Guidance for Industry
Calcium DTPA and Zinc DTPA Drug Products —
Submitting a New Drug Application
(PDF
version of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2004
Clinical Medical
Revision 1
Guidance for Industry
Calcium DTPA and Zinc DTPA 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. You can use an
alternative approach if the approach satisfies the requirements of
the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff responsible
for implementing this guidance. If you cannot identify the
appropriate FDA staff, call the appropriate number listed on the
title page of this guidance.
This guidance is intended to assist
manufacturers wishing to submit new drug applications (NDAs) for
pentetate calcium trisodium (Ca-DTPA) and pentetate zinc trisodium
(Zn-DTPA) drug products for the treatment of individuals with known
or suspected internal contamination with plutonium, americium, or
curium. In the Federal Register of September 15, 2003 (68 FR
53984), we announced the availability of this guidance, explained in
detail our findings regarding safety and effectiveness, and included
a list of citations to the literature on which we partially based
those findings. Draft product labeling was prepared for Ca-DTPA
supplied as 1 g in a 5 mL sterile aqueous solution for
administration either by inhalation (with a 1:1 dilution with saline
and delivered by nebulization) or intravenous injection. Draft
product labeling was also prepared for Zn-DTPA supplied as 1 g in a
5 mL sterile aqueous solution for intravenous injection.
On August 11, 2004, we revised the draft
product labeling for Ca-DTPA and Zn-DTPA to incorporate information
considered from additional literature citations and other available
clinical data. We are revising this guidance to explain our
labeling revisions. These labeling revisions reflect our current
thinking on (1) routes of administration, (2) duration of therapy,
and (3) safety risks reported in patients with severe
hemochromatosis who received four times the recommended daily dose
of Ca-DTPA by intramuscular injection.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe our current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory
or statutory requirements are cited. The use of the word should
in our guidances means that something is suggested or recommended,
but not required.
Diethylenetriaminepentaacetate (DTPA) is a
ligand that chelates certain transuranium elements.
The calcium salt of DTPA is known as pentetate calcium
trisodium and is referred to as Ca-DTPA.[2]
The zinc salt of DTPA is known as pentetate zinc trisodium and is
referred to as Zn-DTPA. For several decades, Ca-DTPA and Zn-DTPA
have been used investigationally to enhance the excretion of
transuranium elements from the body by means of ion exchange,
chelation, and, ultimately, excretion through the urine. The
calcium or zinc ions of the Ca-DTPA and Zn-DTPA drugs are readily
exchanged for the transuranium elements, and the transuranium-DTPA
complex is rapidly excreted in the urine.
Ca-DTPA and Zn-DTPA in sterile aqueous solution
have been used under investigational new drug applications (INDs)
held by the Radiation Emergency Assistance Center/Training Site (REAC/TS).
REAC/TS is part of the Oak Ridge Associated Universities (ORAU).
ORAU operates the Oak Ridge Institute for Science and Education (ORISE)
under a contract with the Department of Energy. The INDs are for
treatment of internal contamination resulting from nuclear power or
other industrial accidents.
REAC/TS has retained the medical case reports
on 646 individuals treated with Ca-DTPA and Zn-DTPA for radiation
contamination during the last 40 years. Data from bioassays
measuring urinary radioactive elimination were available for 286
individuals. Of these, 18 had matched pre- and post-chelation
therapy urine bioassay results and are considered the efficacy
cases. To facilitate the development and ultimate approval of
Ca-DTPA and Zn-DTPA drug products, we received permission to obtain
and review the medical reports on the individuals included in the
REAC/TS database. We also reviewed the related available published
literature.
After reviewing the REAC/TS database and the
published literature, we have concluded that Ca-DPTA and Zn-DTPA
drug products, when produced under conditions specified in approved
NDAs, can be found to be safe and effective for treatment of
individuals with known or suspected internal contamination with
plutonium, americium, or curium to increase the rates of
elimination.
III. NDAs
Submitted for Ca-DTPA and Zn-DTPA
Drug Products
An NDA for a Ca-DTPA or Zn-DTPA 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 Ca-DTPA or Zn-DTPA drug
product has been approved, abbreviated new drug applications (ANDAs)
that refer to the approved Ca-DTPA or a Zn-DTPA 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) and our
evaluation of the REAC/TS data 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 Ca-DTPA or a Zn-DTPA drug product. A 505(b)(2)
application could rely entirely on the published literature that we
have already reviewed and our evaluation of the REAC/TS data for the
clinical data required for approval of an NDA (see the Federal
Register notice announcing the availability of this guidance).
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, the listed reports we relied on in making our determination
of safety and effectiveness. However since the Federal Register
notice was published, we have become aware of additional published
reports of studies regarding Ca-DTPA and Zn-DTPA. You should submit
copies of these studies as part of your NDAs. You should contact
the Center for Drug Evaluation and Research's Division of Medical
Imaging and Radiopharmaceutical Drug Products (HFD-160), Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301-827-7510 for additional information on submitting reports of
these additional studies.
As mentioned above, you can also submit a
505(b)(1) application. This type of NDA relies only on studies that
you have 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 Ca-DTPA and Zn-DTPA drug products,
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 Ca-DTPA and Zn-DTPA 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 Ca-DTPA and Zn-DTPA efficacy after an accidental or
hostile exposure to a transuranium radioactive element might be
infeasible. We encourage persons who wish to submit 505(b)(1)
applications for Ca-DTPA and Zn-DTPA 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.
In addition to the clinical data discussed in
the Federal Register notice announcing the availability 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).
On August 11, 2004, we revised the draft
labeling for 1 g of Ca-DTPA in 5
mL of sterile aqueous solution for intravenous or inhalation
administration and 1 g of Zn-DTPA
in 5 mL of sterile aqueous solution for intravenous
administration. We considered information from additional
literature citations and other available clinical data and
incorporated new recommendations into the draft product labeling for
Ca-DTPA and Zn-DTPA, which may be summarized as follows:
- The inhalation route of administration would
benefit adults whose internal contamination is by inhalation
only. We revised the labeling for Zn-DTPA to add inhalation as a
route of administration.
FDA believes that availability of Zn-DTPA by the inhalation route
will be of particular benefit to the pregnant woman for whom Zn-DTPA
is the preferred chelator. The safety and effectiveness of Ca-DTPA
and Zn-DTPA administered by inhalation has not been established
for pediatric patients.
- We revised the Ca-DTPA and Zn-DTPA labeling
to state that the safety and effectiveness of the intramuscular
route of administration have not been established.
- We revised the Ca-DTPA and Zn-DTPA labeling
to recommend that the duration of chelation therapy depends on the
amount of internal radioactive contamination and the individual’s
response to therapy.
- We revised the labeling for Ca-DTPA to warn
about safety risks in patients with severe hemochromatosis who
received four times the recommended daily dose of Ca-DTPA by
intramuscular injection.
Although a causal association between these events and the drug
cannot be established, we recommend caution in treating patients
with severe hemochromatosis with Ca-DTPA.
You can use this revised draft labeling as part
of a 505(b)(2) application for Ca-DTPA or Zn-DTPA drug products.
This revised labeling reflects both our conclusions based on the
reports cited in the Federal Register notice, and our
tentative conclusions based on additional reports that we have
become aware of since publication of the Federal Register
notice regarding the potential safety and effectiveness of Ca-DTPA
and Zn-DTPA drug products for treatment of individuals with known or
suspected internal contamination with plutonium, americium, or
curium, to increase the rates of elimination.
If you wish to change the draft labeling to
include a different or broader indication or different dosage, or if
you wish to make any other significant changes to the 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 Ca-DTPA or Zn-DTPA drug
product, you may not use this labeling because it is based on our
review of the published literature and the REAC/TS data. If you
submit a 505(b)(1) application for Ca-DTPA or Zn-DTPA, your labeling
must be based on the data contained in your NDA (section 355(b)(1)
of the Act and § 314.50).
The revised draft labeling for 505(b)(2)
applications is available on the Internet.
You can also contact the Center for Drug
Evaluation and Research's Division of Medical Imaging and
Radiopharmaceutical Drug Products (HFD-160) for a copy of the
labeling.
If you submit an NDA (including a 505(b)(2) NDA)
for either Ca-DTPA and Zn-DTPA, you must file with your NDA a
complete patent declaration form (Form FDA 3542a) for each patent
that is required to be submitted under section 355(b)(1)(F) of the
Act and §§ 314.50 and 314.53. You also must submit an additional
patent declaration form (Form FDA 3542) 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 and 314.53). 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 Ca-DTPA and Zn-DTPA 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, Ca-DTPA and
Zn-DTPA 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[9]
as certain previously approved drug products. The active moiety of
a Ca-DTPA or Zn-DTPA drug product would be the
diethylenetriaminepentaacetate (DTPA) ligand.
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 Ca-DTPA and Zn-DTPA drug product. They should not be read as
statements of our general policy 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 not previously approved a drug
product that contains the DTPA ligand as the active moiety, the
first NDA approved that contains the DTPA ligand as the active
moiety will likely receive 5 years of marketing exclusivity. If an
NDA containing the DTPA ligand as the active moiety is entitled to
5-year exclusivity, we cannot file
a subsequent 505(b)(2) application for a Ca-DTPA or Zn-DTPA drug
product 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 Ca-DTPA or Zn-DTPA drug product,
review and approval of your 505(b)(2) application would not be
blocked by the marketing exclusivity obtained by the first Ca-DTPA
or Zn-DTPA drug product approval (54 FR 28872 at 28901; July 10,
1989). However, after we have approved the first NDA for a Ca-DTPA
or Zn-DTPA drug product, 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 Ca-DTPA and Zn-DTPA 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 Ca-DTPA or
Zn-DTPA, FDA may not approve a 505(b)(2) application or an ANDA for
that dosage form of Ca-DTPA or Zn-DTPA 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 Ca-DTPA or Zn-DTPA,
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 Ca-DTPA or Zn-DTPA
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 from filing a
505(b)(1) application.
If you are
entitled to any type of exclusivity for a Ca-DTPA or Zn-DTPA drug
product, you may waive that exclusivity after approval of your NDA.
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 Ca-DTPA or Zn-DTPA
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 Ca-DTPA or Zn-DTPA.
We encourage the development of drug products
containing Ca-DTPA or Zn-DTPA for the treatment of internal
contamination with transuranium elements 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 a
subsequent drug product represents an innovation that 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 subsequent
drug product.
For purposes of this notice Ca-DTPA refers only to pentetate calcium
trisodium, which has an empirical formula of Na3CaC14H18N3O10
and the Chemical Abstracts Service (CAS) registry number
12111-24-9. Zn-DTPA refers only to pentetate zinc trisodium,
which has an empirical formula of Na3ZnC14H18N3O10
and the CAS registry number 125833-02-5.
Active moiety
is defined in 21 CFR 314.10(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.
Back
to Top
Back to Guidance Page
Date created: August 19, 2004 |