[Senate Hearing 114-]
[From the U.S. Government Publishing Office]
PRIORITIZING PUBLIC HEALTH: THE FDA'S ROLE IN THE GENERIC DRUG
MARKETPLACE
----------
WEDNESDAY, SEPTEMBER 21, 2016
U.S. Senate,
Subcommittee on Agriculture, Rural Development,
Food and Drug Administration and Related Agencies,
Committee on Appropriations,
Washington, DC.
The subcommittee met at 3:02 p.m. in room SD-192, Dirksen
Senate Office Building, Hon. Jerry Moran (chairman) presiding.
Present: Senators Moran, Collins, Daines, Merkley, Tester,
and Udall.
OPENING STATEMENT OF SENATOR JERRY MORAN
Senator Moran. Good afternoon, everyone. Thank you for
joining us.
Senator Merkley, the ranking member, is en route and his
proxy--at least he has described himself as Senator Merkley's
proxy--is here and we are going to begin. I will give my
opening statement and perhaps by then Senator Merkley will be
here, and then we will go to testimony. The Senator from
Montana has a scheduling issue, and we will try to get to him
very quickly.
We are pleased to have with us today--Dr. Janet Woodcock.
She is at the Food and Drug Administration's (FDA's) Center for
Drug Evaluation and Research, and that agency's mission is to
make certain that the public has access to safe and effective
drugs.
Earlier this summer, Kansans and American families
discovered that--particularly those families that had
allergies, or their children had allergies, that they were
faced with a dramatic increase in the cost of epinephrine
injectors, or EpiPens. And in my view, that raises issues for
us as appropriators for the Food and Drug Administration in
this sense.
The Food and Drug Administration does not have jurisdiction
over the cost or price of drugs. They are not a regulator in
that regard, but their role is to make certain that drugs are
effective, as well as safety. Part of that process of safety
and efficacy is bringing generics to market, and I think it
would be useful for our subcommittee to hear the developments
at FDA in regard to that process.
I think all of us have an interest in making certain that
drugs that are effective and useful are made available to
consumers across the country at prices that are affordable. And
one of the ways that I think we can address that is to make
certain that the process that FDA utilizes to bring generics to
market is working the way it should.
And so this hearing is designed for us to elicit
information from FDA, from Dr. Woodcock as to that process and
what role that we should pursue as members of the
appropriations subcommittee responsible for the Food and Drug
Administration.
Congress approved the Generic Drug User Fee Act (GDUFA) in
2012. It was designed to address the issues that I have talked
about, speeding up the process to bring generic drugs to
market. In the past 3 years under this act, the FDA has
collected $1 billion from generic drug manufacturers, which has
translated into the hiring of an additional thousand employees
at FDA and replacing, presumably, an antiquated information
technology system.
Despite that, despite the thousand employees and a new
computer system, there are more than 4,000 generic drug
applications currently awaiting approval, and the average time
it takes for FDA to approve a generic is now 47 months, nearly
4 years.
It is also my understanding that FDA is close to finalizing
its negotiations with the industry on a new round of fee and
regulatory requirements to address that backlog. And my guess
is that Dr. Woodcock cannot speak about the details of those
negotiations, but I am hoping this hearing will allow us to get
a better understanding of how FDA plans to tackle that backlog
and that extension of the waiting time, all in a process that
still provides safety and efficacy.
On a final note, doctor, I would like to take the
opportunity to acknowledge your efforts to advance the
accelerated approval process for patients who have no other
treatment options. And in this regard, I want to just mention
particularly the Duchenne muscular dystrophy issue that has
occurred at FDA, and I want to express my support for the
efforts that bring that drug to market in a timely way.
[The statement follows:]
Prepared Statement of Senator Jerry Moran
This hearing will come to order.
Good afternoon. Today's hearing will focus on the Food and Drug
Administration's role in the generic drug marketplace. I would like to
thank Dr. Janet Woodcock for being here today. I greatly appreciate
your work at the FDA's Center for Drug Evaluation and Research (CDER)
whose mission is to make certain that the public has access to safe and
effective drugs.
I would be remiss if I failed to note that, earlier this summer,
parents of children who suffer from allergies were suddenly faced with
dramatic increases for epinephrine injectors or Epipens. I have an
interest in working to ensure that drugs are available to all Americans
at affordable prices. The FDA's role in the drug approval process is
critical to expanding the pharmaceutical market and driving down costs
for consumers.
While drug pricing is not the topic of this hearing, the FDA's
responsibility to approve generic drugs in a timely fashion should be
part of the larger discussion on pharmaceuticals. And, Dr. Woodcock,
you wrote a piece on this topic recently and it is something my
colleagues may be interested in reviewing.
With regard to FDA's role in the generic drug marketplace, Congress
approved the Generic Drug User Fee Act in 2012 to speed up efforts to
bring generic drugs to the market. In the past 3 years under this act,
the FDA has collected $1 billion from generic drug manufacturers, which
has translated into hiring an additional 1,000 employees and replacing
antiquated information technology systems. However, despite this influx
of resources, there are more than 4,000 generic drug applications
currently awaiting approval, and the median time it takes for the FDA
to approve a generic is now 47 months or nearly 4 years.
It is my understanding that the FDA is close to finalizing
negotiations with industry on a new round of fees and regulatory
requirements to address the backlog.
And while Dr. Woodcock cannot speak to specifics of this
negotiation, I am hoping that this hearing will allow us to get a
better understanding on how the FDA plans to tackle the generic drug
backlog and streamline the drug approval process to increase
transparency, efficiency and predictability.
One final note: I would like to take this opportunity to
acknowledge Dr. Woodcock's efforts to advance the accelerated approval
process for patients who have no other treatment options. I know this
is an issue of critical importance to patient advocacy groups, as we
see with the recent approval of the first therapy for Duchenne muscular
dystrophy, and I want to express my support for your efforts on that
front.
I look forward to discussing these topics with our witness today.
We have a lot to cover this afternoon, so I will now turn it over to
Senator Merkley for any remarks he may wish to give.
Senator Moran. I look forward to discussing these topics
with you, and we look forward to my colleagues asking you
questions in just a moment.
Senator Tester, we can defer to Senator Merkley when he
arrives. You have a scheduling issue, and I would be glad to
yield my time to you so that you could begin the questioning.
Senator Tester. Does the doctor have a statement?
Senator Moran. Yes.
Senator Tester. Perfect.
Senator Moran. Dr. Woodcock, the floor is yours.
STATEMENT OF HON. DR. JANET WOODCOCK, M.D., DIRECTOR,
CENTER FOR DRUG EVALUATION AND RESEARCH,
FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF
HEALTH AND HUMAN SERVICES
Dr. Woodcock. Thank you, Mr. Chairman and members of the
committee, for this opportunity to testify.
As was already said, FDA has no role in setting drug
pricing, but our actions serve to enhance competition which has
been shown to decrease drug prices. For example, I would like
to go through some of the actions we do take that enhance
competition.
MARKETPLACE COMPETITION
We often approve multiple drugs in a therapeutic class.
They are separate drugs, but for example, there are a lot of
cephalosporin antibiotics out there. And so even within a class
or an anti-hypertensive of a certain class, there may be a lot
of drugs that compete in the market.
Also, we often approve different versions of a marketed
drug once patents and exclusivity have expired that are not
exact copies under our 505(b)(2) program, which is not a
generic but is part of the Hatch Waxman legislation. And these
copies also can compete with the marketed drug.
Under the generics program, multiple exact copies of a
branded drug can be approved once all exclusivity and patents
have expired. And we frequently approve several copies at once.
For example, very recently we approved eight generic Crestors
on the same day. So there is a first generic, but there might
be eight first generics and the introduction of multiple copies
into the market often can really lower the pricing of the drug.
And finally, our new biosimilars program, which was
authorized by Congress a number of years ago, introduces
competition for biologic drugs which, of course, generally are
very expensive protein drugs. And we have approved so far three
biosimilars, and we have a robust program growing in the
biosimilar area.
Now, I think in the generic space particularly, there have
been a number of misconceptions circulating about the generics
program. It is kind of easy to misunderstand the generics
program.
GENERIC APPROVAL TIME
The first one is that the program takes 47 months overall
to approve a generic application. Senator, you said that.
Senator Moran. Are you telling me I am under a
misunderstanding?
Dr. Woodcock. Well----
Senator Moran. That is fair.
Dr. Woodcock. For the really old products that were in the
backlog before the new GDUFA program started, the user fee
program started, they already are 4 years old. And so they are
not getting any younger. And as we approve them, they are going
to have very long times to market because they started before
that program even was put in place.
But starting October 1 of this year, if a company sends us
an approvable generic drug application, we will approve it in
10 months.
Part of the problem is the generic industry does not have a
high level of meeting our standards on the first try, and so
they have to go through multiple cycles.
After the Prescription Drug User Fee program was put into
place--now it has been 20 years--we have an extremely high rate
of first cycle approvals for new drugs, which are much more
complicated. So it is possible to approve drugs very rapidly if
in fact the application meets our standards.
But we cannot approve substandard generic drugs because,
first of all, those are our standards, but it would erode the
confidence of the public in the generic drug program and really
take us back to the time when generic drugs were not well
accepted by the medical community.
GENERIC APPROVAL BACKLOG
Another misconception is that a lot of first generic drugs
are moldering in this backlog that has been there for so long.
And that is really not true. There are fewer actually than 100
applications in that backlog that manufacturers have not gotten
feedback from FDA on their application.
And we had a goal of reviewing and providing deficiencies
for 90 percent of the backlog by the end of the GDUFA program.
That is not this coming October but next October. We already
exceeded that goal 15 months ahead of schedule. So 90 percent
of those backlog applications have already received
communications from FDA about what their deficiencies are. And
there is a large number. There are 1,700 applications, most of
them from this backlog, that are with the manufacturers
awaiting them returning them to the FDA with improved
information. So we have really exceeded the goal that was set
for us under the first user fee program by 15 months of dealing
with this backlog in its first iteration.
And 500 of those that are sitting with the manufacturers
have actually been there for longer than a year. And it may be
that our huge activity in getting all these questions and
applications back to the manufacturers for repair has somewhat
overwhelmed their ability to get back to us promptly.
And there is also a belief that a large number of important
generic applications are sitting untouched at the FDA, and
there are almost no applications that are not touched except
maybe ones that are recently submitted to us and are going
through the filing process.
So it is true, however, that we are not at a steady state
yet. We had built up a huge backlog, as I said in the
testimony, before the Generic Drug User Fee program started,
and we are still working our way through that in the sense that
they will return again and again until which time they meet our
standards and they can be approved. But this year alone, as you
see in the slides I left at your places, we have 1,700
applications pending industry. And this year, we approved 700.
In the program, we have approved 2,207 approvals and tentative
approvals since the GDUFA program started. So that is the
number.
PRIORITIZATION OF GENERIC APPLICATIONS
We also prioritize generic applications that may have
public health implications. Sometimes we have those that are
first generics that are sole source. In other words, there
might be only one product out there and it is a generic. So we
still prioritize the second one. And, of course, shortage of
drugs, if there is a shortage, we will prioritize generic
applications. We will move them to the front of the line, like
the express line, to try to get them through.
I would like to say I am really proud of the work our staff
has done in setting up the new generic program and the
biosimilar programs. They were very tough. They required
multiple changes, a very heavy lift. And I think we are showing
that we are getting that work done. It has really been an
enormous effort, though, on many people's part and that
continues.
I am confident we will continue to improve these programs,
and they will provide a pathway for competition in the market
that will be very robust.
I look forward to your questions.
[The statement follows:]
Prepared Statement of Janet Woodcock, M.D.
introduction
Good morning Chairman Moran, Ranking Member Merkley, 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). Thank you for the opportunity to appear today to
discuss FDA's role in executing the nation's generic drug review
program. I would also like to thank the Subcommittee for its past
investments in FDA, particularly the Human Drugs program. The funding,
most recently provided in fiscal year 2016, has helped us meet the
demands of our increasingly complex and diverse mission at home and
abroad.
FDA recognizes the critical importance that generic drugs play in
the U.S. healthcare system. At FDA, we recognize that when more than
one version of a drug, especially when a generic version of a drug is
approved, it can improve marketplace competition and help to provide
additional options for consumers. Although FDA does not have a
regulatory role in the pricing of drug products, we do play a critical
role in ensuring patients have access to beneficial medicines. With
this role in mind, and as I discuss more fully below, FDA is working
hard to support the timely, scientific and efficient development of new
generic drug products for the U.S. market.
the rise of generics
Recognizing the need to increase the availability of low cost
generic drugs, over thirty years ago, Congress enacted the Hatch-Waxman
Amendments to the Food, Drug, and Cosmetic Act (FDCA).The Hatch-Waxman
Amendments represent a great success in facilitating the widespread
availability of safe, effective and high-quality generic drugs.
According to the IMS Institute for Healthcare Informatics, generic
drugs now account for nearly nine out of ten prescriptions dispensed in
the United States and saved the U.S. health system $1.68 trillion from
2005 to 2014.
abbreviated pathways to approval
The Hatch-Waxman Amendments formally establish two abbreviated
approval pathways for drug products, while at the same time provide
incentives for the continuing development of innovative new drug
products. One of the two abbreviated approval pathways allows for the
approval of Abbreviated New Drug Applications or ANDAs. Drugs approved
under this pathway are commonly referred to as generics.
Unlike an innovator drug application, a generic drug application
does not need to independently establish the safety or effectiveness of
the drug. Instead, the generic drug has to show that it is the same as
an innovator drug in several fundamental ways, such as in active
ingredient, dosage form, route of administration, strength, and
labeling (except for certain permissible differences in labeling); that
the generic drug is absorbed and available at the site where it will
act in the body at the same rate and to the same extent as the
innovator drug (which is known as bioequivalence); and that it meets
the same high standards for drug quality and manufacturing as an
innovator product. If the ANDA meets these requirements, the generic
applicant can rely on FDA's previous finding of safety and
effectiveness of the branded innovator drug, and need not conduct its
own clinical investigations to establish safety or effectiveness.
FDA approval of an ANDA indicates that FDA considers the generic
drug to be therapeutically equivalent to the innovator drug. This means
that the Agency has concluded, among other things, that the generic and
innovator drugs can be substituted with the full expectation that the
generic drug will produce the same clinical effect and safety profile
as the innovator product when administered under the conditions
specified in the labeling. Therapeutic equivalence ratings are
published by FDA in what is commonly known as the Orange Book. Although
FDA does not itself determine when a pharmacy would substitute a
generic drug in filling a prescription, state pharmacy laws and other
regulations that determine substitutability often refer to these Orange
Book ratings.
The Hatch-Waxman Amendments also established a second abbreviated
pathway for drug applications. This pathway, commonly referred to as
the ``(b)(2) pathway,'' can be thought of as a hybrid between the
pathway for an entirely innovative product and the ANDA pathway for a
generic drug. Unlike generic drugs, products approved under the (b)(2)
pathway on approval are not presumed to be therapeutically equivalent
to the innovator drug and, if a (b)(2) applicant seeks a determination
of therapeutic equivalence, it must demonstrate this separately.
keeping up with demand
The expansion of the generic market has brought new challenges. The
last several decades have seen substantial growth in the size of the
generic industry, the number of ANDAs submitted to FDA for review, and
the number of foreign facilities making generic drugs. As a result,
FDA's generic drug program became increasingly under-resourced. Its
staffing did not keep pace with the growth of the industry.
Because the program could not keep up with its workload, a backlog
of submitted ANDAs developed and grew. It overwhelmed the FDA staff and
created unpredictability and delay for industry.
generic drug user fee program
In response to this backlog issue, Congress enacted the Generic
Drug User Fee Amendments of 2012 (GDUFA I), under which industry agreed
to pay user fees each year of the five-year program and FDA committed
to certain performance goals.
A major commitment of GDUFA I was to take a ``first action'' on 90
percent of the ``backlog'' applications, defined as pre-GDUFA
applications pending before the Agency on October 1, 2012, by the end
of fiscal year 2017. As of October 1, 2012, the backlog included 2,866
ANDAs and 1,873 prior approval supplements (PASs). A ``first action''
on an application means granting an approval or tentative approval, or,
if there are deficiencies that prevent approval, identifying those
deficiencies to the applicant in a complete response letter or in a
refusal to receive the application. As of July 1, 2016, FDA had taken
``first actions'' on 90 percent of the backlog applications, achieving
this performance goal 15 months ahead of schedule. In addition, FDA has
met or exceeded all performance goals under GDUFA I with respect to
ANDA's submitted after GDUFA had commenced.
The cumulative result of all this effort is a huge increase in the
productivity of the generics program. We ended last year at a new
monthly high of 99 approvals and tentative approvals \1\ in December.
By July, with 2 months still remaining in this fiscal year, we had
already achieved a new record of 702 approvals and tentative approvals.
---------------------------------------------------------------------------
\1\ Tentative approval applies if a generic drug product is
otherwise ready for approval before the application may otherwise be
approved because of issues related to any patents or exclusivities
accorded to the reference listed drug product. In such instances, FDA
issues a tentative approval letter to the applicant. FDA delays final
approval of the generic drug product until all patent or exclusivity
issues have been resolved. A tentative approval does not allow the
applicant to market the generic drug product.
Some of the backlog applications, mentioned above, had been pending
or in review for a long time prior to GDUFA. At this point in time, as
FDA acts on a backlogged application, the ``time to approval'' of such
application will be recorded as, at minimum, 47 months (i.e., we are
now 3 years and eleven months (47 months) into GDUFA implementation).
Applications submitted in fiscal year 2016 have a GDUFA first-
action goal date of 15 months. For fiscal year 2017, which begins in 10
days, an incoming ANDA will receive a 10 month GDUFA goal date. If the
ANDA is for a priority product--such as a first generic--its review
will be further expedited. This year, we have achieved a record number
of ANDA approvals and a record number of first cycle approvals.
how did fda achieve these results?
Deep, foundational restructuring
These successes were achieved by restructuring our organization for
generic drug review, to build a modern generic drug program. This
involved major reorganizations. We reorganized the Office of Generic
Drugs and elevated it to a ``Super-Office'' status, on par with the
Office of New Drugs. We established a new Office of Pharmaceutical
Quality to integrate the quality components of the review.
We developed an integrated informatics platform to support the
generic drug review process. This platform is a significant improvement
over our earlier fragmented, legacy systems, and has enhanced our
productivity.
We hired and trained more than 1,000 new employees, achieving our
GDUFA hiring goals well ahead of schedule.
fda creates a pathway for generics development
In addition to the work that FDA does with individual companies to
support their development of specific products, FDA also works to
create a publicly available roadmap describing what companies need to
do to bring various types of medical products to market.
FDA is continuing to develop, publish, and update guidance
documents, which are a kind of roadmap for industry sponsors,
explaining FDA's recommendations for the kind of information that
should be included in a marketing application. Guidance documents can
provide vital information to drug and device developers for a class of
products.
FDA also recognizes that for more complex products, in addition to
guidance, one-on-one advice may be needed so FDA can address technical
and regulatory questions about the pathway to market. Such meetings
occur now for both new drugs and generic drugs under development. In
addition, FDA regularly responds to specific product-development
questions from industry that FDA answers in writing to help companies
develop generic drug applications through the process known as
Controlled Correspondence. We hope to expand our ability to engage with
generic product sponsors through a reauthorization of the Generic Drug
User Fee Amendments (or GDUFA II), where complex product meetings have
been described as a key provision of the proposed program.
Further, FDA prioritizes the resources we make available to focus
on areas of high public health needs. For example, FDA's Office of
Generic Drugs (OGD) has a prioritization and expedited review policy
for certain generic drug applications. The policy is set forth in a
publicly available document called a Manual of Policy and Procedures
\2\ (MAPP), which can be found on the FDA website. Pursuant to OGD's
prioritization policy, ANDAs for drugs that have ``first filer'' status
or that otherwise are eligible to be the first generic approved are
prioritized and given expedited review.
---------------------------------------------------------------------------
\2\ http://www.fda.gov/downloads/AboutFDA/CentersOffices/
OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/
UCM407849.pdf
---------------------------------------------------------------------------
Each of these, and other efforts of FDA, help clarify our
expectations and prioritizations concerning specific products so
industry can develop and obtain approval of generic versions of branded
drugs more quickly.
While FDA is working to lay out a roadmap to support efficient
development of complex products, we cannot, and will not, allow a
substandard product to come onto the market. In addition to working to
assure the safety and efficacy of drugs, it is critical that they be
manufactured to high quality standards to assure they can be used
safely by patients when they are needed. FDA's new Office of
Pharmaceutical Quality plays a critical role in ensuring the quality of
both generic and new drugs.
fda's role in the intellectual property landscape
Although FDA can and does encourage generic drug development and
has and continues to streamline and improve its review and approval of
generic drug applications, the decisions of whether to seek approval
for a proposed generic drug and whether to market an approved generic
drug are controlled by the generic drug industry. Further, the extent
to which the approval or marketing of generic drugs is delayed because
of intellectual property rights or marketing exclusivities is largely
controlled by the innovator-drug manufacturers and others that hold
those rights.
With respect to patents, FDA has only a ``ministerial'' role. As
noted earlier, the Hatch-Waxman Amendments sought to balance two
competing goals: (1) increasing the availability of generic drugs, and
(2) increasing incentives to develop new and innovative drug products.
In addition to creating certain marketing exclusivities, the Hatch-
Waxman Amendments established a set of procedures intended to align the
generic drug approval process with an opportunity for the owners of
innovator drugs to assert certain rights for patents covering the
innovator drug before generic drug approval. While FDA plays a role in
this process, our role is very limited.
First, sponsors of innovator drugs must submit to FDA information
regarding certain patents related to their products. FDA lists these
patents in the Orange Book. In any application that seeks to rely on a
previously approved NDA, which includes (b)(2) applications and generic
drug applications, the applicant must describe whether it intends to
challenge those listed patents in court. Specifically, the applicant
may inform FDA that there are no patents listed, or that the applicant
is not seeking approval until after a patent listed in the Orange Book
expires. Alternatively, an applicant can also notify FDA that it
intends to challenge a listed patent as invalid, unenforceable or not
infringed. Where an applicant seeks to challenge a patent, the
applicant is required to submit to FDA certain information regarding
its patent challenge and any resulting patent litigation as part of its
application; but, the challenge and litigation take place between the
applicant and the patent holder(s) in the courts and outside FDA's
regulatory authority. If an applicant is challenging a patent, the law
describes when FDA can approve the application in a complex scheme,
including a potential 30-month stay of an approval if the ANDA
applicant is sued soon after making the patent challenge. In each case,
the ANDA applicant's decision regarding whether to challenge a patent,
and when applicable, the innovator sponsor's response, and the court's
decision on the patent can affect when FDA may (and may not) approve
the generic drug application.
As drug applicants often publicly acknowledge, they routinely take
the intellectual property rights of previously approved drugs into
account when making determinations regarding the design and development
of their proposed drugs. While our approval standards are the same
whether or not an applicant designs its proposed product around a
competitor's intellectual property rights, the proposed products that
FDA receives for review and consideration for approval are no doubt
impacted by patent considerations.
overview of the epinephrine auto-injector market
Epinephrine auto-injectors, with the most widely used and
recognizable product being Mylan's EpiPen, are a critically important,
and potentially life-saving, product for patients who suffer from a
severe allergic reaction called anaphylaxis. These products are
considered combination products since they consist of a drug component
(epinephrine) and a device component (auto injector). When a patient
requires the medication, seconds count, and the epinephrine auto-
injector must work every single time. To ensure this, it is critical
that both the drug, and the device that delivers the drug, perform as
designed.
At FDA, we are aware of the recent spike in the price of the
EpiPen. FDA has approved four epinephrine auto-injector products to
treat anaphylaxis; two of which are currently on the market. While
there are currently no FDA-approved generic epinephrine auto-injectors,
we stand ready to quickly review additional applications that come to
us from both generic and innovator drug companies.
Mylan's EpiPen is the market leader for epinephrine auto-injectors
in the United States, and Mylan has recently publicly announced they
also will offer an authorized generic version \3\ to be available in
the near future. Another firm, Amedra holds an approval for
Adrenaclick, which is also an epinephrine auto-injector. Currently,
while the Adrenaclick brand name product is not being marketed, Amedra
is marketing its own authorized generic version of the drug. Amedra
also previously marketed Twinject, but this product has been
discontinued. Finally, FDA also approved Auvi-Q as an epinephrine auto-
injector, although this product was voluntarily recalled from the
market in 2015 by Sanofi. We note that Auvi-Q was recently purchased by
Kaleo, though this product has not yet returned to the market. In
support of increasing the number of epinephrine auto-injector products
on the market, FDA is committed to working with both Amedra and Kaleo
to facilitate greater availability of their products.
---------------------------------------------------------------------------
\3\ An ``authorized generic" is made under the brand name's
existing new drug application using the formulation, process, and
manufacturing facilities approved for use by the brand name
manufacturer. The labeling is changed to remove the brand name or other
trade dress. An authorized generic is not synonymous with an FDA-
approved generic, the latter of which requires a separate application
and approval from that of the brand name product.
---------------------------------------------------------------------------
conclusion
Thank you for your interest in the important topic. FDA takes
seriously its role in executing the nation's generic drug program, and
we understand the importance of generic products in the U.S.
marketplace. We anticipate that our ongoing efforts to continue to
improve generic drug development will provide dividends in both
protecting the health of Americans as well as in cost savings long into
the future. We hope that our efforts, coupled with the work of other
groups that also have roles to play, will continue to ensure
medications are readily available to patients. I am happy to answer any
questions.
Senator Moran. Doctor, thank you very much.
Let me now turn to the ranking member, Senator Merkley, for
any opening statement you would like to make.
STATEMENT OF SENATOR JEFF MERKLEY
Senator Merkley. Thank you very much, Chairman Moran.
I think there is a lot of interest in this hearing and the
role of generic drugs and the role that they can play in
diminishing drug prices in America, which are a significant
factor in the overall costs of our health care system and
certainly a significant factor for families that have
deductibles, as so many working families do have.
We have had a series of cases where a drug company controls
a single product in a particular segment of the medical market,
a single drug or has a large share of the market, putting them
up for sale at vastly increased prices, very sudden, very
dramatic price increases. It seems like about every month there
is some prominent story that catches the attention of America.
The most recent of those is the EpiPen and the Mylan company,
the dramatic increase from roughly $100 to $600 for a pack of
two, despite the fact that the drug within them, I understand,
costs very little in terms of what is inside those injectors.
So as we ponder all of these cases, we are very interested
in the approval process. There are other dimensions of this as
well. Such as a challenge when companies buy up generics in
order to keep them off the market or use patent changes to try
to keep them off the market or pay generic companies to keep
them off the market, market manipulations of this kind. These
may not be things that you are able to be part of in your role
of looking at the effectiveness and reliability of drugs, but
they are part of the broader picture that is of great concern
to Americans.
So I look forward to hearing my colleagues and hearing from
you and exploring this because there is a lot of room for
improvement. Thank you.
Senator Moran. Senator Merkley, thank you very much.
I would yield my time to the Senator from Montana.
GENERIC DRUG PRICE INCREASES
Senator Tester. You are very kind, Mr. Chairman. I thank
you for the courtesy.
And you are right. This is a very, important issue. As I go
home, I hear from not only patients and friends and family, but
I hear from doctors about what is going on with
pharmaceuticals. Even though my questions do ultimately end up
applying to money, it deals really with your job, and the
ranking member talked about this briefly.
But can you tell me how a company can take a generic and
change it very, very slightly and end up to be able to go take
it back on the market and jack the price up when it is
basically the same generic it was before they modified it very,
very modestly? Talk to me about how that process works.
Dr. Woodcock. Certainly. The generics have to be copies of
a reference listed drug, in other words, a brand drug
originally.
Senator Tester. Yes.
Dr. Woodcock. And so they have to stay being copies. So
they cannot substantively modify the generic. They may make it
look different or something like that, but in our experience,
the price rises for generics or innovative products, as you
were referring to, have to do with no competition in the
market, where they may be the only game in town. Overall,
generic drug prices are going down, and have been going down.
But in these cases that you are referring to where, for some
reason, there is no competition, there may be other approved
generics, but as Senator Merkley said, their market share may
be so small or for other reasons that there is not effective
competition.
Senator Tester. Well, I will tell you I appreciate that.
And I do not have any problem with a pharmaceutical company
getting their research and development money back. I also think
that if we are funding part of that R&D, we ought to get a
break on some of that R&D money. But that aside, I think it is
important they are able to do their research.
But I have heard from many docs--not just one or two, many
docs--that say that if a patient is using a generic, the
company will pull that back, somebody pulls it back, changes it
not significantly at all, and then puts is back on the market
for 5 or 10 times the money or more.
Dr. Woodcock. What you may be referring to is the ownership
changes. So one generic company may own a product. It is then
sold so that it looks different. It has a different
manufacturer.
Senator Tester. But it is the same stuff basically.
Dr. Woodcock. It has to be under the generic laws.
Senator Tester. Is there anything we can do about that, or
is that just the way it is?
Dr. Woodcock. FDA, as I said earlier, does not regulate the
prices of drugs. We have nothing to do about that.
Senator Tester. Okay.
Dr. Woodcock. What our actions do is we try to, if there is
a sole source, we try to get more copies into the market.
BIOSIMILARS
Senator Tester. I have got a friend who was diagnosed with
child diabetes at the age of 13. He is the same age I am. He is
60. So this is 1970 when he first became a diabetic. And I
cannot remember the number because it has been over a month
ago, and my memory does not last that long. But he had told me
that insulin back in 1970 was less than $10, and now it is
significantly much, much higher than that. Has insulin changed
over the last 40 years, or is insulin insulin?
Dr. Woodcock. There are many new forms of insulin that have
been introduced, and modern diabetic care usually includes a
long-acting insulin and some short-acting insulins. There are
insulin pens that people can auto-inject so it is less painful.
So there have been different changes in technology, but some of
the basic insulins have not changed.
Senator Tester. I mean, is it just pure greed that they
would increase the prices like that?
Dr. Woodcock. Well, I cannot comment on the motives, but I
can say that Congress passed a number of years ago legislation
for biosimilars so that the biologic products--would have
additional competition.
Senator Tester. Yes.
Dr. Woodcock. Now, insulin right now is regulated as a
drug. This is complicated. But it will be regulated as a
biologic. Under the biosimilars act, it will transition over.
And therefore, the insulins will be subject to the biosimilars
copies.
Senator Tester. Well, I appreciate your testimony today. I
am going to have to get the companies in and visit with them to
find out what is going on. Like I say, I get it. You got to
recoup your cost of research and development, but man, oh, man,
I am just hearing so many stories on the street where there are
minor modifications on a drug that is really the same drug that
has been around for 45 or 50 years and is getting priced out of
the marketplace, and we are driving people into poverty in the
process. And quite frankly, that concerns me.
Thank you very much, and thank you for your courtesy, Mr.
Chairman.
Senator Moran. Thank you, Senator Tester.
EPINEPHRINE AUTO INJECTORS
There is no doubt but what the cost and price of drugs is
an important public policy issue. It has significant
consequences to Kansas families. It has significant
consequences to taxpayers as we look at Medicare costs. And I
hope our focus in this hearing will continue to be how do we
make certain that FDA is doing its job well to create
competition and opportunities for families to make other
choices and to hold down the cost, those prices of those drugs
as a result.
Let me ask a couple of questions. First of all, EpiPen in
particular is a combo. It is a combination between a device and
a drug. Are there unique circumstances that make the generic to
be more difficult in that circumstance because of the
combination?
Dr. Woodcock. Yes. The firm that markets EpiPen has patents
on the device component that go through 2025. So any firm
wishing to make a generic would have to be able to get around
those patents somehow and not infringe upon those patents or
challenge them successfully to market a copy.
Senator Moran. I think your column talks about generics for
the drug, but they are not widely used.
Dr. Woodcock. This is confusing too. There is another brand
of epinephrine auto-injector that FDA has approved. We have
approved a number of them, but they are in the first category I
talked about. They are all standalone new drug applications. So
they are not generic copies. They are each one separate. Each
of them does the same thing. It treats anaphylaxis, though.
There is something that people call an authorized generic.
It is very confusing because it is not a generic. It is when a
brand name company decides to market their product, usually
along with marketing their brand product, they take the brand
name off of the label and they make it look like a generic and
then they market that, usually at a lower price. And so some
people have the brand loyalty who stay with the brand, but then
they can also compete in the generic market with the authorized
genric version. It is the same product. They make it in the
same plants usually and everything. It just has a different
label on it.
And so the other manufacturer of the current epinephrine
auto-injector, which is not called ``EpiPen,'' it is
Adrenaclick--that one has an authorized generic, and that is
what is currently being marketed.
Senator Moran. Thank you, I think, for that clarification.
[Laughter.]
Dr. Woodcock. Sorry.
GENERIC DRUG APPROVAL BACKLOG
Senator Moran. First of all, let me ask this question. I
indicated in my opening statement about a backlog. You did a
pretty persuasive set of statements that indicate that there
really is not a backlog. And so if we were asking you what are
you going to do to solve the backlog problem, you would tell us
that the FDA is on path in the way that it should be. Is that
fair?
Dr. Woodcock. At the very back of the papers I passed out,
there is this chart, and what it shows is right now there are
2,300 abbreviated new drug applications (ANDAs), which is the
generic drug applications, in the process of FDA reviewing
them. The pre-GDUFA ones are here at the top. They were the
backlog. Now they have come back in. We are reviewing them
again, not all of them. And then each year, the goals become
shorter for us to do the first review. And as I said, next
year, 2017, it is going to be 10 months.
So to be honest and completely straightforward about this,
these are more applications than we would like to have in
process. It would be better if we had fewer applications in
process.
Dr. Woodcock. I have given authorization to our
manufacturing reviewers to hire 50 more people, temporary
people, who are going to work on trying to get this down. But
mainly this is going to be up to the manufacturers to submit to
us approvable applications, and then we will be able in a cycle
to approve them. If they still have deficiencies, then they
have to go back and it takes longer.
Senator Moran. The way, Doctor, that I understood your
testimony is that what I described as a backlog really is
applications that are pending that have been reviewed to some
extent but not yet approved, sent back to the drug manufacturer
for further actions on their part.
Dr. Woodcock. That is correct. There are about 1,700 with
the manufacturers.
Senator Moran. And are those problems with the
application--are they process in the proverbial sense? They did
not cross the T and dot the I? Or these are substantive issues,
did not provide the necessary justification for an FDA
decision?
Dr. Woodcock. We have tried to make these all substantive.
Part of the changes we made for GDUFA was that we are calling
the people all the time while reviewing their application--we
call that information requests--so that these minor issues do
not delay a decision on an application. And so we are back and
forth. We send out thousands of these information requests and
try to get the application fixed up as much as possible. But
then when we send it out as a complete response, then the
manufacturer has substantive work to do.
Senator Moran. I have a series of other questions, but let
me turn now to Senator Merkley.
EPINEPHRINE AUTO-INJECTOR PATENTS
Senator Merkley. Well, thank you very much, Mr. Chair.
You mentioned, Dr. Woodcock, that there is a competitor. I
believe the name is Adrenaclick.
Dr. Woodcock. Yes.
Senator Merkley. So that competitor also has an injectable
device.
Dr. Woodcock. Yes.
Senator Merkley. But you also mentioned that anyone who
wishes to compete has to get around the patents that EpiPen or
Mylan has. What is the difference in these two products, and
how much of a barrier are those patents? And does Adrenaclick
also have its own set of patents so the world of figuring out
how to easily inject something is now wrapped up by these two
companies?
Dr. Woodcock. Well, we actually have approved over the
years five different epinephrine auto-injectors. Three of them
are not on the market right now. I do not know what
Adrenaclick's patents might look like. We can get back to you
on that. We do not know.
[The information follows:]
Adrenaclick was approved on November 25, 2009 as a supplement to
the Twinject NDA. The manufacturer of Adrenaclick has chosen to market
Adrenaclick without a trade name, i.e., as an `authorized generic' for
Adrenaclick. An ``authorized generic'' is made under the brand name's
existing NDA using the formulation, process, and manufacturing
facilities approved for use by the brand name manufacturer. The
labeling is changed to remove the brand name or other trade dress.
The Orange Book does not currently list any patents for
Adrenaclick.
Dr. Woodcock. But that does not mean copies cannot be made.
It simply means that because of the intellectual property
rights, that they would either have to be challenged or an
auto-injector would have to be made that performed similarly
but did not use the technology.
Senator Merkley. Precisely. But it sounds like you are
saying there have been five different approaches that have all
been approved at different points in time.
Dr. Woodcock. None of them generics. Correct.
Senator Merkley. So Adrenaclick has one of the authorized
generics that you referred to, a version of itself, I gather.
And EpiPen is planning to do so.
EPINEPHRINE DRUG PRICING
What is the cost of the actual amount of epinephrine that
is in one of these pens?
Dr. Woodcock. The cost of the epinephrine is probably
insignificant. There is a cost, obviously. It is a chemical.
But it has been around for 100 years.
Senator Merkley. So I have been told it is probably about
$1. Does that sound feasible?
Dr. Woodcock. That would be probably a generous estimate.
Senator Merkley. So if I am somebody at risk for this
challenge of my throat closing down and I am unable to breathe,
then I would suffocate, can I legally acquire a little amount
of the drug and put it into a syringe and inject myself?
Dr. Woodcock. Yes. A doctor can write a prescription for
you to have that available for you. I myself personally have
treated patients because I ran an allergy clinic for a while,
and I did not have an auto-injector. I injected them with
epinephrine. The problem is if you are suffering an acute
reaction and you are sick----
Senator Merkley. You want to move fast.
Dr. Woodcock. [continuing]. You got to move fast. And if
you do not do this all the time, it is not something that is
intuitive. So it is not as good as using an auto-injector.
EPINEPHRINE MARKETPLACE COMPETITION
Senator Merkley. So I am challenged to understand why
competition does not kick in more quickly. If someone out in
our audience today said, there are three other companies that
have approved auto-injectors, I will go to one of them, I will
rent their technology, I will get a pen up on the market that
will cost--instead of $600 for two pens, I will sell it for
$200. I will make a ton of money. Why does that not happen? Is
your agency so difficult to deal with that it is just a huge
inhibiting factor to people who would ordinarily see an
opportunity?
Dr. Woodcock. Well, according to my staff here, we have
approved four auto-injectors. So we cannot be too difficult.
Not five but four. We cannot be too difficult to deal with.
It is harder, though, to get a generic copy approved
because of the patents that have to be----
Senator Merkley. Right, but you said these others are no
longer on the market. So somebody could conceivably make a
purchase, license, rent the patent, pay a payment for the
patent. And it is not happening. And yet, there is this vast
amount of money being made.
What is the barrier for entrepreneurs stepping into this
gap? It just seems like it is a dysfunctional market. Let us
say someone here wanted to do this. Would they have to go
through an approval process through you from scratch even
though the pen has already been approved?
Dr. Woodcock. No. Companies frequently, as we were
discussing earlier sell their rights to something to someone
else, including the new drug application can be sold, and then
picked up by someone else. They can reintroduce the product.
They have to show us their manufacturing and so forth then, but
they do not have to go through again showing safety and
effectiveness.
Senator Merkley. So when you ask yourself the question why
has somebody not jumped into this gap, is it because in getting
their manufacturing approved that that is so difficult that
although there are bazillions of dollars to be made, they just
think it is an unworkable process? What is this huge barrier to
market entry when there are available patents out there that
are not being utilized for an auto-injector?
Dr. Woodcock. I do not know. We have approved--as I said,
since GDUFA started, we have approved 2,207 approvals or
tentative approvals for generics. So clearly, the barrier is
not insuperable for many companies to get generics onto the
market.
Senator Merkley. I am hoping somebody with an
entrepreneurial spirit will jump in here tomorrow and figure
out how to create some competition here. We would like to see a
generic certainly, but as you pointed out, these are pathways
given other auto-injectors have been approved.
My time is up. I am going to defer to my colleagues. But
something is fundamentally difficult that is preventing
ordinary investments and market entry from occurring, and I
think we have to understand that better.
Senator Moran. The Senator from Maine, Senator Collins.
AUTHORIZED GENERICS
Senator Collins. Thank you, Mr. Chairman.
Good to see you, Dr. Woodcock.
I know that you are very familiar with the investigation
that the Aging Committee under my leadership and Senator
McCaskill's leadership has conducted into the pricing of
certain prescription drugs.
I want to follow up on your comments about Mylan's decision
to introduce what is called an authorized generic of the
EpiPen. I have to say that strikes me as gaming the system.
Essentially what Mylan is doing, as you confirmed, is just
changing the label on its product and then selling it for a
lower price. But does that not have the effect of reducing the
incentive for a true first generic to come onto the market?
I know that you have approved others and that some have
been recalled due to problems.
But in general, the idea of a brand name company simply
swapping the label on its product and then issuing it as a
generic strikes me as greatly reducing the incentive for a true
first generic to come on the market. Could you comment?
Dr. Woodcock. I am no economist, but I would say that would
depend on how much a generic company felt they could make in
the market based on what they could price their generic at.
In the Food and Drug Administration Safety and Innovation
Act (FDASIA), I believe Congress asked us to require companies
to tell us if they are making an authorized generic in their
annual report and for us to post that information. And so far,
we have noted 980 authorized generics that we have been
notified about of different drugs. So it appears to be a
relatively common practice in the industry.
Senator Collins. And I think it is one, personally, that
does need more examination as far as its impact on discouraging
a true first generic or second generic to come onto the market.
Let me switch to a different issue that came up in the
course of our investigation, and that is, we found that certain
drug companies were putting their brand name drugs into
restricted distribution systems. And that made it difficult,
according to our investigation, for generic companies to get a
sufficient amount of the drug in order to conduct the
bioequivalence studies that FDA requires.
What can be done about that?
Dr. Woodcock. Well, we agree. We have received over 100
inquiries from generic companies about problems they have been
having in getting enough of the reference listed drug. In some
cases, this relates to REMS that we have, a restricted program
for safety. However, we have tried to remedy that by writing a
letter to the reference company saying use of the product for
this purpose is acceptable and it does not violate the REMS.
Nevertheless, companies even have their own restricted
distributions outside of REMS, as well as the REMS, and clearly
this is impeding the ability to obtain enough drug to compare.
With respect to what could be done about it by Congress, we
remain concerned that many of these drugs are so valuable that
companies will do a great deal to delay generic competition. It
is worthwhile. So any type of legislation that would have a lot
of extra steps and so each one of those would be an opportunity
to sue us or send us a citizen petition or say we did not do
the process right or whatever and get into court and delay
introduction of the generic or delay availability of that
product. So I think in considering what you might do about
this, you have to consider--fines and everything might simply
be considered a cost of doing business because there is so much
at stake in delaying generic competition.
Senator Collins. I think this is another real problem
because the system is not supposed to work that way. The REMS
system is, as you said, safety-oriented. It is not intended to
restrict distribution in a way that prevents the generic
company from gaining access to a sufficient quantity of the
drug so that they can do the bioequivalence studies.
So I hope you will work with us to try to come up with
something that does not have the kinds of unintended
consequences that you said and yet prevents companies--and we
found all sorts of examples of this and other means that
companies were using to try to block or delay the introduction
of generics.
Thank you.
Senator Moran. Senator Collins, thank you very much. And I
know that your committee with your leadership has a significant
interest in this topic, and I appreciate your presence today.
The Senator from New Mexico, Senator Udall.
RISING DRUG PRICES
Senator Udall. Thank you, Chairman Moran and Ranking Member
Merkley.
Dr. Woodcock, it seems like every few months, we hear about
another pharmaceutical company raising the cost of a certain
drug or device to a new astronomical price. The EpiPen auto-
injector is the most recent to draw national attention. The
EpiPen has become so expensive that families in my home State
of New Mexico and across the country are struggling to afford
it, even though their doctors say they must carry it in the
event of an allergic reaction. But Mylan, the manufacturer, has
increased the price of the EpiPens in the United States by over
480 percent since 2009.
And I have received messages from many of my constituents
in New Mexico who are directly impacted. I have heard from
worried parents across the State, one of them like a woman name
Paige Vest from Truth or Consequences, New Mexico. Her daughter
suffers from a severe peanut and tree nut allergy. She needs to
carry an EpiPen with her at all times to prevent a possible
life-threatening reaction. Paige wrote to me about her family's
struggles to pay for the medication. She even had to change
jobs in order to get insurance that would help cover the cost,
you know, change jobs in order to get the medication for her
child.
And I am also worried about the impact these price
increases will have on families who can no longer afford the
EpiPen. Linda Thompson from El Prado, New Mexico, wrote to me
that because of rising costs in recent years, she has stopped
buying and carrying an EpiPen. She is forced to go against the
advice of her doctor who prescribed the EpiPen after a severe
reaction to a bee sting. So no one should have to go without a
medically necessary product because of how much it costs.
And that is why I wrote to Commissioner Califf last week,
along with members of the New Mexico congressional delegation,
requesting that the FDA utilize all available resources to
build a robust pipeline of EpiPen alternatives.
You know, listening to those constituents, I would like you
to answer for them because I think the real question they have
of you and the FDA is how did we get to this point. What
happened to create this situation, how we got into a monopoly
situation that we are talking about? And could you just
describe that as simply as possible how you think we got here?
And is it not terribly troubling that this company now is
further trying to encroach into the market because they are
apparently going to put out a generic. So they are trying to
keep the market to themselves. They have their own EpiPen that
is brand named, but then they are going to put a generic out on
the market. So could you try to answer that as simply as
possible? How did we get here?
Dr. Woodcock. Well, for most drugs, once they lose their
patent protection and so they can have generics, most drugs do
get generics. But some drugs do not. Either they have patents
that--in this one, the EpiPen has patents that go through 2025.
And so it is not easy to make a generic that does not infringe
upon those patents and still works.
In other cases, it might be a small market--I am talking
about for other patients in New Mexico who have seen price
rises--or a single source drug. In other words, only one
company sells it.
And so in all these cases, they do not have competition.
And in the United States, that is what keeps prices down, is
competition. So for many of these situations, when we have
looked, there is some reason that competitors have not
effectively entered the market and brought the prices down.
EPIPEN MARKETPLACE COMPETITION
Senator Udall. And what is causing that? Because you said
you have approved four of these, and yet, as Senator Merkley
asked, why is somebody not stepping up and saying, you know,
there is a lot of money to be made here? Who do you point to to
say what has caused this monopoly situation that has these
astronomical prices?
Dr. Woodcock. Well, there is one other competitor to the
EpiPen on the market.
Senator Udall. Yes, this Adrenaclick.
Dr. Woodcock. Yes. Several others were pulled off. One was
pulled off for performance problems. For a drug like this in a
situation like this, you want it to work. So you do not want to
say, well, FDA should rush something through even though it
might not work all the time because if that were your life that
were at stake, you would want it to work every time. So we have
to make sure that if there is competition here that it still
works as an epinephrine auto-injector, and it is going to
deliver the lifesaving medication when we have a life-
threatening anaphylaxis happening.
Senator Udall. Mr. Chairman, just to wrap up, you mentioned
the patents over and over again that seem to be part of this.
And I know it is not in the jurisdiction of this committee, but
I think that is something we really should be looking at, is
what the patents are doing to create monopoly situations.
But we appreciate your service and thank you very much for
being here today with us.
Senator Moran. I thank the Senator from New Mexico.
I now recognize the Senator from Montana.
DRUG PRICE INCREASES
Senator Daines. Thank you, Mr. Chairman, Ranking Member
Merkley.
Dr. Woodcock, thank you for coming here today.
And we are here today because of huge spikes in the prices
of some specific prescription medications. And I share Senator
Udall's concerns, what he is seeing in New Mexico where we have
seen a 400-percent increase in the price of that EpiPen. That
has kind of been the poster child of late here as it relates to
what is going on in pricing. It is a lifesaving drug. It is a
delivery system that not only people in New Mexico rely on,
people in Montana and all across the Nation.
Without the competition, of course, on the market, these
spikes will go unchecked. I am greatly concerned about the
impact on Montanans, some of whom have to choose between buying
their prescription drugs and buying food. We need to increase
competition, as you have already mentioned, creating market
checks on the price of drugs and decreasing costs for those who
need them.
ENHANCING GENERIC DRUG COMPETITION
In your testimony, you highlight the savings that generic
drugs afford, saving some $1.68 trillion over the past 10
years. In Montana, that has translated to $682 million saved in
2014. For example, according to the Generic Pharmaceutical
Association's forthcoming generic drug savings in the United
States report, Lipitor, a common cholesterol drug--it was $3.29
a pill before the generic was introduced in 2011. That generic
now sells for 14 cents a pill, a 96-percent savings.
So my question is, what are the FDA and the Office of
Generic Drugs doing to incentivize the production of more
generics, particularly when there is little or no competition
while maintaining, of course, drug quality and drug safety?
Dr. Woodcock. Well, what we do is, number one, we expedite
applications where there is no competition. So if it is a first
generic, if there is just a brand, we expedite that
competition. And as I said, often nowadays with the modern
program we have, we will approve multiple copies at once
because that often will drive the price down more than a single
copy. If there is just one generic, and the reference drug has
been withdrawn, so we have a sole source situation, then we
will expedite that as well--that application or multiple
applications because we do not know which one is going to
actually get approved.
Senator Daines. So kind of going along that line of
thinking, reducing the barriers to generics entering the market
would clearly help create other examples like Lipitor by
reducing the turbulence we see in the market and decreasing
costs. The FDA has proposed a rule to modify labeling
requirements for generics, but there are significant concerns
that this would prevent some generics from actually getting to
market. Since you have delayed the publication of the final
rule now until next year, what revisions are you considering to
help bring generics to the market?
Dr. Woodcock. Well, this rule is not about helping to bring
generics to the market. We got a lot of comments on the rule.
We had a public meeting after the proposed rule was published,
and we have received a large number of comments from the
stakeholders and we are still evaluating those comments.
GENERIC DRUG USE FEE PERFORMANCE GOALS
Senator Daines. In looking at what do you mean by
turbulence in terms of a concrete example, it was brought to my
attention that there are certain applications now being
assigned what they call target goal dates instead of target
action dates. As you know, a goal date is not binding, giving
little clarity to the applicant. What are you doing to address
those concerns?
Dr. Woodcock. Well, under the agreement we made under the
Generic Drug User Fee Act, we agreed to have goals for 2014,
2015, and 2016. And so in 2016, there will be a goal of 10
months, and if someone sends in October 1 of this year, if they
send in an approvable application, it can be reviewed and
responded to and on the market in 10 months.
Senator Daines. But a goal date is not binding.
Dr. Woodcock. Well, sometimes there are other factors that
come in. We have goals. Our goal is we would do 90 percent of
them within the 10 months. That is how our PDUFA program works
too, Prescription Drug User Fee program.
Senator Daines. So do you think by shifting more to these
goal dates versus action dates, it would actually speed up the
process and create more certainty?
Dr. Woodcock. The earlier dates, the target action dates,
were for the backlog that did not have any goals associated
with it. Our agreement under that was we would take an action
on 90 percent of those by the end of the 5 years, and we
already did that. So we exceeded that by 15 months. We have
acted on almost all of those.
Senator Daines. My time is up, Dr. Woodcock.
Just to conclude, I understand there is currently more than
14,000 approved generics, and I believe that incentivizing new,
safe, and effective generics and promoting competition is very
important for Montanans and all Americans.
So thank you for your thoughtful comments. I encourage you
to facilitate this by reducing these barriers to entry and by
providing stability for manufacturers to be able to plan
effectively and to continue to bring safe and quality generic
drugs to market. Clearly, we have seen a lot of great successes
there.
Thanks, Dr. Woodcock.
GENERIC DRUG APPROVAL PROCESS
Senator Moran. Thank you, Senator.
Doctor, you indicated earlier that you have the ability to
prioritize within the backlog, and you listed a few criteria by
which you might prioritize. You indicated in your comments to
my colleague, the ranking member, you used the word ``only game
in town.'' What you mean is little or no competition. Is that a
criteria by which you can prioritize from that backlog?
Dr. Woodcock. Yes.
Senator Moran. And you do that?
Dr. Woodcock. Yes, and it is not just the backlog because
there really are not so many in there. Even an application we
would get today or tomorrow or October 1, we would still try to
prioritize that if it were a single source, like if there was
only one drug on the market.
Senator Moran. Okay.
And you indicated in your testimony and in part in response
to my questions that often substance within the application
process, substance within that application is insufficient for
an approval, and therefore that application is still pending
and would be considered in my words part of the backlog. But it
is really waiting on then the applicant to do something more to
make that application more viable and potentially approvable.
Is that a summary of what we are talking about?
Dr. Woodcock. Yes.
Senator Moran. And you indicated to me, which I was pleased
to hear, that this is not about crossing the T's and dotting
the I's. This is substantive issues as far as whether the drug
application should be approved. And then again, you indicated
that you let the drug companies know throughout the process
where there might be problems. They have the opportunity then
to correct those issues as the application is going through the
process.
Dr. Woodcock. That is correct.
Senator Moran. Is that still true?
Dr. Woodcock. That is correct.
Senator Moran. And so it is not like starting over at the
end. So you do not deny an application and say to the drug
company, I am sorry you do not qualify, you do not get our
approval, go fix something, and come back and apply again.
Dr. Woodcock. No. What we do is send what is called a
complete response. We do not send out denials. We send out a
complete response. It says these are the things you must do
before your application can be considered approvable. And that
has to include the facilities. And often an application may
have, say, 14 facilities around the world that they are relying
upon, say, for testing this part of the manufacturing, this
part of the packaging. We have to make sure all those
facilities are in good standing. And so perhaps they may have
to work on improving a facility--it might be in another
country--or switching to a different facility. And these are
the kind of problems they face sometimes.
Senator Moran. Does that approval process involve
inspection of a facility?
Dr. Woodcock. Yes.
Senator Moran. Or this is a paper process?
Dr. Woodcock. There are a large number of facilities around
the world that make drugs, generic drugs, for the United States
or test the drugs or do the bioequivalence testing. So we try
to have a schedule for inspecting those and inspecting them
every several years on a regular basis. But sometimes there
will be new facilities that will come in with the application
or they will be doing something they never did before, like
they will be making a sterile product, which is very different
than making a tablet. And so we would go and inspect them as
well. So sometimes if they have had a fairly recent inspection
and are in good standing, we will not inspect them again.
Senator Moran. Is there a common denominator for drug
companies who are required to submit additional information
during the approval process? Those that are in a, quote,
backlog--is that a smaller company as compared to a larger
company, someone who is new to the market, a new entrant to the
pharmaceutical business?
Dr. Woodcock. We wish. I mean, we have tried to discern
this and what is causing this problem because before the
Generic Drug User Fee program, almost no generic drugs were
approved on the first cycle. They were all deficient. And often
they went through four cycles. I think that was the median. So
there was a tremendous amount of work and kind re-picking it up
and looking at the application again, and it was a long period
of time. Of course, many of them could submit before the
patents expired, so they had some time to work on their
application.
So we are trying to do a lot of analysis to answer your
question because we want to know that too. How can we remedy
this situation?
In PDUFA, the new drug side, the prescription Drug User Fee
Act, we are way up to 85-90 percent first cycle approvals. So
over the 20 years of that program, we have taught the industry
what they need to do to send in an approvable application. And
we meet with them before and so forth so that we can get
through the application efficiently.
Senator Moran. I will follow up on that as soon as I turn
to Senator Merkley and he has concluded his questioning.
ANTICOMPETITIVE PRACTICES
Senator Merkley. So the competitor that was taken off the
market--I believe it was Auvi-Q--came off at their own
decision--they were not forced off--roughly a year ago. Do we
know if Mylan is paying them to keep that product off the
market?
Dr. Woodcock. I do not know anything about those business
arrangements.
Senator Merkley. Would that be legally allowed under the
law?
Dr. Woodcock. You know, what we do is refer these type of
things to the Federal Trade Commission. You know, we get
different inquiries and we find different things----
Senator Merkley. I know you are not a decider on that type
of issue, but I am sure you are familiar with the general law.
Is that allowed under the law for one company to pay another to
keep a device off the market?
Dr. Woodcock. I do not know actually.
Senator Merkley. You do not know?
Dr. Woodcock. I am not a lawyer. I am a doctor.
Senator Merkley. It certainly is the type of issue that has
been widely discussed in the public sector of companies paying
other companies to keep their products off the market.
Dr. Woodcock. Okay.
Senator Merkley. And also buying up other companies to keep
their products off the market.
So in your interest in seeing--you mentioned--and I do not
want to put words in your mouth, but that essentially you
referred to generics having a potentially powerful, positive
effect on lowering the cost of drugs.
Dr. Woodcock. Right.
Senator Merkley. So in the interest, should Congress be
looking at making sure that there are not strategies in which
name brand drug companies keep generics off the market?
Dr. Woodcock. Yes. We believe that we are subject to some
of these, as Senator Collins was talking about with the
problems getting the reference listed drug, the brand drug, to
do the bioequivalence studies, sometimes using the REMS, our
restricted program for safety, as a reason not to give the
product out.
Senator Merkley. Indeed, I was appalled to hear that, that
somehow a name brand company can prevent their competitor from
getting enough of the drug to do the very studies that you are
requiring. And should that not be grounds for them being
penalized in some way for essentially--that is another strategy
to prevent a competitor legally entering the marketplace.
Dr. Woodcock. Yes. Well, we have certainly been talking to
members of Congress about these problems. We have a long
history of citizen petitions, which Congress had taken some
actions on before, filing of citizen petitions to prevent the
availability of generics based on various scientific issues
that are raised.
Senator Merkley. Is Auvi-Q currently trying to get approval
for a modified product to address the dosing issues that it
had?
AUVI-Q
Dr. Woodcock. I am not allowed to discuss anything like
that.
Senator Merkley. So if they were attempting to do so, would
you be prioritizing their application?
Dr. Woodcock. If we were doing that, if another new drug
application came in, because that is not a generic, those have
a very rapid time frame already for review and approval.
Senator Merkley. So we are talking about a combination
product. The drug is already approved. So it is really just the
device. You are saying it would be fast-tracked if they were to
reapply with a modified device to address the dosage issue that
they had previously.
Dr. Woodcock. I am saying that it would be under the new
drug review process, which is governed by the prescription drug
user fee timelines, which is very speedy.
PRIORITIZATION OF DRUG APPLICATIONS
Senator Merkley. You have authority in cases where there is
market dysfunction to prioritize applications. Is that correct?
Dr. Woodcock. Market dysfunction I do not think enters into
our statutory language. What we have done under our procedures
for generics is we prioritize for public health----
Senator Merkley. Let me put it differently. When there is a
single product in a marketplace and the costs are so high
people cannot afford it, do you have the ability to help
address that by prioritizing an application whether it is a
competitor or a generic--a competitor name brand or a generic,
put that at the top of the list to try to address a big problem
faced by millions of Americans who cannot afford the drug and
whose lives are at risk as a consequence? Do you have the
ability to prioritize that?
Dr. Woodcock. We do prioritize that for generics where
there is a single source, whether it is----
Senator Merkley. How about for a competitor?
Dr. Woodcock. We do not have a procedure to do that.
EPINEPHRINE AUTO-INJECTOR MARKETPLACE RE-ENTRY
Senator Merkley. So we have heard some real horror stories
about devices getting approved. So if a company comes back and
they say, hey, we had a slight manufacturing defect that caused
us to have a dosage problem, we have fixed it, here is our new
version, are you going to send them out for clinical trials
that cost $10 billion--I am exaggerating--and 10 years, or are
they going to be able to get that modification approved and
back on the market?
Dr. Woodcock. If you are talking about an epinephrine auto-
injector, they really do not need clinical trials. This is
not--you need to show that you are injecting the epinephrine
where it is supposed to go and that you can do that reliably
every time under emergency circumstances.
Senator Merkley. Right. I am trying to get some sense of
how much money, how much time for a slight modification of an
injector, because their injector had a problem. Is that a big
obstacle for them reentering the market?
Dr. Woodcock. I do not know about a big obstacle. They may
have to do----
Senator Merkley. How much time? How much money in general
terms? The public would like to understand how big the obstacle
is posed by the FDA to enable the market to function. I
understand it is very important that things work. It is also
very important that there be a functioning system to allow
products to get back on the market. How much time? How much
money would it take?
Dr. Woodcock. I would say the time might it take them, if
they were able to solve--this theoretical company--a
manufacturing problem, and they had to change things, depending
on how they change their auto-injector, then they might have to
do a human factor study again to make sure that people could
use it properly. Or they might not. If the change was just
inside, they might not have to do that. But if the change was
how you actually went about injecting yourself, they might have
to test that again on people to make sure that it would work
for them.
Senator Merkley. I am just hoping there is some common
sense. We are talking essentially about a pre-loaded syringe
that costs $600 and people cannot afford it. It should not be
impossible to enter the market. I encourage you--I am just
wrapping up, so I will turn this back to you--to ponder from
that direction of whether there are unreasonably difficult,
expensive procedures that make it very hard for competitors to
enter the market because clearly, if it was easier, there would
be people entering the market and we would not have this
problem.
And then we have all these tricks of the system in which
the name brand is seeking to prevent those competitors. And if
you essentially have procedures that are complicit in that,
that is a problem. We really need to examine that very, very
carefully because it is not this one drug. This is a whole
systemic problem in our drug approval process, and the price of
drugs are making health care the most expensive in the world
here in the United States, out of reach to millions of
Americans. They bypass their drugs because they cannot afford
to buy them under their deductible. It is a very big deal.
Thank you.
GENERIC DRUG APPROVAL WORKLOAD
Senator Moran. Doctor, I think we are about to wrap up our
hearing, assuming I do not talk so long that other members and
other Senators arrive.
Just a couple of follow-ups. I indicated in my opening
statement that at least the understanding is that the FDA is
close to finalizing negotiations with the industry on a new
round of fees and regulatory requirements. You indicated in
your response to my question that--again, it goes back to the
definition of a backlog. This is a process by which it takes a
number of steps.
Dr. Woodcock. That is right.
Senator Moran. Are you able to tell me? Is that part of the
negotiations with the industry? From their perspective, I do
not know one way or another whether they would say the same
thing that you indicated. Were there issues that could be
negotiated with the companies in this process that reduce the
number of times it is necessary to have the application
reconsidered?
Dr. Woodcock. Well, I think that is definitely on their
mind and our minds. To Senator Merkley's questions, one of the
things that we need to do is get a process for generics where
we give advice to complicated generics before they come in and
send in an application. That is what we negotiated under the
Prescription Drug User Fee Act for the new drugs, and that is
something that there is great interest in, in having a program
so that for these complicated things--it is not just a pill--we
can interact with companies and give them advice and tell them
what to do.
So both this workload--let us not call it a backlog, but
our large workload we have now, part of which is inherited from
the things that are cycling multiple times, is on everyone's
mind, and it is definitely part of our discussions, how to deal
with that.
Senator Moran. Can you report anything about the status of
those negotiations, or is that beyond your----
Dr. Woodcock. I could say with the industry, they have
concluded. Obviously, there are many other steps. We would have
to have a public meeting as described in the statute, and then,
of course, we will hope to provide the consequences to
Congress.
Senator Moran. Is there a timeframe in which you would
expect that consequences to Congress to occur?
Dr. Woodcock. I think that was written in the statute. If
you will excuse me, I will ask my colleague here.
Sorry. I wanted to give you accurate information.
We hope to post those notices soon, and then we would
transmit to Congress by January.
Senator Moran. And that is your expectation?
Dr. Woodcock. I would certainly hope so, yes.
DUCHENNE MUSCULAR DYSTROPHY
Senator Moran. I also mentioned that you were able--I know
this is not a generic drug, but we were talking about Duchenne
and the muscular dystrophy drug. It is not a generic, but at
least the reports are that you found a way to accelerate the
process. Is that an accurate analysis or statement or
description of what occurred?
Dr. Woodcock. The description of what occurred is that the
product was approved under something called accelerated
approval. That may be a little bit of a misnomer, but that is
what it is called. What it means is you do not have clinical
trials that showed the produce gave benefit to patients. You
approve it on a surrogate endpoint that we feel is reasonably
likely to predict clinical benefit. That is how we approved a
lot of HIV drugs over the years, and cancer drugs and many
other drugs have been approved under accelerated approval. Then
the company has to prove with later studies that the product
really does have the predicted benefit.
Senator Moran. Is there anything to learn from that process
that would apply to generics?
Dr. Woodcock. I do not think so because that has to do with
showing effectiveness, and generics get their effectiveness by
showing they are the same as the reference drug.
Senator Moran. So a different standard.
Dr. Woodcock. Yes.
Senator Moran. And the generic ought to be more easily met?
Dr. Woodcock. Yes. The generic does not have to do clinical
studies. In fact, they are not allowed to do clinical studies
of efficacy or else they cannot be a generic.
Senator Moran. Doctor, do you have anything you would like
to tell us that we have not gotten from you from our
questioning?
Dr. Woodcock. Well, I do think that we are very focused on
making sure that any drugs that can be approved and are safe
and effective can get on the market, that the pathways are
clear, that there are not unnecessary barriers to getting on
the market. However, I would say that our standards have to do
with making sure those drugs work for patients and that they
are reasonably safe and that they are of adequate quality so
that the drug supply in the United States is a very reliable,
high quality drug supply. And we do try to expedite where we
can to improve availability. We are sensitive to that.
ADDITIONAL COMMITTEE QUESTIONS
Senator Moran. Dr. Woodcock, thank you very much for your
testimony today. In my view, this hearing was what a
congressional hearing in most instances should be, an
opportunity to be educated and to learn. And you have certainly
helped me in that process.
For members of the subcommittee, any questions that you
would like to submit for the hearing record should be turned
into the subcommittee staff within 1 week, which is Wednesday,
September the 28th.
And we would appreciate it, Doctor, if FDA could respond
within 4 weeks thereafter.
[The following questions were not asked at the hearing, but
were submitted to the Department for response subsequent to the
hearing:]
Questions Submitted by Senator Jerry Moran
safety protocols for products with risk evaluation and mitigation
strategies (rems)
Question. Who has the most appropriate expertise to determine the
safety protocols necessary for safe bioequivalencey testing? For
example, if a product has a REMS with elements to assure safe use, and
the FDA has made a determination that those elements are necessary to
ensure the benefits of the drug outweigh the risks (taking into account
that the absence of those elements to assure safe use the agency would
be unable to approve the product). Do these determinations fall under
the control of the FDA, or can/should these issues be decided through
the judicial process--ie with courts and juries?
Answer. FDA determines what safety measures are necessary for
approval of a drug product, including whether a risk evaluation and
mitigation strategy (REMS) should be required for any particular
product. A REMS will only be imposed if FDA--based on its assessment of
the relative risks and benefits of the drug--determines that a REMS is
necessary to ensure that the benefits of the drug outweigh its risks.
If FDA makes a determination that a REMS is necessary for approval of a
particular product, FDA also determines each of the specific elements
that the REMS must contain in order to address the safety issues
associated with the product.
Given that FDA determines whether a REMS is necessary and what
specific safety protections the REMS must contain, FDA has the most
appropriate expertise to determine whether the protocols submitted by a
generic company for bioequivalence testing contain safety protections
comparable to those in the REMS.
cost of doing business
Question. During questioning by Senator Collins about restricted
distribution systems preventing access to samples by generic drug
manufacturers, Dr. Woodcock indicated that a solution to this problem
which included providing FDA with the authority to penalize brand drug
manufacturers for denying access to samples with fines might not be
effective, as brand drug companies might not alter their behavior and
view the fines as ``a cost of doing business.'' It is my understanding
that the FDA has the authority to penalize conduct beyond mere fines,
including the levying of civil monetary penalties (CMPs).
Are you aware of instances where brand drug manufacturers decided
to pay civil monetary penalties to FDA and not correct their behavior
and come into compliance with the FFDCA? In other words, are you aware
of any instances where brand drug manufacturers decided purposefully to
violate the act after the imposition of CMPs, and consider the CMPs as
``a cost of doing business?''
Answer. To date, FDA has not assessed penalties for brand drug
manufacturers under the FFDCA, so we do not have specific examples of
the type requested.
risks of counterfeit and unauthorized drugs coming in from overseas
Question. I understand that the FDA's Office of Criminal
Investigations includes in its mission protecting American citizens
from the risks of counterfeit and unauthorized drugs coming in from
overseas. For example, in one case the FDA helped prosecute in 2013,
the defendant smuggled more than $12.4 million in non-FDA approved
chemotherapy drugs and injectable cosmetic drugs and devices. Many of
these drugs were subject to strict temperature controls to protect drug
potency, but the defendant shipped them without the dry ice used by
legitimate distributors and one shipment took more than two weeks to
arrive in Virginia from overseas during a heat wave in 2012. While not
all of the investigations result in criminal convictions such as this
one, they do all help impede this dangerous, illicit flow of drugs. Dr.
Woodcock, I would appreciate your assurance that the FDA will continue
to make it a priority to protect Americans in this manner. I would also
appreciate periodic updates from the FDA on its enforcement activities
in this area.
Answer. FDA is committed to protecting U.S. consumers against
unsafe and ineffective drugs, including those that come in from
overseas. We recognize that the importation of unapproved drug
products, some of which might be counterfeit or substandard, poses a
risk to Americans' health. We are also aware that adverse events
flowing from the importation of such unapproved products could lead to
diminished confidence in FDA-approved products. The Agency is taking
steps to bolster the security of the drug distribution system through
its implementation of Title VII of the Food and Drug Administration
Safety and Innovation Act and the Drug Supply Chain Security Act.
Information about our implementation of these statutes is available on
the Agency's Web site at http://www.fda.gov/AboutFDA/Transparency/
track/ucm328907.htm and http://www.fda.gov/Drugs/DrugSafety/
DrugIntegrityandSupplyChainSecurity/DrugSupplyChainSecurityAct/
ucm388726.htm, respectively. For information about our enforcement
activities involving unapproved drug products from overseas, please
visit the Web page for FDA's Office of Criminal Investigations: http://
www.fda.gov/ICECI/CriminalInvestigations/default.htm.
______
Questions Submitted by Senator Jon Tester
Question. What challenges does the FDA face when trying to improve
the efficiency of the generic drug application review process?
Answer. By far the biggest challenge FDA faces when trying to
improve the efficiency of the generic drug application review process
is multiple review cycles. Historically, it takes on average 3.8 review
cycles to approve an abbreviated new drug application (ANDA). A review
cycle begins each time an applicant submits an ANDA for FDA review. If
the ANDA does not meet FDA's standards, then FDA will not approve it,
but instead will communicate deficiencies to the applicant. The
applicant then addresses the deficiencies and re-submits the ANDA in
the form of an ANDA amendment to FDA. The back and forth continues
until the ANDA is approved (or withdrawn).
One reason for this, is known as the ``file first, fix later''
approach. The applicant does not know what FDA is looking for, submits
an incomplete application, and relies on FDA as a consultant,
iteratively, to improve the submission until it becomes approvable. The
proposed GDUFA II agreement targets this problem. Among other things,
the agreement would enhance the pre-ANDA program for complex products
to clarify regulatory expectations earlier in product development and
help applicants develop more ANDAs that are ``right the first time.''
The other main reason for multiple review cycles is that the ANDA
review process until recently was under-developed. FDA and Industry
spent a great deal of time working together to improve it over the past
several years. The proposed GDUFA II agreement is much more
prescriptive about how each stage of the ANDA review process would
work, from start to finish. Roles and responsibilities, sequencing, and
timelines are clearly delineated. Enhanced communications would give
applicants many more opportunities to address deficiencies within a
review cycle, instead of deferring the work until a later review cycle.
Question. Would increased funding help the FDA review generic drug
applications more quickly, or does it need additional authorities from
Congress? If lack of funding is an issue, to which specific programs or
initiatives should the Appropriations Committee consider directing
increased resources? If lack of authority is an issue, what legislative
fixes should Congress consider?
With respect to funding, FDA and industry recently negotiated a
proposed GDUFA II agreement, pursuant to which industry would pay FDA
approximately $493.8 million per year, adjusted for inflation, each
year for the next 5 years. In exchange, FDA commits to achieve agreed-
upon metric goals for the review of generic drug submissions and make
numerous other significant program enhancements.
Additional funding directed to the generic drugs program would
enhance FDA's capacity to support the review of generic drug
submissions.
With respect to new or modified authorities, FDA is currently
evaluating the extent and nature of industry conduct intended to
frustrate and delay generic competition.
Question. What impact has the backlog of generic drug applications
had on the prices of prescription drugs? How much of the rising costs
of drugs is attributable to the backlog?
Answer. First and most importantly, the generic drug program
decreases, not increases, drug costs. According to the IMS Institute
for Healthcare Informatics, generics saved the U.S. healthcare system
$1,680,000,000,000 from 2005-2014. The generic drug program has been an
extraordinary success at expanding access to affordable medicines.
FDA does not agree that there is currently a backlog of generic
drug submissions pending at FDA. There was a backlog of generic drug
applications in fiscal year 12, prior to the start of the GDUFA
program. At the beginning of fiscal year 12, about 2,800 submissions
were pending at FDA and about 100 were pending with Industry. Pursuant
to GDUFA, the Agency committed to take action on 90 percent of these
pre-GDUFA backlog submissions by the end of fiscal year 17. FDA
achieved that goal 15 months ahead of schedule.
At present, there are about 2,200 applications pending at FDA.
Virtually all applications submitted before fiscal year 16 are under
active review, meaning FDA has communicated at least one deficiency to
the applicant. FDA is currently achieving record levels of output, and
these increases are expected to continue. While there are more
applications than FDA would like to have in process, it is important to
note, the generic pipeline needs to contain a certain volume of
submissions. Zero submissions would indicate that no one is developing
new generic products.
There are also currently about 1,700 applications pending with
Industry. FDA can't act on these submissions until applicants correct
deficiencies and re-submit them to us. Forty percent of these
applications have been pending with Industry for more than 8 months,
and 27 percent of them have been pending with Industry for more than a
year.
Considering pending abreviated new drug applications (ANDA) is only
part of the big picture.
--65 percent of innovator drugs have some form of FDA-approved
competition.
--For 24 percent of innovator drugs, FDA has not yet approved a
generic, because by law the innovator is still protected by
patents or exclusivity.
--For 10 percent of innovator drugs, FDA has not approved a generic
because FDA has not received a generic application. These are
generally small markets with low reimbursement where companies
do not perceive an opportunity to make money.
--For 2 percent of innovator drugs, there is a pending, unapproved
ANDA.
Even after FDA approves a submission, a company may not market it.
Generic companies frequently defer marketing pursuant to patent
settlement (so-called ``pay to delay'') agreements. In addition, while
marketing typically reduces price, it does not always.
Question. For what commonly-used prescription drugs do patients not
have access to an effective and interchangeable generic alternative?
What steps can the FDA take to address this lack of generic
alternatives?
Answer. There are many commonly-used prescription drugs where FDA
can lawfully approve a generic (because patent/exclusivity bars to
approval have expired), and FDA has received an ANDA that is not yet
approved.
To increase the number of ANDA approvals, FDA proposes to
reauthorize the generic drug user fee program. FDA also has funded
regulatory science projects to help develop the science needed for
generic drug development. In addition, the Agency is currently
evaluating industry practices that delay access to generics.
In many cases when there is no approved generic product, it is
either because patent and exclusivity have not expired for the
innovator product and FDA can't lawfully approve a generic or because
FDA has not received a generic drug application in the first place.
That is, the obstacles are often legal and economic, not regulatory or
scientific. As for FDA, the Agency determines whether it can approve a
generic but companies decide whether to market them or to defer
marketing, sometimes pursuant to a settlement agreement with the brand
drug company.
______
Questions Submitted by Senator Patrick J. Leahy
Question. One reason consumers face high drug prices is that some
brand name pharmaceutical companies have used inappropriate delay
tactics to limit the ability of generic competitors to enter the
market. For example, some brands refuse to provide samples needed for
testing by generic manufacturers. You discussed this issue briefly
during the hearing and expressed concern about the incentives brands
may have to use tactics such as these to delay market entry.
Can you explain what role access to these samples plays with
respect to market competition and lower cost drugs?
Answer. Generic competition can significantly lower the price of a
drug product. To obtain approval for a generic drug, however, the
generic company must show, among other things, that its version of the
drug product is bioequivalent to the brand drug (also called the
``reference listed drug,'' or ``RLD''). This usually requires the
generic company to do bioequivalence studies comparing their product to
the RLD. To do these studies and submit a generic application, they
need to get access to samples of the RLD.
Typically, generic companies are able to get samples of the RLD
through normal distribution channels (i.e., via wholesalers). But
sometimes they cannot because limitations on the distribution of the
drug are in place. RLDs may be unavailable through normal distribution
channels because the brand company limits the distribution of the
product on its own initiative. In other cases, a risk evaluation and
mitigation strategy (REMS) with elements to assure safe use (ETASU)
(such as a pharmacy certification requirement) might impact the way the
product is distributed.
Question. What is the magnitude of this problem?
Answer. FDA has received more than a hundred inquiries from generic
companies that want to develop generic drugs but tell us they are
unable to do so because they cannot get supplies of the RLD to do
testing. Many of these brand drug products are quite expensive. A
significant majority are listed online at a retail price of over $600
per patient per month, and many are in the range of thousands of
dollars per patient per month. These inquiries have involved both REMS
and non-REMS products.
Question. What is the most effective way to assure that generic
companies can obtain the samples necessary for bioequivalence testing?
Is a legislative solution required?
Answer. Legislation that creates a clearly defined pathway and
legal obligation for RLD access, coupled with a strong remedy to deter
brand companies from blocking access to samples of the RLD could help
significantly to facilitate and expedite generic development.
Question. What role should the FDA play in the process of obtaining
samples by generic companies?
Answer. FDA has issued draft guidance describing the Agency's
current views on its role in facilitating the provision of RLD samples
for bioequivalence testing (see draft guidance for industry on How to
Obtain a Letter from FDA Stating that Bioequivalence Study Protocols
Contain Safety Protections Comparable to Applicable REMS for RLD
(Protocols Guidance), available at http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM425662.pdf).
As described in the Protocols Guidance, in cases where limitations
on the distribution of a drug product occur in connection with a REMS,
FDA (upon request) reviews the bioequivalence study protocols, informed
consent documents, and informational materials submitted by the generic
company to ensure that they have safety protections comparable to those
in the applicable brand REMS. Once we've determined that they do, we
send the brand company a letter ensuring them that selling the RLD to
the generic company for testing and development will not be considered
a violation of the REMS.
We also encourage companies to contact the Federal Trade Commission
if they believe a company's refusal to sell samples to them constitutes
anticompetitive behavior. This is a recommendation that we also make to
companies that inquire about products for which the distribution
limitations are voluntarily imposed by the brand company with no REMS
in place (for which we do not conduct a protocol review).
Question. Some have suggested that providing access to samples of
prescription drugs with known safety risks to generic companies for
bioequivalence testing endangers patients. Are these concerns well
founded? Are additional protections, such as increased regulatory
requirements, necessary to ensure patient safety?
Answer. FDA does not believe that the concerns about bioequivalence
testing are well-founded, nor does FDA believe that protections beyond
those described in the Protocols Guidance are necessary to ensure
patient safety. FDA notes that bioequivalence testing typically
involves a relatively small number of human subjects and a small number
of doses (often only one dose) and, therefore, a lower level of risk.
The regulatory regime applicable to bioequivalence testing--including
the exemption of most bioequivalence testing from the IND
requirements--reflects the generally lower level of risk associated
with bioequivalence testing when compared with other kinds of clinical
testing that occur during the drug development process. Additionally,
the protections in the REMS are designed to mitigate risks that occur
during real world, every day use by patients, and safety concerns are
likely to be lower in the more tightly-controlled context and limited
scope of bioequivalence testing.
Further, FDA regulations (at 21 CFR Part 56) require that before
bioequivalence testing can begin, it must be reviewed and approved by
an Institutional Review Board (IRB) to ensure that risks are minimized.
The steps outlined in FDA's Protocols Guidance provide additional
confirmation that the bioequivalence study protocols contain safety
protections comparable to those in the REMS for the brand product. We
do not believe that additional steps are necessary at this time.
Question. Recent headlines have highlighted pharmaceutical company
Mylan's dramatic price increase of the EpiPen auto-injector. With a
more than 480 percent price increase on a two-pack of EpiPens since
2009, consumers--including parents, first responders, and school
leaders--have faced financial difficulty in obtaining this lifesaving
and necessary drug. There are currently no approved generics on the
market in the United States, but Mylan claims it will soon launch a
generic EpiPen at a reduced price.
Can you provide the Committee with an estimate for how many generic
alternatives to the EpiPen are being reviewed by the agency and at what
stage of review each product currently stands?
Answer. To date, FDA has approved four epinephrine auto-injectors:
EpiPen, Twinject, Adrenaclick, and Auvi-Q. Twinject is no longer
marketed. Auvi-Q was voluntarily recalled by the manufacturer in
October 2015. EpiPen is being marketed and has the large majority of
market share at this time. The application holder for Adrenaclick has
chosen to market Adrenaclick without a trade name, i.e., as an
`authorized generic' to Adrenaclick. There are currently no approved
generics for epinephrine auto-injectors.
FDA is restricted from disclosing to the public confidential
information about applications pending before the Agency. Although FDA
may not disclose this information, a sponsor is able to disclose
information about its products, and can share any communication
received from FDA concerning any of its products. Teva and Sandoz have
publicly acknowledged that they have submitted abbreviated new drug
applications (ANDAs) listing EpiPen (epinephrine injection) as the
reference listed drug (RLD). However, consistent with longstanding
Agency practice, we do not discuss the substance of matters pending
before the Agency. Such a practice helps to ensure the integrity of the
review process.
As a general matter, we note that FDA's Office of Generic Drugs has
a prioritization and expedited review policy for certain generic drug
applications, including potential first generics. This policy is set
forth in the Center for Drug Evaluation and Research's Manual of Policy
and Procedures (MAPP) 5240.3, Revision 2, ``Prioritization of the
Review of Original ANDAs, Amendments and Supplements.''\1\ Pursuant to
our prioritization policy, ANDAs for drugs from generic applicants that
have ``first filer'' status or that are otherwise eligible to be the
first generic approved are often prioritized and given expedited
review.
---------------------------------------------------------------------------
\1\ For more information, please see http://www.fda.gov/downloads/
AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/
ManualofPoliciesProcedures/UCM407849.pdf.
---------------------------------------------------------------------------
Question. EpiPen is a drug/device combination product that
incorporates a drug that is no longer under patent into a device for
which Mylan still has patent protection. What is the process the agency
uses to approve generic applications for drug/device combination
products? What criteria are considered to determine equivalence? Are
there any generic drug/device combination products on the market,
including but not limited to epinephrine auto-injectors?
Answer. In determining whether to approve an ANDA referencing a
drug-device combination product such as EpiPen, FDA considers the same
factors as are required for all ANDAs.\2\ More specifically, a generic
drug applicant seeking approval of a drug-device combination product,
such as an epinephrine auto-injector, will need to demonstrate that its
proposed generic product is bioequivalent to the RLD. In addition, a
proposed generic product must generally contain the same active
ingredient, same route of administration, same dosage form, same
strength, and (with certain permissible differences) same labeling as
the RLD. An ANDA is generally not required to be the same as the RLD in
certain other respects (e.g., it can differ in inactive ingredients or
container closure system). However, where differences in these aspects
of the products are significant enough that they require clinical
studies to demonstrate safety or effectiveness of the proposed generic
drug, or necessitate such significant labeling differences that the
generic drug labeling is no longer ``the same'' as the RLD's, FDA will
deny approval of the proposed generic product.
---------------------------------------------------------------------------
\2\ EpiPen is categorized as a drug-device combination product,
with a drug primary mode of action. As a result, the Center for Drug
Evaluation and Research (CDER) would be the lead FDA center from a
review and jurisdiction perspective, while the Center for Devices and
Radiological Health (CDRH) would be consulted for review of the device
component of the product.
---------------------------------------------------------------------------
FDA's assessment of a device constituent part of a proposed generic
product is made on an application-by-application and product-by-product
basis in the context of the review of a specific generic drug
application. FDA will evaluate the significance of any design
differences between the innovator product (RLD) and a proposed generic
product in light, among other things, of the intended users and uses of
the product, including the environment in which such product is used
and in light of the requirements for an ANDA to have, among other
things, the same labeling as the RLD.
As noted above, there are currently no approved generics for
epinephrine auto-injectors. Although Mylan has announced publicly its
intention to market an ``authorized generic'' of EpiPen,\3\ it is
important to clarify that these statements have not indicated that
Mylan is intending to market a generic version of EpiPen under an ANDA
submitted under section 505(j) of the Federal Food, Drug, and Cosmetic
Act (FD&C Act), which requires the submission of an abbreviated new
drugapplication and FDA's approval of such application prior to the
marketing of such generic product. Rather, Mylan intends to market an
``authorized generic'' of EpiPen. An authorized generic is made under
the brand name's existing new drug application using the formulation,
process, and manufacturing facilities approved for use by the brand
name manufacturer. The labeling of the brand name product is changed to
remove the brand name or other trade dress. An authorized generic is
not synonymous with an FDA-approved generic, the latter of which
requires a separate application and approval from that of the brand
name product.
---------------------------------------------------------------------------
\3\ See Mylan Press Release (Aug. 29, 2016), http://
newsroom.mylan.com/2016-08-29-Mylan-to-Launch-First-Generic-to-EpiPen-
Auto-Injector-at-a-List-Price-of-300-per-Two-Pack-Carton-a-More-than-
50-Discount-to-the-Brand-Product.
---------------------------------------------------------------------------
FDA has approved ANDAs for several different drug-device
combination products. These include ANDAs for sumatriptan injection
(RLD: Imitrex STATdose Injection), mometasone furoate nasal spray (RLD:
Nasonex Nasal Spray), sumatriptan nasal spray (RLD: Imitrex Nasal
Spray), triamcinolone acetonide nasal spray (RLD: Nasacort AZ Nasal
Spray), fluticasone nasal spray (RLD: Flonase Allergy Relief Nasal
Spray), and norelgestromin and ethinyl estradiol transdermal system
(RLD: Ortho Evra Transdermal System).
Question. In addition to expanding the availability of generic
alternatives on the market in order to reduce out-of-pocket costs for
consumers, it is critical that generic manufacturers take the necessary
steps to ensure the safety of their products. In 2013, Congress urged
the FDA to revise its rules to require generic drug manufacturers to
promptly update their labeling to include new safety information. In
response to the Supreme Court ruling in PLIVA v. Mensing, which held
that generic drug companies could not be sued under state law over a
failure to provide adequate labeling about potential drug side effects,
consumers have had no remedy in the event they are injured as a result
of outdated generic labeling.
In November 2013, the FDA released a proposed rule which recognized
the importance of generic manufacturers being held accountable for
outdated and incorrect labeling. Unfortunately, the agency has yet to
finalize this critically important Proposed Rule.
Can you provide the Committee with an update on the agency's
finalization of its Proposed Rule on generic labeling?
Answer. The proposed rule is intended to improve the communication
of important drug safety information to healthcare professionals and
patients. FDA has received a great deal of public input from
stakeholders during the comment period on the proposed rule regarding
the best way to accomplish this important public health objective.
FDA is carefully considering comments submitted to the public
docket established for the proposed rule from a diverse group of
stakeholders including: consumers and consumer groups, academia
(including economists), healthcare associations, drug and pharmacy
associations, brand and generic drug companies, law firms, state
governments, and Congress, including comments proposing alternative
approaches to communicating newly acquired safety-related information
in a multi-source environment (see Docket No. FDA-2013-N-0500). These
comments include a summary of FDA's meeting with the Generic
Pharmaceutical Association (GPhA) on September 8, 2014, to listen to
their comments and views regarding the proposed rule. In addition, FDA
held a public meeting at which any stakeholder had the opportunity to
present or comment on the proposed rule, or on any alternative
proposals intended to improve communication of important, newly
acquired drug safety information to healthcare professionals and the
public. In the February 18, 2015 notice announcing the public meeting,
FDA reopened the docket for the proposed rule until April 27, 2015, to
allow the submissions of written comments concerning proposals advanced
during the public meeting. FDA will determine next steps based on our
analysis of comments on the proposed rule and additional information
submitted as part of the public meeting.
CONCLUSION OF HEARING
Senator Moran. Again, I thank everyone for their attendance
today, and I will conclude this hearing. The meeting is
adjourned.
[Whereupon, at 4:12 p.m., Wednesday, September 21, the
hearing was concluded, and the subcommittee was recessed, to
reconvene subject to the call of the Chair.]