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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 

( 

Available via the World Wide Web: http://www.gpo.gov/fdsys/ 

COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS 

LAMAR ALEXANDER, Tennessee, Chairman 

MICHAEL B. ENZI, Wyoming 

RICHARD BURR, North Carolina 

JOHNNY ISAKSON, Georgia 

RAND PAUL, Kentucky 

SUSAN M. COLLINS, Maine 

LISA MURKOWSKI, Alaska 

MARK KIRK, Illinois 

TIM SCOTT, South Carolina 

ORRIN G. HATCH, Utah 

PAT ROBERTS, Kansas 

BILL CASSIDY, M.D., Louisiana 

PATTY MURRAY, Washington 

BARBARA A. MIKULSKI, Maryland 

BERNARD SANDERS (I), Vermont 

ROBERT P. CASEY, JR., Pennsylvania 

AL FRANKEN, Minnesota 

MICHAEL F. BENNET, Colorado 

SHELDON WHITEHOUSE, Rhode Island 

TAMMY BALDWIN, Wisconsin 

CHRISTOPHER S. MURPHY, Connecticut 

ELIZABETH WARREN, Massachusetts 

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 

SUSAN M. COLLINS, Maine 

MARK KIRK, Illinois 

TIM SCOTT, South Carolina 

ORRIN G. HATCH, Utah 

PAT ROBERTS, Kansas 

BILL CASSIDY, M.D., Louisiana 

LISA MURKOWSKI, Alaska 

LAMAR ALEXANDER, Tennessee (ex officio) 

BERNARD SANDERS, Vermont 

BARBARA A. MIKULSKI, Maryland 

MICHAEL F. BENNETT, Colorado 

SHELDON WHITEHOUSE, Rhode Island 

TAMMY BALDWIN, Wisconsin 

CHRISTOPHER MURPHY, Connecticut 

ELIZABETH WARREN, Massachusetts 

PATTY MURRAY, Washington (ex 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) 

(1) 

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 

2 

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 

3 

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 

4 

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:] 

5 

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. 

6 

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 

7 

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. 

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. 


96258-1.eps
8 

• 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. 

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. 


96258-2.eps
9 

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 multiphase 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 


96258-3.eps
10 

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 

11 

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? 

12 

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 de ́ja`

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. 

13 

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 

14 

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. 

15 

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 

16 

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. 

17 

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 

18 

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. 

19 

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? 

20 

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. 

21 

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 ratVerDate Nov 24 2008 17:05 Oct 19, 2017 Jkt 000000 PO 00000 Frm 00025 Fmt 6633 Sfmt 6601 S:\DOCS\96258.TXT CAROL
22 

ings 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 barVerDate Nov 24 2008 17:05 Oct 19, 2017 Jkt 000000 PO 00000 Frm 00026 Fmt 6633 Sfmt 6601 S:\DOCS\96258.TXT CAROL
23 

riers 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.] 

24 

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. 

25 

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 

26 

1 ‘‘Scientific Consideration in Demonstrating Biosimilarity to a Reference Product,’’ http:// 

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 

291128.pdf. 

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 guidance1 because prior to finalizing this guidance, FDA 

announced it would issue a draft guidance on labeling for biosimilar products. 

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 prodVerDate Nov 24 2008 17:05 Oct 19, 2017 Jkt 000000 PO 00000 Frm 00030 Fmt 6633 Sfmt 6621 S:\DOCS\96258.TXT CAROL
27 

uct 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. 

28 

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 

29 

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? 

30 

2http://www.fda.gov/Drugs/evelopmentApprovalProcess/HowDrugsareDevelopedand 

Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm. 3http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand 

Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241719.htm. 4http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm. 

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 consumer2 and health care professionaI3 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. 

FDA also released a Consumer Update4 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 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. 

31 

5http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevlopedand 

Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm. 6http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand 

Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241719.htm. 

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 consumer5

and health care professional6 audiences. The content includes definitions of biosimilar products and interchangeable products, information on how health care proVerDate Nov 24 2008 17:05 Oct 19, 2017 Jkt 000000 PO 00000 Frm 00035 Fmt 6633 Sfmt 6621 S:\DOCS\96258.TXT CAROL
32 

7http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm. 

fessionals can prescribe these products, and the differences between biosimilar products and generic drugs. 

FDA also released a Consumer Update7 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. 

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. 

33 

• 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 

34 

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 

35 

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. 

36 

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 productspecific 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 

37 

8Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, http:// 

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 

291128.pdf. 9 ‘‘Scientific Consideration in Demonstrating Biosimilarity to a Reference Product,’’ http:// 

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/UCM 

291128.pdf. 

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 Guidance8 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? 

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 guidance9 because prior to finalizing this guidance, FDA announced that it expected to issue a draft guidance on labeling for biosimilar products. 

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 

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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 postmarket 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 

39 

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. 

40 

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.] 

Æ