[Senate Hearing 115-851]
[From the U.S. Government Publishing Office]




                                                        S. Hrg. 115-851
 
                             RARE DISEASES:
                   EXPEDITING TREATMENTS FOR PATIENTS

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

                                HEARING

                               BEFORE THE

                 SUBCOMMITTEE ON CHILDREN AND FAMILIES

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                     ONE HUNDRED FIFTEENTH CONGRESS

                             SECOND SESSION

                                   ON

EXAMINING RARE DISEASES, FOCUSING ON EXPEDITING TREATMENTS FOR PATIENTS

                               __________

                            OCTOBER 3, 2018

                               __________

 Printed for the use of the Committee on Health, Education, Labor, and Pensions
 
 
 
 
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               U.S. GOVERNMENT PUBLISHING OFFICE 
 22-387  PDF             WASHINGTON : 2020        
        
        
        
          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                  LAMAR ALEXANDER, Tennessee, Chairman
                  
MICHAEL B. ENZI, Wyoming           PATTY MURRAY, Washington
RICHARD BURR, North Carolina       BERNARD SANDERS (I), Vermont
JOHNNY ISAKSON, Georgia            ROBERT P. CASEY, JR., Pennsylvania
RAND PAUL, Kentucky                MICHAEL F. BENNET, Colorado
SUSAN M. COLLINS, Maine            TAMMY BALDWIN, Wisconsin
BILL CASSIDY, M.D., Louisiana      CHRISTOPHER S. MURPHY, Connecticut
TODD YOUNG, Indiana                ELIZABETH WARREN, Massachusetts
ORRIN G. HATCH, Utah               TIM KAINE, Virginia
PAT ROBERTS, Kansas                MAGGIE HASSAN, New Hampshire
LISA MURKOWSKI, Alaska             TINA SMITH, Minnesota
TIM SCOTT, South Carolina          DOUG JONES, Alabama

                                    
                                    
               David P. Cleary, Republican Staff Director
         Lindsey Ward Seidman, Republican Deputy Staff Director
                 Evan Schatz, Democratic Staff Director
             John Righter, Democratic Deputy Staff Director
                                 ------                                

                 SUBCOMMITTEE ON CHILDREN AND FAMILIES

                     RAND PAUL, Kentucky, Chairman
LISA MURKOWSKI, Alaska               ROBERT P. CASEY, JR., 
RICHARD BURR, North Carolina             Pennsylvania, Ranking Member
BILL CASSIDY, M.D., Louisiana        BERNIE SANDERS, Vermont
TODD YOUNG, Indiana                  MICHAEL F. BENNET, Colorado
ORRIN HATCH, Utah                    TIM KAINE, Virginia
PAT ROBERTS, Kansas                  MAGGIE HASSAN, New Hampshire
LAMAR ALEXANDER, Tennessee (ex       TINA SMITH, Minnesota
    officio)                         PATTY MURRAY, Washington (ex 
                                         officio)
                                         
                                         
                            C O N T E N T S

                              ----------                              

                               STATEMENTS

                       WEDNESDAY, OCTOBER 3, 2018

                                                                   Page

                           Committee Members

Paul, Rand, Chairman, Subcommittee on Children and Families, 
  Opening statement..............................................     1
Casey, Robert, Jr., Ranking Member, a U.S. Senator from the State 
  of Pennsylvania, Opening statement.............................     2

                               Witnesses

Dant, Mark, Chair, EveryLife Foundation for Rare Diseases, 
  Louisville, KY.................................................     4
    Prepared statement...........................................     6
Patterson, Marc, M.D., Professor of Neurology, Pediatrics, and 
  Medical Genetics, Mayo Clinic, Rochester, MN...................     8
    Prepared statement...........................................    10
Strupp, Michael, M.D., Professor of Neurology, University of 
  Munich, Munich, DE.............................................    13
    Prepared statement...........................................    15
Tsang, Lincoln, F.R.Pharm.S., Partner, Arnold and Porter, Kaye, 
  Scholer, LLP, London, England, UK..............................    21
    Prepared statement...........................................    23
Factor, Mallory, Founder and CEO, IntraBio, Inc., Oxford, 
  England, UK....................................................    27
    Prepared statement...........................................    29


                             RARE DISEASES:

                   EXPEDITING TREATMENTS FOR PATIENTS

                              ----------                              


                       Wednesday, October 3, 2018

                                       U.S. Senate,
                     Subcommittee on Children and Families,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The Subcommittee met, pursuant to notice, at 2:31 p.m. in 
room SD-430, Dirksen Senate Office Building, Hon. Rand Paul, 
Chairman of the Subcommittee, presiding.
    Present: Senators Paul [presiding], Cassidy, Alexander, 
Casey, and Hassan.

                   OPENING STATEMENT OF SENATOR PAUL

    Chairman Paul. I will call this Subcommittee to order.
    We are a Subcommittee from the general Committee of Health, 
Education, Labor, and Pensions. We are here today to have a 
hearing entitled, ``Rare Diseases: Expediting Treatments for 
Patients.'' I will begin with an opening statement before we 
introduce the panel.
    Through our hearing today, I intend to examine regulatory 
barriers to entry for drugs that treat rare diseases, also 
known as orphan drugs. The F.D.A. defines orphan diseases as 
those with fewer than 200,000 patients.
    There are over 7,000 conditions that science has identified 
affecting nearly 30 million patients just in the U.S. 
Unfortunately, about 90 percent of these are serious or life-
threatening conditions, and most have no F.D.A. approved 
treatment.
    The standard of approval for orphan drugs is similar, if 
not the same, as those for more common conditions. It can take 
upwards of a decade, sometimes, for a drug to make it from the 
bench to bedside, and costs can be upwards of $2 billion.
    For terminal patients waiting for the cure that may never 
come, or one that comes too late, is simply not an option. 
Therefore, families and patients often resort to importation of 
drugs approved overseas, off label use, or may turn to 
dangerous chemical grade products.
    As a physician, I understand how rare diseases affect the 
body and manifest themselves through devastating and 
debilitating symptoms. Even in my family alone, I have a nephew 
who has Neurofibromatosis 2 and we have had to deal with a 
disease that is not very common and many people have not seen, 
even many physicians have not seen.
    As a parent, I can only imagine, though, the overwhelming 
desperation and hopelessness of being confronted with a fatal 
diagnosis and being told to simply enjoy the remaining time 
that their child has left.
    To the extent that government can improve efficiencies to 
speed access to treatments for patients and families facing 
such a situation, such action should be taken without delay.
    Despite providing the F.D.A. with numerous tools to 
expedite approvals, and continually increasing resources, 
review times have not decreased. Over the life of the current 
User Fee Agreement, the F.D.A. will take in more than $4 
billion in user fees from the drug industry, amounting to over 
70 percent of the agency's review budget for these products.
    Since the beginning of my time in the Senate, I have worked 
to ensure that the F.D.A. has had the authority to accept data 
from foreign countries. Yet, despite these efforts, duplicative 
trials and testing are still required in order to bring most 
drugs to market.
    In addition, drugs approved in Europe are not harmonized 
with the F.D.A.'s process, causing problems in an increasingly 
globalized scientific community.
    I hope we can work together today, and in the future, to 
find solutions that work to expedite treatment for these 
patients.
    With that, I would like to recognize the Ranking Member, 
Senator Casey.

                   OPENING STATEMENT OF SENATOR CASEY

    Senator Casey. Thank you, Chairman Paul, for calling this 
important hearing.
    I want to thank the witnesses for being here and thank the 
Chairman of our Committee, Senator Alexander, for his presence 
here.
    I wanted to apologize in advance. I have to leave in about 
20 minutes. This hearing was scheduled at a time when I had a 
conflict. I wish that had not happened, but it did, so I have 
to leave early.
    I will be submitting questions in writing for the witnesses 
and I look forward to your responses.
    We are here today to talk about a critically important 
issue: the development of drugs to treat rare diseases. Thirty-
five years ago, Congress passed the landmark Orphan Drug Act. 
This legislation represented the first concerted Federal effort 
to incentivize the development of new treatments specifically 
for rare diseases.
    The Orphan Drug Act established grants to assist in the 
development of new orphan drugs. It established the Orphan Drug 
Tax Credit to further offset the research and development 
costs, and provided a longer period of exclusivity, a full 7 
years, for orphan drugs.
    As a result of the Act, over 600 orphan drugs have been 
approved and many more are in development. This compares to 
just 34 orphan drugs approved in the 15 years before the Act 
was in effect.
    In recent years, Congress has taken a number of additional 
steps to streamline and speed up the development of new 
therapies for rare diseases. The first I will mention is one 
that I am quite proud of because I developed this policy with 
Senator Isakson.
    This incentive is the Pediatric Rare Disease Priority 
Review Voucher Program, which rewards the development of a drug 
for a rare, pediatric disease with a voucher that can be used 
to give another drug priority review by the F.D.A., cutting the 
review time from 8 months to 6 months. Companies can keep the 
voucher to use it for another drug in their portfolio, and they 
can sell it and reinvest it in their own research.
    I am grateful for the work of Senator Isakson on this with 
me.
    Since the Pediatric Rare Disease Priority Review Voucher 
Program was established in 2012, 13 vouchers have been awarded 
for new drugs to treat rare pediatric diseases, for diseases 
ranging from cancer to a genetic cause of blindness to the 
first marijuana-derived cannabidiol drug to treat two rare 
forms of epilepsy.
    The F.D.A. has a number of other tools at its disposal to 
aid in the development and approval of drugs for rare diseases, 
several of which have been enacted in the last two years. The 
same law that extended and strengthened the Pediatric Priority 
Review Voucher Program, the 21st Century Cures Act, also 
required the F.D.A. to develop guidance on how to use adaptive 
trial designs, a Bayesian method for clinical trials. The 
F.D.A. published the draft version of that guidance last month.
    The same day, the F.D.A. also published guidance on the so-
called Master Protocols which can allow a single clinical trial 
to evaluate multiple drug candidates, multiple disease types, 
and more than one patient population under the same clinical 
trial structure, potentially reducing the time and cost of 
generating the necessary data for approval.
    One of the common points we hear from the patient 
community, and the companies working to develop new drugs, is 
that patients are, and understandably so, desperate for access 
to new drugs when it is hard to enroll them in clinical trials.
    Congress has given the F.D.A. specific authority in the 
F.D.A. Reauthorization Act to consider ways to design clinical 
trials that incorporate data from expanded access use of 
investigational drugs.
    The F.D.A. is also learning from the adaptive trial designs 
employed during the Ebola outbreak in 2014 and using those 
lessons to inform other clinical trials where the standard 
randomized, double-blind, placebo trial is not possible or is 
not ethical.
    The agency has noted that these new study designs are 
relevant to the growing field of gene therapy and thus also to 
the rare disease community where so many of the diseases are 
genetic in origin.
    I look forward to continuing to work with the patient 
community, other stakeholders, and Members of the Committee to 
advance drug development for rare diseases, while continuing to 
ensure patients can trust their drugs and trust that those 
drugs are both safe and effective.
    Thank you very much.
    Chairman Paul. I would like to recognize the Chairman, 
Senator Alexander.
    The Chairman. Thank you, Mr. Chairman.
    I would like to thank the witnesses for coming. We look 
forward to this.
    Senator Paul and Senator Casey have been real leaders in 
our efforts to put a spotlight on rare disease. I want to thank 
Senator Paul for the hearing. I want to thank Senator Casey for 
his work over the years, his contributions to the 21st Century 
Cures Act, as was Senator Paul. I look forward to the 
testimony.
    We have a vote. I am managing the opioid bill on the floor 
with the votes at 3:15, so I will have to leave a little before 
that, but I look forward to the hearing. I salute Senators Paul 
and Casey for their focus on such an important topic.
    Chairman Paul. Well, thank you both for coming.
    As you will see, if you have not been to a hearing before, 
we have multiple hearings going on everywhere around, as well 
as votes on the floor. So sometimes you will see people come 
and go, but I do thank Senator Casey and Senator Alexander for 
coming.
    We are going to start with testimony from Mark Dant, who is 
the Chairman of the EveryLife Foundation for Rare Diseases, and 
also from the great Commonwealth of Kentucky.

STATEMENT OF MARK DANT, CHAIRMAN, EVERYLIFE FOUNDATION FOR RARE 
                    DISEASES, LOUISVILLE, KY

    Mr. Dant. Chairman Paul, Chairman Alexander, Ranking Member 
Casey, and distinguished Members of the HELP Committee.
    I am Mark Dant. I am the Chairman of the Board of the 
EveryLife Foundation for Rare Diseases and the parent of a 
child with a rare disease. The EveryLife Foundation is a 
science-based advocacy organization that works to bring 
lifesaving treatments to the 30 million Americans with rare 
diseases.
    We represent the one in ten Americans affected by more than 
7,000 known rare diseases with 50 percent of the rare disease 
patients being children many of whom will not live to see their 
fifth birthday. It is imperative that we significantly increase 
the number of F.D.A. approved rare disease treatments now.
    My son Ryan was diagnosed at three years old with MPS-I, a 
rare lysosomal storage disorder. The cells in Ryan's body 
lacked a crucial enzyme that it needed to break down sugar. The 
hospital told us that children with MPS-I rarely, if ever, 
lived past their teens as there was no treatment for his 
disorder.
    Because MPS-I was so rare, affecting only a few thousand 
children around the world, drug companies were not interested 
in funding the research. My wife, Jeanne, and I were told there 
would be little other that we could do for Ryan other than take 
him home and love him for as long as he lived.
    I refused to accept the recommendations and I spent all my 
spare time trying to understand Ryan's condition. After a year 
my wife, Jeanne, and I founded the Ryan Foundation to raise 
money to find a treatment for MPS in time for our son Ryan. Our 
first fundraiser was a bake sale that netted $342.
    Eventually, I learned of a pediatric researcher who was 
working to find treatments for children with MPS, Dr. Emil 
Kakkis, at Harbor UCLA. It was 11 years after the passage of 
the Orphan Drug Act, yet Dr. Kakkis had no funding for 
research.
    Over the next several years, the all-volunteer Ryan 
Foundation raised more than $1 million for Dr. Kakkis' work, 
which culminated in a new drug therapy. This therapy would 
never have come to fruition without the formation of a small 
biotech company, which pulled Ryan's drug through the pipeline 
in time to help him survive.
    Rare disease absolutely needs biotech partners. Family 
organizations like my own simply do not have the capital 
necessary to bring treatments to approval.
    In 2003, the F.D.A. approved Aldurazyme for the treatment 
of MPS-I, five years after Ryan and nine other children began a 
trail at UCLA.
    Enzyme replacement therapy later turned out to be 
instrumental in treating several other previously untreated and 
devastating disorders, proving again that biotech involvement 
in one disorder leads to not one, but countless more disease 
treatments.
    Ryan is now 30 years old, a graduate of the University of 
Louisville, and is the longest treated person with MPS-I in the 
world. Unfortunately, Ryan's story is the exception.
    We are now 35 years since the Orphan Drug Act was signed 
into law, yet fewer than 400 of the 7,000-plus known rare 
diseases have F.D.A. approved treatments.
    We call on Congress to close the innovation gap for the 95 
percent of rare diseases that have no treatment by 
incentivizing companies to repurpose already approved drugs for 
rare disease. Many patients are using drugs off label including 
my own son Ryan. Drugs used off label do not have the 
appropriate safety, efficacy, and dosing information. They also 
lack coverage for the cost of the drug, as many insurers will 
not pay for off label use.
    The bipartisan OPEN ACT, S. 1509, introduced by Senators 
Hatch and Menendez, is a patient-driven solution supported by 
more than 300 organizations, including my own, modeled after 
the bipartisan Best Pharmaceuticals for Children Act, which 
resulted in over 600 labeling changes.
    The OPEN ACT has the potential to double the number of 
F.D.A. approved therapies for rare disease patients, and at a 
lower average cost than current rare disease treatments.
    I urge Congress to pass the OPEN ACT before the end of this 
year. In addition, we call on Congress to do the following 
steps:
    Fund a Center of Excellence for rare diseases;
    Allow innovators to use novel biomarkers for rare disease 
research;
    Shorten the seven years it takes to obtain an accurate 
diagnosis;
    Pass the Newborn Screening Saves Lives Act; and,
    Pass legislation to ensure coverage of de novo sequencing.
    In conclusion, I ask all of you gathered here today--
Republicans, Democrats, Independents--to please put your 
policies and politics aside and join the rare party. The F.D.A. 
is not our enemy. Biotech companies are not our enemy. Our 
enemies are the rare diseases that steal livelihoods, mobility, 
vision, minds, and in the worse cases, lives.
    All of us, patients, policymakers, innovators must work 
together to speed the development of, and access to, safe and 
effective treatments for the rare disease patients across the 
Nation.
    Thank you.
    [The prepared statement of Mr. Dant follows:]
                    prepared statement of mark dant
    Chairman Paul, Ranking Member Casey and distinguished Members of 
the Senate Health, Education, Labor, and Pensions Committee. I am 
privileged to be here today to present my perspective as the parent of 
a child with a rare disease, and to represent the 1 in 10 Americans 
affected by the more than 7,000 known rare diseases. I serve as 
chairman of the board of the EveryLife Foundation for Rare Diseases, a 
science-based advocacy organization that works to bring lifesaving 
treatments to the 30 million Americans with rare diseases. There are 
more Americans who live with a rare disease than those who have HIV, 
heart disease, or stroke combined. 50 percent of rare disease patients 
are children, many of whom will not live to see their fifth birthday. 
Only 5 percent of rare diseases have FDA-approved treatments.

    When my son Ryan was 3 years old, he was diagnosed with MPS 1--a 
rare lysosomal storage disorder. The cells in Ryan's body lacked a 
crucial enzyme they needed to break down sugar. The geneticist at 
Dallas Children's Hospital told us that children with MPS 1 almost 
never lived past their teens, as there was no treatment for his 
disorder. Because MPS I was so rare, affecting only a few thousand 
children around the world, drug companies were not interested in 
funding the research. My wife Jeanne and I were told there were no 
options other than to take Ryan home and love him for as long as he 
lived.

    I refused to accept the doctor's recommendations. Despite working 
the night shift after recently being promoted to Lieutenant in the 
Carrollton, Texas Police Department, I spent all my off-duty time 
trying to understand Ryan's condition. After a year of lying on the 
floor next to our son's bed at night and crying, my wife Jeanne and I 
founded a non-profit called the Ryan Foundation to raise money to find 
a treatment for MPS in time for our son. Our first fundraiser was a 
bake sale that netted $342. After several years of going door-to-door 
asking for donations and a series of conversations with leading 
scientists across the United States and Europe, I was told about a 
pediatric researcher who was working to find treatments for children 
with MPS 1: Dr. Emil Kakkis at Harbor UCLA. It was late 1994, 11 years 
after the passage of the Orphan Drug Act, yet Dr. Kakkis had no funding 
for his research and was working out of a one-story World War II era 
bungalow behind the county hospital in Torrance, California in a lab 
he'd constructed with the help of his own family members.

    Over the course of the next several years, the all-volunteer Ryan 
Foundation managed to raise more than $1 million for Dr. Kakkis' work 
on MPS 1, which culminated in a new drug therapy. This therapy would 
never have come to fruition in enough time for Ryan without the 
formation of a small biotech company, which pulled Ryan's drug through 
the pipeline in time for him to survive. Rare disease absolutely needs 
biotech partners. Family organizations simply do not have the capital 
necessary to bring treatments to approval. There are simply not enough 
companies to bring science already available to approved therapies.

    In 2003, the FDA approved Aldurazyme for the treatment of MPS I--
five years after Ryan and nine other children began the trial at UCLA. 
Enzyme Replacement Therapy later turned out to be instrumental in 
treating several other previously untreated and devastating disorders, 
proving again that biotech involvement in one disorder leads to not 
one, but countless more rare disease treatments.

    Ryan is now 30 years old and the longest treated MPS I person in 
the world. Unfortunately, Ryan's story is the exception. So many 
parents hope to be able to find the right experts and raise enough 
money in time to save their children, but most of them will not be as 
lucky as we were.

    We are now 35 years since the Orphan Drug Act was signed into law, 
yet fewer than 400 of the 7,000 plus known rare diseases have FDA-
approved treatments. We know from our work on Aldurazyme that it is 
possible to generate the commitments needed to bring rare disease drugs 
through the development process. It is often even faster and simpler to 
repurpose existing therapies for rare disease indications. We must 
incentivize industry to invest in rare disease therapies and to 
repurpose existing therapies for rare disease indications.

    We call on Congress to help close the innovation gap for the 95 
percent of rare diseases that have no treatment by incentivizing 
companies to repurpose already approved drugs for Rare Diseases. Many 
patients are using drugs off-label; including my own son Ryan. Even 
rare disease patients who are fortunate enough to be treated with an 
FDA-approved therapy have multiple unmet needs that continue to alter 
their ability to live life without the pain and disability typically 
associated with their rare disease. Drugs used off-label to meet these 
needs do not have the appropriate safety, efficacy, and dosing 
information. They also often lack coverage for the cost of the drugs, 
as many insurers will not pay for off-label use. The bipartisan OPEN 
ACT (S. 1509), introduced by Senators Orrin Hatch (R-UT) and Robert 
Menendez (D-NJ), is a patient-driven legislative solution supported by 
more than 300 rare disease patient organizations. Modeled after the 
bipartisan Best Pharmaceuticals for Children Act of 2002, which 
resulted in over 600 labeling changes and provided substantial clinical 
data on drug safety and efficacy in pediatric populations, the OPEN ACT 
has the potential to double the number of FDA-approved therapies for 
rare disease patients at a lower average cost than current rare disease 
drugs. I urge Congress pass the OPEN ACT before the end of this year.

    I also ask Congress to fund a Center of Excellence for Rare 
Diseases and more specialized review divisions at the Food and Drug 
Administration. The FDA must have specialized personnel who understand 
the complexity of rare disease drug development to allow more flexible 
clinical trial designs, such as an ``allcomers'' trial that will allow 
our very small, heterogeneous patient populations to participate. 
Additionally, rare diseases still do not have access to the Accelerated 
Approval Pathway as novel biomarkers for rare diseases are not accepted 
as endpoints. Allowing the use of a biomarker as a surrogate endpoint 
will lower the cost of rare disease drug development by 62 percent. 
Ensuring that the FDA has the expertise and understanding needed for 
rare disease trial design will help de-risk the regulatory process and 
encourage investment in ultra-rare diseases.

    Finally, I ask Congress to seek policy solutions to alleviate the 
devastating diagnostic odyssey for our community. For a rare disease 
patient, the diagnostic odyssey, or the time it takes for an individual 
to be accurately diagnosed, is about 7 years. This is unacceptable. The 
devastating effects of many diseases are irreversible. Early diagnosis 
is critical to ensure patients have access to clinical trials and 
lifesaving therapies. Congress must reauthorize the Newborn Screening 
Saves Lives Act before it expires on Sept. 30, 2019. Additionally, the 
Senate should introduce companion legislation to the House's Precision 
Medicine Act to help mitigate and eventually end the diagnostic odyssey 
so many patients and their families endure. 80 percent of rare diseases 
are genetically based so coverage for genomic sequencing is critical.

    I ask all of you gathered here today--Republicans, Democrats, 
Independents--please put your politics aside and join the rare party. I 
have spoken to countless rare disease families like my own across the 
country and their message is the same: Drug companies are not the 
enemy, nor is the FDA. Our enemies are the rare diseases that steal 
livelihoods, mobility, vision, minds, and in the most devastating 
cases--lives.

    I work with many parents who have raised the money to develop the 
science, yet no drug company is interested in developing the treatment. 
My advice is for them is to start their own drug company. However, I 
ask you: Should that also be their burden? We need Congress to 
incentivize drug companies and innovators to partner with us to bring 
lifesaving treatments to patients before it's too late.

    I have personally felt the pain of finding no hope because a rare 
disease has stolen the promise of our tomorrows. I have attended 
countless funerals of children who lost their battle to a rare disease 
and witnessed the pain in their parents as they say goodbye. We must 
work together to change our system to increase the speed of safe and 
effective treatments from the scientific bench to the bedside by 
removing the barriers to novel trial designs. We must consider the 
heterogeneity of ultra-rare diseases and understand the true value of 
``all comer trials'' so that our small patient populations are no 
longer overlooked, and the value of their data understood. Treatments 
come from the partnership of patients, science, industry, and the FDA.

    Our children's lives depend on it.
                                 ______
                                 
    Chairman Paul. Well put. Thank you for your testimony.
    Our next witness is Dr. Marc Patterson, who is a Professor 
of Neurology, Pediatrics, and Medical Genetics at the Mayo 
Clinic.

  STATEMENT OF MARC PATTERSON, M.D., PROFESSOR OF NEUROLOGY, 
  PEDIATRICS, AND MEDICAL GENETICS, MAYO CLINIC, ROCHESTER, MN

    Dr. Patterson. Chairman Alexander, Chairman Paul, Ranking 
Member Casey, and Members of the Committee.
    I wish to thank you for the opportunity to testify before 
you today, for your interest in this important topic, and the 
work that you have already done. I am honored to have this 
opportunity to advocate on behalf of children and families 
afflicted by rare diseases.
    My name is Marc Patterson. I am a pediatric neurologist and 
I currently serve as a Professor of Neurology, Pediatrics, and 
Medical Genetics at the Mayo Clinic in Rochester, Minnesota.
    I completed my fellowship training in rare diseases at the 
National Institutes of Health some three decades ago, and I 
have dedicated my career to children and families with rare 
disorders since that time.
    I have cared for many hundreds of children and families. As 
you can gather from the testimony of the previous speaker, you 
can understand why I admire the courage, the creativity, and 
resilience of these extraordinary families who are my personal 
heroes.
    Congress has recognized the plight of people with rare 
diseases for more than a generation to provide needed 
incentives for researchers to devote resources to investigate 
and develop therapies for rare diseases; and strengthen 
interest in rare diseases at the National Institutes of Health; 
and to encourage the Food and Drug Administration.
    These acts of Congress are widely regarded as having been 
highly successful in stimulating the interest of industry in 
developing orphan drugs, and I thank Congress for that work and 
the work that you have done in furthering those ends.
    I would like to emphasize the fact that advances in 
diagnostic techniques, particularly the next generation 
sequencing of DNA, have led to the rapid expansion of the 
number of recognized rare and ultra rare diseases; by which I 
mean, diseases that affect fewer than 2,000 individuals, 
sometimes as few as 10 or 20.
    Collectively, these diseases affect a very significant 
proportion of the population, as you have heard, yet few of 
them have approved therapies.
    Moreover, the increasing use of next generation sequencing 
means that disorders, which we currently think of as common 
diseases, will likely prove to be families of rare disorders in 
the future. So I think there is considerable urgency in finding 
better ways to develop treatments more rapidly.
    As you already gathered from Mark Dant's testimony, every 
family's story is unique, but there are certain common themes.
    The initial symptoms of rare and ultra rare diseases are 
often mistaken for those of more common disorders. Families 
will travel from physician to physician, from medical center to 
medical center enduring extensive, expensive, and sometimes 
invasive investigations before the correct diagnosis is 
eventually made. And often, that diagnosis is delayed by years. 
By this time, the opportunity for early and effective 
intervention has often passed.
    The patient and their families then enter a new, and 
equally frustrating, stage like those caregivers and others who 
are unfamiliar, sometimes even with the name, let alone with 
the burdens of such a diagnosis. And they have to deal with a 
bureaucracy, which is largely designed to care for adults with 
common diseases, not children and young adults who have 
progressive disorders. Often, families are told, 
inappropriately, that nothing can be done for their child.
    The process of developing any new treatments, specifically 
pharmaceutical therapies, is long and complex. Typically, this 
process requires large numbers of subjects, who will ultimately 
participate, as we have heard, in randomized, double-blind, 
placebo-controlled clinical trials. But this pathway is 
inappropriate and has many barriers for rare and ultra rare 
diseases.
    As we have already heard, there is a small potential pool 
of participants. Not all individuals are suitable candidates 
who are willing to participate, and there is wide, individual 
variation from individual to individual in terms of the 
symptoms, the age of onset, and the rate at which the disease 
progresses. All of this makes the assembly of well-matched 
cohorts of patients for controlled trials well nigh impossible.
    Another challenge is how to measure the effects of drugs in 
rare diseases because traditional measures are usually lacking.
    While there have been many attempts to address these 
deficiencies, and there has been progress at the F.D.A. and the 
N.I.H., there are still fundamental challenges remaining.
    The bottom line is that we need more effective methods and 
pathways for drug approval for rare and ultra rare diseases. I 
suggest that Congress and the administration consider a variety 
of approaches, a few of which I describe in my written 
testimony and which I will highlight now. I had three themes:
    One is trial design, which Senator Casey has already 
addressed.
    The second is the use of data from outside studies.
    Finally, I would like to address the issue of registries.
    First of all, I think that we should ensure that the F.D.A. 
will accept alternative study designs including adaptive trial 
designs and Bayesian trial designs, which have been mentioned, 
and ensure that patients will have access to the study drug to 
encourage participation.
    Secondly, the F.D.A. should be required to accept the 
results of well-conducted clinical trials supervised by 
national regulatory agencies outside the United States, or by 
such agencies acting in concert with the F.D.A.
    Finally, we should require the F.D.A. to work with family 
groups, academic medicine, industry, and other international 
regulatory agencies to develop disease registries, which 
contain secure patient and parent entered data, which can be 
used to enhance understanding of natural history to develop 
outcome measures and to support clinical trials.
    I thank you for the opportunity to present these 
suggestions to the Subcommittee, and I urge Congress to 
consider providing regulators with a new, improved set of tools 
to ensure the translation of scientific and technological 
advances to safe and effective medicines for the millions of 
Americans suffering from rare and ultra rare diseases.
    I look forward to answering any questions you may have.
    Thank you.
    [The prepared statement of Dr. Patterson follows:]
                prepared statement of marc c. patterson
    Chairman Paul, Ranking Member Casey, and Members of the Senate 
Subcommittee on Children and Families, I thank you for the opportunity 
to testify before you today, and for your interest in this important 
program and topic. I am honored to have this opportunity to advocate on 
behalf of children and families afflicted by rare diseases.

    My name is Marc Patterson. I am a pediatric neurologist, and I 
currently serve as a Professor of Neurology, Pediatrics and Medical 
Genetics at Mayo Clinic in Rochester, Minnesota. Since my fellowship 
training at the National Institutes of Health almost 30 years ago, I 
have focused my practice, education and research on children and 
families with rare disorders, specifically inherited metabolic 
diseases. I have had the privilege of caring for many hundreds of 
children and families burdened by rare diseases, supporting them 
through service on advisory boards of lay foundations, by educating my 
peers and the public about these disorders, and by planning and 
executing clinical trials. I have come to admire the courage, 
creativity and resilience of these extraordinary American families; 
they are my personal heroes.
                      The Burden of Rare Diseases
    Congress has recognized the plight of people with rare diseases for 
more than a generation. The Orphan Drug Act of 1983 (PL 97-414) 
provided needed incentives for researchers to devote resources to 
investigate and develop therapies for rare diseases affecting small 
patient populations, where otherwise the projected returns or risks of 
failure might have been overwhelming deterrents stifling innovation. 
The Rare Diseases Act of 2002 (PL 107-280) further strengthened 
interest in rare diseases at the National Institutes of Health. At the 
time the Rare Diseases Act was enacted, more than 6,000 such diseases 
affected approximately 25,000,000 US citizens. But each rare disease 
alone often did not have a sufficiently sized patient population to 
adequately interest prospective investigators. These acts of Congress 
are widely regarded as having been highly successful in stimulating the 
interest of industry in developing Orphan Drugs.

    Advances in diagnostic techniques, particularly next generation 
sequencing of deoxyribose nucleic acid (DNA), have led to the rapid 
expansion of the number of recognized genetic diseases, a substantial 
proportion of which are described as ultra-rare. These disorders have 
typically been recognized in less than a thousand or so individuals, 
sometimes as few as 10 or 20. Rare and ultra-rare diseases individually 
affect relatively few people. But because there are so many of these 
disorders, they collectively affect a very significant proportion of 
the population, and constitute a national burden far in excess of their 
individual numbers. Few of these disorders have approved therapies, or, 
until recently, even the prospect of disease specific treatments. Most 
have multisystem manifestations, and the most severe forms typically 
involve the nervous system, causing debilitating symptoms in varying 
combinations, including intellectual delays or dementia, impairment of 
speech language, hearing, vision, epileptic seizures and a variety of 
movement disorders, leading ultimately to complete dependence for 
activities of daily living, and premature death.

    Although each family's story is unique, certain common themes 
emerge. The initial symptoms of rare and ultra-rare diseases are often 
non-specific in character, insidious in onset, and are often mistaken 
for those of more common disorders. Accurate diagnosis is typically 
delayed, often by years, sometimes by decades, as families travel from 
physician to physician and medical center to medical center, enduring 
extensive, expensive, and sometimes invasive, investigations, before 
the correct diagnosis is eventually made. By this time, symptoms are 
well established, and the opportunity for early and effective 
intervention has often passed, because irreversible tissue damage has 
occurred.

    Once a diagnosis has been made, the affected individuals and their 
families have not reached the end of their journey, but simply enter a 
new, similarly exacting phase. They face incomprehension on the part of 
caregivers and the community, who are unfamiliar with the disease and 
its burdens, and a bureaucracy and rehabilitation system designed 
primarily to care for older adults with common diseases, not children 
and young adults with progressive disorders. Often families are told--
inaccurately and inappropriately--that nothing can be done for their 
child. Thus, the burden of caring for a family member with profound 
disabilities is compounded by struggles with a system that erects 
barriers to care for the most innocent and deserving of our citizens--
children with rare and ultra-rare diseases. Disease modifying therapies 
are usually lacking, although the potential for such therapies is 
growing rapidly as the relevant science continues to advance.
     Challenges in Developing Disease-modifying Therapies for Rare 
                        and Ultra-rare Diseases
    The process of developing new treatments--specifically 
pharmaceutical therapies--is a long and complex process, most often the 
product of discovery by academic scientists in the preclinical phase, 
with subsequent translation to an approved product in cooperation with 
an industry sponsor. The multiphase, stepwise process of studying 
potential therapies requires the participation of increasingly large 
numbers of subjects, ultimately in double blind, randomized, controlled 
clinical trials. This pathway is challenging, but feasible, for 
diseases in which the potential pool of clinical trial participants is 
measured in the thousands, and in which the assembly of cohorts of 
well-matched subjects is readily accomplished.

    Industry sponsors are easier to identify for diseases with a 
potential market of thousands, or even millions, than for rare and 
ultra-rare disorders. For these diseases, the conventional pathway to 
drug approval raises hurdles that cannot be easily overcome, if at all. 
The potential pool of participants is small, and within that 
circumscribed group, not all individuals are willing participants or 
suitable candidates for clinical trials. Moreover, broad variability in 
the symptoms and signs of rare diseases, in the age at which they first 
present, and the rate at which they progress, may render the assembly 
of well-matched cohorts of patients for controlled trials impossible.

    Another important factor that limits the applicability of the 
traditional clinical trial model to rare and ultra-rare diseases is the 
use of unapproved drugs or unstudied supplements in patients with these 
disease disorders. Parents are understandably desperate to explore any 
potential remedy for their child's illness, and when a drug that is a 
candidate for a clinical trial in the United States is available as an 
approved product in another country, or as a supplement here, parents 
will often import the drug, or administer the supplement--thus 
excluding the child as a candidate for a conventional clinical trial.

    Another challenge is how to measure the effects of drugs in rare 
diseases. Ideally, clinical measures based on prospective natural 
history studies, validated biomarkers and surrogate biomarkers should 
be available to define clinically meaningful outcome measures. Such 
measures are usually lacking in rare and ultra-rare diseases, and 
assembling cohorts of patients to perform such studies has historically 
been difficult, owing to lack of funding support. The development of 
Rare Disease Clinical Research Networks with support from the National 
Institutes of Health, has been a welcome development in addressing this 
deficiency. The establishment of The Therapeutics for Rare and 
Neglected Diseases (TRND) program, which is designed to facilitate the 
development of new therapeutics for rare and neglected diseases, 
represents another step forward. Still, neither of these advances has 
addressed the fundamental challenges in planning and executing clinical 
trials for rare and ultra-rare diseases.

    Clinical trials are overseen by the Food and Drug Administration 
(FDA). The current framework for drug approval dates back to the Food, 
Drug and Cosmetic Act of 1938 (PL 75-717), which required that such 
agents be safe. Following the thalidomide disaster in the late 1950's, 
the Kefauver Harris Amendment of 1962 (PL 87-781) strengthened safety 
provisions, and added the requirement that manufacturers demonstrate 
the efficacy of drugs prior to approval. Neither this Act, nor many 
subsequent amendments to the Food, Drug and Cosmetics Act, has made 
specific provisions for the approval of drugs for children and adults 
with rare and ultra-rare diseases.
    Recommendations to Accelerate the Approval of Drugs by the FDA 
                 to Treat Rare and Ultra-rare Diseases
    As the number of recognized rare and ultra-rare diseases continues 
to increase, and as precision medicine begins to dissect out the rare 
disorders which are currently contained within common syndromes, the 
need for better pathways to drug approval becomes increasingly urgent, 
and proactive legislation by Congress is critical.

    I urge Congress to legislate specific pathways for the approval of 
drugs to treat rare and ultra-rare diseases. I suggest the following 
specific measures regarding drug approval for rare and ultra-rare 
diseases, to provide FDA regulators with a more refined set of tools to 
benefit this underserved population:

        A. Require the FDA to accept alternative study designs that are 
        better suited for these small, inhomogeneous, populations. 
        These include, but are not limited to:

        1. Adaptive trial designs, which allow for changes to made to 
        the trial as it proceeds (Chow and Chang, 2008; Gupta, 2011; 
        Cornu, et al 2013);

        2. The use of Bayesian methods for the analysis of trial data 
        (Hampson, et al 2014; Johnson, et al, 2009).

        3. The use of trial designs that attract more participants by 
        either guaranteeing access to the study drug for all 
        participants, or ensuring more prolonged access to the study 
        drug. Such designs include randomized placebo-phase, randomized 
        withdrawal, early escape, stepped wedge and crossover trials 
        (Gupta, et al 2011; Cornu, et al, 2013).

        4. N-of-1 studies to address the type 2 errors that are 
        frequent when the effects of drugs that fail to meet a 
        predetermined level of statistical significance, owing to lack 
        of power, usually owing to insufficient numbers of participants 
        and large variation in outcome baseline measures. The N-of-1 
        trial design allows each participant to serve as his or her own 
        control, permits multiple crossovers between placebo and active 
        therapies, and provides data suitable for meta-analysis to make 
        estimates of group effects (Gupta, et al 2011; Shamseer, et al 
        2016, Zucker, et al 2010). Recommendations for the 
        standardization of N-of-1 trial reporting have been published 
        (Vohra, et al 2015).

        B. Require the FDA to accept the results of well-conducted 
        clinical trials supervised by national regulatory agencies 
        outside the United States, or by such agencies acting in 
        concert with the FDA. By their nature, studies in rare and 
        ultra-rare diseases include all willing and eligible subjects, 
        and requiring that study populations be exclusively recruited 
        from the United States in order to ensure broad representation 
        of the US population, is neither feasible nor appropriate in 
        these circumstances;

        C. Require the FDA to work with lay groups, academic medicine, 
        industry and other international regulatory agencies, to 
        develop disease registries, ideally patient owned and managed, 
        containing secure, professionally entered and patient/parent 
        entered data, which will be used to enhance understanding of 
        natural history, to develop outcome measures, and to support 
        clinical trials. The International Niemann-Pick Disease 
        Registry (INDR) is one such example of a collaborative, 
        patient-initiated and owned venture (https://inpdr.org).

    Current advances in the basic science of biology are leading to 
better understanding of disease mechanisms that hold great promise to 
alleviate the burden of rare and ultra-rare disease. I thank you for 
the opportunity to present these suggestions to the Subcommittee, and 
urge Congress to provide regulators with a new, improved set of 
legislative tools to facilitate the translation of those advances to 
safe and effective medicines for the millions of Americans suffering 
from rare and ultra-rare diseases.

    References:

    1. Chow SC, Chang M. Adaptive design methods in clinical trials--a 
review. Orphanet J Rare Dis. 2008; 3:11.

    2. Cornu C, Kassai B, Fisch R, Chiron C, Alberti C, Guerrini R, 
Rosati A, Pons G, Tiddens H, Chabaud S, Caudri D, Ballot C, Kurbatova 
P, Castellan AC, Bajard A, Nony P; CRESim & Epi-CRESim Project Groups, 
Aarons L, Bajard A, Ballot C, Bertrand Y, Bretz F, Caudri D, Castellan 
C, Chabaud S, Cornu C, Dufour F, Dunger-Baldauf C, Dupont JM, Fisch R, 
Guerrini R, Jullien V, Kassai B, Nony P, Ogungbenro K, Perol D, Pons G, 
Tiddens H, Rosati A, Alberti C, Chiron C, Kurbatova P, Nabbout R. 
Experimental designs for small randomised clinical trials: an algorithm 
for choice. Orphanet J Rare Dis. 2013;8(48).

    3. Gupta S, Faughnan ME, Tomlinson GA, Bayoumi AM. A framework for 
applying unfamiliar trial designs in studies of rare diseases. J Clin 
Epidemiol. 2011 Oct;64(10):1085-94. doi: 10.1016/
j.jclinepi.2010.12.019. Epub 2011 May 6.

    4. Hampson LV, Whitehead J, Eleftheriou D, Brogan P. Bayesian 
methods for the design and interpretation of clinical trials in very 
rare diseases. Stat Med. 2014;33(24):4186-4201.

    5. Johnson SR, Feldman BM, Pope JE, Tomlinson GA. Shifting our 
thinking about uncommon disease trials: The case of methotrexate in 
scleroderma. J Rheumatol. 2009;36:323-9.

    6. Shamseer L, Sampson M, Bukutu C, Schmid CH, Nikles J, Tate R, 
Johnston BC, Zucker D, Shadish WR, Kravitz R, Guyatt G, Altman DG, 
Moher D, Vohra S; CENT group. CONSORT extension for reporting N-of-1 
trials (CENT) 2015: explanation and elaboration. Journal of Clinical 
Epidemiology 76 (2016) 18e46.

    7. Vohra S, Shamseer L, Sampson M, Bukutu C, Schmid CH, Tate R, 
Nikles J, Zucker DR, Kravitz R, Guyatt G, Altman DG, Moher D; CENT 
Group. CONSORT extension for reporting N-of-1 trials (CENT) 2015 
Statement. J Clin Epidemiol. 2015 Aug 10. pii: S0895-4356(15)00225-5. 
doi: 10.1016/j.jclinepi.2015.05.004. [Epub ahead of print].

    8. Zucker DR, Ruthazer R, Schmid CH. Individual (N-of-1) trials can 
be combined to give population comparative treatment effect estimates: 
methodologic considerations. J Clin Epidemiol 2010;63:1312-1323.
                                 ______
                                 
    Chairman Paul. Thank you, Dr. Patterson, for your testimony 
and also for your lifelong work in trying to find cures for 
these awful diseases.
    Our next witness is Dr. Michael Strupp, who is a Professor 
of Neurology at the University of Munich. When you conclude 
your testimony, if you want to introduce and show a couple of 
videos right at the end of your testimony, we would love to see 
the videos.

  STATEMENT OF MICHAEL STRUPP, M.D., PROFESSOR OF NEUROLOGY, 
                UNIVERSITY OF MUNICH, MUNICH, DE

    Dr. Strupp. Senator Paul, Senator Casey, Senator Alexander, 
and Senator Cassidy.
    Thank you for the opportunity to present our suggestions. 
In my statement, I am going to focus on four topics:
    First, what is meant by ultra rare diseases?
    Secondly, what are the specific problems in such diseases 
in terms of designing and performing a clinical trial to get 
approval?
    Third, what would be the impact of an adopted approval 
process on research and even investments by pharmaceutical 
companies?
    Fourth and finally, my vision.
    What does rare and ultra rare mean? Senator Paul already 
mentioned that rare diseases are defined by fewer than 200,000 
people affected by a certain disease in the U.S. If you take 
into consideration a population of 325 million Americans, you 
will end up with a prevalence of less than 60 in 100,000.
    There are, however, ultra rare diseases with a prevalence 
of less than a hundredth of that. Two examples are Niemann-Pick 
type C with a prevalence not of 60, but of 0.07 in 100,000; 
Tay-Sachs, 0.3 in 100,000.
    This means, for instance, for Washington, DC with a 
population of 650,000 inhabitants, 5 patients with Niemann-Pick 
type C and just 2 with Tay-Sachs.
    What about clinical trials in ultra rare diseases? 
Designing and performing a clinical trial in such diseases is 
very challenging for four reasons.
    First, the small number of individuals that can be 
theoretically recruited.
    Secondly, patients with these diseases are often severely 
impaired, are not able or willing to participate.
    Most patients are children. For instance, a Niemann-Pick 
type C, 50 percent of the children die before the age of 13, 
which makes recruitment, of course, even more difficult.
    Finally, the statistical design, which was already 
mentioned by my colleague. The conventional use--the so-called 
sample size calculation with a sufficient statistical power--
can only be theoretically implied in such diseases, but will 
not be useful if you have, for instance, only 16 patients in 
the U.S. suffering from a rare gangliosidosis.
    Nevertheless, we have to perform clinical trials to get an 
approval in ultra rare diseases. From my point of view, there 
are three prerequisites which have to be fulfilled for such 
trials and which can be called the ``Triple D's'': disease, 
drug, and the design of the trial in particular in terms of 
outcome measures and statistical analysis.
    Disease in terms of four aspects:
    The prevalence should be really low, less in 1 in 100,000.
    The precise diagnosis has to be made, nowadays by genetic 
testing.
    The disease should have a high impact in terms of signs and 
symptoms, but also functioning and quality of life, not only of 
the patient, but also the caregivers.
    There is a high medical need and no other treatment 
available yet.
    When it comes to the drugs, there are also four aspects:
    Ideally, a drug should already be approved for a different 
indication, but means repurposing of drugs.
    It should have a very good safety profile.
    The efficacy should be shown in animal studies without a 
placebo effect.
    The mode of action should be known on every level. That 
means histopathology, electrophysiology, even up to proteomics.
    Finally, the design of the study and the outcome measures, 
they should always be clinically meaningful in terms of 
functioning and quality of life.
    Imagine a patient is now able to walk or use their hands 
properly, take the tablets, take the meals by him or herself as 
you will see in one of the videos. This is a major improvement.
    What could be the impact of adjusting the approval measures 
for pharmaceutical companies and research? We live in a world 
of commerce, investment, making money also by pharmaceutical 
companies. This is important, not only for the shareholders, 
but also for patients.
    How is this related to the topic? If the approval of drugs 
for ultra rare diseases is adapted to the real world and 
transparent for such diseases, I think these diseases will 
become commercially more attractive. Companies will invest 
money because they have a chance that the drug is going to be 
approved within a reasonable time.
    What is my personal vision? We live in the century of 
personalized medicine, and this attitude, I think, should also 
be transferred to rare diseases so that we have an 
individualized and harmonized approval process for therapies 
based on solid science and the safety of drugs.
    Finally, as a passionate doctor seeing 2,000 patients per 
year, a final statement; one should not withhold effective 
drugs from currently severely affected individuals because of 
regulatory approval processes, which may no longer be 
justified.
    I am going to show, we have several examples. One patient 
with Niemann-Pick type C, we have published a case series, 
which is our approach to find new drugs on 13 patients.
    [Video Presentation.]
    Dr. Strupp. Here you see a 14-year-old girl, who should 
perform the so-called 9-hole peg test, which is a standard test 
to evaluate hand coordination.
    In a few moments, you will see what happens if this girl is 
on medication. This is just a simple case and that is our 
approach.
    We use a drug which has been approved for other 
indications, which is definitely safe, and then we start with 
small case series. Knowing the mode of action of the drug, this 
drug normalized membrane potential.
    We complement that by back translational research with this 
drug with the Department of Pharmacology in Oxford in 
appropriate animal models showing the same effects with this 
drug in the dosages which are per kilogram identical to the 
patients.
    Chairman Paul. This is approved where?
    Dr. Strupp. What?
    Chairman Paul. This drug is approved where?
    Dr. Strupp. This drug was approved since 1957 in France to 
treat patients with vertigo and dizziness.
    My background is electrophysiology. I know the mode of 
action. It normalizes membrane potential and therefore I 
thought it may have an impact on various neurological disorders 
to bring neurons, which are still alive, but which are not 
working properly, into a normal state, and this we have seen 
for Tay-Sachs disease.
    Chairman Paul. Do you know how long the application process 
has been going on in the United States for this drug?
    Dr. Strupp. We had on July 17 an F.D.A. meeting. That was 
our first meeting with the F.D.A. We were able to introduce two 
new outcome measures for our trials, and the F.D.A. was quite 
positive that we can run a Phase II trial in the U.S.
    We have also got an approval by the European agencies in 
U.K., Spain, and the Netherlands, which were quite 
enthusiastic, in particular since this drug has an excellent 
safety profile. It is well-tolerated.
    By the way, hundreds of patients take the drug, now 
worldwide, off label, of course, from the Philippines, India, 
to Latin America and also in the U.S.
    [The prepared statement of Dr. Strupp follows:]
                  prepared statement of michael strupp
    1. Chairman Paul, Ranking Member Casey and Distinguished Members of 
the Subcommittee, my name is Dr Michael Strupp, a Professor of 
Neurology at the University of Munich, Germany in the Department of 
Neurology and German Centre for Vertigo and Balance Disorders.

    2. Thank you for the opportunity to discuss the current status of 
orphan drug development, and how the process of getting new treatments 
to patients with rare, fatal, genetic conditions can be improved so 
that patients have access to potentially life-changing treatments 
sooner, and the extremely high medical need of too many orphan 
disorders can be met.

    3. My clinical expertise is concentrated on diagnosis and therapy 
for vestibular, ocular motor, and cerebellar disorders, namely by 
discovering, investigating, and the ``repurposing'' of drugs by 
initiating, designing, and performing randomized controlled clinical 
trials (mainly investigator initiated) that include multinational 
studies. This also involves performing back-translational research in 
animal models.

    4. Some of my major achievements in discovering and assessing new 
treatments have been: First, demonstration of the effectiveness of 
vestibular exercises in acute vestibular neuritis in a controlled 
clinical trial. Second, demonstration of the benefit of steroids in 
acute vestibular neuritis, a placebo-controlled, four-arm trial 
published in the New England Journal of Medicine. Third, introduction 
of three new pharmacotherapeutic principles for the treatment of rare 
diseases: (1) aminopyridines, as potassium channel blockers, for the 
treatment of downbeat, upbeat and central positioning nystagmus as well 
as episodic ataxia type 2 (now the treatment of choice for episodic 
ataxia type 2 according to the American Academy of Neurology, 2018); 
(2) chlorzoxazone for the therapy of downbeat nystagmus; and, more 
recently, (3) N-acetyl-leucine for the treatment of ataxias (such as 
inherited cerebellar ataxias like Ataxia-Telangiectasia and 
Spinocerebellar Ataxias), Niemann-Pick Type C (NPC), Tay-Sachs disease, 
as well as additional rare lysosomal storage disorders and 
neurodegenerative diseases.

    5. I have been the principal investigator of the following 
randomized controlled trials on: episodic ataxia type 2 (in 
collaboration with Dr Joanna Jen, UCLA), downbeat nystagmus (in 
collaboration with Dr Christopher Kennard, Oxford), Meniere's disease, 
vestibular neuritis, vestibular migraine, vestibular paroxysmia, benign 
paroxysmal positional vertigo and ataxias.

    6. Since 2016, I have been the head of the task force for the 
pharmacotherapy of cerebellar disorders.

    7. I have also extensive experience in managing patients with rare, 
neurodegenerative diseases, in particular, cerebellar ataxias, NPC 
(including the 2017 ``Recommendations for the detection and diagnosis 
of NPC'' with Dr Marc Patterson, Mayo Clinic) and Tay-Sachs disease. I 
have also carried out both experimental researches to identify 
potential therapies for these patients. The background for this basic 
and clinical research has been an international collaboration requiring 
colleagues and experts' involvement from around the world. Back-
translational research has also been done in various animal models, 
e.g., in close collaboration with Professor of Pharmacology and 
Neurology from various global institutions.

    8. I have authored 366 PubMed listed papers and four books on 
vertigo, dizziness, ocular motor and cerebellar disorders. Currently I 
am the Editor-in-Chief of Frontiers in Neurootology, Joint Chief Editor 
of The Journal of Neurology, and a Member of the Editorial Board of 
Neurology. I have received many clinical and scientific awards, 
including the Hallpike-Nylen Award 2106, am a very engaged teacher and 
was awarded `Best Teacher' by the German Neurological Society.

    9. Finally, I am a very passionate doctor, and personally see more 
than 2000 patients per year, and am a proud father of four kids.

    10. My curriculum vitae is attached.
                           Problem Statement

    11. The responsibility of any clinician is to provide their 
patients with the best standard of care to manage their underlying 
conditions. Diagnosis is the traditional basis for decisionmaking in 
clinical practice and can provide crucial information on treatment 
options that influence outcome. Clinical management of rare, genetic, 
orphan diseases--a majority of which are progressive, debilitating, and 
display a large degree of clinical heterogeneity--follows a similar 
clinical practice paradigm to precisely diagnose the disorder, for 
instance, by genetic testing. In other words, delivering the best 
standard of care ideally requires clinicians do not simply treat 
symptoms of unknown etiology but identify the disease with a known 
underlying pathophysiological mechanism to apply a specific 
individualized therapy.

    12. In my professional experience spanning 20 years as a 
neurologist, I have continuously diagnosed and treated patients with 
various different rare, genetic diseases. Such diseases often manifest 
in early childhood and are often associated with a decreased life-
expectancy. Almost all of these diseases are associated with a severe 
impairment of functioning and quality of life. There is therefore a 
need to recognize the significant disease burdens on both the patient 
as well as their families and caregivers.

    13. For a majority of rare diseases, there are currently very few, 
if any, effective treatment options. For over 95 percent of orphan 
diseases, there is no US Food and Drug Administration (FDA) approved 
treatment medically available to help treat their condition. \1\
---------------------------------------------------------------------------
    \1\  https://globalgenes.org/rare-diseases-facts-statistics/.

    14. As part of my clinical practice, I have been fully committed 
throughout my career to identifying novel pharmacotherapeutics which 
could positively impact the quality of life of my patients and improve 
their standard of care. Throughout my research efforts, I have 
discovered three new potential therapeutic options (use of 
aminopyridines, Acetyl-Leucine and chlorzoxazone) for the treatment of 
rare diseases based on a therapeutic rationale to justify further 
clinical development. Specifically: the pharmacological agent should be 
approved for other indications so that it can be ``repurposed'' for 
therapeutic use in a rare disease setting; there should be available 
evidence in other disease settings to establish an acceptable safety 
profile in humans; there should be sound scientific evidence from 
animal studies elucidating the compounds mode of action and specific 
effects in particular diseases to establish the therapeutic potential 
---------------------------------------------------------------------------
of the re-purposed agent to treat a rare disease.

    15. In my 20 years' experience in treating rare, often fatal, 
genetic disease, I have become acutely aware of the barriers which 
often limit potentially life-changing treatments from becoming 
available for rare disease patient communities. My personal perspective 
has also been shaped by my own experience as the initiator and 
principal investigator of seven ``investigator initiated trials'' 
(IITs), as well as my interactions and relationships with my rare 
disease patients and their families.

    16. These experiences and interactions have helped me to identify 
specific considerations that are of practical relevance to research and 
development of new treatments for orphan diseases. From this basis, I 
believe the following issues ought to be considered and resolved in 
order to facilitate research and development of new treatments for 
orphan diseases.
          New ``Gold Standard'' for Rare Disease Trial Design
    17. In a progressive, life-threatening condition, there is a 
greater immediacy for trials to be carried out and in a maximally 
efficient manner so that the new treatment can be made available before 
the possible window of therapeutic opportunity is lost. There is an 
urgency from patients with rare, fatal diseases to have access to 
potentially life-changing treatments before they are too far 
progressed, or pass-away due to an absence of therapies.

    18. Patients with rare, fatal diseases would benefit if regulatory 
authorities could collaborate more closely to design non-clinical 
programs, clinical trials, and endpoint assessments that are relevant 
to what is known both about the product-specific nature of the active 
pharmacological substance, and the patient population it intends to 
treat.

    19. For example, non-clinical safety pharmacology studies in 
animals that assess the reproductive and developmental toxicity, 
carcinogenicity, and fertility and early embryonic development for 
diseases that predominately affect pediatric patients and are highly 
debilitating, rapidly progressive, and fatal, could be agreed to be 
conducted post-approval, or waived in exceptional circumstances on a 
case-by-case basis taking account of the severity of the disease and 
the patient characteristics.

    20. The current conventional ``gold standard'' for a randomized, 
controlled trial (RCT) that shows statistical significance of p < 0.05 
is often not an appropriate approach for a trial designed for rare, 
fatal, orphan diseases that progress rapidly and have high clinical 
heterogeneity. While RCT are desirable to establish clinical efficacy 
against a very high regulatory standard, their practical implementation 
can be challenging in a rare disease setting. Moreover, there are 
important medical and ethical concerns about certain RCT against a 
placebo to establish the therapeutic effects of the new treatment that 
may inhibit the rate of patient enrollment.

    21. Parents and caregivers often have legitimate ethical concerns 
about placebo-controlled trials. This makes recruitment a long, 
difficult and complicated process, delaying the time it takes to get 
treatments to patients. It also greatly increases the costs of studies 
as multinational centers are needed to recruit a likely even smaller 
pool of willing patients.

    22. This risk is even greater for trials involving drugs that are 
already approved for use in another clinical setting, i.e. ``repurposed 
drugs'' and could be readily accessed by patients for use in an off-
label/unlicensed setting. In such circumstances, patients or their 
families may be reluctant to participate in a placebo-controlled study 
where there is a 50 percent chance that the trial participants receive 
an inactive treatment.

    23. The standard approach to statistical significance is a 
prerequisite for large trials in diseases with a high incidence or 
prevalence, but for orphan populations this is hard to achieve in view 
of the rarity of occurrence of the disease and limited number of 
patients who are eligible for enrollment.

    24. Many rare diseases are at a dual disadvantage due to the small 
sample sizes and the combination of high inter-individual variability 
in clinical course of the disease. This significantly diminishes a 
study's statistical power to detect a therapeutic effect.

    25. In too many instances, when a compound fails, it is not clear 
if this is due to a lack of a biological effect rather than a failure 
due to an inadequate study design that was not compatible with what can 
be reasonably asked of, and measured within the rare disease patient 
population. Early collaboration with the regulators allows for 
alternative trial designs, in particular clinically relevant end-
points, and statistical techniques that maximize data from a small and 
heterozygous patient population and increase ability to demonstrate 
effects of a treatment.

    26. In rare diseases, a more balanced approach using smaller sample 
sizes and a wider array of assessments may be justified to establish 
the true clinical effects and patient-oriented benefits of the new 
treatment.

    27. Clinical programs should be designed to consider the realities 
of the demographics of the patient population and their unique medical 
need should be the ``gold standard'' for developing orphan drugs so 
that they get to patients sooner.
                 Assessing Clinical Meaningful Effects
    28. To get treatments more speedily to patients, the therapeutic 
effects should be established by reference to a wider range of data, 
including animal models, compassionate use data and patient/family 
self-reporting should be used to assess the efficacy and risk-benefit 
of a treatment. Such a holistic approach to evidence generation will 
serve our patients better, particularly in view of a clear unmet need 
for new treatments, and provide our patients with the optimal care that 
treating physicians strive to achieve as the clinical objective.

    29. In orphan diseases that are rapidly progressive and display a 
wide range of debilitating symptoms, the best measurement clinicians 
have to determine whether a treatment improves patients' functioning 
and quality of life is to actually listen to the voices of patients and 
their families/caregivers' voices.

    30. In patient populations with a huge variability of clinical 
symptoms, medications often produce different benefits in different 
patients, and it is not responsible to select a single measurement that 
is described as ``clinically meaningful'' for every patient success of 
the trial hinges upon.

    31. In addition, quantifiable endpoints like biomarkers or symptom-
rating scales may in fact be irrelevant for a patient's quality of 
life, level of functioning, or capabilities.

    32. Therefore, in orphan disease trials, a wider use of clinical 
outcomes, including clinical impressions from neurologists experienced 
in treating rare conditions and familiar with the patient's individual 
disease presentation, as well as patient/family/caregiver reported 
outcomes should be the standard of success, and prioritized over 
statistical significance on a single primary endpoint.
         Conditional Approvals and Continued Safety Monitoring:
    33. A greater use of conditional approvals should be applied by the 
regulatory authorities to get drugs sooner to patients with high unmet 
medical needs. If an acceptable risk-benefit profile of the drug is 
established, albeit based on a dataset that is less than perfect, in 
the circumstances of treating rare, fatal, rapidly progressive 
diseases, it should be made available for clinicians to treat their 
patients in a controlled setting without delay.

    34. In cases of fatal conditions and small patient populations 
which makes trials more difficult, post-approval rolling monitoring of 
safety and efficacy in patient populations is preferable as it provides 
direct evidence on whether the drug is used safely and effectively in a 
real-world clinical practice. Such evidence is far more relevant than 
data generated in an artificially designed clinical trial setting.

    35. Similarly, individual, personalized assessment could be a more 
feasible way to assess the treatment effect in ultra-small patient 
populations. In this scenario, the expert clinician assess the 
patient's condition while on medication for a defined treatment period, 
as well as their condition after stopping the medication, to determine 
the individual's response and if the medication can be continued. This 
approach is contingent on the safety and tolerability of the drug, but 
allows patients with unmet medical needs access to potentially life-
changing treatments faster.

    36. Conditional approvals and individual assessments could be 
excellent ways to meet the extremely high unmet medical need of far too 
many rare diseases. These are also often preferable to long development 
programs because many of these rare conditions are fatal in the early 
phase of childhood and children do not survive to adulthood. As 
clinical presentation evolves, these young and small populations will 
face difficulties transitioning from pediatric to adolescent while 
waiting for new treatments, and often regress too much or die before 
effective treatments are available.

    37. Use of conditional approvals, based on the considerations of 
the unique risk-benefit profile an orphan drug has for its target 
patient population, and even, an individual patient, will get 
treatments to patients who simply cannot wait for perfect study data to 
be generated in pursuit of a specific scientific endeavor.

    38. In summary, the non-clinical and clinical development programs 
for rare diseases should be realistic and implementable so that the 
right level (while not perfect according to the ``gold'' standard 
commonly applied to new treatments for larger populations) of evidence 
is generated to make an informed assessment of whether the benefits 
outweigh the risks. For re-purposed substances, the risks of the 
pharmacological agents in humans would have been established and such 
experience is highly relevant in the overall benefit/risk assessment.
                      Case Studies: Acetyl-Leucine
    39. An example of a novel drug I discovered that is a potential 
treatment for rare, genetic diseases is a modified amino acid ester 
that is orally delivered: N-Acetyl-Leucine (which can be formulated as 
the racemic compound N-Acetyl-DL-Leucine, or single enantiomers N-
Acetyl-L-Leucine and N-Acetyl-D-Leucine). Based on the available 
evidence, N-Acetyl-L-Leucine is believed to be the optimal form. Given 
the high unmet medical need, N-Acetyl-L-Leucine is initially being 
developed by IntraBio Inc for the treatment of three rare, genetic 
diseases: Tay-Sachs diseases, NPC, and inherited cerebellar ataxias 
(such as Ataxia telangiectasia, spinocerebellar ataxias, and Ataxia 
with Oculomotor Apraxia) before it is investigated for the treatment of 
broader neurodegenerative conditions such as Alzheimer's.

    40. N-Acetyl-DL-Leucine has been approved in France since 1957 for 
the treatment of vertigo. The drug has been used in 10's of millions of 
people and over 100's of millions of dosages, and has a very well-
established safety profile.

    41. Based on evidence that N-Acetyl-Leucine impacted vestibular 
symptoms, I hypothesized the compound could have effects on ataxia 
patients because of the close anatomical, physiological and 
pathophysiological interaction between the cerebellar and vestibular 
systems.

    42. Due to its established safety profile in vertigo, and what is 
known about the active pharmaceutical substance, compassionate use 
studies in Europe began for a limited number of patients with rare 
lysosomal storage disorders and neurodegenerative diseases. The effects 
of N-Acetyl-Leucine have now been observed in 18 indications, including 
Niemann-Pick type C (NPC), Tay-Sachs disease, and inherited cerebellar 
ataxias, as well as Lewy Body Dementia and Parkinsonian syndromes. In 
these diseases, the compound has been observed to have an effect on 
improving various neurological symptoms, including ataxia, 
coordination, gait and cognition as well as ``functioning'', and 
quality of life.

    43. Subsequent in vitro and in vivo animal studies in diseases 
models such as NPC and Tay-Sachs disease have demonstrated symptomatic 
and even neuroprotective effects of the compound in both diseases. The 
dosage per KG in the animal models was equivalent to the dose used in 
patients, further evidence for its potential safe and effective 
clinical benefit.

    44. In total, the large body of research formed over the past 10 
years, produced by myself and fellow neurologists and clinicians, as 
well as pharmacologists and chemists, is evidence that shows the 
compound is safe and offers a good risk-benefit profile for these rare, 
genetic diseases. This is supportive of 60 years of established safety 
data generated by the compounds approved use in acute vertigo in 
France.

    45. However, despite what is known about the active pharmaceutical 
substance, and the nature of these rare, fatal, rapidly progressive 
diseases with no available treatments, the development of N-Acetyl-
Leucine has been almost the same as drugs intended to treat broad, 
common, non-serious diseases.

    46. As an example: the FDA requests a juvenile animal toxicity 
study (a year-long study) be conducted before N-Acetyl-Leucine is 
trialed in the US for pediatric patients (although they are over 50 
percent of the patient population). Taking into account what has 
already been documented in another clinical setting regarding the 
active pharmaceutical substance, which provides reasonable confidence 
in the safety based on prior human exposure, this study does not 
complete the ``knowledge gaps'' and provide a greater understanding of 
pharmacological properties, but it does significantly delay clinical 
trials for patients with high unmet medical need.

    47. Similarly, the clinical development of N-Acetyl-Leucine is 
still contingent upon demonstrating its success in randomized 
controlled trials with quantifiable data. However, from compassionate 
use experience, where quantifiable data demonstrating N-Acetyl-
Leucine's statistical significance has been generated, we have also 
observed the significant value of assessing wide range of evidence, 
including reports from clinicians and families qualifying the compounds 
effect, to dozens of videos demonstrating the treatment effects. In a 
randomized controlled trial setting, these clinician and patient 
reported outcomes are still considered to be secondary and not relevant 
for regulatory approval, because they cannot be quantified and turned 
into traditional statistics. This has the potential of demonstrating a 
false-negative for the efficacy of a compound which could be indeed 
beneficial.

    48. Evidently, the current regulatory requirements for every new 
proposed drug create barriers for getting potential treatments to 
patients with huge medical needs. Although it is necessary to properly 
establish the good risk-benefit profile of any treatment, the longer 
this process, the higher the potential patients turn to dangerous 
alternatives, like unlicensed use or using chemical grade products, due 
to their extremely high unmet medical need.
                                Actions
    49. As a clinician, it is my responsibility that patients receive 
products whose quality is suitable for clinical use. Especially for 
conditions that are fatal and debilitating, it is important these 
products are investigated under the supervision of a clinical expert or 
specialist to determine their true risk-benefit profile.

    50. That treatments of clinical quality can be made available 
sooner for clinicians use to care for their patients with rare, fatal 
diseases, the necessity of demonstrating a good risk-benefit profile 
needs to be defined within the context of the rare patient population's 
unique, unmet medical needs. Regulators and orphan drug developers have 
to exercise a sense of proportion when designing development programs 
so that the development process is ethical, efficient, and achievable, 
and patients must always come first with the prerequisite that an agent 
has been shown to be safe.

    51. Most importantly, to improve the lives of patients with rare, 
fatal, often rapidly progressive, debilitating genetic diseases, we 
must listen to the voices of patients, their families, and caregivers 
so that the clinical effects are put into a proper clinical context.

    52. There is no better judge to determine if a treatment will 
improve a patient's functioning and quality of life than the patient, 
their families, or caregivers, because no one will know better than 
what life with such diseases entails than patients, their caregivers, 
and their families--even neurologists like myself (and as a father of 
four children).
                                 ______
                                 
    Chairman Paul. Thank you. Since I have already broken the 
rules, and I know Senator Casey has to leave, do you want to 
inject with a question now before you leave?
    Senator Casey. Maybe I will just wait for the testimony of 
the following group.
    Chairman Paul. That is fine.
    Our next testimony will come from Lincoln Tsang, a partner 
at Arnold & Porter in London.

  STATEMENT OF LINCOLN TSANG, F.R.PHARM.S., PARTNER, ARNOLD, 
       PORTER, KAYE, SCHOLER, L.L.P., LONDON, ENGLAND, UK

    Dr. Tsang. Mr. Chairman, Ranking Member, and distinguished 
Members of the Subcommittee.
    My name is Lincoln Tsang. I am grateful for the opportunity 
to discuss certain technical and regulatory issues relevant to 
facilitating research and development approval of new 
treatments to ensure their timely access by patients with rare 
diseases.
    My statement is drawn upon my experience as a medical 
scientist, a former regulator, and now a private legal 
practitioner.
    We have heard the dispassionate and very powerful 
statements from the patient representative and two eminent 
clinicians with extensive experience in the care and management 
of patients with rare diseases, as well as expertise in 
clinical trials for innovative products in these disease 
settings.
    I therefore will limit my statement to reinforce what they 
have already said, but will place great emphasis on the 
regulatory policy based on my experience and understanding of 
the regulatory landscape in the United States, as well as in 
the European Union.
    There is a greater need now for new methods of diagnosis 
and treatment for rare diseases. Health care delivery is now 
increasingly focused on planning the patient journey to improve 
quality and efficiency of clinical management, and to alter the 
focus of care tools and the activities most valued by patients.
    The regulatory landscape may need to reflect more 
accurately the advances in science and technology, and a 
changing treatment paradigm which is increasingly patient-
focused.
    Many developed countries have introduced, at different 
times, orphan legislation to incentivize development of orphan 
drugs. Contrary to general belief, being designated as an 
orphan drug does not automatically allow a regulatory authority 
to approve it more quickly or with less evidence than drugs 
intended for non-orphan populations. The standard for a product 
approval is still based on satisfying the criteria for safety, 
quality, and efficacy.
    Given their statutory role as guardians of public health 
and patient safety, regulatory authorities understandably 
require a robust and comprehensive dataset to be provided to 
reduce scientific uncertainty.
    Clinical development to prove safety and efficacy of a new 
product is most costly. It is also most challenging for new 
therapies intended to treat orphan diseases given the limited 
pool of patients that the clinicians have alluded to earlier 
on.
    The problem from a resource perspective is the need to set 
up multiple trials to meet different regulations and 
requirements. The solution would be a common trial design, but 
this may not be possible; although, international authorities 
may establish so-called parallel scientific advice, such as 
between the European Medicines Agency and the Food and Drug 
Administration. The respective agencies do not have to arrive 
at the same view on the study design.
    The standard for approval of orphan drugs is legally the 
same as the standard for approval of all other drugs in the 
United States, as I understand it. The F.D.A. requires 
substantial evidence of effectiveness derived from adequate and 
well-controlled investigations.
    The F.D.A. has the authority to apply the regulations 
flexibly, and has done so in many cases, but there is no 
obligation for the agency to do so.
    In Europe, it adopts essentially the same regulatory 
standard. However, it is recognized by the E.U. legislature 
that in certain exceptional circumstances, a product license 
may be granted on the basis of less comprehensive data. In 
addition, for certain rare, life threatening, and debilitating 
conditions, the E.U. legislature has created a regulatory 
pathway for a temporary license, so-called conditional 
approval, to be granted subject to annual renewal based on 
reassessment of the benefit risk assessment.
    The temporary conditional approval accepts that there is 
uncertainty of the submitted data, but recognizes also the 
immediate access to the product in view of an unmet medical 
need is sufficient to justify its approval. The uncertainty of 
the scientific dataset will be addressed post-approval to 
generate more comprehensive data.
    A delegated regulation has been adopted by the European 
Commission to give greater clarity of the situation in which 
post-approval of efficacy may be required. The legislative 
directions encourage greater use of alternative clinical trial 
design and post-approval real world evidence.
    It is my understanding the U.S. Congress has the 
legislative power to provide clearer directions to the F.D.A. 
to fully embrace less conventional and/or less commonly seen 
methodological approaches to establish clinical safety and 
efficacy in exceptional circumstances so that a new therapy is 
not unjustifiably denied or delayed.
    True regulatory risks and scientific uncertainties can be 
managed through specific enforceable post-approval safeguards 
or commitments to monitor safety and efficacy. This flexible 
and pragmatic approach may serve the public health imperative 
of improving patient care in a setting where there is a 
demonstrable unmet medical need.
    It has been said in various published literature that when 
a treatment method fails, researchers must be clear that there 
is a true lack of biological effect, rather than failure due to 
inadequate study design. Therefore, the approval process ought 
to take full account of the detailed knowledge of the broader 
sources of information to help determine what is the right 
level of evidence to support safety and efficacy of a new 
therapy.
    In this context, Mr. Chairman and Senators, consideration 
should be given to the following points:
    First, what constitutes an adequate level of scientific 
evidence to presume strongly a favorable benefit-risk balance 
to support product approval?
    Secondly, is it feasible or practical to generate 
comprehensive data within a reasonable timeframe following 
approval?
    Thirdly, can the scientific uncertainty of the submitted 
dataset be resolved by specific and enforceable post-
authorization studies, including real world evidence?
    Clinical development, as my colleagues on my right have 
already said repeatedly, clinical development is increasingly 
globalized. Greater cooperation amongst various national and 
regional regulatory authorities to agree on a design of 
multiple center clinical trials will greatly facilitate the 
efficient execution of product development in this particular 
rare disease to serve the patients with rare diseases and to 
optimize their care and management.
    We can strive to obtain the perfect dataset, but the 
patients cannot wait. It is possible with international 
cooperation to rely upon one well designed clinical study to 
elucidate the true treatment effects of a transformative method 
of treatment.
    Mr. Chairman, Senators, I thank you again for your 
attention, and I am very happy to take any questions.
    [The prepared statement of Dr. Tsang follows:]
                  prepared statement of lincoln tsang
    Mr Chairman, Ranking Member and Distinguished Members of the 
Subcommittee, my name is Lincoln Tsang.

    Thank you for the opportunity to discuss certain technical and 
regulatory issues that are viewed as relevant to facilitating research 
development and approval of new methods of treatment to ensure their 
timely access by patients with rare diseases. My statement is drawn 
upon my experience as a medical research scientist, a regulator and now 
a private legal practitioner.

    I am a partner in the international law firm of Arnold & Porter. I 
am based in its London office. My practice is focused on regulatory, 
compliance, enforcement, market access and public policy concerning the 
life sciences sector. Much of my practice involves cross-border related 
matters. Prior to joining the law firm in November 2002, I was a senior 
official of the UK regulatory agency, the Medicines and Healthcare 
products Regulatory Agency (formerly the Medicines Control Agency) 
where I worked for nearly 13 years and latterly as its head of 
biologicals and biotechnology. During my tenure in the UK regulatory 
agency, I served as the UK representative on various advisory 
committees within the European Medicines Agency, and as an advisor to 
the European Commission, the Council of Europe, and the World Health 
Organisation. I also liaised on behalf of the UK regulatory agency with 
other regulatory authorities including Food and Drug Administration 
(FDA) in the United States, HealthCanada, Australia Therapeutic Goods 
Administration on certain matters of common interest. I was previously 
appointed by the European Commission to represent the European Union on 
the International Conference on Harmonisation on the technical 
requirements for pharmaceuticals, an international cooperative effort 
which was initially founded by the United States, the European Union 
and Japan. This cooperative initiative has been expanded considerably 
in terms of its geographical reach and the adopted regulatory technical 
guidelines are accepted world-wide.

    I have also been appointed by UK Ministers to serve on various 
advisory committees in such capacity as a non-executive director of the 
National Institute for Biological Standards and Control, a Commissioner 
of the British Pharmacopoeia Commission where I have served as Chair of 
its Subcommittee on Biologicals and Biotechnology and Vice Chair of its 
Subcommittee on Nomenclature, and a non-executive member of the 
Regulatory Oversight Committee of the Health Protection Agency. Most 
recently, I was appointed by the Council of Europe to serve as its 
special advisor to assist in developing its Convention on combatting 
counterfeit medical products.

    Before I joined the UK government services, I was a medical 
research scientist of a research team funded by Cancer Research 
Campaign (now Cancer Research UK) that involved in the development of 
anti-cancer drugs, one of which has now been approved for clinical use 
worldwide for treating brain tumours, namely glioblastoma in adults, 
and gliomas in children and adults. I started my career working in the 
National Health Service in the UK.

    I have lectured on life sciences regulatory law and public policy 
at various universities including Yale University, University College 
London, King's College London.

    My brief curriculum vitae is attached.
       Challenges in Developing New Treatments for Rare Diseases
    Innovative medical technologies and medicines are critical to 
improving health and well-being.

    Medical advances in science and technology, including genomics, 
will open up avenues to develop new therapeutic approaches in advanced 
therapies based on gene, cell and tissue engineering, and to re-purpose 
already approved drugs for new therapeutic indications with a view to 
addressing diseases and conditions where there is an unmet medical 
need.

    However, the potential for these new therapeutic approaches can 
only be realised if they are approved for clinical application to 
optimise care and management of patients.

    Healthcare delivery is now increasingly focused on planning the 
patient journey, to improve the quality or efficiency of clinical 
management and to alter the focus of care toward the activities most 
valued by the patient. There is a greater need now for new methods of 
diagnosis and treatment for rare diseases. There may be as many as 
7,000 rare (commonly known as ``orphan'') diseases, \1\ many of which 
are life-threatening or debilitating, where there exists no authorised 
or satisfactory method of treatment. They affect most critically the 
very young who often do not survive beyond adolescence. Without 
treatment, their quality of life will be seriously affected and their 
lives may be shortened. This represents the grim reality that many of 
these patients and their families are facing.
---------------------------------------------------------------------------
    \1\  The US defines an orphan condition based on disease incidence 
of less than 200,000 patients which would represent approximately 61 
cases per 100,000 based on the current estimate of US population of 326 
million. In the EU, an orphan condition is defined as a life-
threatening or debilitating disease or condition affects less than 5 in 
10,000 persons in the EU. In Japan, a disease or condition is 
considered rare if it affects fewer than 50,000 patients or less than 
40 in 100,000 based on the population in Japan.

    Orphan legislation varies amongst the developed countries and was 
introduced at different times. The United States led the way by 
enacting the Orphan Drug Act of 1983 which introduced an incentive 
system for the development of orphan products in the US. Following the 
introduction of the US Orphan Drug Act, a number of developed countries 
and regions built a regulatory framework designed to provide incentives 
for companies to develop products for orphan diseases, which would not 
normally justify investment in research development or marketing, owing 
to their poor financial return. Apart from the EU, countries such as 
Japan, Australia and Singapore have developed their own regulatory 
frameworks to encourage the development of products for orphan 
---------------------------------------------------------------------------
diseases.

    The clinical development of new technologies intended to treat rare 
diseases is fraught with practical challenges. There may be disease-
specific complexities, such as poor understanding of the natural 
history of the therapeutic indication due to there being little 
information available about disease progression, variable phenotypic 
characteristics of the patient populations and clinical courses, 
geographical dispersion of a small number of patients and the relative 
paucity of published clinical trials to inform study execution.

    In order to establish the clinical efficacy and safety of new 
methods of treatment, the randomised controlled trial has been accepted 
by regulatory authorities around the world as the gold standard. This 
trial design minimises selection bias in order to elicit the true 
treatment effect of the new therapy.

    Whilst this classic study design is commonly used in studies of new 
therapies designed to treat common diseases as it may involve a large 
number of more readily available clinical trial subjects, this may not 
be feasible in a small population. By necessity, clinical trials in 
rare diseases enrol fewer trial subjects who may not necessarily be 
concentrated in a particular geographical region. In combination with 
significant clinical differences between trial subjects (commonly known 
as inter-subject variability) observed in many rare diseases, this 
diminishes the `power' of the study to detect a therapeutic difference. 
Statistical power is the likelihood that a study will detect an effect 
when there is an effect there to be detected.

    Given the rarity of orphan diseases, the timely and adequate 
recruitment of eligible trial participants is recognised as a challenge 
to initiate and complete a study. For new treatments intended for a 
larger patient population, regulatory authorities may often demand two 
or more pivotal confirmatory studies sufficiently powered to be carried 
out, and this may necessarily involve a relatively large patient 
population. As has been recognised by the US and EU regulatory 
authorities, such a requirement is more challenging to satisfy for 
treatments intended for orphan conditions.

    Because of the low incidence of the disease in each country given 
its rarity, there is often a need to enrol patients from a number of 
countries to obtain a large enough sample size of trial subjects to 
establish the clinical efficacy. Since trial subjects are 
geographically dispersed, multi-centre studies must be initiated in 
various international centres of excellence. Technically speaking, the 
problem (from a resource perspective) is the need to set up multiple 
trials to meet different regulations and requirements. The solution 
would be a common trial design but this may not be possible, given 
varying regulatory approaches. The demand to satisfy various regulatory 
requirements is obviously more critical for small and medium sized 
enterprises with very limited resources.

    Whilst certain authorities have established parallel scientific 
advice, such as FDA and EMA, the respective agencies do not have to 
arrive at the same view on the study design, such as the parameter(s) 
used to measure the clinical outcome following administration with the 
new therapy (commonly known as an endpoint or variable). This may 
become a practical issue in the final analysis of the data derived from 
studies with disparate trial designs.

    In a rare disease setting, there is clearly a tension between the 
need for transformative innovation to treat such devastating conditions 
which require a considerable time, financial investment in research and 
development, and the need for timely patient access to such innovation. 
Innovation will not serve the public health imperatives, and most 
importantly patients, if it is not approved, adopted and diffused in 
the healthcare system for the benefit of society at large.

    In this highly regulated sector, the need for timely approval of 
innovative treatments to be accessed by patients with orphan conditions 
has attracted a great deal of debate and attention in recent years.
              Approval of Treatments for Orphan Conditions
    Given their statutory mandate as guardians of public health, 
regulatory authorities understandably require a dataset submitted for 
product approval to be sufficiently robust in the sense of its 
scientific certainty. On the other hand, patients and those involved in 
the care and management of such patients with rare, life-threatening 
and debilitating conditions, not unreasonably, expect expedited product 
approval to ensure timely access to such life-saving methods of 
treatment, whilst accepting the scientific uncertainty of the pre-
approval dataset.

    Regulatory authorities are mandated by their respective legislature 
to supervise product approval and post-approval processes to ensure 
that the marketed products are clinically safe and effective and of an 
acceptable quality standard. Timely access by patients to innovative 
methods of treatment in therapeutic areas with unmet medical need 
serves an important public health purpose, especially for those patient 
populations with a high disease burden, that represents the impact of a 
health problem as measured by financial cost, mortality, morbidity, or 
other health-related indicators.

    In an evolving regulatory framework, striking the right balance of 
these competing interests relating to (a) regulatory control of 
innovation based on robust evidence and (b) timely patient access to 
transformative innovation, has been a continuing debate amongst the 
regulatory authorities, legislature, payers, healthcare professionals 
and most importantly the patients.

    That said, although more flexibility could be introduced, 
regulatory authorities generally have the authority and some regulatory 
latitude to determine the level of evidence that is required to inform 
a benefit/risk assessment that underpins product approval.

    Contrary to the general belief, being designated as an orphan 
product does not automatically permit a regulatory authority to approve 
it more quickly or with less evidence than drugs intended for non-
orphan populations.

    As a general matter, it is my understanding that the standard of 
approval for orphan product is legally the same as the standard of 
approval for all other drugs in the US. The FDA requires `substantial 
evidence' of effectiveness derived from `adequate and well controlled 
investigations'. Whilst FDA has the power to apply the regulations 
flexibly, \2\ and have often done so in the orphan drug context, it is 
under no obligation to do so. \3\
---------------------------------------------------------------------------
    \2\  While the statutory standards apply to all drugs, the many 
kinds of drugs that are subject to the statutory standards and the wide 
range of uses for those drugs demand flexibility in applying the 
standards. Thus FDA is required to exercise its scientific judgment to 
determine the kind and quantity of data and information an applicant is 
required to provide for a particular drug to meet the statutory 
standards. FDA makes its views on drug products and classes of drugs 
available through guidance documents, recommendations, and other 
statements of policy. (Code of Federal Rules Section 314.105).
    \3\  Saskinowski F. et al. Quantum of Effectiveness Evidence in 
FDA's Approval of Orphan Drugs DIA Therapeutic Innovation & Regulatory 
Science (2015) Volume: 49 issue: 5, page(s): 680-697.

    In the EU, the adopted regulatory standard for approval \4\ is that 
clinical data should be based on `controlled clinical trials' if 
possible, randomised and (as appropriate) versus placebo and versus an 
established medicinal product of proven therapeutic value. Any other 
design must be justified. The treatment of the control groups will vary 
from case to case and also will depend on ethical considerations and 
therapeutic area; thus it may, in some instances, be more pertinent to 
compare the efficacy of a new medicinal product with that of an 
established medicinal product of proven therapeutic value rather than 
with the effect of a placebo.
---------------------------------------------------------------------------
    \4\  Part I Section 5.2.5.1 of Annex I to Directive 2001/83/EC.

    The EU legislature has recognised that in certain exceptional 
circumstances, a marketing authorisation may be granted on the basis of 
less comprehensive data \5\ either where because the disease is rare 
that comprehensive clinical data cannot reasonably be generated under 
normal conditions of use, or where in the present state of scientific 
knowledge, comprehensive information cannot be provided, or where 
because it would be contrary to generally accepted principles of 
medical ethics to collect such information it would not be possible for 
a manufacturer to provide comprehensive data. These are all 
circumstances in which it may be justified to grant a marketing 
authorisation in order to address an unmet medical need under 
exceptional circumstances to advance patient interests.
---------------------------------------------------------------------------
    \5\  Part 3 Section 5 of Annex I to Directive 2001/83/EC.

    In addition, for certain rare, life-threatening and debilitating 
conditions, the EU legislature has created a regulatory pathway for a 
conditional marketing authorisation to be granted, subject to annual 
renewal, based on a re-assessment of the benefit/risk. \6\ The grant of 
such an essentially ``temporary'' marketing authorisation is based on 
certain specific conditions being satisfied. Whilst accepting that 
there is uncertainty as to whether the submitted clinical data can 
comprehensively elucidate the benefit/risk balance of a medicinal 
product, the immediate access to the product in view of an unmet 
medical need is sufficient to justify its authorisation, provided that 
the manufacturer is able to provide the comprehensive data post-
authorisation to confirm the benefit/risk balance.
---------------------------------------------------------------------------
    \6\  Article 14(7) of Regulation (EC) No 726/2004 laying down 
Community procedures for the authorisation and supervision of medicinal 
products for human and veterinary use and establishing a European 
Medicines Agency; Commission Regulation (EC) No 507/2006 on the 
conditional marketing authorisation for medicinal products for human 
use falling within the scope of Regulation (EC) No 726/2004 of the 
European Parliament and of the Council.

    A specific Delegated Regulation has been adopted by the European 
Commission in order to provide the EMA and the EU national regulatory 
authorities with greater clarity of the situations in which post-
authorisation efficacy may be required, such as (a) where concerns 
relating to some aspects of efficacy of the product are identified and 
can be resolved only after the product has been marketed; (b) where the 
understanding of the disease, the clinical methodology or the use of 
the product under real-life conditions indicate that previous efficacy 
---------------------------------------------------------------------------
evaluations might have to be revised significantly.

    The requirement for post-authorisation efficacy studies may arise, 
for example: if the initial efficacy assessment is based on surrogate 
(i.e. not clinical) endpoints which requires verification of the impact 
of the intervention on clinical outcome or disease progression or 
confirmation of previous efficacy assumptions; or uncertainties with 
respect to the efficacy of a product in certain sub-populations that 
could not be resolved prior to marketing authorisation and require 
further clinical evidence.
                          Regulatory Latitude
    Many established regulatory authorities including the FDA in the US 
and EMA in the EU have declared in their respective mission statements 
that in addition to their role to safeguard public health and patient 
safety, they are responsible for advancing public health by helping to 
facilitate or otherwise expedite the approval of medical innovations to 
maintain and improve the health of patients.

    In this case, it is my understanding that the US Congress has 
legislative power to provide clearer directions to FDA to fully embrace 
less conventional and/or less commonly seen methodological approaches 
to elucidate benefit/risk balance in exceptional circumstances so that 
a new method of treatment is not unjustifiably delayed or denied 
subject to certain specific post-authorisation safeguards to monitor 
the ongoing benefit/risk balance of the approved product. \7\ Such an 
explicitly flexible and pragmatic approach may serve the public health 
imperative of improving patient care in a clinical setting where there 
is a demonstrable unmet medical need.
---------------------------------------------------------------------------
    \7\  This may be similar to the approach taken by the EU as 
explained above (see paragraphs 27-29).

    It has been said when a method of treatment fails, researchers must 
be clear that there is a true lack of biological effect, rather than 
failure due to inadequate study design. \8\ Therefore, approval process 
ought to take full account of the detailed knowledge of the 
pathophysiology (meaning the disordered physiological processes 
associated with disease or injury) of the orphan disease and the 
pharmacology (meaning uses, effects, and modes of action) of the new 
method of treatment to facilitate the design of efficient clinical 
development which will in turn help determine the amount of clinical 
data required to inform an assessment of clinical efficacy and safety.
---------------------------------------------------------------------------
    \8\  Dickson P.I. et al. Research challenges in central nervous 
system manifestations of inborn errors of metabolism. Mol Genet Metab 
(2011); 102: 325-338.

    In the context of product approval in a rare disease setting where 
there is an unmet medical need, consideration should be given to the 
---------------------------------------------------------------------------
following points:

          What constitutes an adequate level of scientific 
        evidence to presume strongly a favourable benefit/risk balance 
        to support product approval?

          Is it feasible or practical to generate comprehensive 
        data within a reasonable timeframe following product approval?

          Can the scientific uncertainty of the submitted 
        dataset can only be resolved by specific and enforceable post-
        authorisation studies, including real-world evidence?

    As indicated above, patients to be enrolled in clinical trials for 
rare disease are geographically dispersed and many clinical studies are 
conducted in various centres of excellence. Therefore, greater 
cooperation amongst various national and regional regulatory 
authorities to agree on the design of the multi-centre clinical trials 
will greatly facilitate the efficient execution of product development 
to serve the patients with rare diseases and to optimise their care and 
management. With strong international cooperation, it will often be 
possible to rely upon only one well-designed clinical study to 
elucidate the true treatment effects of a transformative method of 
treatment for all global regulatory authorities.

    However, note also that even though the trial data demonstrate a 
favourable benefit/risk, in many countries, patient access may not be 
realised if the new therapies are not accepted on grounds relating to 
cost-effectiveness and affordability, given the increasingly cost 
conscious healthcare delivery systems.

    Mr Chairman, Ranking Member and Members of the Subcommittee, thank 
you once again for the opportunity to provide this testimony. I am 
happy to answer any question.
                                 ______
                                 
    Chairman Paul. Thank you, Dr. Tsang.
    Our last witness is Mallory Factor, who is a Professor at 
Oxford, and the Founder and CEO of IntraBio, Inc., which was 
founded for the purpose of developing novel therapies for rare 
diseases.

 STATEMENT OF MALLORY FACTOR, FOUNDER AND CEO, INTRABIO, INC., 
                      OXFORD, ENGLAND, UK

    Mr. Factor. Thank you, Senator Paul, and thank you also 
Senator Casey, for participating in this, as well as the other 
Senators.
    My colleagues to my right, I think, have covered a great 
deal of material already. I am here today to share with you 
some observations on some of the obstacles that delay, and even 
restrict, novel orphan therapies from getting to patients. And 
some of the ideas how orphan drug developers in the Food and 
Drug Administration, the F.D.A., could collaborate more closely 
to bring treatments for rare genetic diseases to the point of 
approval, so that they are available to patients with 
conditions or diseases for which there are high, unmet medical 
needs.
    Rather than go over some of the same material that my 
colleagues have done, what I am going to do is I am going to 
give you a quick case study. A case study based on the actual 
compound you saw being used there.
    IntraBio is a small biopharmaceutical company whose mission 
fundamentally is to advance patient interest and to develop 
novel therapies to treat fatal, rare, rapidly progressing 
genetic diseases with high, if not totally, unmet medical 
needs.
    The company is developing a compound, N-Acetyl-Leucine, 
which is supported by both animal studies and numerous 
compassionate use studies in patients, to be a potential 
treatment for rare disorders like inherited Cerebellar Ataxias: 
Ataxia Telangiectasia, Spinocerebellar Ataxias, and Ataxia with 
Ocular motor Apraxia; Tay-Sachs disease, which there is another 
video, which I am sure can be distributed; Niemann-Pick disease 
Type C, which you just saw; as well as common neurodegenerative 
diseases like Lewi Body Dementia, a form of Alzheimer's; and 
Parkinson's disease.
    Given the extreme medical need, IntraBio is prioritizing 
the development of N-Acetyl-Leucine for the treatment of rare, 
genetic diseases. Three in particular: Tay-Sachs, Niemann-Pick 
C, which you saw the video of, and inherited cerebellar ataxia 
subtypes. These predominately affect pediatric patients and are 
fatal, and they are rapidly progressive, and display a huge 
range of debilitating neurological as well as physical 
symptoms, and they have no treatments medically available.
    IntraBio has commissioned further safety pharmacological 
studies to characterize the safety profile and further non-
clinical studies to investigate the optimal form and the mode 
of administration for patients.
    I have a lot of this material in here and rather than just 
read from it, I will talk to you extemporaneously.
    Hundreds of millions of doses have been used of this drug 
since 1957; hundreds of millions. Tens of millions of people 
have been on this drug. Its safety profile has been shown to be 
safer than aspirin, and yet we cannot even begin to put it into 
people here yet in a trial.
    I can go into great detail in the interactions with the 
F.D.A. The F.D.A. is first and foremost concerned with risk. 
What they need to be concerned with is risk benefit and 
timeliness. They do not understand the risk benefit analysis.
    I am not sure what we can do, but the real problem is 
trying to reach somebody at the F.D.A. You cannot. It is 
impossible to sit down other than in a formal setting with 
months. It took us eight months to get a meeting, and I will 
not tell you how many children passed away from these diseases 
during those eight months, just to begin to have a discussion 
with them.
    We submitted a 150-page briefing book, which I am not sure 
anybody really read thoroughly.
    What we need is the ability to sit down with the F.D.A. And 
these are good people at the F.D.A., but we need to be able to 
sit down with them and have simple conversations.
    There is a disease called GM1, which we have shown efficacy 
with our drug. We cannot do a trial because there are 16 people 
right now alive in the United States. You could not get 
statistical significance. What are we going to do? Nothing. We 
cannot. But we would love to be able to sit down and say, ``How 
do we help these people?'' since we are aware of these people 
using it unlicensed. Some of the people are even forced to buy 
chemical grade.
    Our goal is very simplistic. We would like to work with the 
F.D.A. and the regulators to move forward on a timely manner 
and look at the risk benefit analysis. And that is what, I 
think, is vital.
    The acts, the Orphan Drug Act and things like this are 
terrific, but they help after these trials. They do not get 
into the trials. They are after you get your N.D.A., your drug 
approval. That is where the benefit comes in. Not getting it to 
the people.
    I thank you and again, the script will give you a lot more 
information than I have just given you.
    [The prepared statement of Mr. Factor follows:]
                  prepared statement of mallory factor
    1. Chairman Paul, Ranking Member Casey and Distinguished Members of 
the Subcommittee, thank you for the opportunity to discuss the 
regulation of drug development for patients with rare genetic diseases.

    2. My name is Mallory Factor and my statement is drawn upon my 
experience as chairman of an orphan drug development company, IntraBio 
Inc., and our interactions with regulatory agencies in the United 
States and Europe on matters relating to our clinical development 
programs for orphan drugs. IntraBio was founded with the purpose of 
developing novel therapies for rare patient populations with genetic 
and neurodegenerative conditions, such as inherited Cerebellar Ataxia 
(e.g. Ataxia-Telangiectasia, Spinocerebellar Ataxias, and Ataxia with 
Ocular Motor Apraxia) and Lysosomal Storage Disorders like Tay-Sachs 
and Niemann-Pick Disease Type C, which are predominately fatal 
conditions and for which patients have extremely high, unmet medical 
needs.

    3. Before founding IntraBio in 2015, I have advised numerous early 
stage companies over my 30-year career, including two medical devices 
companies.
                               Background
    4. I am here today to share with you my observations on some of the 
obstacles that may delay and even restrict novel orphan therapies from 
getting to patients, and some ideas for how orphan drug developers and 
the Food and Drug Administration (FDA) could collaborate more closely 
to bring treatments for rare, genetic diseases to the point of approval 
so that they are made available to patients with conditions or diseases 
for which there is a high unmet medical need.

    5. The FDA defines an ``orphan drug'' as a ``drug intended to treat 
a condition affecting fewer than 200,000 persons in the United States, 
or which will not be profitable within 7 years following approval by 
the FDA.'' It is estimated there are over 7,000 rare (``orphan'') 
diseases, \1\ a number of which are life-threatening, debilitating, and 
have patient populations much smaller than this standard, with numbers 
in the mere hundreds.
---------------------------------------------------------------------------
    \1\  The US defines an orphan condition based on disease incidence 
of less than 200,000 patients which would represent approximately 61 
cases per 100,000 based on the current estimate of US population of 326 
million.

    6. However, while the patient population for individual orphan 
diseases may be small, is estimated that in total, some 30 million 
Americans are affected by orphan diseases. For a large majority of 
these rare patient populations, there is no FDA approved therapy 
---------------------------------------------------------------------------
available to treat their condition.

    7. A possible explanation for why a majority of orphan diseases do 
not have approved treatments is that the process for developing and 
getting marketing approval for orphan drugs is almost the same as for 
drugs with common, non-serious disorders.

    8. In this pathway, there are several requirements for assessing 
the safety and effectiveness of a new drug. These are concerned with 
the need to: establish the compound's safety and tolerability profile; 
design feasible trials with clinically relevant outcome measurements 
that assess the clinical efficacy of a treatment; select the correct 
sample size and eligible patients; recruit trial subjects according to 
established ethical principles; and secure adequate resources and funds 
to execute the study and address the regulatory requirements.

    9. In the case of rare diseases, which often have an ultra-small 
patient population where the diseases are rapidly progressive, a large 
clinical variability between patients, and fatal without treatment, 
traditional regulatory requirements can often become monumental 
challenges.

    10. This is because, as for all drug development, orphan drug 
developers cannot feasibly conduct development programs without consent 
from expert clinicians and the patient community regarding the 
scientific and ethical rational of development programs. In addition, 
there must be consent from regulatory agencies regarding the 
appropriateness of the development programs for regulatory approval.

    11. However, for orphan drugs, the traditional regulatory pathways 
for non-clinical and clinical development are less likely to be 
compatible with the scientific and ethical rational deemed appropriate 
by clinicians and the patient community. The process of getting all 
three bodies of experts--regulatory agencies, clinicians, and patient 
communities--to agree is often particularly time-consuming, expensive, 
and uniquely challenging for orphan drug developers.

    12. Large pharmaceutical companies that have the resources to 
navigate the complex and costly orphan development process have 
traditionally had very little involvement, especially in the early 
stages, as rare disease therapeutics are assumed to have small markets 
and therefore small returns on investment.

    13. Orphan drug development therefore relies on the province of 
startups or small companies who have significantly less resources and 
funding. However, due to the challenges of developing drugs for small 
patient populations with debilitating, fatal diseases, developing 
treatments for many orphan conditions is simply not economic.

    14. For example, GM1 Gangliosidosis is a rare, genetic lysosomal 
storage disorder that predominately affects infants and early juveniles 
and is extremely debilitating, rapidly progressive, and has less than 
200 known cases. Because the non-clinical and clinical requirements for 
novel GM1 therapies are the same as drugs for common, non-serious 
indications, these fixed long timelines and high costs cannot be 
justified due to the very-limited potential economic return.

    15. The costs and difficulty of conducting trials for GM1 are even 
greater than for other conditions because it is a challenge to develop 
a clinical trial programs that accommodate the ultra-orphan patient 
population and rapidly progressive conditions, and also meet the 
regulatory ``gold standards'' for large, randomized, controlled trials.

    16. Sadly, the unique challenges and costs of orphan drug 
development mean that too many promising treatments for orphan diseases 
are abandoned even before they are trialed in patients, as companies 
exhaust their resources or pivot to treating common diseases which can 
provide return on their investment.

    17. While orphan drug developers are commercial ventures, their 
work on developing new treatments ultimately serves the patient 
communities. Anything that Congress can do to facilitate and encourage 
more efficient orphan drug development for these underserved patient 
populations should be done, of course bearing in mind the safety as 
well as the needs of the patients.
                  Current Problem, Proposed Solutions
    18. To facilitate the development of orphan drugs, a new regulatory 
pathway which differs from the traditional development program is 
needed to expedite promising treatments into the hands of patients with 
rare genetic diseases is needed.

    19. This pathway for the development and approval of treatments for 
rare genetic diseases should be designed so that there is earlier, more 
frequent interactions between the FDA and drug developers so that they 
are able to collaborate and design non-clinical and clinical programs 
that take into consideration the scientific and ethical considerations 
of clinicians and the patient community, such as the very small number 
of patients, the rapidly progressive, debilitating nature of the 
diseases, the clinical variability between patients, and fact that 
there is no approved treatment, for a majority of rare, fatal genetic 
conditions, leaving patients with high unmet medical needs and 
desperate for treatment.

    20. If these measures were implemented, I believe orphan drug 
development would become more efficient, as non-clinical and clinical 
development programs would be conducted that are appropriate for the 
patients being treated and considerate of the product-specific risk-
benefit profile. As such, the much-needed orphan drugs would reach 
patients with rare, fatal, genetic diseases faster while maintaining 
the high standards for safety.
 Challenges: Orphan Drug Act and Breakthrough Therapy Designation are 
                             not Sufficient
    21. Due to these unique challenges, as well as long timelines, and 
high costs of development, rare disease therapies are assumed to have 
small markets and thus development of treatment for orphan conditions 
are generally considered to provide insufficient economic incentives 
for developers, given the limited potential return on investment.

    22. In light of this, Orphan Drug Act/Designation was put in place 
to aid and encourage the development of drugs for rare diseases. The 
Orphan Drug Act was a pioneer legislation that has aided in helping new 
treatments get to patients: before the legislation was enacted in 1983, 
only 38 orphan drugs had been approved; by 2014, 468 indication 
designations covering 373 drugs have been approved. \2\
---------------------------------------------------------------------------
    \2\  Hadjivasiliou, Andreas (October 2014), ``Orphan Drug Report 
2014'' (PDF), EvaluatePharma, retrieved 28 June 2015.

    23. However, the orphan drug act has not entirely solved the 
problem, as the proportion of orphan drugs approved today is 
disproportionately smaller than the number of non-orphan drugs 
approved. A plausible explanation for this difference is that a 
majority of the benefits of the Orphan Drug Act are not triggered until 
after clinical trials have already been conducted and New Drug Approval 
(NDA) is sought through which drug developers formally propose that the 
---------------------------------------------------------------------------
FDA approve a new pharmaceutical product.

    24. Similarly, designations like ``Breakthrough Therapy 
Designation'' are granted too late in the development process, only 
after Investigational New Drug (IND) applications for clinical trials 
are filed. As a consequence, the interaction between orphan drug 
developers and the FDA is significantly limited throughout the early 
research stage and while designing clinical trials.

    25. Since orphan drug development still predominantly relies on the 
province of startups or small companies that have significantly less 
resources and funding than Big Pharma, these provisions therefore do 
not actually help orphan drug developers bring new treatments through 
the trial approval process.

    26. In the absence of early and frequent contact and collaboration 
between orphan drug developers and the FDA, novel therapies often fail 
orphan drug developers face too much uncertainty in designing non-
clinical and clinical programs that satisfy patients, clinicians, as 
well as regulatory requirements, and thus many valuable treatments 
never become available to address the extremely high unmet medical 
need.
   Proposed Solutions: Earlier and Greater Consultation With the FDA
    27. New legislation which introduces benefits of orphan designation 
earlier in the development process, such as specific programs to 
enhance closer and greater early engagement with FDA, would enable drug 
developers consult the FDA about the acceptability of their non-
clinical data, trial design, and endpoint assessments early and 
frequently in the development process and to deploy limited resources 
more effectively.

    28. The FDA has flexibility to decide on the approvability of a new 
treatment, including the required non-clinical profile, as well as the 
appropriateness of the ``gold-standard'' randomized controlled trial. 
This flexibility can greatly benefit rare disease patients if it is 
applied early and throughout both the non-clinical and clinical 
development process for orphan drugs.

    29. Greater interaction between the FDA and orphan drug developers 
from an early stage in the drug development and market approval process 
would provide regulators with more complete scientific and ethical 
background of the risk-benefit of a proposed treatment. Given this 
``whole picture'' view, regulators could exercise this flexibility in 
regard to both non-clinical and clinical programs based on what is 
already known about the pharmacological properties of the orphan drug 
and the patient population it intends to treat.

    30. Regulators would be able to identify what data is relevant and 
must be generated before trials can be approved--and leave aside other 
requests for additional data that would be nice to have but is not 
necessarily critical to the overall benefit/risk assessment.

    31. Early and frequent interactions between orphan drug developers 
and the FDA also reduces the guesswork about what is acceptable in 
terms trial designs and assessment endpoints and realistic to achieve 
given the demographics of the patient population.

    32. Early, frequent interaction would help ensure that cost-
effective nonclinical development programs, ethical trial design, and 
appropriate clinical outcomes for patients with fatal, rapidly 
progressive, rare diseases are being used. This would make orphan drug 
development a much more expedited and streamlined process so that new 
treatments would reach and benefit patients sooner.
                          Case Study--IntraBio
    33. IntraBio is a small biopharmaceutical company whose mission is 
to advance patients' interest, and to develop novel therapies to treat 
fatal, rare, rapidly progressive genetic diseases with high unmet 
medical needs.

    34. The company is developing a compound, N-Acetyl-Leucine, which 
is supported by both animal studies and numerous compassionate use 
studies in patients to be a potential treatment for both rare genetic 
disorders like inherited Cerebellar Ataxia (e.g. Ataxia-Telangiectasia, 
Spinocerebellar Ataxias, and Ataxia with Ocular motor Apraxia) Tay-
Sachs disease and Niemann-Pick disease Type C (NPC) as well as common 
neurodegenerative diseases like Lewi Body Dementia and Parkinson's 
disease. Given the extreme medical need, IntraBio is prioritizing the 
development of N-Acetyl-Leucine for the treatment of rare, genetic 
diseases (Tay-Sachs, NPC, and inherited cerebellar ataxia subtypes) 
which predominately affect pediatric patients and are fatal, rapidly 
progressive, display a huge range of debilitating neurological and 
physical symptoms, and have no treatments medically available.

    35. IntraBio has commissioned further safety pharmacology studies 
to characterize the safety profile and further non-clinical studies to 
investigate the optimal form and mode of administration for patients.

    36. This data forms a good scientific basis for IntraBio to advance 
research and development with N-Acetyl-L-Leucine. IntraBio's objective 
is to conduct clinical programs as efficiently as possible by taking 
full account of what is already known about the active pharmaceutical 
substance and the demographics of the patient populations it intends to 
treat so to design clinical trials that are appropriate to study the 
clinically meaningful effects of the drug.

    37. Medical need for these conditions is extremely high: Patient 
groups are asking for the drug to be available in the US and for trials 
to commence in the US to bring possible relief to terminal patients who 
are very young.

    38. However, although orphan drug designation has been given to N-
Acetyl-L-Leucine by the FDA for various conditions, this designation 
has not expedited the regulatory process, or increased the level of 
engagement with the FDA, which would have facilitated clinical 
development.

    39. Because of limited interaction with regulators, a large degree 
of uncertainty remains around the implementation of trial designs and 
primary endpoints that would be adequate and appropriate for the 
patient populations intended to be treated with N-Acetyl-L-Leucine. 
This uncertainty remains despite the fact that the trial design, 
including the chosen endpoints to assess clinical effectiveness, is 
based on extensive input from the world leading clinical experts 
specializing in treating these patients and conducting clinical trials 
in these diseases, as well as patient advocates representing the 
patient communities.

    40. In our view, regular engagement between orphan drug developers 
and the FDA would allow regulators to get a full picture of the 
scientific rational behind the design of non-clinical and clinical 
programs for N-Acetyl-L-Leucine, and significantly expedite the 
regulatory process, making the development process more feasible and 
cost-effect, and getting treatments to patients faster.
                                 ______
                                 
    Chairman Paul. Thank you, and thank you to the entire 
panel.
    I would like to recognize Senator Casey for any questions.
    Senator Casey. I will be very brief.
    You were all so compelling and your testimony was so 
captivating that I stayed longer than I had planned, and I am 
grateful that I did that, and grateful that you are here.
    I will submit written questions because they are written 
with the aid of capable staff; they will be much more 
articulate than I could muster today, but we are grateful for 
the work.
    Each one of you presented, I think, a challenge to us on 
these issues and we are grateful you took the time to be here 
and to provide your experience, your scholarship, and your 
passion. We heard that throughout the testimony.
    Thanks very much.
    Chairman Paul. Senator Casey, thank you.
    Hopefully, maybe we could talk some more about any updates 
to the Orphan Drug Act. We have heard some things maybe from 
Europe and other places that are working better.
    Maybe you and I could work together and see if there is 
something we could do to streamline, to even do a better job. 
It sounds like there have been some benefits, but maybe there 
is something else we could do.
    Senator Casey. It is on the record. Yes.
    Chairman Paul. All right. Thank you.
    I think we have had a good discussion. I want to go into it 
just a little more, and then also encourage everyone on the 
panel and everyone who is interested in this--I know Mr. Dant 
and your group, and other groups like yours that exist--to come 
together. Let us try to have an organization that brings 
together these suggestions for how we would update the Orphan 
Drug Act.
    It sounds like, though, there was some success. Senator 
Casey mentioned that there were 15 drugs approved before the 
Act, and then all of sudden there are 600. But I think science 
is developing so rapidly--and we mentioned DNA sequencing and 
the individuality of treatment--that there may be a disease 
that only one person in the world has. You cannot really have a 
double blind clinical study for one person. You cannot have it 
for 15 people.
    One of my questions, this might be for the scientists, is 
the idea that you have to have a double blind, randomly 
controlled study. Is that stopping a lot of what goes on with 
the Orphan Disease Act? Or does the Orphan Disease Act actually 
understand and already make some accommodations for the fact 
that the numbers are not big enough?
    We will start with Dr. Strupp.
    Dr. Strupp. I totally agree. This is a very big issue. 
Personally, I have designed eight investigator-initiated 
trials, and very much moved in the design and also the 
statistical analysis. The key number is that you do a sample 
size calculation.
    Doing a proper sample size calculation requires that you 
first have to estimate was this a clinically meaningful 
difference? So that is one of the parameters.
    Then you have to add the power of the study and the alpha 
value, and then you often end up with sample sizes of 50, or 
100, or 200 patients.
    Chairman Paul. That is then being accepted by the F.D.A. 
with the understanding that you cannot do 1,000 people?
    Dr. Strupp. Of course.
    Chairman Paul. Okay.
    Dr. Strupp. Two hundred would be accepted, but if you only 
have 50 in the U.S., you cannot do a proper statistical design 
and analysis in the conventional way.
    Marc Patterson pointed out in his statement what are the 
potential alternatives for such analyses based on up to date, 
sophisticated statistics.
    Chairman Paul. But given the current situation, and you are 
saying currently it is not working, it is difficult to get the 
F.D.A. to approve studies for orphan diseases. Yes?
    Dr. Strupp. Yes.
    Chairman Paul. Dr. Patterson.
    Dr. Patterson. Senator, thank you.
    Just to come back to your point, the Orphan Drug Act, as 
you know, initially really incentivized companies to do 
studies, but it did not direct the F.D.A. as to how these 
studies should be conducted in rare diseases.
    Chairman Paul. Right.
    Dr. Patterson. The Cure America Act, I think, was terrific. 
It was very encouraging in terms of asking the F.D.A. to 
explore adaptive trials, for example, and Bayesian approaches. 
But it did not say, ``You shall do this.''
    I think that would be very important to give regulators 
those tools to say, ``You have explored this. You have shown it 
is appropriate.'' There is quite a literature that shows that 
these trial designs may be effective.
    Chairman Paul. Right. We have had some of this debate in 
the past, like on using European studies or Asian studies. We 
had words put into the bill that said, ``The F.D.A. shall do 
it,'' actually or, ``must do it.'' Everybody said, ``No, no. We 
can say that, `They can.' ''
    The people softened the words because they said, ``We do 
not want to tell the F.D.A. how to do their job.'' But at the 
same time, maybe sometimes we need to be more directive in the 
language because I think given the choice, often the status quo 
persists.
    Dr. Patterson. Senator, I would agree with you completely. 
Thank you.
    Mr. Dent. Senator, I would also add that patients across 
the Nation are jumping as fast as they can to get into the line 
to enter a trial.
    The negative is the trial designs are sometimes so narrow 
that many do not qualify because the clinical endpoints are so 
very precise, even drugs during trial that seem to help. And 
the parents will tell you, ``Yes, my child was speaking 
afterwards, and now they are not.'' And yet, the trial fails.
    Trial designs of all-comer trials where, because of the 
heterogeneity of the disease, three siblings can sit next to 
each other, but they present completely differently. The drug 
may help one, but not the other two. We should look at all 
comers.
    Trial designs like the Multi-Domain Responder Index, which 
really takes all comers, looks how they can succeed.
    Chairman Paul. I think that might be something that you 
could help us with particularly those who design trials. We 
talked about trial design being one of the things.
    We have random, double blind studies as this gold standard 
that has been out there, and we have 1,000 people, it has to 
be, and it has to be half get it, half do not get it. That is 
not appropriate for terminal illnesses, small illnesses.
    But if you could help us not just today, but as we go 
through this process, if we were going to talk to the F.D.A. or 
legislate how these are designed, because it still has to have 
some latitude as to how the designs are. But maybe we have a 
standard now for a design and maybe you can help us with 
defining what the new design would be to allow the process to 
work better.
    Dr. Strupp.
    Dr. Strupp. May I add to that?
    You saw this girl and if you just measure the time, that 
may be misleading because if coordination improves, they will 
often take longer time because they do it more precisely.
    Based on that observation, the F.D.A. was very open minded 
when we suggested a so-called Clinical Global Impressions of 
Change. That means experts evaluate the changes having a look 
at videos. They are blinded; on-off, on-off the drug.
    Chairman Paul. I think even a layperson might be able to 
discover that drug seems to be helping.
    But the only thing I would say is the only thing you would 
have to do to convince me is that it is not random. So you 
would have to have enough videos to show me that this little 
girl is not better some days and worse some days without drugs.
    If there is no random improvement like that and you have 
that dramatic improvement, it should not take us 10 minutes to 
figure out that there is a great deal of benefit there.
    Dr. Strupp. Right. And then you do not need 50 patients. If 
I present you someone----
    Chairman Paul. Exactly.
    Dr. Strupp ----who is fluent in Spanish, it does not help 
to speak additionally Chinese.
    Chairman Paul. Right.
    Dr. Strupp. That is very convincing.
    Chairman Paul. Was this also the drug that has been treated 
for decades in France and so it is not something that is 
poison? It is not something that people are dying from. There 
are no safety problems.
    Dr. Strupp. You mention a very, very important point, and 
we always have very vivid discussion with the F.D.A. in terms 
of teratogenicity and carcinogenicity.
    Imagine most of these diseases affect children. So 
teratogeneity is unfortunately not an issue because they will 
not have children. So why do we have to do animal studies in 
two animal models if we treat children at the age of 13? The 
same is true for carcinogeneity. If you have a life threatening 
disease with a significantly reduced life expectancy----
    Chairman Paul. It looks like you need a way to be able to 
short step this; that is able to look at this. Maybe like what 
Dr. Tsang was saying in Europe, that you give a temporary 
approval much quicker.
    What you need is something that a CEO in a company will do, 
but the government is very, very hard to develop things that 
are adaptable. The government is very, very rigid.
    I know the F.D.A. wants the best. They do not want a 
horrible occurrence like we had with some of the things that 
were approved too quickly. But at the same time, I think, we 
are maybe, the pendulum is over here, and it needs to come back 
toward the middle.
    You need to give someone the prerogative to actually look 
at a video like this and say, ``My goodness, though. There are 
16 people with this disease. Why do we not start more 
aggressively getting this to the people?'' and still continue 
to study it. Maybe have a temporary, and have a review each 
year for safety.
    We need to do something. I do not think we are doing 
enough.
    Dr. Strupp. I think we would even have a more impressive 
video with Tay-Sachs. I do not know if you have it in the 
files.
    Chairman Paul. We can show it if someone can find it.
    Let us go to Professor Factor.
    If someone wants to cue up, whoever is in charge of the 
video, if they can find the Tay-Sachs, we will look at that.
    Mr. Factor. The key, really, from our perspective is early 
and frequent interactions with the F.D.A. to make the 
development programs, before the program begins even, before 
you do your filings that you have a working relationship with 
the F.D.A.
    What the F.D.A. has to recognize more than anything else is 
the endpoint should be quality of life. And the patient and 
caregivers really know those endpoints better than anybody 
else. Quality of life should be the key.
    They really need to have a separate track for fatal orphan 
drugs with high unmet medical needs. There has to be a separate 
track, which they do not have.
    Chairman Paul. Right.
    Mr. Factor. I can give you--at some point I hope I have the 
opportunity--an example of how it took us eight months just to 
get a meeting.
    Chairman Paul. Well, I think all of those things are 
important. What we need to do is just take them and turn this 
into something constructive, and take the problems we are 
having, and let us look at the law specifically and see how we 
can change the law.
    Like I say, some of this, we need the input of scientists 
on how to look at the parameters of what the government is 
saying we need for design to say, ``How can we adapt that?''
    I think it is a point well taken that the Orphan Disease 
Act was mostly about encouraging companies to invest in this, 
but it did not necessarily make the F.D.A. process easier.
    Dr. Tsang.
    Dr. Tsang. Thank you, Chairman.
    I think that my colleagues what they have been saying is 
that the requirements must be applied in a proper clinical 
context. That is the key test so that we are not applying the 
requirements disproportionately.
    Very often, it is very convenient for, as a former 
regulator, very convenient for regulators to say that, ``I need 
to check all the boxes and do it mechanically.'' But very 
often, the law actually provides----
    My understanding of the U.S. legislation is no different 
from other jurisdictions. There is flexibility. The question 
here is whether or not regulators are prepared to exercise 
flexibility to be a bit more bold applying the requirements 
proportionately. That is a key test.
    Chairman Paul. Mr. Dant.
    Mr. Dant. Thank you. I would add one thing, jumping on that 
as well.
    There is great science already available that goes to what 
is referred to often as ``the valley of death'' where, because 
it takes so long to move great science through the pipeline to 
the F.D.A. and then to treatment, it costs too much. So 
companies cannot invest in science to move it along and so the 
therapies do not come forward.
    That is the value of the Open Act, and the value of 
repurposing drugs, and how we can get those companies to jump 
into safe drugs that already are proven safe that may help 
treat.
    Chairman Paul. See, this has been the problem that I have 
been carping on for a while.
    There is idiopathic pulmonary fibrosis. My political 
director's sister has it and the drug she uses, fortunately she 
lived in New York City had a family that had the wherewithal to 
get her into a trial. So having some means, you do not 
necessarily have to be rich, but you have to have the means to 
get to a center and then a family that was able to get her into 
a trial, but the drug had been legal in Japan for a decade.
    The problem I have is that we are so rigid. Let us say 
there is a blood pressure drug, maybe 15 million people are 
taking it. Fifteen million people in France have been taking a 
blood pressure drug for 15 years. We are going to start over 
with all of the safety trials? Instead of having a great deal 
that the preponderance of evidence is that we should really 
shortcut these things.
    I think wanting to have zero tolerance, we do not want to 
approve drugs that either do not work or are unsafe. But I 
think we have too much rigidity and as Dr. Tsang was saying, 
maybe some of it is getting people who are more open minded to 
do that.
    We will talk with the F.D.A. director as well, who is a 
medical doctor, and see if we can talk some about the human 
element of being less rigid. But also, I think something needs 
to be done to the Orphan Drug Act to actually maybe separate a 
category or have a separate pathway just dedicated for the 
orphan drugs. But it is not going to be just orphan drugs. 
There is going to be----
    I think people's individual cancer is already being treated 
in an individual way. We have had testimony from people with 
ALS or Lou Gehrig's disease, about how there are different 
varieties of it, and you are going to discover, and have a 
treatment, probably, for one person or ten people that are a 
variety of that. So we just have to figure out how to get 
beyond that rigidity.
    Are we able to watch another video? Do you want to 
introduce it, Dr. Strupp?
    [Video Presentation]
    Dr. Strupp. This was before treatment. It is an eight year 
old patient with a genetically proven Tay-Sachs disease. So 
without treatment, he could hardly stand unaided.
    Now click on the other one on the football field.
    That was 7 weeks later.
    Chairman Paul. You are convinced that this is not random? 
There is not that kind of random?
    Dr. Strupp. He was off, on, and off. Colleagues who saw him 
could not believe how much he improved. He did not support our 
football team, but nevertheless, he improved very much.
    Go to the next slide, please. Click on the animal on the 
left and the right.
    These are the complementary studies we are doing. This is a 
nice thing. This animal gets the same drug and the same dosage 
per kilogram. You see the major difference. Again, if you will 
measure the time it takes until the animal reaches the bottom, 
the non-treated will be faster because it falls down. So we 
just have to have a global impression.
    Chairman Paul. These studies are being done in Germany?
    Dr. Strupp. No. This is done in collaboration with Oxford, 
Frances Platt from the Department of Pharmacology.
    Chairman Paul. But then my question is if you want to show 
these studies, what are the odds that the F.D.A. is going to 
look at these studies that you have already performed or make 
you do them over?
    Dr. Strupp. They liked the videos very much on July 17.
    Chairman Paul. But are they going to be an acceptable part 
of your presentation, do you think, to the F.D.A.?
    Dr. Strupp. Yes.
    Chairman Paul. Good.
    Dr. Patterson.
    Dr. Patterson. Senator, just to comment. You very astutely 
mentioned the importance of deciding whether a change is random 
or not.
    I think this is a beautiful example of where you can use an 
N-of-1 trial design where you can blind, in fact, both the 
patient and the observer.
    You can be reviewing a videotape, so they do not know if 
the patient is on the placebo or the control. You can do that 
with appropriate trial designs, multiple N-of-1, and get the 
information you need which, I think, is still scientific.
    Chairman Paul. Show the reproductivity. This is somewhat 
the difficulty.
    Alzheimer's does go up and down, the cognitive studies are 
sometimes difficult to prove one or the other because people 
have really good days. If you have had a parent or a 
grandparent with this, they have a really good day and then 
have a bad.
    Once you can eliminate the randomness out of this, though, 
it should not be that much more difficult. We should take into 
account the fact that the drug has been used for a long time in 
France by lots of people.
    Mr. Dant.
    Mr. Dant. Senator, I would also add that in rare disease, 
natural history studies simply are not there because the 
diseases are so rare, which speaks to Dr. Patterson's point 
about the importance of patient owned registries.
    Our partners in industry oftentimes have their own 
registries, but there are silos of information that are not 
shared.
    Chairman Paul. What goes into a registry?
    Mr. Dant. What the parent, what the individual with the 
disorder sees, feels, does. They enter it themselves and it 
becomes a living document that can be reviewed by physicians, 
by scientists, and by industry.
    We need the F.D.A. to also look at those registries and 
understand that there is value in patient-reported outcomes.
    The power of the patient in moving studies forward cannot 
be understated.
    Chairman Paul. We are in the middle of a vote, so we are 
going to wrap up pretty quickly. We have been doing an open 
forum, and I like this. Sometimes you get more from asking 
people what they want to say than asking them a specific 
question.
    I am going to open it one more time and we will see if 
anybody has something they would add to the hearing as we wind 
up here. I am going to have to ask a question if you do not 
come up with anything.
    Professor Factor.
    Mr. Factor. I will add something very quickly.
    The particular drug that we are talking about that is used 
in France contains gluten and things like this in it. We are 
just trying to use the pure form, which causes all sorts of 
other problems by just taking the pure form, the active part of 
it. It is called a racemate in the active form and is only part 
of it.
    But to get rid of the gluten and some of the other stuff 
that people react to, that adds a whole bunch of new tests, 
which makes no sense.
    Chairman Paul. What I would like to do, and we are going to 
wrap up here, because I have to go over to the Senate floor and 
vote, is that I want to thank you all for testifying, for 
coming and taking your time.
    You do not get rich being a congressional witness. You are 
not paid. In fact, actually, many of you probably paid your own 
way here as well, and we really appreciate that because you 
believe in what you are doing.
    I really want to get a result. Just hearing testimony, we 
can do that. If nothing happens, then I am disappointed. So if 
you have further remarks or anything that you would like to 
submit in writing, if there are other groups like yours, Mr. 
Dant, that would also like to submit something in writing, we 
will accept that as well.
    Then, let us continue the collaboration to try to see if we 
can do an update of the Orphan Drug Act that either has a 
separate track, different design perhaps. It is still my belief 
that whether it is an orphan drug or any drug, we live in 
world----
    Look, Dr. Strupp is from Germany, but we do not say we are 
not going to listen to him because he is German. We have great 
doctors in Asia. We have doctors all over the world and all of 
these studies. The world, the modern, civilized world is an 
enormous world of medicine and science now, and we are crazy to 
stop it at the border and say, ``No, you have to Americanize 
all of the studies.''
    I think the scientific community already is very 
international. All the meetings are international. The studies 
are taken and written about in international journals. It is 
just the governments have decided to segment it off. I hate to 
say it, but maybe even the E.U. could tell us something about 
how we should do this better.
    We would like to hear from you and hope the collaboration 
will continue, but thank you very much for your testimony.
    The hearing record will remain open for 10 days. Members 
may submit additional information for the record within that 
time.
    If there is no further business to come before the 
Subcommittee, it stands adjourned.
    [Whereupon, at 3:36 p.m., the hearing was adjourned.]

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