[Senate Hearing 114-700]
[From the U.S. Government Publishing Office]
S. Hrg. 114-700
BIOSIMILAR IMPLEMENTATION: A PROGRESS REPORT FROM FDA
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HEARING
BEFORE
THE SUBCOMMITTEE ON PRIMARY HEALTH AND RETIREMENT SECURITY
OF THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED FOURTEENTH CONGRESS
FIRST SESSION
ON
EXAMINING BIOSIMILAR IMPLEMENTATION, FOCUSING ON A PROGRESS REPORT FROM
FDA
__________
SEPTEMBER 17, 2015
__________
Printed for the use of the Committee on Health, Education, Labor, and
Pensions
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COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS
LAMAR ALEXANDER, Tennessee, Chairman
MICHAEL B. ENZI, Wyoming PATTY MURRAY, Washington
RICHARD BURR, North Carolina BARBARA A. MIKULSKI, Maryland
JOHNNY ISAKSON, Georgia BERNARD SANDERS (I), Vermont
RAND PAUL, Kentucky ROBERT P. CASEY, JR., Pennsylvania
SUSAN M. COLLINS, Maine AL FRANKEN, Minnesota
LISA MURKOWSKI, Alaska MICHAEL F. BENNET, Colorado
MARK KIRK, Illinois SHELDON WHITEHOUSE, Rhode Island
TIM SCOTT, South Carolina TAMMY BALDWIN, Wisconsin
ORRIN G. HATCH, Utah CHRISTOPHER S. MURPHY, Connecticut
PAT ROBERTS, Kansas ELIZABETH WARREN, Massachusetts
BILL CASSIDY, M.D., Louisiana
David P. Cleary, Republican Staff Director
Evan Schatz, Minority Staff Director
John Righter, Minority Deputy Staff Director
______
Subcommittee on Primary Health and Retirement Security
ENZI, MICHAEL B., Chairman
RICHARD BURR, North Carolina BERNARD SANDERS, Vermont
SUSAN M. COLLINS, Maine BARBARA A. MIKULSKI, Maryland
MARK KIRK, Illinois MICHAEL F. BENNETT, Colorado
TIM SCOTT, South Carolina SHELDON WHITEHOUSE, Rhode Island
ORRIN G. HATCH, Utah TAMMY BALDWIN, Wisconsin
PAT ROBERTS, Kansas CHRISTOPHER MURPHY, Connecticut
BILL CASSIDY, M.D., Louisiana ELIZABETH WARREN, Massachusetts
LISA MURKOWSKI, Alaska PATTY MURRAY, Washington (ex
LAMAR ALEXANDER, Tennessee (ex officio)
officio)
Sophie Kasimow, Minority Staff Director
(ii)
C O N T E N T S
__________
STATEMENTS
THURSDAY, SEPTEMBER 17, 2015
Page
Committee Members
Cassidy, Hon. Bill, M.D., a U.S. Senator from the State of
Louisiana, opening statement................................... 1
Murphy, Hon. Christopher, a U.S. Senator from the State of
Connecticut.................................................... 2
Scott, Hon. Tim, a U.S. Senator from the State of South Carolina. 13
Warren, Hon. Elizabeth, a U.S. Senator from the State of
Massachusetts.................................................. 15
Alexander, Hon. Lamar, Chairman, Committee on Health, Education,
Labor, and Pensions............................................ 17
Kirk, Hon. Mark, a U.S. Senator from the State of Illinois....... 18
Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah...... 19
Witness
Woodcock, Janet, M.D., Director, Center for Drug Evaluation and
Research, U.S. Food and Drug Administration, Silver Spring, MD. 4
Prepared statement........................................... 5
ADDITIONAL MATERIAL
Statements, articles, publications, letters, etc.:
.............................................................
Response by the U.S. Food and Drug Administration to
questions of:
Senator Alexander........................................ 24
Senator Collins.......................................... 31
Senator Kirk............................................. 33
Senator Hatch............................................ 33
Senator Cassidy.......................................... 34
(iii)
BIOSIMILAR IMPLEMENTATION: A PROGRESS REPORT FROM FDA
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THURSDAY, SEPTEMBER 17, 2015
U.S. Senate,
Subcommittee on Primary Health and Retirement
Security,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The subcommittee met, pursuant to notice, at 10 a.m., in
room SD-430, Dirksen Senate Office Building, Hon. Bill Cassidy,
presiding.
Present: Senators Cassidy, Alexander, Murphy, Scott,
Warren, Kirk, and Hatch.
Opening Statement of Senator Cassidy
Senator Cassidy. The Committee on Health, Education, Labor,
and Pension, Subcommittee on Primary Health and Retirement
Security will please come to order.
This morning we have a hearing titled Biosimilar
Implementation: A Progress Report from FDA. Ranking Member
Murphy and I will each have an opening statement and then
introduce our witness. After our witness' testimony, Senators
will each have 5 minutes of questions.
First, I thank Chairman Alexander and Chairman Enzi for the
opportunity to chair this hearing on the important issue of
biosimilars, and Senator Murphy for joining as Ranking Member,
and Dr. Woodcock in advance for her preparation and testimony.
Biologics are medicines derived from living cells, which
makes them significantly more complex than the traditional
medicines, which are sometimes called small molecules and are
chemical compounds. The greater complexity of biologics makes
them far more difficult and expensive to develop, manufacture,
and to copy. Biosimilars, which are also called follow-ons, are
biologics that copy so-called reference biologics and reference
biologics are also called innovator drugs. Reference biologics
are defined as the first biologic product released for a
particular therapeutic effect.
Another key concept is interchangeability. If a biosimilar
is so similar in effectiveness to the reference drug, the two
could be swapped for each other. This is the highest bar for
establishing similarity. Establishing biosimilarity, however,
is the rub. While it can be certain that the effect of a small
molecule or a traditional generic is identical to the original
patented medicine, it has been thought that the complexity of
biologics is such that one can never be certain that the
therapeutic effect of a biosimilar is identical to a reference
biologic.
On the other hand, the complexity of biologics is such that
one lot or batch of a reference product may not be identical to
another lot of the same reference product. To put a point on
it, there's a regulatory tension. FDA must ensure that
biosimilars have a substantially similar safety profile and
therapeutic efficacy as the innovator drug, but since a
biosimilar is only similar and not exactly identical to the
innovator drug the question is what evidence is required to
prove biosimilarity and perhaps interchangeability.
The Biologics Price Competition and Innovation Act
authorize the FDA to develop an approval pathway for biosimilar
drugs.
While the regulatory incentive structure of the BPCIA
roughly resembles that of the Hatch-Waxman structure for small
molecules, a structure developed in part by our colleague on
the committee Senator Hatch, there are significant differences.
Because biologics are more expensive to produce and more
difficult to receive patent protection, biologics received 12
years of data exclusivity instead of five. Because a biosimilar
molecule can never be identical to the reference biologic
molecule, or so it's thought, more data is required to
demonstrate safety and efficacy to the FDA than a small
molecule generic, which must only demonstrate bioequivalence.
These are just a few of the differences.
Even though the BPCIA passed nearly 6 years ago and a
biosimilar has already been approved and is now on the market,
there is still uncertainty regarding how the FDA will implement
the biosimilar approval pathway. In particular, the agency has
still not provided final guidance on key issues of naming,
labeling, interchangeability, and data extrapolation. We also
don't know how these products will be reimbursed by CMS.
Our office has met with a number of stakeholders who
requested clarity from the administration regarding these
issues. Dr. Woodcock has graciously agreed to help provide such
clarity. I will now ask Ranking Member Murphy for his opening
statement. Senator Murphy.
Opening Statement of Senator Murphy
Senator Murphy. Thank you very much, Mr. Chairman. Let me
add my thanks to Senator Enzi, Senator Sanders, and the full
committee for allowing us to serve as Chair and Ranking Member
of this hearing.
I'd also like to thank Dr. Woodcock for testifying today
giving us an update on the implementation of the biosimilar
pathway.
Biologics have provided major advances in the treatment of
cancer, rheumatologic disease, and other conditions. They also
come at great costs to our healthcare system due to the expense
of developing and manufacturing these drugs. For example, even
though they account right now for less than 1 percent of
prescriptions dispensed in the United States, expenditures on
biologics amount to 28 percent of prescription drug spending.
Both their use and their costs are forecast to grow sharply
over the coming years. This increased cost is born by our
healthcare system as a whole, but more specifically by patients
as more and more insurance companies place higher cost sharing
burdens on biologics. I hope that we can talk about that today.
This underscores the need to build a robust biosimilar
market. While we may never get close to the price reductions
that are seen in the generic market, biosimilars will likely be
15 to 30 percent cheaper than the referenced biologic. These
reductions will result in significant savings to the healthcare
system and patients as the biosimilar market matures.
Biosimilars present so many interesting scientific and
policy questions that we need to balance these as we look to
promote access to these life changing drugs. Issues that are
relatively easy when it comes to small molecule drugs, like
naming, labeling, interchangeability, extrapolation, or
reimbursement, are much more difficult due to the complex
nature of biologics.
I commend Dr. Woodcock and the scientists at FDA for
working through these challenging issues because I can
understand the benefits of both sides of many of these
arguments.
To that end, I was glad to see FDA finalize some of the
guidances that were proposed in draft form in 2012 and released
the new naming guidance last month, which I'm sure will be a
topic of discussion today.
Providing the public the ability to comment on these
difficult questions as the agency sets the ``rules of the
road'' for the new pathway is critically important.
Understandably, the industry needs to have some certainty on
these outstanding questions as they think about investing
hundreds of millions of dollars into biosimilar. Patient and
provider groups they also need to have confidence in the end
products as well.
We spent $374 billion in 2004 on prescription drugs. That
was a 13 percent increase over the prior year. There's a lot of
reasons for that, but one of those is that there are less
generics on the market than we would have liked. We need to
grapple with this sort of strange world in which we live in
today in which if you're a patient and you get provided a
prescription you are likely going to get that prescription.
Someone's going to pay for it. You're going to pay for it, but
your insurance company is more likely. Patients have to fight
like hell to get all sorts of other healthcare services: to get
reimbursement for outpatient mental health or physical therapy
or nutrition services.
We have a growing disparity between the amount of money
that expended on pharmaceuticals and the amount of money that
is spent on a lot of other very, very important therapies.
Senator Cassidy, thank you for allowing me to say a few
words. I look forward to hearing from the witness.
Thank you. And now to introduce our witness, I'm delighted
to welcome Dr. Woodcock as our only witness. Again, thank you
for your time being here.
Dr. Woodcock is the Director of the Center for Drug
Evaluation and Research, or abbreviated CDER, at the Food and
Drug Administration. As of January 2015, Dr. Woodcock also
assumed the role of Acting Director of CDER's newly formed
Office of Pharmaceutical Quality.
Dr. Woodcock first joined the center in 1994. For 3 years
she served as FDA's commissioner holding several positions
including deputy commissioner served FDA's commissioner holding
these positions as well as deputy commissioner for operations
and chief operating officer. Her responsibilities involved
oversight of various aspects of scientific and medical
regulatory operations.
Before joining the center, Dr. Woodcock served as the
Director of the Office of Therapeutics Research and Review and
Acting Deputy Director in FDA's Center for Biologic Evaluation
and Research. She received her medical doctor degree from
Northwestern Medical School and completed further training and
held teaching appointments at Penn State University and UC San
Francisco. She joined FDA in 1986.
Dr. Woodcock.
STATEMENT OF JANET WOODCOCK, M.D., DIRECTOR, CENTER FOR DRUG
EVALUATION AND RESEARCH, U.S. FOOD AND DRUG ADMINISTRATION,
SILVER SPRING, MD
Dr. Woodcock. Thank you very much and good morning. I
really thank all of you for holding this hearing today. It's a
very important topic.
FDA and I personally have long supported the availability
of a biosimilar pathway. In fact, I've been working on this
since the late 1990s. This is very important to me. I've been
involved in the development of biological therapeutics for
about 30 years.
As a rheumatologist, which is an arthritis doctor, I have
seen a transformation in the treatment of rheumatoid arthritis
by these medicines. Due in large part to the biologic
therapeutics, clinics full of wheelchairs are now a thing of
the past in the rheumatology clinics. Instead of talking about
joint replacements for these patients and ongoing care we talk
about treating them to remission of disease: trying to make
their disease go away.
I hear from my colleagues in rheumatology that these
transformative medicines are still inaccessible to some
Americans because of their costs.
Since the biosimilars pathways created by Congress in 2010,
a lot of progress has been made. As the Chairman said, the
first biosimilar was recently approved in the United States. Of
course people are anxious to see more progress.
Our generics program, the small molecules that Senator
Cassidy referred to, is now hugely successful with over 85
percent of dispensed prescriptions in the United States being
generic drugs. This saves hundreds of billions of dollars to
healthcare system. This success I have to stress did not happen
overnight. It has been the work of many decades developing both
maturity in the industry and gaining the confidence of the
healthcare community to use generics this broadly.
Although the first biosimilar is now marketed, there are
many legal, technical, and policy challenges ahead, and I look
forward to discussing them as the subject of today's hearing.
Nevertheless, I believe there is a bright future ahead for our
biosimilars program and that it will produce the same access to
important medicines that our current generics program is doing.
I'm happy to answer questions.
[The prepared statement of Dr. Woodcock follows:]
Prepared Statement of Janet Woodcock, M.D.
introduction
Mr. Chairman and members of the subcommittee, I am Dr. Janet
Woodcock, Director of the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration (FDA or the Agency), which
is part of the Department of Health and Human Services (HHS). Thank you
for the opportunity to be here today to discuss FDA's implementation of
the Biologics Price Competition and Innovation Act of 2009 (BPCI Act).
FDA is supportive of and fully engaged with the development and
approval of biosimilar and interchangeable biological products. Many of
our most important drugs are biological products. Biological products
are used to treat patients who have serious and life-threatening
medical conditions including rheumatoid arthritis, diabetes, and
cancer. It is important for the public health of the U.S. population to
have access to safe, effective, and affordable biological products.
Biosimilars can provide more treatment options for patients, and
possibly lower treatment costs, enabling greater access for more
patients.
To earn and sustain both physicians' and patients' confidence in
biosimilar and interchangeable products, FDA must apply a
scientifically rigorous review process and approval standard.
Healthcare providers have consistently indicated the importance of
assurance that biosimilars will have the same clinical performance as
the originator, or reference product. FDA is committed to providing
this assurance, and recognizes its importance to the uptake and
acceptance of these products, and the future success of the biosimilars
program.
biologics price competition and innovation act (bpci act) and
biosimilars user fee act (bsufa): important additions to fda statutory
authority
As you know, the Affordable Care Act included the BPCI Act, which
established a new abbreviated approval pathway for biological products
shown to be ``biosimilar to'' or ``interchangeable with'' an FDA-
licensed biological product. With this new abbreviated approval
pathway, a sponsor can get a biosimilar approved by demonstrating,
among other things, that it is highly similar to a reference biological
product already licensed by FDA. Biological products consist of large,
complex molecules that are difficult to define and produce. This is in
contrast to ``small molecule'' drugs that generally are produced
through chemical processes, and can be replicated as ``generic'' drugs
that are essentially exact copies. Unlike generic drugs, biosimilars
must be highly similar to, not the same as, the reference product to
which they are compared. A biosimilar can have certain allowable
differences because it is made from living organisms, but it must
demonstrate no clinically meaningful differences in terms of safety,
purity and potency from its reference product. The complexity of
biological products generally makes it more challenging to demonstrate
biosimilarity, as compared to demonstrating sameness for a generic
drug.
The abbreviated approval pathway permits a biosimilar biological
product to rely on certain existing scientific knowledge about the
safety and effectiveness of the reference product, saving the sponsor
time and resources and thereby encouraging price competition and lower
consumer healthcare costs. The ongoing and future impact of this
relatively new law cannot be overstated. FDA's biosimilars program has
sparked the development of a new segment of the biotechnology industry
in the United States. The development of this new market segment should
expand opportunities for technical innovation, job growth, and patient
access to treatment.
The BPCI Act directed FDA to develop recommendations for a
biosimilars user fee program for fiscal years 2013 through 2017. The
first Biosimilar User Fee Act, or BsUFA, was enacted as part of the FDA
Safety and Innovation Act (Public Law No. 112-144, enacted on July 9,
2012). BsUFA has allowed FDA to begin development of the infrastructure
needed to support this new program. In addition, it has allowed the
Agency to work toward devoting additional resources to meeting with
companies regarding specific products in the pipeline to help
streamline the drug development process leading to the approval of
safe, effective, and possibly less expensive, biosimilar products for
patients.
implementation and accomplishments
Probably the most exciting accomplishment since the enactment of
the BPCI Act is FDA's approval of the first biosimilar in the United
States. On March 6, 2015, FDA approved the first biosimilar, Zarxio
(filgrastim-sndz), a biosimilar to Neupogen (filgrastim), a reference
product licensed by FDA that is used to help stimulate growth of white
blood cells in patients with cancer and help them fight infection.
FDA has worked hard to implement this new abbreviated licensure
pathway. We established an internal cross-center working group, known
as the Biosimilars Implementation Committee, to develop policies and
procedures for implementation of the new law in a manner that best
serves the public health. We created a multi-disciplinary committee
known as the Biosimilars Review Committee, within CDER and the Center
for Biologics Evaluation and Research (CBER), to provide central
oversight and advice to review staff as they review and consider
biosimilar development programs and related issues.
FDA has worked diligently to issue multiple guidances on
biosimilars since enactment of the BPCI Act. Scientific guidance is of
critical importance to lay the foundation for the development of
biosimilar products. Although the BPCI Act does not require FDA to
issue guidances before taking an approval action on a biosimilar
application, we recognize the importance of guidances in helping to
ensure successful implementation of this new pathway. These guidance
documents provide transparency to industry, the healthcare community
and other stakeholders with regard to FDA's scientific standards and
approval criteria.
The necessary first step was to develop guidance regarding
implementation of the BPCI Act and demonstrating biosimilarity. FDA
published draft guidances in 2012 and published final guidances in
April 2015 on the following topics:
Scientific Considerations in Demonstrating Biosimilarity
to a Reference Product.
Quality Considerations in Demonstrating Biosimilarity of a
Therapeutic Protein Product to a Reference Product.
Biosimilars: Questions and Answers Regarding
Implementation of the Biologics Price Competition and Innovation Act of
2009.
We have also published the following draft guidances since 2012:
Clinical Pharmacology Data to Support a Demonstration of
Biosimilarity to a Reference Product.
Reference Product Exclusivity for Biological Products
Filed Under Section 351(a) of the PHS Act.
Formal Meetings Between the FDA and Biosimilar Biological
Product Sponsors or Applicants.
Biosimilars: Additional Questions and Answers Regarding
Implementation of the BPCI Act of 2009.
Nonproprietary Naming of Biological Products.
FDA's most recent draft guidance on the Nonproprietary Naming of
Biological Products describes FDA's current thinking on the appropriate
naming convention to help ensure the safety of patients receiving
biological products and maximize the success of biosimilar and
interchangeable biological products. FDA believes that both reference
products and biosimilars should have nonproprietary names (also called
a proper name) that include a core drug substance name and, in order to
facilitate safe use and pharmacovigilance, an FDA-designated suffix
that is unique for each product. The agency is continuing to consider
whether the nonproprietary name for an interchangeable product should
include a unique suffix or share the same suffix as its reference
product.
Along with this draft guidance, FDA issued a proposed rule that
would designate nonproprietary names that contain a suffix for six
previously licensed biological products. These products include four
originator biological products that are reference products for an
approved or publicly disclosed biosimilar application, a related
biological product to one of these reference products, and a biosimilar
product.
The Agency is committed to carefully reviewing the comments
received as we move forward in finalizing the draft guidances and
proposed rule noted above. Upcoming guidances are expected to include:
Considerations in Demonstrating Interchangeability to a
Reference Product.
Statistical Approaches to Evaluation of Analytical
Similarity Data to Support a Demonstration of Biosimilarity.
Labeling for Biosimilar Biological Products.
review program
The biosimilar review program has continued to mature over time. As
of July 31, 2015, 57 proposed biosimilar products to 16 different
reference products were enrolled in the Biosimilar Product Development
(BPD) Program. The BPD Program was created as a part of BsUFA to
provide a mechanism and structure for the collection of development-
phase user fees to support FDA's biosimilar review program activities.
When a sponsor joins the BPD Program and pays the associated user fee
for a specific product development program, that program is managed by
FDA per the BsUFA performance goals and procedures. The number of
sponsors in the BPD Program is not absolutely reflective of the overall
number of industry programs underway, as a sponsor may be in the early
stages of interacting with FDA and not yet enrolled in the BPD Program.
Sponsors of an additional 27 proposed biosimilar products have had a
Biosimilar Initial Advisory meeting with FDA, but have not joined the
BPD program to pursue the development of these products.
In engaging with sponsors regarding biosimilar development, CDER
holds development-phase meetings and provides written advice for
ongoing development programs. CDER continues to meet with sponsors
interested in developing biosimilar products. The number of meeting
requests increased 69 percent from the fiscal year 2013 level, from 32
to 54. The number of scheduled meetings also increased 57 percent
during the second year of the biosimilar program, from 30 to 47. Based
on the current and projected workload analysis, FDA expects continued
modest growth in the number of meetings requested and scheduled through
fiscal year 2015.
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As biosimilar development programs mature, the type of interaction
with FDA is changing. We have seen a shift in the types of meetings
sponsors request and FDA grants. BsUFA established five meeting types
specific to biosimilar development programs. Sponsors can choose the
type of meeting or a combination of meetings to match development
needs. Sponsors are increasingly requesting Biological Product
Development (BPD) Type 2 meetings to discuss specific aspects of their
development programs. This approach facilitates biosimilar product
development by providing a process for iterative advice and clarity
throughout the development stage.
The BsUFA program established five meeting types specific to
biosimilar development programs:
A Biosimilar Initial Advisory meeting is an initial
assessment limited to a general discussion regarding whether licensure
under section 351(k) of the Public Health Service (PHS) Act may be
feasible for a particular product.
A BPD Type 1 meeting is a meeting that is necessary for an
otherwise stalled BPD program to proceed. Examples of a BPD Type 1
meeting include discussion of a clinical hold, a special protocol
assessment meeting, discussion of an important safety issue, dispute
resolution meetings, and discussion of a Complete Response.
A BPD Type 2 meeting is a meeting to discuss a specific
issue (e.g., proposed study design or endpoints) or questions where FDA
will provide targeted advice regarding an ongoing BPD program. This
meeting type includes substantive review of summary data, but does not
include review of full study reports.
A BPD Type 3 meeting is an in-depth data review and advice
meeting regarding an ongoing BPD program. This meeting type includes
substantive review of full study reports, FDA advice regarding the
similarity between the proposed biosimilar biological product and the
reference product, and FDA advice regarding the need for additional
studies, including design and analysis. This meeting has no counterpart
in the Prescription Drug User Fee Act (PDUFA) program and is unique to
BsUFA to support an evaluation of residual uncertainty regarding the
demonstration of biosimilarity and to support the concept of stepwise
evidence development.
A BPD Type 4 meeting is a meeting to discuss the format
and content of a biosimilar biological product application or
supplement to be submitted under section 351(k) of the PHS Act.
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While we have made significant progress in implementing this new
program, there is more work to do and, as with any new initiative,
challenges to address. There are challenges relating to the BsUFA
statutory requirement that FDA spend a certain level of BA funding in
order to have the authority to collect and spend the user fee funds.
FDA has taken steps to attempt to address this issue. FDA also is
working to recruit additional staff and has continued to allocate
increasing resources for this critical regulatory review program. FDA
has continued to allocate increasing resources to the biosimilar review
program. While the FTE expenditure in fiscal yeaars 2013 and 2014 were
relatively equal, the FTE expenditure in the first two quarters of
fiscal year 2015 was equivalent to the total expenditures in the
previous two fiscal years. FDA projects that the total FTE expenditure
will be significantly greater in fiscal year 2015 than in previous
fiscal years.
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The increase in FTE expenditure is a direct reflection of the
change and increase in workload in fiscal year 2015. To date, there are
four companies that have publicly announced submission to FDA of a
total of five applications (351(k) Biologics License Applications
(BLA)) for proposed biosimilar products. To date, FDA has approved one
of these 351(k) BLAs for a biosimilar product, Zarxio (filgrastim-
sndz).
FDA will continue to need to hire and train additional staff to
support this program. As the BsUFA program matures, FDA expects overall
BsUFA performance metrics will improve in coming years.
global development
Beyond our borders, we continue to support global development of
biologics and biosimilars, and are actively engaged with other national
regulatory agencies. We recognize that biosimilar development and
regulation are of interest worldwide and FDA can be a leader in this
arena. Thus, FDA is an active participant in international regulatory
organizations and at meetings and scientific conferences.
FDA has also worked to ease the burden for sponsors of proposed
biosimilar products that have previously been approved outside the
United States, such as in the European Union, to develop their proposed
biosimilar products for the U.S. market. The BPCI Act requires a
demonstration of biosimilarity to a U.S.-licensed reference product.
This requirement was initially perceived as a barrier to development
that necessitated conducting multiple separate studies with a
regionally approved comparator product. As a global leader, FDA took
steps to address this issue in a scientifically rigorous manner by
issuing guidance describing the use of a non-U.S.-licensed comparator
in certain studies based on an adequate scientific bridge between the
U.S.-licensed reference product and a non-U.S.-licensed comparator
product. Following FDA's publication of draft guidance on this topic,
the European Medicines Agency adopted the same regulatory approach with
the same scientific standards. While, as noted above, the BPCI Act
requires a demonstration of biosimilarity to a U.S.-licensed reference
product, and as a scientific matter, a sponsor will need to directly
compare its proposed biosimilar product with the U.S.-licensed
reference product in certain studies, the scientific approach outlined
above should help prevent unnecessary duplication of other studies.
education and outreach
As previously noted, stakeholder confidence is essential to the
success of the biosimilar program. FDA has and will continue to
actively engage with stakeholders. We have held public and stakeholder
meetings. FDA also is undertaking a multi-phase plan for communicating
with stakeholders and educating them about biosimilars. The first phase
of the communication plan is to lay a solid foundation with
understandable definitions and descriptions that health care
professionals and consumers can easily understand and adopt. To help
guide message development, FDA has a contract to conduct a focus group
study of prescriber and pharmacist knowledge of biosimilar biological
products. FDA also has a contract for Web-based training programs,
which includes a biosimilar course to educate health care professionals
(physicians, nurses, pharmacists, nurse practitioners and physician
assistants) nationwide. FDA plans to communicate information in various
formats to consumers as more biosimilar products are approved and enter
the marketplace. We will continue our outreach activities, including
interacting with physicians and pharmacists and educating consumers and
patients, well into the future.
the path forward
Of course, more work needs to be done. FDA will continue to meet
with companies to provide advice for individual development programs.
Over the past year, we have seen the number of meeting requests and
marketing applications grow. We are excited about this growing demand,
and we will continue to facilitate development, submission, and timely
review of biosimilar product applications.
Even with our challenges, we are optimistic and energized about the
future. This new pathway for biosimilars and interchangeables has the
potential to offer a significant contribution to the public health of
many Americans. At FDA, we are working hard to ensure this impact can
be realized. Thank you for inviting me here to highlight the impact of
this important law. I look forward to your questions.
Senator Cassidy. Dr. Woodcock, I mentioned briefly
interchangeability.
Dr. Woodcock. Yes.
Senator Cassidy. The ultimate in biosimilarity if you will.
First let me say, as I've told you privately, the questions I'm
asking are basically questions that people on the outside have
submitted. I feel as if I'm a conduit and selected from them.
No. 1, is the concern that FDA still has not provided
details on the specifics of interchangeable products. Broadly
what would qualify in your mind as interchangeable? And No. 2,
can we get there?
Dr. Woodcock. First let me answer your second question. We
believe that getting there is both scientifically and
practically feasible and we're going to get there.
Senator Cassidy. OK.
Dr. Woodcock. All right. However, let me tell you what the
statute that Congress passed says interchangeability is first.
First of all, it's expected to produce the same clinical result
as the referenced product in any given patient. Second of all,
we need to find that a product that is administered more than
once to an individual the risks in terms of safety or
diminished efficacy of alternating or switching between the use
of the biosimilar product, I'm paraphrasing, and it's
referenced product is not greater than using the reference
product alone. We have to make an interpretation of that
statutory standard. That is the statutory standard and it sets
a high bar.
The reason for the basic reason is the human immune
response. All right. Because when we approve a biosimilar as a
biosimilar we are going to find that it is highly similar to
the reference product. Meaning that it's expected to produce
the same clinical effects, both safety and efficacy. However,
that raises a question if what happens in our current
healthcare system say with generics you're a patient and you go
get your medicine and you're switched over and over again
between one generic or another, or sometimes you might get the
reference drug, the question is would that cause additional
harm because of unexpected immune responses. Because unlike
most of our small molecule drugs, the body recognizes these
large protein molecules that are biosimilars and often in some
people will make an immune response. What the concern has been
is that this continued switching could raise that immunity,
sort of provide a booster effect and cause unthwarted effects.
There have been several episodes with one biosimilar drug,
erythropoietin, where people made antibodies based on some
small manufacturing changes. This is in the reference world,
not the biosimilar world. People then had antibodies against
their own hormone erythropoietin and it resulted in something
called pure red cell aplasia and meant that they would be
transfusion dependent for the rest of their lives.
Senator Cassidy. Can I interrupt?
Dr. Woodcock. Yes.
Senator Cassidy. Because I think you've just done a nice
job of showing that the products may not be similar. On the
other hand, you had mentioned in our private conversation, and
I mentioned in my statement, that one batch to the next batch
of a reference drug might be different.
Dr. Woodcock. That's correct.
Senator Cassidy. Clearly you can have a little bit of
wiggle room and presumably you don't want to develop that.
What I've been told is that the fingerprinting, if you
will, the ability to really look at the nature, the structure,
the thermodynamic kind of configuration of some of these
biosimilars is now progressing to the point that you can
establish how these are twins almost. A little freckle here,
not there, but otherwise a twin. With that in mind, in your
regulator guidance where you kind of create a possibility for
this advancement in the ability to show similarity
biochemically, et cetera, as part of the way in which you would
establish interchangeability?
Dr. Woodcock. We certainly do in a degree to which
something is highly similar and as similar to a fingerprint
level would be a very strong point in favor. Our problem is the
human immune system is capable of detecting tiny variability.
Senator Cassidy. So the freckle makes a difference?
Dr. Woodcock. Perhaps. Not usually. As you said, not
usually. The problems I was talking about were from a reference
product. They were between different versions of a reference
product, not a biosimilar.
Senator Cassidy. Inherently though you're saying that the
degree of variability even within a reference product means
that you may get an immune difference, and it may not matter
that it's an interchangeable drug. It could have been that the
same innovator drug continued to have been given would have
induced the same effect.
Dr. Woodcock. These had very small manufacturing changes we
believe that brought on these problems.
Senator Cassidy. OK. I thank you.
I now turn to my Ranking Member.
Senator Murphy. Thank you very much, Senator Cassidy.
We talked about the certainty that the industry needs to
start populating the field with more biosimilars. You've
mentioned that you have on your guidance agenda for 2015
guidances including interchangeability and labeling. Are we
still on track to see those by the end of the year?
Dr. Woodcock. We are working very hard to get them out, but
I never give a date for guidances because it's sort of out of
my hands. There's multiple clearances involved and these are
very complex. We are working very hard on these.
Senator Murphy. I've heard a lot about a proposal from CMS
to blend reimbursement for biosimilars of the same reference
product, and I'm hoping you can talk a little bit about this
and whether you can tell us whether assigning the same CMS
billing code is going to impact their use in FDA's opinion.
Dr. Woodcock. CMS billing codes are often used by us, as
well as of course for other purposes, but they're used for
tracking purposes so we can determine who got what drug. Right.
CMS has a proposed rule. They're still in the rulemaking
process. If CMS were to finalize this proposal, FDA and CMS are
developing an approach to use sub codes, or what are called
coding modifiers. These already exist in the CMS world. That
would help us distinguish who got what. They would distinguish
amongst the various biosimilars if there were multiple
biosimilars.
Senator Murphy. I wanted to talk to you a little bit about
education. It took us a long time to educate both providers and
patients about chemical generics. It was really well after the
passage of Hatch-Waxman that there was a level of comfort. And,
given the substantial differences that we've talked about and
the amount of money that the pharmaceutical companies are going
to put behind marketing campaigns to tell both doctors and
patients that they shouldn't take the generic, who's
responsible for the education necessary to provide the level of
comfort ultimately in the biosimilar space that I would argue
we have today in the chemical generic market? Because there is
just going to be all sorts of opportunity for the owners of
that original patent to flood the healthcare space with bad
information about why you shouldn't take that biosimilar, so I
think you referenced in your testimony this issue of education.
Talk to us a little bit about once we have more than one, how
we're going to go about that campaign of getting the truth out
there about biosimilars.
Dr. Woodcock. Yes, well I think to a great extent this does
fall on FDA's shoulders, and also to a great extent as they say
it's deja vu all over again because we did go through this, and
we are still going through this with generics with some
subspecialty groups. Actually we've been doing trials to show
equivalence of generics in the seizure area.
We have laid out a plan of campaigns of education, and
we're also doing focus groups and other activities to determine
what is the current level of understanding and what do people
need to know. My experience, if I may, is that we're going to
have to target the subspecialty groups one by one. Most
clinicians are overwhelmed with people who want to educate them
about things. We are going to be offering CME type of credits,
courses, and so forth. We can go subspecialty by subspecialty
as we approve biosimilars that are targeted and used by a
certain subspecialty group. They're not used generally by all
practitioners. They're also State legislatures and others who
are very interested. Of course this is a very complicated
issue. We have a menu of educational activities planned out of
the next several years.
Senator Murphy. I know this is an issue that doesn't
necessary fit natural to Congress to be funding physician and
provider education, but we're talking about next year reports
suggesting that 8 of the top 10 drugs on the market are going
to be biosimilars. They cost on average 22 times that of
traditional drugs. If we are successful in getting this pathway
to biosimilars moving then my fear is with a product sitting on
the market that could cost 30 percent less we were are going to
be behind this avalanche of pharmaceutical advertising that
will keep the market away from the biosimilars.
I just hope it's a topic for conversation here in this
committee. We can do all of this work on trying to make sure
that we approve biosimilars, but if they're not actually
getting prescribed, if we aren't giving FDA the resources to
make the case that they should be prescribed, we're going to be
spending billions and billions of additional dollars that we
don't need to simply because we're continuing to funnel money
to the makers of the original product who are in competition
with the maker of the biosimilar.
Thank you, Mr. Chairman.
Senator Cassidy. Next will be Senator Scott. And just to
acknowledge that the Chairman is here and he would normally go
first, but he says just go in the order. The order will be
Senator Scott, Senator Warren, Senator Alexander then Senator
Kirk.
Statement of Senator Scott
Senator Scott. Thank you, Mr. Chairman. Thank you, Mr.
Chairman.
Good morning, Dr. Woodcock. Thanks for being here. My
question really goes to the issue of labeling the biosimilars
versus the biologics. It appears to me that early on the goal
was to make sure that the biosimilars were specifically and
correctly labeled so that there would be no question about what
it was. It seems like shortly thereafter or at least in 2012
the purple book play book basically comes out that says that
doctors can go online to figure out what it really is as
opposed to sticking with the clearly specifically labeled drug
itself. Why the change?
Dr. Woodcock. We haven't really made a change. We did not
put anything in that final guidance because it really wasn't
about labeling. We plan to issue a labeling guidance. We also
have a citizen petition before us from AbbVie on a variety of
these issues that's in the docket. We are evaluating that as we
evaluate what we're going to put into our guidance.
Senator Scott. I think to some extent Senator Murphy
started having the conversation about the appropriate education
necessary for the clinicians putting them in the position where
when you look at the absolute onslaught of work that we're
putting on the backs of doctors to find them having to deal
with a new 68,000 different billing codes versus four or five
previously.
Dr. Woodcock. Right.
Senator Scott. You look at the audits that are coming
forward. You look at the medical records that are online or
electronic medical records which seems to be a catastrophe for
many physicians. We had a hearing here recently and so to not
take the original intent on the first biosimilar immediately as
it's coming out seems to me to be a costly delay in the impact
that it could have on patients.
I have had the unfortunate experience of going to a doctor
to get a prescription for medicine, and when I called my
pharmacist she tells me that the two medicines that the doctor
was giving me actually could have a negative impact on my
liver. And so she said, ``Immediately stop taking that
medicine.''
My concern is that as there is a delay in making a clear
decision on the labeling and the importance of labeling that we
may find ourselves with more patients being harmed. Frankly, if
we're looking for a way, as Senator Murphy has inferred to
controlling and/or reducing the cost, whether it's 30 percent
or 20 percent, these can be very expensive, the fact of the
matter is that the clarity needed for the industry so that they
can make economic decisions is incredibly important.
I would just go back to my original question. What can we
anticipate and/or expect as it relates to labeling on the
biosimilars, and when can we expect it?
Dr. Woodcock. I can answer the when because it's still
under consideration. I can't answer the what. We hope to do
that as soon as possible. We understand the criticality of this
issue. It's really important for us to gain and maintain the
trust of the healthcare community in these products. Right now
the biosimilar that we approve is not interchangeable. A
clinician will have to write for that for a patient to get it
just like they would for any other drug. They can write with
the brand name or they can write with the proper name of the
biosimilar product.
Senator Scott. It seems like doctor or Senator Cassidy over
there suggested that the biologics and the biosimilars could be
somewhat like twins. My real question from your answer would
suggest that these are identical twins and not paternal twins.
The fact of the matter is that the similarity of the drugs may
be important. If they are not interchangeable at this point
it's important for us to give the appropriate indications going
down the road, and it appears to me that the best time to do
that is immediately. And if the answer for as soon as possible
seems like the timeline would then be to be determined.
Dr. Woodcock. There are tradeoffs involved in various
labeling decisions.
Senator Scott. Yes, ma'am.
Dr. Woodcock. We have a citizen petition that goes through
some of those. There are folks on either side of this issue. We
need to have a labeling convention that maintains the trust of
the clinicians. I understand they want to know what their
patients are getting.
Senator Scott. That's important.
Dr. Woodcock. Right now you have to write a prescription
for the new biosimilar----
Senator Scott. Yes.
Dr. Woodcock [continuing]. In order for a patient to get
it. They will know that the patient is getting that biosimilar
medicine. It is expected right now to deliver the same clinical
effects as the reference product.
Senator Scott. At this point you are saying the biologic
and the biosimilar are interchangeable and therefore more like
the name brand and the generic versus the concerns that I have
as it relates to the specificity of the way that the drug
interacts with the individual patient?
Dr. Woodcock. They are not interchangeable because we
haven't determined the immune response issues. However, they
will give the same clinical effect. We had an advisory
committee. They voted overwhelmingly that they are biosimilar.
Senator Scott. My last comment would be that I know that
you've been dedicated to this cause for it sounds like nearly
20 years. I would hope that we would be able to get appropriate
labeling if we've been working on this concept and getting to
this point for the last two decades. We could start off with
appropriate labeling maybe even day one if we've been on this
road for 20 years. I know government moves slow.
Senator Cassidy. Senator Warren.
Statement of Senator Warren
Senator Warren. Thank you, Mr. Chairman.
Thank you for being here, Dr. Woodcock. Biologic drugs,
complex products like enzymes and antibodies, are great medical
achievements that allow people to live longer, healthier lives.
These drugs are extremely expensive. According to IMS Health,
biologics accounted for 28 percent of all drug spending in 2013
and we know that this number is rising. Medicare has also been
hit hard. According to the GAO, just eight biologic drugs--just
eight drugs--account for over 40 percent of all Medicare Part B
spending.
The good news is that the Affordable Care Act established a
pathway for biosimilar drugs that, according to a RAND
analysis, have the potential to save us about $44 billion over
the next 10 years. We know from our experience with ordinary
generics that significant cost reductions for drugs don't occur
until two or more follow-on competitors come to market. In
order to foster a robust biosimilars market that is actually
going to drive down the cost of these drugs, drug makers need
to know the rules of the road so they know whether or not to
enter this market.
Dr. Woodcock, it has now been 5 years since Congress
authorized the biosimilars pathway, but so far the FDA hasn't
even produced a draft guidance describing the standard for an
interchangeable biosimilar. In addition, the FDA has not
released guidance on how the products will be labeled and has
not finalized many other guidance documents that will help
companies enter the biosimilars market.
Can you help us understand why the FDA has not completed
this work in 5 years?
Dr. Woodcock. We have a biosimilar program and we have
spent a lot of time. We have 57 products in development, and we
have been giving those sponsors one-to-one advice. There are 16
different reference-listed drugs. So 57 products, 16 reference-
listed drugs, you can see if these products get across the
finish line we will have competition.
Senator Warren. I appreciate that. But, the question is
it's been 5 years now? In doing this, you know, the European
Medicines Agency adopted a biosimilars pathway in 2003 and
approved the first biosimilars in 2006 for the European Union.
Health Canada approved its first biosimilar in 2009. The FDA is
building on nearly a decade of experience within the European
Union, as well as experience from Canada, and yet, 5 years have
gone by and we still don't have any of these guidelines out not
even in draft form.
Dr. Woodcock. We've issued three final guidances and one of
them is the foundational guidance for how you develop a
biosimilar, which is the scientific considerations. It put
forth the scientific framework for what the companies needed to
do to start. Because the statute rightly said that the
comparison had to be a U.S. reference-listed drug and many of
these sponsors had to start by comparing to the U.S. drug,
which might be different than the European reference-listed
drug.
We gave a scientific structure and a framework that said
that the foundation is the analytical similarity and that other
types of studies were put on top of that. The amount of
clinical data needed depended on how much uncertainty remained
about biosimilarity after doing that program. These 57 sponsors
are engaged in the scientific program.
Senator Warren. No, I'm sorry, Dr. Woodcock. I appreciate
that there is a process, and that's what I'm hearing you say
over and over and over. The real question that I'm pushing on
is that it is time now to get this done. The longer it takes
you to set the rules the longer patients will be stuck paying
for only one very expensive option to treat their medical
needs.
There aren't very many things in Washington that
stakeholders on both sides of the aisle agree on and that
people out in industry agree on. I think we all agree that it
is time to get guidance documents.
If the Chair will indulge me? I've got just a few seconds
left. I want to go back to this question about generics, if I
can.
Biosimilars can save an estimated $44 billion over the next
10 years, but that will happen only if patients have confidence
in the quality of the biosimilars and their doctors have
confidence----
Dr. Woodcock. That is correct.
Senator Warren [continuing]. And will actually prescribe
them.
We know from the very established generic drug market that
it suffers from severe misperceptions here. Studies by
researchers at Harvard found that nearly 23 percent of
physicians had negative perceptions about the efficacy of
generics and nearly 50 percent had negative perceptions about
quality. They also found that about 30 percent of patients felt
that brand name drugs were going to be more effective than
their generic counterparts. This is for some drugs that have
been around for a very, very long time.
Given the newness and the complexity of biosimilar drugs,
I'm concerned that misunderstandings about biosimilars could
hamper their uptake in the market. I understand that you're
currently conducting research. You said you're starting to lay
out a plan for how to deal with the public perception of
biosimilars. I just want to underline the urgency of this.
Generics have been on the market for 30 years since Hatch-
Waxman opened up the generic market, and yet even today this is
not a fully open market where physicians will prescribe and
where patients have confidence in the drug.
I want to hear what it is that you're planning to do. If
you could just give me something that's specific about dealing
with the potential negative perceptions of biosimilars? We've
got to create a market here that works.
Dr. Woodcock. Do I have time to answer?
Senator Warren. Is that all right? Could she? Is that all
right? Thank you. I appreciate the indulgence.
Dr. Woodcock. First of all, let me say we have to get the
science right so we can't have problems with the first
biosimilars out of the block or we will cause----
Senator Warren. I totally understand that.
Dr. Woodcock. OK.
Senator Warren. That's why we need guidelines as well.
Dr. Woodcock. The guidances that you're talking about are
about more policy issues. They are not about the scientific
standards. We've issued eight guidances: three final and five
draft guidances.
Senator Warren. I'm looking here at the documents that say,
``A draft guidance for describing the standard for
interchangeable biosimilars is not out.''
Dr. Woodcock. That's correct.
Senator Warren. We've got to have those. I get that you
want to get those. We also need a plan in place that's going to
educate physicians, that's going to educate the public because
there really will be confidence that this work.
Senator Cassidy. Senator Warren, I think we'll----
Senator Warren. I have used my time.
Senator Cassidy [continuing]. Probably have a second----
Senator Warren. The Chair has been most indulgent.
Senator Cassidy. Thank you.
Senator Warren. I will stop. Thank you, Mr. Chairman.
Senator Cassidy. Mr. Chairman.
Statement of Senator Alexander
The Chairman. Thanks, Senator Cassidy. Thanks to you and
Senator Murphy for leading this hearing. This is important and
I've enjoyed the questions. I thank Dr. Woodcock. She's got a
big job. She's done it for a long time and we appreciate her
service to the country.
I'm here mainly to listen and learn more about biosimilars.
I think that comparing the experience between generics and
biosimilars is useful to me as I try to understand this. I
think Senator Warren's questions about the marketplace are
pretty good questions and right to the point.
I have really two questions. Only two. First, is there
anything that you would like for us to do, which would make it
easier for you to do what Senator Warren was just asking about?
Is there anything that we can do to create an environment where
you're more likely to succeed in introducing biosimilars to a
robust marketplace more rapidly, safely, and so we can fulfill
the promise of them, which I know you want to do and which we
want to do?
My second question is, what are the most important guidance
documents? You've got a lot of guidance documents that you
could put out. If you were thinking about the most important
ones that need to come out next what are they and how soon do
you plan to release those?
Dr. Woodcock. For your first question we have the resource
use of this program. The resources that are available to it and
the testimony, and in appropriate dollars there's about $21
million. We're talking about savings of millions of dollars
here. This program didn't contemplate funding for large
educational campaign to the outside world.
We are really highly fully occupied on the 57 development
programs and the 27 other groups that have come and talked to
us about developing individual products plus developing the
guidances and the legal, regulatory, scientific, and policy
framework for how we're going to do this that'll stand up to
legal challenge and also the scrutiny of the scientific
community.
I agree with the committee that the most important next
guidances would be interchangeability and labeling and
finalizing our naming guidance so that people know although
that is an issue for the outside world. It's not a scientific
issue, per say. The most important thing we had to do was set
the scientific framework that's bullet proof, OK, that will
earn the trust of the community and will actually work to
provide biosimilars that are safe, and effective, and have the
same properties as an innovator. That was most important, No.
1.
Clearly we have to conduct the education and we need to get
out all of the framework, not just the fundamental building
blocks, but how do you prove interchangeability. Of course
we're talking to all of these 57 sponsors about how they will
show interchangeability, right. We're learning from that.
They're learning. What we're learning is that each of these 57
products is a little bit different. And so we are learning a
lot from this experience.
There is no doubt that those are very important that we get
out, and we will try to get them out expeditiously.
Senator Cassidy. Senator Kirk.
Statement of Senator Kirk
Senator Kirk. Thank you. I have one question. Do you
believe that further guidance is in the interest of doctors and
patients?
Dr. Woodcock. The guidance is mainly going to be directed
at industry other than the labeling and naming conventions,
obviously which will be of great interest to the healthcare
community. The scientific framework is directed toward the
industry. What do you have to do to show that your product is
first biosimilar, which we have put out a guidance on, and
interchangeable?
Senator Kirk. Let me just sign on with Senator Warren
saying that I also agree with her feelings about how quick the
Canadians and the Europeans have been. I think that the United
States should be able to keep up with those guys.
Dr. Woodcock. I will say that the Europeans had a 6-year
start on us, and some of the products they approved right away
had been approved in the United States for some time because a
number of these we did not approve as biological products. We
approved them as drugs. We were able to put basically similar
versions on the market because the drugs law has had that and
regulations have had those provisions for a long time. It
wasn't present in Europe.
Senator Kirk. Thank you, Mr. Chairman.
Senator Cassidy. We should have kept it as drugs, huh? The
what? What's that? The Chairman wishes to know how many
products are like that that got approved under the previous?
Dr. Woodcock. I'd have to get back to you. Omnitrope is a
good example growth hormone. I don't remember exactly when we
approved that. It might have been In 2004 possibly or 1905. We
don't know. We don't know offhand. We had approved that and it
was on the market already. That's an example. The growth
hormones are an example. Insulin is an example. There are a
number of others.
Senator Cassidy. Interferon.
Dr. Woodcock. Interferon was approved as a biologic. I
approved that when I was over in CDER.
Senator Cassidy. OK. Senator Hatch.
Statement of Senator Hatch
Senator Hatch. Thank you.
Welcome. I'm very pleased with what you do over there, and
I'm particularly pleased with what you're doing in this area.
Dr. Woodcock. Thank you.
Senator Hatch. Let me just ask you a couple of questions
that have bothered me. When FDA approved Phaxio they designated
the placeholder suffix that indicated the name of the company.
The draft guidance of FDA just issued on naming though provides
a random letter suffix.
Dr. Woodcock. Right.
Senator Hatch. What was the FDA's thinking that lead to
this particular change? It's just interesting to me.
Dr. Woodcock. There are a lot of tradeoffs in the naming
convention.
Senator Hatch. Yes.
Dr. Woodcock. We want to be able to know what people go, so
if there is some severe problem out there we won't have to take
every single one off the market. We can deal with the one
that's causing the problem. We want to be able to uniquely
identify them. There's concern that uniquely identifying them
may inhibit switching when interchangeability becomes a
reality. With those tradeoffs there are a lot of different
opinions about what should be done.
In the guidance that we're putting out we ask should we
have the company contraction as the suffix or should we have
the random four letter suffix. So we're asking about that.
The first one out of the box had the contraction of the
company. That one is easier to remember, obviously, but also
then it's tied to that company. If the product is sold or
transferred or--you know there are different tradeoffs involved
if you start thinking through how you do the suffix. We didn't
know the right answer, and there are a lot of different issues.
In the guidance we're also asking about interchangeables.
Should they have the same suffix as the reference drug or
should they retain their unique substance. There are tradeoffs
there too.
Senator Hatch. Is it possible for FDA to trace adverse
events and identify the source without a unique identifier in
the name?
Dr. Woodcock. Currently, no. Not in all settings. A lot of
these, as Senator Warren was talking about, are administered in
the hospital. In a hospital they don't have the NDC code that
we can track. We need a different way to be able to track them
when they're administered in settings where they're billed a
different way. We must be able to figure out which drug is
causing a problem.
Senator Hatch. Has FDA analyzed, No. 1, the extent to which
these cost of changing names is passed on to healthcare payers
and consumers? Or, No. 2, the extent to which passed through
costs will be offset by savings from biosimilar competition
created as the result of this policy?
Dr. Woodcock. We believe there will be some costs----
Senator Hatch. Yes.
Dr. Woodcock [continuing]. In it for the innovators to put
the suffix onto their drugs if that is the policy that is
arrived at the end based on our proposed rule. There is an
analysis of cost accompanying that.
Senator Hatch. OK. Given the similarity between FDA's draft
guidance and the World Health Organization's scheme on
biologics qualifiers, it would be important to consult with a
WHO in arriving at a global solution. Could you please comment
on how the agency is consulting with the WHL and on what
aspects we're consulting with them?
Dr. Woodcock. Certainly. We work with and meet with the INN
committee and the committee on naming at WHO. We have long been
a part of that. We are aware of the convention that they're
considering now. Certainly we have exchanged views with them
and have talked to them about that. I am certainly aware of the
desirability of a common global standard for how this naming is
going to proceed. However, if you look around the world you'll
see that people have been shifting over time to different
conventions.
Right now, in the EU, prescribers are required to identify
the product by the brand name because they started out with the
same name, and now they have to put the brand name and the lot
number in the chart for pharmacovigilance purposes. That would
not be a good solution in the United States. The WHO convention
they're discussing is very similar to what is proposed inter-
guidance.
Senator Hatch. Thank you. I appreciate the work you're
doing very, very much. This is an area of great interest to me
as you know. Thank you.
Senator Cassidy. Thank you, Senator Hatch.
Dr. Woodcock, I think they're calling votes or maybe
they're going into session and they'll call votes shortly. If
we can, each of us just go with a couple of more questions, if
that's OK?
Dr. Woodcock. Certainly.
Senator Cassidy. Going back to the interchangeability
aspect of it, this is a question I was asked to ask. From a
biosimilars developer's point of view, the lack of guidance on
statistical approaches to analytical similarity has been the
most problematic issue to deal with due both to the lack of
transparency on what the requirements are and the evolution of
your thinking.
Dr. Woodcock. Yes.
Senator Cassidy. It's clear from what you're saying that
thinking has evolved.
Dr. Woodcock. Yes.
Senator Cassidy. The questions are, the guidance on the
statistical approaches to analytical similarity is particularly
important as it impacts initial improvability as a biosimilar
under the 351K, when is the agency planning to issue this
specifically? And then related to that, what level of
consultation has the agency had on statistical approaches to
analytical similarity in consultation with EMA, Health Canada,
and the PMDA?
Dr. Woodcock. Certainly. This is part of the foundational
work in determining biosimilarity and the statistical
approaches to analytical similarity is the third guidance after
interchangeability and naming that we need to get out as soon
as possible.
What is this and why do we need it? As you said, the
innovator drug, the reference drug can vary from lot to lot in
its characteristics. That's a statistical matter of how much
variability there is in that reference drug. Then the
biosimilar drug can vary. We have to decide how much those
confidence limits need to overlap for us to declare them
biosimilar. This is of course a matter of analytical chemistry
and statistics.
We have really world class experts working on this. They
have consulted with the EU and we certainly are of like mind
with the EU. I think they think our approach is sound. We hope
to get that guidance out quickly.
We do not believe that rigid limits, such as we have in the
generics world for bioavailability or bioequivalence it's
called, are appropriate in this setting. This is going to be a
more flexible standard. We need to tell people how to run these
statistics and how to----
Senator Cassidy. You say quickly. Can you give a sense of
end of the year?
Dr. Woodcock. I would hope within the next 6 months.
Senator Cassidy. OK. Then related to that, a question I
realize that comes up, it's almost as if you have a suffix that
there truly is not a nonproprietary name in the most meaningful
sense of that. If I'm a physician and I write for a generic
nonproprietary name, but I'm required to put a suffix does that
mean that effectively I'm telling the pharmacist that he or she
must use that particular one as designated by the suffix? Or
the fact that I'm merely using the root, if you will, do they
allow them then to change between those with different whatever
the pool is of suffix?
Dr. Woodcock. Right. There are two tiers to this. One is
we'd have to find them interchangeable first, OK. If we found
something interchangeable then State law will govern pharmacy
substitution.
Senator Cassidy. If there's four different products with
four different suffixes then here's the innovator drug and here
is the one that is deemed interchangeable, so the pharmacist
would have to know that these two are not deemed
interchangeable. If the pharmacist wishes to change it can only
be for this one with this suffix, correct?
Dr. Woodcock. That's correct. That's the use of the purple
book. Right now for generics we use the orange book, and that's
sort of the bible because it has the ratings. Are they
interchangeable ratings because some drugs will not be rated
interchangeable. The pharmacist looks there and can determine
substitutability. We're going to have a purple book for the
biosimilars because they're going to have the same set of
issues.
Senator Cassidy. Let me quickly ask as well. There's
concern that some of the manufacturing plants in India have had
very poor standards. We've discussed this before in a previous
ENC committee hearing when I was on the other side. There's
been some kind of you rapping knuckles at FDA in regards to
recent productions not using good manufacturing practices, and
yet it doesn't seem there's been follow through on that. Since
the biologics are particularly an issue here, any thoughts on
how we're going to guarantee that those products produced in
places like India are safe?
Dr. Woodcock. Currently we think some biologic products are
filled in India, but we don't know of any that are produced
there that are actually destined for the U.S. markets as far as
the actual making of the biologic itself. The laws around and
the regulations around biological products are very stringent
as far as manufacturing because of the long checkered history
of problems that actually originated in the Public Health
Service Act.
As with any biosimilar or any biological product, wherever
it's produced, we go out and inspect all of the facilities
unless they've been very recently inspected. We send someone
from our laboratories and usually another person from the
Office of Pharmaceutical Quality to go out and participate on
those inspections. The manufacturing is very carefully
regulated.
Senator Cassidy. You told us last year in ENC though that
you had a difficult time inspecting plants in India. There was
an issue of whether or not the union contracts allowed
designation, et cetera. Is that no longer a problem?
Dr. Woodcock. We have the ORA, the field organization has
developed a foreign inspectorate and has more people whose job
it is to actually go out and inspect foreign facilities. A lot
of that has to do with the generics program and the requirement
for parody of inspection between United States and ex-United
States, which for me is a very welcomed development. We also
have an office in India. I think we're doing a very thorough
job.
The biologics are different, but they are inspected very
carefully because of the difficulties in manufacturing.
Senator Cassidy. Yes. Senator Murphy.
Senator Murphy. Thank you, Mr. Chairman.
I have a massive feeling of inferiority on this panel with
a practicing physician who knows so much about this issue and
the father of the modern generics industry around the corner.
I just have one additional question and it's back to this
issue of looking ahead to potential barriers to the utilization
of generics. We've got about 31 States that have considered
State laws around how biosimilars would be provided to patients
and they're all different, but they have some common
characteristics.
I guess my just very broad question to you is as FDA has
looked at these laws do you view them as facilitating the
biosimilar market, or in some cases are some of these laws
actually providing barriers or, you know, building in that
potential discriminatory behavior that we worry would present a
barrier?
Dr. Woodcock. There is patchwork and some of them are
facilitatory and some of them may actually cause barriers.
Senator Hatch will know we saw this at the dawn of the generic
age. There were many State laws passed that actually forbade
substitution of certain generics and so forth. We've gotten
over that, but it does take earning the trust and continuing to
maintain the trust of the clinical community about this
program--that it is scientifically sound and that their
patients are not going to suffer at all if they get a
biosimilar. They'll get the same clinical effect.
Senator Murphy. What's the interaction that FDA has with
the State legislatures that are devising these laws?
Dr. Woodcock. We've been asked for explanations of what the
programs are, but we do have an intergovernmental affairs
office that interacts with the States.
Senator Murphy. Interesting. Encourage that team to be
proactive in their approach. Thirty-one States is going to be
50 States very soon. If we get a whole rash of State laws that
erect barriers it doesn't really matter what education you do
if the law prevents the usage of these biosimilars.
Dr. Woodcock. Yes, and we're seeing that patchwork in
Europe even though they're 6 years ahead with their statutory
framework. The interchangeability is administered by the
different countries and it's quite different across Europe.
Senator Murphy. Thank you. Thank you, Mr. Chairman.
Senator Cassidy. Dr. Woodcock, I think I'm supposed to have
a script here as to what I'm supposed to say next.
The hearing record will remain open for 10 days. Members
may submit additional information for the record within that
time if they would like.
Thank you for being here.
The committee will stand adjourned.
Dr. Woodcock. Thank you.
[Additional Material follows.]
ADDITIONAL MATERIAL
Food and Drug Administration,
Silver Spring, MD 20993,
May 9, 2016.
Hon. Bill Cassidy, M.D., Acting Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, DC. 20510-6300.
Dear Mr. Chairman: Thank you for providing the Food and Drug
Administration (FDA or the Agency) with the opportunity to testify at
the September 17, 2015, hearing before the Committee on Health,
Education, Labor, and Pensions, entitled ``Biosimilars Implementation:
A Progress Report from FDA.'' This is the response for the record to
questions posed by several committee members, in a letter we received
on November 2, 2015.
Please let us know if you have any further questions.
We have restated your questions below, followed by our responses.
Sincerely,
Dayle Cristinzio,
Acting Associate Commissioner
for Legislation.
cc: The Honorable Lamar Alexander, Chairman.
______
Response by the Food and Drug Administration to Questions of Senator
Alexander, Senator Collins, Senator Kirk, Senator Hatch and Senator
Cassidy
senator alexander
Question 1a. Under current law, a new biological product can be
brought to market either by being approved as a new drug or by being
licensed as a biological product.
How, if at all, does a manufacturer's decision to use one pathway
or the other affect (1) FDA's premarket review of the product, (2) the
postmarket obligations of FDA and the manufacturer, and (3) the ability
of another manufacturer to use that product as a reference product in a
subsequent biosimilar application?
Answer 1. Although the majority of biological products have been
licensed under section 351 of the Public Health Service Act (PHS Act),
some protein products historically have been approved under section 505
of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The Biologics
Price Competition and Innovation Act of 2009 (BPCI Act) changed the
statutory authority under which certain protein products will be
regulated by amending the definition of a ``biological product'' in
section 351(i) of the PHS Act to include a ``protein (except any
chemically synthesized polypeptide).'' Section 7002(e) of the BPCI Act
requires that a marketing application for a ``biological product'' must
be submitted under section 351 of the PHS Act. This requirement is
subject to certain exceptions during a 10-year transition period ending
on March 23, 2020, which provide that an application for a biological
product may be submitted under section 505 of the FD&C Act not later
than March 23, 2020, if the biological product is in a product class
for which a biological product in such product class was approved under
section 505 of the FD&C Act not later than March 23, 2010. However, an
application for a biological product may not be submitted under section
505 of the FD&C Act if there is another biological product approved
under section 351(a) of the PHS Act that could be a ``reference
product'' if such application were submitted under section 351(k) of
the PHS Act. On March 23, 2020, an approved application for a
biological product under section 505 of the FD&C Act shall be deemed to
be a license for the biological product under section 351 of the PHS
Act (see section 7002(e)(4) of the BPCI Act).
FDA has taken measures to minimize differences in the review and
approval of products approved in Biologics License Agreements (BLAs)
under section 351 of the PHS Act and products approved in New Drug
Applications (NDAs) under section 505(b)(1) of the FD&C Act (see
section 123(f) of the Food and Drug Administration Modernization Act of
1997 (FDAMA)). FDA has been working to ensure that consistent
scientific standards are applied to ``stand-alone'' marketing
applications for biological products irrespective of whether the
application is submitted under the FD&C Act or under the PHS Act.
The BPCI Act provides that the term ``reference product'' means the
single biological product licensed under section 351(a) of the PHS Act
against which a biological product is evaluated in a 351(k) BLA. During
the 10-year ``transition period'' ending on March 23, 2020, a
biological product approved under section 505 of the FD&C Act may be a
listed drug relied upon in an application submitted under an
abbreviated approval pathway under the FD&C Act (e.g., a 505(b)(2)
application).
Question 1b. Please identify each biological product currently on
the market that has been approved as a new drug under 21 U.S.C.
355(b). Has any of these products also been licensed as a biological
product under 42 U.S.C. 262(a)? If so, which one(s)?
Answer 1b. Although the majority of biological products have been
licensed under section 351 of the PHS Act, some protein products
historically have been approved under section 505 of the FD&C Act.
These products include, for example, the following currently marketed
products: chorionic gonadotropin products, desirudin products,
follitropin products, urofollitropin products, menotropins products,
hyaluronidase products, imiglucerase products, insulin products,
insulin mix products, insulin analog products, mecasermin products,
pancrelipase products, pegademase products, pegvisomant products,
sacrosidase products, somatropin products, taliglucerase alfa products,
velaglucerase alfa products, and thyrotropin alfa products.
At this time, none of these biological products has been licensed
under section 351 of the PHS Act.
Question 1c. Does FDA currently receive applications for new
biological products under both pathways? How has the relative frequency
with which the respective pathways are used changed over time? To the
extent there have been changes, to what does FDA attribute them?
Answer 1c. FDA currently receives applications for new biological
products under section 351(a) of the PHS Act or, if the proposed
product falls within the exception described in section 7002(e)(2)-
(e)(3) of the Biologics Price Competition and Innovation Act of 2009,
under section 505 of the FD&C Act. FDA does not track the number of
applications submitted under section 505 of the FD&C Act by whether the
proposed product is a biological product, so FDA cannot address the
relative frequency with which use of the respective pathways has
changed over time for such products.
Question 1d. Please (1) identify any follow-on biological products
that have been approved as generic drugs, and (2) explain how these
products satisfied the statutory requirement that a generic drug be
identical to its reference product, given the complexity and variation
inherent in the development of follow-on biological products.
Answer 1d. FDA approved two related abbreviated new drug
applications (ANDAs) under section 505(j) of the FD&C Act for a
menotropins product in 1997. At that time, the Agency acknowledged the
isoform variation in the active ingredient, but concluded that it was
not clinically significant for the product's intended uses and
therefore did not preclude a finding of ``sameness'' for purposes of
section 505(j) of the FD&C Act. The approval was the subject of a
decision by the U.S. Court of Appeals for the D.C. Circuit, which found
that the
``FDA's determination of what is required to establish
`sameness' for purposes of the Act rests on the `agency's
evaluations of scientific data within its area of expertise,'
and hence is entitled to a `high level of deference' from this
court''
(Serono Laboratories, Inc. v. Shalala, 158 F.3d 1313, at 1320 (D.C.
Cir. 1998) (internal citations omitted)).
FDA regulations implementing section 505(j) of the FD&C Act provide
that an ANDA is suitable for consideration and approval if the proposed
generic drug product is the ``same as'' the reference listed drug,
meaning, among other things, ``identical in active ingredient(s)'' (see
21 CFR 314.92(a)(l)). Because of the complexity of protein molecules
and limitations of current analytical methods, it would be difficult
for manufacturers of proposed protein products to demonstrate that the
active ingredient in their proposed product is identical to the active
ingredient in an already approved product.
Question 2a. In February 2012, FDA published a draft guidance
document in which it stated that a biosimilar's labeling ``should
include all the information necessary for a health professional to make
prescribing decisions,'' including a ``clear statement'' (1) advising
that the product is a biosimilar, and (2) explaining whether the
product has been approved as interchangeable with its reference
product. But FDA subsequently approved a biosimilar without requiring
either statement in its labeling, then deleted this requirement when it
finalized the draft guidance in April 2015. Several months later, FDA
stated in response to a question by members of this committee that
health care professionals instead can find this information in the
``Purple Book,'' FDA's published list of biological products.
Does FDA continue to believe, as it stated in its 2012 draft
guidance, that information about whether a product is a biosimilar, and
whether patients may safely switch between the biosimilar product and
its reference product, is ``necessary for a health professional to make
prescribing decisions''?
Answer 2a. Health care professionals should have product labeling
that includes the essential scientific information about the safety and
efficacy profile of a product necessary to make informed prescribing
decisions for their patients.
FDA's draft guidance on ``Scientific Considerations in
Demonstrating Biosimilarity to a Reference Product'' described a
labeling approach that would include a statement regarding
biosimilarity or interchangeability. However, FDA did not address
labeling issues in its final guidance\1\ because prior to finalizing
this guidance, FDA announced it would issue a draft guidance on
labeling for biosimilar products.
---------------------------------------------------------------------------
\1\ ``Scientific Consideration in Demonstrating Biosimilarity to a
Reference Product,'' http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM
291128.pdf.
---------------------------------------------------------------------------
On March 31, 2016, FDA issued a draft guidance entitled Labeling
for Biosimilar Products. As described in that guidance, FDA recommends
inclusion of a statement in the biosimilar product's Highlights of
Prescribing Information that the product is biosimilar to the reference
product. The draft guidance also recommends a footnote to this
statement explaining that ``Biosimilar means that the biological
product is approved based on data demonstrating that it is highly
similar to an FDA-approved biological product, known as a reference
product, and that there are no clinically meaningful differences
between the biosimilar product and the reference product.''
Question 2b. Under the Food, Drug, and Cosmetic Act, a biological
product must include ``adequate directions for use'' in its labeling.
Does FDA consider the directions for a biosimilar product to be
adequate if (1) they do not identify the product as a biosimilar, or
(2) they do not describe whether a patient may safely switch between
the biosimilar product and its reference product? Why or why not?
Answer 2b. Healthcare professionals should have product labeling
that includes the essential scientific information necessary to make
informed prescribing decisions for their patients. Healthcare
professionals are advised to review the labeling (prescribing
information) of the biosimilar product to determine the conditions of
use for which the biosimilar was approved. A biosimilar applicant may
request licensure for some or all of the same uses as its FDA-approved
reference product.
On March 31, 2016, FDA issued a draft guidance entitled Labeling
for Biosimilar Products. As described in that guidance, FDA recommends
inclusion of a statement in the biosimilar product's Highlights of
Prescribing Information that the product is biosimilar to the reference
product. The draft guidance also recommends a footnote to this
statement explaining that ``Biosimilar means that the biological
product is approved based on data demonstrating that it is highly
similar to an FDA-approved biological product, known as a reference
product, and that there are no clinically meaningful differences
between the biosimilar product and the reference product.''
Question 2c. Does the FDA consider the Purple Book to be a part of
a biological product's labeling?
Answer 2c. FDA created the ``Purple Book'' on its own initiative to
provide a convenient source of information regarding licensed
biological products with reference product exclusivity and
biosimilarity or interchangeability evaluations. Unless the Purple Book
accompanies a specific biological product, it is not considered part of
that product's labeling.
Question 2d. Are health care professionals required to consult the
Purple Book when making prescribing decisions? What information has FDA
reviewed regarding when, and to what extent, health care professionals
actually consult the Purple Book?
Answer 2d. Healthcare practitioners should have product labeling
that includes the essential scientific information necessary to make
informed prescribing decisions for their patients. Healthcare
practitioners are advised to review the product labeling (prescribing
information) to determine the conditions of use for which the product
was approved; the Purple Book is not intended to be a resource for this
information.
The BPCI Act defines an interchangeable product to mean that the
product has met the statutory standard for interchangeability and may
be substituted for the reference product (e.g., by a pharmacist)
without the intervention of the healthcare provider who prescribed the
reference product. The listing of interchangeable products under the
reference product to which interchangeability was demonstrated will
make it easier for pharmacists to consult the Purple Book for
substitution decisions.
FDA is conducting qualitative research with physicians, nurse
practitioners and pharmacists to learn more about their perspectives on
biosimilars, their trusted sources of information, and the kinds of
information that they would like to receive. Additionally, we are
developing a continuing medical education (CME) course for prescribers
about biosimilars. FDA is working to develop communication materials to
educate consumers and health care professionals. These will be posted
on the FDA biosimilar web pages and distributed to stakeholders through
email and conferences.
Question 3a. In April 2015, FDA indicated in a guidance document
that it may allow a biosimilar to be marketed to treat diseases and
conditions for which it has not been studied, if the reference product
has been approved for those indications and the biosimilar's safety and
potency for those indications can be inferred--or ``extrapolated''--
from studies for other indications.
If a product is approved for both studied indications and
extrapolated indications, does FDA intend to differentiate between the
two types of indications in the product's label? If not, how does it
intend to communicate these differences to patients and health care
providers?
Answer 3a. FDA does not intend to differentiate between indications
that were directly studied and those supported through extrapolation in
product labeling. FDA undertakes a rigorous and thorough evaluation to
ensure that a biosimilar product meets the Agency's standard for
approval. When FDA approves a biosimilar product, it has determined the
product meets the Agency's standard for approval for all indications
for which the biosimilar product is approved, including any approved
indications that were supported by extrapolation, and has been
demonstrated to have no clinically meaningful differences from the
reference product in terms of safety, purity, and potency.
FDA has issued final guidance outlining the issues that an
applicant should consider when providing a scientific justification for
extrapolating clinical data sufficient to demonstrate safety and
effectiveness in one condition of use to support a determination of
biosimilarity in one or more additional conditions of use for which
licensure is sought.
Such scientific justification for extrapolation should address, for
example, the following issues for the tested and extrapolated
conditions of use:
The mechanism(s) of action in each condition of use for
which licensure is sought; this may include:
The target/receptor(s) for each relevant activity/
function of the product;
The binding, dose/concentration response and pattern
of molecular signaling upon engagement of target/receptors;
The relationships between product structure and
target/receptor interactions;
The location and expression of the target/
receptor(s).
The pharmacokinetic and bio-distribution of the product in
different patient populations (relevant pharmacodynamic measures also
may provide important information on the mechanism of action);
The immunogenicity of the product in different patient
populations;
Differences in expected toxicities in each condition of
use and patient population (including whether expected toxicities are
related to the pharmacological activity of the product or to ``off-
target'' activities); and
Any other factor that may affect the safety or efficacy of
the product in each condition of use and patient population for which
Iicensure is sought.
Differences between tested and extrapolated conditions of use with
respect to the factors described above do not necessarily preclude
extrapolation, but differences need to be addressed. The applicant
should ensure that the totality of the evidence submitted, including
scientific justification for extrapolation, supports its approach.
To determine which indications have been approved for a biosimilar
product, health care professionals are advised to review the labeling--
prescribing information--of the biosimilar product. On March 31, FDA
issued a draft guidance on labeling for biosimilar products.
Question 3b. What postmarket surveillance will FDA require for
extrapolated indications? How, if at all, will the requirements vary by
circumstance?
Answer 3b. Robust postmarketing safety monitoring is an important
component in ensuring the safety and effectiveness of biological
products, including biosimilar products. There are many factors that
influence postmarketing safety monitoring considerations, including but
not limited to, any particular safety or effectiveness concerns
associated with the use of the reference product and other products in
the class, data on the proposed product obtained during its development
and clinical use (if marketed outside the United States), and the
specific condition(s) of use and patient population(s).
When FDA approves a biosimilar product, it has determined that the
product meets the Agency's standard for approval for all indications
for which the biosimilar product is approved, including any approved
indications that were supported by extrapolation and has been
demonstrated to have no clinically meaningful differences from the
reference product in terms of safety, purity, and potency.
Question 3c. Under what circumstances would FDA rescind approval
for an extrapolated indication? What procedural requirements and
evidentiary standards would apply?
Answer 3c. When FDA approves a biosimilar product, it has
determined that the product meets the Agency's standard for approval
for all indications for which the biosimilar product is approved,
including any approved indications that were supported by extrapolation
and has been demonstrated to have no clinically meaningful differences
from the reference product in terms of safety, purity, and potency. FDA
does not envision a difference in the procedural requirements or
evidentiary standards for withdrawing approval of a 351(k) BLA as
compared to a 351(a) BLA.
Question 4a. Please identify the requirements for manufacturing
practices and inspections that apply to manufacturers of biological
products, including biosimilars.
Does the nature or frequency of establishment inspections differ
between small molecule drugs and biological products? If so, how?
Answer 4a. The nature of small molecule drug and biologics product
inspections do not differ in approach as each inspection is conducted
in accordance with a Compliance Program, which provides instructions on
the scope and direction of the inspection.
All biological products and drug products must be manufactured in
conformance with current Good Manufacturing Practice (CGMP)
requirements as described in section 501(a)(2)(B) of the FD&C Act and
the regulations in 21 CFR parts 210 and 211. Biological products are
also subject to the applicable requirements in 21 CFR parts 600-680.
There are two main types of establishment inspections that are
performed for manufacturers of biological products: premarket (pre-
approval/pre-license) inspections; and postmarket (surveillance)
inspections. Premarket inspections are performed during the review of a
BLA or NDA or supplement, and are part of the assessment used to
determine whether to approve the application. The purpose of premarket
inspection is to assess the manufacturing process and its conformance
to CGMP requirements; data integrity; and, the readiness of the
establishment to manufacture the product. An establishment must operate
in conformance with CGMP and all other applicable standards and should
be ready to manufacture the product in a manner described in the
application before approval is granted. Postmarket inspections are
performed to determine whether inspected firms are operating in
compliance with CGMP requirements and other applicable regulations, and
if not, to document the evidence for appropriate followup actions.
Postmarket inspections may be performed as surveillance inspections, or
for a variety of other reasons, including in response to information
obtained by FDA, such as complaints or adverse events. The initiation
of a premarket inspection is associated with the submission of a BLA or
NDA or supplement. During the course of the review of the BLA or NDA or
supplement, a risk-based decision is made as to which sites need an
inspection relating to the product under review. This decision is based
on the assessment of the relative risk and complexity of the product
being manufactured as described in the application combined with the
history of inspections that have been performed by FDA at that
manufacturing facility. If an inspection is warranted, it is performed
during the review of the application.
The frequency of postmarket inspections for small molecule drug
products and biological drug products is established based on a variety
of risk factors. The Food and Drug Administration Safety and Innovation
Act (FDASIA) Section 705 requires that the frequency be based on the
known safety risks of such establishments, including the compliance
history, recalls, inherent risk of the drug, the inspection frequency
and history of the establishment, foreign government inspections, and
other criteria deemed necessary and appropriate by the Secretary.
Question 4b. Is the manufacturer of a biological product subject to
requirements that differ from those applicable to the manufacturer of a
small molecule drug?
Answer 4b. All FDA-approved drugs and biological products have met
the Agency's standard for approval and have been determined to be safe
and effective under the conditions of use described in approved product
labeling. The requirements for biological products generally are the
same as those for small molecule drug products.
However, there are some different requirements as drugs are
approved under the FD&C Act whereas biologics are licensed under the
PHS Act. Biological products are subject to the applicable requirements
in 21 CFR parts 600-680, in addition to the CGMP requirements generally
applicable to both small molecule drugs and biological products.
Question 4c. If a biological product is approved as a new drug
rather than licensed as a biological product, does it affect which
requirements apply?
Answer 4c. All biological products and drug products must be
manufactured in conformance with CGMP requirements as described in
section 50l(a)(2)(B) of the FD&C Act and the regulations described at
21 CFR parts 210 and 211. Additionally, biological products licensed
under the PHS Act must meet the applicable requirements in the PHS Act
and the regulations described in 21 CFR 600-680.
Question 4d. Are any biological products currently being imported
from India or China? Given recent concerns regarding the quality of
finished drugs and ingredients manufactured in those countries, and the
complexity of biological products relative to small molecule drugs,
what is FDA doing to ensure the safety of any biological products
imported from those countries?
Answer 4d. Our response is inclusive of any establishments that
manufacture the drug substance and drug products under licensed BLAs
and approved NDAs for biological products, and does not include
investigational products or non-application products.
Amphastar Pharmaceuticals, Incorporated, has an approved NDA for
Hyaluronidase Injection USP in which the drug substance is currently
being manufactured by Amphastar Nanjing Pharmaceuticals, Incorporated,
in Jiangsu, China. The drug substance is imported into the United
States in order to manufacture the finished product.
The other drug substance manufacturer that is approved for
Amphastar's application is Shanghai Number 1 Biochemical Pharmaceutical
Company, Limited. (SBPC) in Shanghai, China. Although the facility is
approved for that application, the Hyaluronidase drug substance from
SBPC is not currently allowed entry into the United States due to an
Import Alert that has been in effect since 2009. This Import Alert
requires Detention Without Physical Examination for all Active
Pharmaceutical Ingredients manufactured at this particular facility
because the methods and controls used in its manufacture and control of
drug products do not appear to conform to current Good Manufacturing
Practice.
There are additional establishments in China and India that have
been proposed in applications for biological products as manufacturing
facilities for drug substances and drug products. However, these
applications are pending or have otherwise not been approved or
licensed for marketing in the United States. Therefore, such products
would not be imported for the purpose of commercial distribution within
the United States at this time.
All registered drug manufacturing facilities are subject to
inspection, with inspection frequency determined on the basis of risk
to patients. FDA employs a highly trained inspectorate, which is
skilled in uncovering failures in compliance with good manufacturing
practices. Whenever FDA investigators find product quality issues that
potentially implicate drug safety and efficacy, the Agency takes
appropriate action, which could include issuing a warning letter or
import alert, or taking other enforcement action. All FDA-approved
drugs delivered to patients in the United States are subject to the
same high standards, regardless of country of origin.
Question 5. Please describe what steps FDA has taken, and plans to
take in the future, to educate patients and health care professionals
about the risks and benefits of biosimilars. What has it spent on such
education efforts to date, and what funding is necessary for future
education efforts? How will FDA's education efforts balance the need to
promote health care savings through increased use of lower cost
products against the need to ensure that patients and health care
professionals understand any relevant risks?
Answer 5. FDA has a multi-phase plan for communicating with
stakeholders about biosimilar products. The first phase of
communication is to lay a solid foundation with basic definitions and
descriptions about biosimilar products that health care professionals
and consumers can easily understand and adopt.
Concurrent with the approval of Zarxio, the first biosimilar
product in the United States, FDA updated its website to provide more
information about biosimilar products, including pages specifically for
consumer\2\ and health care professionaI\3\ audiences. The content
includes definitions of biosimilar products and interchangeable
products, information on how health care professionals can prescribe
these products, and the differences between biosimilar products and
generic drugs.
---------------------------------------------------------------------------
\2\ http://www.fda.gov/Drugs/evelopmentApprovalProcess/
HowDrugsareDevelopedand
Approved/ApprovalApplications/TherapeuticBiologicApplications/
Biosimilars/ucm241718.htm.
\3\ http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedand
Approved/ApprovalApplications/TherapeuticBiologicApplications/
Biosimilars/ucm241719.htm.
---------------------------------------------------------------------------
FDA also released a Consumer Update\4\ that outlined the basic
concepts of biosimilar products.
---------------------------------------------------------------------------
\4\ http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm.
---------------------------------------------------------------------------
FDA provided notification about the updated website and Consumer
Update to many stakeholder and health care professional organizations
and encouraged dissemination to their members and patients. FDA plans
to communicate information in various formats to consumers and health
care providers as more biosimilar products are approved and enter the
marketplace, and as FDA issues additional guidance on topics such as
labeling, naming, and interchangeability.
Moving forward, FDA will continue to implement other phases of its
biosimilars communication plan to increase health care provider and
consumer confidence in this new category of products. However,
additional resources for education and outreach would enhance these
efforts.
Question 6a. Under current law, several important responsibilities
for regulating drugs (including biological drugs) are assigned to the
U.S. Pharmacopeial Convention (USP), a nonprofit organization that
publishes an official compendium of drugs. For example, a drug must
meet the standard of identity described in the USP compendium, and
generally must print the scientific name selected by USP--called an
``established name''--on its label.
How, if at all, do USP's responsibilities and activities differ
between biological products and small molecule drugs? Does FDA believe
that USP's current role with respect to biological products is
appropriate?
Answer 6a. It is FDA's view that enforceable monographs and
chapters are not beneficial for biological products. The vast majority
of U.S. Pharmacopeial Convention (USP) monographs relate to small-
molecule chemically synthesized drugs. These products generally are not
complex and can be fully characterized using widely available
analytical tests. On the other hand, biological products are generally
diverse and complex, with a large number of attributes that are
evaluated using analytical and other technologies that develop and
advance rapidly. Tests and assays sufficient to characterize biological
products often are themselves complex, manufacturing-process-specific,
and/or patented. USP has published only a few monographs for biological
products, but the organization recently has initiated the development
of such monographs in greater numbers. Recognizing the complexity of
biological products, FDA has amended its regulations that detail
manufacturing and testing requirements to remove prescriptive standards
in favor of a more flexible approach in order to foster innovative
technologies and facilitate approval of novel biologics including
cellular and gene therapies.
FDA has significant concern that enforceable monographs for
biological products may impede or delay approval of a biological
product that meets the scientific requirements for approval, but does
not meet the related compendia standards established by USP, an
independent, non-governmental organization. For example, the BPCI Act
provides FDA with the authority to approve a biosimilar product that
has been shown to be ``highly similar'' to its reference product,
notwithstanding minor differences in clinically inactive components,
and that also meets other requirements in section 351(k) of the PHS
Act. If a proposed biosimilar product was required to comply with the
same USP drug product monograph as its reference product, it
effectively would require the applicant to demonstrate that its product
contains the ``same'' drug substance as the reference product,
evaluated using the same tests and assays, notwithstanding the
standards set forth in the statute. We anticipate that this may
complicate licensure of biosimilar (and interchangeable) products that
meet the requirements of the BPCI Act, but may not comply with the
provisions of the FD&C Act regarding USP compendia standards.
In addition, FDA has significant concern that enforceable
biological product monographs may impede or delay innovative
technologies for biological products, including improvements to
already-approved products, to the extent that those improvements do not
meet the related USP standards.
We anticipate that enforceable biological product monographs will
be an additional, unnecessary burden on regulated industry and FDA
reviewers.
Question 6b. Despite USP's statutory role in the naming of
biological drugs, FDA's recent draft guidance on naming does not
discuss USP. Has USP been consulted in the development of FDA's policy
on naming conventions? To what extent does USP agree with the current
thinking proposed in the draft guidance? To the extent USP disagrees,
what are the practical implications of any disagreement?
Answer 6b. FDA notified the USP that FDA had proposed a regulation
to designate official names and proper names for certain biological
products (see Designation of Official Names and Proper Names for
Certain Biological Products; Proposed Rule, 80 FR 52224, August 28,
2015). FDA invited USP to submit recommendations for official names,
which will have usefulness and simplicity, for the six products
included in the proposed regulation. FDA also invited USP to provide
recommendations and comments on any other aspect of the proposal that
would designate official names and proper names for these products that
would include distinguishing suffixes composed of four lowercase
letters. USP submitted comments to the public dockets established for
the proposed rule and the draft guidance. FDA will carefully consider
all comments, including comments submitted by USP, as we determine next
steps.
Question 6c. FDA's draft guidance on naming describes how to select
a biological product's ``proper name,'' which is the statutory term for
a biological product's scientific name. But a biological drug's
scientific name also is regulated as an ``established name'' under the
drug statutes, and the draft is silent about how the guidance would
apply to these ``established name'' requirements. Would a ``proper
name'' under this guidance always be the product's ``established
name,'' or are there circumstances in which a product's ``proper name''
and ``established name'' might be different?
Answer 6c. FDA believes that a biological product should have a
single nonproprietary name.
The draft guidance, Nonproprietary Naming of Biological Products,
described FDA's approach to designating the proper name of a biological
product, which is the nonproprietary name designated by FDA in the
license for a biological product licensed under the PHS Act. The
established name of a drug is described in section 502(e) of the FD&C
Act. To the extent a biological product were considered to have an
inconsistent proper name and established name, FDA would take
appropriate action to ensure that a single nonproprietary name is used
for the product.
senator collins
Question 1. Generic utilization in the United States has reached 86
percent since the enactment of the Hatch-Waxman Act in 1984, but it
took many years for utilization to reach that point. One of the keys in
increasing generic utilization was ensuring that the public, as well as
healthcare providers, had confidence in the safety and efficacy of FDA-
approved generic drugs, which can help keep rising drug costs in check.
It will be important that healthcare providers and patients have that
same confidence in the safety and efficacy of FDA-approved biosimilars.
Dr. Woodcock, you mentioned in your written testimony that
stakeholder confidence is essential to the success of the biosimilar
program. Can you elaborate on the types of public education efforts
that the FDA has and will engage in around biosimilars?
Answer 1. FDA has a multi-phase plan for communicating with
stakeholders about biosimilar products. The first phase of
communication is to lay a solid foundation with basic definitions and
descriptions about biosimilar products that health care professionals
and consumers can easily understand and adopt.
Concurrent with the Zarxio approval, FDA updated its website to
provide more information about biosimilar products, including pages
specifically for consumer\5\ and health care professional\6\ audiences.
The content includes definitions of biosimilar products and
interchangeable products, information on how health care professionals
can prescribe these products, and the differences between biosimilar
products and generic drugs.
---------------------------------------------------------------------------
\5\ http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevlopedand
Approved/ApprovalApplications/TherapeuticBiologicApplications/
Biosimilars/ucm241718.htm.
\6\ http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedand
Approved/ApprovalApplications/TherapeuticBiologicApplications/
Biosimilars/ucm241719.htm.
---------------------------------------------------------------------------
FDA also released a Consumer Update\7\ that outlined the basic
concepts of biosimilar products. FDA provided notification about the
updated website and Consumer Update to many stakeholder and health care
professional organizations and encouraged dissemination to their
members and patients. FDA plans to communicate information in various
formats to consumers as more biosimilar products are approved and enter
the marketplace, and as FDA issues additional guidance on topics such
as labeling, naming, and interchangeability.
---------------------------------------------------------------------------
\7\ http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm.
---------------------------------------------------------------------------
In addition to developing communication materials, as part of its
multi-phase plan, FDA is conducting research on prescriber's knowledge
and perceptions of biosimilar products. This research will help inform
future outreach and education efforts to both health care professionals
and consumers. Moving forward, FDA will continue to implement other
phases of its biosimilars communication plan to increase health care
provider and consumer confidence in this new category of products.
Question 2. FDA has announced that it expects to release a draft
guidance on the framework for labeling biosimilars in 2015. For both
biologics and biosimilars, healthcare professionals have mentioned the
need for access to reliable information that is directly relevant to
prescribing decisions. I understand that the FDA's earlier draft
guidance described a labeling approach that would include a statement
regarding biosimilarity or interchangeability, yet the labeling for
Zarxio does not identify it as biosimilar.
Dr. Woodcock, can you discuss how you are approaching the labeling
guidance to ensure providers have easy access to the necessary safety
information for prescribing decisions?
Answer 2. On March 31, 2016, FDA issued a draft guidance entitled
Labeling for Biosimilar Products. As described in the draft guidance,
FDA recommends that the biosimilar product labeling incorporates
relevant data and information from the FDA-approved product labeling
for the reference product, including a description of the clinical data
that supported the safety and effectiveness of an FDA-approved
biological (reference) product. The draft guidance also recommends that
biosimilar labeling should include additional data from a clinical
study of the biosimilar product only when necessary for the safe and
effective use of the product by a healthcare practitioner.
Additionally, the draft guidance recommends a ``biosimilarity
statement'' be added to the beginning of the Highlights section of drug
labeling that describes the relationship of the biosimilar product to
the reference product.
Question 3. In addition to the regulatory approval requirements
necessary for manufacturers to invest in the development of
biosimilars, another major variable is government reimbursement for
their use. In its recently proposed rule on biosimilars reimbursement,
CMS left a number of questions unanswered, questions which are closely
linked to the progress FDA is making on a number of its guidances.
How is the FDA communicating with CMS on these issues?
Answer 3. Though FDA does not have a role in Center for Medicare
and Medicaid Services (CMS) reimbursement decisions, in conjunction
with the Medicare Physician Fee Schedule for 2016 final rule, CMS and
FDA are developing an approach to use subcodes, also known as coding
modifiers, to facilitate pharmacovigilance for biosimilar products that
share a billing code. FDA currently relies on billing data that uses
CMS payment codes to conduct post-market surveillance of products.
Question 4. We have heard from stakeholders how important it
remains for FDA to resolve unsettled questions about the biosimilar
approval pathway to ensure that patients have access to safe and
effective biosimilars. FDA noted in its response to the April letter
signed by several HELP Committee members, that the Agency cannot
provide a specific timeline for the release of any guidance.
Now that the draft guidance on naming has been released, do you
have an update for the committee for when we can expect the additional
guidances--on interchangeability, extrapolation, and labeling--to be
released for comment? When can we expect them to be finalized?
Answer 4. FDA has published the following final guidances:
Scientific Considerations in Demonstrating Biosimilarity
to a Reference Product.
Quality Considerations in Demonstrating Biosimilarity of a
Therapeutic Protein Product to a Reference Product.
Biosimilars: Questions and Answers Regarding
Implementation of the Biologics Price Competition and Innovation Act of
2009.
Formal Meetings Between the FDA and Biosimilar Biological
Product Sponsors or Applicants.
FDA has also published the following draft guidances since 2012:
Clinical Pharmacology Data to Support a Demonstration of
Biosimilarity to a Reference Product.
Reference Product Exclusivity for Biological Products
Filed Under Section 351 (a) of the PHS Act.
Biosimilars: Additional Questions and Answers Regarding
Implementation of the Biologics Price Competition and Innovation Act of
2009.
Nonproprietary Naming for Biological Products.
Labeling for Biosimilar Products.
The Agency is committed to carefully reviewing the comments
received as we move forward in finalizing the draft guidances noted
above.
Upcoming guidances are expected to include:
Considerations in Demonstrating Interchangeability to a
Reference Product.
Statistical Approaches to Evaluation of Analytical
Similarity Data to Support a Demonstration of Biosimilarity.
FDA is diligently working to issue guidance on issues that have
been identified by FDA and stakeholders as key topics of interest.
While the Agency cannot provide a specific timeline for the release of
any guidance, we continue to provide guidance and information to assist
biological product developers--sponsors/companies--with bringing
biosimilar and interchangeable products to market. FDA is continuing to
clarify its approach to implementation of the BPCI Act so that sponsors
know the Agency's expectations.
senator kirk
Question 1. Dr. Woodcock, does the FDA believe that it would be in
the best interest of the Biosimilar pathway if the BPCIA's patent
dispute provisions were interpreted as mandatory, as opposed to an
optional dispute procedure that a biosimilar may choose to follow?
Answer 1. Section 351(l) of the PHS Act describes procedures for
information exchanges and the resolution of certain patent disputes
between a biosimilar applicant and the reference product sponsor. These
procedures are parallel to, but separate from, the FDA review process.
The BPCI Act generally does not describe any FDA involvement in
monitoring or enforcing the patent information exchange described in
section 351(l) of the PHS Act and does not direct FDA to provide
guidance on section 351(l) of the PHS Act.
senator hatch
Question 1. In contrast to generics, biosimilars are large, complex
molecules that are not the ``same'', but are rather ``similar'' to
their purported reference products. To ensure patient safety and
pharmacovigilance, biologic products must be clearly identified through
distinguishable nonproprietary naming. I note that World Health
Organization experts, taking a similar view, are considering the
adoption of a ``biological qualifier'' that could be used in
conjunction with the International Nonproprietary Name (INN) to
accomplish this function. There is clear value in ensuring consistency
internationally in order to avoid proliferation of different systems
and to enhance traceability. Moreover, it appears that the WHO proposal
is aligned with the draft FDA Naming Guidance in that the INN would
correspond to the ``core name'' while the biological qualifier (BQ)
would correspond to the FDA's proposed ``suffix''.
What is the Administration doing to engage the relevant World
Health Organization bodies to ensure adoption of distinguishable naming
for biologics through a BQ as soon as possible?
Answer 1. FDA is an active participant and leader within global
regulatory organizations, including engaging with the World Health
Organization (WHO). We attend WHO's meetings and scientific
conferences, including the International Pharmaceutical Regulators
Forum (IPRF) convened by WHO's Biosimilar Working Group. The purpose of
the IPRF Biosimilars Working Group is to discuss issues and challenges
associated with regulation of biosimilars in the member countries and
promote scientific alignment where possible. FDA also has
representation on the INN Programme, which convenes at several points
throughout the year to discuss and decide on various nonproprietary
naming matters for drug and biological products, including the BQ
proposal.
The draft guidance on Nonproprietary Naming of Biological Products
proposes that originator biological products and biosimilar products
have nonproprietary names (also called proper names) that share a core
drug substance name and, in order to better identify each product, an
FDA-designated suffix that is attached to the core name with a hyphen.
This distinguishing suffix would be composed of four lowercase letters
and devoid of meaning. The core name together with the suffix would be
the nonproprietary name designated by FDA for the biological product
(i.e., the proper name).
In contrast, in the WHO BQ proposal, the BQ would not be attached
to, or considered part, of the international nonproprietary name (INN).
In addition, the latest WHO BQ proposal states that the format would be
four random consonants in 2 two-letter blocks (example, bxsh) with an
optional two-digit checksum (08). Examples would be bxsh; bxsh08,
bx08sh. The WHO proposal is voluntary; it would be up to the individual
national regulatory authorities on whether and how to implement the BQ
proposal.
In the Federal Register notice announcing the availability of the
draft guidance, FDA requested comment on how biological qualifiers
generated by WHO should be considered in the determination of FDA-
designated proper names for the biological products within the scope of
the guidance if WHO adopts a Biological Qualifier proposal. FDA is
carefully considering all comments that have been submitted to the
public docket.
Question 2. What is the Administration doing to ensure that the BQ
or other distinguishable naming paradigm that may be adopted by WHO
would be consistent with and implemented through the proposed Naming
Guidance?
Answer 2. FDA is working closely with WHO to understand the
technical aspects of its proposed naming policy. There are similarities
and differences between FDA's proposed naming convention and the WHO
proposal to assign a four-letter BQ to each biological substance to
complement its INN.
In the Federal Register notice announcing the availability of the
draft guidance, FDA requested comment on how biological qualifiers
generated by WHO should be considered in the determination of FDA-
designated proper names for the biological products within the scope of
the guidance if WHO adopts a Biological Qualifier proposal. FDA will
carefully consider all comments that have been submitted to the public
docket.
senator cassidy
Question 1. Is it possible that FDA might approve an
interchangeable product without first issuing guidance on
interchangeability?
Answer 1. While guidances are an important tool for industry, FDA
does not need guidances to make decisions on applications for
biosimilar products or interchangeable products. The BPCI Act provides
that FDA may issue guidance on the licensure of biosimilar products and
interchangeable products and expressly states that there is no
requirement to issue such guidance before reviewing or taking an action
on an application for a biosimilar product or an interchangeable
product. FDA makes decisions based on relevant law and scientific
evidence. If an applicant submits the data to support an approval,
then, consistent with the BPCI Act, FDA can make a decision regardless
of whether the Agency has issued guidance.
Question 2. Is there anything Congress can do to help FDA speed up
issuing the guidance?
Answer 2. FDA is diligently working to issue guidance on issues
that have been identified by FDA and stakeholders as key topics of
interest, including interchangeability.
Question 3. We hear a lot of concern about consistency, or lack of
consistency, across review divisions. This seems especially important
regarding the willingness and ability of reviewers in different
divisions to embrace the use of 21st century drug development tools--
such as biomarkers and patient-reported outcomes, innovative clinical
trial designs, and new statistical approaches. What are you doing to
try to ensure that application sponsors can reliably get consistent
advice and approaches when they bring new and creative drug development
ideas to FDA, regardless of the review division with which they are
working?
Answer 3. In the area of biosimilar and interchangeable product
development, FDA formed a working group to plan and develop the
Agency's approach to implementing the statute in order to ensure that
the process of evaluation, review, and approval of products within this
newly defined product category will be achieved in a consistent,
efficient and scientifically sound manner. The Biosimilar
Implementation Committee (BIC) is a cross-center group with
representation from the Center for Drug Evaluation and Research (CDER)
and the Center for Biologics Evaluation and Research (CBER), and also
has members from the Office of Chief Counsel and the Office of the
Commissioner. In addition, FDA formed two review committees; the CDER
Biosimilar Review Committee and the CBER Biosimilar Review Committee.
Both groups have members from both CDER and CBER and address product-
specific review and issues relating to scientific methodology. In
addition, the Therapeutic Biologics and Biosimilars Staff (TBBS) in the
Office of New Drugs, CDER, is responsible for ensuring consistency in
the scientific and regulatory approach reflected in recommendations to
sponsors regarding proposed biosimilar development programs.
Question 4. The complexity and uniqueness of each biologic medicine
require that FDA ensure that all biologics and biosimilars are
thoroughly tested and meet the highest patient safety and manufacturing
quality standards. Given the complex manufacturing process when even
slight changes can cause major problems, what resources does FDA have
designated to inspect biosimilar manufacturing facilities? Are FDA
inspectors receiving additional, specialized training to inspect these
facilities? Are there any specific differences in FDA protocol for the
inspection of a biosimilar manufacturer versus a reference biologic
manufacturer? A recent report in the Economic Times indicated that
Indian maker of the Ramuzab an injectable biosimilar for macular
degeneration produced and approved for use in India had curtailed
distribution after a number of adverse events associated with that drug
had been reported. In addition, media reports that some manufacturers
in India that have had serious quality control problems identified in
their manufacturing of much simpler generic drugs are planning to
produce biosimilars. How many FDA inspectors are there in India who
have expertise in reviewing biologics and/or biosimilars manufacturing
facilities? Is this adequate to assure patient safety?
Answer 4. Currently, there are no differences in the protocol for
the inspection of a biosimilar manufacturer versus a reference
biological product manufacturer, as both inspections are conducted in
accordance with a Compliance Program, which provides instructions on
the scope and direction of the inspection.
FDA does place a high level of importance on ensuring that only
high quality reference biological and biosimilar products are approved
for marketing in the United States. Both the manufacturing process and
the facility are critical to ensure that level of product quality. FDA
has the resources to inspect biosimilar manufacturing facilities. We
select individuals that are highly knowledgeable regarding the
manufacturing of biological products to perform reviews of applications
and premarket inspections of manufacturing facilities. By performing
both roles, these individuals further enhance their knowledge of
manufacturing of reference biological and biosimilar products. We have
specialized training on biologics manufacturing for individuals who
perform inspections of biologics manufacturers. Additionally, the more
experienced investigators train less experienced investigators during
the course of inspections. An experienced investigator always leads the
inspection of biological products. This training and mentoring exists
for both reference biological product manufacturers and biosimilar
manufacturers. For postmarket inspections of biological product
manufacturers, investigators with specialized training in biologics
manufacturing are selected for assignments. Thus, there is assurance
that investigators who perform these inspections are well-trained and
qualified.
Please be aware that premarket inspections of biological products
are led by individuals in either CDER or CBER, who are located in
Silver Spring, MD. These individuals travel to the location of the
manufacturing facility to perform the inspection, regardless of where
such facility is located (which would include India and China). The
Center inspection team invites the Office of Regulatory Affairs (ORA)
and the Office of International Programs (including the China and India
Offices) to participate in any overseas inspections that will be
performed. These premarket inspections are performed for any BLA that
is submitted to FDA. We believe that FDA's inspection resources are
adequate to assure patient safety.
FDA has two investigators based in-country to perform food and drug
inspections in India. However, as mentioned above, FDA does not depend
only on its own investigators based in-country. In addition, often with
FDA India Office detailees from ORA with biologics expertise who are
there for a few months, FDA ORA personnel with specific biologics
expertise travel to India for specific surveillance or other biologics
inspection assignments, sometimes with experts from the Centers.
Question 5. I understand that FDA still has not provided details on
the specifics of interchangeable products; but can you tell me broadly
in your mind what an interchangeable looks like?
Answer 5. The BPCI Act defines interchangeability to mean that the
biological product has been shown to meet the statutory standards for
interchangeability and may be substituted for the reference product
without the intervention of the health care provider who prescribed the
reference product.
The BPCI Act provides that FDA shall determine a proposed
biological product to be interchangeable with the reference product if
FDA determines that the information submitted in the application is
sufficient to show that: (1) the biological product is biosimilar to
the FDA-approved reference product, (2) the biological product can be
expected to produce the same clinical result as the reference product
in any given patient, and (3) for a biological product that is
administered more than once to an individual, the risk in terms of
safety or diminished efficacy of alternating or switching between use
of the product and the reference product is not greater than the risk
of using the reference product without such alternation or switch.
Question 6. Can the agency comment on whether the concept of
finger-print like similarity at the analytical level is linked to
interchangeability requirements?
Answer 6. FDA intends to address in guidance how comparative
structural and functional characterization may contribute to the body
of data and information necessary to support a demonstration of
interchangeability.
Question 7. The agency has mentioned plans to issue
interchangeability guidance before the end of the year. Is this still
on track and can you talk to some of the challenges around what seems
to be a very scientifically complex determination.
Answer 7. FDA is diligently working to issue guidance on issues
that have been identified by FDA and stakeholders as key topics of
interest, including interchangeability. FDA anticipates issuing the
biosimilar guidances listed in our guidance agenda, including guidance
on demonstrating interchangeability, within the next 12 months. While
these are our best estimates, they are subject to change and factors
such as workload and a shift in priorities could influence these
estimates.
Question 8. FDA has yet to release guidance on what evidence
companies will be required to present to the Agency to prove they have
met the requirements to receive an interchangeable designation for
biosimilars. At the same time, companies are making significant
advancements in how to analyze biologics with increasing precision,
potentially reducing the necessity for expensive clinical trials. As
the agency develops that guidance, will you leave room for future
advancements in analytical technologies so that these products can be
brought to market faster without unnecessary trials?
Answer 8. FDA intends to exercise appropriate scientific judgment
in determining the data and information necessary to meet the statutory
standard for interchangeability and approval by the Agency.
Question 9. Does FDA believe that biosimilars have the potential to
be different enough from the reference product to require a different
label?
Answer 9. The labeling of a product that meets the statutory
standard for biosimilarity may potentially differ from the labeling of
the reference product for a variety of reasons. For example, there may
be differences between the biosimilar product labeling and the
reference product labeling due to differences in the applicability of
certain labeling format and content requirements. One such example is
that biological products approved since June 30, 2001, must have
labeling that follows the Physician's Labeling Rule (PLR) format; thus,
all biosimilar products but not necessarily all reference products will
have labeling in PLR format. There also may be product-specific
labeling differences that are necessary to inform the safe and
effective use of the product but do not preclude a determination of
biosimilarity.
Question 10. As you know, many have serious concerns regarding the
naming of biosimilars to provide transparency and ensure patient
safety. Given recent efforts by the FDA to protect patient safety by
issuing import alerts and the blacklisting of some manufacturers, has
the FDA considered any labeling requirements to disclose the
manufacturer and country of the origin of biosimilars?
Answer 10. Under current FDA regulations, all biological products
licensed under the PHS Act (including biosimilar products) are required
to include the name, address, and license number of the manufacturer on
the package label and container label. The license holder is the
manufacturer that assumes responsibility for the safety, purity, and
potency of the biological product, and compliance with applicable
product and establishment standards (including compliance by any
contract manufacturers). Contract facilities for biological products
also are subject to FDA inspection and must register with FDA in
accordance with FDA's drug registration and listing provisions.
Regulations enforced by U.S. Customs and Borders Protection
generally require that articles of foreign origin (or their containers)
are marked with their country of origin at the time of importation into
the U.S. Manufacturers seeking to comply with U.S. Customs requirements
may include this information on product or carton labeling if their
product does not fall within an exception, but this U.S. Customs
requirement does not supersede FDA's requirement to list the name,
address, and license number of the manufacturer on the package label
and container label.
Question 11. I appreciate the agencies focus on assimilating the
purple book, but some have suggested that physicians and pharmacists
will continue to utilize the product labeling as they have been
accustomed to do. Do you think that the purple book is sufficient for
providing the necessary safety information to providers? What is the
harm in providing more information to providers about the
characteristics of the product on the label?
Answer 11. Healthcare practitioners should have product labeling
that includes the essential scientific information necessary to make
informed prescribing decisions for their patients. The Purple Book is
not intended to be a resource for this information. FDA created the
``Purple Book'' on its own initiative to provide a convenient source of
information regarding licensed biological products with reference
product exclusivity, or biosimilarity or interchangeability
evaluations.
On March 31, 2016, FDA issued a draft guidance entitled Labeling
for Biosimilar Products. As described in that guidance, FDA recommends
that biosimilar product labeling incorporate relevant data and
information from the reference product labeling, with appropriate
product-specific modifications. The guidance further recommends
inclusion of a statement in the biosimilar product's Highlights of
Prescribing Information that the product is biosimilar to the reference
product.
To determine which indications have been approved for a biosimilar
product, health care professionals are advised to review the labeling--
prescribing information--of the biosimilar product.
Question 12. In 2012, FDA issued a Draft Guidance\8\ stating that
the labeling of a proposed biosimilar product should clearly state that
the product is approved as a biosimilar for a given indication, and
whether the product has been determined to be interchangeable. In the
Final Guidance issued in April, the Agency removed these statements.
Can you please comment on why the Agency removed these statements from
the Final Guidance? Does the Agency disagree with physicians that
believe these two pieces of information to be material to prescribers?
---------------------------------------------------------------------------
\8\ Scientific Considerations in Demonstrating Biosimilarity to a
Reference Product, http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM
291128.pdf.
---------------------------------------------------------------------------
Answer 12. Health care professionals should have product labeling
that includes the essential scientific information about the safety and
efficacy profile of a product necessary to make informed prescribing
decisions for their patients. FDA's draft guidance on ``Scientific
Considerations in Demonstrating Biosimilarity to a Reference Product''
described a labeling approach that would include a statement regarding
biosimilarity or interchangeability. However, FDA did not address
labeling issues in its final guidance\9\ because prior to finalizing
this guidance, FDA announced that it expected to issue a draft guidance
on labeling for biosimilar products.
---------------------------------------------------------------------------
\9\ ``Scientific Consideration in Demonstrating Biosimilarity to a
Reference Product,'' http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatorylnformation/Guidances/UCM
291128.pdf.
---------------------------------------------------------------------------
On March 31, 2016, FDA issued a draft guidance entitled Labeling
for Biosimilar Products. As described in that guidance, FDA recommends
inclusion of a statement in the biosimilar product's Highlights of
Prescribing Information that the product is biosimilar to the reference
product. The draft guidance also recommends a footnote to this
statement explaining that,
``Biosimilar means that the biological product is approved
based on data demonstrating that it is highly similar to an
FDA-approved biological product, known as a reference product,
and that there are no clinically meaningful differences between
the biosimilar product and the reference product.''
Question 13. The complexity and uniqueness of each biologic
medicine require that FDA ensure that all biologics and biosimilars are
thoroughly tested and meet the highest safety standards. If a child is
to be given a biosimilar drug for pediatric arthritis, or pediatric
inflammatory bowel disease, shouldn't their parent have the peace of
mind of knowing that that biosimilar has undergone clinical testing for
those specific conditions?
Answer 13. Approval of a biosimilar product is based on review of
evidence that may include structural and functional characterization,
animal study data, human pharmacokinetic and pharmacodynamics data,
clinical immunogenicity data, and other clinical safety and
effectiveness data that demonstrates that the product is highly similar
to the reference product notwithstanding minor differences in
clinically inactive components and that there are no clinically
meaningful differences between the biosimilar product and the reference
product in terms of safety, purity, and potency. FDA intends to use a
totality-of-the-evidence approach to evaluate all available data and
information submitted in support of a determination of biosimilarity of
the proposed product. The type and amount of analyses and testing that
will be sufficient to demonstrate biosimilarity will be determined on a
product-specific basis.
Question 14. FDA recently released its proposed guidance on the
non-proprietary naming of biosimilars. In it you specifically noted
that you were not addressing future interchangeable biosimilars at this
time, and asked for feedback on how to approach those products. Just a
few months earlier in July, however, CMS proposed reimbursement
policies for biosimilars entering the market without making such a
distinction about interchangeable biosimilars. Is FDA communicating
with CMS on where the regulatory pathway is on interchangeables? Do you
think CMS should be addressing reimbursement for interchangeable
products before your agency has developed the approval pathway?
Answer 14. Though FDA does not have a role in CMS coding decisions,
in conjunction with the final rule on the Medicare Physician Fee
Schedule for 2016, CMS and FDA are developing an approach to use
subcodes, also known as coding modifiers, to facilitate
pharmacovigilance for biosimilar products that share a billing code.
FDA currently relies on billing data that uses CMS payment codes to
conduct post-market surveillance of products.
Question 15. In addition to the regulatory approval requirements
necessary for manufacturers to invest in the development of
biosimilars, the other major variable is government reimbursement for
biosimilars. In its recently proposed rule on biosimilars
reimbursement, CMS left a number of questions unanswered, questions
which are closely linked to the progress FDA is making on a number of
its guidances. Is FDA communicating with CMS on these issues?
Answer 15. As stated above, FDA does not have a role in CMS
reimbursement decisions. We are working together on pharmacovigilance.
Question 16. Under Section 7002(e)(2) of the Biological Price and
Innovation Competition Act, biological products that have been approved
under an NDA under Section 505 of the Federal Food, Drug, and Cosmetic
Act will be transitioned into a BLA under Section 351 of the Public
Health Service Act by March 23, 2020. How does the FDA plan to address
implementation of these transition provisions?
Answer 16. The BPCI Act changed the statutory authority under which
certain protein products will be regulated by amending the definition
of a ``biological product'' in section 351(i) of the PHS Act to include
a ``protein (except any chemically synthesized polypeptide).'' The BPCI
Act requires that a marketing application for a ``biological product''
must be submitted under section 351 of the PHS Act; this requirement is
subject to certain exceptions during a 10-year transition period ending
on March 23, 2020 (see section 7002(e)(1)-(3) and (e)(5) of the BPCI
Act). On March 23, 2020, an approved application for a biological
product under section 505 of the FD&C Act shall be deemed to be a
license for the biological product under section 351 of the PHS Act
(see section 7002(e)(4) of the BPCI Act). On March 11, 2016, FDA issued
a draft guidance document on ``Implementation of the ``Deemed to be a
License'' Provision of the Biologics Price Competition and Innovation
Act of 2009.''
Question 17. What is the FDA's stance on using post marketing data
from countries like India for approval of biosimilars in the United
States?
Answer 17. In order for a product to be licensed as a biosimilar in
the United States, the data and information submitted to FDA must
demonstrate that the proposed product is biosimilar to a U.S.-licensed
reference product. If the product proposed for licensure in the United
States is already approved outside the United States, postmarket data
may be submitted to provide additional data to support the safety of
the proposed biosimilar product. The relevance of the data would be
considered during the review of the marketing application. However,
postmarket data alone cannot provide adequate information to
demonstrate that the proposed product is biosimilar to the U.S.-
licensed reference product.
Information derived from postmarket data could provide some
reassurance about adverse events. However, the quality of the
information is highly dependent on the accuracy and reliability of the
data collected.
Question 18. The BPCIA includes a series of disclosure and patent
exchange provisions that are often referred to collectively as the
``patent dance.'' The goal of the patent dance is to compel the branded
company and biosimilar applicant to identify only those patents that
are relevant for purposes of litigation. However, in July, the Court of
Appeals for the Federal Circuit ruled that the patent dance is
optional.
FDA's Orange Book, which covers small molecule drugs, includes a
listing of all relevant patents, while the Purple Book, which covers
biologics, does not.
Does the FDA have the authority, on its own accord, to require that
sponsors list all of the patents covering their biological products in
the Purple Book?
Answer 18. The ``Orange Book'' is the ``list'' required by section
505(j)(7) of the Federal Food, Drug, and Cosmetic Act, but no similar
statutory requirement appears in the BPCI Act. FDA created the ``Purple
Book'' to provide a convenient source of information regarding licensed
biological products with reference product exclusivity and
biosimilarity or interchangeability evaluations.
Section 351(l) of the PHS Act describes procedures for information
exchanges and the resolution of certain patent disputes between a
biosimilar applicant and the reference product sponsor. These
procedures are parallel to, but separate from, the FDA review process.
The BPCI Act generally does not describe any FDA involvement in
monitoring or enforcing the patent information exchange described in
section 351(l) of the PHS Act, and does not require FDA to publish any
patent-related information other than the notice of a complaint served
to a 351(k) applicant in an action for patent infringement under
section 351(l) of the PHS Act (see section 351(l)(6)(C)(ii) of the PHS
Act).
Question 19. I understand that FDA does not involve itself in
disputes involving pharmaceutical patents; however, is there any reason
why FDA would oppose the mere listing of patents in the Purple Book?
Answer 19. The Biologics Price Competition and Innovation Act of
2009 generally does not describe any FDA involvement in monitoring or
enforcing the patent information exchange described in section 351(l)
of the Public Health Service Act (PHS Act), and does not require FDA to
publish any patent-related information other than the notice of a
complaint served to a 351(k) applicant in an action for patent
infringement under section 351(l) of the PHS Act (see section
351(l)(6)(C)(ii) of the PHS Act).
We note that even FDA's ministerial role in administering the
patent listing provisions of the Hatch-Waxman Amendments and ensuring
compliance with the patent certification requirements of the FD&C Act
has been subject to challenge, and has embroiled the Agency in
litigation. Any similar involvement in the context of the PHS Act could
be expected to be resource-intensive for FDA.
Question 20. Is the FDA concerned about the threat of improperly
listed patents? As part of the Medicare Modernization Act of 2003,
Congress gave generic applicants the ability to challenge the listing
of a patent in the Orange Book by filing a counterclaim against the
branded company in response to an infringement suit. [FFDCA
505(c)(3)(D)(ii)((I)]. Would FDA have any issues with Congress
implementing a similar approach with respect to the Purple Book?
Answer 20. Section 351(l) of the PHS Act describes procedures for
information exchanges and the resolution of certain patent disputes
between a biosimilar applicant and the reference product sponsor. These
procedures are parallel to, but separate from, the FDA review process,
and differ from the patent listing and patent certification
requirements of the FD&C Act. The BPCI Act generally does not describe
any FDA involvement in monitoring or enforcing the patent information
exchange described in section 351(l) of the PHS Act, and does not
require FDA to publish any patent-related information other than the
notice of a complaint served to a 351(k) applicant in an action for
patent infringement under section 351(l) of the PHS Act (see section
351(l)(6)(C)(ii) of the PHS Act).
We note that even FDA's ministerial role in administering the
patent listing provisions of the Hatch Waxman Amendments and ensuring
compliance with the patent certification requirements of the FD&C Act
has been subject to challenge, and has embroiled the Agency in
litigation. Any similar involvement in the context of the PHS Act could
be expected to be resource-intensive for FDA.
The statutory counterclaim provision in the FD&C Act has been
considered by the U.S. Supreme Court in Caraco Pharm. Labs. v. Novo
Nordisk A/S (2012). Justice Sotomayor noted in a concurring opinion:
``The counterclaim cannot restore the smooth working of a
statutory scheme thrown off kilter by an overly broad use code.
At best, it permits the generic manufacturer to do what the
scheme contemplates it should do--file an ANDA with a section
viii statement--but only after expensive and time-consuming
litigation.''
132 S.Ct. 1670 at 1689.
[Whereupon, at 10:59 a.m., the hearing was adjourned.]
[all]