[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
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Available via the World Wide Web: http://www.govinfo.gov
______
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.
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\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
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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\
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\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.
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\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.
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\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.
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\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
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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.]