Calcium DTPA and Zinc DTPA Drug Products-Submitting a New Drug Application

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Calcium DTPA and
Zinc DTPA Drug Products —
Submitting a New Drug
Application
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
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)
August 2004
Clinical Medical
Revision 1

TABLE OF CONTENTS
I. 	INTRODUCTION................................................................................................................. 1
II. 	BACKGROUND ................................................................................................................... 2
III. NDAs SUBMITTED FOR Ca-DTPA AND Zn-DTPA DRUG PRODUCTS .................. 3
A. 	Types of NDAs for Ca-DTPA and Zn-DTPA .............................................................................. 3
1. Submitting 505(b)(2) Applications................................................................................................... 3
2. Submitting 505(b)(1) Applications................................................................................................... 4
B. 	Content of NDAs for Ca-DTPA and Zn-DTPA........................................................................... 4
1. Chemistry, Manufacturing, and Controls Information .................................................................... 4
2. Labeling for Ca-DTPA and Zn-DTPA ............................................................................................. 5
3. Patent Information ........................................................................................................................... 6
C. 	Exclusivity....................................................................................................................................... 7
1. Five-Year Marketing Exclusivity ..................................................................................................... 7
2. Three-Year Exclusivity..................................................................................................................... 8
3. Orphan Drug Exclusivity ................................................................................................................. 9
4. Waiver of Exclusivity ....................................................................................................................... 9
D. 	Innovative Ca-DTPA and Zn-DTPA Drug Products.................................................................. 9

Contains Nonbinding Recommendations
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Guidance for Industry1
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.
I. 	INTRODUCTION
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.
1 This document was developed in the Division of Medical Imaging and Radiopharmaceutical Drug Products in the
Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).

Contains Nonbinding Recommendations
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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.
II. 	BACKGROUND
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
2 For purposes of this notice Ca-DTPA refers only to pentetate calcium trisodium, which has an empirical formula
of Na3CaC14 H 18N 3O 10 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 Na3ZnC14H 18N 3O 10 and the CAS registry
number 125833-02-5.

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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.3
III. 	NDAs SUBMITTED FOR Ca-DTPA AND Zn-DTPA DRUG PRODUCTS
A. 	Types of NDAs for Ca-DTPA and Zn-DTPA
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.
1. 	Submitting 505(b)(2) Applications
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
3 It is likely that other transuranium elements (e.g., berkelium and californium) could be eliminated by Ca-DTPA or
Zn-DTPA. However, there are no clinical effectiveness data to support this recommendation. Elements past
americium are very rarely seen in clinical settings and beyond californium, radioactive decay half-lives are so short
that accumulation of macroscopic amounts of these materials would not be possible.

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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.
2. 	Submitting 505(b)(1) Applications
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.
B. 	Content of NDAs for Ca-DTPA and Zn-DTPA
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.
1. 	Chemistry, Manufacturing, and Controls Information
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).

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2. 	Labeling for Ca-DTPA and Zn-DTPA
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.4 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.5
• 	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.6
4 In the REAC/TS database, an efficacy case internally contaminated with plutonium received three doses of
nebulized Zn-DTPA 1 g each, followed by 6 doses of intravenous Zn-DTPA 1 g. Urinary excretion of plutonium
after the first nebulized dose of Zn-DTPA was increased by a factor of 45. No pulmonary adverse events were
reported for this individual or for 17 other individuals treated with a total of 99 doses of Zn-DTPA via nebulization
in the REAC/TS database. The effectiveness of Zn-DTPA by inhalation is supported by the results of a preclinical
study in rodents contaminated with aerosolized plutonium and americium as described in Stather, JW, GN Stradling,
SA Gray, J Moody, and A Hodgson, "Use of DTPA for Increasing the Rate of elimination of Plutonium-238 and
Americium-241 from Rodents After their Inhalation as Nitrates," Human Toxicology, 4:573-582, 1985.
5 The intramuscular route was used in 8 individuals in the REAC/TS database, none of whom were efficacy cases.
Three of these experienced injection site pain. There are insufficient safety and effectiveness data to recommend
this route.
6 The previously published draft labeling for Ca-DTPA and Zn-DTPA recommended a minimum of 30 days of
chelation therapy. In the REAC/TS database, 72% of individuals who were treated with Ca-DTPA received only
one or two doses, while the remaining individuals received 3 or more doses. Among individuals treated with Zn-
DTPA, 50% received one or two doses, and the remainder received 3 or more. One individual received 338 doses of
Ca-DTPA 1 g over a 6.5-year period, and another individual received 574 doses of Zn-DTPA 1 g over a 3.5-year
period. FDA believes that the duration of therapy depends on the amount of internal contamination and the
individual’s response to therapy and cannot be predicted in advance.

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• 	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.7 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.8 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.
3. 	Patent Information
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
7 FDA is aware of three deaths in patients with severe hemochromatosis who received intramuscular doses of up to 4
g Ca-DTPA per day. One patient became comatose and died after receiving a total of 14 g Ca-DTPA, and the other
two died after 2 weeks of daily treatment. See FDA Medical Officer’s review dated July 29, 2004
(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/). In contrast, the literature contains a report of a patient
with a less severe case of hemochromatosis who received a total of 30 g Ca-DTPA by intravenous injection over 12
days and experienced no adverse events. This case is described in Kemble, JVH, "The New Chelating Agent Ca-
DTPA in the Treatment of Primary Haemochromatosis," Guy’s Hospital Reports, 113:68-73, 1964.
8 See http://www.fda.gov/cder/drug/infopage/dtpa/default.htm.

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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).
C. 	Exclusivity
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 moiety9 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.
1. 	Five-Year Marketing Exclusivity
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
9 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.

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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 file10 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.
2. 	Three-Year Exclusivity
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
10 Our regulations regarding filing an NDA and receiving an ANDA are found at 21 CFR 314.101.

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entitled to marketing exclusivity, you must submit supporting information in your NDA
(§ 314.50(j)).
3. 	Orphan Drug Exclusivity
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.
4. 	Waiver of Exclusivity
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.
D. 	Innovative Ca-DTPA and Zn-DTPA Drug Products
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.