as the pediatric standard of care may be off-
label (e.g., a minimally invasive procedure supersedes a surgical
procedure and becomes the standard of care). Doctors will be reluctant
to randomize pediatric patients to a surgical control arm if the
minimally invasive procedure is the standard of care. Parents will also
be reluctant to have their child participate in such trials. In this
instance, an FDA requirement to randomize pediatric patients to the
surgical procedure creates a barrier that prevents the off-label use of
the device from ever becoming on-label. Where numerous articles
document the effectiveness of a particular off-label use of a device
and it has become the standard of care, FDA should be encouraged to
develop mechanisms that make use of this data.
AdvaMed has a number of recommendations that are intended to make
better use of existing FDA regulatory tools and enhance orphan or
pediatric access to medical devices. To help break down barriers to
orphan and pediatric device development, FDA should provide examples of
these or other types of valid scientific evidence that FDA has in FDA
guidance. Importantly, the proposals below retain the existing standard
of reasonable assurance of safety and effectiveness although some of
the recommendations may be applied to the HUD standard of safety and
probable benefit.
1. Proposal: Where appropriate FDA should use objective performance
criteria (OPCs), historical controls or well-documented case histories
as endpoints to show probable benefit or to demonstrate effectiveness.
Background: Reliance on well-documented case histories and
historical controls would take advantage of the existing literature,
respond to the extremely small numbers of orphan or pediatric patients
with any one condition (which makes it difficult to run statistically
valid clinical trials in a timely fashion--as one person put it ``20
years of literature vs. years to put together a control group'') and
help minimize the use of surgical interventions as the control where
devices have been established as the standard of care.
2. Proposal: Extrapolation of clinical data between different sizes
of the same device based on engineering testing and other non-clinical
data.
Background: Currently, FDA requires clinical evidence on the full
range of device sizes for a particular device and it can be difficult
to assemble enough patients at either end of the size ranges to be
valid. It is often extremely challenging to get significant data on the
smallest and largest sizes. This proposal would allow the use of non-
clinical and bench data as well as the potential to do post-market
clinical work to approve the full range of sizes.
3. Proposal: Reliance on non-clinical data for modifications of
devices specifically approved for pediatric patient populations, when
such modifications are unrelated to changes in intended use and do not
affect safety.
Background: Modifications made to an already cleared or approved
device to improve its performance or safety require that the device be
cleared or approved again. For devices, much of the data about a
product's function can be established non-clinically (e.g., relying on
animal, bench and/or reliability testing). Every time a minor
modification is made (e.g., material changes or minor design changes),
FDA often requires that the device be cleared or approved again. The
requirements for clinical data in the modification process create a
challenge and limit improvements for pediatric devices. Due to the
barriers associated with gathering clinical data for pediatrics (small
populations, widely dispersed populations, parental unwillingness to
have children participate, timeliness, etc.), the intent of this
provision--for devices specifically approved for pediatric use--is to
enable use of engineering and bench testing, rather than clinical
testing for minor device changes when the changes are not related to
changing the intended use of the device and do not affect safety. FDA
has the flexibility to do this--and allows it for adult devices--but
should be specifically encouraged to do so in the case of pediatric
products.
4. Proposal: The acceptance of 510(k) devices intended for adult
populations with the same use as a pediatric device as predicates for
the 510(k) pediatric device.
Background: Similar to the language proposed in the FDAAA 2007
pediatric device law which allows FDA to use adult data to support a
reasonable assurance of safety and effectiveness in pediatric
populations and to extrapolate data between pediatric populations, FDA
has authority, where the course of the disease or effect of the device
is the same in adults and in pediatrics, to use the adult 510(k) device
as a predicate for the pediatric device. Doing so would be responsive
to the extremely small numbers of pediatric patients--particularly of a
given age range--with any one condition (which makes it difficult to
run valid clinical trials in a timely fashion) and would help limit the
number of children exposed to surgical controls. FDA could still
require a clinical trial for a 510(k) device but the trial would be
smaller and pediatric access to the device would be faster.
5. Proposal: The acceptance--as an appropriate control for
investigational pediatric devices--of devices intended for use in adult
populations when such devices provide the only device-related means for
treating, diagnosing or preventing diseases or conditions in pediatric
patients and have become the standard of care for such patients.
Background: Similar to the language proposed in the new pediatric
device law which allows FDA to use adult data to support a reasonable
assurance of safety and effectiveness in pediatric populations and to
extrapolate data between pediatric populations, FDA has authority to
utilize as the control for studies under the Investigational Device
Exemption process, devices that are not approved for pediatric use but
that are already being used in pediatric populations. This would enable
the adult data on already approved devices or these devices themselves
to serve as the ``control'' for the pediatric trial, responding to the
limited number of pediatric patients available for pediatric trials and
reducing the number of children exposed to a surgical control.

Development of Custom Device Guidance
Section 520(b) of the FDCA and 21 CFR 812.3(b) provide for the
manufacture of custom devices that are intended for use by an
individual patient in response to a clinician's order. In the ongoing
pediatric stakeholder dialogue, clinicians have repeatedly reported
that they feel compelled to ``jerry-rig'' or modify existing devices to
treat pediatric patients. Dr. Jon Abramson (representing the American
Academy of Pediatricians) reiterated this point at a July 23, 2008 NIH
workshop. Pediatric patients may also suffer more congenital
deformities which may require customized devices. AdvaMed recommends
that FDA develop guidance for custom devices that clarifies the number
of devices manufacturers may customize for orphan and pediatric
populations, a recommendation that was echoed by former Center for
Devices and Radiological Health Director, David Feigal, Jr., M.D., at a
July 23, 2008 NIH pediatric device workshop.
Manufacturers have been reluctant to develop custom devices because
the rules are unclear. Anecdotal evidence suggests that FDA limits
manufacturers to just one or a few custom devices although this has not
been articulated in FDA guidance. AdvaMed has heard from manufacturers
that they, on occasion, are compelled to choose between complying with
FDA requirements and pediatric patients' needs with the knowledge and
heavy burden that their decision to adhere to FDA requirements may
result in a dire outcome for the child. Given that FDA's formal
definition of pediatric is from neonate to age 21, that so many
different device sizes are required to treat this wide age range, and
the small market sizes that may be associated with this wide size-
range, custom devices may be the only alternative for some medical
devices. FDA guidance on custom devices that relaxed the current
limitation on manufacturing (which we believe is just one or two custom
devices) and that specified the number of orphan or pediatric custom
devices that could be manufactured and distributed would be helpful.
Envisioned here is a special program for unique devices for very small
orphan or pediatric populations or very early device modeling that
could encourage development of these therapies.

Proposal of a Compassionate Use Orphan/Pediatric Device Provision
Finally, AdvaMed recommends the creation of a New Compassionate Use
Orphan/Pediatric Device Provision to be applied in situations where
even the HUD pathway makes little sense. As mentioned elsewhere in our
testimony, clinicians have repeatedly reported that they feel compelled
to ``jerry-rig'' or modify existing devices to treat pediatric
patients. Rather than having pediatric clinicians across the country
individually jerry-rig devices during surgery, AdvaMed proposes a well-
regulated mechanism to provide device access for super-small, orphan or
pediatric populations that are not likely to be served by the HUD
program or the FDAAA 2007 pediatric HUD program. AdvaMed recommends
that FDA be required to develop regulations that would allow
manufacturers to distribute no more than 100 unapproved devices
annually for patients when such patients are afflicted with diseases or
conditions that affect too few patients annually to justify the expense
necessary to achieve an approved device under the HUD program.
Appropriate controls would be statutorily mandated including: (1)
compliance with quality system, labeling, adverse event reporting,
device tracking and postmarket surveillance regulations; (2) device
promotion would be limited to medical professionals and no claims of
safety or effectiveness could be made; (3) the manufacturer would be
required to notify the Secretary upon the first shipment of such a
device; (4) maintenance of records of each shipment of such a device;
(5) limitation of distribution to prescription use only; (6)
institutional review board approval would be required for each use of
such a device; and (7) informed consent prominently informing the
patient and the patient's parent or legal guardian that the device is
not approved by the Food and Drug Administration would be required.
In closing, AdvaMed greatly appreciates this opportunity to provide
our thoughts and recommendations to the Committee on Health, Education,
Labor, and Pensions on rare disease and pediatric device development
issues.

Prepared Statement of Peter J. Hotez, M.D., Ph.D., President,
Sabin Vaccine Institute

On behalf of the Global Network for Neglected Tropical Diseases and
the Sabin Vaccine Institute, our organization welcomes the opportunity
to submit a written statement affirming two specific issues raised
during the committee's hearing on July 21, 2010 entitled, ``Treating
Rare and Neglected Pediatric Diseases: Promoting the Development of New
Treatments and Cures.''
Before outlining the specific issues we would like to address, we
thought it would be best to provide the committee with some background
on the Sabin Vaccine Institute and two of its important initiatives.
Founded in 1993, the Sabin Vaccine Institute is a non-profit 501(c) (3)
organization dedicated to preventing and curing infectious and
neglected tropical diseases worldwide and eliminating the tremendous
human suffering they cause. An essential element of the Sabin Vaccine
Institute's mission to reduce human suffering caused by infectious and
neglected tropical diseases (NTDs) is our vaccine development program
conducted in collaboration with the George Washington University and
other international organizations, including the Oswaldo Cruz
Foundation and Instituto Butantan (Brazil), Queensland Institute of
Medical Research (Australia), the London School of Hygiene and Tropical
Medicine (United Kingdom), and The Institute of Parasitic Diseases
Chinese Center for Disease Control and Prevention (China).
In 2000, Sabin established an innovative non-profit Product
Development Partnership (PDP) to develop new vaccines for human
hookworm infection, schistosomiasis and other NTDs. Our vaccine
development program is the first and only PDP with a mission to develop
a vaccine to confer preventive immunity against human hookworm
infection (``hookworm''), an NTD that threatens vulnerable populations
around the globe. An estimated 576 million people suffer from hookworm,
primarily in the most impoverished communities of sub-Saharan Africa,
Asia, and Latin America. In these countries, hookworm is a leading
cause of anemia and malnutrition. Children are among the most
vulnerable populations, and suffer from severe growth and cognitive
delays as a result of this disease. Women of reproductive age,
including pregnant women, are also highly susceptible.
We have established a vaccine development pipeline that contains
multiple antigens at various stages of development. Our vaccines
undergo clinical testing in Brazil, a country where large numbers of
people are affected by hookworm infection. In addition, Sabin Vaccine
Development is pioneering the creation of some other vaccines that have
no traditional commercial market. The diseases represent the most
common scourges of the world's poorest people, including hookworm,
schistosomiasis, and malaria. Our vaccines enter into clinical trials
following regulatory submissions to the U.S. FDA and ANVISA, the
national regulatory authority in Brazil.
The Global Network for Neglected Tropical Diseases is another
initiative of the Sabin Vaccine Institute dedicated to raising the
awareness, political will, and funding necessary to control or
eliminate the most common NTDs--a group of disabling, disfiguring, and
sometimes deadly diseases affecting more than 1.4 billion people
worldwide living on less than $1.25 a day through mass drug
administration campaigns. The seven most common of these NTDs--
ascariasis (roundworm), trichuri-asis (whipworm), hookworm, schistosomiasis
(snail fever), lymphatic filariasis (elephantiasis), trachoma (blinding
trachoma), and onchocerciasis (river blindness)--account for 90 percent of
the NTD burden around the globe. Research has shown that some of these
diseases, such as LF, onchocerciasis, and trachoma can be eliminated
through mass drug administration, while others such as hookworm can be
controlled temporarily until the vaccine is developed. These mass drug
administration treatments can allow millions to climb out of poverty
through increased access to education and improving economic
performance.
Because of the Sabin's commitment to drug development and its fight
to control and eliminate NTDs globally, we affirm the steps the Food
and Drug Administration (FDA) is taking in implementing Section 740 of
the fiscal year 2010 Appropriation Act (Agriculture, Rural Development,
Food and Drug Administration, and Related Appropriation Act, 2010,
Public Law 111-80) to establish expert review groups and issue guidance
related to rare and neglected diseases. This work conducted by the FDA
will further enhance the work of those in the research and development
field and streamline product availability. In particular, it should
allow for clarity in the review process for products, such as new
vaccines for NTDs that would not necessarily be used within the United
States but could have significant impact on the disease burden
resulting from neglected diseases around the world. Furthermore, the
use of the Priority Review Voucher process to provide incentive for the
development of new products targeting the NTDs is welcomed.
Additionally, Sabin and the Global Network will look forward to
participating in the Part 15 hearing to be held this fall, which will
focus on the development of medical products used in the prevention,
diagnosis, and treatment of neglected tropical diseases and assist the
FDA in the collection of stakeholder comments to update its development
and approval guidance.
Another important issue discussed before the committee is the need
for new incentive mechanisms to de-link the cost of research and
development from the eventual revenues to be obtained from the sale of
new health products or medicines. The concept of de-linking would help
ensure that the right products for NTDs reach the end of the
development pipeline despite the lack of a commercial market.
Alternative incentives, such as prizes or other forms of ``pull
funding,'' are essential to stimulate the development of new vaccines,
drugs, and diagnostics for the NTDs. This concept is something that
Sabin strongly supports.
Again, we appreciate the opportunity to share our views and
contribute to this important global health discussion and the work of
this committee to streamline the development and approval of medicines
and treatments that target rare and neglected diseases. If the
committee should have any further questions about this statement or
programs of the Sabin Vaccine Institute Diseases, please do not
hesitate to contact me.
Thank you.
Prepared Statement of the Huntington's Disease Society
of America (HDSA)

Chairman Harkin and Ranking Member Enzi, on behalf of the
Huntington's Disease Society of America (HDSA), we applaud you for
holding this important hearing to discuss treating rare and neglected
pediatric diseases. We appreciate the committee's commitment to this
issue and hope that through increased awareness and Federal research
dollars we can find a cure for Juvenile Huntington's Disease (JHD).
Huntington's Disease (HD) is a rare, genetic, neurodegenerative
disease that causes total physical and mental deterioration over a 10-
to 25-year period. HD affects 30,000 Americans while another 200,000
are considered ``at risk'' of inheriting it from a parent. Even more
rare is JHD, which affects only 10 percent of individuals with HD.
Early signs of JHD include rigidity, slowness and stiffness,
clumsiness of arms and legs, behavioral changes, decline in cognitive
function, seizures and more. There is no cure for JHD or adult HD.
Today, physicians prescribe a number of medications to control
emotional and movement problems associated with the disease but there
is no treatment to stop or reverse the course of HD or JHD.
Increasing awareness of rare, orphan diseases is one way that we
can find a cure for diseases like JHD. Currently, there is legislation
in the House and shortly to be introduced in the Senate, the
Huntington's Disease Parity Act (H.R. 678), which has received the
support of nearly 140 Members of Congress. Current Social Security
Administration (SSA) guidelines for determining disability for
individuals with HD is more than 30 years out-of-date. Even more
alarming is that the SSA has failed to acknowledge the existence of
JDH. H.R. 678 not only updates the medical criteria and guidelines for
HD, but also directs the SSA Commissioner to include JHD in its list of
Pediatric-Neurological diseases. Further, the bill also removes the 2-
year waiting period for those with HD to receive critical Medicare
benefits.
Another way Congress can promote the development and treatment of
rare diseases is through the expansion of Federal research dollars.
Current HD research examining the processes of HD is helping scientists
and researchers identify new therapies and tools that are applicable to
other neurodegenerative and genetic diseases. While most of the current
research is focused on adults, the symptoms of JHD appear much earlier
and the progression of the disease is much more rapid from symptomatic
onset. Therefore JHD's biological, chemical, metabolic and molecular
processes may be easier to identify and flag--and thus our
understanding of Huntington's disease, other juvenile neurodegenerative
and genetic illnesses, and the means to thwart their progression.
We were also especially pleased to see that the Senate
Appropriations Committee included funding for the Office of the
Associate Director for Rare Diseases at the FDA and increased funding
for Orphan Product Development Grant program in the fiscal year 2011
Agriculture, FDA, and Rural Development Appropriations bill. These two
funding opportunities will further the clinical development of products
used to treat rare diseases.
In conclusion, we thank you for your support for pediatric orphan
diseases and congressional funding for research. We also ask that you
consider reviewing the Social Security Administrator's characterization
of HD and JHD to ensure that the medical guidelines are accurate and up
to date so that people with these diseases can have much-needed access
to Social Security disability and Medicare.

Prepared Statement of the National Venture Capital Association (NVCA)

The National Venture Capital Association (NVCA) appreciates the
opportunity to submit a statement on the role of venture capital
investment in the treatment and cure of rare and neglected pediatric
diseases. The NVCA represents the interests of more than 425 venture
capital firms which comprise more than 90 percent of the capital under
management in the United States. NVCA's mission is to foster greater
understanding of the importance of venture capital to the U.S. economy,
and to support entrepreneurial activity and innovation.
For decades, the U.S. venture capital industry has committed itself
to bringing groundbreaking medical innovation to the American people.
Since the early 1970s, venture capital firms have identified the most
promising breakthroughs in labs across the country, built companies
around these innovations, and worked alongside scientists and
entrepreneurs to safely commercialize these products--improving and
saving millions of lives along the way. In fact, according to Thomson
Reuters, venture capitalists have invested more than $81.5 billion in
over 4,000 start-up life sciences companies in the last four decades.
This represents approximately 30 percent of total venture capital
investment over the same period.
Venture capital-hacked companies have pioneered the development of
important new treatments for a wide range of serious diseases, such as
cancer (including many rare pediatric cancers), cystic fibrosis,
lysosomal storage disorders and other inborn errors of metabolism, and
many more. These kinds of rare diseases represent relatively small
markets that frequently attract little interest from large, established
pharmaceuticals. Venture capital-backed companies have been the engine
of innovation when it comes to breakthrough treatments for rare
pediatric diseases.
NVCA wants to promote greater investment in this important area.
However, the incentives for investment in rare diseases are at risk in
a number of ways, and we must act now to ensure that the venture
capital-backed innovation engine can continue to deliver important new
therapies for rare diseases. Among other issues, we must ensure that
the regulatory environment is conducive to investment in this area.
Development of novel therapies for rare diseases is inherently
difficult and risky. Patient populations are small, and it is
frequently impossible to complete the kind of large clinical trials
that FDA demands. It is essential that regulators recognize the unique
challenges of developing treatments for rare diseases, and show
appropriate flexibility in the application of regulatory standards, to
promote the continued development of new therapies for rare diseases
while continuing to ensure the safety and efficacy of new treatments.
Over the years, the venture capital investment process has remained
largely unchanged--largely because it works. Venture capitalists invest
pools of funds in start-up companies across the country with the goal
of making a significant return for their investors. Historically, these
investments are made in scientific discoveries and novel technologies
that address emerging or complex economic and social needs. This
characteristic adds significant risk to the process, but also enhances
the returns on successful ventures for investors, who are commonly
State pension funds and educational endowments. Because of the high-
risk and long-term nature of the investment, no other asset class is
positioned to invest in these types of companies. Without venture
investment, most of these medical breakthroughs would remain in the lab
and never reach the public.
It is important to understand that venture capital investment
involves more than just money. Venture capitalists invest a significant
amount of time, energy and expertise in each of the companies in their
portfolios. The life cycle of a venture investment typically follows
the same path. Venture capitalists seek out the most promising medical
breakthroughs in their early stages--looking for products or processes
that are ready to move on to the commercialization phase. Most often,
these innovations spring from government-funded basic research
conducted at universities and government labs. Venture capitalists
typically do not fund this basic research, but rather use their funds
to apply the products of basic research to solving real-world problems.
Once an idea is identified by a venture capitalist, the investment
is vetted by the entire firm and the most promising ideas are funded.
Venture capitalists, who are often scientists, engineers or doctors
themselves, will work closely with a company's founders to build the
business by taking a seat on the board of directors and offering
strategic counsel as the company matures. Usually, a venture capitalist
will invest several rounds of financing into a company over a period of
time. The average round of financing into a biotechnology company in
the first half of 2010 was just under $9 million. Companies must reach
specific, pre-determined milestones in order to earn their next rounds
of funding. If a company fails to achieve these goals, the venture firm
may decide that the risk is too great and the chance of success is too
small to continue funding it. In such instances, the company will
likely go out of business.
The goal of the venture capitalist is to one day sell the company
to a larger player or have the company go public, generating a
significant return on the total amount invested. In fact, many venture-
backed life sciences companies are sold to larger pharmaceutical
corporations because it is often the optimal way for large corporations
to acquire innovation. However, the largest returns are realized when a
company goes public. Venture capitalists look for returns that are at
least four times their original investment. Because many venture-backed
companies will fail, the returns generated by the successes must
significantly outweigh the cost of the failures for the venture
capitalist to be successful.
To wit, venture capital investment in life sciences is not for the
faint at heart. It requires tremendous patience and an appetite for
considerable risk. Due to the substantial regulatory path that medical
innovations must travel, investment in life sciences has a
significantly longer time horizon than other industries. Whereas a
venture investment in a software company might last 5 to 7 years, a
biotechnology investment typically lasts 15 years on average and can
cost up to $800 million. Additional regulatory hurdles add to the
length of the investment and the scope of the challenges. Not only do
these small companies face technological and market risk (i.e., will it
work and will it sell?) but also regulatory and pricing risk (will it
be approved by the FDA and receive a fair price by CMS?). Over the
years, the uncertainty surrounding the regulatory process has added
additional risk to an already tenuous path.
Given the role venture capitalists play in guiding life sciences
companies through their start-up and expansion phases, they have a
valuable perspective on the hurdles that emerging businesses confront
and the environments that promote or stifle growth and innovation.
Our members tell us that it is becoming increasingly difficult to
build an investment case for new investments in novel therapies
targeted at rare diseases, including pediatric diseases. The low-
hanging fruit is gone, and new therapies are inherently risky to
develop. Venture investors report that FDA regulation is becoming
increasingly inflexible. Whereas in the past, FDA appeared to show
greater flexibility in evaluating therapies for serious, rare diseases,
recognizing the challenges of developing these therapies, our members
report that FDA is increasingly painting novel therapies for rare
diseases with the same regulatory brush as other kinds of treatments
for more common diseases. If FDA fails to apply flexible standards that
reflect the unique challenges presented by rare diseases, then
investment in these therapies will grind to a halt.
Regulatory uncertainty and inconsistency can delay approvals to the
point of bankrupting innovative companies. This trend is impeding
patient access to critical therapies and medical technologies and is
disrupting critical U.S.-centered research and development. This in
turn greatly reduces the willingness on the part of venture capitalists
to invest in disruptive medical therapies. Strikingly, venture capital
investors are noting with alarm that novel therapies for rare diseases
are increasingly coming to market in Europe, Japan and other parts of
the world before they do in the United States. This points to a serious
risk that the United States could lose its leadership position in
medical innovation and the risk that patients with these diseases may
suffer without access to treatments that are benefiting patients in
other parts of the world.
Today's hearing provides an important opportunity for NVCA to offer
our suggestions on what can be done to create the proper incentives for
investment in the development of new treatment and cures for treating
rare and neglected diseases, including the pediatric population. NVCA
believes that the following suggestions will help alleviate the
challenges facing investors and innovators generated by the U.S.
regulatory framework and will promote the advancement of critical life-
saving therapies, a common goal of the NVCA, the FDA, and patients.
NVCA believes that innovative companies need:

The application of flexible regulatory standards that
reflect the unique challenges of drug development for rare diseases;
A special well-defined regulatory pathway for truly
``novel therapies'' which include therapies for rare and neglected
diseases that is robust, collaborative and flexible, but also
predictable;
A process to assemble a senior tram of highly qualified
regulatory reviewers and expert advisory panel members well-versed in
the current science and current safety and efficacy of novel therapies;
FDA approval requirements based on actual risk; and
A reasonable and predictable review regimen for all
medical therapies, including ``novel therapies.''

FDA approval of a company's innovative product can mean the
difference between success and failure for the business. Moreover,
investment in emerging companies will further decrease if the
regulatory environment remains so uncertain and burdensome as to
jeopardize final clearance of the product. This situation prevents U.S.
patients' access to the most innovative technologies. Unclear
regulatory requirements, inconsistent application of regulatory
requirements and high staff turnover can all lead to lengthy delays in
product review times, costing the emerging company hundreds of
thousands of dollars, or even millions of dollars, and risking future
venture investment in the start-up. These concerns are compounded
during the review of ``novel therapies'' which often raise issues of
first impression for the Agency since new therapies rarely fit into the
normal regulatory pathway.
NVCA believes that creating a special regulatory risk-based pathway
for ``novel therapies'' that is flexible, but predictable, would
mitigate some of these problems, particularly if such a system were to
focus dedicated resources and senior staff on expediting the review of
these therapies and technologies. We suggest that the following
specific changes relative to novel therapies at the FDA.

Clear Definition of ``Novel.'' The term ``novel'' is not
defined by the FDA.
Dedicated Resources for Novel Therapies. NVCA suggests
that the FDA dedicate a pool of cross-disciplinary, highly experienced
staff, and significant resources to the review (including expedited
review) of ``novel therapies.'' NVCA believes that it is important for
the FDA to continue to hire and retain qualified medical reviewers who
are well-versed in the current science and are up-to-date in the
practice of medicine in the specialties by which the therapies and
technologies they are evaluating will be used. A dedicated pool of
qualified reviewers will ensure that the Agency focuses precious
resources on truly innovative products, and that these therapies
receive appropriate and timely attention from experts at the Agency.
Moreover, by offering high-performing staff the opportunity to work
with cutting edge therapies, it may also aid the Agency in retaining
top reviewers, and will reduce delays due to staff turnover. Special
fees could be required for products designated for novel technology
review.
Well-Defined, but Flexible, Review Process for Novel
Therapies. Because novel products often raise new issues of safety and
effectiveness for the Agency, a clear review process and a clear path
for resolving disputes during the review process will provide added
regulatory certainty and additional security for venture investment.
For example, early, pre-clinical discussions with Agency reviewers to
design appropriate study requirements are invaluable to start-up
companies. In addition, continued discussions and an open dialogue with
the Agency during the review process is essential, as is the ability to
use new methods of statistical modeling and cutting-edge clinical trial
designs to speed the review process. All of these items will increase
transparency between the Agency and the sponsor, and reduce regulatory
risk for VC investors in novel therapies.
Regulatory standards that reflect the unique challenges of
drug development for rare diseases. As discussed above, it is essential
that FDA apply standards that reflect the realities of drug development
for rare and neglected diseases. We believe that FDA has statutory
authority to apply its judgment and discretion in the evaluation of
novel therapies for rare diseases. What is needed is clear direction
and leadership from senior FDA officials who recognize these issues,
leading to the articulation of a regulatory policy that encourages an
appropriate balancing of benefit and risk in the context of the
realities of drug development for rare diseases.
Regulation based on risk classification. The level of
approval standards should be based on the risk. Higher levels of
evidence of efficacy and safety would be required for therapies and
technologies which present greater risk concerns.
Ensuring Appropriate External Expertise to Support Reviews
of Novel Therapies. As stated above, the potential for inadequate
expertise at the Agency and on advisory panels to review and rule upon
novel products is a real problem because persons who can provide the
day-to-day input to ensure a knowledgeable, effective and efficient
review are often excluded from the process due to conflict of interest
concerns. Although they can participate at selected moments as part of
the sponsor's team, their value is greatly reduced in that capacity.
NVCA strongly believes that the advisory committee review process must
have persons with intimate knowledge of novel therapies if these panels
are going to properly advise the FDA. Accordingly, we propose that the
FDA request that its legal counsel determine transparent processes and
standards to permit persons with an interest in a novel therapy and
technology to participate in the advisory panel process as an advisor
or a non-voting panel member with adequate disclosure of any conflicts
or potential conflicts. If there are ownership interests, functioning
as a scientific advisor to a panel could be inappropriate. However, if
there are no financial interests, but the individual does have a
financial interest, participation as a non-voting panel member may be
appropriate, again with adequate disclosure of the person's association
or interest in the device. Medical advisory committees must be able to
recruit the most qualified experts in the field in order to provide
meaningful recommendations to the Agency on product approvals. NVCA
believes that the current conflict of interest policies prevent the
best academic researchers and physicians and those from industry from
serving on advisory committees, to the detriment of patients and
innovation.

CONCLUSION

NVCA believes that these suggestions will stimulate innovation and
the development of ``novel therapies'' without compromising the safety
or effectiveness of cleared or approved therapies and will provide the
appropriate incentives that will lead to the development of critical
treatments for rare and neglected diseases. NVCA looks forward to
working with the committee to help accomplish this important goal.

Response to Questions of Senator Harkin, Senator Enzi, Senator Casey,
Senator Hagan, and Senator Franken by the Department of Health and
Human Services, Food and Drug Administration

SENATOR HARKIN

Question. Some suggest that FDA should create a separate division
of rare and neglected diseases within the Center for Drug Evaluation
and Research to bring the proper expertise to bear on the analysis of
drug applications intended to treat such maladies. Can you please
comment on the merits of this idea?
Answer. FDA shares the goal of encouraging and speeding the
development of drugs, vaccines, biologic medical products, and
diagnostic tests for rare and neglected diseases and appreciates
efforts by Congress to achieve these goals. FDA is aware of proposals
to establish a specific review group in the Center for Drug Evaluation
and Research (CDER) for products to treat rare diseases. This approach
may have some challenges that would be important to carefully consider
so as to avoid potential unanticipated consequences. For example, rare
diseases cut across all medical disciplines, from oncology to
obstetrics to rheumatology to infectious diseases to neurology to
inborn errors of metabolism, etc. The scientific and practical
challenges posed by these products require input from our most
experienced scientists and clinicians. Expertise in particular rare
diseases, including expertise in defining appropriate endpoints and
employing flexible clinical trial designs, is currently embedded within
the medical disciplines that also embrace more common diseases.
In February 2010, FDA created a position of Associate Director for
Rare Diseases (ADRD) in CDER. The ADRD coordinates the development of
policies and procedures for the review and approval of treatments for
rare diseases throughout CDER, ensures appropriate training of staff,
establishes consistent processes for providing advice to sponsors, and
advocates for and oversees the efficient development of products for
rare diseases across multiple scientific disciplines. The ADRD is
actively addressing challenges related to rare diseases through
enhancing coordination and identifying and promoting best practices
among FDA's experts in the specific disease areas of interest, bringing
detailed knowledge of flexible approaches to development and review of
drugs to treat rare diseases. In conjunction with the Office of Orphan
Products Development (OOPD) and the Office of the Chief Scientist
(OCS), the ADRD supports collaboration among scientists and clinicians
throughout FDA, promoting scientific and regulatory innovations to help
facilitate timely development and approval of new treatments for
patients with rare diseases.
Thank you again for your interest in rare and neglected pediatric
diseases. If you have further questions, please let us know.

SENATOR ENZI

Question 1. Looking at these different programs at different
agencies, is there any entity that acts as a shepherd for a company or
product along the entire development process, or does each agency just
monitor its own program?
Answer 1. In February 2010, FDA and the National Institutes of
Health (NIH) established a Joint NIH-FDA Leadership Council to
spearhead collaborative work on important public health issues. The
Joint Leadership Council works together to help ensure that regulatory
considerations form an integral component of biomedical research
planning, and that the latest science is integrated into the regulatory
review process. The collaboration will advance the development of new
products for the treatment, diagnosis, and prevention of common and
rare diseases and enhance the safety, quality, and efficiency of the
clinical research and medical product approval enterprise. The
formation of the Leadership Council represents a commitment on the part
of both agencies to forge a new partnership and to leverage the
strengths of each agency toward this common goal.
In addition to the Leadership Council, FDA collaborates with NIH on
multiple levels. FDA's Office of Orphan Products Development (OOPD)
works closely with NIH's Therapeutics for Rare and Neglected Diseases
(TRND) program and the NIH Office of Rare Disease and Research (ORDR),
integrating activities across agency boundaries. OOPD acts as an
ombudsman throughout the drug development process, meeting with
sponsors from the earliest idea all the way through the drug
development process. OOPD has a formal role in granting orphan status
designation and awarding grants and regularly attends review division
meetings, providing overall regulatory advice to all companies that
aspire to make new therapies for people with rare diseases.
FDA's Center for Drug Evaluation and Research (CDER) recently
established a new position of Associate Director for Rare Diseases
(ADRD), which is intended to serve as a focal point within CDER for
communication with rare disease stakeholders, including partner offices
at NIH. In conjunction with OOPD, the ADRD also supports collaboration
among scientists and clinicians throughout FDA, promoting scientific
and regulatory innovations to help facilitate timely development and
approval of new treatments for patients with rare diseases.
Finally, FDA's Office of Pediatric Therapeutics (OPT) works closely
with NIH's Eunice Shriver National Institute of Child Health and Human
Development to shepherd pediatric products through the development
pipeline.

Question 2. I am glad to hear that you are focused on training FDA
reviewers in the science of conducting and analyzing small clinical
trials. Is there a corresponding effort to provide regulatory certainty
via guidance to industry for clinical trial design for these small
populations?
Answer 2. FDA is exploring the development of guidance documents
for rare disease research programs; however, because these trials often
have unique circumstances, guidance will not answer all of the
questions that industry may have. For this reason, FDA is working to
educate industry and other stakeholders about the possibilities for the
science of conducting and analyzing small clinical trials. The FDA
annual course entitled, ``The Science of Small Clinical Trials'' was
originally limited to FDA and NTH participants but was recently opened
to a wider audience. Last year more than 1,500 registrants
participated, many of whom were from industry. In addition, FDA and
NIH, in collaboration with the National Organization for Rare Disorders
(NORD) and Duke University Medical Center, are co-sponsoring a training
course for rare disease investigators, scheduled to take place in
October 2010. The course will focus on special considerations and
regulatory requirements for research on rare diseases and orphan
products. FDA plans to repeat this course annually.

Question 3. Both the orphan drug and Humanitarian Device Exemption
programs are designed to incentivize developing treatments for rare
diseases. The population limit for orphan drug designation is 200,000
people. However, the limit for the Humanitarian Device Exemption is
4,000 people. Do you believe the difference is appropriate? If so, why?
Answer 3. These statutory limits were determined by Congress, not
FDA; however, FDA recognizes that there are reasons why these numerical
differences may exist. The Humanitarian Use Device/Humanitarian Device
Exemption (HUD/HDE) program and the Orphan Drug program are vastly
different in terms of the incentive that they offer. The HUD/HDE
program offers as its major incentive an exemption from the otherwise
applicable effectiveness requirements. To qualify for this exemption,
certain criteria must be met, including a determination by FDA that the
probable benefit outweighs the risk of injury or illness from use of
the device. Arguably, one might wish to be especially restrictive of
the population to which one exposed less well-established therapies. In
contrast, the Orphan Drug Act offers market exclusivity (and other
financial rewards) as its major incentive, but maintains the same
requirements for safety and efficacy as any other drug/biologic.
While FDA has no position on changing the limit for the
Humanitarian Device Exemption, the Agency strongly urges Congress to
ensure that, if a change is made, the population limit is clearly
defined, not variable. Any variation in the system will lead to
unnecessary confusion and may unintentionally disincentivize innovation
in this area.

SENATOR CASEY

Question 1. What sort of data exists on post-marketing surveillance
for children's use of pharmaceuticals and medical devices?
Answer 1. FDA's Adverse Event Reporting System is a computerized
information database designed to monitor new adverse events and
medication errors that occur in marketed, FDA-regulated products. The
system includes data on adverse events experienced by children, though
it is incomplete because reporting of adverse events from the point of
care is voluntary in the United States. Recognizing the need to improve
post-marketing surveillance for children's products, Congress enacted
legislation to address this issue. The Food and Drug Administration
Amendments Act of 2007, which included the Pediatric Research Equity
Act, the Best Pharmaceuticals for Children Act, and the Pediatric
Medical Device Safety and Improvement Act of 2007, requires FDA's
Pediatric Advisory Committee (PAC) to review all adverse events in the
year after a product receives new pediatric labeling resulting from
pediatric studies. Because the legislation increased the number of
pediatric clinical trials, and subsequently, the number of products
with pediatric information in labeling, the number of products up for
pediatric-focused safety review has steadily increased from
approximately 8 products annually to over 40 products per year. As of
June 2010, the PAC reviewed 135 products and recommended labeling
changes on 32 (24 percent) of those products. In addition, the PAC
recommended additional studies for seven products. These products
include both pharmaceuticals and medical devices.

Question 2. Would it be advisable for FDA to better understand the
frequency and practice of ``off-label'' use in children--particularly
those with rare diseases? If so, what should be done?
Answer 2. Off-label use of commercially available drug and
biological products is a concern for both pediatric and adult rare-
disease populations. Products that are approved for other indications
are frequently prescribed off-label for rare diseases, usually in
situations where no other specific treatment for the rare disease is
available. The frequency of off-label prescribing in rare diseases has
not been quantified, though we are aware of the practice through
communication with patient groups and treating physicians. We recognize
that in some cases limiting off-label use would leave patients with
few, or no, treatment options. The best approach for patients would be
to study these products--in children and adults--in the conditions for
which they are being used in order to adequately inform patients and
physicians of their safety and effectiveness. FDA is currently working
to encourage such studies through the work of its OOPD, OPT, and the
Associate Director for Rare Diseases in CDER.

SENATOR HAGAN

Question. One challenge that many of the witnesses today spoke of
is the need to incentivize the device and drug/biotech industry to
develop therapeutics for rare, pediatric diseases. Assuming a device or
compound gets to the clinical trial stage, how long does it take to
conduct the adult trials and then the follow-on clinical trials in
children? Is there a way to speed up this process?
Answer. The time required to conduct clinical trials in adults and
children varies greatly as the Agency must review and evaluate each
device or compound on a case-by-case basis. Although pediatric trials
are usually smaller in size and for some studies, such as
pharmacokinetics, can be completed fairly quickly (weeks), the smaller
number of children with the disease may result in prolonged enrollment
periods.
There are many factors that contribute to the length of the trial.
The condition being studied and the proposed effect of the intervention
on the disease (i.e., endpoints and outcome measures) will be major
determinants for the length of the trial, and will vary considerably
depending on disease, treatment and outcome. Additional considerations
specific to clinical trials conducted in children include the
prevalence of the disease in children, ineligibility to volunteer to
participate in trials, and the fact that trials should not be conducted
in children without the condition are important factors that impact the
availability of children for trials and thus the length of the trial.
Other factors, such as the need or specialized equipment, variable
treatment affect, issues related to individual growth and development,
specialists/nurses, labs, and pediatric-friendly facilities, directly
contribute to the complexity and technical difficulties of pediatric
trials.
One approach that does facilitate the conduct of pediatric trials
is the ability to extrapolate efficacy when the course of the disease
and the response to therapy are thought to be ``sufficiently similar''
in adults and older children. In some cases, the ability to extrapolate
could eliminate the need to replicate efficacy trials, shaving years
off the development process. We also encourage companies to interact
with the Agency in the early stages of product development to identify
a potential use of the product in a pediatric population. Early
dialogue with the Agency may allow the company to obtain approval for
pediatrics close to or concurrent with the adult approval. This is
particularly true when there are limited or no other therapeutic
options and the condition is serious or life-threatening. One should
note, however, when the product is novel or a new molecular entity with
little or no adult experience, it is considered prudent to wait until a
more robust understanding of its effectiveness and safety has been
established before enrolling a population that is as vulnerable and
variable as the pediatric population.

SENATOR FRANKEN

Question 1. A key stipulation for a humanitarian device exemption
is that ``the probable benefit to health from using the device
outweighs the risk of injury or illness from its use.'' How exactly
does FDA determine what constitutes ``probable benefit to health?''
Would FDA be willing to offer guidance on this topic so device
companies can more easily navigate the humanitarian device exemption
process?
Answer 1. The Federal Food, Drug and Cosmetic Act requires that
applicants for Humanitarian Use Device (HUD) designation provide an
explanation of how the probable benefit to health from the use of the
device outweighs the risk of injury or illness from its use, taking
into account the probable risks and benefits of currently available
devices or alternative forms of treatment. This requirement allows FDA
to examine applications on a case-by-case basis, taking into account
the specific circumstances related to the device and its use. We
recognize the challenge that the terminology presents and appreciate
the desire for guidance on this topic, and we will he considering that
in determining future guidance to make this issue clearer.

Question 2. We've heard stories of pediatric patients in Minnesota
who are unable to get the humanitarian use devices they need because
insurance companies consider these devices to be ``investigational.''
Does FDA consider these devices to be investigational?
Answer 2. FDA considers a device that has been approved as a HUD to
be an approved device. FDA's role is to make decisions about safety and
effectiveness, not coverage and payment; however, we view our recent
agreement to establish a memorandum of understanding with the Centers
for Medicare and Medicaid Services (CMS) entitled ``Parallel Review of
Medical Products by the FDA and CMS Agencies'' as an opportunity to
better share information with our sister Agency about HUDs and other
approved products in the future.
FDA staff handle many inquiries from private payers on this issue.
We work directly with the payers to help them understand that an HDE is
an approved product and is not under investigation. We also work with
payers on individual cases to help secure coverage for individual
patients. FDA staff regularly conduct outreach to help the health care
industry and those who make payment decisions understand the status of
HDEs and issue guidance in which it was made clear that an HDE is an
approved product. Recently, FDA issued an updated HDE guidance that
provides additional information and clarity to interested parties.

Response To Questions of Senator Enzi, Senator Brown, Senator Casey,
and Senator Hagan by Alan E. Guttmacher, M.D.

SENATOR ENZI

Question 1. What strategy has the NIH established to ensure the
TRNDs program is successful?
Answer 1. The Therapeutics for Rare and Neglected Diseases program
(TRND) is explicitly intended to tackle a phase within drug development
well-known to be fraught with failure and unpredictability; hence its
moniker in the biopharmaceutical industry as the ``Valley of Death.''
To ensure that the program is successful, NIH has established a number
of strategies to achieve TRND's twin goals of: (1) producing drugs for
rare and neglected diseases ready for clinical research testing; and
(2) developing new paradigms and technologies that will increase
success and decrease costs in this extremely challenging arena. Many
programmatic features integral to TRND are unique and made possible
because TRND is being conducted through NIH. Such features include:

Establishing a project selection and ongoing review
process that utilizes world experts in drug development from the
academic, biotechnology, pharmaceutical, venture capital, and
foundation sectors;
Establishing a diversified portfolio within the drug
development pipeline that includes projects at various stages and with
various degrees of difficulty;
Selecting projects (after a rigorous review process) on
the basis of scientific opportunity and medical need rather than
anticipated financial return;
Choosing projects potentially applicable to multiple
diseases, thus increasing the utility of each drug developed;
Hiring the best talent from the biopharmaceutical industry
to support in-house activities in addition to convening consulting
scientists from all sectors to develop the best strategies for
individual projects;
Focusing activities on technology, paradigm, and systems
engineering development to continuously increase efficiency of
processes within the drug development pathway.

Question 2. How could increasing funding for the Common Fund help
support research for rare and neglected diseases?
Answer 2. Many rare and neglected diseases are multisystem
diseases; that is, they involve multiple organ systems and parts of the
body. Thus, full understanding of their underlying biology and the
development of effective therapeutic and preventive strategies often
require the expertise and perspectives of many NIH Institutes and
Centers and their communities of researchers. The NIH Common Fund
supports programs that require just such multi-Institute expertise and
that go from the most basic science to translational and clinical
research. Supporting the fiscal year 2011 Budget request for the Common
Fund would therefore support rare and neglected diseases in several
ways.
For example, the new Common Fund program entitled Knock-Out Mouse
Program Phenotyping (KOMP2) seeks to build upon an existing resource of
mouse mutant strains to determine their physiological characteristics
(phenotypes). These mutant strains are intended to provide animal
models of genetic disorders, and they therefore provide basic science
tools to understand rare disease etiology as well as translational
tools to study potential therapeutic approaches.
The Interdisciplinary Research Program provides funds for teams to
develop comprehensive approaches to complex health problems, including
provision of core facilities, research projects, and interdisciplinary
training programs focused on the health problem. One consortium funded
through this program addresses Fragile X-Associated Tremor/Ataxia
Syndrome. It focuses on the critical periods of development when
mutations are most problematic, seeking to identify the molecular
targets where therapies might be most effective and to determine
mechanisms of cognitive dysfunction in the disease.
The Human Microbiome Program is designed to identify and
characterize all the microbes that live on and in us, and to determine
their contribution to health and disease. Current projects funded
through this program address the role that microbes play in maintenance
of health and in development of a variety of disorders.
Neglected diseases in Africa are an emphasis area for the Human
Heredity and Health in Africa Program, a new program to be launched in
the Common Fund this year. In conjunction with the Medical Education
Partnership Initiative which is also funded via the Common Fund, this
program provides support to develop research capacity in Africa so that
neglected diseases can be studied in the areas where they are most
common. The funds currently planned through the Common Fund are
intended to facilitate the study of genetic and environmental traits
that underlie differential susceptibility to such diseases.

Question 3. How many therapies or research projects will the Agency
be able to conduct and complete with $24 million? On average, how much
is necessary to successfully develop a candidate compound that is ready
to be tested in patients and licensed to the private sector?
Answer 3. While the cost of developing a project from a ``lead''
stage through an Investigational New Drug (IND) application or a proof-
of-concept study in humans varies widely, the industry standard for
entirely novel targets and diseases (those TRND will work on) is
approximately $10 million over 2 to 5 years. Even with this substantive
financial investment, industry-standard success rates for candidate
drugs targeting diseases of this sort are approximately 1 in 10.
Therefore, with the current budget of $24 million, TRND is initiating
five pilot projects that enter the 2- to 3-year preclinical development
process at various points; those entering later in the process cost
less. Through the pilot projects, TRND is building infrastructure
necessary to support these and future projects, while also working on
several small-scale technology development projects, since each of
these areas will be critical to TRND's long-term success. With over
6,000 rare and neglected diseases at the heart of its mission, TRND
cannot, and will not, simply adopt current industry best practices,
because their cost and failure rates are just too high. Technology
development--the science of preclinical drug development--is critical
to TRND's long-term impact, both for the diseases it works on, and for
the drug development enterprise generally. In fiscal year 2011, TRND
expects to launch an additional three to five projects.

Question 4. Can you provide an overview of the Bench-to-Bedside
Program? How much funding does the program provide for research focused
on rare and neglected diseases?
Answer 4. The Bench-to-Bedside Program was established in 1999 to
integrate the work of basic and clinical scientists on the NIH campus,
aimed at creating collaborations based on high quality science that has
the strong potential to result in new understanding of a disease
process or lead to new therapeutic interventions. The program expanded
in 2006 to encourage partnerships between intramural and extramural
programs. Grants are funded for 2 years of up to $135,000 per year. In
recent years, the Office of Rare Diseases Research (ORDR) has set aside
up to $1 million annually, with matching co-funding from one or more
NIH Institutes. In 2010, ORDR provided $931,412 for 12 projects, six of
which were in their second year. The ORDR contribution was matched by
10 Institutes thereby raising the total for rare diseases to almost $2
million annually. To date, about 600 primary and associate
investigators have collaborated on nearly 200 funded projects with
approximately $40 million distributed in total bench-to-bedside
funding.

Question 5. How much funding does the Agency spend on rare and
neglected diseases? How does that compare to the Agency's overall
budget? What percent of funds targeted for rare and neglected diseases
are spent on rare and neglected cancers?
Answer 5. Since the NIH has not collected information on rare and
neglected diseases as a single category, there are many specific rare
diseases for which total NIH investment cannot currently be reported,
but which are supported by and tracked by individual NIH Institutes and
Centers. For example, the National Cancer Institute reports spending
$192.8 million on childhood cancer research in fiscal year 2009.
Currently, the NIH does not collect information on funding for rare
and neglected diseases research per se. However, three major programs
in recent history have greatly increased NIH's focus on rare diseases
diagnoses and treatments. In 2003, the Office of Rare Diseases Research
(ORDR) partnered with several NIH Institutes and Centers to fund the
Rare Diseases Clinical Research Network (RDCRN). In 2008, at the
conclusion of the first 5-year funding cycle of 10 consortia, the ORDR,
in collaboration with NIH Institutes funded 19 consortia. For the 10-
year duration of the RDCRN, NIH has committed almost $200 million.
In addition, the NIH has committed $24 million annually for fiscal
year 2009 and fiscal year 2010 to the Therapeutics for Rare and
Neglected Diseases (TRND), a new collaborative drug discovery and
development program. The fiscal year 2011 Budget requests $50 million
to expand TRND activities.
The Undiagnosed Diseases Program (UDP) is another effort that
focuses by its very nature on rare diseases. Using a unique combination
of scientific and medical expertise and resources at the NIH, the UDP
provides answers to patients with mysterious conditions that have long
eluded diagnosis. The fiscal year 2011 Budget includes $3.5 million for
this effort.

Question 6. Specifically, how is the Agency working with the FDA
and industry to develop a more seamless process in drug development?
Answer 6. Historically, the NIH and the FDA have established
collaborations largely according to scientific disciplines in order to
address specific research areas and needs. In February 2010, the two
agencies announced an unprecedented effort to work together to help
ensure that regulatory considerations form an integral component of
biomedical research planning and that the latest science is integrated
into the regulatory review process. A joint NIH-FDA Leadership Council
(LC), composed of the NIH Director and FDA Commissioner and senior
leadership from each agency, was formed. The collaboration will advance
the development of new products for the treatment, diagnosis and
prevention of common and rare diseases and enhance the safety, quality,
and efficiency of the clinical research and medical product approval
enterprise. The formation of the Leadership Council represents a
commitment on the part of both agencies to forge a new partnership and
to leverage the strengths of each agency toward this common goal.
In addition, at the program level, the recently launched
Therapeutics for Rare and Neglected Diseases (TRND) program within the
NIH Intramural Research Program has established monthly working group
meetings with representatives from the FDA Office of New Drugs and its
Office of Translational Science. The aim of these meetings is to focus
on conceptual issues presented through TRND projects and develop
potential ideas to address any roadblocks identified in the drug
development process. Furthermore, TRND leadership is working closely
with the FDA Office of Orphan Product Development to coordinate
activities and leverage existing programs to advance mutual goals.
The NIH Office of Technology Transfer serves as one of the NIH's
primary interfaces with both industry and academia in pursuing common
research goals. Government scientists can leverage their own research
resources to facilitate the development and commercialization of health
care pharmaceuticals and products, while private companies can leverage
their own research efforts while collaborating in cutting edge NIH
research. One of the primary tools is a Cooperative Research and
Development Agreement (CRADA), which can make government facilities,
intellectual property and expertise available for collaborative
interactions to turn scientific knowledge into useful, marketable
products through licensing agreements. For products that may be used to
treat rare conditions, this arrangement can prove especially useful by
allowing the NIH to support the initial research on a drug or device
(often the riskiest and most time-consuming part of the process), and
then turning it over to a private company for final testing, FDA
approval, and marketing.

Question 7. What types of research do you support to assist FDA in
establishing guidance to further clarify the requirements for drug
approval?
Answer 7. In February, 2010, the NIH released a new Request for
Applications (RFA), jointly funded with the FDA, titled Advancing
Regulatory Science Through Novel Research Technologies. The purpose of
this funding opportunity is to foster the development, evaluation and
availability of new or improved tools, methods, standards, and applied
science that support a better understanding and improved evaluation of
product safety, quality, effectiveness, and manufacturing throughout
the product lifecycle. The science may range from nanotechnology to the
development of novel experimental models, such as a biological system
on a chip for assessing safety and toxicity, to innovative research on
clinical trial design. By the end of fiscal year 2010, NIH expects to
be supporting several novel cooperative grants in cross-cutting areas
of science.
Research results from investigator-initiated basic and clinical
research supported across the NIH inform and clarify requirements for
drug and device development. Much of this research is focused on
individual diseases and conditions; however, the characterization and
standardization of new and emerging technologies, such as stem cells,
genomics and related technologies, and nanotechnology, is cross-cutting
and serves all research communities and the FDA in establishing
guidance and requirements for development and subsequent approval. For
instance, the NIH funds both intramural and extramural research
directed toward the examination of the fundamental principles of
nanotechnology and their application to the development of diagnostics
and interventions. This research augments existing knowledge and helps
to assess what data are still needed to approve specific drugs and
medical devices. Another cross-cutting type of research is in the area
of clinical trial design. As clinical trials are becoming more complex,
and trials are being conducted in sometimes small sample populations,
investigators are looking to adaptive design methodologies. The NIH
supports biostatistical research projects through a variety of grant-
related mechanisms that informs study design and analyses.

Question 8. Can you provide a specific example of NIH funded
research associated with FDA guidance or overall improvements in the
drug review process?
Answer 8. The NIH and the FDA traditionally have established
collaborations largely according to scientific discipline in order to
address specific research areas and needs. One example of an
intramural-funded collaborative effort that resulted in a guidance
document and associated improvements in the drug development process
can be found in the FDA/NCI Interagency Oncology Task Force (IOTF). The
IOTF was formed in 2003 as an interagency effort to enhance the
efficiency of clinical research and the scientific evaluation of new
cancer medications. Through it, the two agencies share knowledge and
resources to facilitate the development of new cancer drugs and speed
delivery to patients. As a direct outcome of the collaborative effort,
in January 2006 the FDA released its Guidance for Industry,
Investigators, and Reviewers on Exploratory Investigational New Drug
(IND) Studies. Exploratory IND studies enable a sponsor to proceed more
efficiently with the development of promising candidates by allowing a
new drug candidate to provide clinical information at a much earlier
phase of drug development. The guidance document addressed what
preclinical and clinical approaches, including chemistry,
manufacturing, and controls information, should be considered when
planning exploratory studies in humans. This tool enables a faster,
more cost-effective path to early clinical development.
The Patient Reported Outcomes Measurement Information System
Program (PROMIS), an extramural project funded through the NIH Common
Fund, is designed to develop a precise, efficient and valid assessment
of patient outcomes, such as fatigue, that are the result of disease or
treatment. The NIH is working with the FDA in this program to ensure
that the work done with the system takes into account FDA guidance and
perspectives for the assessment of efficacy and safety of new drugs/
treatments. This is critical for the many diseases/conditions where
patient reports are a primary assessment of improvement, including pain
and depression.

Question 9. Can you elaborate on why the Human Genome Project and
why genetic research in general is so important for rare and neglected
diseases?
Answer 9. Fundamentally, approximately 80 percent of rare diseases
are genetic diseases--that is, they are caused by the malfunction of
one or more specific genes. For this reason, the Human Genome Project
has been enormously beneficial to the rare disease community; the
genetic causes of over 2,000 different rare diseases are now known.
While knowledge of the genes involved in a disease is critical
information to developing targeted drugs, it is just the start. Many
diseases whose genetic cause(s) have long been known are still without
sufficiently effective treatment (e.g., Huntington's disease and sickle
cell disease). This difficult reality is why the TRND program is so
critical.

Question 10. I understand the Agency has been working to provide
basic tools to researchers that were previously not available to reduce
barriers for investigators. Can you provide an example of a specific
tool and academic institution or other type of research entity that
benefited from the tools? Who has access to these tools? Are the tools
only accessible to NIH grantees or all public and private research
institutions?
Answer 10. The NIH provides basic research tools, including genome
sequences, gene libraries, knockout mice, and informatics databases of
various kinds, to researchers from all sectors without restriction. For
example, the National Centers for Biomedical Computing program develops
informatics tools for a wide variety of research areas and makes them
publicly available. Among the newest types of tools to be made
available are small molecule tools, which are ``drug-like'' chemicals
that can be used to study diseases in cell and animal models. NIH began
a large-scale program to produce small molecule research tools, and
data on them, in 2003 with the launch of the Molecular Libraries
Program, as part of the original NIH Roadmap. That program has been
enormously successful and has produced hundreds of compounds to study
genes, pathways, and cells in collaboration with researchers throughout
the country and the world. These tool (or ``probe'') compounds are
readily available to any researcher (over 300 investigators have used
the Molecular Libraries resources to date), irrespective of whether the
researcher is an NIH grantee or works within the public or private
sectors. Detailed reports on the research (and tools) are made publicly
available through the NIH Web site, and all the data generated are made
publicly available via the NIH PubChem database, which enables
investigators to see the chemical structures of all compounds that have
been shown to be active in various assays (tests).
One example of the success possible through the access to these
tools is a new compound for studying the cause and treatment of
schistosomiasis, a parasitic disease highly prevalent (affecting more
than 250 million people) in Africa and South America. The NIH Chemical
Genomics Center (NCGC), part of the Molecular Libraries Program,
collaborated with Dr. David Williams at Rush University in Chicago, an
NIH grantee and expert in schistosomiasis, to produce new tool
compounds and then prove that the enzyme inhibited by a particular tool
compound was required for the parasite to live. The tool compound very
effectively kills schistosomiasis worms both in cultures and in mice,
and the work was published in major scientific journals. This work is
also an example of the catalytic effect these kinds of tools can have,
because as a result of the publications, a different researcher--Dr.
Michael Cappello at Yale University--contacted Dr. Williams and NCGC,
who provided Dr. Cappello with the tool compound. Dr. Cappello then
showed that the compound is also very effective at treating a
completely different parasitic infection, hookworm. Dr. Williams, Dr.
Cappello, and the NCGC scientists are now working together to develop
these compounds further, so that they can be tested in humans with
these devastating diseases.

SENATOR BROWN

Question 1. As was discussed in depth at the HELP committee's
hearing, rare pediatric diseases pose a number of challenges. One
barrier is that the number of patients available for clinical trials is
small. As such, the need for sharing and collaboration is all the more
critical for rare pediatric diseases. I have been working with Senator
Bond to advance legislation--the Pediatric Research Consortia
Establishment Act--that envisions a networked consortium of leading
pediatric biomedical research entities that would be competitively
selected by NIH. By operating in such a model, the project would foster
resource sharing, collaboration, and help pool patients to ultimately
develop treatments and therapies for diseases and disorders of both
childhood and adulthood. What are your thoughts on the challenges
associated with pediatric research and the ability to use a networked
consortia approach to overcome these issues and permit a more robust
pediatric biomedical research enterprise? I'd like to ask that NICHD
provide a full written assessment as to the merits of this proposal.
Answer 1. In fiscal year 2009, the NIH, through 22 Institutes and
Centers (ICs), awarded approximately $3.4 billion, including funds from
the American Recovery and Reinvestment Act, in support of pediatric
research activities across the country. This funding was distributed to
the research community through the full range of available funding
mechanisms, including investigator-initiated grants, contracts, and
research networks. This flexibility allows the extensive scientific
expertise at the NIH and across the extramural scientific research
community to judge which mechanism(s) might be best suited for the
specific research needed to answer questions about children's health
and development and pediatric diseases and conditions. Less commonly,
but where the scientific challenge warrants and funding permits, NIH
ICs (often in trans-Institute collaboration) have created
multidisciplinary centers of excellence or research networks for
specific pediatric populations, specialties, or conditions, such as
autism, pediatric oncology, neonatology, and adolescents with HIV/AIDS,
to name a few.
For example, the NIH Office of Rare Diseases was directed by
Congress in the Rare Disease Act of 2002 (P.L.107-280) to establish a
clinical research network focusing on rare and neglected conditions.
Since 2003, the Rare Disease Collaborative Research Centers network of
investigators and patient groups, in partnership with technology
leaders, has been working to develop biomarkers and new approaches to
diagnosis, prevention, and treatment, provide content for a web-based
resource site about rare diseases, and train new clinical investigators
in rare disease research. Of the 19 current member sites of the
network, three are focused on pediatric rare diseases. These three main
sites and their 33 affiliate sites (many located at children's
hospitals) are managed by the Eunice Kennedy Shriver National Institute
of Child Health and Human Development (NICHD) on behalf of the NIH.
In addition, a number of the Clinical and Translational Science
Awards (CTSAs) sites include a strong emphasis on creating
infrastructure to conduct pediatric clinical trials, which will allow
pediatric researchers who focus on a wide variety of conditions to
utilize this new resource and to conduct clinical trials efficiently
and effectively.
The NIH may provide only technical assistance on legislative
proposals on which the Administration has not yet taken a position.
However, in evaluating what mechanism or infrastructure to use to
address any question about health or disease, important considerations
include whether the proposed mechanism provides the range of scientific
expertise required to answer that question, the availability of a
sufficiently sized study population, and whether a currently existing
mechanism might adequately meet these needs. The impact of creating a
new infrastructure on investigator-initiated proposals also must be
weighed.

SENATOR CASEY

Question 1. How is our emerging knowledge of genetics helping us
understand rare childhood diseases--and bring new cures and treatments
to children faster?
Answer 1. Since approximately 80 percent of known rare diseases, a
substantial proportion of which occur in children, are thought to have
a genetic basis, increasing understanding of the role of genetics in
rare diseases will unquestionably have a considerable impact on their
diagnosis, prevention, and treatment. However, a few decades ago, many
scientists assumed that once causative genes were identified,
treatments would be imminent, an assumption that has proven overly
optimistic. Rare diseases are very complex and often affect multiple
organ systems, and phenotypic (physiological characteristics)
expressions of these genes in individuals can be quite diverse.
Nevertheless, by continuing to increase the knowledge base about the
origins of pediatric diseases, and the impact of those diseases over a
lifespan, targeted treatments can be developed that can reduce
morbidity and mortality, and improve the quality of life of children
and their families.

Question 2. Have we made appropriate public investments in
understanding rare childhood diseases?
Answer 2. The NIH spends a substantial amount on research on
various rare diseases, including those affecting children, but with
over 6,000 known rare diseases, not every one has been fully addressed.
Different types of research also are required, including basic,
translational, clinical and natural history studies, which are
essential to understanding the expression of a genetic illness. With
the Rare Diseases Clinical Research Network, the NIH has developed a
model to help move this research forward.

SENATOR HAGAN

Question 1. In your testimony, you mention there are now 29
conditions that States screen newborns for. How many of these are rare
diseases? Is there any effort underway to expand the number of diseases
we screen for? Why or why not?
Answer 1. Newborn screening has the potential to prevent or
ameliorate many serious heritable conditions. The HHS Secretary's
Advisory Committee on Heritable Disorders and Genetic Diseases in
Newborns and Children is responsible for assessing the scientific
evidence on potential conditions eligible for newborn screening and
making recommendations to the Secretary about the addition of such
tests to the 29 (all considered rare by definition) already on the
screening panel that most States have adopted. The committee recently
recommended the addition of Severe Combined Immune Deficiency (SCID), a
rare condition, and the recommendation was accepted by Secretary
Sebelius. Currently under consideration by the committee are severe
critical heart disease and hyperbilirubinemia.
The NIH has supported research for many years that has produced the
evidence necessary to determine the efficacy of screening. One of the
early successes occurred in the 1960s, when NIH-supported researchers
discovered techniques for detecting phenylketonuria (PKU), a metabolic
disorder that was a primary cause of intellectual and developmental
disabilities. PKU, which could be readily treated with dietary therapy
(medical foods), was the first disorder for which newborn screening
became mandatory. While not all diseases detectable through newborn
screening are as manageable, detecting disabling and potentially fatal
conditions provides an opportunity for critical early treatment, often
before an infant shows symptoms of a condition, having a profound
impact on how severe the condition becomes, and improving the quality
of life, usually dramatically, for affected individuals.
In early 2008, the Newborn Screening Saves Lives Act was signed
into law, providing direction to the Secretary's Advisory Committee on
its work, and establishing the Hunter Kelly Research Program within the
Eunice Kennedy Shriver National Institute of Child Health and Human
Development (NICHD). The new law directs the NICHD to support research
to identify, develop, and test promising new screening technologies,
which will lead to the expansion of conditions for which newborn
screening can be done. Along with other Institutes at the NIH, the
NICHD is currently supporting research in newborn screening for spinal
muscular atrophy, Fragile X syndrome, Krabbe disease, and other
conditions.

Question 2. In your testimony, you discuss spinal muscular
atrophy--a terrible disease that is the leading genetic killer of
infants. I met with a family in North Carolina whose 18-month old
daughter was diagnosed with SMA a few months after birth. While she is
progressing like a normal toddler in many ways, she is now confined to
a wheelchair and can no longer sit or roll over on her own. I
understand that NIH through the National Institute of Neurological
Disorders and Stroke (NINDS) has some promising treatments for SMA in
the pipeline. Industry working with advocacy groups has also been
interested in developing therapeutics.
Answer 2. Because the failure rate at each stage of therapy
development is very high for all diseases, the NIH is pursuing multiple
avenues to prime the therapy development pipeline for treatments for
spinal muscular atrophy (SMA). In 2003, the NINDS recognized that
advances in understanding SMA had unlocked the possibility of
rationally developing treatments, and the Institute chose SMA as the
disease on which to test an aggressive new approach to expedite
preclinical therapy development. The SMA Project developed a detailed
drug development plan with the guidance of a steering committee that
included expertise in drug development from academia, industry, and the
FDA. The Project is implementing the plan through a ``virtual Pharma''
organization that engages the expertise and resources to carry out
industry-style drug development via contracts. This allows rapid
response to opportunities as results emerge. The SMA Project is making
encouraging progress, with two patents applied for on new compounds
that show promise against SMA in laboratory models. Advanced
preclinical safety testing of the most promising compounds is underway
with the goal of beginning clinical trials in 2011, and the Project is
also continuing to develop other drug candidates.
The SMA Project is being supported in addition to, rather than
instead of, other therapy development efforts. The NIH supports several
other preclinical therapy development projects for SMA through
investigator-initiated research programs and through SMA-targeted
solicitations. Ongoing projects at the NINDS and the NICHD include
research on gene therapy, stem cells, and drug development. This area
of research received a substantial boost from American Recovery and
Reinvestment Act (ARRA) funds. ARRA-funded projects include Grand
Opportunity (GO) and Challenge grants on gene therapy and on induced
pluripotent stem cells (a type of stem cell derived from adult cells),
as well as research on small-molecule drugs. Industry and patient
voluntary organizations also are interested in working with the NIH on
therapeutics development for SMA. The NIH is supporting substantial
academic-industry collaboration on SMA through an NINDS milestone-
driven therapy development program, and the NIH is convening a meeting
in the fall of 2010 that will bring together the various public and
private groups to discuss SMA therapy development.

Question 3. However, I understand that one of the main obstacles
going forward is identifying a sufficient number of children to
participate in the clinical trial. Can you comment on the Agency's
plans to support the implementation of clinical trials for SMA?
Answer 3. Because therapies for SMA and for several other rare
neurological diseases may be ready for clinical testing in the next few
years, it is important that the NIH be prepared to conduct clinical
trials. Thoughtful selection of the best candidate therapies for
testing is one essential aspect of conducting trials for rare
disorders, and multi-site clinical networks are another important
answer to the need for rapidly recruiting sufficient numbers of
patients. Rather than developing separate clinical networks for each
disease, the NINDS is developing a clinical network that will serve SMA
and other neurological diseases. The program will be open to the best
candidate therapies, regardless of whether they arise from NIH programs
or other sources. For many reasons, this combined network will be not
only more cost efficient but also more effective for SMA and other
diseases. For example, this network will offer expertise in a range of
disciplines, including pediatrics, and provide a breadth of experience
in running clinical trials that will help inform the SMA clinical
research field.

Question 4. Could you also comment on whether SMA could be a
candidate for newborn screening? It seems to me that that might help
identify patients to participate in clinical trials and accelerate
approval of a therapeutic.
Answer 4. The NICHD is currently funding research to pilot test
newborn screening for SMA. While there is no available treatment for
SMA (usually a prerequisite for a Secretary's Advisory Committee
recommendation to add to the newborn screening panel), the NICHD also
is supporting research on potential treatments. As mentioned in an
earlier response above, the NICHD (as well as the NINDS, as described
in the previous response) is cosponsoring an important scientific
conference in October 2010, entitled ``NIH Therapy Development
Conference in SMA.'' The main purpose of this meeting is to review and
address the needs of the research field and the scientific
opportunities for moving forward on the development of SMA
therapeutics.

Response to Questions of Senator Enzi by Alexander J. Silver

Question 1. Do you think that Congress should fund research at the
NIH by specifically providing funds for each disease, or do you think
Congress should provide funds categorized broadly for different types
of research and allow the Agency to allocate those funds based on
research grants that have scientific merit?
Answer 1. I do not believe that Congress should mandate specific
disease research at the NIH. The NIH needs to maintain ultimate
decisionmaking in determining whether research is of high enough
quality to fund. However, given Congress' close relationship with the
American public, it can and should play a pivotal role in promoting
treatments and cures in a timely manner for the devastating diseases
that inflict its constituents. Citizens can advocate for themselves but
also rely on those they elect to do so when needed, especially when
simply caring for a loved one who has a disease consumes all aspects of
life such as Epidermolysis Bullosa (``EB''). For example, when rare
disease research funding composes just a fractional piece of NIH
funding--according to figures provided by the NIH, it provided $118
million in research funds for orphan diseases out of its $30 billion
budget in 2009 or 0.3 percent--even though approximately 10 percent of
the American population suffers from rare diseases, Congress can
highlight this discrepancy and suggest that it be examined.
Furthermore, when private market incentives are not adequate to attract
funding to advance rare disease treatments and cures, Congress should
simultaneously design the correct incentives as well as use all current
tools possible to encourage rare disease treatment and cure
development. In the case of children with EB, parent advocacy coupled
with congressional leadership can lead to a cure.
Another important factor to consider when allocating resources to
fund EB or other orphan disease research is that many medical
breakthroughs impacting a larger group of Americans start with rare
disease research. As I wrote in my testimony, Remicade--which was
developed for the treatment of Crohn's disease, a population of 500,000
people--has been found to effectively treat Rheumatoid Arthritis and
forms of Psoriasis, a population of over 5 million people. Rituxan,
developed for non-Hodgkin's lymphoma--a group of 70,000 people per year
now helps the 1.3 million Americans who suffer from Rheumatoid
Arthritis.
Most recently, the University of Minnesota released the results of
its current stem cell trial for EB; specifically, the procedure
involves transplanting the bone marrow from a donor who can make the
protein needed to adhere the layers of skin together to an individual
who has EB and lacks this protein. The initial results are extremely
promising. Importantly, this is the first time stem cells have been
used to repair skin. The wider implications are potentially enormous--
this could help Americans with burns, diabetic ulcers, wounds or
practically any other skin disorder. Congress can make sure that the
allocation of resources takes both the immediate and bigger pictures
into account. Helping a child with EB also will help other Americans.
While the NIH must maintain autonomy, Congress also must play a
pivotal role in the conversation about the allocation of publicly
funded research resources. If not, telling a child with EB that he or
she needs to wait until we have the perfect incentives in place to help
him or her is equivalent to a death sentence in many cases.

Question 2. What types of treatments are currently available for
your son? How many of them are just to alleviate symptoms?
Answer 2. Currently, the only treatments available, if any, to
those who have EB address the symptoms as they occur. When Jackson, our
son, falls and tears the skin off his palms, we can wrap them with
bandages and hold him through the pain. When the skin in his throat
sheers off from eating, we have to wait days until he starts to drink
and eat again. When Jackson's knee blisters and fills with blood, we
can only lance it with a large needle and painfully compress the blood
out of the wound. When an EB child's fingers and toes fuse, their
parents are powerless to stop their child's lifelong physical deformity
and pain. Children who suffer from EB live in daily agony as their
bodies disintegrate.
There are no approved treatments available that prevent injury or
systematically cure EB. However, researchers know exactly what causes
EB and have extremely encouraging knowledge of how to fix it. The key
factors hindering this dream from becoming reality are sufficient
funding and a streamlined approval process.
As an example of a cure's proximity to becoming a reality, I have
attached the recently published study in New England Journal of
Medicine, a review of the study\1\ and the lead article from CNN on
August 12, 2010 about the stem cell bone marrow transplant study for
children with EB ongoing at the University of Minnesota. As you can
see, the results suggest a cure is within reach. There are more
questions to answer and to do so one needs to conduct more trials. In
order to conduct more trials, one needs more funding. Even with
additional funding, an improved approval process that balances the
safety of treatments and the devastation of EB is necessary to ensure
children are helped before it is too late. In addition to stem cell
therapies, as discussed in my written testimony, protein replacement
and gene therapies are close to the clinical trial stage but again lack
adequate funding and approval in a timely manner. The unifying theme
among all treatments and cures is that they currently only help to cope
with EB's superficial symptoms but it does not have to be this way.
Viable treatments and cures are just a few inches from our fingertips
with the proper support.
---------------------------------------------------------------------------
\1\ The review of the study referred to may be found at
www.nejm.org/doi/pdf/10.1056/nejmoa0910501.

Question 3. Can you provide more detail about the Jackson Gabriel
Silver Foundation? How successful have your fundraiser efforts been?
Are there other EB foundations that you partner with? How do you invest
the funds you have raised?
Answer 3. The Jackson Gabriel Silver Foundation (``JGS
Foundation'') is a recently formed non-profit dedicated to supporting
research focused on curing and treating EB. Given its very recent
Federal approval, the JGS Foundation has not held an official
fundraiser yet. The Foundation plans to hold several major events a
year and has raised over $55,000 without an official campaign in its
few months of existence. We believe the JGS Foundation can become a
significant fundraising vehicle to help children with EB. All funds
raised are kept in FDIC insured checking or savings accounts. Just shy
of 100 percent of every dollar raised is provided to researchers to
advance their work on EB treatments and cures. However, given the small
number of children with EB, raising the funds that are needed to
advance EB treatments and cures to help today's children will not be
possible without both direct and indirect Federal assistance.
I am also a trustee of the Dystrophic Epidermolysis Bullosa
Research Association of America (``DebRA''), which is the largest EB
patient care non-profit in the United States. Within DebRA, my family
and I have raised over $150,000 during the previous 2 years to help
children with EB. The Epidermolysis Bullosa Medical Research Foundation
(``EBMRF'') is the other significant American non-profit focused on
curing EB. The EB community is small; the JGS Foundation, DebRA and the
EBMRF have and should continue to work together to accomplish our
goals.
I estimate that in aggregate, these foundations have raised
approximately $4 million over the last 3 years. To put this in context,
inexpensive clinical trials are in the tens of millions. The cost of a
child to participate in the University of Minnesota stem cell trial is
$1 million. While I do believe the community can and will do a better
job fundraising, we need the leadership of our Federal Government.
Children with EB need both direct Federal support as well as private
market incentives, such as the recently introduced Creating Hope Act of
2010 (refining the rare tropical disease voucher program to include
rare pediatric diseases), if these children are to have a chance of
leading pain free and full lives. While the amount of funding needed to
cure this disease is not small in absolute terms, it is quite small
compared to Federal and private expenditures in every comparison. EB
can be a curable disease and EB research can help other Americans with
wounds and burns lead better lives; we just need to make it a higher
priority.
______

[CNN Article, August 12, 2010]

A Mother's Plea: Heal My Children's Skin

(By Madison Park)

Story highlights
Epidermolysis bullosa is a terminal genetic condition that
causes persistent skin problems.
Patients lose their skin with the slightest friction
because of the lack of a protein.
Bone marrow transplant recipients show improvement in
collagen levels and skin.

For years, Theresa Liao heard there were no cures, no treatments,
no hope to help her son Jake.
``When he was born, his hands looked like they had been boiled in
oil,'' said his mother. ``It looked like someone had taken a potato
peeler and skinned him down to muscle.''
At the slightest friction, Jake's skin would shed, leaving the
newborn wailing in pain. When Jake rubbed his eye, a chunk of his
eyelid would come off in his fingers. He was born with recessive
dystrophic epidermolysis bullosa, a terminal genetic condition in which
persistent skin problems lead to crippling deformities and, eventually,
skin cancer.
Liao's crusade led to the first stem cell treatment for
epidermolysis bullosa, also known as EB.
New research findings, published in The New England Journal of
Medicine this week, show that bone marrow transplants can help repair
wounds and regenerate skin in EB patients. Doctors say it's an
important step in stem cell science.
``I'm not saying this is a cure,'' said co-author Dr. Jakub Tolar,
an associate professor of pediatrics at the University of Minnesota.
``This is a critical step on the road to make this a disease of the
past.''
EB patients lack a protein called collagen 7 that acts as a Velcro,
hooking the layers of skin--the epidermis and the dermis--together.
The transplanted bone marrow contains stem cells that can turn into
skin cells. These new skin cells could produce the missing collagen 7
to stitch the skin layers, gradually healing the blisters and improving
the patient's condition.
The transplant appears to be effective, but doctors don't know
exactly what type of stem cells are responsible for the change.
EB patients have often been called butterfly children, because
their skin is so sensitive. They have also been likened to permanent
second-degree burn victims.
The graze of a diaper can sheer off skin from their waist and inner
thigh. Putting T-shirts over their heads can cut skin off their ears.
In severe cases, children live in the bondage of bandages, like little
mummies, to protect their fragile skin from wounds and infections.
The constant inflammation and blisters can fuse fingers and toes,
creating a webbed look. EB also irritates the lining of the esophagus,
so that many children with the condition get stomach feeding tubes.
The Netherlands allows for euthanasia for patients of this rare
condition. The ones who survive to their 20s usually succumb to skin
cancer.
EB patients require daily bandage changes to protect their skin in
an intensive process that takes about 4 hours. Liao likened it to
``controlled torture.''
For years, Liao, of Princeton, NJ, scoured the Web, and called
companies, dermatologists, hematologists and nurses until one doctor
mentioned that perhaps a stem cell treatment could reboot Jake's entire
body to help him produce the missing collagen.
Liao pounced after learning that Dr. John Wagner, director of
pediatric blood and marrow transplantation and clinical director of the
Stem Cell Institute at the University of Minnesota, would be in New
York for a meeting in 2004. He had a long track record of working on
stem cell and cord blood issues.
Liao approached Wagner with her then-2-year-old Jake in her arms.
Jake had thrown up parts of his esophagus a few days before, and was
still moaning in pain.
``She held him up in front of me and said, `Please, save my child,'
'' Wagner recalled.
The pediatrician was horrified.
He told Liao that he couldn't just start a stem cell treatment--
there had to be animal models, money for research (orphan diseases like
EB are notoriously hard to fund), approval from regulatory bodies, and
he needed to have a track record of treating the disorder. There were
many complicated, time-consuming steps and millions of reasons to
listen politely and walk away.
``Little by little, he tried to avoid me. I kept e-mailing him and
calling him,'' Liao said.
``What affected me more was this mother pleading with me, saying
`You can't say no. Everyone else says no. Everyone else says it's
incurable.' '' Wagner said. ``I was both horrified and feeling horrible
that I can just walk away from this and say, `I'm sorry. I take care of
leukemia patients. I don't want to choose this one.' ''
``My research is developing stem cell-based therapies for kids who
are destined to die. So I deal with many sad cases, but this one is
over the top,'' he said.
Though they had no experience in skin diseases, Wagner and Tolar,
the study co-author, started examining stem cell possibilities for EB.
They implanted several different types of stem cells into mice.
After trial and errors, they eventually found that bone marrow
transplants somehow helped heal wounds and regenerated skin in mice.
In 2007, they started the first human clinical trial with seven EB
patients.
The transplants were risky because they require chemotherapy to
wipe out the recipient's immune system to prevent rejection of the bone
marrow.
Liao knew the risks but said she felt Jake and a younger brother
were ``going to die, relatively painfully and have a difficult
existence'' until passing away from malnutrition or cancer with the
disease.
``Before anyone judges me or my family, I'm not going to ask them
to walk a mile in my shoes, I would say take about three steps,'' Liao
said. ``Somebody had to go first. Somebody had to make a difference.''
By that time, Jake was 5 years old and had a 16-month-old brother,
Nate, who also had EB.
In November 2008, Nate went first in the trial, receiving a bone
marrow transplant from a perfect match--his older brother, Julian.
When doctors examined Nate months after the surgery, the contrast
was striking. Nate was also producing more collagen 7.
``The differences in the way the skin healed, he was very
different,'' Wagner said. ``He gave us hope.''
Seven months later, Jake was patient No. 3 in the trial, receiving
a bone marrow transplant from a cord blood match.
But Jake struggled. Stricken with complications of the transplant
and an infection, he died 183 days after the procedure.
Out of seven children in the trial, two died. The other child had
died in the clinical trial before the transplant. The transplant has
inherent risks, the authors said.
``This is bone marrow transplantation, it's not a trivial
procedure,'' said Dr. Jouni Uitto, professor and chairman of
dermatology and cutaneous biology at Thomas Jefferson University, who
was not part of the study. ``It's a major procedure that has a high
risk component.''
The five participants who survived have all improved. One boy
bought a trampoline and can enjoy activities he never imagined before
the transplant.
``It's an exciting study in the sense it raises cautious optimism
that bone marrow transplantation may be a way of treating the
condition,'' Uitto said.
More research is under way to better minimize risks. Since the
study was published, six more children with EB have received
transplants, and all have shown improvements, doctors said.
Hundreds of EB patients have come to Minnesota hoping to take part.
It's bittersweet for Liao, as she closely monitors Nate's health,
but also grieves for Jake.
``I'm still involved because of Nate. There's a lot more work. I
really want this disease wiped off the planet. It wiped my son off the
planet. It's fair play.''
______

National Organization for Rare Disorders (NORD),
August 19, 2010.
Hon. Tom Harkin, Chairman,
Health, Education, Labor, and Pensions Committee,
U.S. Senate,
Washington, DC 20510.

Dear Mr. Chairman: On behalf of the millions of men, women and
children affected by one of the thousands of rare diseases, the
National Organization for Rare Disorders thanks you for the opportunity
to testify before your committee on July 21, 2010.
Below are the answers to the questions posed by Senators Enzi,
Casey and Franken. Rather than answer each question individually in
some cases, attached please find NORD's testimony before the FDA's Part
15 hearing on June 29, 2010. Frank Sasinowski, who delivered the
statement, is Chair of NORD's Board of Directors. He delivered the
statement before the FDA hearing on ``Considerations regarding FDA
review and regulation of articles for the treatment of rare diseases.''
Respectfully Submitted,
Diane Edquist Dorman,
Vice President, Public Policy.
______

Response to Questions of Senator Enzi, Senator Casey and Senator
Franken by Diane Edquist Dorman

SENATOR ENZI

Question 1. Are existing incentives sufficient to support the
development of therapies for rare diseases? How might these incentives
be improved or increased?
Answer 1. Please see attached document.

Question 2. Some of the incentives available for pediatric and rare
and neglected diseases are stackable--a business can get more than one
for a given product. Do the different programs work well together?
Could they be more coordinated?
Answer 2. NORD agrees with the American Academy of Pediatrics that
``the orphan drug exclusivity provided by the Orphan Drug Act and the
pediatric exclusivity offered by the Best Pharmaceuticals for Children
Act (BPCA) work well together to improve access to safe and effective
drugs for children and patients with rare diseases.
The Orphan Drug Act incentivizes the development of drugs for rare
diseases and BPCA incentivizes the study of drugs in pediatric
populations. Pediatric exclusivity under BPCA is only granted in
response to fulfilling the requirements of a written request issued by
FDA and is not given in conjunction with any other incentive program.
Both incentive programs are necessary and serve distinct purposes.
Whereas BPCA may be used to add pediatric labeling information to a
popular adult drug, the Orphan Drug Act may be used to incentivize the
development of that same drug to treat an entirely different condition
that classifies as a rare disease.''

Question 3. Given the genetic basis of many rare diseases, has the
Human Genome Project helped rare disease research and development of
treatments?
Answer 3. Yes. NORD believes that the National Institutes of Health
has made important strides towards increased research into rare
diseases and the development of treatments for them. The NIH recently
announced the establishment of the Therapeutics for Rare and Neglected
Diseases (TRND) initiative. It was recognized that of the 7,000 human
diseases, fewer than 300 are of interest to the biopharmaceutical
industry, due to limited prevalence and/or commercial potential. More
than 6,000 of these diseases are rare (defined by the Orphan Drug Act
as <200,000 U.S. prevalence), and the remainder are neglected because
they affect impoverished or disenfranchised populations. Researchers
have now defined the genetic basis of more than 2,000 rare diseases and
identified potential drug targets for many rare and neglected diseases
(RND) (http://rarediseases.info.nih.gov/Resources.aspx?PageID
=32).

Question 4. Can you elaborate on striking the correct balance
between the safety and risk of treatments for patients suffering from
rare diseases versus for patients with more common conditions?
Answer 4. Please see attached document.

SENATOR CASEY

Question 1. In your testimony, you talked about how FDA reviews
safety and efficacy data for orphan diseases and say that ``without a
statement of policy on rare diseases and orphan products, it is not
possible [for the FDA] to ensure consistency in that process.'' Can you
elaborate on why this is necessary and what sort of information you
would like to see in such a policy statement? How should such a
statement take children with rare diseases into consideration?
Answer 1. Please see attached document.

Question 2. Can you comment on the balance between public
investment and private investment in finding cures for rare and
neglected diseases?
Answer 2. Unlike patients with conditions that affect very wide
populations, the rare disease community has always taken a pro-active
approach towards rare disease research and the development of orphan
therapeutics. Patients and the organizations and foundations that
represent them attempt to raise small sums of money with the hope of
raising sufficient funds to interest an academic researcher in
conducting the needed basic research on their particular rare disease.
But progress can be very slow. For that reason alone, the rare disease
community is very dependent on the cutting-edge basic and translational
research being conducted at the National Institutes of Health and other
healthcare-related Federal agencies.
In order to move the basic and translational research to actual
treatments, there must be increased coordination of efforts between
Federal agencies, the biopharmaceutical and medical device industries,
as well as patient organizations.
For this reason, NORD is working closely with the NIH, FDA,
academic investigators and industry to find better pathways to orphan
product development. More detailed information is included in the
attachment.
Attached you will find the ORDR Newsletter on Rare Diseases (May
2010) providing information about all programs and initiatives related
to rare diseases within the NIH. NORD is unable to estimate the funding
for these programs.

SENATOR FRANKEN

Question 1. I recently heard about a 14-month old boy who's being
treated at the University of Minnesota. He was ill as an infant, has
intestinal problems, and can't eat normally. He survives with IV
nutrition and an investigational drug that's approved in Germany. This
drug enables him to absorb nutrients so he can survive beyond the age
of 3. At first, his mother's insurance covered the investigational
drug. Then his mom lost her job and his father's insurance refused to
cover the monthly cost of $1,200. The family can't afford the cost and
so this child will stop receiving the treatment, which will lead to
liver disease or liver transplant, and very possibly, his death, even
though the treatment is working for him! This is just not right. What
can we do to encourage insurers to cover treatments in such cases?
Answer 1. Unfortunately, Senator Franken, this scenario is one NORD
hears many times a day. If a therapy is considered ``experimental'' by
insurers, they may refuse to pay for it, leaving patients and their
families few alternatives. When families contact NORD with these types
of situations, we often refer them to the insurance commissioner in
their State, who is sometimes able to intervene. One part of the
solution is increased cooperation between European and U.S. regulators,
and NORD is working with FDA and EMA in Europe to encourage that. Also,
in very serious situations where there is no FDA-approved alternative
for the patient, it may be possible for advocates such as NORD to help
patients obtain life-saving medications through Expanded Access
Programs. FDA has an Office of Special Health Issues that is sometimes
able to help individuals obtain access to investigational drugs. Today,
these scenarios are addressed on a case-by-case basis but it would be
wonderful if insurers could be required to pay when patients face
severe consequences and have no approved alternatives.
______

Attachment 1.--Prepared Statement of the National Organization
for Rare Disorders (NORD)
(presented at the u.s. food and drug administration part 15

PUBLIC HEARING--JUNE 29, 2010)

Good morning. The National Organization for Rare Disorders (NORD)
welcomes this opportunity to be the initial presenter at the FDA's
first public hearing on rare disorder therapies. I am Frank Sasinowski,
Chair of the Board of NORD, and we want to share our views on the FDA's
exercise of its responsibilities for regulating therapies for Americans
with rare disorders.
NORD is the leading advocate for the 30 million Americans with rare
disorders. NORD is justifiably proud of our history as the principle
force behind the effort that culminated in the 1983 Orphan Drug Act.
And, NORD is just as equally proud of our current activities to advance
the interests of Americans who have 1 of 6,000 rare disorders. I only
have time to merely list some of NORD's major initiatives over the past
13 months.

1. NORD organized a full-day Summit on orphan disorders at the
Willard Hotel in May 2009 which was chaired by former FDA Commissioner
Kessler and key participants which included Dr. Janet Woodcock and Dr.
Francis Collins. A summary of this Summit is available on the NORD Web
site.
2. NORD, with the assistance of John Crowley, CEO of Amicus, one of
NORD's Corporate Council members, was responsible for organizing a
Congressional Caucus on Rare and Neglected Diseases this year.
3. NORD was a key player involved in Section 740 of the fiscal year
2010 Appropriations Act (the so-called Brownback/Brown amendment) which
is the impetus for this hearing.
4. NORD suggested and supported that the FDA and the Center for
Drug Evaluation and Research (CDER) establish its first position
dedicated to issues related to the regulation of medicines for those
with rare disorders, and in February FDA created the post of CDER
Associate Director for Rare Diseases.
5. NORD worked for the passage of comprehensive health care reform,
and in particular, those two provisions of vital interest to those with
rare disorders: eliminating pre-existing conditions and eliminating
lifetime and annual insurance caps. To see that what was gained in
Congress is not lost in the courts, NORD is currently participating in
an amicus brief to defend the constitutionality of the health care
reform law.
6. NORD, with the involvement of FDA Commissioner Hamburg and NIH
Director Collins, set up a Task Force on rare disorders in January. In
several meetings at which senior FDA and NIH officials participated,
NORD has explored ways to facilitate the development of therapies for
rare disorders, including holding a series of four focus groups, each
separately meeting with representatives of patient organizations, the
medical and scientific research community, the pharmaceutical industry
and the financial investment community.
7. And, finally, on the seventh day, NORD rested.

Both at the NORD Summit last May and at the NORD Task Force
meetings, including focus groups, NORD has learned much and we want to
share some of those key findings with FDA today.
First, over the 27 years since its enactment the Orphan Drug Act
has proven a resounding success. This is best seen in the over 350 new
medicines for more than 200 different rare disorders approved by FDA
over the first quarter of a century of the law's existence. However,
what NORD learned at its Summit and in its Task Force proceedings is
that there are still about 5,800 disorders for which there are no FDA-
approved therapies. Perhaps most discouraging is that many affected
with these rare disorders do not even see any research being conducted
in their conditions. To NORD, this seems as though the proverbial low
hanging fruit have already been harvested in the first quarter of a
century of the law's existence, while the vast majority of therapies
are currently out of reach of those in need of an FDA-approved
medicine. In sum, much has been accomplished by FDA, by NIH, by medical
and scientific researchers, by the pharmaceutical industry, by the
financial community and by patient advocates in these first 27 years,
but much, much, much, much more beckons each of us to respond to the
needs of those with rare disorders.
Second, how best can each of us respond to those in need of
therapies? As part of the NORD Task Force, NORD--with senior FDA and
NIH officials--in April held a series of four focus groups to listen
and learn what are the barriers slowing or barring the development of
new therapies for rare diseases, especially the 5,800 rare disorders
for which there are no FDA-approved medicines. We had a separate focus
group with each of the four major stakeholders involved in developing
new therapies--the patient community, the academic research community,
the pharmaceutical industry and the financial investment community. In
those Task Force proceedings and at the NORD Summit, we heard many
ideas. Several of those ideas would require new legislation and so
those are beyond the scope of today's hearing.
What we at NORD heard which can be addressed by FDA is the benefit
that would be gained from FDA action on the following two NORD
recommendations:

I. For a clearer, more granular expression of FDA's historic
commitment to exercise flexibility in its review of therapies for rare
disorders; and
II. For an FDA expression of ways to reduce regulatory uncertainty
in the development and review of orphan disorder therapies.

Let's explore each of those.
nord recommendation #i--for an fda statement of policy on fda's

HISTORIC FLEXIBILITY IN REGULATING ORPHAN DRUGS

NORD heard, especially from the investment community and the
pharmaceutical industry, that FDA delivers a consistent, repeated
message that the statutory standards for safety and efficacy are the
same for both rare disorders and prevalent diseases. What is not often
heard is the companion portion that completes that statement which is
that, while the statutory standards are the same, the FDA
interpretation and application of those same standards have
historically been tailored by FDA to the unique facts of each
particular medicine under FDA review. Moreover, there are FDA
regulations and guidances that express this flexibility. In addition,
FDA actions on marketing applications eloquently embrace and express
this concept of flexibility. This exercise of FDA scientific judgment
in applying these statutory standards flexibly to various situations
apparently is not being heard by some of the key stakeholders in this
system.
So, today NORD is asking the FDA to develop and issue a specific
Statement of Policy on FDA's role in regulating therapies for rare
disorders which includes an explanation and affirmation of the FDA's
historic position that FDA flexibly applies the standards of safety and
effectiveness with respect to therapies for those with rare disorders.
What we, NORD, have heard is that the investment community and
pharmaceutical industry may benefit from such a formal, explicit
statement of policy that will encourage investment in, research of and
development of medicines for those with rare disorders, especially for
those 20 million Americans with one of the 5,800 rare disorders for
which there still is not a single FDA-approved therapy.

1. FDA REGULATIONS AND GUIDANCES

A. In responding to the AIDS crisis that was becoming apparent
around the same time that FDA was implementing the Orphan Drug Act in
the mid-1980s, FDA promulgated Subpart E of the IND regulations for
``drugs intended to treat life-threatening and severely-debilitating
illnesses.'' FDA stated that the purpose of Subpart E is,

``to establish procedures designed to expedite the
development, evaluation, and marketing of new therapies
intended to treat persons with life-threatening and severely-
debilitating illnesses, especially where no satisfactory
alternative therapy exists. As stated [in section] 314.105(c)
of this chapter, while the statutory standards of safety and
effectiveness apply to all drugs, the many kinds of drugs that
are subject to them, and the wide range of uses for those
drugs, demand FLEXIBILITY in applying the standards. The FDA
has determined that it is appropriate to exercise the broadest
FLEXIBILITY in applying the statutory standards, while
preserving appropriate guarantees for safety and effectiveness.
These procedures reflect the recognition that physicians and
patients are generally willing to accept greater risks or side
effects from products that treat life-threatening and severely-
debilitating illnesses, than they would accept from products
that treat less serious illnesses. These procedures also
reflect the recognition that the benefits of the drug need to
be evaluated in light of the severity of the disease being
treated.'' (Emphasis added.)

B. The regulation that was referenced in the Subpart E regulation
is section 314.105(c) which even predates the Subpart E regulation and
illustrates again FDA's historic position on applying the same
statutory standards in a flexible way depending upon the circumstances.
Section 314.105(c) states that:

``FDA will approve an application after it determines that
the drug meets the statutory standards for safety and
effectiveness, manufacturing and controls, and labeling. While
the statutory standards apply to all drugs, the many kinds of
drugs that are subject to them and the wide range of uses for
those drugs demand FLEXIBILITY in applying the standards. Thus
FDA is required to exercise its scientific judgment to
determine the kind and quantity of data and information an
applicant is required to provide for a particular drug to meet
them. FDA makes its views on drugs products and classes of
drugs available though guidelines, recommendations and
statements of policy'' (emphasis added).

C. An example of a formal regulatory policy or guidance that
expresses this concept of ``flexibility'' in FDA's application of the
statutory standards of safety and efficacy is seen in the ICH E1A
guidance. That FDA-adopted international guidance stipulates the
minimum quantum of safety exposures necessary for FDA to even accept a
marketing application for review when the medicine is intended for a
chronic condition. Most rare disorders are chronic in nature and not
acute, and so this guidance applies to most rare disorder therapies.
The guidance states that the minimum number of safety exposures to meet
the statutory standard for safety are 1,500 persons exposed to the
investigational therapy with 300 to 600 of those exposed for at least 6
months and with at least 100 exposed for 1 year. However, the guidance
states that these minimum safety thresholds do not apply to therapies
for rare disorders. Importantly, the guidance then does NOT state what
is required in the alternative whereas it could have stated an
algorithm such as at least 1 percent of the U.S. population with the
rare disease must be exposed with half of them for at least 1 year. No,
instead the guidance relies upon the exercise of FDA's scientific
judgment to determine what is appropriate to meet the statutory
standard for safety in each particular rare disorder therapy.

2. fda actions on rare disorder therapy marketing applications
Instead of reviewing many such precedents, NORD refers to but one
recent example as illustrative. In March of this year, FDA approved
Carbaglu for NAGS deficiency, the rarest urea cycle disorder, with only
10 patients in the United States generally at any time. In the FDA
briefing document for the January 13, 2010 Advisory Committee meeting,
FDA explained that while Congress in 1962 added a new statutory
standard requiring that a drug prove its effectiveness,

``FDA has been FLEXIBLE within the limits imposed by the
congressional scheme, broadly interpreting the statutory
requirements to the extent possible where the data on a
particular drug were convincing . . . Thus, evidence obtained
from retrospectively reviewed case series could be considered
as substantial evidence of effectiveness . . . The fact that
the case series presented in this application is retrospective,
un-blinded, and uncontrolled precludes any meaningful formal
statistical analyses of the data. Under these conditions, any
statistical inference from confidence intervals and/or p-values
is uninterpretable and, consequently, should not be utilized to
inform clinical decisionmaking.'' (See pages 9 & 10 of the
briefing document attached to Dr. Griebel's December 16, 2009
memo to the Advisory Committee, emphasis added.)

3. dr. goodman's june 23, 2010 statement to congress
Dr. Jesse Goodman, FDA Chief Scientist and Deputy Commissioner for
Science and Public Health, testified last week before the Senate
Appropriations Committee Agriculture Subcommittee on ``FDA's efforts on
rare and neglected diseases.'' In Dr. Goodman's commendable testimony
he cites to the Carbaglu example as well as several others to
illustrate that:

``FDA is fully committed to applying the requisite
FLEXIBILITY in the development and review of products for rare
diseases, while fulfilling its important responsibility to
assure that the products are safe and effective for these
highly vulnerable populations. There are numerous examples of
drugs approved for treating rare diseases where FDA's
FLEXIBILITY and sensitivity to the obstacles of drug
development for rare diseases has brought forth a successful
treatment'' (emphasis added).
4. personal example from meeting this month with fda
In a meeting I had this month the FDA told the sponsor at an End of
Phase 2 meeting for a therapy to treat a very troublesome symptom of a
very serious and common (that is, prevalent) disease that the sponsor
had not only to prove the effectiveness of the drug to treat the
symptom but also had to rule out that the drug did not increase
unacceptably the risk of death in that patient population with this
serious disease. FDA stated that the sponsor would have to show what
increase in the risk of death could be excluded by reference to the
upper 95 percent confidence interval. While we did not at that meeting
arrive at an agreement on the size of the magnitude of risk that had to
be excluded, even ruling out only a doubling of the risk of death would
likely require a study of thousands of subjects for a long period of
time. While I have been involved in scores, maybe hundreds, of
therapies for rare disorders, I have never heard FDA express a similar
requirement for a therapy for a rare disease. Why? This is likely
because FDA is being flexible in interpreting and applying the
statutory standards for safety and efficacy in that FDA knows that to
require a similar type of showing for a therapy for a rare disorder
would be impossible for almost all orphan drugs given the limited pool
of potential subjects for clinical trials. The statutory standards are
the same both for the prevalent disease and the orphan condition, but
FDA rightly interprets and applies the standards in light of the
disease and investigational therapy.
In other areas FDA can exercise similar flexibility. For instance,
where the potential number of subjects is limited, the degree to which
FDA demands dose selection be optimized in pre-approval studies may be
reduced as can be FDA's requirements for validation of a patient
reported outcome instrument in a rare disorder population or proof of
the sensitivity, specificity and clinical meaningfulness of a primary
endpoint. Given that each investigational therapy for a rare disorder
will present unique features, NORD understands that the granularity of
the requested statement of policy on rare disorder therapies may
necessarily be limited. However, even cataloging the nature and scope
of the orphan product precedents that illustrate FDA's flexibility may
enable key stakeholders to better understand FDA's position. That is,
even while FDA states correctly that the statutory standards are the
same for prevalent and rare conditions, FDA will have a formal
companion statement of the equally important and consistent FDA
historic position that FDA will exercise its scientific judgment to
interpret and apply those statutory standards in a flexible manner,
tailored to each rare disorder therapy.
NORD looks forward to the FDA issuance of an FDA Statement of
Policy on FDA's regulation of therapies for rare disorders and to the
day when every FDA official who speaks to patients or to other
stakeholders, including researchers and sponsors, about the FDA
policies on regulating therapies for rare disorders does so in the
complete and balanced way that Dr. Goodman did last week when he
testified to both that as to the identical statutory standards that
rare disorder therapies must meet as well as to the historic FDA
flexibility in interpreting and applying those standards, exercising
FDA's scientific judgment in light of the particular circumstances of
that unique rare disorder and specific investigational therapy.

NORD RECOMMENDATION #II--REDUCING REGULATORY UNCERTAINTY IN THE
DEVELOPMENT OF MEDICINES FOR RARE DISORDERS

In addition to the willingness of persons with rare, serious
diseases to accept more safety risks and less rigorous evidence of
effectiveness than for a prevalent disease or for a less serious
disease or for one with some already approved therapy, and in addition
to learning that some key stakeholders would benefit from a formal FDA
statement of policy on FDA's exercise of its flexibility, the other
consistent message we at NORD learned from our research and
interactions since the NORD Summit in May 2009 is that the development
of therapies for rare disorders could additionally benefit from a
reduction in regulatory uncertainty.
It is axiomatic that the perfect is the enemy of the good. In the
world of rare disorders, there is much that is often not known or not
known well, starting with the etiology and pathophysiology of the
condition, including its natural history, and ranging to a lack of
agreement among even a small handful of world experts on the most
common clinical manifestations of some conditions. Against this
backdrop, it is entirely understandable that FDA on occasion will find
it difficult to concur in advance with a development program, even the
design of a registrational trial under a special protocol assessment.
However, researchers, industry and FDA, as well as most importantly,
persons with the condition, may find that sometimes a study needs to
proceed because patients are suffering and can not wait for the perfect
trial design with the ideal primary endpoint to be eventually
determined or developed and consensually accepted.
Research resources in the universe of rare disorders are precious,
with the most precious being the persons with the rare disorders who
are heroically volunteering to participate in a trial, usually under
conditions where there is less known than in trials of therapies for
prevalent diseases about the safety and potential effectiveness of the
investigational therapy from animal models, animal toxicology and early
human trials. So, when these trials are conducted, sometimes with
designs with which all parties may not be in full concurrence,
including the FDA, great deference should be afforded the design of
these trials and flexibility applied in the interpretation of their
results. If such a principle were to be addressed and accepted by the
FDA, much good would come of it.

CLOSING

On behalf of all those with rare disorders, NORD commends the FDA
on its stellar, worldwide leadership role on orphan product issues for
the past 27 years, and NORD exhorts FDA to continue to embrace even
more fully the historic flexibility FDA has long noted and exercised in
FDA's regulation of medicines for those Americans with rare disorders
and to grapple with ways that can be managed by FDA to reduce the
regulatory uncertainty in the development and review process.
NORD commits to do all it can to continue to provide input to FDA
on matters related to FDA's vital responsibilities for the regulation
of investigational therapies for each of the 30 million Americans with
rare disorders, but especially for those more than 20 million who have
the 5,800 rare disorders for which there are no current FDA-approved
therapies.
Finally, NORD would like to publicly and formally express NORD's
deep appreciation to the FDA for holding this hearing today on these
critically important issues to so many Americans.
Thank you.

Attachment 2.--Office of Rare Diseases Research Newsletter
Focus on Rare Diseases--Highlights

RARE DISEASES CLINICAL RESEARCH NETWORK (RDCRN II) UPDATE

In the fall of 2009, the NIH Office of Rare Diseases Research
(ORDR) in collaboration with seven NIH Institutes (NICHD, NHLBI, NIDDK,
NIAMS, NINDS, NIDCR, and NIAID) renewed and expanded the RDCRN Program.
The level of support received from the ICs (institutes and centers) has
increased, and in the expanded RDCRN (called RDCRN II) ORDR was able to
provide support for 19 consortia. The Data and Technology Coordinating
Center has been continued in RDCRN II as the Data Management
Coordinating Center with a slightly different charge. In RDCRN II, 56
Patient Advocacy Groups (PAGs) are participating and collaborating in
the clinical studies of more than 90 rare diseases at over 130 research
sites. The first Steering Committee and Orientation Meeting for the
Principal Investigators (PIs) was held on October 1-2, 2009. This
meeting was also attended by PAGs, co-PIs, and relevant program staff
from the ICs.
Below is a link to the NIH press release about the expansion of
Rare Diseases Clinical Research Network. http://www.nih.gov/news/
health/oct2009/od-05.htm.

COLLABORATION, EDUCATION, AND TEST TRANSLATION PROGRAM FOR RARE GENETIC
DISEASES (CETT)

People affected by rare inherited diseases need the reliable
information that comes through quality genetic testing. The goal of the
CETT Pilot Program is to help facilitate the translation of new tests
for rare genetic diseases. The program's objectives are to translate as
many appropriate tests as possible, ensure that the best possible test
is offered in light of current knowledge, and ensure that the test
meets the needs of the community. All tests are important whether the
specific condition affects 5 people or 50,000.
The CETT Pilot Program's objectives require a strong collaboration
between researchers, clinicians, patient advocates and clinical
laboratories. The program has several new enhancements to facilitate
the development of collaborations, researcher consultation, and
educational materials. The program also supports the electronic
collection of genetic and clinical data in public databases to
accelerate access to the information for new research and treatment
possibilities.
Discussions are underway to determine the future function of this
pilot program and how to move it to permanent status within the NIH to
best serve the public. For more information, please visit: http://
rarediseases.info.nih.gov/cettprogram/about.aspx.

NIH UNDIAGNOSED DISEASES PROGRAM

The National Institutes of Health (NIH) launched the Undiagnosed
Disease Program (UDP) in May 2008 to evaluate patients with disorders
that have evaded a diagnosis. Often such patients, seek help from
multiple physicians and other health care providers over many years
before a diagnosis is made. The UDP has been organized by the National
Human Genome Research Institute (NHGRI), the Office of Rare Diseases
Research (ORDR), and the NIH Clinical Center. The program's main goals
are to provide answers to patients with mysterious conditions that have
long eluded a diagnosis and to advance medical knowledge about rare and
common diseases.
By all accounts, the program has been successful. More personnel
have been hired and funding has been increased. Over the year and a
half since its inception, there have been more than 3,000 inquiries,
more than 1,200 medical records submitted, 300 patients accepted, and
about 220 of these patients seen so far at the NIH Clinical Center in
Bethesda, MD. It is interesting that over half of the applications fall
into the realm of neurology. As an indication of the seriousness of the
illnesses for which patients are applying, 13 who have applied have
died, most before they could be seen at the Clinical Center. There have
been 5 to 10 true diagnoses made. In one of these, a family with
arterial calcifications of the lower extremities, a causative mutation
was found in a gene not known to be involved in any other disease. The
UDP provides both diagnostic support and new insights into rare
diseases.
Additional information can be found at: http://
rarediseases.info.nih.gov/Resources
.aspx?PageID=31.

THERAPEUTICS FOR RARE AND NEGLECTED DISEASES (TRND) PROGRAM

Both the need and opportunity for Therapeutics for Rare and
Neglected Diseases (TRND) are enormous. Of the 7,000 human diseases,
fewer than 300 are of interest to the biopharmaceutical industry, due
to limited prevalence and/or commercial potential. More than 6,000 of
these diseases are rare (defined by the Orphan Drug Act as <200,000
U.S. prevalence), and the remainder are neglected because they affect
impoverished or disenfranchised populations. Researchers have now
defined the genetic basis of more than 2,000 rare diseases and
identified potential drug targets for many rare and neglected diseases
(RND).
TRND received $24 million in the NIH budget for fiscal year 2009.
TRND is a collaborative drug discovery and development program with
governance and oversight provided by Office of Rare Diseases Research.
Program operations will be within the intramural research program
administered by the National Human Genome Research Institute.
For more information, please see the Program to Advance Development
of Drug Candidates for Rare and Neglected Diseases Request for
Information (RFI) Web page: https://www.fbo.gov/spg/HHS/NIH/NHLBI/
NHLBI-NHGRI-2010-112/listing.html .

CREATING A GLOBAL RARE DISEASE REGISTRY

In January 2010, the Office of Rare Diseases Research (ORDR)
organized a workshop, Advancing Rare Disease Research: The Intersection
of Patient Registries, Biospecimen Repositories, and Clinical Data, to
discuss the development of an infrastructure for an internet-based rare
disease patient registry, which would also include access to
biospecimens. The workshop was sponsored by ORDR and the National Eye
Institute (NEI), the National Center for Research Resources (NCRR),
patient advocacy groups, and the private sector. Workshop attendees
discussed approaches to creating a federated registry that would
collect and aggregate patient data, serve as a core data repository and
also link to other existing registries. This would allow expanded data
access for patients, families, clinicians and researchers seeking
accurate information. As an additional aid to research, the registry
would also link to biorepositories of rare disease biospecimens.
During the presentations and breakout sessions, attendees
representing advocacy groups, researchers, information technology
experts, and government and private sector personnel dealt with issues
related to this umbrella infrastructure. Workshop attendees expressed
an enthusiasm and a commitment to getting involved and making it
happen. Post workshop committees will guide the effort as it moves
forward.

NIH ANNOUNCES GENETIC TESTING REGISTRY

The NIH announced on March 18 that it is creating a public database
that researchers, consumers, health care providers, and others can
search for information submitted voluntarily by genetic test providers.
The Genetic Testing Registry aims to enhance access to information
about the availability, validity, and usefulness of genetic tests. For
more information please see: http://www.nih.gov/news/health/mar2010/od-
18.htm.

NIH BIOSPECIMEN INTEREST GROUP

On Thursday, April 15, 2010, the NIH Biospecimen Interest Group
(BIG) held a meeting that featured a series of presentations on
biospecimen resources within and supported by the NIH. BIG is sponsored
by the Office of Rare Diseases Research and the Office of
Biorepositories and Biospecimen Research, National Cancer Institute
(OBBR/NCI).
The event, which took place in the Masur Auditorium in the Clinical
Center, was well attended, and the attendees found it very informative.
The interest group offers a forum for trans-NIH interactions and
enhanced information sharing. Members were asked to share ideas for
future meetings. The meeting included the following presentations:

``The NIDDK Central Repositories''
``eyeGENE (NEI) Genotype/Phenotype Database, Repository and
Registry''
``Tissue Biospecimens in Cancer Epidemiology Studies"
``The National Cancer Institute's Cooperative Human Tissue
Network''
``BioLINCC: Access to NHLBI Biospecimens and Data''

The event was videocast and is available for viewing. (http://
videocast.nih.gov/summary.asp?live=8662)
vi international conference on rare diseases and orphan drugs in buenos

AIRES (ICORD 2010)

A global meeting on international cooperation and policies for rare
diseases and orphan products was held in Buenos Aires, Argentina on
March 18-20, 2010. The VI International Conference on Rare Diseases and
Orphan Drugs (ICORD 2010) convened for the first time in the southern
hemisphere in agreement with its aim of globalization of rare diseases
research and orphan products development activities.
Individuals and organizations from patient groups, academic
research investigators, the pharmaceutical, biotechnology and medical
device industries, and government policy and decisionmakers were
invited to participate in this unique forum. Specialized courses, and
open meetings with key people in the field were available for
participation during the days previous to the conference (March 16 and
17), as well as a pre-meeting about the Latin American and Caribbean
initiatives (ER2010LA) in rare diseases and orphan products.
Because of its nature, rare diseases would be better researched and
managed within an international landscape, and this conference offered
the opportunity to join the discussion of the ideas and global needs of
the rare diseases community. The economic impact of introducing new
therapies and how cooperative strategies may influence the cost of
these treatments was a special topic along with the special
informational and individual needs of the patients and families across
the lifespan. Also of interest were the particular needs of the
developing world in the management of diseases that are rare in
developed countries but neglected in the environments where the
diseases occur more frequently.
GEISER Foundation, the first non-profit umbrella organization for
rare diseases in Latin America and the Caribbean hosted the conference
and the pre-activities. Information about the conference is found on
the ICORD 2010 conference Web site. (Presentations will be available
later on www.icord.se). GEISER Foundation on the web: http://
www.fundaciongeiser.org.

INTERNATIONAL COLLABORATIONS: JAPAN AND KOREA

The Office of Rare Diseases Research held two meetings in early
2010 with overseas visitors interested in rare diseases research and
orphan products development. The first meeting took place in January
with visiting scientists from the Japanese Ministry of Health, Labour
and Welfare and the National Institute of Public Health. The second
meeting was held in February with scientists from the Korean National
Institute of Health, Sungkyunkwan University and Seoul National
University.
The NIH agenda topics included:

Genetic and Rare Diseases Information Center (ORDR)
Undiagnosed Diseases Program (NIH: ORDR, Clinical Center,
Institutes)
Clinical Trials.gov (NIH)
Therapeutics for Rare and Neglected Diseases Program
(NHGRI)
Rare Diseases Clinical Research Network (ORDR, Institutes)
Genetic Test Translation Program (CETT/ORDR)
Clinical Center programs and protocols
Clinical and Translational Science Awards, Clinical
Research Network Program (NCRR)
Office of Orphan Product Development (FDA)

Presentations were also made by the Japanese and Korean visitors
describing their health and research organizations, and their research
and product development activities. The meeting agendas allowed ample
opportunity for discussion following each talk. ORDR also included a
presentation on an educational module on rare diseases designed for
middle school students, which when completed, will be available at no
expense not only in the United States but also to other countries for
their use.
The NIH and other U.S. presenters and the Japanese and Korean
presenters agreed that their meeting was successful in advancing
communication, sharing knowledge, and stimulating potential research
collaborations in rare diseases research and orphan products
development.

SCIENCE OF SMALL CLINICAL TRIALS COURSE

``The Science of Small Clinical Trials,'' a course created jointly
by the FDA's Office of Orphan Products Development (OOPD) and NIH's
Office of Rare Diseases Research, deals with issues concerning the
design and analysis of clinical trials based on small study
populations. While small clinical trials are a necessity in the context
of rare diseases, being able to conduct small trials with scientific
rigor is of increasing importance in other contexts, particularly as
genomic science begins to provide opportunities for individualized
pharmacology. Over 1,500 individuals requested for the course. http://
small-trials.keenminds.org/http://videocast.nih.gov/PastEvents
.asp?c=88.

RARE CANCERS WITH HIGH MORTALITY: CHALLENGES FOR CANCER PREVENTION
AND TREATMENT

Recently a workshop, Rare Cancers with High Mortality: Challenges
for Cancer Prevention and Treatment, was held to discuss the issues and
challenges associated with rare cancers and to facilitate
collaborations among the participants. Approximately 200 participants
including scientists, clinicians, industry, government, and patient
advocates met for the workshop.
The day and a half workshop was structured with plenary sessions
for the first half-day followed by three Breakout Groups for
facilitating discussions among the participants. The Breakout Groups
were divided into the following areas: (A) Building a Knowledge Base--
Biology, Epidemiology, and Etiology; (B) Facilitating Clinical Studies
in Rare Cancers; and (C) Development of New Detection, Prevention
Methods/Strategies, and Therapies. On the second day, the moderators of
each Breakout Groups presented a summary for discussion to all
participants.
All three Breakout Groups identified similar issues and challenges
in the study of rare cancers and common themes for addressing these
challenges. This report outlines the outcome of this workshop and the
recommendations provided by the participants of this workshop: http://
rarediseases.info.nih.gov/RARE_CANCERS_
WORKSHOP/.

RESEARCH CHALLENGES IN CNS MANIFESTATIONS OF INBORN ERRORS
OF METABOLISM WORKSHOP

On December 7 and 8, 2009, the Office of Rare Diseases Research,
the National Institute of Neurological Disorders and Stroke and the
Food and Drug Administration's Center for Drug Evaluation and Research,
Division of Gastroenterology Products, hosted a workshop on the central
nervous system (CNS) and inborn errors of metabolism, Research
Challenges in CNS Manifestations of Inborn Errors of Metabolism. More
than 150 participants attended the meeting to discuss the barriers to
the development of therapies for central nervous system disease in
inborn errors of metabolism (IEM). The conference focused on the
challenges in clinical translation including the regulatory
requirements to move from preclinical to the clinical stage of research
and development, consideration of specific clinical trial design for
rare diseases, the identification of appropriate outcome measures for
evaluation of interventions, and ethical issues related to the
investigation of products for these diseases.
Additional meeting information can be found at: http://
www.rarediseases.info.nih
.gov/Inborn_Errors_Metabolism/AddContact.aspx.

OPSOCLONUS MYOCLONUS SYNDROME (OMS) WORKSHOP

The Opsoclonus Myoclonus Syndrome (OMS) Workshop was held on April
10, 2010 at the Westin Harbour Castle in Toronto, Canada. Approximately
35 researchers, patient advocates, and industry representatives from
seven countries met along with several NIH representatives to discuss
issues of importance to the OMS community, including the differences
between pediatric OMS and adult onset OMS, therapeutic strategies in
the United States and Europe, diagnostic criteria, current research
activity and future directions. It was felt that there was enough
agreement in several areas that consensus documents could be drafted.
It is hoped that another OMS conference can be scheduled in
approximately a year both to leverage the momentum from the first
meeting into real collaborative progress in the OMS community and to
fit better with the biennial meetings held in Europe. http://
rarediseases.info.nih
.gov/oms_workshop/.

ORDR SCIENTIFIC CONFERENCE PROGRAM

ORDR collaborates with Institutes, Centers, and Offices at NIH to
stimulate rare diseases research by cosponsoring scientific conferences
where research is lagging or to take advantage of scientific
opportunities. In 2009, ORDR co-supported over 90 conferences. This
year, ORDR will co-support up to 50 conferences.
Since the program inception in 1995 ORDR has co-supported almost
1,100 conferences. For more information please visit http://
rarediseases.info.nih.gov/Scientific_Conferences.aspx.

ABOUT ORDR

The Office of Rare Diseases Research (ORDR) was established in 1993
within the Office of the Director of the NIH, the Nation's medical
research Agency. Public Law 107-280, the Rare Diseases Act of 2002,
established the office in statute. The goals of ORDR are to stimulate
and coordinate research on rare diseases and to respond to the needs of
patients who have any one of the almost 7,000 rare diseases known
today.
Definition of rare diseases: (Orphan Drug Act as amended in 1984 by
P.L. 98-551 to add a numeric prevalence threshold to the definition of
rare diseases.)
``. . . the term, rare disease or condition means any disease or
condition which (a) affects less than 200,000 persons in the U.S. or
(b) affects more than 200,000 persons in the U.S. but for which there
is no reasonable expectation that the cost of developing and making
available in the U.S. a drug for such disease or condition will be
recovered from sales in the U.S. of such drug.''

Response to Questions of Senator Enzi by John F. Crowley

Question 1. Your industry is among the most innovative there is. I
think when it comes to incentives for innovation in the area of rare
and neglected diseases, we should take an ``all of the above''
approach, and try a variety of different mechanisms to encourage
innovation. Can you weigh for me the pros and cons of different types
of incentives, including prize funds?
Answer 1. I agree completely regarding an ``all of the above''
approach relative to utilizing a variety of mechanisms to encourage
continued innovation and entrepreneurship in the biotechnology and
biopharmaceutical industries to develop medicines and devices to
satisfy unmet medical need amongst those suffering from rare and
neglected diseases.
One of the key intentions of the Orphan Drug Act of 1983 was to
encourage innovation in our industry by providing extended patent
exclusivity and tax incentives to foster a new market dynamic. At this
point now 27 years later, we need to reassess existing mechanisms, and
to put in place a new series of incentives that will foster the risk
taking and capital investments from private industry to develop a whole
new generation of medicines to treat a range of rare and neglected
diseases. Some possible mechanisms to consider include:

The Therapeutic Discovery Project Tax Credit of $1 billion
as provided in the Patient Protections and Affordable Care Act (PPACA)
was a first step, utilizing tax credits intended to encourage
investments in new therapies to prevent, diagnose and treat acute and
chronic diseases by companies with 250 or fewer employees. The
potential ``con'' to this is having the greatest number of potentially
eligible applicants benefit from the funds rather than focusing on
scientifically innovative projects. The final HHS/Treasury process may
potentially dilute the funds allocated; reducing the likelihood of any
particular project being awarded the resources it needs to have a
significant impact. This tax grant program should be considered for
extension and expansion beyond the current allotted 2009 and 2010
credits/grants to the extent that it can leverage private capital and
provide meaningful capital through the tax credit mechanism.
Investment tax credits for angel and venture capital
investors can provide incentives for those whose participation early on
in the drug development process is essential to getting start-ups off
the ground and compound identification and similar early drug discovery
projects initiated. Capital markets have dried up in recent years and
IPOs are no longer options for most biotechs. Investment tax credits
could facilitate risk and encourage these important investment dollars
early in the process, rather than later where they now are.
R&D tax credits for drug discovery companies should become
permanent, as an ongoing incentive. The United States has fallen behind
because of foreign tax havens that other nations offer to attract drug
manufacturing.\1\
---------------------------------------------------------------------------
\1\ Gone Tomorrow? A Call to Promote Medical Innovation, Create
Jobs, and Find Cures in America, Prepared for The Council for American
Medical Innovation, June 10, 2010.
---------------------------------------------------------------------------
SBIR--Small Business Innovation Research (SBIR) program grant
eligibility rulings need to be changed, reverting to pre-2001
definitions. Current requirements prevent small businesses that receive
venture capital investment in excess of 50 percent from qualifying for
these grants. SBIR eligibility should be restored to businesses reliant
on VC financing. Both the House and Senate have passed a series of
short-term extensions of SBIR in the past year, but no final
reauthorization of the bill has been reached. It is again before the
current Congress and should be passed this session.

Question 2. In the late 1980s and early 1990s, Europe was approving
new medicines faster than the United States. The medical product user
fee programs turned that around, but I am hearing that the pendulum is
swinging back the other way. Now that we have a solid foundation, what
can we learn from the incentives in place in Europe?
Answer 2. In the 1990s, national drug approvals, in general were
taking variable lengths of time in Europe and there were rigid review
clocks associated with these (perhaps the models for today's PDUFA
clocks). Sponsors could seek approval in the EU nationally, by using
the mutual recognition (decentralized) procedure or by using the
centralized procedure. While the national route is now obsolete and
there is the common EU route, a unified approval is not synonymous with
unified access. Market availability of a medical product, i.e.,
reimbursement, is still very much determined on a country-by-country
basis. Today, the rare disease community is advocating for ``no
borders'' when it comes to accessing diagnoses and medical care at
centers of excellence across countries. However, with diagnosis in one
EU country, access to an approved drug is not guaranteed in another.
In terms of the pendulum swinging, PDUFA has been widely credited
as an innovative program that has strengthened FDA's capacity to
evaluate expeditiously and efficiently the safety and effectiveness of
new drugs and biologics, thereby making needed new safe and effective
therapies available to patients in a timely and responsible fashion.
However, recent FDA review data suggests that the Agency has been
struggling to complete reviews in a timely manner. This drop in
performance may be due in part to a lag in recruitment that coincided
with additional workload from implementation of the FDA Amendments Act
of 2007, but also calls for a thoughtful evaluation of the Agency's
human drug review processes. Patients deserve a clear and predictable
drug review process that is science-based, judicious, timely and one in
which they can have confidence. We look forward to working with FDA and
Congress to continue to strengthen the new drug review process and
refocus on the original intent of the program: to provide the FDA with
adequate resources to fulfill its essential public health mission of
assuring the safety and effectiveness of new medicines.
Lastly, the quality and completeness of sponsors' marketing
applications matters in both the United States and in Europe. Sponsors
across the board would serve themselves well by submitting well-
written, high quality applications. Seeking and applying guidance from
the regulatory agencies throughout the process is important and can
help with this.

Question 3. Some have proposed a new division within FDA to
evaluate therapies for rare diseases. While I think this approach has
merits, I wonder if one set group could ever have the necessary
expertise to address the thousands of rare diseases we hope to treat.
Would a ``swat team'' approach where experts from other parts of the
Agency are brought together on an as-needed basis be more efficient?
Answer 3. A new division within the FDA dedicated to evaluating
therapies for rare diseases is essential. One, discrete review division
comprising expertise in rare diseases will enhance the Agency's ability
to follow an orphan drug product application from its earliest stages
through clinical trial design and implementation, data evaluation and
final review and approvals. Organizing the best and brightest from rare
disease science and medicine will result in a concentrated think tank
that can establish its own organizational alignment, but not function
within a vacuum. It will have an assembly of those who best understand
myriad scientific and clinical elements of disease, drug development,
trial design and analysis. And with time and a multitude of reviews,
that collective body of knowledge will enhance as it progresses. Should
additional knowledge or perspectives be needed, those can be drawn upon
from elsewhere within NIH or from outside academic or medical
institutions to augment a particular review process on an ad hoc basis,
as the exception, however, rather than the norm.
Currently, the Office of Orphan Product Development (OOPD) has
limited long-term effect on any particular rare disease once an orphan
designation is granted to a product. That product, and its potential,
is handed back to the applicant; there is no direction or strategy
beyond designation. OOPD staff become involved in the FDA review
process only upon request and on a consultative basis. Presently,
orphan product reviews are assigned across different review divisions
at FDA. Expertise for particular rare diseases can build, during the
course of a product's clinical trials and review period, if that
disease assignment has been with a particular division for a while, and
if a disease has more than one product indication under review.
However, division assignments change and a group that reviews programs
for a particular disease may be moved off that disease within just a
couple of years' time. Staff turnover within these divisions also has
been a significant hindrance. Expertise often leaves with those
employees, necessitating training anew and impeding progress. Within
the framework of one rare disease division, clear career development
could be established, thereby attracting and retaining the talent that
can both establish and evolve the evaluation process to most
efficiently bring safe and effective treatments to satisfy unmet
medical needs.

Question 4. You use the term venture philanthropy in your
testimony. This is a new concept to me, and I'd like to learn more. How
does venture philanthropy compare to venture capital endeavors?
Answer 4. Venture philanthropy initially applied to efforts that
brought business or venture-oriented systems and processes to nonprofit
organizations in the social service sector. Some examples of this
concept include Venture Philanthropy Partners in Washington, DC, Social
Venture Partners, throughout the United States, and the Acumen Fund.\2\
Now, more frequently, the term describes the efforts of patient
advocacy and other nonprofit disease organizations to fund research and
development in the commercial sector. It also refers to the activities
by these advocacy groups who use business models to organize their
activities.
---------------------------------------------------------------------------
\2\ Venture Philanthropy: An Emerging Source of Capital for Drug
Discovery and Development, Timothy Coetzee, Ph.D., Executive Director,
Fast Forward, LLC, December 2008.
---------------------------------------------------------------------------
They have taken more aggressive postures because they are
frustrated with the typical pace of translational research in their
respective disease areas. This is increasingly the case in the rare
disease field, where the risk/reward profile for orphan product
development is often viewed as a disincentive by the capital markets.
In addition to their obvious passion for change, these venture
philanthropists bring their financial resources, extensive disease
knowledge, access to patient communities, and sometimes early registry
data that emerging companies may not have. Venture philanthropists
usually come in to the process at the second state of preclinical drug
development: between drug discovery that often occurs at NIH and other
academic institutions when a large number of candidates are identified,
but before the clinical trial stage when the number of drug candidates
has been narrowed to the select one or few and the capital markets and
larger pharmaceutical companies' are ready to become involved. This
translational research stage of ``valley of death'' has experienced a
dearth of momentum and health venture philanthropy fills some of the
void. We need to find additional ways to fill that void.
The funding models used vary, and range from fairly straight
forward grants or sponsored research agreements to convertible loans by
private foundations, to equity arrangements that include company stock
or royalties. Grants or research agreements can run from under $100,000
to upwards of $50 million, or in the case of the Cystic Fibrosis
Society (CF) and Vertex Pharmaceuticals, more than $100 million back in
the middle of the last decade. Around that same time period, the
Leukemia and Lymphoma Society allocated $3.5 million to Aegera for drug
development and the ALS Association committed the same amount to
Cambria Biosciences. In 2008, CF Foundation Therapeutics, Inc., the
nonprofit affiliate of the CF Foundation, expanded its collaboration
with PTC Therapeutics by committing an additional $25 million in
support of the company's Phase 2 trials.

Response to Questions of Senator Enzi and Senator Casey by Suerie Moon

SENATOR ENZI

Question 1. My colleague here on the committee, Senator Brown, was
involved in the development of an innovative incentive for developing
therapies for rare and neglected diseases. Do you feel this type of
non-exclusivity incentive is sufficient to entice more and bigger
industry players into developing treatments for rare and neglected
diseases?
Answer 1. The Priority Review Voucher (PRV) is one mechanism to
stimulate R&D for neglected diseases.\1\ While the PRV has the
potential to increase innovation for rare and neglected diseases, an
array of complementary policies is necessary to ensure effective and
affordable new product development for neglected diseases, and the PRV
is unlikely to be sufficient on its own, as explained further below.
---------------------------------------------------------------------------
\1\ The PRV in the presently enacted form does not require non-
exclusivity though its original proposal did outline a structure in
which the neglected disease drug developed would not be patent-
protected, and also in which manufacturing commitment was ensured. In
the original conception of the PRV outlined in this article, a sponsor
would need to meet the following conditions in order to receive a PRV:
(1) treat designated neglected diseases; (2) receive approval from the
United States or European drug regulatory authority; (3) be clinically
superior to existing treatment options; (4) forgo patent rights; and
(5) ensure at least one manufacturer. Ridley D, et al. Developing Drugs
For Developing Countries. Health Affairs 25.2 (2006): 313-24, http://
content.healthaffairs.org/cgi/content/full/25/2/313.
---------------------------------------------------------------------------
The PRV was introduced as part of the FDA Amendments Act of 2007
(FDAAA) which amended the FDC Act to add 524: ``Priority Review to
Encourage Treatments for Tropical Diseases.'' FDC Act 524 established
a transferable priority review mechanism for drugs and biologics for
certain specified tropical diseases. Drugs for qualified diseases
approved by the Food and Drug Administration (FDA) are entitled to a
PRV that allows for expedited review--of 6 months instead of the
typical 10 months or more--of a drug or vaccine. The voucher is
transferable, including by sale, and does not need to be applied to
drugs in specified disease areas.
As applied to neglected diseases, the PRV effectively provides an
incentive estimated to be worth more than $300 million for the
development of drugs for particular diseases.\2\ The transferability of
the PRV to a producer of a blockbuster medicine makes this a
potentially lucrative incentive for neglected disease development.
---------------------------------------------------------------------------
\2\ Ridley D, et al. Developing Drugs For Developing Countries.
Health Affairs 25.2 (2006): 313-24, http://content.healthaffairs.org/
cgi/content/full/25/2/313.
---------------------------------------------------------------------------
While the PRV can be a useful tool if structured appropriately, it
is insufficient on its own to stimulate new product development for
neglected diseases, and as currently enacted also has several important
shortcomings.
First, PRVs leave to the company entirely the choice of diseases to
prioritize for R&D. While current legislation identifies diseases for
which the PRV may be applicable, it remains at the company's discretion
whether to invest in drug development in these diseases. This means
that priority diseases may be left unaddressed despite unmet needs.
Second, the ability of the PRV to incentivize innovation of new
neglected diseases R&D remains untested. While it is important to
explore new approaches to incentivizing needs-driven R&D, new
mechanisms should be designed carefully to maximize the public
interest; they should also be monitored closely so that we learn from
the experience and make improvements to policies along the way.
In April 2009, the FDA granted the first PRV to Novartis for its
combination anti-malarial medicine of artemether and lumefantrine
(Coartem) although this medicine had been on the market many years
prior: Novartis developed Coartem in 1996 and the medicine has been
used, including by MSF, for more than a decade in developing countries.
It had not previously been submitted to the FDA, but it had been
submitted to and approved by other drug regulatory authorities. Whether
companies will actually be motivated for neglected disease drug
development by a transferrable PRV is not yet known and should be
monitored closely.
Third, the PRV in its current form does not ensure that products
developed for neglected diseases are made available and affordable to
patients in developing countries. The new incentive is not tied to
agreements to license patents and other intellectual property rights in
order to enable generic competition or more efficient procurement of
products in developing countries.
Fourth, the PRV is not available for re-purposed drugs, a possibly
important area for the development of new treatments for neglected
diseases.
Proposed S. 3697 \3\ is legislation newly introduced by Senators
Brownback, Brown, and Franken that responds to some of these problems.
In particular, it would eliminate from eligibility for the PRV a drug
approved more than 24 months prior outside of the United States for
commercial marketing for tropical diseases. This would help to
eliminate the possibility that a company would receive a windfall for a
drug developed years earlier and it would reserve the PRV as an
incentive for new drug development as intended. The act also expands
the list of diseases eligible to benefit from the PRV to include Chagas
disease. Chagas disease, the largest parasitic killer in the Americas,
affects 300,000 in the United States and 15 million people around the
world. The proposed amendment still would not require that a company
ensure production, but it would expand the reporting requirements to
include a good faith intent to make the drug available in developing
countries.
---------------------------------------------------------------------------
\3\ Creating Hope Act of 2010, or ``A bill to amend the Federal
Food, Drug, and Cosmetic Act to improve the priority review voucher
incentive program relating to tropical and rare pediatric diseases.''
---------------------------------------------------------------------------
A variety of push and pull mechanisms are necessary to respond to
the current lack of incentives for drug and vaccine development for
neglected diseases. One of the reasons MSF supports delinkage
principles generally, and innovation prizes in particular, to
complement other mechanisms is that they can incentivize R&D without
the limitations described above. A prize would bring attention to
priority areas and could be structured to ensure affordability and
accessibility principles.

Question 2. Although rare and neglected diseases share some
challenges, such as access issues, unlike rare diseases, neglected
diseases have huge numbers of sufferers. Do the incentives for
developing treatments for rare diseases carry over to neglected
diseases? Which ones may not be applicable? Are there incentives for
neglected diseases that may not be applicable to rare diseases?
The primary incentives in the United States for the development of
drugs to respond to rare diseases, with relatively few domestic
sufferers, are established within the Orphan Drug Act (ODA). The ODA
provides exclusive marketing protection, substantial tax benefits,
grant support for R&D, and FDA counseling related to conditions for
approval to the sponsor of a drug for diseases with fewer than 200,000
domestic sufferers. The FDA reports that the ODA has incentivized the
development and registration of more than 200 drugs and biological
products to respond to rare diseases since the introduction of the act
in 1983, compared to 10 in the decade before the introduction of the
act.\4\
---------------------------------------------------------------------------
\4\ U.S. Food and Drug Administration. Developing products for rare
diseases and conditions, http://www.fda.gov/ForIndustry/
DevelopingProductsforRareDiseasesConditions/default.htm.
---------------------------------------------------------------------------
The ODA incentive of exclusive marketing protection would be
largely inapplicable to neglected diseases because exclusive marketing
protection as an incentive relies on U.S. consumers being able to pay
very high prices during a period of market exclusivity. It is debatable
whether the exclusive marketing protection is even advisable for U.S.
populations given the extraordinary prices charged due to the market
exclusivity.
Forbes Magazine recently explored the most expensive drugs, and
identified nine that are priced at more than $200,000 per patient per
year; most treat rare genetic diseases. ``For these diseases, there are
few if any other treatments. So biotech companies can charge pretty
much whatever they want.'' \5\
---------------------------------------------------------------------------
\5\ Herper M. The World's Most Expensive Drugs. Forbes, Feb. 22,
2010, http://www.forbes
.com/2010/02/19/expensive-drugs-cost-business-healthcare-rare-
diseases.html.
---------------------------------------------------------------------------
The high prices of the treatments for these rare diseases create
barriers and burdens for patients, employers, governments, or others
who provide insurance or reimbursements for such treatments in the
United States and abroad. But high prices are not the only problem of
an incentive mechanism based on providing market exclusivity. Some
companies use this exclusivity to delay the entry of competing products
that may be better for some patients, or have superior delivery
mechanisms.\6\
---------------------------------------------------------------------------
\6\ See, e.g., Pollack A. Genzyme Drug Shortage Leaves Users
Feelings Betrayed. New York Times, 15 Apr. 2010.
---------------------------------------------------------------------------
Those affected by neglected diseases will not be able to compensate
manufacturers through high drug prices. Similarly, companies will not
be able to recoup R&D costs for drugs for neglected diseases through
exclusive marketing and resultant high prices to these resource-poor
consumers.
Tax credits available through the ODA to incentivize drug
development for rare diseases are equivalent to up to 50 percent of the
cost of qualified investments in clinical testing of products.
Insufficient information is available about how the tax credit is used
in practice. Grant support to investigate treatments can be a useful
push mechanism to subsidize R&D for both rare and neglected diseases.
Incentives for neglected diseases that are based on delinkage, such
as prizes, should work as well for rare diseases. While compensating
for R&D at the outset, when appropriately structured, these incentives
have the added benefit of minimizing access barriers. The few patients
suffering from a rare disease will not be doubly burdened with health
costs of hundreds of thousands of dollars annually for their lifetimes.
Patients suffering from neglected or rare diseases would benefit from
price-lowering generic competition or other cost control mechanisms as
soon as a product is developed.

Question 3. Innovation prize funds have been successful in
aerospace and engineering fields. Are there any health-based funds that
have awarded prizes for treatments?
Answer 3. Over time, there have been a number of prizes for health
care related innovations. For a comprehensive review of existing
innovation prize funds through 2008, including for medical innovations
but also for innovations in other areas, please see Selected Innovation
Prizes and Reward Programs, by Knowledge Ecology International
(KEI).\7\ Further information is available in the 2009 McKinsey Prize
Report, ``And the winner is . . .'': Capturing the Promise of
Philanthropic Prizes.\8\
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\7\ The information described below is largely drawn from this
compendium. Knowledge Ecology International (KEI). Selected Innovation
Prizes and Reward Programs, Research Note 2008:1, http://keionline.org/
misc-docs/research_notes/kei_rn_2008_1.pdf.
\8\ McKinsey & Company, ``And the winner . . . ''; Capturing the
Promise of Philanthropic Prizes, 3 Mar. 2009, www.xprize.org/about/the-
mckinsey-report.
---------------------------------------------------------------------------
Prizes for medical innovations have been used since the 1800s to
incentivize and/or reward R&D. There is tremendous variation in the
prize amount, the specificity of the requirements for the prize to be
awarded, and the level of development and utility required for the
prize to be awarded.
In the 19th century, a number of prizes were offered to advance
medical science, including in particular prizes offered by various
French academies, and British or U.S. scientific groups. Many among
these focused on developments in tuberculosis treatment.
More recently, Eli Lilly developed a program of small prizes to
address discrete challenges that were part of larger efforts on drug
development. This was later spun off as InnoCentive, a for-profit
entity that currently manages hundreds of prize competitions, many of
which involve biomedical inventions.
Through InnoCentive, the Rockefeller Foundation offered a prize
related to developments in tuberculosis research. This prize, like a
number of others, was successful in inducing the desired innovation. In
2007, for instance, the Gotham Prize was launched to reward the sharing
of knowledge to accelerate progress in cancer research. The prize was
used to reward a researcher $1 million for a new approach to cancer
treatment; and to reward another $250,000 for developments in pediatric
cancer.
The following prizes have been used since the 1980's in the medical
field:

The Armand Hammer Cancer Prize (1981), offering $1 million
for the scientist who found a cure for some form of cancer over the
next decade;
Rockefeller Prize (1994), offering a $1 million prize for
developing a low-cost and efficacious test for gonorrhea or chlamydia
useful in developing country contexts;
InnoCentive (2001), a company established by Eli Lilly,
hosted several prize funds for companies in need of scientific
research; and expanded in 2006 with support from the Rockefeller
Foundation including into the public health arena; prizes included in
at least one instance an obligation that the awardee not patent or
otherwise prevent the use of the innovation;
Methuselah Mouse Prize (2003), offering a $4.5 million
prize for research into aging;
Project Bioshield (2004), a U.S. government-sponsored
prize fund, provides for automatic payment for the development of
bioterrorism countermeasures;
Archon X-Prize for Genomics (2006), offering $10 million
for genome sequencing developments;
Prize4Life (2006), offering prizes for developments
related to ALS (Lou Gehrig's disease);
Hideyo Noguchi Africa Prize (2006), offering a 100 million
yen (then approximately $860,000, now approximately $1.2 million) every
5 years;
Stop TB Partnership Kochan Prize (2006), offering a prize
for achievements in combating tuberculosis;
Gotham Prize for Cancer Research & Ira Sohn Conference
Foundation (2007), offering annual rewards of $1 million and $250,000
respectively for cancer and pediatric oncology, and described further
above;
Piramal Prize for Innovations that Democratize Healthcare
(2007) offering 10 lakh rupee ($25,000) for health improvements
benefiting the Indian poor; and
InnoCentive Tuberculosis Prize for PA-824 (2007), offering
a $20,000 prize funded by the Rockefeller Foundation, for a ``safe and
economical synthetic route'' for a candidate drug for tuberculosis, and
InnoCentive described further above.

There have also been various unrealized proposals for medical
innovation prizes in the United States and elsewhere. This includes the
Medical Innovation Prize Act introduced in the U.S. Congress as H.R.
417, 109th Congress; and S. 2210, 110th Congress. This legislation
would establish a U.S. government-sponsored prize fund for drug
development based on the medical or public health benefit of new tools
developed. According to the proposed legislation, the prize would
compensate for R&D for pharmaceuticals in place of patent exclusivity
and monopoly prices, thereby allowing for price-lowering generic
competition upon FDA approval rather than after patent expiry.
From the historic experience of innovation prize funds, lessons
have been learned about the importance of offering a sufficiently
remunerative prize to compensate the R&D and appropriately value the
objectives set out in the prize fund; permitting flexibility and the
possibility of both interim ``milestone'' as well as end-stage rewards;
and specifying with sufficient detail the desired end product, as well
as including affordability and accessibility requirements.
One lesson learned from the experience thus far is that prizes can
generate private investment even exceeding the prize amount. The X
Prize Foundation reports that the 26 teams competing for the $10
million Ansari X Prize in aviation combined spent more than $100
million to win the prize.\9\ As stated in the McKinsey Prize Report:
``One of the prizes' great strengths is their ability to attract
investments from competitors many times greater than the cost of
delivering and awarding a prize.'' \10\
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\9\ See http://spacexprize.org/ansari-x-prize.
\10\ McKinsey & Company, ``And the winner is . . . '': Capturing
the Promise of Philanthropic Prizes, 3 Mar. 2009, www.xprize.org/about/
the-mckinsey-report.
---------------------------------------------------------------------------
However, the funds dedicated to prizes have been quite limited.
Whereas approximately $1 million has been made available annually for
prizes to incentivize medical R&D, approximately $17-$20 billion has
been made available annually to fund R&D through NIH grants while
private sector R&D has been facilitated with the promise of substantial
rewards, estimated at approximately $150 billion, earned through high
prices paid by consumers.\11\
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\11\ Love J & Tim Hubbard. An Agenda for Research and Development.
Lecture. Meeting on The Role of Generics and Local Industry in
Attaining the Millennium Development Goals (MDGs) in Pharmaceuticals
and Vaccines. The World Bank, Washington, 24-25 June 2003,
www.cptech.org/ip/health/rndtf/lovehubbard06242003.doc.
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SENATOR CASEY

Question 1. Can you comment on the balance between public
investment and private investment in finding cures for rare and
neglected diseases?
Answer 1. According to recent estimates, international financing
for health-related R&D exceeds $160 billion and includes a diversity of
sources: 51 percent private for-profit, 41 percent public, and 8
percent private not-for-profit.\12\
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\12\ See Feletto M and Stephen Matlin. Global R&D financing for
communicable and noncommunicable diseases: a report to the WHO Expert
Working Group on R&D Financing, Oct. 2009, http://www.who.int/phi/
ewg3rdmeet/en/index.html. According to Feletto and Matlin's study:
``The gap between LMIC [low- and middle-income country] relevant R&D
and all health R&D is considerable.''
---------------------------------------------------------------------------
Drug development for diseases where a profitable market exists--
i.e., because there are a significant quantity of people suffering from
the diseases in upper income countries--generally relies on both public
and private investment. Even highly profitable so-called
``blockbuster'' drugs often benefit from significant outlays of public
funds in the early stages of development.
Typically, earlier stages of development, such as drug discovery
and research, benefit from a high level of public funding, including
both university research and research in government laboratories.
Pharmaceutical companies generally focus private resources on the later
stages of R&D.\13\
---------------------------------------------------------------------------
\13\ Notably, this means that consumers typically pay twice. First,
they pay through tax dollars for publicly funded early stage research.
Then, where the research is transferred without obligations for
affordability, the consumers pay through high prices during the patent
term. In recent years, some universities and the National Institutes of
Health (NIH) have begun to respond to concerns raised by various actors
that the licensing agreements made to transfer university and public
sector research to the private sector for subsequent development should
include certain critical humanitarian terms.
See, e.g., Universities Allied for Essential Medicines.
Universities Allied for Essential Medicines, BIG VICTORY: 6
Universities, AUTM and NIH Agree to Access Principles/Universities
Allied for Essential Medicines, 11 Nov. 2009 (National Institutes of
Health). Check E. Universities Urged to Do More for Poor Nations.
Nature 444 (2006): 412-13. 22 Nov. 2006, (University of California at
Berkeley). Kelbie P. Edinburgh University Forces Firms to Supply Cheap
Medicines to Developing World. The Guardian, 26 Apr. 2009 (University
of Edinburgh). Lin B. Rethinking Drug Development: A New Commitment to
Global Access. UBC Public Affairs. University of British Columbia, 8
Feb. 2010 (University of British Columbia).
The transfer from the public sector to the private sector also
comes without obligations for product development and accessibility.
---------------------------------------------------------------------------
One of the primary differences between R&D for diseases which
affect a significant number of people in high-income countries, and for
rare and neglected diseases where the small number or great poverty of
the afflicted does not suggest the likelihood of a profit, is whether
private sector investment can be motivated by the promise of high
profits from monopoly prices during the patent term.
One study found, for instance, that in a 25-year period (1975-99),
there were 179 drugs developed for cardiovascular disease whereas only
16 drugs were developed for tropical diseases and tuberculosis (TB). At
the time, both cardiovascular disease, and tropical diseases and TB
represented a roughly equivalent global disease burden (11 percent and
12 percent respectively), but R&D for tropical diseases and TB is
underfunded because it disproportionately affects poor populations in
developing countries.\14\ Few drugs used to respond to tropical
diseases were even developed intentionally targeting these diseases or
relying primarily on private funding.\15\
---------------------------------------------------------------------------
\14\ Trouiller P, et al. Drug Development for Neglected Diseases: a
Deficient Market and a Public-health Policy Failure. The Lancet, 22
June 2002, http://www.thelancet.com/journals/lancet/article/PIIS0140-
6736(02)09096-7/fulltext.
\15\ The two primary drugs for Chagas disease (benznidazole and
nifurtimox), as well as the drugs for schistomiasis (praziquantel and
oxamnaquine), and the drugs for helminth infections and onchoceriasis
(albendazole and ivermectin respectively), were developed in the
context of veterinary research. Maskalyk J. New Prescriptions for
Neglected Diseases. pen Med. 1.2 (2007): 89-91, http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC2802011; Trouiller P., et al. Is
Orphan Drug Status Beneficial to Tropical Disease Control? Comparison
of the American and Future European Orphan Drug Acts. Tropical Medicine
& International Health 4.6 (2002): 412-20. Wiley Online Library. 5 Jan.
2002, http://onlinelibrary.wiley.com/doi/10.1046/j.1365-
3156.1999.00420.x/full.
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The requirement of public sector investment in neglected disease
research is apparent through looking at current clinical trials. The
four diseases considered to be most neglected, which MSF prioritizes in
our programming and which the World Health Organization (WHO)
identifies as in need of innovative and intensified disease management
(IDM),\16\ are Chagas disease, leishmaniasis, sleeping sickness (or
human African trypanosomiasis), and Buruli ulcer. Each have a limited
number of ongoing clinical trials, and all clinical trials are
disproportionately funded by public funds, including the NIH, and/or
universities or philanthropic organizations.
---------------------------------------------------------------------------
\16\ World Health Organization, Neglected tropical diseases:
innovative and intensified disease management (IDM), http://
www.who.int/neglected_diseases/disease_management/en/.
---------------------------------------------------------------------------
There are seven reported ongoing clinical trials related to
sleeping sickness; public, university or organizational funds support
all seven while three have some industry funding. There is one ongoing
clinical trial related to Buruli ulcer; it is publicly funded. There
are 38 clinical trials related to Chagas disease; 29 are funded by the
public sector, university or organizations, and 9 funded by industry.
Lastly, there are 76 ongoing clinical trials related to leishmaniasis,
but virtually all (73) are funded by the public sector, university or
organizations; 7 receive some industry funding. For perspective, there
are 243 ongoing clinical trials related to erectile dysfunction; 172
receive industry funding.\17\
---------------------------------------------------------------------------
\17\ This information was obtained through clinicaltrials.gov, a
service of the NIH, on August 19, 2010, and may include some overlap in
funding sources.
---------------------------------------------------------------------------
Neglected diseases for which there is no or limited anticipated
profitability require a higher level of public investment because the
private sector will not be motivated by the possibility of exclusive
marketing. The populations affected are unable to compensate drug
development through high prices during the patent term because, even
where they are numerous, they are too poor.
Major benefits of public sector investment in health-related R&D
are that (1) funds can be directed to identified public needs rather
than areas of likely profit where the incremental health benefit is
less substantial; (2) the cost of compensating R&D is not borne
exclusively by the most vulnerable, i.e., afflicted patients, through
out-of-pocket expenditures or insurance premiums, and the costs are
dispersed rather than targeted at these patients alone; (3) public
sector resources can be directed towards ensuring the accessibility of
drug development even where the development is less profitable, i.e.,
ensure that R&D does not result in a product that does not reach the
potential beneficiaries; (4) open source innovation models, in which
new knowledge is shared, in real time to accelerate innovation and
access, can be more easily implemented; and (5) public sector research
may be more cost-effective and efficient than the patent system as an
innovation tool as it has been estimated that U.S. taxpayers pay ``at
least $150 billion per year in higher prices . . . to fund $20 billion
in private sector R&D.\18\
---------------------------------------------------------------------------
\18\ Love J & Tim Hubbard. An Agenda for Research and Development.
Lecture. Meeting on The Role of Generics and Local Industry in
Attaining the Millennium Development Goals (MDGs) in Pharmaceuticals
and Vaccines. The World Bank, Washington, 24-25 June 2003,
www.cptech.org/ip/health/rndtf/lovehubbard06242003.doc.
---------------------------------------------------------------------------
Therefore MSF supports both public sector and private investment in
both rare and neglected disease R&D, but recognizes the essential role
that public sector funding plays in these areas. MSF also considers
that a variety of push and pull incentive mechanisms are necessary to
support R&D for these diseases. As explained, grants and NIH funding as
push incentives are essential for the development of treatments,
vaccines, and diagnostics for rare and neglected diseases. Pull
incentive mechanisms are also necessary. MSF favors pull incentives,
like prizes, that delink the cost of R&D from the price of the products
and that do not rely on marketing exclusivities, for the reasons
described above.

Response to Questions of Senator Enzi and Senator Franken
by Daniel A.C. Frattarelli, M.D., FAAP

SENATOR ENZI

Question 1. Are existing incentives sufficient to support the
development of therapies for rare diseases? How might these incentives
be improved and increased?
Answer 1. The development of therapies to treat rare diseases is
challenging, and it is especially so in pediatrics. We must be
constantly thinking of new and creative ways to incentivize more and
better therapies. One area that needs specific attention is older, off-
patent drugs. Current incentives for pediatric and rare disease
therapies can only offer added exclusivity to drugs that are still
protected by patents and marketing exclusivity. Many off-patent drugs
lack pediatric safety and efficacy data and the National Institutes of
Health (NIH) has worked to identify many of these gaps in pediatric
therapeutics. However, there are no existing incentives available to
remedy this problem. We look forward to working with Congress to
explore new policy solutions to increasing the number of these older
drugs studied for the benefit of children.

Question 2. Some of the incentives available for pediatric and rare
and neglected diseases are stackable--a business can get more than one
for a given product. Do the different programs work well together?
Could they be more coordinated?
Answer 2. The orphan drug exclusivity provided by the Orphan Drug
Act and the pediatric exclusivity offered by the Best Pharmaceuticals
for Children Act (BPCA) work well together to improve access to safe
and effective drugs for children and patients with rare diseases. The
Orphan Drug Act incentivizes the development of drugs for rare diseases
and BPCA incentivizes the study of drugs in pediatric populations.
Pediatric exclusivity under BPCA is only granted in response to
fulfilling the requirements of a written request issued by FDA and is
not given in conjunction with any other incentive program.
Both incentive programs are necessary and serve distinct purposes.
Whereas BPCA may be used to add pediatric labeling information to a
popular adult drug, the Orphan Drug Act may be used to incentivize the
development of that same drug to treat an entirely different condition
that classifies as a rare disease.

Question 3. You recommend a central repository for data on rare
conditions so that fragments of data do not reside with different
physicians. We have a database called ClinicalTrials.gov that could be
used for such a purpose. Do you think this is a possible way to do what
you suggest?
Answer 3. ClinicalTrials.gov is a useful tool now available to
patients, providers, and researchers to share and disseminate
information on ongoing clinical trials. This can be particularly
helpful for families that cope with rare diseases and are desperately
seeking treatment. The unique nature of rare and pediatric disease
research, however, may require specially designed data sharing networks
not currently in place.

Question 4. What more can be done to speed the diagnosis of rare
disorders?
Answer 4. The National Organization for Rare Disorders (NORD) has
been a leader for decades in the effort to increase information on the
diagnosis and treatment of rare disorders. More investment into
activities like these will be necessary to continue to improve the
standard of care. There is much we do not yet know about rare
disorders, but we must make sure that what we do know is readily
available to patients, families, and providers. We need more outreach
to primary and specialty care physicians, medical societies, and
medical schools. Newborn screening also plays an important role in the
early diagnosis of rare disorders and deserves our continued support.

SENATOR FRANKEN

Question 1. The FDA has recently appointed a point person for
oversight of orphan drug development in FDA's Center for Drug
Evaluation and Research's Office of New Drugs. This appointment seems
like a positive step. Do you think establishing a similar ombudsman for
Orphan and Pediatric Devices in the FDA's Center for Devices and
Radiological Health would encourage innovations and development of
medical devices for these populations?
Answer 1. The Center for Devices and Radiological Health (CDRH) is
currently in the process of hiring a Chief Pediatric Medical Officer
who will report directly to the CDRH Director. This Chief Pediatric
Medical Officer will be tasked with coordinating and integrating
pediatrics across the center. The American Academy of Pediatrics
strongly supports this move.
Similar efforts to integrate pediatrics in the Center for Drug
Evaluation and Research (CDER) have been successful. The Pediatric and
Maternal Health Staff and the Pediatric Review Committee (PeRC) have
helped standardize high quality pediatric research across the review
divisions of CDER and Center for Biologics Evaluation and Research
(CBER). The Office of Pediatric Therapeutics in the Office of the
Commissioner continues to do excellent work coordinating pediatric
efforts across the centers at FDA.

Question 2. You mention in your testimony that physicians often
don't recognize many of these diseases because they are so rare. What
can we do to help physicians to get the best information to diagnosis
and care for these patients?
Answer 2. The National Organization for Rare Disorders (NORD) has
been a leader for decades in the effort to increase information on the
diagnosis and treatment of rare disorders. More investment into
activities like these will be necessary to continue to improve the
standard of care. There is much we do not yet know about rare
disorders, but we must make sure that what we do know is readily
available to patients, families, and providers. We need more outreach
to primary and specialty care physicians, medical societies, and
medical schools. Newborn screening also plays an important role in the
early diagnosis of rare disorders and deserves our continued support.

[Whereupon, at 12:19 p.m., the hearing was adjourned.]