U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2003
Clinical Medical
Guidance for Industry
Prussian Blue Drug Products — Submitting a New Drug Application
Additional copies are available from:
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2003
Clinical Medical
Guidance for Industry
Prussian Blue Drug Products —
Submitting a New Drug Application
This guidance represents the
Food and Drug Administration's (FDA's) current thinking on this
topic. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statutes and regulations.
This guidance is intended to assist
manufacturers wishing to submit new drug applications (NDAs) for
prussian blue drug products for the treatment of internal
contamination with radioactive thallium, nonradioactive thallium,
or radioactive cesium. The Federal Register notice
announcing the availability of this guidances explains in detail
the Agency's findings regarding safety and effectiveness and
includes a list of the literature on which it based those
findings.
Prussian blue was first synthesized in 1704
by a Berlin color maker named Diesbach. It is used as an
industrial and artists' pigment.
Since the 1960s, prussian blue also has been used
investigationally as an orally ingested drug to enhance the
excretion of isotopes of cesium and thallium from the body by
means of ion exchange. Prussian blue has a very high affinity for
cesium and thallium. Cesium and thallium ions are ordinarily
excreted into the intestine, reabsorbed from there into the bile,
and then excreted again into the gastrointestinal tract. Orally
administered prussian blue traps thallium or cesium in the
intestine, interrupts its reabsorption from the gastrointestinal
tract, and thereby increases fecal excretion of thallium and
cesium. Prussian blue itself is not absorbed across the
intestinal wall in significant amounts.
The Agency has concluded that prussian blue,
when produced under conditions specified in approved NDAs, can be
found to be safe and effective for the treatment of internal
contamination with radioactive thallium, nonradioactive thallium,
or radioactive cesium. As described below, our conclusion is
based upon our review of published information.
III. NDAs
Submitted for Prussian Blue Drug Products
An NDA for a prussian blue drug product may
be either:
·
a 505(b)(2) application, which is an NDA in which
you rely for approval on studies that you did not conduct, that
were not conducted for you, or for which you do not have a right
of reference (described in section 505(b)(2) of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 355(b)(2))
or
·
a 505(b)(1) application, an NDA that relies
exclusively on studies that you conducted, that were conducted for
you, or for which you have a right of reference (submitted under
section 505(b)(1) of the act.
After an NDA for a prussian blue drug product
has been approved, abbreviated new drug applications (ANDAs) that
refer to the approved prussian blue drug product can be submitted
and approved (see 21 CFR part 314, subpart c). Because ANDAs
cannot be submitted until an NDA is approved, we primarily discuss
505(b)(1) and 505(b)(2) applications in this guidance.
If you rely on published literature,
including the literature we have already reviewed (see the
Federal Register notice announcing the availability of this
guidance) for approval of your application, your NDA will be a
505(b)(2) application.
A 505(b)(2) application could be considered
the more direct and, probably, the quickest approach to gaining
approval of an NDA for a prussian blue drug product. A 505(b)(2)
application could rely entirely on the published literature that
we have already reviewed for the clinical data required for
approval of an NDA (see Federal Register notice). If you
took this approach to approval, you would not need to submit
copies or summaries of the reports we have cited. The clinical
sections of your NDA would only have to cite the Federal
Register notice and the listed reports we relied on in making
our determination of safety and effectiveness.
As mentioned above, you can also submit a
505(b)(1) application. This type of NDA relies only on studies
that you conducted, that were conducted for you, or for which you
have a right of reference. These NDAs are sometimes called
full NDAs and are the type of application most frequently used
to gain approval for drug products whose active ingredient is not
in a previously approved drug product.
We recognize the importance of continuing the
development of products, such as prussian blue, to treat or
prevent radiation and other types of toxicity. We also recognize
that you might not be able to conduct definitive human efficacy
studies for prussian blue because it would be unethical to
deliberately expose healthy human volunteers to a lethal or
permanently disabling toxic substance, and new field trials to
study prussian blue's efficacy after an accidental or hostile
exposure to cesium-137 or thallium might be infeasible. We
encourage persons who wish to submit 505(b)(1) applications for
prussian blue drug products to contact us, before starting any
studies, to discuss the development of data to establish safety
and effectiveness.
NDAs submitted to the Agency for approval
must include chemistry, manufacturing, and controls information.
They must also contain labeling and the appropriate patent
information. These requirements are contained primarily in
' 314.50
(21 CFR 314.50).
In addition to the clinical data discussed in
the Federal Register notice announcing the availability of
this guidance and in section 1.A.2 of this guidance, your NDA must
also include a complete chemistry, manufacturing, and controls
section describing the composition, manufacture, and specification
of the drug substance and drug product (section 355(b)(1) of the
act and '
314.50). You also must meet all other applicable requirements
regarding the content of an NDA (section 355(b)(1) of the act and
'
314.50).
HEYL's
500-mg prussian blue capsules were used in the majority of the
recent published studies. If you rely on the published literature
we reviewed in making our determination about the potential safety
and effectiveness of prussian blue, you should submit the results
of in vitro studies showing that your product's binding to
thallium and nonradioactive cesium is comparable to that of HEYL's
product.
We have prepared draft labeling for orally
administered drug products containing 500-mg prussian blue
capsules. You can use this labeling for drug products as part of
a 505(b)(2) application for 500-mg prussian blue capsules. This
draft labeling reflects our conclusion on the potential safety and
effectiveness of 500-mg prussian blue drug products for treatment
of internal contamination with radioactive thallium,
nonradioactive thallium, or radioactive cesium. If you wish to
change the labeling to include a different or broader indication,
different dosage, or make any other significant changes to the
draft labeling, you should provide, as part of your 505(b)(2)
application, additional literature or other studies to support
your requested changes. If you submit a 505(b)(1) application for
a prussian blue drug product, you cannot use this labeling because
it is based on our review of the published literature. If you
submit a 505(b)(1) application for prussian blue, your labeling
must be based on the data contained in your NDA (section 355(b)(1)
of the act and § 314.50).
The draft labeling for 505(b)(2) applications
is available on the Internet.
You may also contact the Center for Drug Evaluation and Research's
Division of Medical Imaging and Radiopharmaceutical Drug Products
for a copy of the draft labeling.
If you submit an NDA (including a 505(b)(2)
NDA) for prussian blue, you must file with your NDA a list of the
patent numbers and expiration dates for each patent required to be
submitted under section 355(b)(1)(F) of the act and § 314.50. You
also must submit additional patent information within 30 days of
approval of your NDA or, in the case of newly issued patents,
within 30 days of issuance of the patent (section 355(c)(2) of the
act and § 314.50). If your NDA is approved, we will publish the
patent information in "Approved Drug Products with Therapeutic
Equivalence Evaluations" (the Orange Book).
We publish information regarding patents and
exclusivity periods for approved drug products in the Orange
Book. This information is important if you are considering
submitting ANDAs or 505(b)(2) applications for prussian blue drug
products. If a drug product listed in the Orange Book has
listed patents, the 505(b)(2) application or ANDA seeking to rely
on the finding of safety or effectiveness for that listed drug
must contain certifications regarding those patents (see
'
314.50(i) for 505(b)(2) applications, and § 314.94(a)(12) for
ANDAs).
In addition to the protection provided by
patents issued by the U.S. Patent and Trademark Office, prussian
blue drug products approved by us may be protected from
competition by periods of marketing exclusivity that are
administered by us. The act provides for periods of marketing
exclusivity that prevent us from filing or approving 505(b)(2)
applications or ANDAs for drug products that contain the same
active moiety[5]
as certain previously approved drug products. The active moiety
of a prussian blue drug product would be the prussian blue
molecule (i.e., the ferric hexacyanoferrate (II) molecule).
The following summaries of marketing
exclusivity and orphan drug exclusivity are provided solely for
the general information of manufacturers considering submitting an
NDA for a prussian blue drug product. They should not be read as
statements of our general policies regarding marketing exclusivity
and orphan drug exclusivity. Our policy can be found in the
regulations cited in this guidance.
A 5-year period of marketing exclusivity is
provided by section 505(c)(3)(D)(ii) and (j)(5)(D)(ii) of the act
when a sponsor obtains approval of an NDA for which no active
moiety has been previously approved by the FDA. The 5-year period
of marketing exclusivity generally prohibits us from filing a
505(b)(2) application or receiving an ANDA for a drug product that
contains the same active moiety as the first drug product
containing the active moiety to be approved.
The 5-year period of marketing exclusivity begins on the approval
date of the first NDA approved for a drug product containing the
active moiety. Both 505(b)(1) and 505(b)(2) applications may be
entitled to benefit from 5-year marketing exclusivity, but only
505(b)(2) applications and ANDAs are blocked by 5-year marketing
exclusivity.
Because we have never approved a drug product
that contains the prussian blue molecule as the active moiety, the
first NDA approved that contains prussian blue as the active
moiety will likely receive 5 years of marketing exclusivity. If
5-year exclusivity is awarded for an NDA containing prussian blue,
we cannot file
a subsequent 505(b)(2) application for 5 years after the approval
date of that NDA. If you have submitted an essentially complete
505(b)(2) application before we approve the first NDA for a
prussian blue drug product, review and approval of your 505(b)(2)
application would not be blocked by the marketing exclusivity
obtained by the first prussian blue drug product approval (54 FR
28872 at 28901, July 10, 1989). However, after we have approved
the first NDA for prussian blue, 5-year marketing exclusivity
would prohibit us from filing your 505(b)(2) application, no
matter how soon after the first approval we received your
application.
A 3-year period of marketing exclusivity may
be applicable to prussian blue drug products sometime in the
future. Three-year marketing exclusivity is provided by section
505(c)(3)(D)(iii) and (j)(5)(D)(iii) of the act. Drug products
whose active moiety is the same active moiety as that in a
previously approved drug product are entitled to 3-year
exclusivity if a new clinical study (other than a bioavailabilty
or bioequivalence study) is needed for their approval. If a drug
product, or change to a drug product, is given 3 years of
exclusivity, we are barred for 3 years from approving any
505(b)(2) application or ANDA for the same drug product, or change
to the product, that was granted exclusivity. For example, if an
applicant obtains 3 years of exclusivity for a new dosage form of
prussian blue, FDA may not approve a 505(b)(2) application or an
ANDA for that dosage form of prussian blue for 3 years. However,
we can approve a 505(b)(2) application or an ANDA for any
previously approved dosage form not protected by the exclusivity.
Our regulations in § 314.108 provide more
details on marketing exclusivity. If you are interested in how
marketing exclusivity could affect your NDA for prussian blue, you
are encouraged to discuss the issue with the Center for Drug
Evaluation and Research's Division of Medical Imaging and
Radiopharmaceutical Drug Products. If you believe your drug
product is entitled to marketing exclusivity, you must submit
supporting information in your NDA ('
314.50(j)).
In addition to 3- or 5-year marketing
exclusivity, orphan drug exclusivity may apply to prussian blue
drug products approved for orphan indications. Obtaining orphan
drug exclusivity is a two-step process. The regulations require
that you seek orphan drug designation for the active moiety of
your drug product for an orphan indication before you submit an
NDA. If we designate the drug as an orphan drug and then approve
it for the designated indication, the drug will receive orphan
drug exclusivity. The issues involved in determining which drug
products are entitled to orphan drug exclusivity and which drug
products are blocked by orphan drug exclusivity are described in
our regulations in part 316 (21 CFR part 316). However, we note
that orphan drug exclusivity is for a 7-year period and can
prohibit us from approving a 505(b)(1) application, a 505(b)(2)
application, or an ANDA for the same active moiety for the same
indication during the period of exclusivity. This differs from
5-year marketing exclusivity, which prohibits us from filing a
505(b)(2) application or receiving an ANDA, but would not prohibit
us filing a 505(b)(1) application.
If your right to any type of exclusivity for
a prussian blue drug product has vested, you can waive that
exclusivity. Your waiver would allow one or more applicants to
submit applications for the product. For example, if you obtain
5-year exclusivity with a 505(b)(2) application for a prussian
blue drug product, your complete waiver of such exclusivity would
enable other applicants to immediately submit 505(b)(2)
applications and ANDAs for drug products containing prussian
blue.
We encourage the development of drug products
containing prussian blue for the treatment of internal
contamination with radioactive thallium, nonradioactive thallium,
or radioactive cesium that represent improvements in safety,
effectiveness, or convenience. However, your submission of a
505(b)(2) application for such an innovative product may be
blocked by marketing exclusivity if the exclusivity is not
waived. If the innovative product is clinically superior to the
previously approved drug product, its approval might not be
blocked by orphan drug exclusivity (see
'
316.3(b)(13)). Once approved, an innovative product may qualify
for 3-year marketing exclusivity. If the innovation presents a
commercial advantage over the drug product that enjoys marketing
exclusivity, it may be possible to reach an agreement with the
person holding the exclusivity to allow marketing of the
innovative drug product.
The chemical name for
prussian blue is ferric hexacyanoferrate(II). The name
prussian blue has been used for various different, but
chemically related, compounds used as a blue pigment.
However, for purposes of this notice prussian blue refers only
to insoluble ferric hexacyanoferrate (II), which has an
empirical formula of Fe4[Fe(CN)6]3 and the Chemical Abstracts
Service (CAS) registry number 14038-43-8.
Active moiety is defined in 21 CFR 314.100(a) as the molecule
or ion, excluding those appended portions of the molecule that
cause the drug to be an ester, salt (including a salt with
hydrogen or coordination bonds), or other noncovalent
derivative (such as a complex, chelate, or clathrate) of the
molecule, responsible for the physiological or pharmacological
action of the drug substance.