[Senate Hearing 111-841]
[From the U.S. Government Publishing Office]


                                                        S. Hrg. 111-841
 
  FOOD AND DRUG ADMINISTRATION'S REVIEW PROCESS FOR PRODUCTS TO TREAT 
             RARE DISEASES AND NEGLECTED TROPICAL DISEASES 

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

                                HEARING

                                before a

                          SUBCOMMITTEE OF THE

            COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE

                     ONE HUNDRED ELEVENTH CONGRESS

                             SECOND SESSION

                               __________

                            SPECIAL HEARING

                     JUNE 23, 2010--WASHINGTON, DC

                               __________

         Printed for the use of the Committee on Appropriations


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                      COMMITTEE ON APPROPRIATIONS

                   DANIEL K. INOUYE, Hawaii, Chairman
ROBERT C. BYRD, West Virginia        THAD COCHRAN, Mississippi
PATRICK J. LEAHY, Vermont            CHRISTOPHER S. BOND, Missouri
TOM HARKIN, Iowa                     MITCH McCONNELL, Kentucky
BARBARA A. MIKULSKI, Maryland        RICHARD C. SHELBY, Alabama
HERB KOHL, Wisconsin                 JUDD GREGG, New Hampshire
PATTY MURRAY, Washington             ROBERT F. BENNETT, Utah
BYRON L. DORGAN, North Dakota        KAY BAILEY HUTCHISON, Texas
DIANNE FEINSTEIN, California         SAM BROWNBACK, Kansas
RICHARD J. DURBIN, Illinois          LAMAR ALEXANDER, Tennessee
TIM JOHNSON, South Dakota            SUSAN COLLINS, Maine
MARY L. LANDRIEU, Louisiana          GEORGE V. VOINOVICH, Ohio
JACK REED, Rhode Island              LISA MURKOWSKI, Alaska
FRANK R. LAUTENBERG, New Jersey
BEN NELSON, Nebraska
MARK PRYOR, Arkansas
JON TESTER, Montana
ARLEN SPECTER, Pennsylvania

                    Charles J. Houy, Staff Director
                  Bruce Evans, Minority Staff Director
                                 ------                                

     Subcommittee on Agriculture, Rural Development, Food and Drug 
                  Administration and Related Agencies

                     HERB KOHL, Wisconsin, Chairman
TOM HARKIN, Iowa                     SAM BROWNBACK, Kansas
BYRON L. DORGAN, North Dakota        ROBERT F. BENNETT, Utah
DIANNE FEINSTEIN, California         THAD COCHRAN, Mississippi
RICHARD J. DURBIN, Illinois          CHRISTOPHER S. BOND, Missouri
TIM JOHNSON, South Dakota            MITCH McCONNELL, Kentucky
BEN NELSON, Nebraska                 SUSAN COLLINS, Maine
JACK REED, Rhode Island
MARK PRYOR, Arkansas
ARLEN SPECTER, Pennsylvania
DANIEL K. INOUYE, Hawaii (ex 
    officio)

                           Professional Staff

                             Galen Fountain
                        Jessica Arden Frederick
                             Dianne Nellor
                      Fitzhugh Elder IV (Minority)
                        Stacy McBride (Minority)

                         Administrative Support

                          Molly Barackman-Eder






















                            C O N T E N T S

                              ----------                              
                                                                   Page

Opening Statement of Senator Herb Kohl...........................     1
Statement of Senator Sam Brownback...............................     2
Statement of Dr. Emil Kakkis, President and Founder, Kakkis 
  Everylife Foundation...........................................     5
    Prepared Statement...........................................     7
Statement of Diane Edquist Dorman, Vice President for Public 
  Policy, National Organization for Rare Disorders...............    14
    Prepared Statement...........................................    16
Statement of Thomas J. Bollyky, Visiting Fellow, Center for 
  Global Development.............................................    16
    Prepared Statement...........................................    18
Statement of Gloria Steele, Senior Deputy Assistant Administrator 
  for Global Health, U.S. Agency for International Development...    28
    Prepared Statement...........................................    31
Statement of Christopher P. Austin, Director, Chemical Genomics 
  Center; and Senior Advisor to the Director for Translational 
  Research, Office of the Director, National Human Genome 
  Research Institute, National Institutes of Health, Department 
  of Health and Human Services...................................    34
    Prepared Statement...........................................    36
Statement of Dr. Jesse Goodman, Chief Scientist and Deputy 
  Commissioner for Science and Public Health, Food and Drug 
  Administration, Department of Health and Human Services........    39
Two Challenges...................................................    39
TB, Malaria and HIV..............................................    40
Science-based Decisions..........................................    40
Orphan Drug Act..................................................    41
Orphan Product Office............................................    41
TRND Programs....................................................    41
Neglected Diseases...............................................    42
Prepared Statement of Dr. Jesse Goodman..........................    44
Addressing TRND Delay............................................    50
Role of FDA......................................................    52
Challenges.......................................................    53
Resource Constraints.............................................    53
NIH Collaboration................................................    54
TRND Quarterbacking Methodology..................................    55
Review Groups....................................................    55


  FOOD AND DRUG ADMINISTRATION'S REVIEW PROCESS FOR PRODUCTS TO TREAT 
             RARE DISEASES AND NEGLECTED TROPICAL DISEASES

                              ----------                              


                        WEDNESDAY, JUNE 23, 2010

        U.S. Senate, Subcommittee on Agriculture, Rural 
            Development, Food and Drug Administration, and 
            Related Agencies, Committee on Appropriations,
                                                    Washington, DC.
    The subcommittee met at 2:05 p.m., in room SD-192, Dirksen 
Senate Office Building, Hon. Herb Kohl (chairman) presiding.
    Present: Senators Kohl, Pryor, and Brownback.


                 opening statement of senator herb kohl


    Senator Kohl. Good afternoon to all of you. And we 
appreciate your being here, particularly appreciate our 
witnesses who are with us today.
    Senator Brownback asked me to convene this hearing.
    And I will be brief.
    It reflects Senator Brownback's longstanding concern about 
lack of therapies for rare diseases in the United States and 
neglected tropical diseases, such as malaria and tuberculosis 
throughout the world.
    In the United States, rare diseases are defined as those 
which affect fewer than 200,000 people. According to the NIH, 
there are close to 7,000 rare diseases. In total, more than 25 
million people in the United States have one.
    Beyond our shores, the World Health Organization estimates 
that over 1 billion people, one-sixth of the world's 
population, suffer from one or more neglected tropical 
diseases. They often afflict the poorest populations, who live 
in remote rural areas, urban slums, or conflict zones. Three 
hundred to 700 million people get malaria each year, and an 
estimated 1.3 million people died from tuberculosis in the year 
2008.
    Last year, we included language in the appropriations bill, 
at Senator Brownback's, request to establish review groups that 
focus on these issues. Their mission was to look at the 
procedures by which both rare and neglected tropical diseases 
are approved, and to provide recommendations on how these 
procedures can be improved upon. These review groups have been 
created and are actively working, at this time.
    Due to scheduling conflicts, I will not be able to stay on, 
and so I will now turn the hearings over to Senator Brownback.
    Again, we thank all of our witnesses for their presence 
here today.
    Senator Brownback.


                   statement of senator sam brownback


    Senator Brownback [presiding]. Thank you very much, Mr. 
Chairman.
    And, to everybody here, I want to say, and to you directly 
Mr. Chairman, how much I appreciate your willingness to engage 
this topic and work on it. You've been absolutely outstanding 
and wonderful to do this. It's a key topic. It's an important 
topic.
    But, you're in the majority, and I'm in the minority, and 
you don't need to do this. You are, because of your care and 
concern for this issue. And I deeply appreciate it. I know a 
lot of people around the world will, and do, as well.
    The chairman noted the problem, and it is enormous, it's 
significant. I've got two charts that show some of the 
statistics. I just want to flip these up here for people to be 
able to see and notice what this problem is.

[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]


    Less than 3 percent of the rare diseases have an FDA-
approved treatment. So, if you get one of these diseases, God 
bless you. That's just about all we can say, because we don't 
have any treatment for you. And in my way of looking at the 
world, that's just not a sufficient answer, particularly not 
with the technology and the ability that we have today, that 
you just say, ``We've got 200 approved FDA treatments for 7,000 
rare diseases.'' It's just simply not. Rare diseases affect 
nearly 1 in 10 Americans, so we'd have several people probably 
in this room with a rare or neglected disease that there's no 
treatment for--none.
    The old model of a billion dollars to develop a drug 
doesn't work in this category, because there's just not a 
billion dollars of market with it. And we all recognize that. 
There's not a billion dollars, probably, of government subsidy 
to go into each one of these 7,000 different areas. So, we've 
got to do something different, and the model has to be 
different.
    What I'm hearing, Mr. Chairman, from people I'm talking 
with, is that people are working very closely and carefully to 
try to come up with a different model. And we need to do that.
    I've got a second chart here I just wanted to show you 
quickly, as well. This goes more for diseases around the world. 
We can look at it, and it's terrible what happens in the United 
States. We're talking millions in the United States, but you go 
around the world and we're talking billions of people that are 
affected. The chairman and I have both been in places around 
the world where somebody gets a tropical disease, and, again, 
you can just say, kind of, ``God bless you,'' and that's about 
all we can do. It's just not good enough. I know we can do 
better than this.

[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]


    About 1 percent of approved drugs are developed to treat 
neglected tropical diseases--21 out of 1,556. And you can say, 
``Well, that's not our responsibility. It's around the world.'' 
One in six people are affected. Yet, I also know that in the 
places around the world where the United States invests in 
helping people save lives, like we did with AIDS treatment, 
particularly in Africa, or like we've done recently with 
malaria, that people tend to really like the United States if 
we help save their life. It's a strange thing. I mean, I just 
am amazed about that. But, people really tend to appreciate 
that.
    I think continents like Africa are continents in play. 
We're certainly seeing the Chinese play aggressively in Africa. 
And if we're there, helping people to save lives, and investing 
to save lives, they're going to appreciate that. One of the 
best things we can possibly do.
    Again, I think a big piece of it is that we've got to get 
our system adjusted so it doesn't cost a billion dollars to 
develop the drug, and that you can, hopefully, tempt companies, 
and us, as a government, into saying, ``Okay, we can do this on 
a cheaper basis and develop, still, the quality product.'' So 
if you get one of these diseases you don't have to say, ``I'm 
sorry, all I can say to you is, `God bless you.''' I think this 
is really important.
    I'm delighted at our first panel. I'm even more pleased 
about the second panel, which is the government panel, and the 
amount of effort that they're doing to work together to develop 
some different models and ways forward in this area, because in 
my way of thinking and looking around the world, there's this 
great parable about the good Samaritan. In the core of the 
parable, all these good people walk by somebody that's sick, 
and they walk on the other side of the road, because they don't 
want to really look at the sick person; they don't want to have 
their conscience pricked by the sick person. But, then somebody 
finally stops and helps them. And then, that's the one we hold 
up, ``They're doing the right thing.''
    Well, let's not just walk by them. Yes, we have people that 
are sick, but let's not just walk by them. Let's see what we 
can do to invest just a little bit of money, and go and look at 
our system, and adjust our system, to see if we can save a 
whole bunch of lives.
    And I am absolutely convinced, Mr. Chairman, we can do 
this. I'm absolutely convinced we can do it without 
jeopardizing our quality standards that we have. I know we can 
get this moving forward. And I know if we do, we're going to be 
a stronger country, and it's going to be a better world for it. 
And it will have been worth my time in the Senate, if we get 
something like this to move forward.
    So, I'm deeply appreciative of the panel and of you, Mr. 
Chairman, for being willing to engage in this difficult but 
very important topic.
    Mr. Chairman, I'll call and introduce the first panel, 
then.
    I want to thank you very much for being here and willing to 
be a part of this hearing. This is also highly unusual for me, 
as a minority member, to be chairing the hearing, and the 
chairman has just been so kind to hold this hearing. I promise 
not to pass any bills out of committee--as if I could.
    Our first panel is Dr. Emil Kakkis. He's president and 
founder of Kakkis EveryLife Foundation, and has worked in these 
areas for some period of time; Ms. Diane Edquist Dorman, vice 
president for public policy, the National Organization for Rare 
Disorders; and Mr. Thomas Bollyky, visiting fellow, Center for 
Global Development.
    We're going a little bit backwards in this panel, in that 
we're having the private-sector panel ahead of the public-
sector panel. But, I thought, really, that the private-sector 
panel had a lot of thoughts to offer to the public-sector, and 
so, it was my hope, actually, you could put forward ideas that 
we'd have the public-sector panel react to afterwards. So, I 
hope you feel empowered to do that.
    We have your written testimony. I appreciate that. And 
we'll now call on you to make your presentations.
    Doctor, please, if you'd like to start.
STATEMENT OF DR. EMIL KAKKIS, PRESIDENT AND FOUNDER, 
            KAKKIS EVERYLIFE FOUNDATION
    Dr. Kakkis. Thank you, Senator Brownback. I appreciate and 
thank you for your leadership in the rare disease community, in 
putting on this hearing, and everything else you have been 
doing.
    I'm the founder and president of the Kakkis EveryLife 
Foundation, a foundation I established and funded to help 
improve the regulatory process for rare diseases. I have been 
working in the rare disease drug development area for 18 years, 
both in academia and in industry, developed three approved 
products, and put seven more into development. And, despite 
that success, I saw many challenges, both then and now, that 
make it more difficult to get drugs developed, and I think 
things could be improved.
    There are still many patients out there; and every week, I 
get calls from patients and families that have been essentially 
struck by genetic lightning with some terrible, unusual, 
unpronounceable disease. And they call because the mother and 
the father are setting up a foundation so they can raise money 
and do drug development, an impossible task for many, and yet 
they still have to do it, for their children.
    After some time in the development area, I decided to leave 
industry and develop this foundation and develop the Cure the 
Process Campaign. And this campaign is focused on what we felt 
were practical solutions to some of the problems that affect 
rare disease drug development, which I believe would greatly 
encourage drug development and successful treatment for 
patients.
    We currently have 129 formal endorsements from rare disease 
patient organizations, other patient organizations, as well as 
the physician groups that specialize in genetic diseases.
    What we have learned over the years, I think, can best be 
exemplified by what we know in the Aldurazyme example. 
Aldurazyme was a treatment that I developed--it was my original 
research--for a disease called MPS I, a very rare metabolic 
disease. There are only a couple hundred patients on therapy. 
Right? And it's a miracle that the treatment got developed at 
all, but I did it, through however I could, and managed to 
eventually get a biocompany to help us do it.
    What we found out during the development is the number of 
the problems. One, that surrogate endpoints were very difficult 
to use--in fact, were rejected--because there was inadequate 
clinical information. In addition, clinical study design 
statistical issues caused some problems, as well, which caused 
further delays. Ultimately, the program went to advisory 
committee, which voted, 12-0, that the drug was effective and 
was approved, which maybe seems successful, however, it was a 
3-year delay. And, I mean, at that time, a number of MPS I 
patients passed away. But, more importantly, the company 
canceled programs to treat MPS VII and MPS IV A, two other MPS 
disorders, because without the surrogate approval pathway, the 
costs that were going to be involved made it impossible for us 
to do the product development.
    Ten years later, MPS IV--Morquio disease--and MPS VII still 
do not have approved treatments.
    So, when we look at some of the problems, one of the areas 
is the access to accelerated approval pathway. And I think, if 
you look at what's happened in genetic disease areas, there's 
really been only one approval using the accelerated approval 
pathway. Now, this pathway was designed to give access to life-
threatening disorders, and it's been very helpful in cancer and 
HIV. And in HIV, it's been, I think, miraculous in taking a 
death-sentence disease to a chronic-managed disease. But, only 
one approved for genetic diseases, and even that one was 
approved only after an advisory committee voted that the 
endpoint was acceptable.
    I think that there are clearly many biochemical disorders, 
which could be approved by this pathway, where the endpoints 
are even better than some of the ones that are currently 
accepted for drug approval.
    Our foundation has done some work and shown that if you 
allowed the accelerated approval pathway to work it's possible 
that, for a $1 billion investment in clinical development 
costs, you could develop 40 drugs with the accelerated approval 
pathway, versus 10 to 12 by using a clinical development 
endpoint. So, I think that's a substantial boost in the kind of 
work we can achieve for a given investment.
    Now, our hope in this campaign was also to develop a review 
group that would help develop these guidances and improve the 
review process. And we believe it's necessary to have 
specialists who know the disease area to develop these 
guidances, as well as to be involved in the review of drugs. 
This is what we're calling the Special Biochemical and Genetic 
Review Division. We think that having the right specialized 
people within the agency, with the right kind of academic 
connections to NIH to allow them to keep up to date with what's 
going on, is really a critical step in achieving adequate and 
great reviews.
    We think the group could be creating guidances, and we 
think that the creation of guidance for studies and the 
surrogate endpoint accelerated approval pathway are also 
critical. If we make these changes, we believe that there would 
be immediate impact on new treatments.
    It would be a strong signal, to the biotechnology industry, 
that the FDA and Congress is serious about improving the 
development path to rare diseases. And I think would stimulate 
substantially more investment.
    Our estimate, based on analysis of other companies in rare-
disease genetic areas, is that there is something like 300 to 
600 new, high-paying quality jobs for each drug approval, 
direct jobs within that company, and probably five times as 
many in the surrounding groups.
    For HIV, for example, the 29 drugs approved generated 
something like 78,500 jobs in the companies that made those. 
These are good jobs, ones that don't go away when the economy 
goes south.
    We think that the improvement that we are proposing, which 
is a specialized review division, as well as improved access to 
the accelerated approval pathway and better clinical trial 
design paradigms, are the things that are very practical, 
sensible, not expensive, that could help improve the process 
and improve the investment and transformation of good science 
into great medicine.


                           prepared statement


    So, I want to thank you for your leadership, again, and the 
opportunity to testify today.
    Senator Brownback. Thank you, Dr. Kakkis.
    And also, thank you for your leadership on this. I know 
you've worked in the field, then got frustrated because you had 
the problems that you did in experiencing the system. But, 
instead of just taking your ball and going home, or taking your 
money and leaving the field, you've stayed in it. And that's 
really an important thing. And it's a great contribution to the 
overall effort. Appreciate that very much.
    Dr. Kakkis. Thank you.
    [The statement follows:]
                Prepared Statement of Dr. Emil D. Kakkis
    Chairman Kohl and Ranking Member Brownback: Thank you for this 
opportunity to address the subcommittee today and for your leadership 
in working to improve the treatment of patients affected by rare 
diseases.
    I am the founder and president of the Kakkis EveryLife Foundation, 
a 501(c)(3) public charity established to improve the development of 
treatments for patients with rare disorders. I have spent the last 18 
years focused on developing treatments for rare diseases working both 
as an assistant professor at UCLA, and as chief medical officer at 
BioMarin. At BioMarin, I developed three approved products for rare 
genetic disorders, and despite this success, I saw many problems and 
challenges in development that prevent many rare diseases from ever 
being treated. To resolve these problems, I founded the Kakkis 
EveryLife Foundation to improve the regulatory process by proposing 
efficient and effective science-based changes that would improve the 
predictability and accessibility of many complicated rare diseases to 
treatment development. I provide the vast majority of the funds to 
support our Foundation's efforts and we do not accept financial support 
from industry for our initiatives.
    Mr. Chairman, I am here today to support an additional funding 
appropriation to the Food and Drug Administration (FDA) to create a 
more specialized drug review division focused on the rare biochemical 
and genetic disorders. We respectfully request an incremental $10 
million in the fiscal year 2011 Ag-Rural Development-FDA Appropriations 
bill for the FDA to establish a new review division for Biochemical and 
Genetic Diseases within the Center for Drug Evaluation Research, Office 
of New Drugs.
    This is the first step toward the larger goal of improving the rare 
disease drug development process. My testimony today will provide the 
rational basis for this request and the greater context of how this 
first critical step will move rare disease treatments forward to 
patients.
    The new rare disease review division or office is one core part of 
our three CureTheProcess campaign goals (Exhibit A). The campaign is 
now formally endorsed by 128 unique patient organizations and physician 
societies. Our three goals are:
  --To establish a new specialized Division/Office of Drug Evaluation 
        for Genetic and Biochemical Diseases.
  --To improve the accessibility of the Accelerated Approval process by 
        creating new criteria for surrogate and biomarker endpoints 
        used to evaluate treatments for rare disorders.
  --To establish efficient clinical study design and analysis paradigms 
        for rare disease clinical studies.
    By making these three changes, we can quickly and dramatically 
improve the current regulatory process for rare diseases without having 
to reinvent an entirely new process or a new approval pathway.
    Why do we need change? There are more than 7,000 rare disorders 
that together affect over 25 million Americans and their families. The 
Orphan Drug Act (enacted in 1983) encourages pharmaceutical companies 
to develop drugs for diseases that have relatively small patient 
populations and has been very successful. Despite the success in the 
first 25 years with 1,892 orphan designations and 326 treatments 
approved \1\, 95 percent of rare disorders remain without a specific 
treatment approved by the FDA. Treatments for many of these diseases 
may never be developed because the complexities of the regulatory 
environment make it difficult to attract investment for some very rare 
or difficult diseases, even though the science may be available.
---------------------------------------------------------------------------
    \1\ Braun MM, Farag-El-Massah S, Xu K, Cote TR., 2010, Emergence of 
orphan drugs in the United States: a quantitative assessment of the 
first 25 years. Nat Rev Drug Discov. 2010 Jun 7. [Epub ahead of print].
---------------------------------------------------------------------------
    In Exhibit B, orphan designations are increasing while approvals 
are flat over time. The approvals for ultra rare disorders (arbitrarily 
defined as those affecting less than 6,000 patients) show that only two 
or three are approved each year despite the fact that more than 80 
percent of all rare diseases are in this ultra rare category \2\.
---------------------------------------------------------------------------
    \2\ BioMedical Insights report, ``Ultra-Rare Disease Drug 
Development Trends'', June 10, 2010, commissioned by the Kakkis 
EveryLife Foundation; Data based on information contained in the 
Orphanet database and other sources.
---------------------------------------------------------------------------
    To understand how current science is only generating 2 or 3 ultra-
rare disease approvals each year, we evaluated the science to look for 
where the block to development might exist. Our analyses of the 
scientific literature found approximately 25 rare diseases for which 
good science exists for a treatment but for which little effort has 
occurred to translate this to patients. Some of these diseases are very 
rare, or they may have more difficult biology, but they could be 
treated. We must do more with the science we already have and turn the 
billions of dollars of promising research into life saving treatments.
    While these data may define the statistics that describe the 
breadth and depth of the problem, the pain and tragedy of the problem 
is better captured by my personal experiences with rare disease. Nearly 
every week for the last few years, I have received calls and counseled 
families struck by genetic lightning, their small child affected by a 
devastating unpronounceable biochemical or genetic disease. These 
parents are seeking hope and inspiration that somehow their newly 
established foundation can manage to navigate the inner workings of 
drug development in order to save their kids, because no one else seems 
to be investing in those treatments. I do my best to help and support 
their efforts, but today I hope that we can do much more to change 
their tragedy into opportunity for all Americans affected by rare 
diseases.
    To understand the challenges facing rare disease drug development, 
I would like to review the case of the enzyme replacement treatment 
Aldurazyme (laronidase) used to treat the ultra-rare disorder 
mucopolysaccharidosis type-1 (MPS I). MPS I is caused by the body's 
inability to produce a specific enzyme required for the breakdown of 
specific sugar-like compounds. The deficiency causes the accumulation 
of these sugar-like materials in virtually every cell of the body. As a 
result, cells and tissues do not function properly and progressive 
damage accumulates throughout the body, including the heart, bones, 
joints, respiratory system and central nervous system. The disease is 
usually fatal by the first or second decade. Only about 200 patients in 
the United States have MPS I and treated with Aldurazyme today. From 
the development experiences of Aldurazyme, I will extract some of the 
key lessons that apply to many rare disease treatments and why these 
experiences form the basis for the CureTheProcess campaign.
    The Aldurazyme project began in 1991 when I started my work in a 
World War II-era research bungalow at Harbor-UCLA with minimal funding 
to develop an enzyme replacement therapy. My work received critical 
financial support from the Ryan Foundation, formed by Mark and Jeanne 
Dant for their son Ryan, who has MPS I \3\. I completed development of 
the treatment at a startup biotech company, BioMarin. Our work was 
ultimately successful leading to the approval of the enzyme treatment 
called Aldurazyme and I am proud to report that Ryan is now a healthy 
22-year-old young adult working for the Texas Rangers and going to 
college part-time. He has been on Aldurazyme for 13 years. The 
challenges encountered during this program are instructive.
---------------------------------------------------------------------------
    \3\ Recounted by Margery Stein, ``Saving Ryan'', Reader's Digest, 
May 2001, p75.
---------------------------------------------------------------------------
    Despite the ultimate success of Aldurazyme, our work on this enzyme 
highlights the difficulties encountered in development that our 
CureTheProcess campaign aims to improve. There are only about 200 or so 
patients in the United States on Aldurazyme today, and this ultra-rare 
disease had never been considered for treatment prior to our efforts 
beginning in 1991. Exhibit C outlines the major challenges that 
affected this program, and almost every development program for a rare 
disease.
    First, we were unable to use a reasonable biomarker based on the 
best science available to measure the improvement in our patients 
because there was no other independent clinical data to support its 
use. For rare diseases that have never been studied before, no prior 
clinical data exist. Somehow, we should still be able to use a 
biomarker and the Accelerated Approval pathway when the science is 
reasonable as it was in this case. The inability to use a reasonable 
marker that we believed (and still believe) ``reasonably predicted 
clinical benefit'', resulted in a substantial delay of the program. 
Today, there is no guidance on what can be qualified as a reasonable 
surrogate endpoint to meet Accelerated Approval requirements, meaning 
that no rare disease treatments can reasonably expect to be approved 
via this pathway.
    Second, we ran into problems with our statistical analyses in which 
we were not allowed to use the more powerful methods that would help 
rare disease studies overcome the variable nature of the patients. The 
slight miss on one endpoint with the weaker statistical method, led to 
a requirement to collect additional clinical data, again delaying the 
program. For rare diseases, some understanding and agreement is needed 
to allow the very best and most powerful approaches to be used to help 
compensate for the small study sizes and variable patients. If these 
most efficient and powerful approaches are not allowed in order to best 
control of variation and extract the most information from the data, 
most rare disease studies will fail to achieve significance, even when 
the drugs are effective. Currently there is no guidance on the 
acceptable or optimal design and analyses for rare diseases.
    Finally, it is very clear to me after 11 years at BioMarin, and 
with three drugs approved for three different rare genetic disorders, 
that the FDA is under increasing duress with limited resources for drug 
reviews, and is unable to provide the optimal level of time and staff 
required for complicated rare disorders. The Agency has been unable to 
support the sufficient degree of specialization of their review 
divisions that would allow them to hire specialists trained in the rare 
disease areas that are currently not well covered. Aldurazyme was 
reviewed by a neurologist, an oncologist and a pulmonologist, with no 
experience in MPS or biochemical genetic disorders. While they were 
intelligent and capable physicians, there is no adequate substitute for 
training and experience in the specific field of medicine. Reviewing 
drugs is an extraordinarily difficult challenge and the FDA needs to 
have the resources to be able to hire enough people with the right 
training and experience to accomplish this difficult task.
    Aldurazyme was eventually approved and so this might not seem so 
important. However, the problems encountered during Aldurazyme 
development led to the canceling of programs for two other rare 
diseases, MPS IV A and MPS VII due to financial concerns and the 
inability to use the Accelerated Approval pathway. These diseases still 
do not have treatments approved. Currently, rare biochemical and 
genetic diseases cannot use the Accelerated Approval pathway because 
they are so rare that they lack the historical clinical data that is 
required to qualify surrogate endpoints, even though their scientific 
basis is strong. To see the breadth of this problem, we summarized the 
data in the table posted on FDA's Web site regarding Accelerated 
Approvals since implementation in 1992 \4\. In Exhibit D, only one 
genetic disease has been approved via this pathway in 16 years. This 
particular approval did not have FDA agreement on the surrogate until 
after an Advisory Committee recommended its acceptance after all the 
studies were done.
---------------------------------------------------------------------------
    \4\ Taken from the FDA Web site and collated by disease category. 
Genetic treatments include only those drugs specifically targeted to an 
individual genetic disease. For example, iron binding treatments were 
not considered genetic disease specific.
    http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/
ucm121597.htm.
---------------------------------------------------------------------------
    Scientists, patients, Congress and regulatory authorities need to 
come to agreement quickly as to what science should be sufficient to 
allow access to the accelerated pathway and it must take into account 
the effect that rarity has on both the amount of clinical data that 
exists, as well as on the risk-benefit to society of the use of the 
surrogate endpoint. To achieve these changes in policy, we believe it 
is essential that a specialized review division be established to lead 
the way in guidance formation and policy based on the joint work of 
experienced FDA reviewers and disease experts.
    A dedicated FDA review division will improve the development path. 
Providing funding for a new review division for biochemical and genetic 
diseases will help create a more specialized drug review by experts who 
understand complex genetic diseases (see Exhibit E). The new division/
office should be structured to allow the reviewers to focus and gain 
experience on specific rare disease areas that need increased 
expertise. Reviewers may also provide assistance, as needed to other 
review offices with rare disease issues. By helping to facilitate 
collaboration with the Office of Orphan Product Development and links 
with the National Institutes of Health, the division/office will 
improve the overall academic environment and assure that the reviewers 
are keeping up with the latest scientific issues and advances. This 
division/office will also be essential to help implement the policy 
changes recommended by the Brownback/Brown Amendment \5\ committee's 
findings and assure that the excellent work of Drs. Cote, McNeil and 
other FDA staff will not be lost.
---------------------------------------------------------------------------
    \5\ Brownback Brown Amendment for Rare and Neglected Diseases in 
the Fiscal Year 2010 FDA Appropriations Budget, H.R. 2997, Section 740.
---------------------------------------------------------------------------
    We recommend that this new review division be responsible for 
rapidly creating new guidances for industry that could make the 
Accelerated Approval pathway available for more rare diseases and 
improve the clinical trial process. Among many possible recommendations 
from the FDA committee, we believe that two guidances should be 
included:
  --New standards for the use of surrogate and biomarker endpoints for 
        rare disorders, to allow treatments for these diseases to have 
        full access to the Accelerated Approval pathway. Due to the 
        rarity of the disorders, the use of direct, relevant surrogate 
        or biomarker endpoints as primary endpoints in clinical studies 
        is essentially impossible for some rare disorders because none 
        of these surrogates have been validated or ever evaluated in 
        clinical studies and are therefore unavailable for development 
        use. However, biochemical markers relevant to biochemical 
        genetic disorders may be far better predictors of disease and 
        treatment effect than many of the approvable surrogate markers 
        currently accepted for use in drug approvals for more common 
        disorders \6\.
---------------------------------------------------------------------------
    \6\ Patricia Dickson, Maryn Peinovich, Michael McEntee, Thomas 
Lester, Steven Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, 
Merry Passage, and Emil D. Kakkis Immune tolerance improves the 
efficacy of enzyme replacement therapy in canine mucopolysaccharidosis 
I (2008), J. Clin. Invest. 118: 2868.
---------------------------------------------------------------------------
  --New clinical study design and analysis paradigms for rare diseases 
        that properly account for clinical heterogeneity and disease 
        complexity to accurately and efficiently establish treatment 
        effects. While traditional randomized, controlled studies have 
        been used in rare diseases, this design is relatively 
        insensitive to changes in heterogeneous patients and fails to 
        allow the assessment of all types of patients with all types of 
        disease outcomes. A creative effort is needed to develop new 
        paradigms in study design and optimal statistical analyses that 
        capture individual benefit in a broad array of patients, 
        utilizing all the clinical data to establish efficacy. The 
        medical science needs to drive the statistical analysis.
      An improved development path for rare diseases is good for 
        patients and the economy.
  --New Treatments.--A streamlined development path will shorten 
        timelines and reduce the financial risk associated with 
        development of rare disease therapeutics. The result should be 
        a surge in development activity for even the rarest disorders. 
        Certain treatments for rare biochemical or genetic disorders 
        that are now unaddressed because of the difficulty in assessing 
        the clinical outcome, will now be targets of drug development 
        as appropriate surrogate markers are identified. More patients 
        with rare biochemical and genetic disorders will get earlier 
        access to specific, effective treatments.
  --Improved FDA.--A new division or office with experts trained and 
        knowledgeable in the disease area will allow for an improved 
        and more specialized FDA review. Allowing the reviewers to stay 
        focused and gain experience, will allow them to become more 
        expert in the details and nuances of science and medicine of 
        their specialized areas that is required for excellent 
        regulation.
  --New Jobs.--Improved FDA regulation will drive more U.S. 
        biotechnology job creation. The creation of the new division 
        will also provide a strong signal to the biotechnology industry 
        and investors that the FDA is working to improve the regulatory 
        path for thousands of rare disorders. This new review division, 
        combined with new policy, will drive more investment in early 
        stage biotechnology companies focused on rare diseases while at 
        the same time producing a positive impact in local communities 
        by creating new, high-paid, U.S.-based biotechnology jobs. Our 
        estimate is that each new rare disease product will likely 
        create 300-600 direct new jobs \7\ in biotechnology and about 
        five times that many in the greater economy.
    Small regulatory changes can make a huge impact. In the early 1990s 
the FDA was uncertain about blood markers predictive value for HIV/AIDS 
treatments. The need for clinical endpoints would require substantially 
more time and cost for clinical studies, which would have impaired 
investment and innovation, and lead to many deaths. Activists spurred 
the FDA to create ``Subpart H--Accelerated Approval of New Drugs for 
Serious or Life-Threatening Diseases'' in 1992. This allowed FDA to 
accept a surrogate endpoint for a measurement of the treatment effect 
if the surrogate was ``reasonably likely to predict clinical benefit''. 
At the time T-Cell counts were qualified as surrogate endpoints based 
on sound scientific data that the T-Cell count directly correlated to 
how sick the patient was.
    Over time, better science improved the marker choice to viral load, 
but the explosion in innovation was remarkable. As you can see in 
Exhibit F, over the following 16 years, 29 new drugs were approved that 
used six different mechanism of action, devised by multiple startup 
companies generating approximately 78,500 new jobs \7\. Four of those 
drugs were complex combinations that would never be developed without 
an efficient marker endpoint like viral load. More importantly, HIV 
went from a certain death sentence to a managed disease for many 
patients.
---------------------------------------------------------------------------
    \7\ BioMedical Insights report ``Ultra-rare Therapeutic Employment 
Analysis'' commissioned by Kakkis EveryLife Foundation, June 15, 2010.
---------------------------------------------------------------------------
    The changes we are proposing can do the same thing for rare 
diseases as Accelerated Approval did for HIV. By our Foundation's 
analyses of relevant clinical development costs, access to the 
Accelerated Approval process could potentially treat three to fourfold 
more diseases for the same investment. We estimate that a billion 
dollars spent on clinical development costs using the current pathway 
would cover only 10-12 products; with access to Accelerated Approval 
you could develop nearly 40 products for the same investment.
    Mr. Chairman, thank you for your time. I commend your efforts to 
convene this hearing and your leadership to improve the FDA's review 
process for products to treat rare diseases. Given the considerable 
impact an improved regulatory process would have on the economy and the 
millions of patients without treatment, we hope that you will join the 
128 patient and physician organizations and support our request to 
appropriate $10 million to establish a new Division/Office of Drug 
Evaluation for Genetic and Biochemical Diseases and start us down the 
path to an improved development process for rare disease treatments.

[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

    Senator Brownback. Ms. Dorman.
STATEMENT OF DIANE EDQUIST DORMAN, VICE PRESIDENT FOR 
            PUBLIC POLICY, NATIONAL ORGANIZATION FOR 
            RARE DISORDERS
    Ms. Dorman. Senator Brownback, thank you so very much for 
having me here today.
    The National Organization for Rare Disorders was founded in 
1983 to advocate for the enactment of the Orphan Drug Act, and 
remain today the leading advocate for the 30 million American 
patients with the estimated 7,000 known rare diseases.
    In addition to our advocacy efforts, we also run patient 
assistance and patient support programs, have compiled the 
largest database of information about rare diseases in the 
world.
    There are many Federal agencies and State agencies whose 
programs and policies affect people with rare diseases, 
including the NIH and CDC and SSA, but none is more important 
than the Food and Drug Administration. The FDA is the 
gatekeeper for the drugs, devices, and medical foods that are 
needed by patients with rare diseases. The FDA sets the 
standards for studying new medical products, and therefore 
plays a central role in research, as well as product approvals.
    NORD advocates for full funding for the FDA. We were 
instrumental in founding an organization, now known as the 
Alliance for a Stronger FDA, which now includes more than 180 
members representing all of FDA's stakeholders, and which has 
the singular purpose of advocating for increased funding for 
the entire agency.
    We have witnessed what happens when FDA is underfunded. The 
agency cannot meet its review times for new drugs and medical 
devices, cannot provide the guidance that researchers so 
desperately need and seek, and cannot maintain the public's 
confidence in the regulatory system.
    Delays in review times and lack of guidance affects our 
patient constituency especially hard, because, despite the 
great advantages in medicine, there are approved drugs for 
only, as you have said, about 200 of the estimated 7,000 known 
rare diseases.
    Many of our patients are treated with approved products 
being used off-label. And many are not being treated at all, 
because there are no treatments at all.
    NORD's top priority, in addition to the support services we 
provide to the patients with rare diseases, is to advance 
medical research and the development and approval of new 
therapies for our patients. This with this perspective that we 
support, in principle, any steps that would advance medical 
research or provide FDA with the resources it needs to carry 
out its critical public health functions.
    We were encouraged by the creation, earlier this year, of a 
new position within the FDA's Center for Drug Evaluation and 
Research, a position dedicated exclusively to rare diseases. We 
advocate for more training and support for FDA personnel who 
interface with the researchers who develop orphan products. And 
we support more transparency in the regulatory system so that 
investigators and drug and device manufacturers can make the 
right decisions as they develop new products.
    The current leadership of the FDA has demonstrated its 
sensitivity to the vulnerability and special challenges of 
people with rare diseases. We understand the constraints on the 
budgets of Federal agencies, but, at the same time, the FDA 
needs more resources if it is to fill the commitment it has 
made to the rare-disease community.

                           PREPARED STATEMENT

    Mr. Chairman, I would be pleased to answer any questions 
you may have. And, again, thank you very much for allowing me 
this opportunity.
    Senator Brownback. Thank you, Ms. Dorman. Appreciate it.
    [The statement follows:]
                   Prepared Statement of Diane Dorman
    Mr. Chairman, thank you for the opportunity to testify before you 
today. I am Diane Dorman and I am the vice president for public policy 
of the National Organization for Rare Disorders, or NORD. We were 
founded in 1983 to advocate for the enactment of the Orphan Drug Act, 
and we remain today the leading advocate for the 30 million American 
patients with the estimated 7,000 known rare diseases. In addition to 
our advocacy efforts, we also run patient assistance and patient 
support programs and have compiled the largest database of information 
about rare diseases in the world.
    There are many Federal and State agencies whose programs and 
policies affect people with rare diseases, but none is more important 
than the Food and Drug Administration. The FDA is the gatekeeper for 
the drugs, devices and medical foods that are needed by patients with 
rare diseases. The FDA sets the standards for studying new medical 
products and therefore plays a central role in research as well as 
product approvals.
    NORD advocates for full funding of the FDA. We were instrumental in 
founding an organization now known as the Alliance for a Stronger FDA, 
which now includes more than 180 members representing all of FDA's 
stakeholders and which has the singular purpose of advocating for 
increased funding for the FDA. We have witnessed what happens when FDA 
is underfunded: the agency cannot meet its review times for new drugs 
and medical devices; cannot provide the guidance that researchers so 
desperately seek; and cannot maintain the public's confidence in the 
regulatory system.
    Delays in review times and lack of guidance affects our patient 
constituency especially hard, because despite the great advances in 
medicine, there are approved drugs for only about 200 of the estimated 
7,000 rare diseases. Many of our patients are treated with approved 
products being used off-label, and many are not being treated at all 
because there are no treatments.
    NORD's top priority, in addition to the support services we provide 
to patients with rare diseases, is to advance medical research and the 
development and approval of new therapies for our patients.
    It is with this perspective that we support in principle any steps 
that would advance medical research or provide FDA with the resources 
it needs to carry out its critical public health functions. We were 
encouraged by the creation earlier this year of a new position within 
the FDA's Center for Drug Evaluation and Research, a position dedicated 
exclusively to rare diseases.
    We advocate for more training and support for FDA personnel who 
interface with the researchers who develop orphan products, and we 
support more transparency in the regulatory system so that 
investigators and drug and device manufacturers can make the right 
decisions as they develop new products.
    The current leadership of the FDA has demonstrated its sensitivity 
to the vulnerability and special challenges of people with rare 
diseases. We understand the constraints on the budgets of Federal 
agencies, but at the same time the FDA needs more resources if it is to 
fulfill the commitment it has made to the rare disease community.
    Mr. Chairman, I would be pleased to answer any questions you have. 
Again, thank you for the opportunity to appear before you on behalf of 
the 30 million men, women and children with rare diseases.

    Senator Brownback. Mr. Bollyky, good to have you here.
STATEMENT OF THOMAS J. BOLLYKY, VISITING FELLOW, CENTER 
            FOR GLOBAL DEVELOPMENT
    Mr. Bollyky. Ranking Member Brownback, Senator Pryor, thank 
you for recognizing the importance of neglected diseases to 
global health and U.S. interests.
    I'm grateful for this opportunity to testify today about 
ways in which FDA may expand its leadership role in supporting 
the development of drugs, vaccines, and diagnostics for these 
diseases that afflict the world's poorest and threaten 
Americans at home and abroad.
    My testimony today reflects the work I have the honor of 
leading at the Center for Global Development, as well as the 
substantial input of the Global Health Technologies Coalition.
    Over 1 billion people, including 400 million children, 
suffer from one or more neglected diseases. As defined under 
law, these diseases include malaria and tuberculosis, which, as 
you mentioned, kill 2.5 million people annually, but also other 
diseases, such as Dengue fever and Rotavirus, which may be less 
familiar, but have a large and often lethal toll.
    Neglected diseases do not just kill, they adversely affect 
pregnancy outcomes, undermine the development of school 
children and worker productivity, and perpetuate the cycle of 
poverty, insecurity, and infirmity in the communities in which 
they are endemic. In short, neglected diseases rob the world's 
poorest community of their hopes for a better future.
    Neglected diseases, however, are not just a concern for the 
developing world. Americans, when they travel abroad, are 
exposed to these diseases, as they are when they serve in the 
U.S. military. Neglected diseases cross borders with trade and 
travel, and the health and economic consequences of their 
outbreaks are significant.
    Given that one out of six people worldwide suffer from 
neglected diseases, it may seem surprising that there are few, 
if any, effective treatments for many of these diseases. The 
extreme poverty of those afflicted, however, greatly undermines 
the potential market return on the substantial investment that 
you mentioned it takes to develop a drug or a vaccine. 
Accordingly, of the nearly 1,400 products, new chemical 
entities that were approved between 1975 and 1999, fewer than 
40 were for neglected diseases.
    The good news is that there is a potential for this to 
change. Over the last decade, there have been efforts led by 
public-private partnerships and the support of the U.S. 
Government and the Bill and Melinda Gates Foundation, there are 
now dozens of products in the pipeline for neglected diseases. 
These drugs, vaccines, and diagnostics will be, for many 
neglected diseases, the first product in a generation available 
to address those diseases. For other neglected diseases, they 
will simply be the first tool ever available.
    The challenge is that there are regulatory gaps and 
inefficiencies that undermine the development of these products 
in the pipeline. Those challenges are twofold:
    First, the regulatory environments in many developing 
countries are inadequate to support the clinical trials 
necessary to complete the clinical development of the products 
in the pipeline.
    Second, the pathway for approval for these neglected 
disease products is poorly coordinated and a multistep process 
that involves the FDA, the World Health Organization, and 
regulators in the developing countries in which these products 
will ultimately be used.
    Gaps and inefficiencies abound throughout this pathway. FDA 
reviewers may not have the experience and expertise with the 
particular target neglected disease, as it is not endemic to 
the United States. The WHO's prequalification program, which 
assesses products for procurement by U.N. agencies, lacks 
sufficient dedicated resources, and is often slow. Regulators 
in developing countries often do not have the mandates, the 
experience, or the expertise to assess and approve products.
    Through the efforts of this subcommittee, FDA has recently 
established a review group for neglected diseases, which offers 
a good opportunity to address these gaps and inefficiencies.
    As part of that effort, we would recommend that they pursue 
three measures:
    First, a collaborative review process for neglected disease 
products in which FDA review and WHO prequalification are 
effectively simultaneous and mutually supporting.
    Second, capacity-building arrangements with the World 
Health Organization and developing countries, priority 
developing countries, which would involve dedicating more FDA 
reviewers to conduct prequalification assessments on behalf of 
WHO, working with NIH and USAID to support regional platforms 
for a clinical trial regulation in developing countries, and an 
exchange program with WHO and developing-country regulators.
    Last, FDA should issue detailed guidance and initiate a 
mentoring program for public-private partnerships and other 
nontraditional product developers which may not have the 
experience with late-stage clinical development and product 
registration.

                           PREPARED STATEMENT

    I provide further details on all these proposals in my 
testimony.
    I look forward to your questions, and thank you for your 
time and your leadership on this issue.
    Senator Brownback. Thank you, Mr. Bollyky.
    [The statement follows:]
                Prepared Statement of Thomas J. Bollyky
    Chairman Kohl, Ranking Member Brownback, and other distinguished 
members of the Subcommittee: Thank you for recognizing the importance 
of neglected diseases to global health and U.S. interests. I am 
grateful for this opportunity to testify about ways in which the U.S. 
Food and Drug Administration (FDA) may expand its leadership role in 
supporting the development of products (drugs, vaccines, and 
diagnostics) for diseases that afflict the world's poorest.
    The essence of the problem is this: while philanthropists and 
private companies have increasingly seen the value in devising products 
for heretofore neglected diseases, the regulatory infrastructure 
necessary to develop and introduce these therapies to the developing 
world is sadly inadequate. Regulatory inefficiencies and gaps add costs 
to product development, deter private investment, and delay patients' 
access to potentially life-saving treatments. Building the needed 
regulatory infrastructure is a substantial challenge and unprecedented 
opportunity to improve the lives of millions around the globe and 
promote the well-being of Americans at home and abroad. The United 
States Government and FDA in particular should take a leadership role 
in improving the clinical development and regulatory pathways for 
neglected disease products.
    My testimony will proceed in four parts. First, I will summarize 
the burden that neglected diseases impose on affected people and their 
communities. Second, I will discuss the tremendous promise of the 
current pipeline of candidate products to address neglected diseases. 
Third, I will give an overview of how novel therapies are developed and 
approved for use in the developing world and the persistent regulatory 
gaps that undermine this process. Last, I will offer recommendations on 
how FDA can help bridge those gaps.
    My testimony today reflects the work I have the honor of leading at 
the Center for Global Development with the support of the Bill & 
Melinda Gates Foundation and the substantial input of the public 
private development partnerships (PDPs) and nongovernmental 
organizations that comprise the Global Health Technologies Coalition.
                    the burden of neglected diseases
    Neglected diseases are a heterogeneous collection of predominantly 
infectious conditions for which few, if any, effective therapies exist. 
An estimated one billion people, including 400 million children, suffer 
from one or more of these diseases. As defined under U.S. law, 
``neglected diseases of the developing world'' include malaria, 
tuberculosis (TB), and a dozen other parasitic, soil transmitted, 
bacterial, and tropical infections endemic to Africa, Asia, tropical 
regions of Latin America, and parts of the Middle East.\1\
---------------------------------------------------------------------------
    \1\ Section 524(a)(3) of the U.S. Food, Drug, and Cosmetic Act (21 
U.S.C. 360n(a)(3)).
---------------------------------------------------------------------------
    Neglected diseases have a staggering impact on the individuals and 
communities which they afflict. Many of these diseases exact a large 
and lethal toll, with tuberculosis and malaria alone killing an 
estimated 2.6 million people annually.\2\ Other neglected diseases are 
less deadly, but disable, deform, and increase their sufferers' 
vulnerability to other infectious diseases like HIV/AIDS. Children and 
pregnant women suffer disproportionately. In 2008, an estimated 8.8 
million children worldwide under the age of five died from largely 
preventable causes, many of which are related to neglected diseases.\3\ 
Neglected diseases cause adverse pregnancy outcomes and impair 
children's cognitive development, school attendance, and earning 
potential for the decades that follow.\4\ In sum, neglected diseases 
rob the world's poorest communities of their hope for a better future. 
They sap current and future worker productivity, undermine economic 
development, and perpetuate the cycle of poverty, insecurity, and 
infirmity in the communities in which these diseases are endemic.
---------------------------------------------------------------------------
    \2\ WHO, Global tuberculosis control: A short update to the 2009 
report (2009) and WHO, World malaria report 2009 (2009).
    \3\ UNICEF, Table of Basic Indicators, accessed at http://
www.unicef.org/rightsite/sowc/pdfs/statistics/
SOWC_Spec_Ed_CRC_TABLE%201.%20BASIC%20INDICATORS_EN_111309.pdf (last 
visited June 16, 2010).
    \4\ Hotez PJ, Ferris MT. The antipoverty vaccines. Vaccine 2006; 
24: 5787-99.
---------------------------------------------------------------------------
    Neglected diseases also threaten the well-being of Americans at 
home and abroad. These diseases cross borders with trade and travel; 
the health and economic consequences of outbreaks are significant.\5\ 
Americans travel to neglected disease-endemic countries and the women 
and men of the U.S. military serve there. Neglected diseases undermine 
the security of our allies and the economic development of our 
potential trading partners.
---------------------------------------------------------------------------
    \5\ Ruth Levine, Healthy Foreign Policy: Bring Coherence to the 
Global Health Agenda in White House and the World, Center for Global 
Development 43-45 (Birdsall ed. 2008).
---------------------------------------------------------------------------
    Given that approximately one out of six people worldwide suffer 
from one or more neglected diseases, it may seem surprising that there 
are few, if any, effective therapies for them. The extreme poverty of 
those afflicted, however, greatly limits the potential market return on 
the substantial investment needed to develop therapies for neglected 
diseases.
    Accordingly, of the nearly 1,400 new chemical entities approved 
worldwide between 1975 and 1999, fewer than 40 were for neglected 
diseases.\6\
---------------------------------------------------------------------------
    \6\ Tufts Center for the Study of Drug Development, Drug Approvals 
for neglected diseases increase along with more R&D Funding, 11 Impact 
Report (2009).
---------------------------------------------------------------------------
       the promise of the current pipeline of candidate therapies
    A confluence of private philanthropy and enlightened government 
intervention has dramatically changed the landscape for neglected 
diseases over the last decade. Led by the efforts of PDPs and fueled by 
the support of the Gates Foundation and U.S. Government actors 
(including members of this subcommittee, National Institutes of Health, 
USAID, FDA, and Department of Defense), dozens of such products are now 
in development.
    The therapies, diagnostics, and preventative tools in the product 
pipeline will be, for many neglected diseases, the first new tools in a 
generation and, for others, they will be simply the first. Promising 
examples include:
  --A malaria vaccine candidate in late-stage clinical testing which, 
        if approved, will be the first vaccine against malaria (a 
        disease that kills 900,000 annually) and the first vaccine 
        against a parasite approved for use in humans.
  --Nine new TB vaccine candidates in clinical trials worldwide, 
        including the first late-stage infant study of a TB vaccine in 
        over 80 years. There are also eight new TB drug candidates in 
        testing, which, if approved, would become the first new TB 
        drugs in over 40 years. These therapies could help reduce the 8 
        million new TB infections and 1.7 million TB-related deaths 
        that happen each year.
  --New vaccines for rotavirus (the most common cause of childhood 
        diarrhea) and pneumoccus pneumonia, which together kill 
        millions of children under five each year.
 the persistent gaps in the development pathway for neglected disease 
                               therapies
    Discovery of a novel therapeutic which may be effective against a 
target disease is only the first step in bringing that therapy to 
patients. Developers must demonstrate the safety and efficacy of the 
candidate therapy in a series of clinical trials and register that 
therapy for use in disease endemic settings. In the case of neglected 
diseases, substantial gaps and inefficiencies in the development and 
regulatory pathway for these products threaten to delay or derail their 
introduction to patients.
    Late-stage clinical trials must be conducted in settings where 
individuals suffer from the target disease and under the circumstances 
in which the product will be ultimately used. For neglected diseases, 
those settings are generally developing countries, with, in many cases, 
limited clinical research capacity and under-developed regulatory 
systems. It is difficult to conduct ethical, sufficiently regulated 
trials in such environments. Lack of regulatory capacity and clear 
rules hinders trial planning, initiation, and patient recruitment, and 
may lead to regulatory non-compliance. That risk of non-compliance and 
harm to subjects deters private investment. The shortcomings of these 
regulatory environments are further exacerbated by the complexity of 
the diseases and products involved and highly vulnerable, often 
pediatric subjects.
    Upon completion of the necessary trials, sponsors must usually 
advance through multiple regulatory processes in order to register 
their product for use in the target neglected disease-endemic 
countries.
FDA Approval
    In practice, most sponsors first submit their novel therapy for 
marketing approval by a developed country regulator, like FDA, in order 
to minimize the risk of liability and to take advantage of that 
regulator's experience in assessment, resources, and clear protocols 
and rules. The challenge is that FDA may be unfamiliar with the 
neglected disease (since it is not endemic in the United States) and 
the conditions and patient populations in which the product will be 
used. This may delay FDA's assessment of the safety and efficacy of the 
product and reduce the value of that assessment for the national 
regulatory authority (NRA) in the disease endemic country where the 
product will be used.
WHO Prequalification
    Upon receiving marketing approval, the sponsor will next submit its 
product to the WHO prequalification program, which ensures that drugs, 
vaccines, and diagnostics meet prescribed standards of quality, safety, 
and efficacy and are appropriate for procurement by U.N. agencies. WHO 
is not a regulatory authority. A novel therapy must first be approved 
by an NRA which the WHO deems to be ``fully functional'' (such as FDA) 
in order to be eligible for prequalification. Many developing country 
regulators, however, rely heavily on WHO prequalification and will not 
approve a novel therapy without it.
    Unfortunately, WHO prequalification can be a slow process. The 
average time to prequalify is 18 and 24 months for drugs and vaccines, 
respectively.\7\ These delays often result from the inexperience of 
nontraditional product developers in preparing dossiers and the time 
required for WHO to assemble each assessment team ad hoc.
---------------------------------------------------------------------------
    \7\ The George Institute, Registering New Drugs: The African 
Context 13, 18 (2010).
---------------------------------------------------------------------------
Approval by the Local Regulatory Authority
    Once WHO prequalifies a novel drug or vaccine, the sponsor can 
finally submit it to the NRA in the target neglected disease-endemic 
country for its approval. Even with WHO prequalification, substantial 
delays may occur at this step. Many NRAs, particularly in Africa and 
Southeast Asia, have limited experience, resources, and mandates for 
assessing, approving, and registering innovative products. Assessment 
of novel products can be complicated even for well-resourced and 
experienced developed country regulators; the historical mission of 
many developing country NRAs has been to provide their population with 
affordable generic medicines, rather than assuring timely access to 
innovative products.
    The average time required for a novel drug or vaccine to advance 
through this multistep regulatory pathway is approximately 3 years.\8\ 
These delays and the uncoordinated and sequential nature of these 
processes defer patients' access to potentially life-saving treatments, 
deter private investment, and add significant expense. Realizing the 
promise of the current product pipeline for neglected diseases will 
require not only increased funding for clinical trials and developing 
country NRA capacity building, but also greater attention to how 
clinical development and regulatory pathways for these products may be 
improved to reduce unnecessary costs and delays.
---------------------------------------------------------------------------
    \8\ Id. at 18.
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   how fda can improve the development pathway for neglected disease 
                               therapies
    FDA already plays a central role in the development of safe, 
effective, and high quality therapies for neglected diseases. FDA 
administers the Orphan Drug Act and priority review voucher program to 
provide useful incentives for developing novel therapies for neglected 
diseases. FDA pathways for priority review and accelerated and fast 
track approval offer important opportunities for consultation on 
clinical development plans and submissions, and expedited product 
assessment. In 2008, the FDA Center for Biologics Evaluation and 
Research (CBER) issued guidance confirming the scope and availability 
of the FDA approval process for developers of vaccines against 
infectious diseases or conditions not endemic in the United States.\9\
---------------------------------------------------------------------------
    \9\ Food and Drug Administration, U.S. Department of Health and 
Human Services, General Principles for the Development of Vaccines to 
Protect Against Global Infectious Diseases (2008).
---------------------------------------------------------------------------
    While FDA has performed admirably in its role, there remain 
significant organizational and logistical challenges particular to 
reviewing therapies intended for foreign use. The challenges are 
twofold.
    First, resource limitations and FDA reviewers' unfamiliarity with 
neglected diseases and the conditions and patient populations in which 
the product will be used often delay and reduce the utility of FDA's 
product assessment. Put simply, FDA is performing a job it is not fully 
empowered, resourced, or designed to do.
    Second, FDA regulatory pathways and programs are not well 
coordinated with or sufficiently supportive of the other entities 
involved in developing and approving these products. FDA approval is 
important, but it is a component of a larger, multistep process that 
also involves WHO and developing country NRAs. Accordingly, while it is 
important that the resources and pathway for FDA approval of products 
for neglected diseases be improved, it will not be sufficient if those 
improvements do not address the gaps and inefficiencies in the larger 
process for approving therapies for use by the patients who need them.
    Pursuant to the efforts of this subcommittee and the requirement in 
the fiscal year 2010 Department of Agriculture appropriations bill, FDA 
recently established a new review group to prepare recommendations for 
the FDA Commissioner and Congress on ``appropriate preclinical, trial 
design, and regulatory paradigms and optimal solutions for the 
prevention, diagnosis, and treatment of neglected diseases of the 
developing world.'' \10\ This review group provides an excellent 
opportunity for FDA to develop new mechanisms and strategies for 
bridging the persistent gaps in the development pathway for neglected 
disease therapies.
---------------------------------------------------------------------------
    \10\ Fiscal Year 2010 Agriculture, Rural Development, Food and Drug 
Administration, and Related Agencies Appropriations Bill,  740 (2009).
---------------------------------------------------------------------------
    As part of that effort, I respectfully recommend that FDA consider 
adopting the following measures:
An Integrated, Sufficiently Supported Neglected Disease Product 
        Approval Process
    Simultaneous, coordinated reviews by all the regulatory entities--
FDA, WHO, and the developing country NRA--involved in the approval of a 
potential therapy would minimize duplication of scarce regulatory 
resources and reduce delays in product approval and introduction. It 
would combine FDA's resources and expertise in assessing novel and 
complex therapies with WHO and developing country NRAs' understanding 
of neglected disease presentation and local conditions, patient 
populations, and health care delivery platforms.
    FDA should consult with WHO to develop a formal collaborative 
process, akin to that which exists between the European Medicines 
Agency (EMA) and WHO, in which FDA would commit to address the 
requirements for prequalification as part of its approval process and 
WHO would commit to an expedited decision on prequalification post-FDA 
approval. This collaborative process should be formal and the details 
of its operation made public in order to improve its predictability for 
prospective product developers. The process should also include:
  --WHO and Developing Country Expert Observers.--FDA reviews of 
        neglected disease products should include, with the consent of 
        the sponsor, WHO and developing country experts as formal 
        observers.
  --Confidential Information Sharing Arrangements.--There should be 
        arrangements in place between all FDA Centers, WHO, and 
        priority developing country NRAs to share confidential data and 
        inspections reports on neglect disease product submissions.
  --Developing Country Experts on Advisory Committees.--The budgets of 
        advisory committees should be sufficient to enable the active 
        participation of developing country experts.
  --More FDA Reviewers With Relevant Expertise.--FDA should hire more 
        full-time reviewers with tropical disease expertise and 
        experience.
    There is precedent for such an approach. In conjunction with the 
U.S. President's Emergency Plan for AIDS Relief (PEPFAR), FDA has a 
program to review the safety, efficacy, and quality of HIV/AIDS 
medications manufactured in countries where they are off-patent, prior 
to the expiry of those patents in the U.S. FDA works with eligible 
sponsors to help prepare applications for this program and for 
inspections. It prioritizes review of submissions and, as part of its 
assessment process, engages with the WHO prequalification program and 
developing country NRAs to facilitate the products' assessment and 
adoption.
Strengthen FDA's Ability To Support Its WHO and Developing Country NRA 
        Partners
    The efficiency and productivity of the development pathway for 
neglected disease therapies depends on the capacity of the WHO 
prequalification program and priority developing country NRAs. FDA 
should support that capacity with:
  --More Resources for WHO Prequalification.--FDA should commit 
        additional experienced and qualified FDA reviewers to conduct 
        prequalification assessments on behalf of WHO in priority 
        neglected disease areas (similar to FDA's role in prequalifying 
        PEPFAR products) or a fixed number of neglected disease product 
        dossiers per year.
  --Regional Platforms for Clinical Trial Regulation and Product 
        Registration.--Regional approaches can pool scarce regulatory 
        resources and provide a more efficient vehicle for FDA 
        technical assistance. WHO has used ad hoc regional, joint 
        reviews to support African countries' regulation of vaccine 
        clinical trials; working with partner U.S. Government agencies 
        such as NIH and USAID, FDA could help foster the improvement, 
        expansion, and formalization of those programs.\11\
---------------------------------------------------------------------------
    \11\ See Thomas J. Bollyky, Bridging the Gap: Improving the 
Clinical Development and Regulatory Pathway for Health Products for 
Neglected Diseases, Center for Global Development, forthcoming June 
2010.
---------------------------------------------------------------------------
  --Employee Exchanges With WHO and Developing Country NRAs.--
        Initiating a pilot project for 1- to 2-year rotations of mid-
        career FDA reviewers into developing country NRAs and WHO 
        prequalification programs would help build the capacity of 
        regulatory counterparts and improve mutual understanding. If 
        successful, this program could be expanded to other areas such 
        as food and drug safety and serve as the foundation of a FDA 
        version of the successful Epidemic Intelligence Service (EIS) 
        at the Centers for Disease Control.
Enhance FDA Support and Guidance for Nontraditional Developers (I.e., 
        PDPs).
    Intermediary nonprofit organizations and PDPs manage a significant 
portion of global neglected disease product development, but may not 
have experience with late stage clinical development, dossier 
preparation, or product registration. FDA should support these PDPs and 
intermediaries and attract more interest in neglected disease product 
development with:
  --Guidance for Prospective Developers of Neglected Disease 
        Therapies.--FDA should issue clear and detailed public guidance 
        on the full menu of support services that FDA offers for 
        neglected disease drug, vaccine, and diagnostic candidate 
        development and registration, including incentives, fee 
        waivers, and accelerated reviews.
  --More Support for Neglected Disease Product Submissions.--FDA should 
        institute a program to work with PDPs and other nontraditional 
        product developers on their submissions to ensure clinical 
        development plans are both scientifically sound and cost-
        effective, and that those developers take full advantage of the 
        tools, incentives, and expedited pathways available to them 
        under the FDA's Investigational New Drug (IND) and Therapeutic 
        Biologic Applications (BLA) application processes.
    By adopting these measures and assuming a leadership role in 
improving the development and regulatory pathways for neglected disease 
therapies, FDA can do much to further the interests of all Americans in 
controlling these diseases and improve the lives of millions around the 
globe.

    Senator Brownback. I've been joined by Senator Pryor from 
Arkansas.
    Delighted to have you here, Senator Pryor. I gave an 
opening statement. I'd sure invite you to give one.
    Senator Pryor. Thank you.
    Senator Brownback. Okay.
    I'm going to have a few questions, and then I'll turn it to 
you, Senator Pryor, on this, as well.
    But, I want to thank the panel for putting these ideas 
forward and for your work on this issue.
    You're right, about Americans traveling and then getting 
exposed to these diseases. My oldest son did a study abroad 
program, and his roommate had Dengue fever. And we weren't 
exactly sure what it was, but it sounded really bad. It's one 
of those things that as people travel more, you're going to 
have more exposure, and so, there's good reason for us to work 
in it.
    I am very appreciative of people and groups, particularly 
the Gates Foundation that you mentioned, that are working on 
these issues. I think they've just brought an energy, a focus, 
an intensity, and an efficiency into this field, that I think 
has been very helpful, from what I've observed over the years. 
So, I really applaud them or anybody that may be associated 
with them that are here.
    Let me start with you, Mr. Bollyky, if I could. To your 
last point about a detailed guidance, I take it what you're 
saying is, it's not a change of the process. Perhaps just 
saying to alternate pathway groups rather than large 
pharmaceutical companies, ``If you will go this route, you'll 
be successful.'' Is that what you're saying with that proposal?
    Mr. Bollyky. Thank you, Senator.
    To your question, it's less of a guarantee of success, of 
course, but a lot of these public/private partnerships are new 
initiatives to develop products specifically for these 
neglected diseases. And they may not have the experience to 
know all the benefits available to them, both under the IND, 
investigational new drug, process or the BLA process, for 
vaccines. FDA has recently issued guidance, its Center for 
Biological Evaluation Research (CBER) has issued guidance 
specific for vaccines. We'd like to see more extensive guidance 
on that front, but also guidance issued around drugs and 
diagnostics, as they're an important part of this program.
    Senator Brownback. And you think that would encourage more 
people to get into those fields, then, if they did that?
    Mr. Bollyky. I think that's exactly right. It would do 
both. It would encourage more investment in development of 
neglected-disease products, as well as allowing them to 
capitalize on the investments that have already occurred in the 
products in the pipeline, by helping them through this last 
stage of the process.
    Senator Brownback. Dr. Kakkis, we've talked, previously, 
about this special review group that you were talking about, 
the new Division of Biochemical and Genetic Diseases. You've 
been kind enough to come by my office and talk about that. 
There are some people in the system that don't care for that 
idea. They don't want to see a separate division. Why do you 
believe that this is an important innovation that needs to take 
place within FDA?
    Dr. Kakkis. Well, the FDA currently does have separate 
divisions that are assigned different scope of diseases. What 
we're saying here is that they need to have a division that has 
particularly trained people in these diseases that are both 
biochemical or neuromuscular or some of the other genetic rare 
disorders that require specialized expertise. And that group 
needs to be a group that is trained in the pediatric 
subspecialties, not in other specialties.
    In the Aldurazyme case, I had a neurologist, a 
pulmonologist, an oncologist review a disease that they never 
see in training, and are not knowledgeable about. And in order 
to get the best regulation, you should have physicians that are 
actually very knowledgeable and have been trained in the field 
of medicine. And, throughout FDA, there are certainly 
specialists in every area, but, in certain areas, there's not 
good coverage. And I think that, in this rare genetic disease 
area, there is not as good a coverage as there could be.
    So, we're hoping you take some of the experienced people 
within FDA that are scattered in different places, consolidate 
them, bring in additional staff, and build a division, where 
people can get expertise and leverage their experience, and 
stay together as a group, rather than having the expertise 
diffuse and not leveraged over time.
    Senator Brownback. You don't think they could just do that 
on almost a task-force basis, as drugs come through--you're 
saying the expertise is there throughout FDA, that you could 
pull it together for particular reviews?
    Dr. Kakkis. Well, when you apply to go in a clinical trial, 
you get a particular division applied. I think it's very hard 
to have other people impacting a review that are not really the 
ones who have to be responsible as reviewer and division head. 
We think that it makes sense to have that division group be 
specialized so they can gain experience over time. When you 
have them disseminated, that causes them to have to review 
things, for example, that are large market drugs, or different, 
or expect people to be able to shift from different types of 
large market diseases to small rare diseases. And we think it 
requires more training and experience and focus to be able to 
make that happen. This is why we believe a specialized group is 
necessary.
    It's not something that's unusual; the FDA has a lot of 
groups that are designed. We just think that there are certain 
areas that are not well covered. We're not expecting this 
review group to be for all rare diseases. We're expecting for 
certain areas of the rare disease groups that are not currently 
well represented at FDA. There are definitely people that are 
talented and experienced at FDA that have reviewed these, but 
very often they are called on to do other tasks. And we think 
it would be better to have them focused and develop experience 
and get that group to be efficient and understand the process 
well. And I think that's where you can get better 
decisionmaking.
    Senator Brownback. Ms. Dorman, you heard Dr. Kakkis say 
that there was only one product for genetic disorders that went 
through the accelerated pathway. And there's been a number that 
have been cancer drugs approved in that accelerated pathway, I 
believe this was his testimony. You've worked and tracked this 
field for some period of time.
    Why do you think the accelerated pathway has not been more 
accessible or used in this rare and neglected disease category?
    Ms. Dorman. Well, that's something that we're attempting to 
address right now. We're working with the FDA and the NIH right 
now, in a task force, to address some of those issues. And I 
think the FDA is trying to do the same thing, as well, with Dr. 
Pariser's Office of Rare Diseases at FDA. There have been two 
courses on the development science of small clinical trials. 
And, in October, we're going to be working with FDA and NIH and 
Duke University to address some of these really important 
issues with people in academia, because we see a great lack of 
knowledge in the world of academia. They don't understand how 
to develop a product. They don't understand the regulatory 
process.
    So, we recognize that there are certain roadblocks and 
issues, but I think both the FDA and NIH have been really 
proactive in that space, to try to address them. So, we're 
really excited about that.
    And also, you know, next week, FDA is going to be having a 
public hearing on orphan products, a public hearing for 2 days, 
at which NORD will speak, as well, looking at those problems, 
and trying to fix them in some way.
    Senator Brownback. I hope we can.
    Senator Pryor.
    Senator Pryor. Thank you. And thank you for conducting this 
hearing today.
    I have a question--let me start with you, Ms. Dorman--and 
that is really a followup to Senator Brownback's question, of a 
moment ago, that it's not universally accepted that people 
should follow Dr. Kakkis's recommendations there. Do you have 
any views on whether--does NORD have any views concerning his 
proposal?
    Ms. Dorman. We are somewhat concerned because we feel a 
separate division would in some way create additional silos.
    And I'll use the example of the Office of Rare Diseases at 
NIH. They're a small office, under the Office of the Director, 
and their Director is able to leverage opportunities across all 
centers and all Institutes, all 27 of them, because he doesn't 
have any barriers to opportunities. And we think that's very, 
very important, the possibility of setting up an ad hoc group 
of sort at the FDA to address some of these problems. But, 
creating an additional silo, in our opinion, may cause 
additional problems to access. And I would hope that the FDA 
would also be willing to work with the NIH to, you know, tap 
into the experts there.
    Senator Pryor. Dr. Kakkis, do you have any response to 
that?
    Dr. Kakkis. Well, I think the challenge is that if you 
don't have the expertise among those actually doing the 
reviews, I think it's very difficult to expect other people 
from elsewhere to have input. So, the Office of Orphan Product 
Development does advocate across the agency. But, they cannot 
affect the review process for drugs in a way that's 
fundamental. If the reviewers don't want to approve your drug, 
there's nothing the Orphan Product Office can do. Truth is 
that, within the group or division, they're personally 
responsible, as reviewers, to make those decisions. And it is 
important to have them have the right training.
    Just like you wouldn't want to go get heart surgery from a 
pediatrician, I think you'd want your drugs that are being 
reviewed to be reviewed by people trained in the area, and that 
specialize in it and really understand it. It's fairly simple.
    They do have this in various areas at FDA. It's just 
certain areas that are not well covered. We certainly don't 
expect all rare diseases to be included in this one group. 
We're talking about only certain ones that are not well 
covered. Other rare diseases can be elsewhere. And we're highly 
supportive of the Office of Rare Disease that has been created, 
with Acting Director, Ann Pariser, who's here today, to help 
coordinate across the agency, within the review division. But, 
I still think there are certain groups that are not well 
covered, and that we do need some additional support.
    Senator Pryor. Thank you.
    Mr. Bollyky, let me ask you a quick question, and that is, 
From your standpoint, are there things the FDA has done, or 
could do, related to the approval process for medicines to 
treat rare diseases, that you believe could be beneficial to 
the treatment of neglected diseases?
    Mr. Bollyky. Thank you for asking that question, because it 
also provides me the opportunity to say something that I didn't 
emphasize enough in my testimony, which is, the men and women 
on the FDA, I find, on this issue, to be excellent, and really, 
in the last couple years, particularly committed to the issues 
around neglected diseases. And I think on the part of CBER, 
they've done quite a bit, in terms of, as I mentioned to 
Ranking Member Brownback, issuing guidance about infectious 
diseases that are not endemic. We'd certainly love to see them 
do more along those lines on the drug and diagnostic side. We'd 
certainly, as I mentioned in testimony, like to see more 
cooperation with the WHO to reduce the time gap that occurs 
currently between FDA's approval process and the WHO's approval 
process. The thing to recognize is, FDA is really just a step 
in the pathway for these products to get to the patients in the 
countries in which they will be used.
    So, we'd love to see that. I know that they're starting to 
take steps in that direction as part of this review group. We 
encourage that. We'd love to see it go forward.
    Senator Pryor. Okay.
    Ms. Dorman, let me ask you a couple of last questions. And 
that is--you know, one doesn't have to be too observant--just 
basically turn on the television, and see that there apparently 
are a lot of economic incentives out there for drugs to treat 
baldness, toenail fungus, sexual performance, and a lot of 
other things that you see all these ads for. Are there steps 
you believe that Congress should take to encourage private 
enterprise to address more pressing public health issues, 
instead of develop just more lifestyle medicines? That maybe 
seems to be where the money is, but I don't know.
    Ms. Dorman. Well, that's the $64,000 question, Senator. 
I've been asking myself that question for about 10 years right 
now.
    I really have to say, when we're talking about neglected 
diseases, NORD has always encouraged research and product 
development into neglected diseases, because they can realize 
the 7 years of marketing exclusivity under the Orphan Drug Act. 
Unfortunately, they have never taken the bite, so to speak. 
But, that always has been a holy grail for orphan product 
development. And companies willing to develop these products 
for neglected diseases can take advantage of that, 50-percent 
tax credit for clinical trials, as well as being free of the 
user fees for an NDA or a BLA. So, there are a lot of 
opportunities.
    Were you addressing, specifically, neglected diseases?
    Senator Pryor. Uh-huh.
    Ms. Dorman. Okay.
    Senator Pryor. Let me ask another question.
    And, Mr. Chairman, this will be my last one. You've been 
patient with me.
    But, I've noticed that there are a lot of--seems like, in 
recent years--more private foundations and patient groups who 
are pushing very hard to get certain things through the 
approval process. And is that a trend, that you're seeing more 
of that? And are the pharmaceutical companies themselves, at 
least in some areas, not pushing very hard and leaving it up to 
foundations and patient groups?
    Ms. Dorman. Right. I mean, you know, it's interesting; in 
the rare disease world, it's somewhat unique, because so many 
of the diseases are so small in numbers. And, I mean, they work 
really hard to have their bake sales and their lemonade stands 
to amass just a little bit of money to encourage the 
development and do research of possible product development. 
So, they're intimately aware, probably more than their 
physicians are, about the mechanism of their disease.
    So, they play a very, very key role in the process and work 
very closely with academia, with medical hospitals, and also 
with industry, to encourage them to develop those products. And 
that's very, very important.
    So, it's a very different, unique kind of place for people 
with rare diseases. So, they play a very key role. For example, 
the Cystic Fibrosis Foundation and MS Society are seeing where 
things are not moving fast enough, and they're kind of taking 
control of that.
    Senator Pryor. So, let me go back----
    Ms. Dorman. But, in a smaller space----
    Senator Pryor. Let me go back----
    Ms. Dorman [continuing]. Is a little bit different.
    Senator Pryor [continuing]. To the economics, as well, 
though----
    Ms. Dorman. Yes.
    Senator Pryor [continuing]. Because the drug companies may 
want to do the ones that they can really mass-produce have a 
big market for, and some of these are very small markets.
    Ms. Dorman. Very small. I mean, I understand that the 
development of orphan products can be very, very challenging. 
They're small populations. Sometimes, they're dispersed 
worldwide. There are not a lot of people willing to take on 
that risk, especially companies willing to take on that risk. 
So, I sometimes find as if I'm walking around with a Damocles 
sword around my neck. On the one hand, I really do want to 
encourage them to develop the products. I intellectually 
understand why so many of them are expensive. But, on the other 
hand, I want to ensure that the patients get access to them as 
quickly as possible.
    Senator Pryor. Thank you.
    And thank you.
    Senator Brownback. Thank you, Senator Pryor.
    I've had the same question many times.
    Thank you, panel. Appreciate that very much, your input and 
your thoughts, your life commitments. And I'm glad that you 
were able to give that in front of the public-sector witnesses, 
as well, who I know you're engaged with.
    I'd call for our second panel on this: Ms. Gloria Steele, 
Senior Deputy Assistant Administrator for Global Health, U.S. 
Agency for International Development; Dr. Christopher P. 
Austin, Director of Chemical Genomics Center, and Senior 
Advisor to the Director for Translational Research at the 
National Institutes of Health; and Dr. Jesse Goodman, Chief 
Scientist and Deputy Commissioner for Science and Public Health 
at the Food and Drug Administration.
    Delighted to have this panel here.
    We do have some wonderful Kansas connections that I would 
be remiss if I didn't acknowledge. Let's see, Ms. Steele, I 
believe, got a advanced degree from Kansas State University, 
the always fighting, and sometimes successful, Mighty Wildcats. 
She was there at that institution to get a master's degree in 
agriculture economics which is what I got my undergrad in at K 
State.
    And then, I'm also appreciative of Dr. Austin and the 
National Chemical Genomic Center, National Institutes of 
Health, for your partnership with one of the Nation's leading 
pharmaceutical research universities, University of Kansas 
School of Pharmacy. In fact, the University of Kansas has its 
own drug discovery pipeline, which includes potential drug 
targets associated with today's hearings, and that's on rare 
and neglected diseases. They've got a rapid throughput process 
that they can test these chemicals on. And I've certainly been 
encouraging them, saying this is a fabulous area.
    And I also think it's a market trendsetter that, while we 
may be looking at lifestyle drugs now, as the rest of the world 
develops, if we develop the drugs that they need in a lot of 
these areas, we're going to be first there, with the right 
piece of the market. And so, I'm appreciative of your working 
with KU Pharmacy School on that, as well.
    We've heard from the experts outside. I know a number of 
you have worked with them, as well. So, we appreciate the 
chance of this panel coming together and telling us how you're 
working together, and what, if any, legislative support or help 
you may need.
    Ms. Steele, we'll start with you.
STATEMENT OF GLORIA STEELE, SENIOR DEPUTY ASSISTANT 
            ADMINISTRATOR FOR GLOBAL HEALTH, U.S. 
            AGENCY FOR INTERNATIONAL DEVELOPMENT
    Ms. Steele. Senator Brownback, thank you very much for 
inviting me to testify today on interventions to combat rare 
and neglected diseases.
    As you know, the Agency for International Development is 
the principal agency providing development in humanitarian 
assistance worldwide. We are particularly concerned about the 
neglected diseases that you presented earlier on.
    I especially want to thank you and Senator Brown for your 
efforts over the years to promote access to medicines for 
neglected diseases, such as TB, malaria, and other infectious 
diseases, that, as you said, primarily afflict the poor people 
in poor countries around the world.
    We are delighted that the Brownback-Brown provisions have 
led to initiatives, such as the Priority Review Voucher Program 
and the establishment of the Technical Review Group in FDA, 
that will help us have access to the medicines and the 
diagnostic tools that we need to be able to do our job as we 
help developing countries fight the neglected diseases. We are 
very hopeful and are very interested in working with FDA in 
this process, because it does benefit us to have the drugs and 
the vaccines and diagnostic tools out, available.
    The question that you raised with Administrator Shah during 
the budget hearing is very timely. As you're aware, we have 
launched the Global Health Initiative, which promotes exactly 
the kinds of measures that are needed to help accelerate the 
availability of drugs, vaccines, and diagnostic tools. One of 
them is the importance of working in a whole-of-government 
approach, so that we don't work in silos, you know, working by 
ourselves, without looking at what FDA is doing, or NIH, or 
CDC. So, we are working very hard to collaborate and work in an 
integrated manner.
    We are also focused on developing local capacity. We have 
talked about the need to develop drugs and vaccines and 
diagnostic tools. And that is a very important issue. But, an 
issue, too, is the ability--is developing the ability of the 
countries in which we work to be able to access this--to have 
the local systems, and to have the technical expertise to be 
able to distribute and administer the drugs that they need in 
order to address the issues that they are faced with. And so, 
we are really very mindful of the help that you have given in 
this area, and the work that NIH and FDA have done in order to 
make our work more viable for us.
    We have developed considerable experience, both upstream 
and downstream, around FDA's regulatory process. By 
``upstream,'' I mean by supporting late-stage pharmaceutical 
product development, as well as providing technical assistance 
for pharmaceutical companies to be able to help meet product 
quality standards. And ``downstream,'' by actually purchasing 
the drugs and making this available and enabling the countries 
in which we work to be able to access and use them.
    I would like to describe in more detail the support that 
USAID is currently providing around the approval process by FDA 
and other regulatory authorities. We are, in particular, 
employing a research-to-use strategy to guide our investment in 
innovations of low-cost and effective health products. Through 
our product development plans, we work to ensure that, as new 
products become available and proven to be effective, that they 
can be quickly introduced and scaled up in the countries in 
which we work.
    In the area of malaria, for example, we are providing 
support to product development through the Medicines for 
Malaria Venture, which is a nonprofit public/private 
partnership that was created in 1999 with the World Health 
Organization, the World Bank, and other bilateral donors. The 
focus of the Medicines for Malaria Venture is on discovery and 
development of drugs that will be affordable to populations 
living in areas where malaria is endemic, and to drugs that can 
be used safely by young children and pregnant women, which are 
the primary target population of our presidential malaria 
initiative. In 2010, we are going to make available $2,500,000 
to MMV.
    Just last year, USAID was pleased to see the approval of 
the first drug that made use of FDA's Priority Review Voucher 
Program, which is a fixed-dose combination tablet of an 
antimalaria drug that belongs to the most effective class of 
antimalarials, which is the artemesinins. And, additionally, 
with USAID support through MMV, and Novartis, a dispersible 
formulation of the same drug was launched. This is significant. 
It's very important in our efforts in malaria.
    We are also funding the Malaria Vaccine Development Program 
to accelerate the development of a vaccine that can be used as 
part of our malaria control efforts. The program emphasizes 
support for promising vaccine candidates through production and 
testing of investigational vaccines. The MVDP works closely 
with academia, the commercial sector, and other government 
agencies.
    In the area of TB, another neglected disease, the USAID 
supports late-stage product development of needed TB drugs to 
the Global Alliance for TB Drug Development and through the 
Tropical Disease Research Partnership. We are supporting the 
continuation of late-stage clinical trials of four medicines, 
or compounds, with the aim of shortening the duration of TB 
treatment. Our research strategy for TB also funds new 
diagnostic technologies that will increase the sensitivity and 
specificity of TB testing and enable or promote more rapid 
detection of drug resistance.
    Finally, in the area of neglected tropical diseases, USAID 
focuses, currently, on seven diseases which are ``tool 
ready''--in other words, diseases for which medicines are 
available for mass drug administration. We hope, moving 
forward, working with NIH, FDA, and CDC, that more tool-ready 
medicines will become available for other neglected tropical 
diseases that you highlighted in your chart.
    On the downstream side, USAID supports the introduction in 
countries of many high-impact medical products that have 
achieved proof of principle. For example, we have helped 
introduce zinc as a treatment for childhood diarrhea through 
supporting product manufacturers, promoting policy adoption by 
national governments, and training of service providers.

                           PREPARED STATEMENT

    In conclusion, we stand ready to support initiatives to 
shorten pathways for medicines against neglected diseases. 
Neglected diseases can be beaten, as you have said, if there is 
full engagement of all government agencies, in collaboration 
with the private sector and the foundations, to be able to 
develop the drugs, the vaccines, and the diagnostics. USAID is 
one link in the chain, and we all need to work together in 
order to be able to combat the neglected diseases that we are 
all very concerned about.
    Thank you.
    Senator Brownback. Thank you. Thank you for the work in 
that area.
    And I have noticed that a lot of key scientists around the 
world, some of the most cost-effective things we could do to 
improve lives of the most people is micronutrients. And it's 
pretty cost-effective, and it can impact a lot of lives. So, 
it's one of those really good areas that I think we need to 
watch a lot more.
    [The statement follows:]
                  Prepared Statement of Gloria Steele
                              introduction
    Chairwoman Kohl, Ranking Member Brownback, distinguished members, 
thank you for inviting me to testify on interventions to combat rare 
and neglected diseases.
    The U.S. Agency for International Development (USAID) is the 
principal U.S. agency providing development and humanitarian assistance 
in more than 100 countries. On behalf of my staff at USAID and the 
people we serve, I want to thank members of Congress for your 
longstanding support of health programs.
    I especially want to thank Senators Brownback and Brown for their 
efforts over the years to promote access to medicines for neglected 
diseases such as tuberculosis, malaria, and other infectious diseases 
that primarily afflict developing countries. These diseases 
disproportionately impact poor and rural populations who lack access to 
basic health services and essential medicines.
    We are delighted that the Brownback-Brown provisions have led to 
such initiatives as the ``priority review voucher'' program and the 
establishment of a technical review group on neglected diseases within 
the Food and Drug Administration to consider and make recommendations 
to the FDA Commissioner on the appropriate pre-clinical, trial design 
and regulatory paradigms and on optimal solutions for the prevention, 
diagnosis and treatment of neglected diseases in the developing world. 
USAID is pleased that the FDA review group for neglected diseases held 
its first meeting in March. We look forward to the recommendations it 
will issue by March 2011.
    USAID is hopeful that the FDA priority review voucher program will 
encourage private sector companies to invest more of their research 
dollars and talent in the fight against these terrible diseases.
    USAID welcomes Senator Brownback's recommendation to Administrator 
Shah to support the review process to shorten pathways for neglected 
diseases. The suggestion is timely, given that the recently launched 
Global Health Initiative applies a ``whole-of-government'' approach to 
global health, mandating that USAID build upon and complement the 
innovative work of other U.S. Government agencies. The ambitious 
targets of the Initiative also give us a mandate to increase our focus 
on supporting innovation and applying new technologies.
    USAID is eager to support the review process and ensure that the 
U.S. Government makes maximum use of the fruits of FDA's regulatory 
efforts to encourage development of new health products for neglected 
diseases.
    USAID has developed considerable experience both upstream and 
downstream of the FDA regulatory process: (1) upstream by supporting 
late-stage pharmaceutical product development as well as providing 
technical assistance for pharmaceutical companies to help meet product 
quality standards, and (2) downstream by actually purchasing these 
drugs and working with developing country Ministries of Health to make 
sure they are aware of innovative new products, and that these products 
are quickly introduced and scaled up within national programs. USAID 
stands ready to share its experience and knowledge of product 
development and introduction in developing countries. This knowledge 
and experience may be useful to the FDA review group on neglected 
diseases as it works to identify ways that could help shorten the 
pathways for bringing medicines for neglected diseases to the market 
and to the patient. USAID also stands ready to contribute to 
implementation of any recommendation by the FDA review committee within 
the confines of its mandate as a development agency.
    I would like to describe in more detail the support USAID currently 
is providing around the approval process by the FDA or other regulatory 
authorities. This is the area of most immediate interest to the FDA 
review committee. I will focus in particular on product development 
efforts in malaria, tuberculosis, and neglected tropical diseases.
    USAID and the Global Health Initiative place a high priority in the 
rapid introduction of new technologies in the field. USAID employs a 
``research to use'' strategy to guide its investment in innovations of 
low-cost and effective health products. Through its product development 
plans, USAID works to ensure that as new products become available and 
are proven to be effective, they can be quickly introduced in 
developing countries.
              usaid promotion of pharmaceutical innovation
    In the area of malaria, USAID provides support to product 
development through the Medicines for Malaria Venture (MMV), a non-
profit, public-private partnership created in 1999 by the World Health 
Organization, the World Bank, and bilateral donor governments. MMV's 
goal is to register at least one new antimalarial drug every 5 years; 
its focus is on discovery and development of drugs that will be 
affordable to populations living in malaria endemic areas; that are 
effective against drug-resistant strains of P. falciparum; and that can 
be used safely in young children and pregnant women. MMV's current 
portfolio contains more than thirty projects actively pursuing novel 
compounds and promising analogues. USAID will contribute $2.5 million 
to MMV in fiscal year 2010.
    USAID also funds the Malaria Vaccine Development Program (MVDP) to 
accelerate the development of a vaccine that can be used as part of 
malaria control efforts. The Program emphasizes support for promising 
vaccine candidates through the production and testing of 
investigational vaccines. The MVDP works closely with academia, the 
commercial sector, and other government agencies. Experimental vaccines 
manufactured by several companies have been tested under the program.
    In the area of TB, USAID supports late-stage product development of 
needed TB medicines through the Global Alliance for TB Drug Development 
and Tropical Disease Research partnership. USAID is supporting the 
continuation of late-stage clinical trials of four medicines or 
compounds with the aim of shortening the duration of TB treatment. Our 
TB Research Strategy also funds new diagnostic technologies that 
increase the sensitivity and specificity of TB testing and evaluates 
new diagnostic technologies that more easily detect TB, enable rapid 
detection of drug resistance, and detect latent TB infection.
    Finally, in the area of neglected tropical diseases, USAID focuses 
currently on approaches that are ``tool ready,'' in other words, for 
which medicines are already available and have proven to be safe and 
effective and amenable to mass drug administration. Going forward, 
USAID hopes to support late-stage trials of new drugs that may 
accelerate progress toward the elimination of some NTDs and may enable 
the inclusion of other NTDs as ``tool ready.'' As safe and effective 
new drugs and tools become available for other neglected diseases, 
USAID looks forward to adding these diseases to its program.
       neglected diseases and the global health initiative (ghi)
    All of USAID's work is coordinated with other donors, the private 
sector and host country groups through operational partnerships in each 
of the priority countries, as well as with other Federal agencies such 
as the Centers for Disease Control and Prevention.
    This approach guides not only all USAID-led programs, but also 
whole-of-government Presidential Initiatives in global health, global 
climate change, and food security.
    So let me take a few minutes to describe the core components of the 
Global Health Initiative, and how they relate to neglected diseases. 
The goal of the Global Health Initiative is to achieve dramatic 
improvements in sustainable health outcomes, with a particular focus on 
improving the health of women, newborns and children. USAID's efforts 
to reach the goals of the GHI will depend on significant progress 
against neglected diseases.
    The United States will invest $63 billion to help the approximately 
80 partner countries where the U.S. Government provides health 
assistance to improve health outcomes, including the continuation of 
commitments for HIV/AIDS, tuberculosis and malaria, with a particular 
focus on improving the health of women, newborns and children. The GHI 
is a global commitment to invest in healthy and productive lives, 
building off of, and expanding, the U.S. Government's successes in 
addressing specific diseases and issues. Addressing wide-ranging health 
needs in partnership with governments, communities and other partners 
represents an ambitious agenda that can be met only if we work 
together, aligned toward common goals, with a commitment to 
fundamentally improve the way we do business.
    Achieving major improvements in health outcomes is the paramount 
objective of the Initiative. To that end, the GHI supports the 
following goals and targets with regard to rare and neglected diseases:
  --Malaria.--USAID, in partnership with the Centers for Disease 
        Control and prevention, will seek to reduce the burden of 
        malaria by 50 percent for 450 million people, representing 70 
        percent of the at-risk population in Africa. USAID was very 
        pleased that malaria was included in the definition of 
        neglected diseases within the context of the Brownback-Brown 
        amendment.
  --Tuberculosis (TB).--The U.S. Government's tuberculosis program will 
        save approximately 1.3 million lives by reducing TB prevalence 
        by 50 percent. This will involve treating 2.6 million new TB 
        cases and 57,200 multi-drug resistant (MDR) cases of TB. The 
        Brownback-Brown amendment's inclusion of TB drugs within the 
        review committee's purview will be essential in helping us 
        address the long-term challenge of tuberculosis control, 
        particularly with the emergence of multi-drug resistant strains 
        of the disease.
  --Maternal and Child Health.--Save approximately 360,000 women's 
        lives by reducing maternal mortality by 30 percent across 
        assisted countries. The GHI strategy seeks to improve health 
        systems in ways that particularly target maternal health, 
        including through the expansion of support for antenatal care, 
        and for significant increases in the number of trained health 
        care providers. These health systems can also provide a 
        foundation for the diagnosis, treatment and prevention of 
        neglected diseases, ensuring that newly developed drugs are 
        procured and prescribed as needed.
  --Child Health.--Save approximately 3 million children's lives, 
        including 1.5 million newborns, by reducing under-5 mortality 
        rates by 35 percent across assisted countries. Some of the 
        highest mortality and morbidity associated with rare and 
        neglected diseases occurs in children. The GHI cannot meet its 
        goal of reducing mortality of children under 5 years of age 
        without addressing rare and neglected diseases.
  --The Neglected Tropical Diseases (NTDs) Program.--USAID's NTD 
        Program seeks to reduce the prevalence of 7 NTDs by 50 percent 
        among 70 percent of the affected population, contributing to: 
        (1) the elimination of onchocerciasis in Latin America by 2016; 
        (2) the elimination of lymphatic filariasis globally by 2017; 
        and (3) the elimination of leprosy. This program began in five 
        countries in 2006 and has since expanded to integrated NTD 
        control in 14 countries--Bangladesh, Burkina Faso, Cameroon, 
        Democratic Republic of Congo, Ghana, Haiti, Mali, Nepal, Niger, 
        Sierra Leone, Southern Sudan, Tanzania, Togo, and Uganda. As 
        anticipated, following 4-6 years of repeated mass drug 
        administration, transmission of some NTDs is being interrupted. 
        Ghana, supported by USG efforts since 2006, has eliminated 
        trachoma as a blinding disease and may be able to stop annual 
        drug administration for lymphatic filariasis after the coming 
        year.
                         innovation and the ghi
    And finally, one of the hallmarks of the GHI is its emphasis on 
innovation. The GHI strategy puts at its an understanding of the 
importance of United States leadership in research and robust use of 
rigorous peer-reviewed research that is already available. The U.S. 
Government recognizes that advancements in health often occur through 
the discovery and development of new biomedical technologies, including 
not only new drugs but also diagnostics and vaccines; medical devices, 
such as the female condom; and information and communication 
technologies, such as mobile telephones and other data transmitting 
devices that have the potential to improve people's health.
    Although the GHI is not expected to make direct investments in 
clinical trials for new products, we will take advantage of 
opportunities to link the results of these trials with the means for 
improving service delivery. The GHI also will look to accelerate the 
appropriate use of existing technologies as well as create favorable 
conditions for more rapid introduction and successful scale-up of 
technological advances that have been demonstrated to improve health 
outcomes.
    The GHI will work with in-country partners to overcome bottlenecks 
and accelerate delivery pathways to ensure that innovative technologies 
can be widely adopted, including improving demand forecasting for new 
products, supporting evidence-based decision making within partner 
countries, and conducting operational and implementation research. 
These systems will pay particular attention to the FDA review 
processes, to ensure that they translate discoveries in the lab into 
success in clinical care in developing countries. Operational and 
implementation research will help identify critical problems and 
improvements, including: sustainable and cost-effective service 
delivery approaches; obstacles to rapid scale-up and approaches to 
reduce such obstacles; and strategies to help improve health service 
delivery models.
    Given the whole-of-government approach of the GHI, the Initiative 
will work through existing governmental mechanisms and partner with 
private sector donors and foundations to support research. Synergies 
will be sought between GHI programmatic activities and existing 
research partnerships of the National Institutes of Health, the Centers 
for Disease Control and Prevention, and other agencies that have active 
biomedical and public health research programs, and the FDA priority 
review voucher program and the neglected diseases review group will be 
important parts of those efforts.
                               conclusion
    In conclusion, USAID stands ready to support initiatives to shorten 
pathways for medicines against neglected diseases. Neglected diseases 
can be beaten if there is full engagement of all concerned government 
agencies throughout the product development continuum: from basic 
research to efficacy trials, to regulatory review and promotion and 
distribution of new products into the hands of health care workers. 
USAID is one link in this chain. We will work with our colleagues 
across the U.S. Government to ensure that innovative new products are 
developed and put to use in developing countries to combat malaria, TB, 
and other neglected diseases.
    Thank you.

    Senator Brownback. Dr. Austin, thank you for being here. 
Appreciate your attendance. And the floor is yours.
STATEMENT OF CHRISTOPHER P. AUSTIN, DIRECTOR, CHEMICAL 
            GENOMICS CENTER; AND SENIOR ADVISOR TO THE 
            DIRECTOR FOR TRANSLATIONAL RESEARCH, OFFICE 
            OF THE DIRECTOR, NATIONAL HUMAN GENOME 
            RESEARCH INSTITUTE, NATIONAL INSTITUTES OF 
            HEALTH, DEPARTMENT OF HEALTH AND HUMAN 
            SERVICES
    Dr. Austin. Good afternoon, Mr. Chairman. Thank you for the 
opportunity to speak to you this afternoon about NIH's 
activities to promote the development of therapeutics for rare 
and neglected diseases.
    I'm pleased to tell you about some of the exciting new 
scientific programs and partnerships we've initiated, and 
particularly with those with the FDA, to bring about more 
efficient development of treatments for patients afflicted with 
these devastating diseases.
    Scientifically and medically, we live in exciting though 
paradoxical times. Thanks to the Human Genome Project and other 
spectacular scientific successes, we know more about ourselves 
than we ever have in health and disease. At the same time, 
however, the number of new drugs approved every year has stayed 
constant, or even declined, over the last decade. This paradox 
is no more acute than in rare and neglected diseases.
    As a neurologist--my original training is in neurology and 
as a doctor in rural Africa--I routinely took care of patients 
with these illnesses, and felt the hopelessness of those for 
whom medicine had little or nothing to offer.
    But, now the genetic sequences, the genetic basis of over 
2,000 rare diseases, is known, and we have the full genome 
sequences of almost every organism that causes a tropical 
neglected disease. Thanks to research performed at NIH and 
funded by NIH over the last 50 years, we're finally at the 
point of being able to translate these discoveries, sometimes 
rather directly, into therapeutics. But, achieving this promise 
for rare and neglected diseases will require new kinds of 
science, new collaborations, and new ways of operating. Under 
Dr. Collins' leadership, and with the support of the Congress, 
NIH is moving aggressively to realize this promise.
    A fundamental problem, that you noted, is that rare and 
neglected disease drug development requires expertise that has 
traditionally been present, virtually exclusively, in 
biotechnology and pharmaceutical companies. But, these diseases 
do not offer a return on investment sufficient for companies to 
work on them.
    Incentives such as the Orphan Drug Act and, more recently, 
the Voucher Program for Tropical Disease Therapeutics, have 
done a great deal to encourage companies to work on these 
diseases. However, the scale of the need, as you described--
over 6,000 rare diseases with no treatment--tell us that 
fundamental changes in the way therapeutic development has 
always been done are needed.
    The NIH Therapeutics for Rare and Neglected Diseases, or 
TRND, program is directly addressing the structural and 
scientific issues that limit drug development for these 
diseases. It was congressionally mandated beginning in fiscal 
year 2009. TRND is a collaborative program to develop new drugs 
for rare and neglected diseases, as well as technologies and 
paradigms to improve the success rate of drug development more 
generally. TRND combines new internal NIH drug discovery and 
development resources with specific disease expertise that 
exists in university researchers, in patient advocacy groups, 
foundations, and biotechnology and pharmaceutical companies. 
Importantly, every project TRND does is a collaboration across 
what have traditionally been separate domains.
    TRND has already had early successes in its pilot programs 
that will move three projects into the clinic for rare diseases 
in the next 12 months. Among these is a potential new drug for 
Niemann-Pick-C disease, which is a devastating 
neurodegenerative disease of children. It's a joint project 
between ourselves, TRND-NIH investigators, university 
researchers at Washington University in Saint Louis and Albert 
Einstein College of Medicine in New York, and a patient 
advocacy foundation who is deeply involved in the project.
    Other TRND pilot projects include the one that you 
mentioned, the collaboration with the University of Kansas and 
a nonprofit disease foundation on a drug for chronic 
lymphocytic leukemia, a project with a Boston-area 
biotechnology company on sickle cell anemia, and a project with 
the NIH Clinical Center on a rare muscle wasting disease. 
TRND's pilot neglected disease project is a collaboration with 
Rush University in Chicago and Yale University, on 
schistosomiasis and hookworm, two diseases that affect--
together, infect over 500 million people worldwide.
    Importantly, while TRND is, and will, develop drugs for 
individual rare and neglected diseases, it is also intensely 
focused on the scientific and systems problems that hold back 
efficient drug development for these diseases more generally. A 
key partner for TRND, and NIH more broadly in these efforts, is 
the FDA. A TRND-FDA working group meets every month to discuss 
issues in TRND projects and to develop new ideas to address the 
roadblocks in drug development for these diseases. TRND is 
working closely with the FDA Office of Orphan Product 
Development to coordinate activities, including leveraging the 
excellent FDA Rare Disease Repurposing Database that was 
released by FDA last week.
    In addition to these staff contacts, the FDA and the NIH 
recently formed a flagship partnership announced by Drs. 
Collins and Hamburg, which will support research programs in 
regulatory science.

                           PREPARED STATEMENT

    In summary, the NIH, through TRND and other research 
initiatives across the agency, is poised to make fundamental 
advances in the development of therapeutics for rare and 
neglected diseases. The availability at NIH, for the first 
time, of resources and expertise previously restricted to the 
biopharmaceutical community, and the generation of vitally 
needed alternatives to traditional drug development pathways, 
in partnership with the FDA, provides new hope for millions of 
patients and families afflicted with these devastating 
diseases.
    Thank you very much for the opportunity to testify today, 
and I'd be glad to take any questions.
    Senator Brownback. Thank you, Dr. Austin. I appreciate 
that, and it's encouraging. I want to dig into it some more 
during the questions.
    [The statement follows:]
            Prepared Statement of Dr. Christopher P. Austin
    Good afternoon, Mr. Chairman and distinguished members of the 
subcommittee: Thank you for the invitation to speak to you this 
afternoon about the National Institutes of Health (NIH) activities to 
promote the development of novel therapeutics for the treatment of rare 
and neglected diseases. In particular, I am pleased to talk to you 
about some of the exciting scientific opportunities that we are 
pursuing and the strong partnerships that we and others at the NIH have 
built with the Food and Drug Administration (FDA) over many years to 
facilitate the efficient development of treatments for patients 
afflicted with these devastating diseases.
    Over the last 60 years, the research and drug development 
infrastructure of the United States, contributed to by the public and 
private sectors, has produced medicines that have reduced suffering and 
death from many diseases, including heart disease, diabetes, 
osteoporosis, many types of cancer, and infections such as AIDS and 
pneumonia. However, due to the high cost of developing a new drug, most 
drug development resources are focused on diseases that are highly 
prevalent in the developed world. While this focus has contributed 
greatly to the public health of the Nation, it has left many in the 
United States who suffer from rare diseases (those defined by the 
Orphan Drug Act as affecting fewer than 200,000 Americans), and many 
more in developing nations who suffer from neglected diseases, without 
treatments. In fact, of the 7,000 human diseases, over 90 percent are 
classified as ``rare'' or ``neglected'' \1\ \2\. Collectively, these 
affect more than 25 million people in the United States.
---------------------------------------------------------------------------
    \1\ http://rarediseases.info.nih.gov/.
    \2\ Hopkins AL, Witty MJ, Nwaka S. (2007). Mission possible. Nature 
449:166-169.
---------------------------------------------------------------------------
    Biopharmaceutical companies are reticent to take on rare and 
neglected disease studies due to the historically high rate of failure 
and the relatively low return on investment. The recent contraction of 
the biopharmaceutical sector has further exacerbated this problem.
    The success of the research performed and funded by NIH over the 
last 50 years, and especially over the last decade, has brought us to 
the point where basic scientific discoveries can be more rapidly and 
efficiently translated into medical treatments. Thanks to the Human 
Genome Project and related initiatives, the genetic basis of over 2,000 
rare diseases is now known, and the infectious organisms that cause 
neglected tropical diseases are understood in unprecedented detail 
(see, for example \3\). Over the years, NIH has supported basic 
research and the elucidation of biological pathways as a means to 
understand human health and disease. Since much basic mechanistic 
research remains to be done in these areas, it is critical that NIH 
continue to support these avenues of scientific inquiry. NIH also 
recognizes the opportunity and the imperative to pursue translational 
initiatives to apply basic scientific knowledge to health needs. Our 
conviction is that these more applied projects will accelerate 
diagnostic and treatment development, particularly for rare and 
neglected diseases.
---------------------------------------------------------------------------
    \3\ Berriman M, Haas BJ, LoVerde PT, et al. (2009). The genome of 
the blood fluke Schistosoma mansoni. Nature 460:352-358.
---------------------------------------------------------------------------
    The Molecular Libraries Initiative, funded by the NIH Common Fund, 
for example, has made tools and resources accessible to academic 
researchers that were previously only available in large pharmaceutical 
companies. Specifically, scientists at universities and medical centers 
have been provided access to industry-style assay development, high-
throughput screening, and medicinal chemistry infrastructure not 
previously available in academic settings. In doing so, this program 
has produced more than a hundred chemical ``probe'' compounds that are 
used to study rare and neglected diseases in cellular or animal models. 
These compounds are traditionally referred to as ``small molecules''--
they are organic chemicals made up of carbon, hydrogen, nitrogen, 
oxygen, and a few other atoms in a wide variety of combinations, and 
can be thought of as chemical ``shapes'' that can interact with a host 
of cellular targets. Such compounds are the first steps toward drug 
development, but the development of small molecules suitable for 
testing in humans requires an additional 3-4 years of development.
    The academic sector currently lacks the infrastructure and 
expertise required for the pre-clinical pharmaceutical development 
needed to transform a chemical research probe into a candidate compound 
suitable for testing in patients. Individual NIH Institute and Center 
programs have been established to move candidate compounds further down 
the development path--the Neuroscience Blueprint Neurotherapeutics 
program, the NINDS Spinal Muscular Atrophy Project, NCI's Experimental 
Therapeutics (NExT) program, and the NIAID BioDefense Product 
Development Program are but a few examples. These programs, as critical 
as they are, together address fewer than 100 individual diseases.
    Announced in May 2009, the Therapeutics for Rare and Neglected 
Diseases initiative, abbreviated TRND, is a collaborative research 
program that builds on efforts across NIH to develop candidate 
compounds for clinical testing en route to developing therapeutics for 
rare and neglected diseases. TRND is a trans-NIH program overseen by 
the Office of Rare Diseases Research in the Office of the Director, 
NIH, and administered by the National Human Genome Research Institute. 
Building on the Molecular Libraries Initiative, TRND will empower 
academic investigators to pursue pre-clinical work through high-
throughput resources not previously available outside the 
biopharmaceutical sector. In most cases, the starting point for TRND 
will be a chemical ``probe,'' or compound, known to have some 
biological effect in laboratory models of a given rare or neglected 
disease. The end-point deliverable will most often be a candidate 
compound with sufficient data for an Investigational New Drug (IND) 
application to the FDA.
    The pursuit of novel partnerships with biopharmaceutical companies 
and patient advocacy groups will be another hallmark of this program 
that brings together the necessary expertise and patient communities to 
realize therapeutic development success in the rare and neglected 
disease realm. It is expected that in most cases, TRND's candidate 
compounds will ultimately be licensed to biopharmaceutical companies 
for clinical development, permitting TRND to focus on the most 
scientifically challenging stages of pre-clinical drug development. In 
this way, TRND intends to ``de-risk'' projects sufficiently to make 
them enticing to groups outside of NIH to pursue final development, 
even for less common diseases with limited markets. TRND's scientific 
activities will include everything from iterative medicinal chemical 
modification of promising compounds to testing optimized compounds in 
laboratory disease models; in cases that lack sufficient private-sector 
interest and present compelling health needs, NIH may even conduct the 
early clinical trials necessary for safety and efficacy analyses, using 
the substantial resources of the NIH Clinical Center and the network of 
46 Clinical and Translational Science Awards (CTSAs) across the 
country.
    Significantly, beyond delivering candidate compounds for clinical 
testing in individual rare and neglected diseases, TRND will focus on 
improving the overall efficiency of drug development for these types of 
diseases. Currently, drug development is an unavoidably long and 
failure-prone process, requiring 4-8 years and carrying a failure rate 
well over 90 percent. This high-failure rate and extended timeline is 
due in large part to the unpredictable nature of the biological effects 
of new candidate compounds. NIH aims to advance the underlying drug 
development processes through open and broad dissemination of the 
information learned in the course of candidate compound development. To 
achieve this goal, TRND will focus on mechanisms able to cut across 
traditional disease or organ system boundaries, allowing each drug 
developed potentially to target the underlying pathology for more than 
one disease. Successes and failures will be investigated and published, 
and specific technology development programs addressing the two most 
common causes of new drug failure--toxicity and efficacy in humans--
will be launched.
    To expand some of the unrealized potential of earlier drug 
development projects, an alternative approach--known as drug 
``repurposing''--will seek to identify drugs for rare or neglected 
diseases from among those already approved for use in people by FDA or 
another regulatory agency outside the United States. The opportunity of 
this approach is that it potentially allows for rapid therapeutic 
advances, with a treatment available 1-2 years after the initial tests. 
The challenge is the relatively small number of compounds (i.e., drugs) 
that have been approved for human use, and therefore that are available 
for repurposing (approximately 3,000, compared to 100-1,000 times the 
number of new candidate compounds available). As part of its program to 
take every approach to speeding the development of new drugs for rare 
and neglected diseases, TRND will be testing clinically approved drugs 
for new activities in assays related to 100 rare diseases. This effort 
will complement TRND's traditional compound development pathway, and 
will provide information on the critical question of what percentage of 
rare and neglected diseases can be treated to some extent by the 
current pharmacopoeia.
    Since one of the organizing principles of TRND is a systems 
approach to drug development, all rare and neglected disease areas will 
be suitable for TRND. Because TRND is explicitly designed to address 
any rare or neglected disease, and identify and capitalize on 
biological/pathway commonalities among these diseases regardless of the 
organ systems they affect, the program's success will rely and actively 
draw upon the knowledge and expertise resident in all the NIH 
Institutes and Centers. TRND will draw many of its projects from 
extramurally supported investigators as well, and look to them for 
insights into the molecular pathogenesis of diseases, and for 
collaborations on pharmacological and animal models for lead 
optimization and pre-clinical testing. This coordinated and universal 
approach to rare and neglected diseases should with time lead to 
therapeutic strategies for additional diseases not directly studied by 
TRND.
    To launch the scientific program and begin to develop the 
operational processes necessary for the management of these types of 
atypical research partnerships, five initial projects--at a variety of 
stages of development, with different types of collaborators, and with 
different disease types--have been initiated in fiscal year 2010.
  --The first pilot is focused on schistosomiasis and hookworm, which 
        are highly prevalent and neglected tropical parasitic diseases 
        that affect over 500 million people worldwide. This project is 
        an early pre-clinical (``probe optimization'') stage project, 
        and involves a collaboration with two extramurally-funded NIH 
        investigators.
  --The second project is a mid-stage drug ``repurposing'' project for 
        a rare disease, Niemann-Pick Type C (NPC), which is allowing 
        the piloting of the later stages of pre-clinical development 
        including formulation, pharmacokinetics, pharmacodynamics, 
        blood-brain barrier penetration issues, and challenging 
        clinical trial design. NPC is a rare pediatric 
        neurodegenerative disease, and the project is a collaboration 
        with both extramural and intramural scientists. Importantly, 
        this project also involves several patient advocacy groups who 
        support and coordinate NPC research.
  --A third project is a collaboration with a research-driven disease 
        foundation and extramural collaborators, focusing on 
        repurposing an approved drug for treatment of Chronic 
        Lymphocytic Leukemia. This project is currently at the later 
        ``pre-IND'' stage of the drug development pathway.
  --A fourth TRND project involves a rare muscle-wasting disorder that 
        occurs in mid-life, known as Hereditary Inclusion Body 
        Myopathy. In this instance, the project involves a new 
        candidate compound, but is also at a late stage, requiring only 
        discrete toxicology studies before moving into clinical 
        testing. This project involves a collaboration with an 
        investigator at the NIH Clinical Center and a biotechnology 
        company, and is allowing TRND to pilot processes to incorporate 
        the unique resources of the NIH Clinical Center and also to 
        work through business issues related to partnering with the 
        private sector.
  --The final pilot project focuses on sickle cell disease, and brings 
        together non-profit, intramural and extramural investigators to 
        focus on a new candidate compound at the mid-stage of pathway 
        development.
    If TRND is to succeed in achieving its objective to increase the 
number of therapeutics available to combat rare and neglected diseases, 
an integral part of the commitment must be regular dialog and 
coordination with the FDA. To accelerate and enhance TRND activities, a 
working group of TRND and FDA staff meet monthly to discuss conceptual 
issues in existing TRND projects, and to develop new ideas to address 
the principal roadblocks in drug development for these diseases. FDA 
participants include representatives from the Office of New Drugs and 
the Office of Translational Science, with expertise in rare disease 
drug development, toxicology, and policy. The NIH staff includes TRND 
leadership and individual scientists working on the particular projects 
being discussed. Separately, TRND is working closely with the FDA 
Office of Orphan Product Development (OOPD) to coordinate activities 
and leverage OOPD programs to advance mutual goals.
    In addition to these critical staff contacts for TRND, the NIH 
recently formed a flagship partnership with the FDA. Through a recently 
announced Joint Leadership Council, co-chaired by NIH Director Francis 
Collins and FDA Commissioner Margaret Hamburg, the two agencies will 
work closely together to ensure that sound regulatory considerations 
are an integral part of research planning. The initiative involves two 
interrelated scientific disciplines: translational science (the shaping 
of basic scientific discoveries into treatments); and regulatory 
science (the development and use of efficient and effective tools, 
standards, and approaches to develop products and evaluate product 
safety, efficacy, and quality). Both disciplines are needed to turn 
biomedical discoveries into products that benefit people. Through 
research programs in regulatory science, innovative mechanisms and 
processes will be explored to devise optimal methods for drug 
development and review.
    This multi-pronged approach for collaboration between FDA and NIH 
in support of the development of novel products to treat and diagnose 
rare and neglected diseases will promote the development of new 
pathways through which safety, quality, and efficacy can be assessed, 
improving the overall efficiency of clinical research as a whole.
    In summary, the NIH, through TRND and other research initiatives 
across the agency, is poised to make extraordinary advances in the 
development of potential therapeutics and treatment strategies for rare 
and neglected diseases. The opportunity to pursue new scientific 
directions through the availability of resources traditionally 
restricted to the biopharmaceutical community, and to generate vitally 
needed alternatives to traditional drug development pathways in 
partnership with the FDA, presents new hope for the ultimate success of 
bringing better clinical options to patients afflicted with rare and 
neglected diseases.
    Thank you very much for the opportunity to testify before the 
committee this afternoon. I would be happy to take any questions that 
the panel may have.

    Senator Brownback. Dr. Goodman, most of the bulk of the 
effort falls on your shoulders. Everybody's here to help, but 
it's the FDA approval process, I think, that most of the focus 
tends to be on. And so, I hope you can illuminate us on what's 
taking place, and what we can do to try to help out and get 
more products through the system in this rare and neglected 
disease category.
STATEMENT OF DR. JESSE GOODMAN, CHIEF SCIENTIST AND 
            DEPUTY COMMISSIONER FOR SCIENCE AND PUBLIC 
            HEALTH, FOOD AND DRUG ADMINISTRATION, 
            DEPARTMENT OF HEALTH AND HUMAN SERVICES
    Dr. Goodman. Thank you very much, Senator Brownback. And 
I'm really happy to be here today to represent FDA and talk 
some about our efforts in this area.
    My biggest message for you is that we're very engaged, and 
it's exciting for me to be here and hear some reflections of 
that engagement, you know, from numerous people we're 
partnering with, whether its patient groups, our colleagues at 
NIH, the nongovernmental organization community, or across the 
government in the Global Health Initiative. So, thank you.

                             TWO CHALLENGES

    I hope, because the scope of our activities and my 
inability to ever compress things into the tiniest little oral 
statement, that you'll be a little patient with me. So, I'm 
going to try to cover the waterfront a little, and also make an 
effort to be responsive to some of the issues that have been 
raised.
    First of all, I want to say, I'm a practicing infectious 
disease physician. I still take care of patients, including at 
Walter Reed, in the Navy, so I still see tropical diseases. And 
I'm also trained in oncology. So, I certainly have seen, and 
still see, the devastating impacts of these diseases, and 
appreciate the concern and compassion you're bringing to this.

                          TB, MALARIA AND HIV

    Another point I frequently make in my job is that 
infectious diseases like TB, malaria, HIV--most recently, 
pandemic influenza--these diseases have no boundaries, and if 
they're a threat to anyone in the world, they're a threat to 
us, as well. So, not only there are these compelling 
humanitarian reasons we should do--take care of this problem, 
there are also really pressing U.S. and global security and 
public health reasons for our country.
    You know, I want to say--and, again, I appreciate the 
recognition that, in my former position as director of the 
Biologic Center at CBER, we made this a very high priority, 
including our engagement in WHO. And this is a very high 
priority for me in my new position and, I know, for Dr. 
Hamburg, as well.
    Now, for both rare diseases and those that are perceived, 
at least, to affect primarily impoverished communities and 
people, I think there are really two major challenges. You 
know, and we've heard about them.
    First, is that clear-cut and sufficient market incentives 
to drive product development to the degree that we see in other 
areas are often lacking.
    The second one is that there are actually some real 
scientific challenges here. And, as Chris said, even though we 
know lots and lots, and know things on the molecular level, 
that doesn't always translate into ability to treat a disease 
or come up with a product. And, in fact, I like to say to 
people that these same diseases that are so clever in infecting 
people all over the world, like HIV and TB and malaria, they do 
that, for example, on the vaccine front, because we don't make 
a very good immune response to them, or a very effective one. 
And then, when we turn around and our colleagues at NIH try to 
make vaccines against them, you find it's very hard to get a 
vaccine that makes an effective immune response. So, there are 
some real scientific challenges there, but it's exciting to see 
them--the investment in solving those challenges.
    I want to also emphasize that the standards and 
expectations that we have in this country, that products be 
safe and effective, are important. People with rare and 
neglected diseases are classic examples of people in a 
vulnerable situation, or a vulnerable population. They're 
vulnerable because they have that disease, and we need to get 
them the treatment, and we share that motivation. They're also 
vulnerable to potential misuse or ineffective products, due to 
their poverty or where they live, et cetera, or to--how 
important it is for them to get treatment.

                        SCIENCE-BASED DECISIONS

    And people everywhere, all over the world, look to FDA to 
make solid risk-based, science-based decisions. And people 
everywhere want medicines that they take, or vaccines their 
children take, to be safe and effective. So, we take that very 
particular responsibility we have at FDA very, very seriously.
    I also want to be sure that there isn't any 
misunderstanding that, you know, if a product is promising, we 
are going to work closely with the sponsors. And if that 
product works, we're going to approve it. Okay?
    There's--a big problem here is, there are not enough 
effective products to fill in that circle which we would all 
like to do. And there are a lot of reasons. But, we want to do 
all we can to facilitate that process, from development to 
evaluation.

                            ORPHAN DRUG ACT

    Now, I'd just like to go through some of the things we're 
doing to try to help, and acknowledge your help; Congress has 
really helped. As you've heard from Ms. Dorman, the Orphan Drug 
Act provided incentives and assistance to developers of drugs. 
Prior to it, there was almost nothing out there. And, while we 
need much more, there were 357 products shown to be safe and 
effective, and approved as a result, since that time. And 
that's good. And, thanks to you and Senator Brown, we got the 
Priority Review Voucher Program, which is going to provide 
additional incentives for neglected diseases.

                         ORPHAN PRODUCT OFFICE

    Our Orphan Product Office, which Dr. Tim Cote, who is right 
here with us, is the Director, and who's here with me, is a 
focal point for the agency, of these activities. And there are 
many, many things they do, but just some major examples is 
providing assistance to the kind of people we've heard about 
who might lack product development experience; to work with 
patient advocacy groups and patients themselves, who we think 
have an important voice in this; to identify drugs that could 
be promising for rare diseases, and try to encourage partners 
to study those drugs, and help them to do it; to conduct 
outreach and training that will help in this.
    And you've heard about some of the recent activities. We've 
had a course to teach small science behind small clinical 
studies. Fifteen hundred people participated in that last 
course, including many FDA reviewers.
    And you heard about our cosponsorship with NORD and NIH of 
the first rare disease investigator course that's going on this 
year. This is a substantial effort, here.

                             TRND PROGRAMS

    And then, as Chris said, we're collaborating closely, as 
they bring about this program. We're very excited, in the TRND 
program, to help bridge the gap from very basic science to get 
promising concepts and drugs ready to go into studies in 
humans.
    And you heard that, just this February, FDA created this 
new position of Associate Director for Rare Diseases in the 
Center for Drug Evaluation and Research. And again, Anne 
Pariser, who is here--I'm delighted--is in that position now. 
And what she's really doing is very consistent with the goals 
that we share with Dr. Kakkis, you know, for a coordinated 
high-quality, consistent science-driven review process. So, 
she's working to have the best guidances, the best policies, 
the best practices across the very large and diverse Center for 
Drugs. And part of that is bringing the best people to bear on 
specific applications, and really making this process go 
smoothly.
    Now, I want to also point out that we're very committed to 
flexibly applying standards that are risk-based to the review 
of these products, and to point out that, for many rare 
diseases, they've been, in fact, approved on studies with 
extremely limited numbers of patients, often less than 20. So, 
when there are very few patients there, we work with sponsors 
to go out and get them. And if the data are strong, we can 
approve it, if they're effective.
    When good information is available, we also have supported 
assessing the benefit of a drug by comparing it to historically 
untreated controls in our databases. And we've helped sponsors 
do that.
    And I'll come back to it, but where surrogates or 
biomarkers are available to predict benefit, we can take an 
accelerated approval, or even a full approval, pathway, if 
those surrogates are well validated, and get effective products 
to patients faster. But, this is only possible when the science 
is there that tells us that that will predict benefit to 
patients. Because we don't want patients to find out, 10 years 
later, that something didn't work.
    Now, while there have been many successes, the unmet needs 
are huge. And you've profiled them very graphically here. And 
we want to work with you to meet those needs.
    Thanks to your leadership, we've established the Rare 
Disease and Neglected Disease Workgroups that you've heard 
about. And they're going to look at all of the ideas we've 
heard here, the ideas we're soliciting in public meetings. And 
also, they're working with our review staff to get their ideas, 
because many of them have seen how things work, and what 
doesn't work. So, we're looking forward to providing a report 
to Congress and issuing guidance, as instructed by this 
legislation.

                           NEGLECTED DISEASES

    I want to talk briefly about neglected diseases. We fully 
support the Global Health Initiative, which you heard about 
today from Ms. Steele. We've--I've been tremendously excited, 
personally, about how the NGOs, the NIH, and industry have 
gotten interested in neglected and global diseases. I think 
that's great. We need to do more. But, as part of this, we've 
dramatically increased our engagement.
    Examples are: issuing the guidance you heard about for 
vaccine development against global disease. We also are, in 
fact, meeting early and working very closely with NGOs and 
these public/private partnerships, to try to help them when 
they don't have experience in product development. We provide, 
hundreds of times a year, technical support, expertise to WHO, 
both at working technical level and at a high leadership level. 
That's a very constructive engagement. The Biologic Center 
serves as a reference national regulatory authority, and does 
prequalification of vaccines for global use for WHO. And Dr. 
Bollyky's comments about coordination of that process are very 
good. And we, in fact, are working with WHO on an evaluation of 
their process to try to strengthen it. And we're very active 
partners with them.
    Also consistent with Mr. Bollyky's suggestions, the 
countries that these products are used in need the capacity, 
themselves, to feel that they can evaluate them, that clinical 
trials can take place safely in their countries, that they can 
monitor the safety of the products. And we have a very large 
effort, particularly in the vaccine area, to--working with 
WHO--to help train and have scientific interactions with 
regulatory colleagues around the world, including in Africa and 
through something called the Developing Country Vaccine 
Regulators Network. And this has been very fertile. Both the 
Biologic Center and the Drug Center and the Device Center have 
put on training courses in regulation, and have frequent 
scientific exchanges with other regulators throughout the 
world.
    And then, finally, I want to talk a little bit about 
science, because in this area we have a unique research program 
that is designed to help define new measures of safety and 
efficacy, and improved approaches to product quality, 
particularly for vaccines against diseases like TB, malaria, 
HIV, meningitis, Leishmania--the list goes on.
    I want to mention our efforts in regulatory science, as, in 
almost every aspect, all the problems that we're looking at 
today have science at the root. And science is also--often what 
determines whether a project is successful, or fails. As we 
heard from Chris, we've defined the genetic basis of thousands 
of diseases, and identified even potential drug targets for 
many of these diseases. But, that hasn't really translated into 
products yet. So, the promise is incredible, and it's another 
reason why we need to act now. And we think that regulatory 
science can help bridge this gap.
    The tools we develop in regulatory science are particularly 
critical for rare and neglected diseases. For example, we heard 
from Dr. Kakkis about the desire to take advantage of 
accelerated approval mechanisms, which really means, instead of 
approving it on something like ``you survived longer,'' that we 
have a marker in the patient's response--it could be a blood 
test, a urine test, a tissue biopsy, or whatever--that predicts 
for us that that will happen, or that that will likely happen. 
I--we need much more of that, and that takes science, to be 
able to safely predict that, rather than have a situation 
where, 10 years later, we find out it didn't work, and somebody 
else didn't develop a product that did work, because they 
thought this product was there, and there was no market.
    This is very important.
    I want to correct something--or, not really correct it, but 
supplement it, and point out that we have approved many drugs 
for metabolic disorders based on surrogate markers. Many of 
these are full approvals. There--for example, in 
phenylketonuria, where we know that the levels of the substance 
correlate with the clinical response, we've been able to 
approve those products, based on surrogates, and for many rare 
cancers, too, where those surrogates exist. But, we need much 
more science, to move that forward more broadly. And I agree 
that we can take advantage of that much more.
    So, for example, recently we sponsored a TB workshop that 
is really aimed at trying to develop surrogate markers of 
response to TB drugs, and the diagnostic tests to measure those 
responses.
    A couple of other examples of how collaborative regulatory 
science can really help things. FDA's biochemists developed an 
improved method for complex biochemistry around meningitis 
vaccines. And this has helped a vaccine that was stalled become 
a candidate for development to prevent meningitis all over the 
world, in a partnership supported by PATH, a major nonprofit.
    Now, the good news is that, you know, thanks in part to 
Congress and the administration, our 2011 budget contains the 
first dedicated funding for FDA to begin to rebuild its 
scientific infrastructure and develop these kinds of tools. We 
really appreciate that.
    You heard about how Drs. Collins and Hamburg, with all of 
our support, have announced a new partnership and joint grants 
in regulatory science, and we're very excited about that. And I 
think we see that as an avenue where, in the rare disease 
field, we can make an impact.
    This enhanced science needs to inform, also, our review 
processes and interactions. We've heard a lot about, how can we 
make that as strong as possible? And we think the scientific 
backbone there is critical. Strong science is in critical--is 
critical in supporting an intense interactive review process 
that we know can help improve product development and the odds 
for success. And I want to second what others said, that not 
only are the beneficiaries of success in this product 
development the patients--and that's what we really care 
about--but, our economy and the innovation power of this 
country also--often benefit--also benefits. And that's 
important.
    We want FDA scientists to be able to meet with sponsors 
early in development. They can identify and resolve critical 
issues. They can comment on proposed development plans. And 
these interactions, even though they're labor- and resource-
intensive, are really important for rare and neglected 
diseases.
    And one very specific recommendation I want to close with 
here is that sponsors, developers, our work with TRND at NIH, 
some of the work with NORD and others, that you come to us 
early in development. We want to be available. We want to work 
with you. We want to be sure there's good understanding of the 
pathways. If there are scientific gaps that need to be filled, 
we're much better off to identify those and work together with 
our colleagues at NIH and academia to solve those early, rather 
than to discover them several years down the line. So, this is 
very important.

                           PREPARED STATEMENT

    So, in conclusion, we are really committed to doing what we 
can in this area. We share with you the compelling need and 
vision and desire to make a difference here.
    So, I really appreciate your having this hearing. And we 
welcome all these suggestions and are going to consider them 
very carefully.
    [The statement follows:]
                Prepared Statement of Dr. Jesse Goodman
                              introduction
    Good afternoon Chairman Kohl and members of the subcommittee. I am 
Dr. Jesse L. Goodman, Chief Scientist and Deputy Commissioner for 
Science and Public Health at the Food and Drug Administration (FDA). I 
appreciate the opportunity to be here today to describe the role of FDA 
in encouraging and speeding the development of drugs, vaccines, and 
diagnostic tests for rare and neglected diseases.
    There are more than 6,000 rare diseases, defined by the Orphan Drug 
Act as a disease affecting fewer than 200,000 people in the United 
States, and numerous neglected tropical diseases that predominantly 
affect impoverished or disenfranchised populations of the developing 
world. Around the world, more than 1 billion people are affected by at 
least one neglected tropical disease, such as tuberculosis (TB), 
malaria, hook worm infection, and leprosy. As a practicing physician 
and a researcher specializing in infectious diseases and also trained 
in oncology, I have personally witnessed the devastating human face and 
social impacts of many of these diseases.
    As a physician and a public health official, I want to take this 
opportunity to remind our Nation that infectious diseases know no 
boundaries. Threats to health anywhere are threats to everyone. Witness 
the risks to the United States from multi-drug resistant TB and the 
disruption that a single infected traveler caused in 2007. In May 2010, 
the Centers for Disease Control and Prevention (CDC) reported that, for 
the first time, cases of dengue--the most common mosquito-borne viral 
disease, causing 50 to 100 million infections and 25,000 deaths each 
year around the world--were identified in Florida residents who had not 
traveled overseas. Thus, there are compelling global humanitarian as 
well as U.S. health and national security reasons to bring the best 
possible science to bear in protecting against what are often 
considered ``tropical diseases.''
    Yet, for both rare diseases and diseases that are perceived to 
affect primarily poor regions and people, market incentives are often 
lacking to drive the commercial interest and investment critical for 
developing medical products. In addition, some of the major diseases, 
such as malaria, TB and HIV, present scientifically formidable 
challenges in drug and vaccine development. Finally, clinical studies 
of rare diseases, or of diseases occurring in resource poor 
environments, are often hard to accomplish. For all of these reasons, 
the needs and opportunities are enormous and FDA can help make a real 
difference.
    I welcome your shared interest and commitment to this issue and 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 rare and neglected diseases.
                      the orphan drug act and fda
    The 1983 Orphan Drug Act (ODA) created financial incentives, 
including grants, for the developers 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 for their products. 
If products so designated are subsequently shown to be safe and 
effective and receive marketing approval, the developers receive market 
exclusivity for 7 years.
    FDA Office of Orphan Products Development (OOPD) serves as the 
contact for all parties interested in making new therapies for people 
with rare diseases, often providing 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 week 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 357 of these 
therapies have gone on to receive full marketing approval. This program 
also benefits those affected by rare and neglected tropical diseases, 
as drugs for the treatment of the neglected diseases of the developing 
world generally also qualify as orphan drugs because most neglected 
diseases affect fewer than 200,000 persons in the United States.
    OOPD's engagement in the area of neglected tropical diseases is 
exemplified by an ongoing project to stimulate manufacturers to 
identify and evaluate certain products approved for the treatment of 
intestinal parasites in veterinary medicine for potential human use.
    The FDA Amendments Act of 2007 (FDAAA) granted FDA the authority to 
award priority review vouchers beginning in 2009 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. 
Under the law, developers of treatments for neglected diseases are 
rewarded with priority review vouchers to be applied to other drugs, 
such as profitable cardiovascular therapies, that would not otherwise 
qualify for such an expedited review. For a blockbuster drug, these 4 
months of earlier market access could translate into hundreds of 
millions of dollars. Already, one such voucher has been issued to 
Novartis, for its anti-malarial drug Coartem. OOPD 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 tropical 
diseases listed in the legislation. It also should be noted that many 
orphan designated products, other than those for products to treat the 
16 identified neglected tropical diseased, qualify for FDA priority 
review.
    ODA has established FDA's largest grants program, $16 million per 
year, 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. The humanitarian use device (HUD) program is another 
legislative program established in 1990, which creates an alternative 
pathway for getting market approval for medical devices that help 
people with rare diseases. For example, the adjustable titanium rib, 
which for children with thoracic insufficiency syndrome prevents the 
child's body from collapsing on itself, was a HUD-designated device 
invented by a pediatric orthopedic surgeon who received an OOPD grant; 
this surgeon recognized the need for such a device that could be 
adjusted as a child grows. Also, in 2007 Congress established a system 
of pediatric device consortia, also administered by OOPD, for creating 
new medical devices for children.
    Along with a rapid expansion in new drugs for people with rare 
diseases, the 27 years since enactment of ODA have seen remarkable 
growth in the biotech industry. The incentives offered by ODA motivated 
investments by biotech firms in products aimed at rare diseases, and 
the financial success of key biotech companies has further stimulated 
this sector. Consequently, ODA's fundamental principles have been 
adopted by many other countries, most notably by the European 
Medicine's Agency (EMA) in 1999. While FDA remains the world leader in 
orphan drug regulation, this international expansion of ODA, combined 
with Internet linkages among patient groups and a pharmaceutical 
industry without borders, has made global harmonization an important 
component of the work at OOPD. Accordingly, EMA and FDA now have a 
joint application form for orphan designation.
fda efforts to enhance development and review of products to treat rare 
                                diseases
    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 the position of Associate Director for 
Rare Diseases in the Center for Drug Evaluation and Research (CDER). 
The activities led by the Associate Director for Rare Diseases 
complement the work of FDA's OOPD.
    The Associate Director for Rare Diseases serves as CDER's focal 
point within the Center and to the rare disease drug development 
community and assists stakeholders and developers of drug and biologic 
products in navigating the complex regulatory requirements for bringing 
safe and effective treatments to patients in need. In conjunction with 
OOPD, the Associate Director for Rare Diseases 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.
    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 rare diseases. In October 2010, FDA will 
co-sponsor the 1st 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 Office of Rare Diseases Research (ORDR), Therapeutics for 
Rare and Neglected Diseases Program (TRND), the National Institute of 
Neurological Disorders and Stroke (NINDS), patient advocacy groups, 
academia, and the Institute of Medicine (IOM).
    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. Many of the 357 
approved orphan drugs have been successfully tested on extremely 
limited numbers of patients, serving as a testament to FDA's commitment 
to these patients. This is possible when the best science is flexibly 
applied and when therapies are truly effective. Successful examples 
include:
  --Carbaglu (carglumic acid) for the treatment of NAGS deficiency, the 
        rarest of the Urea Cycle Disorders (UCDs).--This disease 
        affects fewer than 10 patients in the United States at any 
        given time and fewer than 50 patients worldwide. This drug was 
        approved in March 2010 based on a case series derived from 
        fewer than 20 patients and comparison to a historical control 
        group.
  --VPRIV (velaglucerase) for the treatment of Gaucher disease, a rare 
        genetic disorder.--This disease affects approximately 2,000 
        people in the United States and approximately 5,000 worldwide. 
        This drug was approved in February 2010 based on a development 
        program that included about 100 patients and a pivotal study of 
        25 patients.
  --Myozyme (alglucosidase alfa) for the treatment of the infantile 
        variant, and rapidly fatal, form of Gaucher disease.--The 
        variant of this disease affects about 1,000 patients in the 
        United States and about 3,000 patients worldwide. This drug was 
        approved in April 2006 based on a clinical development program 
        of fewer than 80 patients and a pivotal study that included 18 
        patients.
  --Ceprotin (human plasma derived protein C concentrate) for the 
        treatment of severe congenital Protein C deficiency.--There are 
        fewer than 20 known patients with this disorder in the United 
        States. This biologic drug product was approved in March 2007 
        based on a study of 18 patients using comparison to historical 
        control data.
             fda rare and neglected diseases review groups
    While there have been many successes in the development of products 
for rare and neglected diseases, because of the remaining needs and 
great interest on the part of multiple stakeholders, it is timely to 
examine what more may be possible. With the support of Senator 
Brownback, 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) directs 
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. The Rare Disease Review Group includes 24 expert 
FDA staff scientists from a broad array of pre-clinical and clinical 
disciplines. They have been asked to consider how FDA currently 
evaluates drugs, biologics and medical devices for treating rare 
diseases and how that process can be optimized. The Neglected Disease 
Review Group is composed of experts in infectious diseases from all FDA 
medical product Centers and the Office of the Commissioner. This group 
is reviewing present FDA guidance and the different local and 
international programs that encourage development of medical products 
for these diseases and, similarly, will identify opportunities to 
enhance FDA's efforts.
    These review groups are already active and on track in evaluating 
current activities and plan to present recommendations to the FDA 
Commissioner regarding potential options to further support and 
facilitate the development and evaluation of medical products to 
prevent, diagnose, and treat rare diseases and neglected diseases of 
the developing world.
    FDA believes public input to be very important in this evaluation 
and will also be holding meetings for that purpose. A meeting on rare 
diseases is scheduled for June 29 and 30, 2010, and 26 speakers are 
already signed up to provide comments. Another Part 15 hearing, to 
allow FDA to seek public input on the challenges and possible solutions 
encouraging development of products for neglected tropical diseases, is 
planned for September 2010. Finally, FDA and NIH are co-sponsoring an 
IOM study, begun 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.
    Based on the Working Groups' deliberations, and the input we 
receive from stakeholders, I look forward to issuing a report to 
Congress, as well as development and issuance of guidance, and taking 
whatever further steps are feasible to enhance these programs.
                     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 applied product development and 
evaluation research, a gap that is reflected in the lack of real 
products getting to patients for many such diseases, despite advances 
in basic sciences. FDA is launching a new regulatory science initiative 
to help bridge this gap and to facilitate development and availability 
of safe and effective products to meet public health needs.
    Regulatory science is the development of new tools, methods, 
assays, standards, and models that help speed and improve the 
development, review, and approval of innovative products. These tools, 
and better improved evaluation methods, are particularly critical for 
facilitating development of products for which commercial incentives 
may be weak or uncertain, or where scientific complexities in 
evaluating product effectiveness are major challenges. Examples 
relevant to our hearing today include the need for better, faster ways, 
including biomarkers and novel clinical trial designs, to predict and 
monitor effectiveness of treatments both for rare diseases and for many 
neglected tropical diseases, such as TB.
    With this regulatory science initiative, FDA seeks to rebuild its 
critical scientific infrastructure and capacity to leverage the 
opportunities provided by 21st century science and to enhance its 
scientific collaborations. Through collaboration, FDA will foster new 
opportunities for patients and consumers. One recent example of a 
collaborative success involved the work of FDA biochemists to help 
improve a complex vaccine manufacturing process and making the 
information available to collaborators engaged with PATH, a major 
international non-profit organization, in developing new meningitis 
vaccines for the developing world.
    Investments in regulatory science will allow FDA to develop 
standards for products employing new and emerging technologies, 
modernize the standards for evaluating existing products, and 
accelerate the development of essential medical therapies, while at the 
same time assuring the new products are safe and effective. FDA's 
initiative to advance regulatory science seeks to improve efficiency of 
clinical trials, speed product development, and reduce attrition rates 
of products under development. 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.
    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 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 rare and neglected diseases.
Tuberculosis--A Case Study
    The World Health Organization (WHO) estimates that one in three 
people in the world is infected with latent, or dormant, tuberculosis 
bacteria that can become active as a result of a weakened or senescent 
immune system. Today, there are no simple, rapid and accurate tests to 
diagnose tuberculosis. This gap impedes timely detection and treatment 
of this contagious, and too often deadly, infectious disease.
    The conference report for the fiscal year 2010 Appropriations Act 
directs that not less than $6,000,000 be used for FDA Critical Path 
Partnerships. $2,000,000 of this appropriation is to support research 
partnerships encouraging the development of treatments or rapid 
diagnostic tests for tropical diseases, with an emphasis on 
tuberculosis.
    On June 7 and 8, 2009, FDA hosted a TB diagnostics workshop, in 
collaboration with the CDC and NIH. The workshop identified scientific 
gaps in the TB diagnostic armamentarium, opportunities to harness new 
technologies, and the feasibility of prospectively collecting specimens 
from patients participating in TB trials to support the development of 
new diagnostic tests. The workshop was attended by approximately 150 
registrants from government, academia, industry, and non-profit 
organizations, both from the United States and overseas. The workshop 
laid the groundwork for interagency collaboration on programs for 
developing TB diagnostic tests and for establishing a repository of 
specimens from participants in TB clinical trials. This repository may 
serve to identify biomarkers that can expedite future clinical trials.
    FDA established a TB cross-center working group to recommend 
priority areas for TB medical product development. As a result of this 
effort, FDA will soon publish a Request for Applications (RFA) 
soliciting proposals from outside scientists for collaborative 
initiatives to address areas of need in the treatment, diagnosis, and 
prevention of TB and other tropical diseases.
    FDA is also collaborating with the Clinical Data Interchange 
Standards Consortium (CDISC). This consortium is working to develop 
uniform data collection standards to be used in clinical trials for 
tuberculosis. This type of collaborative effort is critical to 
facilitate the collection of standardized clinical data and expedite TB 
drug development.
fda collaboration with the world health organization (who) on vaccines 
                    for rare and neglected diseases
    FDA recognizes the tremendous unmet need to engage globally in an 
effort to assist other regions and nations in assessing vaccines for 
approval by their governments and in helping to ensure their quality 
and safety. Further, FDA recognizes the need to develop new innovative 
regulatory pathways for candidate vaccines for global diseases to reach 
developing countries.
    FDA has traditionally worked with manufacturers to approve vaccines 
for the U.S. population. However, new paradigms of vaccine development 
supported by the Gates Foundation and other initiatives, along with an 
increase in regulatory submissions to FDA for global vaccines--to 
prevent or treat diseases often endemic outside the United States--have 
provided an impetus for the development of new regulatory strategies at 
FDA. In 2008, FDA issued guidance on the development of vaccines to 
protect against global infectious diseases. The guidance was extremely 
well received by the global health community.
    A core component of FDA's efforts in this regard is its commitment 
to support and complement the efforts of the WHO. FDA's contribution to 
the WHO vaccine quality and safety goals is long-standing and was 
formalized in 1998 with its designation as a Pan American Health 
Organization (PAHO)/WHO Collaborating Center for Biological 
Standardization. In recent years, FDA's support has grown beyond the 
routine collaboration of providing expert input to WHO consultations 
and laboratory collaborations for international reference standards. 
FDA now is an active partner with the WHO in its vaccine 
prequalification program and its efforts to build regulatory capacity 
in developing countries.
The WHO Vaccine Prequalification Program
    The vaccine prequalification program is a service provided by WHO 
to United Nations (U.N.) agencies that purchase vaccines, providing 
independent guidance and advice to the United Nations on the quality, 
safety, and efficacy of vaccines being considered for purchase. This 
assistance helps to ensure that each vaccine under consideration is 
suitable for target populations and complies with established standards 
of quality. In 2007, WHO designated FDA as a ``reference'' national 
regulatory authority (NRA) for WHO prequalified vaccines. In 2008, FDA 
and WHO signed confidentiality agreements specific to communications 
that would be undertaken in the context of the WHO vaccine 
prequalification process. Currently, CBER is the referenced NRA for a 
total of seven U.S. licensed vaccines.\1\
---------------------------------------------------------------------------
    \1\ Rotavirus Vaccine, Live, Oral, Pentavalent (Tradename: 
RotaTeq); Prequalified October 7, 2008;
    Influenza Virus Vaccine (Tradename: Fluvirin); Prequalified 
December 4, 2009;
    Influenza A (H1N1) 2009 Monovalent (No tradename; Manufacturer: 
Novartis Vaccines and Diagnostics Limited), Prequalified by WHO 
December 9, 2009;
    Pneumococcal 7-valent Conjugate Vaccine (Diphtheria 
CRM197 Protein) (Tradename: Prevnar), Prequalified by WHO 
December 28, 2009;
    Influenza Virus Vaccine (Tradename: Fluzone), Prequalified January 
21, 2010;
    Influenza A (H1N1) 2009 Monovalent (No tradename; Manufacturer: 
Sanofi Pasteur, Inc.), Prequalified January 27, 2010; and
    Influenza A (H1N1) 2009 monovalent (No tradename; Manufacturer: 
MedImmune LLC), Prequalified February 25, 2010.
---------------------------------------------------------------------------
Building the Requisite Regulatory Capacity in the Developing World
    CBER provides support to several WHO regional vaccine networks to 
enhance scientific and regulatory capacity needed to assure the 
development of high quality vaccines. Specifically, CBER actively 
engages with the WHO Developing Country Vaccine Regulator Network 
(DCVRN), a WHO-funded network of NRAs from Brazil, China, Cuba, South 
Korea, India, Indonesia, the Russian Federation, South Africa, and 
Thailand. The DCVRN builds regulatory capacity among vaccine-producing 
developing countries through information sharing, training, and 
mentoring activities. Representatives from member DCVRN countries meet 
on a biannual basis to gain timely information from independent experts 
and developers on specific issues relating to vaccine trials occurring 
in developing countries and to develop institutional plans and other 
activities that aim to strengthen regulatory capacity.
    CBER also provides expert input to the WHO African Vaccine 
Regulatory Forum (AVAREF). WHO coordinates this forum in conjunction 
with the WHO African Regional Office to assist in defining the role of 
NRAs of African nations in regulating clinical trials of vaccines, in 
interactions with national and local IRBs and ethical committees and in 
strengthening the capacity of the NRAs to regulate new products. In 
this capacity, FDA participates as expert advisors, in particular 
sharing the regulatory mechanisms used to evaluate the safety and 
efficacy of investigative products.
                               conclusion
    FDA is fully committed to doing all we can to help facilitate the 
availability of safe and effective therapies to patients in need. FDA 
has an ongoing broad range of vibrant programs to facilitate the 
development and improve access to medical products to treat and prevent 
rare and neglected diseases, and these activities have helped benefit 
people in our country and globally. Advances in regulatory science 
offer tremendous promise to improve product evaluation and translation 
of advances in basic science to products that can benefit people in the 
United States and globally. Thank you again for this opportunity to 
discuss rare and neglected diseases. I welcome your comments and 
questions.

                         ADDRESSING TRND DELAY

    Senator Brownback. Thank you, Dr. Goodman.
    I want to thank the panel. And please express my 
appreciation, to all the heads of your organizations, for your 
interest and your focus on this issue. I've been working in 
this space for 5, 6 years now, and I've not seen any 
collaborative effort near this degree. So, I'm deeply 
appreciative of that.
    Having said that, I'm frustrated, because I've been working 
in this space for 5 or 6 years, and I'm kind of, ``All right. 
Where's the product, here?'' I appreciated, Dr. Austin, your 
statement about a couple of products that you're seeing coming 
through the TRND process. I had hoped there would be a lot 
more.
    If I could just have a blunt conversation with you and I 
appreciate, really, what everybody is doing, and I think it's 
very important, and there's a lot that's going on, but it seems 
like we just haven't either been able to get the market signals 
right, or the regulatory approval process right, or maybe it's 
just too complicated, or the science isn't there. But, we did 
the priority approval process bill, Senator Brown and I did, 
and Washington Post did an article and said that the program's 
been rarely used. It's out there. It's tempted some people to 
look at these diseases. But, it hasn't been used that much. 
We've had accelerated approval process in some fields, but it 
hasn't been used much, or it hasn't tempted many people.
    And I get frustrated, in that I remember our early days in 
the AIDS crisis, and people just said, ``Look, we have got to 
get on top of this.'' And we threw everything at it and moved 
forward. And people are alive today because we did that. It 
doesn't seem like we're getting there yet with rare and 
neglected diseases. Now, maybe this more recent collaborative 
effort will work.
    But, I wonder if you, Dr. Goodman, did a scientific 
internal review, and you said, ``We're going to put a matrix 
together of the number of people impacted by a particular 
disease, and the likelihood of us getting a success based on 
what we know today, technology-wise, about a particular set of 
drugs and we're going to take the top 100 of the 7,000 that are 
here, and we're going to quarterback a process to get a drug 
approved in this area, not just as a regulator, but we're going 
to quarterback the process. And we're picking the top 100 with 
potential success.'' We've got to be able to have a reasonable 
prospect of getting a product through. And it affects a whole 
bunch of people. And then, you say ``We're going to go out and 
shop for the team to develop this product. We're going to go to 
the University of Kansas Pharmacy School, and say, `We want 
your vast throughput process.' We're going to go to Gates 
Foundation and say, `We want you to put some money into this 
one.' We're going to go to the scientists at the University of 
Washington that know his field, and have been working on it and 
we're going to tell them, `Look, we're going to put you in the 
priority approval process. We're going to court our friends at 
AID to put a little money behind you. Not going to put a lot of 
money behind you, because we don't have a lot of money. But, 
we're going to put a little money behind you, and we are going 
to do everything we can to move this product through.' ''
    ``Now, I'm a regulator. I don't work this way, normally. 
What's in my in basket is what I take.''
    I'm not saying you do that but I used to run a regulatory 
agency, and it's generally what comes in your in basket is what 
you deal with.
    ``But, I'm out here on these hundred products, because I 
think we can really move this forward.''
    What about doing that sort of quarterbacking process, by 
FDA or NIH? But, it does seem like, to me, FDA is the place 
that that would prove to do that.
    Dr. Goodman. Well, I think it's a very good vision, in many 
ways. You know, I want to comment on it, specifically, and 
provide some perspectives, and, again, back up to the big 
picture.
    I think that, for things to work--you know, I give talks, 
and I say that, you know, really the product development and 
achieving health--you know, not just for rare diseases; for 
anything--were--it takes many, many people, and it's a very 
complex system. So, it really is about bringing people 
together, and bringing the best people together in multiple 
different domains. So, I think you've really hit on something 
there, with the team approach. And this is the kind of thing 
where, you know, I think in our partnership with NIH, we can 
help broker that.
    I do want to say that there is a huge issue around what 
people see as the markets are, because, you know, even if you 
have very targeted and effective product development, it does 
cost real money, and people will expect a return on investment. 
So, that economic issue you've identified--and try to tackle in 
some of the ways you've mentioned--is a real issue, and there 
may need to be other inputs in that domain to help drive it.
    But, given all that, I think having teams work together--
and both within the FDA, and with others--on things that are 
high-priority and offer real promise for health benefit, is a 
very good approach. And that's what we are working toward with 
NIH. And you heard about some of the collaborations with NORD 
and others.
    And that's also--now, what I did want to say is, you know, 
recently--and I mentioned, right before the hearing, I've been 
involved as FDA's point person, both for our pandemic response 
and preparedness, and then in our review of the medical 
countermeasure enterprise of the United States for the 
Secretary and for the President. And what we've seen there is, 
on the positive, what people talking--working together across 
the agencies, partnering with industry in many cases, could 
achieve, in terms of, even though we have a long way to go, 
advancing our pandemic preparedness and response, such as was 
done. That took investment, but it also took the kind of 
partnerships and teamwork you described. And I believe those 
models can be applied.
    One of the things, in discussing the countermeasure 
enterprise that also has been attractive, is this kind of 
working together and bringing all the resources together from 
diverse places around our highest public health goals.
    So, I think the principle is a very good one. It does take 
investment. It does take commitment by leadership. And it does 
take diverse organizations, with different cultures, as you 
point out, that are used to doing x, y, or z, to say, ``What 
we're really focusing on here is the outcome.''
    The good news, and the reason I think you're seeing what 
you're seeing in this room in the last couple years, that you 
commented on, is because there is leadership and culture within 
many of our organizations, and people who really do care, 
around--about the outcome.
    So, I think we're well positioned to work together to 
change how we do this. And that's needed. But, I would not 
underestimate some of the challenges.

                              ROLE OF FDA

    Senator Brownback. With FDA quarterbacking the process? I 
don't want to give somebody leadership, if you guys have worked 
it out internally, but it sure seems like----
    Dr. Goodman. I think that this may differ, for a lot of 
different situations. And I would--one thing I would comment 
about the role of FDA, for both the American public and 
everyone--it's also very important that people know that we are 
also there to do this very important, unique job, which is, at 
the end of the day, to look very carefully at this and be sure 
it's safe for people, it's well made, and that----
    Senator Brownback. But, you----
    Dr. Goodman. You know, we say, sometimes, there's a thin 
line between hype and hope.

                               CHALLENGES

    Senator Brownback. I agree. But, your ability to identify 
areas to work on----
    Dr. Goodman. Yeah.
    Senator Brownback [continuing]. And to tempt companies and 
other entities to put money into something, if the FDA says, 
``We'd really like a product in this field. And it looks to us, 
after surveying the scientific field and NIH and AID and 
everybody else, that there's a real prospect here,'' I wouldn't 
discount the possibilities of that really tempting money from 
private groups, private companies, and other governmental 
entities, saying, ``You know, if FDA is sending that kind of 
signal, and they're saying, `We're not going to approve 
something that's not good and doesn't meet our scientific 
rigors.' '' You say that at the outset, ``But, having said 
that, we think there's a real prospect here.'' I wouldn't 
discount the ability of a regulator to tempt the marketplace to 
respond.
    Dr. Goodman. Well, and I think one thing--I--you know, and 
I think that's even more powerful when it's together with our 
entire----
    Senator Brownback. Sure.
    Dr. Goodman [continuing]. Public health and health 
enterprise.
    Senator Brownback. Yeah.
    Dr. Goodman. You know, I was going to say, one area where 
we can really help is say that, in these high-priority areas--
and I'm saying it today about rare diseases, and you--we're 
meaning it, within the ability of our resources, by--you know, 
seeing Dr. Cote and Dr. Pariser here--we are saying this is a 
priority. And one area where FDA can help is to try to do what 
we can to have the best evaluation process to identify 
challenges, and work with people to resolve them in a very 
interactive way. So, I think--and that does start--it has to 
start earlier on, as I said. And, in that sense, bringing teams 
like this together earlier on is a good thing.
    I think it's a great model. I also think, honestly--you 
know, think about people with common diseases, you know----
    Senator Brownback. Yeah.
    Dr. Goodman [continuing]. Diabetes and----
    Senator Brownback. Yeah.

                          RESOURCE CONSTRAINTS

    Dr. Goodman. You know, there's a lot we can bring to bear 
there, too. And one of the things--again, this is a key part of 
our Regulatory Science Initiative--one of the things we do 
uniquely see--the gap between the basic science and what it 
takes to have a product that people can make and consistently 
give people and help people. So, we can really work with NIH 
and academic investigators and small companies, you know, to 
help them cross that space and identify issues.
    And, frankly, we also see the development of our scientists 
and review staff, such as Dr. Kakkis mentioned, as an important 
thing in that space, because, by our people interacting with 
people innovating in the newest technology, it benefits our 
capacity, too.
    So, we're very supportive of this. We just have to be very 
careful about the--protecting the integrity of the FDA role. 
And we're also very--we also are limited--you know, even though 
we have tremendous resources--and, frankly, we really 
appreciate it, and we recognize all the constraints, you know, 
on the Federal budget, et cetera--we are constrained by our 
resources, in terms of how much we can do.

                           NIH COLLABORATION

    Senator Brownback. Dr. Austin, you've heard the 
conversation here. Do you have any technical response or 
thoughts to it?
    Dr. Austin. Yeah, I appreciate the opportunity to comment 
on that. And I loved your term, ``quarterbacking the process,'' 
because, as a matter of fact, when I talk about this, I 
frequently refer to it as a football game, actually. And so, 
let me explain what I mean by that. There are two things.
    One is that drug development, particularly for these 
diseases, is a team sport. And one of the things that holds 
back development is the fact that science is culturally, for 
the most part, a game of golf. It's viewed--scientists are 
viewed as sort of rugged individualists who work alone and they 
need to--and that's the model of basic research. And it's 
appropriate for basic research. But, you can't do drug 
development that way. So, one of the things that we're doing 
within NIH, which is a cultural battle which we're waging and I 
think we're having some success on, is getting people used to 
the idea that, yes, you need a quarterback, but you also need a 
wide receiver and you need some blockers. You need people who 
are excellent in their own fields, but can bring expertise, if 
you're going to score a touchdown.
    The second way it's relevant is that--if we think about the 
journey from a gene to a drug as a football field, which is 
actually how I think about it and how I talk about it, the 
traditional handoff from the public sector to the private 
sector was on about the 5-yard line. Right? So, the public 
sector would discover a gene, put it out there, and the private 
sector would do everything else. Now, you must not have used 
that analogy, if you didn't know football well enough to know 
that if you take possession on the 5-yard line, the likelihood 
of your scoring is very low. So, what NIH started doing, about 
6, 7 years ago, was a process of going from a target to about 
the 30-yard line. So, now we take it further down the field 
through something called the Molecular Libraries Program and 
some other programs that NIH has.
    TRND is going from about the 30-yard line to about the 40-
yard line on the other side of the field. And so, when we hand 
off from the public sector to the private sector, the private 
sector says, ``Huh. I can see my way though here. The defense 
is still pretty strong, but my special return team has made my 
likelihood of scoring good enough that now I'm going to pick 
this up. I'm going to take a risk on this that I'm going to be 
able to score.'' And so, that's really the direction that NIH 
has been going in.
    Fundamentally, trying to attract private-sector 
organizations to this area is strictly a business question.
    Senator Brownback. Right.
    Dr. Austin [continuing]. And it makes great sense, from 
their standpoint, that, if you have something which is very 
expensive, and it has a 99 percent failure rate, it's hard to 
argue to your board that that's what you ought to use their 
shareholders' dollars to do. And so, if you want to attract 
partners, and particularly for a disorder where you have low 
return on investment, you have to have a lower investment 
requirement. And so, what that means is, someone else has to do 
more of the work to carry the football down further down the 
field to de-risk that program--and that's probably a term that 
you've heard to ``de-risk'' the program enough that it can be 
picked up, with reasonable certainty of having a return on 
investment, even if the population is small. And so, that's the 
sort of role that NIH is seeking.

                    TRND QUARTERBACKING METHODOLOGY

    I think the last thing to say is that TRND is a 
quarterbacking initiative. That is exactly the model of TRND. 
We will bring in projects, and TRND people will drive the 
project. And we're doing that already. And our collaborators, 
whether they would be in a biotech or an academic organization 
or a foundation, they rely on us for the quarterbacking, which 
we call ``project management.'' But, it's exactly the point 
that you're saying, because you can't score a touchdown without 
a quarterback and a coach. And so, that's exactly the model.

                             REVIEW GROUPS

    Senator Brownback. It's my hope we can move this process on 
forward, and in doing that, target this. I think just, maybe 
because of the randomness that we've placed on this issue 
previously, that it would be helpful and probably tempt more 
money out of the private sector if we were more targeted, where 
we were out there saying, ``We really would like something in 
this area.''
    You're going to start, the next few days the public 
meetings that we had set up, in this subcommittee a year ago, 
on rare and neglected diseases. Do you want to update me on 
that, Dr. Goodman, where that's set to go--
    Dr. Goodman. The review groups----
    Senator Brownback. Yes.
    Dr. Goodman [continuing]. And their activities?
    Senator Brownback. Yes. You and Dr. Austin are both----
    Dr. Goodman. They've all met. The review groups have met 
multiple times. They are collecting information and ideas 
internally. They have these plans for, as you've heard, 
external information-gathering. Folks are also meeting groups 
and appropriate, you know, partners, as well. And so, this 
process is ongoing. We're looking forward to looking--getting 
all these ideas and putting together some options and--as well 
as taking information from our colleagues here, and providing 
ideas to Dr. Hamburg for consideration. So, this is--people are 
very engaged and excited about it.
    Senator Brownback. I hope you'll be willing to come to the 
Congress if there's statutory authority that's needed by you, 
NIH, AID, others, and tell us how we move this process forward.
    Dr. Goodman. Absolutely.
    Yeah. And we're always happy to work with you and your 
staff to provide assistance on ideas that you have and put 
forward.
    Senator Brownback. Ms. Steele, I haven't engaged you as 
much in this, as I wanted to get honed in right at FDA on it. 
Anything that you'd----
    Ms. Steele. Well----
    Senator Brownback [continuing]. Like to add?
    Ms. Steele [continuing]. I can't speak football-speak. And 
I did go to school where football--we tried very hard to do 
well in football. But, I did want to speak as an----
    Senator Brownback. Now, you're not speaking of Kansas State 
University, here, are you?
    Ms. Steele. I was talking about University of Wisconsin.
    Senator Brownback. Oh, okay. All right. There you go. 
That's better.
    Ms. Steele. I do want to go back to the--a key issue here, 
which is the economics. And I think that if we look more--look 
at it more broadly and provide incentives beyond--where the 
costs are lower--for instance, offshore companies that could 
produce--if our interest is in addressing the issue and making 
drugs available at a more affordable cost, then maybe we should 
look beyond our shores and see where pharmaceutical companies 
can develop the drugs at a less expensive cost, and therefore 
make it more accessible, still realizing, of course, that a 
very strict regulatory system is necessary.
    The other thing I think is, we need to take a look at more 
innovative ways of financing this. I just want to--in the 
health sector, and particularly in the area of immunization and 
vaccines for childhood diseases, we have--under GAVI, for 
instance, other donors have come together to look at ways where 
they could support the marketing and the shaping of the markets 
for drugs and vaccines so that they become more affordable to 
the countries where we need to get them delivered; assuring 
markets for some of the drug companies, for instance, for a 
certain period of time, to give them an incentive to produce; 
and also--and making them committed with us to address some of 
the issues.
    I think we should really look at a key issue, which is the 
economics of--you know, FDA and NIH can do all the work they 
can, but if the drug companies do not step in and deliver for 
us, it'll continue to be a major challenge.
    Senator Brownback. Ms. Steele, may I ask you, you know, in 
your position with AID, and your working with so many 
developing countries around the world, it would seem to me to 
be a valuable thing if you surveyed some of the countries you 
work with the most, and asked them what drug development would 
be the highest priority--or, what 10 would be the highest 
priority for them--because you're out there--I've been with 
many AID----
    Ms. Steele. Yes.
    Senator Brownback [continuing]. People in the field. 
They're always out there trying to work within the space that 
they're in to help out as much as possible. But, I wonder if 
you've surveyed some of the countries and places you're 
working, and ask them for the top 10 priorities that they had, 
if that would be an interesting piece of data to feed back into 
the system.
    Ms. Steele. That's absolutely one of the most important 
things. And, again, under the GHI, making it a country-led 
approach----
    Senator Brownback. Right.
    Ms. Steele [continuing]. So that they will own the 
processes that drives the vaccines that we come up with, and 
help us deliver them, looking at what their priorities are--
What are the most important things? And then, you know, a 
company--we are also working with local organizations, NGOs, to 
make them understand what each of the diseases mean and what 
it--how it impacts their social and economic progress. And so, 
its effect--you know, looking at their priorities, but also, 
informing them, as they develop what their priorities are, and 
making sure they understand what the implications are, as they 
make decisions about where they put their resources.
    Senator Brownback. So, on how they might be willing to 
invest their dollars----
    Ms. Steele. That's right.
    Senator Brownback [continuing]. To help out. So, it's not 
just us putting funding in----
    Ms. Steele. That's----
    Senator Brownback [continuing]. But it's them investing 
some themselves.
    Ms. Steele. That's exactly right. In--for instance, in the 
Global Alliance for Vaccine and Immunization, one of the things 
that we have done is get proposals from the countries, but also 
ask them to cofinance.
    Senator Brownback. Yeah.
    Ms. Steele. You know----
    Senator Brownback. Absolutely.
    Ms. Steele [continuing]. Because it's really important for 
them to own this process. And we're not going to be there 
forever, but for them to understand, this is important for 
them, as well as for the global community, as a whole.
    Senator Brownback. Thank you.
    Dr. Goodman?
    Dr. Goodman. Yeah, I was very stimulated by some of the 
points, to make a couple of additions here.
    You know, one is that I think, both in this domain, but 
more generally, it will benefit health if we can actually 
reduce the cost of development of these products. And I think 
there's a whole science around that, again, that, you know, we 
think FDA can really be helpful with, because we see what works 
and what doesn't. We see where a lot of costs are built in. And 
I think we can work with people, including with industry, to do 
that. And I think industry is realizing there need to be some 
new models--the small clinical trials, personalized medicine; 
those are domains where we ought to be able to both improve 
outcomes and reduce costs. You know, maybe sometimes we can 
actually do that.
    The other comment I was going to make is, people--even 
though we focus on medical products at FDA, and it's tremendous 
that everybody's engaged in trying to develop these products, 
certainly once you get out of this country into developing 
nations, and--you know, often, our--the priorities of people, 
and people who care about x disease and y disease, may be very 
different from the priorities in those countries. So, it's very 
important to recognize that, you know, if--people may have much 
more pressing priorities at that time, or they may not have a 
delivery system or a public health system. So, I think the 
Global Health Initiative, efforts of USAID to not just treat 
medical interventions in isolation, are very important. And 
certainly, even in this country, we have issues with people 
getting access, you know, to the care they need.
    And the other thing I was, finally, going to say is, in 
terms of the team we're talking about that can work--you know, 
and there could be many different people driving it, or 
quarterbacks--in some cases, industry does see economic 
markets. I mean, they have developed some products for rare 
diseases, some of which are quite profitable, in fact. But, in 
all of these cases, to bring benefits to people--and certainly 
in these partnerships involving government, nonprofit, et 
cetera--you know, I think it is very important that FDA and FDA 
scientists be there at an early time point, because we often 
will know--you know, an investigator could be the--I mean, 
because, I was in academia before, and you could be the world's 
expert in infection A or B or--and, as you heard, not really 
have a clear concept of what it takes to show that something 
could work in people, to investigate whether it's going to be 
safe, to be able to then manufacture it. The kind of pilot 
programs we've heard at NIH can help with that, but it's--we 
really want to offer, to the ability we can, our engagement 
throughout that process, because we can often identify much 
better-defined early, if there's a problem, in terms of the 
cost of development, or where we've seen a good solution, to 
bring that to bear and help share it, like some of the examples 
I mentioned.
    So, we really do want to be able to do that.
    Senator Brownback. Well, I want to thank the panel.
    It's my hope that, in the future, when the good Samaritan 
story is told, it's the United States that's the one that stops 
and helps. And I think we can. I think the people that are here 
that have a good heart are willing to do that. So I hope we can 
move forward with this process, and really develop some of 
these products that can make a life-and-death difference for a 
whole bunch of different people.
    I thank you very much.
    The hearing record will remain open the requisite amount of 
time, if there are additional statements that you want to put 
into the record for use.
    All my best, and Godspeed to this process, because we 
really need some solutions.

                         CONCLUSION OF HEARING

    The hearing is recessed.
    [Whereupon, at 3:39 p.m., Wednesday, June 23, the hearing 
was concluded, and the subcommittee was recessed, to reconvene 
subject to the call of the Chair.]

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