[Senate Hearing 114-700]
[From the U.S. Government Publishing Office]





                                                        S. Hrg. 114-700

         BIOSIMILAR IMPLEMENTATION: A PROGRESS REPORT FROM FDA

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

                                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

                              ----------                              


                      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]