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FDA
STEVEN
K.
GALSON,
M.D.,
M.P.H.,
ACTING
DIRECTOR
CENTER
FOR
DRUG
EVALUATION
AND
RESEARCH
U.S.
FOOD
AND
DRUG
ADMINISTRATION
DEPARTMENT
OF
HEALTH
AND
HUMAN
SERVICES
BEFORE THE
SENATE
COMMITTEE
ON
HEALTH,
EDUCATION,
LABOR,
AND
PENSIONS
HEARING
ON
“FEDERAL
AND
STATE
ROLE
IN
PHARMACY
COMPOUNDING
AND
RECONSTITUTION:
EXPLORING
THE
RIGHT
MIX
TO
PROTECT
PATIENTS”
OCTOBER
23,
2003
INTRODUCTION
Mr. Chairman and Members of the Committee, I am Steve Galson, the Deputy Director of the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA or the Agency). I am also the Acting Director of the Center while Dr. Janet Woodcock is on detail to the Office of the Commissioner.
I appreciate the opportunity to discuss FDA’s role with regard to pharmacy compounding. In my testimony, I will discuss the Agency’s activities and strategies for addressing public health issues associated with pharmacy compounding. I will touch on our current statutory and regulatory authority, how the Agency has exercised that authority, and our future plans in this area.
BACKGROUND
By most estimates, pharmacy compounding is a growing business. Many compounding pharmacies have established Internet web sites to promote and sell their products. The Agency’s strategies for addressing pharmacy compounding have had to evolve to respond to the public health challenges associated with this growing area while at the same time preserving the benefits that pharmacy compounding offers in meeting a public health need.
FDA views traditional pharmacy compounding as the combining, mixing, or altering of ingredients to create a customized medication for an individual patient in response to a licensed practitioner’s prescription.1 In its simplest form, it may involve taking an approved drug substance and making a new formulation to meet the medical needs of a specific patient. For example, it may involve formulating the product without a dye or preservative in response to a patient allergy. Or it might involve making a suspension or suppository dosage form for a child or elderly patient who has difficulty swallowing a tablet or a capsule. These traditional forms of pharmacy compounding are an important component of our pharmaceutical armamentarium. Although these products technically may be considered unapproved new drugs because they differ from the approved formulation of the drug, FDA has exercised enforcement discretion to allow these legitimate forms of pharmacy compounding, which are regulated under state laws governing the practice of pharmacy.
We believe that the vast majority of pharmacies engaging in pharmacy compounding provide a valuable medical service that is an integral part of our modern health care system. However, we have become aware of instances involving compounding in which the risks of obtaining a product of substandard quality may outweigh the benefits of obtaining the compounded drug. In addition, we have seen abuses, such as large-scale drug manufacturing under the guise of pharmacy compounding.
In recent years, we have witnessed some compounding pharmacies creatively marketing new compounded products that they assert are “better” than available therapies. We are not aware of data supporting these claims. Sometimes these pharmacies compound a product containing a form of an active ingredient that has not been approved by FDA, such as 4-aminopyridine, an experimental drug compounded for patients with multiple sclerosis. In other instances, drugs are compounded even though FDA has removed them from the market after determining that they were unsafe. We also have seen drugs compounded that are essentially copies of commercially available products. Compounding pharmacies then sell these copies for less than the approved commercially available product. These appear to be compounded for economic reasons rather than genuine medical need. In such cases, we believe the consumer would be better served by the commercially available drug, which has been determined to be safe and effective and manufactured under rigorous good manufacturing practice requirements.
Although
there
is
limited
hard
data
on
the
actual
amount
of
pharmacy
compounding
that
is
occurring
in
this
country,
pharmacy
compounding
appears
to
be
a
big
and
growing
business.
In
April
2001,
we
commissioned
a
study
on
the
compounding
industry
by
the
Eastern
Research
Group,
Inc.
According
to
their
August
2001
report,
over
650
pharmacies
fill
more
than
13
million
prescriptions
for
compounded
products
per
year.
Although
many
more
pharmacies
compound
(some
estimates
put
the
number
at
more
than
3,000
compounding
pharmacies)
this
relatively
small
number
of
pharmacies
that
specialize
in
compounding
appear
to
account
for
a
majority
of
the
drugs
compounded
nationally.
Some
estimate
that
compounding
represents
one
percent
of
all
of
the
prescriptions
filled
each
year.
In
2003,
according
to
one
estimate,
this
would
amount
to
30
million
prescriptions
for
compounded
products.
In
some
cases,
these
prescriptions
may
be
compounded
in
pharmacies
that
dispense
only
compounded
medications
or
in
other
pharmacies
for
which
compounding
is
a
large
percentage
of
their
business.
Pharmacy
compounding,
by
definition,
involves
making
a
new
drug
whose
safety
and
efficacy
have
not
been
demonstrated
with
the
kind
of
data
that
FDA
ordinarily
would
require
in
reviewing
a
new
drug
application.2
Although
most
pharmacists
are
well-trained
and
well-equipped
to
safely
compound
certain
medications,
not
all
pharmacists
have
the
same
level
of
skills
and
equipment,
and
some
products
that
are
compounded
may
be
inappropriate
for
compounding.
In
some
cases,
we
have
reason
to
be
concerned
about
the
quality
of
the
drugs
being
compounded
and
the
potential
risks
to
patients
who
may
take
them.
In
some
instances,
compounders
may
lack
sufficient
controls
(equipment,
training,
testing,
or
facilities)
to
ensure
product
quality
or
to
compound
difficult
products
such
as
sterile
or
modified
release
drugs.
If
compounding
is
done
on
a
large
scale
and
is
not
done
properly,
compounders
can
expose
large
numbers
of
patients
to
health
risks
associated
with
unsafe
or
ineffective
medications.
This
may
be
of
particular
concern
if
patients
are
taking
an
ineffective
compounded
product
in
lieu
of
a
proven
therapy.
In
addition,
compounding
large
quantities
of
drugs
and
copying
commercially
available
approved
products
in
compounding
pharmacies
circumvents
important
public
health
requirements
and
undermines
the
drug
approval
process
–
the
evidence-based
system
of
drug
review
that
consumers
and
health
professionals
rely
on
for
safe
and
effective
drugs.
RECENT ENFORCEMENT ACTIVITY
The following examples of recent FDA enforcement actions against compounding pharmacies illustrate some of these concerns:
Fentanyl “Lollipops”: In August 2002, during in a joint FDA/New Hampshire inspection, FDA determined that a pharmacy was compounding Fentanyl “Lollipops” and dispensing them without the labeling and other packaging and patient safety features required by FDA for the approved product. Fentanyl is a narcotic analgesic that could pose a safety hazard to children if distributed without appropriate safety measures. FDA issued a “warning letter” to the firm and the firm agreed to cease distribution of this product.
Methylprednisolone Acetate: In September 2002, a compounding pharmacy in South Carolina recalled all lots of its methylprednisolone acetate products based on reports of four patients who developed a rare fungal infection after taking the drug. Ultimately, a total of six patients were infected, and one died. A joint FDA/South Carolina inspection revealed that the firm did not have adequate controls over its compounding operations to ensure the necessary sterility. When the firm refused to voluntarily recall other injectable products or to provide FDA with a complete list of all products distributed, FDA issued a nationwide alert on all injectable drugs prepared by the firm. FDA is aware of several other cases of contamination and adverse events associated with compounded sterile injectable products.
Large Volume Interstate Shipments: In September 2002, FDA issued a “warning letter” to a California pharmacy after it determined during a joint FDA/California inspection that the firm was not operating as a retail pharmacy. The firm was using commercial scale manufacturing equipment and making large quantities of drugs for shipment across California and to patients in other states. In March of 2002, the firm issued a recall of compounded inhalation solutions due to microbial contamination.
In each of these cases, as is the case in most pharmacy compounding actions, FDA has proceeded jointly with the state in which the pharmacy is located. In many of the cases, however, questions have arisen concerning FDA’s authority over the compounding activities. In some cases, FDA had difficulty obtaining access to the compounding pharmacy to determine whether the firm was engaging in dangerous practices. The pharmacies argued that they were not subject to FDA regulation because they were compounding pharmacies. FDA had to get a warrant to obtain access to the facilities and records of compounding activities. One of these incidents is discussed in more detail below.
Wedgewood Village Pharmacy: On July 7, 2003, a U.S. Magistrate Judge in the U.S. District Court of New Jersey denied Wedgewood Pharmacy’s motion to quash FDA’s warrant for administrative inspection of the pharmacy. The warrant application was filed after the U.S. Drug Enforcement Agency’s (DEA) requested assistance from FDA in conducting an on-site inspection of Wedgewood.
The Magistrate Judge held, in part, that (1) FDA had authority to apply for a warrant to inspect the pharmacy; (2) it is not FDA’s burden to prove that the entity it seeks to inspect is not entitled to the pharmacy-related exemptions from FD&C Act; and (3) the Compliance Policy Guide stating that FDA would not attempt to regulate traditional pharmacy compounding practices was a reasonable interpretation of the FD&C Act. The pharmacy owner appealed to the District Court Judge the magistrate’s order denying the motion to quash the administrative inspection warrant. The District Court held a hearing on October 16, 2003. A ruling in this case is pending.
Because FDA was not permitted to complete its inspection in this case and several others, the Agency has been delayed, from obtaining the evidence needed to assess whether drug manufacturing is occurring under the guise of compounding or if compounding practices that raise public health concerns are present.
STATUTORY
AND
REGULATORY
AUTHORITY
Although
compounding
was
widespread
when
the
FD&C
Act
was
first
enacted
in
1938,
there
were
no
provisions
specifically
dedicated
to
compounding,
as
distinguished
from
manufacturing
of
drugs.
After
the
1962
amendments
to
the
Act
expanded
the
universe
of
drugs
that
require
FDA
pre-market
approval
to
include
drugs
that
are
not
already
generally
recognized
by
experts
as
effective,
courts
have
interpreted
expansively
the
Act’s
provisions
to
require
pre-market
approval
of
virtually
all
prescription
drugs.
It
is
widely
recognized,
however,
that
compounded
drugs
could
not
meet
the
approval
requirements,
in
part
because
they
traditionally
are
made
in
small
amounts
for
individual
patients
according
to
a
prescription.
In
addition,
it
is
usually
not
feasible
to
study
them
in
clinical
trials
to
establish
their
safety
and
efficacy
or
prepare
new
drug
applications
for
all
of
the
different
types
of
compounded
products
that
might
be
prescribed.
Several of the Act’s provisions that pertain to drugs generally include compounded drugs. The specific statutory provisions that may apply to compounded drugs are: (1) the definition of “drug” (section 201(g) of the Act); (2) the misbranding and adequate directions for use requirements for drugs (section 502 of the Act); (3) the adulteration and current good manufacturing practice (cGMP) requirements for drugs (section 501(a)(2)(B) of the Act); and (4) the new drug approval provisions (section 505 of the Act). Literal application of these statutory drug authorities could mean that, technically, virtually all compounded drugs violate the Act, despite the long history of allowing certain types of compounding and the important public health benefits provided by such compounding of medically necessary drugs that are not otherwise available. Until the 1997 provision discussed below, Congress had not explicitly exempted compounded drugs from the preceding requirements of the Act.
Today, the Act does specifically address compounding in two specific provisions; the registration provisions and the inspection provisions. In each case, it provides an exemption that is narrowly tied to the specific requirements of those two provisions. Under the requirements for drug registration, although compounding is specifically included among the activities that would require an establishment to register with FDA (section 510(c) of the Act), an exemption is provided for pharmacies that, among other conditions, do not compound for sale “other than in the regular course of their business of dispensing or selling drugs . . . at retail” (section 510(g)(1) of the Act). The same language limits the types of records that FDA may review during an inspection of a pharmacy (section 704 of the Act).
Because these exemptions do not extend to other statutory requirements, such as pre-approval requirements that would significantly restrict compounding, FDA has historically exercised its enforcement discretion in a manner that defers to the states, as the regulators of the practice of pharmacy, to serve as the primary regulators of the practice of pharmacy compounding. FDA’s focus in recent years has been on drug manufacturing that operates under the guise of pharmacy compounding. FDA also has worked cooperatively with the National Association of Boards of Pharmacy (NABP) and the U.S. Pharmacopeial Convention (USP) to address good compounding practices, and with the states on a case-by-case basis to address instances of compounding that raise public health and safety issues.
Compliance
Policy
Guide
of
1992
In
March
1992,
FDA
issued
a
compliance
policy
guide
(CPG),
to
delineate
the
Agency’s
enforcement
policy
on
pharmacy
compounding.
This
CPG
relied
on
the
exercise
of
enforcement
discretion
rather
than
legal
exemptions
from
new
drug
and
other
statutory
requirements.
The
pharmacy
community
expressed
concerns
about
how
FDA
intended
to
exercise
its
enforcement
discretion
and
sought
legislation
to
clarify
the
boundaries
of
FDA’s
authority
over
pharmacy
compounding.
In
1997,
Congress
enacted
the
Food
and
Drug
Administration
Modernization
Act
of
1997
(FDAMA)
to
specifically
addressed
FDA’s
role
in
the
regulation
of
pharmacy
compounding.
Food
and
Drug
Administration
Modernization
Act
of
1997
On
November
21,
1997,
the
President
signed
FDAMA
(P.L.
105-115).
Section
127
of
FDAMA
added
sections
503A
to
the
FD&C
Act,
to
clarify
the
status
of
pharmacy
compounding
under
Federal
Law.
Under
section
503A,
drug
products
that
were
compounded
by
a
pharmacist
or
physician
on
a
customized
basis
for
an
individual
patient
were
entitled
to
exemptions
from
three
key
provisions
of
the
Act:
(1)
the
adulteration
provision
of
section
501(a)(2)(B)
(concerning
the
good
manufacturing
practice
requirement,
or
cGMP);
(2)
the
misbranding
provision
of
section
502(f)(1)
(concerning
the
labeling
of
drugs
with
adequate
directions
for
use);
and
(3)
the
new
drug
provision
of
section
505
(concerning
the
approval
of
drugs
under
new
drug
or
abbreviated
new
drug
applications).
To
qualify
for
these
exemptions,
a
compounded
drug
product
was
required
to
satisfy
several
requirements,
some
of
which
were
to
be
the
subject
of
FDA
rulemaking
or
other
actions.
Section
503A
of
the
Act
took
effect
on
November
21,
1998,
one
year
after
FDAMA
was
signed
into
law.
Thompson
v.
Western
States
Medical
Center
In
November
1998,
the
solicitation
and
advertising
provisions
of
section
503A
were
challenged
by
seven
compounding
pharmacies
as
an
impermissible
regulation
of
commercial
speech.
The
U.S.
District
Court
for
the
District
of
Nevada
ruled
in
the
plaintiffs’
favor.
FDA
appealed
to
the
U.S.
Court
of
Appeals
for
the
Ninth
Circuit.
On
February
6,
2001,
the
Court
of
Appeals
declared
section
503A
to
be
invalid
in
its
entirety
(Western
States
Medical
Center
v.
Shalala,
238
F.3rd
1090
(9th
Cir.
2001)).
The
government
petitioned
for
a
writ
of
certiorari
to
the
U.S.
Supreme
Court
for
review
of
the
Ninth
Circuit’s
decision
that
the
solicitation
and
advertising
provisions
of
section
503A
were
unconstitutional
restrictions
on
commercial
speech.
The
Supreme
Court
granted
the
writ
and
issued
its
decision
in
the
case
on
April
29,
2002.
The Supreme Court affirmed the Ninth Circuit’s decision that section 503A of the FD&C Act was invalid in its entirety because it contained unconstitutional restrictions on commercial speech (i.e., prohibitions on soliciting prescriptions for and advertising specific compounded drugs). The Court did not rule on, and therefore left in place, the Ninth Circuit’s holding that the unconstitutional restrictions on commercial speech could not be severed from the rest of section 503A. Accordingly, all of section 503A is now invalid.
Compliance
Policy
Guide
of
May
2002
Once
the
statutorily
created
exemptions
from
the
new
drug,
misbranding
and
adequate
directions
for
use
requirements
were
deemed
invalid
for
compounded
drugs,
FDA
determined
that
it
needed
to
issue
guidance
to
the
compounding
industry
on
what
factors
the
Agency
would
consider
in
exercising
its
enforcement
discretion
in
this
area
under
current
law.
In
May
2002,
FDA
issued
a
Guidance
for
Industry
–
Pharmacy
Compounding
–
Compliance
Policy
Guide,
which
is
based
on
the
CPG
of
March
1992.
The guidance states that FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of drugs upon receipt of a valid prescription for an individually identified patient from a licensed practitioner. This traditional compounding activity is not the subject of the guidance.
However, when the scope and nature of a pharmacy’s activity raise the kinds of concerns normally associated with a drug manufacturer and result in significant violations of the new drug, adulteration, or misbranding provisions of the FD&C Act, the guidance states that FDA will consider enforcement action. In determining whether to initiate such an action, the guidance states that the Agency will consider whether the pharmacy engages in any of the following acts:
The above list of factors is not intended to be exhaustive, as other factors may be appropriate for consideration in a particular case.
Although
the
CPG
was
immediately
effective
when
it
was
issued
in
May
2002,
the
Agency
indicated
it
would
be
interested
in
receiving
public
comments
on
the
guide.
FDA
received
public
comments
and
is
in
the
process
of
revising
the
CPG
in
response
to
the
comments.
The
Agency
plans
to
publish
a
new
draft
of
the
CPG
and
will
seek
comments
on
it.
LIMITED
FDA
SURVEY
OF
COMPOUNDED
DRUG
PRODUCTS
Since 1990, FDA has become aware of more than 55 product quality problems associated with compounded products, many of which resulted in product recalls. In 2001, FDA’s Division of Prescription Drug Compliance and Surveillance conducted a limited survey of drugs compounded by 12 compounding pharmacies that allowed compounded products to be ordered over the Internet. The goal of the survey was to gather information on the quality, purity, and potency of compounded drug products in the marketplace. The compounded products surveyed were selected from a cross-section of commonly compounded dosage forms based on FDA’s assessment of the potential health risks resulting from improper compounding. FDA collected the samples via air mail order in the same manner a consumer would order the products over the Internet.
The 29 products sampled included hormonal products, antibiotics, steroids, anesthetics and drugs to treat glaucoma, asthma, iron deficiency anemia, and erectile dysfunction. Five different dosage forms (i.e., sterile injectables, ophthalmic products, pellet implants, inhalation products, and oral dosage forms) were sampled.
Ten (34 percent) of the 29 sampled products failed one or more standard quality tests performed. Nine with failing analytical results failed assay (potency) testing, with a range of 59 percent to 89 percent of expected potency.
Each year, FDA routinely samples drug products made by commercial manufacturers and analyzes these samples in FDA laboratories. More than 3,000 products from commercial manufacturers have been sampled and analyzed by FDA since fiscal year 1996. The analytical testing failure rate for commercially produced samples has been less than two percent for all tests, but for assay (potency) tests there were four failures out of 3,000. Compared to the two percent failure rate, the percentage of sampled compounded products failing analytical testing in our 2001 survey (34 percent) was higher than expected. Although the 2001 survey had several limitations including a small sample size, it provided valuable preliminary information on the quality of selected compounded drug products currently marketed. We believe that these laboratory results need to be interpreted cautiously and should not be generalized beyond the particular drugs and pharmacies involved. Further, we believe that the results call for additional study and consideration by FDA, the state regulatory authorities, professional organizations, and pharmacies.
OUTREACH ACTIVITIES
FDA has interacted on many occasions with stakeholders involved with pharmacy compounding. We have attended the annual meetings of the International Academy of Compounding Pharmacists participating on panels with representatives of the American Pharmacists Association (APhA), NABP, the USP, the National Association of Community Pharmacists, and others. In addition, we met separately with many of these stakeholders seeking to find common ground in how to approach the regulation of pharmacy compounding. We have participated in stakeholder meetings sponsored by the USP to address various initiatives including the accreditation of pharmacies that compound medications.
POSITIVE ACTIONS AND CHALLENGES
Some of the stakeholder groups with whom we have interacted are engaged in activities intended to provide greater confidence in the quality of compounded medications. For example, the NABP has a model code governing pharmacy compounding that substantially has been adopted by ten states. The model code provides State Boards of Pharmacy with a framework for developing requirements for compounding pharmacies. The USP has developed a new chapter in the U.S. Pharmacopeia addressing sterile drug compounding practices. The chapter sets standards for the preparation of sterile compounded drugs. The American Society of Health-System Pharmacists also has such guidelines. The APhA, NABP, and USP have been discussing the possibility of developing an accreditation program that would set standards for and monitor compounding pharmacies. All of these activities are positive steps in ensuring that pharmacy compounding is done with appropriate protections for patients, and we support them.
FDA
recognizes
that
states
have
the
direct
ability
to
regulate
pharmacy
compounding
and
direct
access
to
prescription
records.
However,
limited
state
resources
and
varying
standards
and
regulatory
requirements
are
factors
that
affect
the
adequacy
of
state
regulation.
Pharmacy
self-inspection
is
allowed
in
four
states,
which
consists
of
pharmacist
self-evaluation
by
questionnaire
of
the
pharmacy’s
compliance
with
laws
and
regulations.
In
addition,
there
is
variability
in
commitment
to
regulate
pharmacy
compounding
among
the
states.
Sometimes
there
is
conflict
between
State
Boards
of
Pharmacy
and
Health
Departments
based
on
disparate
regulatory
philosophies.
Clearly,
when
pharmacy
compounding
more
closely
approximates
commercial
manufacturing,
FDA
has
an
interest
in
regulating
that
practice
as
it
does
all
other
drug
manufacturing.
One
difficult
issue
is
where
to
draw
that
line.
If
the
line
is
to
be
drawn
based
on
volume,
how
much
volume
makes
a
compounder
a
manufacturer?
There
are
many
large
compounding
pharmacies,
some
of
which
are
exclusively
drug
compounders.
Similarly,
there
are
many
small
drug
manufacturers
that
make
drugs
under
approved
new
drug
or
abbreviated
new
drug
applications.
Through
our
review
of
these
applications,
we
ensure
that
the
drugs
are
safe
and
effective
and
that
the
processes
by
which
the
drugs
are
made
produce
consistently
high
quality
products
that
maintain
their
safety
and
efficacy
throughout
their
shelf
life.
This
system
of
evidence-based
medicine
provides
public
health
benefits
to
American
consumers
and
health
professionals
because
patients
are
able
to
rely
with
confidence
on
the
medications
they
take
and
avoid
ineffective
therapies
or
those
for
which
the
risks
do
not
exceed
the
benefits.
It is important to ensure that the production of drugs in pharmacy compounding does not undermine the incentives to develop and submit new drug applications to FDA with evidence of the safety and efficacy. At the same time, we recognize that pharmacy compounding is necessary where there is a medical need of a particular patient for a product that is not commercially available in an approved form. We must exercise our regulatory authority in such a way as to support pharmacy compounding that is necessary, while curbing abuses.
With this in mind, we can describe a few key areas where the Agency has taken action and where we believe a Federal role is appropriate:
CONCLUSION
In summary, FDA welcomes this Committee’s interest in pharmacy compounding and would like to assure the Committee that the Agency’s efforts to address pharmacy compounding issues are designed to balance the need to allow legitimate forms of pharmacy compounding with the need for Federal oversight when pharmacy compounding threatens to compromise public health.
This concludes my testimony, Mr. Chairman. I will be glad to answer any questions you may have.
FOOTNOTES:
1 Under the compounding-related provisions of the Food and Drug Administration Modernization Act, pharmacy compounding was not defined to include mixing or reconstituting commercial products in accordance with the manufacturer’s instructions or the product’s approved labeling. Reconstituting means the return, usually by adding liquid, of a drug previously altered for preservation and storage to its original state for administration to a patient. This type of manipulation, when done in accordance with approved labeling, should not adversely affect the safety or efficacy of the drug. (The provisions were struck down by the Supreme Court on April 29, 2002.)
2 In some cases, it may simply involve taking an approved drug and making a new formulation.