**Guidance for Industry**

**Internal Radioactive Contamination ---Development of Decorporation
Agents**

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 90 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit
comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All
comments should be identified with the docket number listed in the
notice of availability that publishes in the *Federal Register*.

For questions regarding this draft document contact (CDER) Patricia A.
Stewart at 301-827-7510.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**February 2005**

**Clinical Medical**

**Guidance for Industry**

**Internal Radioactive Contamination ---Development of Decorporation
Agents**

*Additional copies are available from:*

*Office of Training and Communication*

*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)**

**February 2005**

**Clinical Medical**

**TABLE OF CONTENTS**

#####  {#section .TOC-5}

#  {#section-1 .TOC-1 .unnumbered}

# I. INTRODUCTION [1](#i.-introduction)II. background [1](#ii.-background) {#i.-introduction-1ii.-background-1 .TOC-1}

## A. Radiation Contamination Scenarios [2](#a.-radiation-contamination-scenarios) {#a.-radiation-contamination-scenarios-2 .TOC-2}

## B. Uptake and Clearance of Radioactive Contaminants [3](#b.-uptake-and-clearance-of-radioactive-contaminants) {#b.-uptake-and-clearance-of-radioactive-contaminants-3 .TOC-2}

## C. Management of External Radioactive Contamination [4](#c.-management-of-external-radioactive-contamination) {#c.-management-of-external-radioactive-contamination-4 .TOC-2}

## D. Treatment of Internal Radioactive Contamination [4](#d.-treatment-of-internal-radioactive-contamination) {#d.-treatment-of-internal-radioactive-contamination-4 .TOC-2}

### 1. General Principles [4](#general-principles) {#general-principles-4 .TOC-3}

### 2. The Gastrointestinal Tract as a Route of Elimination [5](#the-gastrointestinal-tract-as-a-route-of-elimination) {#the-gastrointestinal-tract-as-a-route-of-elimination-5 .TOC-3}

### 3. Prevention or Reversal of Radiocontaminant Interaction with Tissues [6](#prevention-or-reversal-of-radiocontaminant-interaction-with-tissues) {#prevention-or-reversal-of-radiocontaminant-interaction-with-tissues-6 .TOC-3}

### 4. Potential Radioactive Contaminants and Possible Treatments [8](#potential-radioactive-contaminants-and-possible-treatments) {#potential-radioactive-contaminants-and-possible-treatments-8 .TOC-3}

## E. Animal Efficacy Rule [9](#e.-animal-efficacy-rule) {#e.-animal-efficacy-rule-9 .TOC-2}

### 1. Applying the Animal Efficacy Rule to Decorporation Agents [10](#applying-the-animal-efficacy-rule-to-decorporation-agents) {#applying-the-animal-efficacy-rule-to-decorporation-agents-10 .TOC-3}

### 2. Three Requirements for Approval under the Animal Efficacy Rule [11](#three-requirements-for-approval-under-the-animal-efficacy-rule) {#three-requirements-for-approval-under-the-animal-efficacy-rule-11 .TOC-3}

# III. PRODUCT DEVELOPMENT PLAN FOR AN NDA, BLA, OR EFFICACY SUPPLEMENT [11](#iii.-product-development-plan-for-an-nda-bla-or-efficacy-supplement) {#iii.-product-development-plan-for-an-nda-bla-or-efficacy-supplement-11 .TOC-1}

## A. Study Sequence [11](#a.-study-sequence) {#a.-study-sequence-11 .TOC-2}

## [B.]{.smallcaps} Chemistry, Manufacturing, and Controls [12](#b.-chemistry-manufacturing-and-controls) {#b.-chemistry-manufacturing-and-controls-12 .TOC-2}

## C. Animal Efficacy Studies [13](#c.-animal-efficacy-studies) {#c.-animal-efficacy-studies-13 .TOC-2}

### 1. Considerations Regarding the Efficacy Study Supporting Approval [13](#considerations-regarding-the-efficacy-study-supporting-approval) {#considerations-regarding-the-efficacy-study-supporting-approval-13 .TOC-3}

### 2. Good Laboratory Practice (GLP) Compliance [14](#good-laboratory-practice-glp-compliance) {#good-laboratory-practice-glp-compliance-14 .TOC-3}

## [D.]{.smallcaps} Animal Safety Pharmacology and Toxicology Studies [14](#d.-animal-safety-pharmacology-and-toxicology-studies) {#d.-animal-safety-pharmacology-and-toxicology-studies-14 .TOC-2}

### 1. Safety Pharmacology Studies [14](#safety-pharmacology-studies) {#safety-pharmacology-studies-14 .TOC-3}

### 2. Toxicokinetic and Pharmacokinetic Studies [15](#toxicokinetic-and-pharmacokinetic-studies) {#toxicokinetic-and-pharmacokinetic-studies-15 .TOC-3}

### 3. Toxicology Studies [15](#toxicology-studies) {#toxicology-studies-15 .TOC-3}

## [E.]{.smallcaps} Clinical Pharmacology and Biopharmaceutics Studies [16](#e.-clinical-pharmacology-and-biopharmaceutics-studies) {#e.-clinical-pharmacology-and-biopharmaceutics-studies-16 .TOC-2}

## F. Safety Assessment in Humans [17](#f.-safety-assessment-in-humans) {#f.-safety-assessment-in-humans-17 .TOC-2}

## G. Benefit-Risk Assessment [19](#g.-benefit-risk-assessment) {#g.-benefit-risk-assessment-19 .TOC-2}

# IV. POSTAPPROVAL COMMITMENTS FOR PRODUCTS APPROVED UNDER THE ANIMAL EFFICACY RULE [20](#iv.-postapproval-commitments-for-products-approved-under-the-animal-efficacy-rule) {#iv.-postapproval-commitments-for-products-approved-under-the-animal-efficacy-rule-20 .TOC-1}

# GLOSSARY [1](#glossary) {#glossary-1 .TOC-1}

##  {#section-2 .TOC-2 .unnumbered}

**Guidance for Industry**[^1]

**Internal Radioactive Contamination ---**

**Development of Decorporation Agents**

This draft guidance, when finalized, will represent 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 document provides guidance to industry on the development of
decorporation agents for which evidence is needed to demonstrate
effectiveness but for which human efficacy studies are unethical or
infeasible. In such instances, the *Animal Efficacy Rule*, 21 C.F.R.
Part 314 Subpart I, may be invoked to approve new medical products not
previously marketed or new indications for previously marketed products.
Specifically, this document provides guidance on (1) chemistry,
manufacturing and controls (CMC) information, (2) animal efficacy,
safety pharmacology, and toxicology studies, (3) clinical pharmacology,
biopharmaceutics, and human safety studies, and (4) postapproval
commitments, for such products.

FDA's guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency's 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 Agency guidances means that
something is suggested or recommended, but not required.

# II. background

Internal radioactive contamination can arise from accidents involving
nuclear reactors, industrial sources, or medical sources. The potential
for such accidents has been present for many years. Recent events also
have highlighted the potential for nonaccidental radioactive
contamination as a result of malicious, criminal, or terrorist actions.
Internal contamination occurs when radioactive material is ingested,
inhaled, or absorbed from a contaminated wound. As long as these
radioactive contaminants remain in the body, they may pose significant
health risks. The risks are largely long term in nature and depend not
only on the type and concentration of the radioactive contaminant
absorbed, but also on the health status of the exposed individual. The
potential for development of cancers of the lung, liver, thyroid,
stomach, and bone, among others, are principal long-term health
concerns, as are fibrotic changes in tissues such as lung, which may
lead to restrictive lung disease and other chronic debilitating
conditions. The only effective method of reducing these risks is removal
of the radioactive contaminants from the body.^2^ The long latency of
these conditions means that evaluation and treatment of internal
contamination should not take precedence over treatment of conventional
injuries that may be acutely life-threatening. However, early
recognition of internal contamination provides the greatest opportunity
for radiocontaminant removal.[^2]

For the purposes of this guidance, the term *decorporation agents*
refers to medical products[^3] that increase the rate of elimination or
excretion of absorbed, inhaled, or ingested radioactive contaminants.
The effectiveness of most decorporation agents for the treatment of
internal radioactive contamination cannot be tested in humans because
the occurrence of accidental or nonaccidental radioactive contamination
is rare, and it would be unethical to deliberately contaminate humans
with potentially harmful amounts of radioactive materials for
investigational purposes.

## A. Radiation Contamination Scenarios

A *radiological dispersal device* (RDD) (sometimes called a \"dirty
bomb\") is a device that causes the purposeful dissemination of
radioactive material across an area using conventional (nonnuclear)
explosives. The material dispersed could originate from any location
that uses radioactive sources, such as a nuclear power plant, an
industrial complex, or medical and research facilities. The radioactive
material would be scattered as radioactive debris across an area that
depends on the size of the explosive and how high above the ground the
detonation occurs. Considering radioactive half-life and commercial
availability, some of the radioactive contaminants that might be used in
an RDD include strontium-90, cobalt-60, cesium-137, iridium-192,
radium-226, and americium-241. Within the blast zone, this type of
weapon would cause conventional blast casualties contaminated with
radioactive material and would complicate medical evacuation within the
contaminated area. In addition, individuals outside the conventional
blast zone, including rescue workers, would be at risk for internal
contamination through inhalation of radioactive debris if not properly
protected.

Significant amounts of radioactive material may be deposited on surfaces
not only through RDDs but also through the use of a nuclear weapon, the
destruction of a nuclear reactor, or an industrial or military nuclear
accident. Persons living or working in contaminated areas could receive
sufficient radioactive contamination to suffer acute symptoms of
radiation injury and could develop late sequelae such as cancer or
genetic damage.

## B. Uptake and Clearance of Radioactive Contaminants

The uptake and retention of a radioactive contaminant is influenced by
its portal of entry, chemistry, solubility, metabolism, and particle
size.Error: Reference source not found^,^[^4]^,^[^5] Internal
contamination occurs by three main routes: inhalation, ingestion, and
wound contamination. A fourth and infrequent route is percutaneous
absorption, which applies almost exclusively to radioactive tritium in
association with water.

Of the exposure routes, inhalation poses the greatest threat, especially
in a fallout environment.Error: Reference source not
found^,Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found^
The size of the radioactive particle influences lung deposition, because
particles with an aerodynamic diameter greater than 10 microns tend to
be deposited in the upper respiratory tract. Particles that are
deposited in the lower respiratory tract may be more easily absorbed
into the body and later taken up by target organs. Insoluble particles
(especially plutonium from unspent fuel or industrial accidents) pose a
particular threat to the lung because prolonged exposure of the lower
respiratory tract to alpha emitters such as plutonium causes an
increased incidence of pulmonary malignancy.Error: Reference source not
found^,^[^6] Depending on the aerodynamic diameter of the particles and
other factors, about 25 percent of inhaled radioactive particles may be
immediately exhaled, leaving the remaining 75 percent to be deposited
along the respiratory tree.Error: Reference source not found About half
of the retained particles are deposited in the upper bronchial tree,
where they are moved by the ciliary epithelium to the nasopharynx, where
some may be expectorated but some are swallowed, thereby entering the
gastrointestinal path. Ingestion is thus usually secondary to
inhalation, but direct ingestion from contaminated foodstuffs may also
occur. The degree of intraluminal gastrointestinal exposure and possible
absorption of certain radioactive contaminants depends on transit time
through the gut, which will vary widely from person to person.Error:
Reference source not found^,Error:\ Reference\ source\ not\ found^ The
much slower rate of movement in the large intestine places its luminal
lining at higher risk for damage from nonabsorbed radiocontaminants.
Gastrointestinal transit time may be shortened by use of emetic and/or
purgative agents.

Some relatively soluble radioactive contaminants may not be absorbed due
to acidic or caustic properties that fix them to tissue proteins.Error:
Reference source not found Systemic absorption through the intestine
varies widely, depending on the radioactive contaminant and its chemical
form and characteristics. For instance, clear differences exist between
radioiodine, which is rapidly and completely absorbed, and plutonium,
which is not absorbed to any appreciable extent (0.003 percent).Error:
Reference source not found The gastrointestinal tract is the critical
target organ for the many insoluble radioactive contaminants that travel
its length almost unabsorbed.

Wounds contaminated by fallout and shrapnel may provide continuous
irradiation of surrounding tissues and increase the likelihood of
systemic incorporation.Error: Reference source not
found^,Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found^
This hazard remains until the contaminant is removed by irrigation,
surgical debridement, or decay.

## C. Management of External Radioactive Contamination

Radioactive contamination of the skin is usually not immediately
life-threatening to either the patient or medical personnel, especially
after the removal of clothing and external decontamination, unless the
dose rate is several Gray (Gy) per hour.

Following the removal of clothing and external decontamination,
evaluation and monitoring by a medical professional or health physicist
should be performed as soon as possible to provide qualitative and
quantitative information about residual external contamination as well
as internal contamination.Error: Reference source not found If the
external radioactive contaminant persists in spite of initial washing
with soap or detergent and water, further decontamination should be
supervised by an appropriately trained physician.Error: Reference source
not found

## D. Treatment of Internal Radioactive Contamination

The goals of internal decontamination are to reduce absorption and to
enhance excretion of radioactive contaminants. Treatment is most
effective if it is started as soon as possible after contamination.
Radioactive contaminants may be internalized via inhalation, ingestion,
or through wounds and skin. Treatment should be directed by knowledge of
the specific radiocontaminant. Ideally, internal decontamination should
begin during the first few hours if the treating physician suspects that
radiocontaminants may have been internalized. Currently, as discussed
below, Prussian blue, KI, Ca-DTPA and Zn-DTPA, when manufactured under
conditions specified in an approved NDA, have been found safe and
effective for the treatment of internal contamination with radioactive
cesium, iodine, and plutonium, americium, or curium, respectively.
Currently, Prussian blue, potassium iodide, and Ca- and Zn-DTPA are
approved products in the United States.

### 1. General Principles 

Early information on the history of the incident may identify the major
radioactive contaminants involved and provide some dosimetry
information. Patients will likely present with no clinical symptoms of
contamination, but may have sustained burns, lacerations, or other more
serious trauma. Immediate treatment for physical injuries should be
initiated to stabilize the patient. After the patient is stabilized,
critical decisions on initiating treatment for internal radioactive
contamination will need to be made based on historical information (to
determine the level of contamination and the possible radiocontaminants
involved), as well as knowledge of the metabolism of the
radiocontaminants, human physiology, and the pharmacology of available
treatments. Treatment for internal contamination should begin as soon as
possible after contamination,Error: Reference source not
found^,Error:\ Reference\ source\ not\ found^^,Error:\ Reference\ source\ not\ found,^[^7]^,^[^8]
and appropriate monitoring for excretion of radiocontaminants (a measure
of treatment efficacy) should follow. Radiation dose estimates obtained
by appropriate whole-body counting, by bioassay or biodosimetry, or by
urinary or fecal sampling, may be used to determine the treatment
course. If feasible and the route of elimination is known, it is helpful
to obtain a baseline measurement of radiation excretion.

Physicochemical properties of radiocontaminants will play a significant
role in determining treatment. The solubility of the contaminant may
determine its absorption and distribution within the body. Because most
potential contaminants are at least partially soluble, some small
fraction of the contaminant will usually become internalized from the
lung or through a wound. On the other hand, normally soluble materials
may be present in an insoluble form, or may become insoluble under
systemic physiological conditions. Therefore, without initial knowledge
of the identity of the contaminant or its solubility, treatment based on
an estimate of the most probable radiocontaminants present should begin
as soon as possible to significantly increase the probability of
successful internal decontamination.Error: Reference source not
found^,Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found^

In a complete nuclear detonation (e.g., a complete fission event), more
than 400 radioactive contaminants would be released. Of these, only
about 40 are potentially hazardous to humans.Error: Reference source not
found^,Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found^
The most significant radiocontaminants from unspent nuclear fuel
(potentially used in an RDD) or nuclear weapons accidents are tritium,
plutonium, and uranium. Radiocontaminants of immediate medical
significance are listed in Table 1, with descriptions of their
properties, target organs, and treatment (either with an FDA approved
product or as suggested in the literature).

### 2. The Gastrointestinal Tract as a Route of Elimination 

It may be appropriate to remove or enhance transit of gastrointestinal
contents after radioactive contamination if contamination has recently
occurred via ingestion. It is recommended that the current standard of
care as it applies to other poisonings and overdoses by the oral route
be used unless consciousness is impaired or ingestion of corrosive
agents has occurred.

Certain nonabsorbed binding resins may have utility in inhibiting the
uptake of radioactive contaminants in the gut. For example, Prussian
blue, a nonabsorbed pigmented resin, has been used since the 1960s as an
investigational agent administered orally to enhance the fecal excretion
of cesium and thallium by means of ion exchange. Prussian blue was used
to treat victims in the 1987 cesium-137 contamination incident in
Goiânia[^9]^,^[^10] and has been well tolerated in humans.
^Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found,^[^11]^,^[^12]
In Goiânia, contamination occurred primarily via the oral route, but the
radiocontaminant was no longer present in the GI tract in substantial
amounts when treatment with Prussian blue was begun. Prussian blue may
be continued for 30 days or longer, as dictated by the level of
contamination; it was used for prolonged periods in several of the
Goiânia casualties.

After review of the published literature and other available data, FDA
concluded in 2003 that Prussian blue, when produced under conditions
specified in approved new drug applications (NDAs), is safe and
effective for the treatment of internal contamination with radioactive
thallium, nonradioactive thallium, or radioactive cesium.[^13] At the
same time, FDA announced the availability of a guidance document,
*Prussian Blue Drug Products: Submitting a New Drug Application,* to
assist manufacturers who plan to submit NDAs for Prussian blue. One
manufacturer (HEYL Chemisch-pharmazeutische Fabrik GmbH & Co. KG) has
since received approval for its Prussian blue product (Radiogardase).

There are suggestions in the literature that other nonabsorbed binding
resins, such as sodium polystyrene sulfonate, may also have utility in
inhibiting the uptake of radioactive contaminants in the gut.Error:
Reference source not found Sodium polystyrene sulfonate is approved in
the United States under the name Kayexelate but is not approved as a
decorporation agent.

Aluminum-containing antacids are relatively well-tolerated and have been
recommended for reducing the absorption of radioactive strontium.Error:
Reference source not found^,Error:\ Reference\ source\ not\ found^ There
are preliminary data to suggest that either aluminum phosphate gel or
aluminum hydroxide, given immediately after exposure, may decrease the
absorption of radioactive strontium in the gut. Error: Reference source
not found^,Error:\ Reference\ source\ not\ found^ The efficacy of these
products as potential decorporation agents has not been established,
however, and none is approved in the United States for that indication.

### 3. Prevention or Reversal of Radiocontaminant Interaction with Tissues 

#### a. Blocking and Diluting Agents 

> For radiocontaminants already in the blood, *blocking and diluting
> agents* will reduce uptake at target tissues. Administering a blocking
> agent such as potassium iodide (KI) allows for saturation of metabolic
> processes in the thyroid with stable, nonradioactive iodine thereby
> preventing uptake of radioactive iodine. In 1978, FDA announced its
> conclusion that KI is safe and effective for use as a blocking agent
> to prevent the uptake of radioactive iodine by the thyroid in a
> radiation emergency under certain specified conditions of use.[^14] In
> 1982, FDA announced its final recommendations on the administration of
> KI to the general public in a radiation emergency.[^15] These
> recommendations were formulated after reviewing studies relating
> radiation dose to risk of thyroid disease. FDA relied on estimates of
> external thyroid irradiation after the nuclear detonations at
> Hiroshima and Nagasaki and analogous studies among children who
> received therapeutic radiation to the head and neck. The agency
> concluded that, at a projected dose to the thyroid of 25 cGy or
> greater from ingested or inhaled radioactive iodine, the benefits of
> short-term use of small quantities of KI outweighed the potential risk
> of thyroid cancer.
>
> In 2001, after careful review of the data from the Chernobyl accident
> relating estimated thyroid radiation dose and cancer risk in exposed
> children, FDA revised its recommendation for administration of KI
> based on age, predicted thyroid exposure, and pregnancy and lactation
> status.[^16] In its revised guidance, FDA emphasized that KI should be
> used as an adjunct to evacuation (although that may not always be
> feasible), sheltering, and control of foodstuffs. [^17]
>
> Dilution is achieved by the administration of large quantities of the
> stable, nonradioactive isotope so that incorporation of the
> radioactive contaminant is minimized. As an example, forced hydration
> can increase the excretion of tritium.Error: Reference source not
> found For maximum effectiveness, the stable isotopes that are used as
> the blocking or diluting agents should be at least as rapidly absorbed
> and metabolized as their radioactive counterparts.

#### b. Mobilizing Agents 

> *Mobilizing agents* are compounds that enhance and increase the
> natural turnover processes of radioactive contaminants and thereby
> accelerate their release from tissues. They are most effective when
> given immediately following contamination, but they may retain some
> effectiveness for up to 2 weeks after contamination. Drugs that have
> been recommended for this purpose include antithyroid drugs, ammonium
> chloride, diuretics, expectorants and inhalants, parathyroid extract,
> and corticosteroids.Error: Reference source not
> found^,Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found^
> These agents require experienced consultation, treatment, and
> management and are not currently FDA approved as decorporation agents.

#### c. Chelating Agents 

> *Chelators* are substances that bind with certain metals to form a
> stable complex that can be more rapidly eliminated from the body via
> excretion by the kidneys. Diethylenetriaminepentacetate (DTPA), as the
> calcium or zinc salt, has been used as an investigational agent for
> many years in this capacity.Error: Reference source not
> found^,Error:\ Reference\ source\ not\ found,24,Error:\ Reference\ source\ not\ found,Error:\ Reference\ source\ not\ found,^[^18]
> DTPA forms stable complexes with transuranium elements, and these
> complexes are renally excreted, thus decreasing body burden. The
> calcium and zinc salts of DTPA have both been used investigationally
> for the treatment of plutonium, americium or curium internal
> contamination under an IND (investigational new drug) application held
> by the Radiation Emergency Assistance Center/Training Site (REAC/TS).
> Ca-DTPA is administered as a single intravenous injection or inhaled
> dose as soon as possible after contamination and repeated doses of
> Zn-DTPA administered intravenously may be given daily as necessary as
> maintenance therapy. Based on a review of the data maintained by
> REAC/TS, in 2003 FDA determined that Ca-DTPA and Zn-DTPA, when
> produced under conditions specified in an approved NDA, can be safe
> and effective for the treatment of internal contamination with
> plutonium, americium, and curium.[^19] At the same time, FDA announced
> the availability of a guidance document, *Calcium DTPA and Zinc DTPA
> Drug Products: Submitting a New Drug Application*, to assist
> manufacturers who plan to submit NDAs for Ca-DTPA and Zn-DTPA.
> Recently, FDA has approved NDAs submitted by Hameln Pharmaceuticals
> GmbH for Ca- and Zn-DTPA.
>
> DTPAs bind uranium less well and are not expected to be effective for
> uranium contamination (see Ca-DTPA and Zn-DTPA product labeling at
> http://www.fda.gov/cder/drug/infopage/DTPA/default.htm). Uranium
> contamination has been treated with oral sodium bicarbonate, regulated
> to maintain an alkaline urine pH, and accompanied by diuretics.Error:
> Reference source not found Oral sodium bicarbonate has not been
> approved in the United States for this indication.

### 4. Potential Radioactive Contaminants and Possible Treatments

Radioactive contaminants of immediate medical significance and possible
treatments are listed in the following table.

**TABLE 1. RADIOACTIVE CONTAMINANTS WITH MEDICAL SIGNIFICANCE AND
POSSIBLE TREATMENTS** [^20]

  --------------------------------- --------------- ----------- ----------------- --------------------
  **Radioactive Contaminant**       **Radiation**   **Target    **Contamination   **Treatment**
                                    **Type**[^21]   Organ**     Mode\***          

  Americium-241                     α, γ            Bone        I/W               CaDTPA, ZnDTPA†

  Californium-252                   γ, α, η         Bone        I/W               CaDTPA, ZnDTPA†

  Cerium-141, 144                   β, γ            GI, lung    I/GI              CaDTPA, ZnDTPA†

  Cesium-137                        β, γ            Total body  I/S/GI            Prussian blue£

  Curium-244                        α, γ, η         Bone        I/GI              Ca-DTPA, Zn-DTPA†

  Iodine-131, 132, 134, 135         β, γ            Thyroid     I/GI/S            KI ¥

  Plutonium-239, 238                α, γ            Bone        I/W               CaDTPA, ZnDTPA†

  Polonium-210                      α               Lung        I                 Dimercaprol‡

  Strontium-89, 90                  γ               Bone        I/GI              AlPO4\*\*

  Tritium (^3^H)                    β               Total body  I/S/GI            Forced H2O§

  Uranium-238, 235, 239             α, β, γ         Bone        I/S/W             NaHCO3\*\*\*

  \* Contamination Mode: I by                                                     
  inhalation; GI by                                                               
  gastrointestinal absorption; S by                                               
  skin absorption; W by wound                                                     
  absorption                                                                      

  \*\* The antacid aluminum                                                       
  phosphate in gel form used as a                                                 
  gastrointestinal adsorbent for                                                  
  radiostrontium                                                                  

  \*\*\* Sodium bicarbonate to                                                    
  maintain alkalinity of urine used                                               
  in conjunction with diuretics                                                   

  † Calcium and Zinc DTPA, metal                                                  
  complexes of                                                                    
  diethylenetriaminepentaacetate.                                                 
  Both are currently FDA approved.                                                
  The calcium form is recommended                                                 
  for the first decontaminating                                                   
  dose, followed with the zinc form                                               
  for subsequent doses.                                                           

  ‡ A mercury and arsenic poisoning                                               
  chelation agent (very toxic)                                                    

  ¥ Agent blocking radioiodine                                                    
  absorption in tissues resulting                                                 
  in its dilution                                                                 

  § Simple forced intake of water,                                                
  resulting in tritium dilution                                                   

  £ A dye used as an ion exchanger,                                               
  currently FDA approved                                                          
  --------------------------------- --------------- ----------- ----------------- --------------------

## E. Animal Efficacy Rule

## 

In May 2002, FDA promulgated a rule allowing for approval of new drug
and biological products based on animal data when adequate and
well-controlled efficacy studies in humans cannot be ethically conducted
because the studies would involve administering a potentially lethal or
permanently disabling toxic substance or organism to healthy human
volunteers, and field trials are not feasible prior to approval. The
intent of the \"Animal Efficacy Rule\"[^22] is to facilitate the
development of medical countermeasures to treat or prevent injury from
chemical, biological, nuclear, or radiological agents. The rule does not
apply to products that can be approved based on other efficacy standards
(e.g., accelerated approval based on surrogate markers or clinical
endpoints other than survival or irreversible morbidity), nor does it
address the safety evaluation of the products to which it does apply.

Emergencies may arise necessitating human use of a decorporation agent
still under development and for which approval under the Animal Efficacy
Rule is not immediately feasible. Should this situation arise, it is
conceivable that the product could be used under FDA\'s investigational
new drug regulations in 21 CFR Part 312 or under the emergency use
authorization provision in § 564 of the Federal Food, Drug, and Cosmetic
Act.

## 

### 1. Applying the Animal Efficacy Rule to Decorporation Agents

For decorporation agents used to enhance elimination or excretion of
absorbed radioactive contaminants, animal studies may be used to provide
substantial evidence of effectiveness only when (1) there is a
reasonably well-understood pathophysiological mechanism of the toxicity
of the radioactive contaminant and its elimination or excretion by the
decorporation agent, (2) the effect is demonstrated in more than one
animal species expected to react with a response predictive for humans,
unless the effect is demonstrated in a single animal species that
represents a sufficiently well-characterized animal model for predicting
the response in humans, (3) the animal study endpoint is clearly related
to the desired benefit in humans, and (4) pharmacokinetic and
pharmacodynamic data or information in animals and humans are sufficient
to allow selection of an effective dose in humans. It should be noted
that animal efficacy studies are subject to the same good laboratory
practice (GLP) requirements as animal toxicology studies (see below).

In some situations, human efficacy studies using nontoxic levels of the
radioactive contaminant or a stable, nonradioactive counterpart may be
feasible and ethical. In such cases, approval could be based on efficacy
standards described elsewhere in FDA\'s regulations, and evidence of
effectiveness from animal studies alone would not be sufficient to
support approval of a new product or a new indication for an already
marketed product. Human efficacy studies would be needed to support
marketing approval (*see* 21 CFR 314.600 and 601.90).

Even if a new decorporation agent is eligible for approval under the
Animal Efficacy Rule, that agent must still be evaluated for safety in
humans; animal data is not sufficient to demonstrate safety (21 CFR
314.600 and 601.90). Products evaluated for effectiveness under the
Animal Efficacy Rule must be evaluated for safety under preexisting
requirements for establishing the safety of new drug and biologic
products (21 CFR 314.600 and 601.90). FDA believes that the safety of
these products (unlike their effectiveness) can be studied in human
volunteers.

### 2. Three Requirements for Approval under the Animal Efficacy Rule

Approval of a decorporation agent under 21 CFR part 314 subpart I and 21
CFR part 601 subpart H requires: (1) submission of a plan or approach to
postmarketing studies that would be feasible should an accidental or
intentional release of radiation occur, (2) postmarketing restrictions
to ensure safe use, if deemed necessary, and (3) product labeling
intended for the patient to be provided prior to product administration
or dispensing, advising, among other things, that the product's approval
was based on efficacy studies conducted in animals alone.

# III. PRODUCT DEVELOPMENT PLAN FOR AN NDA, BLA, OR EFFICACY SUPPLEMENT

We recommend that a sponsor planning to develop a decorporation agent
for submission as (1) a new drug application (NDA) or biologic license
application (BLA), or (2) an efficacy supplement for a marketed product
in support of a new use as a decorporation agent, meet with
representatives of the Division of Medical Imaging and
Radiopharmaceutical Drug Products and the Office of Counter-Terrorism
and Pediatric Drug Development in CDER regarding the specifics of a
product's development plans. This is particularly important if the
sponsor intends to seek approval under the Animal Efficacy Rule.

A comprehensive search of the medical literature and available
scientific databases may reveal important information regarding a
product's chemistry, animal safety pharmacology, toxicology and
efficacy, or human pharmacology and safety and inform the sponsor
regarding additional studies that may be needed. Sponsors are encouraged
to attempt to access primary data and perform an independent review of
published findings to the extent possible. In most instances, literature
references alone will not provide substantial evidence of effectiveness
of a new product or new use, and additional well-controlled, animal
efficacy and human pharmacology and safety studies will be needed.[^23]

## A. Study Sequence 

A typical sequence for the requisite animal and human studies to support
approval under the Animal Efficacy Rule is represented below. Additional
detailed information is contained in the specified subsection.

-   Search of the published literature and available scientific
    databases and review of source documents, if available

-   Tests of effectiveness in vitro*;* assay development and validation
    (i.e, chemistry, manufacturing, and controls) (Subsection III.B)

-   Preliminary or exploratory animal efficacy studies, typically in
    rodents or other suitable small animal model (Subsection III.C)

-   Animal safety pharmacology and toxicology studies (Subsection III.D)

-   Single-dose, dose escalation, safety, and tolerability studies in
    humans (initial first in human studies), using doses supported by
    animal data, as required (Subsection III.E)

-   Selection of the most appropriate animal species for the definitive
    efficacy study, the one on which approval will be based; the animal
    species selected should be similar to humans with respect to the
    pharmacokinetic profile of the decorporation agent and the
    distribution of the radioactive contaminant.

-   Efficacy study supporting approval, conducted in the most
    appropriate animal species (Subsection III.C)

-   Safety studies in humans; FDA recommends that these studies be
    conducted at the highest dose anticipated to be marketed and be
    performed in parallel with the pivotal animal efficacy study,
    assuming the product is reasonably likely to produce clinical
    benefits in humans (Subsection III.F).

## [B.]{.smallcaps} Chemistry, Manufacturing, and Controls 

###  

The same standards for chemistry, manufacturing, and controls (CMC)
apply to decorporation agents as with other pharmaceuticals. We
recommend sponsors consult the

appropriate FDA guidances for drug substances, drug products, and
biological products. We also recommend that sponsors consider developing
pediatric-appropriate dosage forms (e.g., liquid preparations, powder
formulations for suspension), as appropriate.

Specifications for new drug substances (also referred to as new chemical
entities) and new indications for previously approved drug or biological
products should be adequate for the intended dosage form and route of
administration to ensure identity, strength, quality, purity and
potency.[^24]

FDA recommends that sponsors develop and validate in vitro tests
intended to predict the effectiveness of isotope (radioactive or
nonradioactive) uptake by a decorporation agent. FDA also urges sponsors
to establish the time course of uptake, generally as part of the
specification for product release and stability. For example, in the
case of Prussian blue, FDA used the mass uptake of nonradioactive cesium
per gram of Prussian blue as a function of time as a measure of its
probable effectiveness. This in vitro test measures not only the total
uptake of cesium, but also the kinetics of the solution to solid
(heterogeneous) exchange reaction. The synthetic procedure for
manufacturing Prussian blue can produce insoluble solids of highly
variable particle size, porosity, hydration, and defect impurities. In
FDA's experience, it was important to consider the effects of all of
these factors on Prussian blue's cesium exchange properties.

## 

## C. Animal Efficacy Studies

Under the Animal Efficacy Rule, a sponsor can rely on animal studies to
provide substantial evidence of effectiveness for certain new drug or
biological products intended to reduce or prevent the toxicity of
chemical, biological, radiological, or nuclear substances. Under 21 CFR
314.610(a)(2) and 601.91(a)(2), one of the requirements for approval
based on effectiveness data from animals alone is that the effect is
demonstrated in more than one animal species expected to react with a
response predictive for humans, unless the effect is demonstrated in a
single animal species that represents a sufficiently well-characterized
animal model for predicting the response in humans. Determination of the
number of animal studies needed to support approval of a particular NDA
or BLA will be made on a case by case basis, as will the determination
of what constitutes a sufficiently well-characterized animal model for a
given product or indication. In FDA\'s experience, animal efficacy
studies found in the published literature or conducted without the
expressed purpose of supporting regulatory submissions have often lacked
adequate scientific rigor. Furthermore, unless there are sufficient
pharmacokinetic and/or pharmacodynamic data to conclude that a rodent
species will adequately predict the human response, FDA believes that
the effectiveness of a proposed decorporation agent will need to be
demonstrated in a second, probably non-rodent, animal species.

### 1. Considerations Regarding the Efficacy Study Supporting Approval 

We recommend that the following factors be considered in the design and
interpretation of the animal efficacy study or studies that will support
product approval (this list is not comprehensive):

1\. Conducting the study in an appropriate animal species; the
pharmacokinetic profile of the product and the distribution of the
radioactive contaminant in the selected species should be similar to
what is observed or expected in humans.

> 2\. Inclusion of both male and female animals; the number of animals
> and the inclusion of appropriate controls should be adequate for
> proper statistical analysis.
>
> 3\. Use of a test product that is pharmaceutically equivalent to that
> intended for humans.
>
> 4\. Evaluation of a range of doses and calibration of a dose-response
> relationship.
>
> 5\. Use of a dosing frequency and route of administration that are
> similar, if not identical, to that intended for humans; determination
> of the efficacy window (i.e., the timing of product administration
> relative to radioactive contamination and duration of treatment).
>
> 6\. Efficacy can be based on direct measurement of the elimination of
> the radioactive contaminant through feces and/or urine (or exhalation,
> as appropriate) at various time points after administration of the
> decorporation agent; alternatively, measurement of the residual body
> burden may be evaluated. These measurements can then be used to
> calculate changes in *whole-body committed radiation dose* following
> product administration. It is generally acknowledged that the
> long-term risk of cancer is a function of the radiation dose received.
> Clinically meaningful reduction in *whole-body committed radiation
> dose* (see Glossary definition) following administration of a
> decorporation agent in the pivotal animal efficacy study or studies is
> "clearly related to the desired benefit in humans, generally the
> enhancement of survival or prevention of major morbidity" under 21 CFR
> 314.610(a)(3).[^25]
>
> 7\. Designing the study using the relevant characteristics of an
> adequate and well-controlled study as described in 21 CFR 314.126,
> including reduction of bias, a clear protocol, and a statistical plan.
> To support approval, the decorporation agent should demonstrate a
> statistically superior and clinically meaningful reduction in
> whole-body committed radiation dose compared to control.

### 2. Good Laboratory Practice (GLP) Compliance 

Because efficacy studies will not be conducted in humans when a product
is approved under the Animal Efficacy Rule, it is essential to ensure
the quality and reliability of the animal efficacy data. Therefore
pivotal efficacy studies supporting approval must be conducted in
compliance with GLPs (see 21 CFR Part 58).

## [D.]{.smallcaps} Animal Safety Pharmacology and Toxicology Studies

We urge sponsors to conduct animal safety studies to define
pharmacological and toxicological effects prior to initiation of
first-in-human clinical trials to establish a safe starting dose for
decorporation agents that are new molecular entities (NMEs). FDA
recommends that the product used for definitive animal safety
pharmacology and toxicology studies be pharmaceutically equivalent to
the product proposed for human studies. If the decorporation agent is a
product that has already been approved for marketing, or if
comprehensive animal or human data are available under another NDA or
BLA that the sponsor either owns or has a right of reference to,
additional safety pharmacology and toxicology studies may not be
required, unless the route of administration, dosing regimen, and/or
formulation is new.

### 1. Safety Pharmacology Studies 

Safety pharmacology studies investigate potential undesirable
pharmacodynamic effects on physiologic functions in relation to exposure
in the therapeutic range and above. FDA recommends that sponsors perform
safety pharmacology studies assessing effects on the cardiovascular,
central nervous, pulmonary, and renal systems prior to first
administration in humans.[^26]^,^[^27] Follow-up or supplemental studies
may also be needed if there is cause for concern. Information from
adequately designed and conducted toxicology studies that address safety
pharmacology endpoints may result in reduction or elimination of some of
the safety pharmacology studies.Error: Reference source not found For
products that are not systemically absorbed, it may be necessary to
conduct safety studies using intravenous administration to assess the
potential risk that may arise in special populations (e.g., ulcerative
colitis patients). FDA urges sponsors to thoroughly evaluate local
gastrointestinal toxicity for such products.

### 2. Toxicokinetic and Pharmacokinetic Studies 

FDA recommends that exposure in animals be evaluated prior to human
safety studies.[^28] FDA believes that absorption, distribution,
metabolism, and excretion (ADME) data in animals should be available to
compare human and animal pharmacokinetic profiles.

### 3. Toxicology Studies 

FDA recommends that toxicology studies include the following:

-   Expanded single- and repeat-dose toxicity studies in two mammalian
    species (one non-rodent). FDA recommends that the duration of the
    repeat-dose toxicity studies be equal to or exceed the duration of
    the intended treatment in humans.[^29]

-   Genotoxicity studies in vitro and in vivo[^30]^,^[^31]

-   Reproductive toxicity studies (Segment I & II).[^32]^,^[^33] For
    oral decorporation agents that are not systemically absorbed,
    reproductive studies may not be needed.

-   Local tolerance studies in animals using routes relevant to the
    proposed clinical route of administration. The assessment of local
    tolerance may be part of other toxicity studies.

-   Safety studies in juvenile animals may be needed as decorporation
    agents are likely to be used in pediatric populations.[^34]

-   Carcinogenicity studies, typically needed only if there is cause for
    concern, such as evidence of preneoplastic lesions in repeat-dose
    toxicity studies

Any special toxicology study requirements will be determined on a
case-by-case basis, depending on product characteristics. Animals used
to determine efficacy may also be assessed for toxicity. For example,
safety endpoints may include assessment of physiologic functions during
the study, as well as determination of histology of tissues obtained at
necropsy.

We recommend sponsors refer to the appropriate Agency guidances for
information regarding (1) the conduct of safety pharmacology and
toxicology studies, (2) the timing of these studies relative to the
initiation of human studies, and (3) appropriate methods for dose
extrapolation that may be used for estimating a safe starting dose in
human clinical trials.[^35]

## [E.]{.smallcaps} Clinical Pharmacology and Biopharmaceutics Studies 

Under 21 CFR 314.610(a)(4) and 601.91(a)(4)) of the Animal Efficacy
Rule, the data or information on the kinetics and pharmacodynamics of a
decorporation agent in humans, as well as in animals, must allow
selection of an effective dose in humans. We recommend that sponsors
attempt to evaluate as heterogeneous a human study population as
possible, with a reasonable balance of males and females, young and
elderly, and members of differing racial groups.

FDA believes that a complete clinical pharmacology and biopharmaceutics
evaluation of a decorporation agent will provide detailed information on
(1) general attributes, (2) general clinical pharmacology, (3) extrinsic
and intrinsic factors, (4) general biopharmaceutics, and (5)
bioanalytical methods. In particular, sponsors are urged to consider the
following issues relating to these topics:

***General attributes,*** including the physico-chemical properties of
the drug substance and the formulation of the drug product.

**General clinical pharmacology**, including (1) the proposed mechanism
or mode of action of the product and (2) the proposed human dosage
regimen and its justification. FDA recommends that pharmacologic
assessment address the following in detail:

> 1\. The basis for selecting the response endpoints in animal models
> and how they are extrapolated to humans; establishment of
> pharmacokinetic (PK)/ pharmacodynamic (PD) relationships in animals;
> time to the onset and offset of the pharmacological response
>
> 2\. Product absorption, distribution, metabolism, and excretion in
> humans (a mass balance study using radiolabeled product would be
> useful in this regard). FDA believes that the route of administration
> should be designated and be the same in both animal and human studies.
>
> 3\. Identification and quantification of the active moieties in plasma
> (or other appropriate biological fluid) and characterization of
> pharmacokinetic parameters in humans, including the following:

-   The degree of linearity or nonlinearity in the dose-concentration
    relationship evaluated in a dose escalation study

```{=html}
<!-- -->
```
-   The change in pharmacokinetic parameters with time following
    multiple dosing, if multiple dosing is indicated

```{=html}
<!-- -->
```
-   The metabolic profile, pharmacokinetic parameters, and plasma
    protein binding in humans as compared to animals

```{=html}
<!-- -->
```
-   Characteristics of the exposure-response relationships (i.e.,
    dose-response or concentration-response) for safety parameters

***Extrinsic and intrinsic factors**,* including the effect of age,
gender, race, and organ dysfunction (e.g., renal impairment and hepatic
impairment) on exposure-response relationships, as necessary; evaluation
of drug-drug interactions, as appropriate

***General biopharmaceutics,*** including the solubility, permeability,
and dissolution of the drug product, if applicable; the effect of food
on bioavailability of the drug product, if applicable

***Bioanalytical methods for determination of active moiety and
metabolite(s),*** including methods to assess metabolite concentrations.
FDA recommends that sponsors provide the rationale for selecting
metabolites for analysis and describe the range of the standard curve
and curve fitting techniques. FDA also recommends that sponsors identify
the upper and lower limits of quantification (ULOQ/LLOQ) and describe
the accuracy, precision, and selectivity of analytical methods at these
limits. Sponsors are also urged to address sample stability during
freeze-thaw cycles, sample transport, and long-term storage.

## F. Safety Assessment in Humans

The goal of human safety studies is to characterize the adverse effects
of the product in humans, so that this toxicity can be weighed to the
extent possible against the benefits of use, both generally and for
particular patients. When designing safety studies for decorporation
agents that may be approved under the Animal Efficacy Rule, the sponsors
are urged to consider the following:

> 1\. What safety information should be generated preapproval, and in
> particular, what specific safety risks or animal findings should be
> explored preapproval?
>
> 2\. What safety information reasonably may be delayed to postmarketing
> studies?

***Considerations for Safety Studies Supporting Approval.*** At a
minimum, FDA urges sponsors to conduct a randomized, placebo-controlled
safety study in humans to support approval of a product under the Animal
Efficacy Rule. Additional safety studies may be needed to address
specific concerns not addressed by, or raised by, the results of the
placebo-controlled trial. Sponsors are encouraged to consider the
following factors in the design and interpretation of human safety
studies that will support product approval (this list is not
comprehensive):

> 1\. Enrollment and assessment of a sufficient number of adult male and
> female subjects to allow for proper statistical analysis
>
> 2\. Use of a test product that is bioequivalent to, and delivered by
> the same route of administration and dosing regimen as, that intended
> for marketing
>
> 3\. Evaluation of a range of doses and establishment of a
> dose-response relationship
>
> 4\. Inclusion of complete physical examinations with vital signs and
> laboratory parameters (e.g., electrolytes, chemistry and hematology
> profiles, tests of renal and liver function) as part of the clinical
> evaluation. Additional evaluations may be needed, as appropriate. FDA
> recommends that evaluations be performed at baseline and at specified
> follow-up time points, as dictated by the dosing regimen and
> preclinical or other available human safety findings.
>
> 5\. Incorporation of population PK/PD studies using sparse sampling
> techniques (i.e., three to four data points per subject). Such studies
> may be useful in identifying factors causing intersubject variability
> and in relating individual drug exposure to safety outcomes.
>
> 6\. Monitoring for adverse events that includes collection of the
> following: the timing of the event relative to product administration,
> the duration and severity of the event, clinical management of the
> event, outcomes (e.g., need for hospitalization, event resolved
> spontaneously)

In 2004, the Agency published a draft guidance, *Premarketing Risk
Assessment,* which addresses preapproval risk assessment in more detail,
including generation, analysis, and presentation of human safety data in
an application for approval.

***Size of the NDA or BLA Safety Database.*** We recommend that a
sponsor planning to submit an NDA or BLA for a new decorporation agent,
or an efficacy supplement for a previously marketed product in support
of a new use as a decorporation agent, under the Animal Efficacy Rule or
other regulatory mechanism, meet with the appropriate representatives in
CDER to discuss the size of the human safety database. The following
factors may increase or decrease the size of the requisite NDA or BLA
safety database (this list is not comprehensive):

> 1\. Whether additional studies focused on risks to a specific target
> organ or addressing specific animal or clinical safety concerns are
> needed preapproval
>
> 2\. Whether the product is intended to treat otherwise healthy
> individuals on a large scale or a defined, seriously ill subpopulation
> for whom some risk would be acceptable
>
> 3\. Whether the product will be used chronically or for acute, one
> time only use
>
> 4\. Whether the product treats a condition for which there are no
> available therapies
>
> 5\. Whether the product meets an unmet medical need (e.g., is superior
> in efficacy to or avoids serious toxicities associated with available
> therapies, or provides benefits to patients who are unresponsive to or
> intolerant of available therapies)[^36]
>
> 6\. Whether the product is already marketed and known to have an
> acceptable safety profile for the populations that would receive a
> decorporation agent
>
> 7\. Whether the product is first in its class or relatively similar to
> other products on the market

An NDA or BLA safety database generally will include human subjects
exposed to a variety of product doses as well as placebo-treated
subjects. Although the requisite number of subjects may vary across
applications for reasons cited above, FDA believes that in many cases
200 to 300 subjects who (1) have been exposed to the decorporation agent
at doses and durations comparable to those anticipated in marketed use
and (2) have had a minimum battery of safety testing, will be sufficient
to support approval.

## G. Benefit-Risk Assessment

Benefit-risk assessment relates the potential or actual benefit that a
particular patient or population derives from using a product to the
risks incurred through its use. If a decorporation agent is highly
effective in eliminating absorbed radiocontaminants from the body and is
relatively free of risk, its benefit-risk assessment would be highly
favorable. Such a product would provide enormous benefit, especially to
those most heavily exposed to radioactive contamination, or to those who
might suffer greater consequences as a result of even lesser amounts of
exposure (e.g., pediatric populations). Situations may arise, however,
in which there is a question of whether or not to administer such a
product to a less heavily exposed population. Therefore, there is a
great need for a careful assessment of benefit-risk in populations with
varied levels of radioactive contamination. If a product\'s approval is
subject to the Animal Efficacy Rule, prior to its approval such
assessments will generally be based primarily on experience with animal
models. In the event of accidental or nonaccidental radioactive
contamination, serious efforts to evaluate the benefit-risk of a
decorporation agent in humans should be made, to the extent possible.

# IV. POSTAPPROVAL COMMITMENTS FOR PRODUCTS APPROVED UNDER THE ANIMAL EFFICACY RULE

Sponsors planning to submit an NDA or BLA for a new decorporation agent,
or an efficacy supplement for a marketed product in support of a new use
as a decorporation agent, for approval under the Animal Efficacy
RuleError: Reference source not found are encouraged to meet with the
appropriate representatives in CDER regarding the specifics of
postapproval commitments. Postapproval issues for products approved
under the Animal Efficacy Rule are discussed at 21 CFR 314.610(b) (for
drugs)and 21 CFR 601.91(b) (for biological products).

One of the requirements for approval under the Animal Efficacy Rule is
that sponsors must conduct postmarketing studies to verify and describe
a decorporation agent's clinical benefit and to assess its safety when
used as indicated when such studies are feasible and ethical (see 21 CFR
314.610(b)(1) for drug products and 21 CFR 601.91(b)(1) for biological
drug products). Except in the case of accidental or nonaccidental
radioactive contamination, such studies would be infeasible. Under the
rule, sponsors must, therefore, include as part of their NDA, BLA or
efficacy supplement a plan for conducting postmarketing studies. Such
studies could include field studies of subjects with radioactive
contamination.

To the extent possible, postmarketing studies conducted after accidental
or nonaccidental radioactive contamination may be useful for addressing
safety and efficacy concerns for populations that were not studied or
were only studied to a limited degree preapproval, including (1)
pediatric populations, (2) the elderly, (3) pregnant or lactating women,
(4) subjects with hepatic or renal impairment, (5) subjects of different
ethnic or racial backgrounds, or (6) subpopulations with genetic
polymorphisms.

At a minimum, FDA recommends that sponsors design postmarketing studies
to collect the following information on subjects with radioactive
internal contamination[^37]:

-   The date of the occurrence, and the cause for and extent of the
    initial contamination

-   The radiocontaminant(s) involved

-   Demographic information on the subject(s), including age, gender,
    and race/ethnicity

-   The initial clinical status of the subject(s) immediately after
    contamination

-   Pertinent medical history of the subject(s)

-   The estimated total body radiation in cGy

-   Ancillary methods used in decontamination, if any

-   Details on the decorporation agent(s) used, including the dose,
    frequency, timing of administration relative to the initial
    contamination, duration of therapy, and reasons for premature
    discontinuation if this occurs

-   Other pharmaceutical or detoxifying agents used, if any

-   Any beneficial outcomes observed, including evidence for reduction
    in internally absorbed radiocontaminant(s)

-   Any adverse events, not just those deemed product-related

-   Any short- and long-term serious outcomes observed (e.g., death,
    hospitalization, cancer diagnosis)

# GLOSSARY

**Alpha Particles.** Alpha particles are helium nuclei, charged
particles with a mass four times that of a neutron. Because of their
mass and charge, alpha particles penetrate short distances and are fully
stopped by the dead layers of the skin or by clothing. Alpha particles
are a negligible external hazard, but become hazardous when internalized
through inhalation, ingestion, or wounds. Alpha particles can cause as
much as 10 times more damage to tissue per unit dose than gamma rays.

**Beta Particles**. Beta particles are electrons, charged particles that
are emitted by several radiocontaminants present in fallout. These
particles can travel a short distance in tissue; if large quantities are
involved, they can produce damage to the basal stratum of the skin. The
lesion produced, a "beta burn," can appear similar to a thermal burn.

**Blocking and Diluting Agents**. Medical products that decrease the
likelihood of radiocontaminant absorption by decreasing its
availability.

**Chelating Agents**. Medical products that bind with certain metals
more strongly than others to form a stable complex that, when soluble,
can be more readily excreted by the kidneys.

**Committed Radiation Dose**. The total radiation dose accumulated in an
organ or tissue over time, usually 50 years for adults and 70 years for
children. The magnitude of the dose depends on the amount of ingested
radioactive material and the time it stays in the body. Whole-body
committed dose is the sum of weighted radiation doses in all the organs
and tissues of the body.

**Decorporation Agents**. Medical products that increase the rate of
elimination or excretion of absorbed, inhaled, or ingested
radiocontaminants.

**Gamma Rays**. Ionizing radiation emitted from many radiocontaminants.
Gamma rays are a form of uncharged radiation similar to x-rays. X-rays
cannot be distinguished from gamma rays when they are the same energy.
Their differences are due to their origin. Gamma rays are intranuclear
in origin, while x-rays are extranuclear. Both are highly energetic and
pass through matter easily. Because of their high penetrability, gamma
radiation can result in whole-body exposure from external sources.

**Gray (Gy)**. The Standard International (SI) unit of absorbed
radiation dose equal to 1 joule of energy absorbed per kg of mass. 1 Gy
is equal to 100 rads. The rad was replaced by the Gy.

**Mobilizing Agents**. Medical products that enhance and increase the
natural turnover processes and thereby induce the release of
radiocontaminants from tissues.

**Neutrons**. Neutrons are uncharged particulate radiation. Compared to
gamma rays, neutrons can cause twenty times as much damage to tissue per
unit dose.

**Rad.** Acronym for ***r***adiation ***a***bsorbed ***d***ose. The old
unit of measurement of the radiation absorbed dose corresponding to an
energy transfer of 100 ergs per gram of any absorbing material including
tissues. The rad has been replaced by the Standard International SI unit
of Gray, 1 joule/kilogram, and 1 Gy is equal to 100 rads.

**Radiological Dispersal Device or RDD**. Sometimes referred to as a
\"dirty bomb,\" a radiological dispersal device is any device that
causes the purposeful dissemination of radioactive material across an
area using conventional (non-nuclear) explosives. The radioactive
composition of the dispersed radioactive material usually will be
unknown until an assessment is made by qualified personnel.

**Radiation**. Ionizing radiation may consist of alpha particles, beta
particles, or neutrons, which are particulate; x-rays, gamma rays, or
photons which are electromagnetic in nature.

**X-rays**. Electromagnetic radiation, photons, similar to gamma rays.
X-rays and gamma rays do not differ from one another when they are the
same energy. X-rays are produced extranuclearly, either from the
deceleration of a high-energy electron usually associated with a
machine, or from an internal energy transition from a higher to a lower
state within an atom, referred to as characteristic x-rays. X-rays from
such internal transitions are not considered hazardous relative to other
emissions.

[^1]: This draft guidance has been prepared by the Radioeliminators
    Working Group, which includes members from the Center for Drug
    Evaluation and Research (CDER) and the Center for Biologics
    Evaluation and Research (CBER) at the Food and Drug Administration.

[^2]: *See* National Council on Radiation Protection and Measurements
    (1980), *Management of Persons Accidentally Contaminated With
    Radionuclides,*(NCRP Report 65), Washington, DC, National Council on
    Radiation Protection and Measurements, for additional information on
    management of internal radioactive contamination.

[^3]: For ease of reference, this guidance uses the term *product* to
    refer to all products (excluding blood products) regulated by CDER.
    Similarly, for ease of reference, this draft guidance uses the term
    *approval* to refer

    to both drug approval and biologic licensure.

[^4]: See Durakovic, A (1987), Internal Contamination with Medically
    Significant Radionuclides. In *Military* *Radiobiology*, edited by
    JJ Conklin and RI Walker, 241-264, Orlando, FL, Academic Press.

[^5]: See Cerveny, TJ (1988), Treatment of Internal Radionuclide
    Contamination. In *Medical Consequences of Nuclear War*, edited by
    RI Walker and TJ Cerveny, 55-65, Falls Church, VA, TMM Publications,
    Office of the Surgeon General.

[^6]: See Jarrett, DG (1999), *Medical Management of Radiological
    Casualties*, Bethesda, MD, Armed Forces Radiobiology Research
    Institute.

[^7]: See Commission of European Communities Radiation Protection
    Program (2000), Decorporation of Radionuclides from the Human Body.
    Edited by MH Henge-Napoli, GN Stradling, and DM Taylor. *Radiat
    Prot* *Dosimetry* 87:1-57

[^8]: See Waller EA, Stodilka RZ, Leach K, and Prud'homme-Lalonde
    (2002), *Literature Survey on Decorporation of Radionuclides from
    the Human Body*, Ottowa, Defense R&D Canada Technical Memorandum TM
    2002-042.

[^9]: See Farina, R, Brandao-Mello, CE, and Oliveira, AR (1991), Medical
    Aspects of ^137^Cs Decorporation: The Goiania Radiological Accident.
    *Health Physics* 60:63-66.

[^10]: See Melo DR, Lipzstein, JL, de Oliveira, CAN, and Bertelli, L
    (1994), ^137^Cs Internal Contamination Involving a Brazilian
    Accident, and the Efficacy of Prussian Blue Treatment, *Health
    Physics* 66:245-252.

[^11]: See Volf, V (1978), *Treatment of Incorporated Transuranium
    Elements.* Vienna, International Atomic Energy Technical Reports
    Series No. 184.

[^12]: See Fasiska, BC, Bohning, DE, Brodsky, A, and Horm, J (1971),
    Urinary Excretion of ^241^Am Under DTPA Therapy, *Health Physics*
    21:523-529

[^13]: See the *Federal Register,* Vol. 68, p. 5645, February 4, 2003.

[^14]: See the *Federal Register*, Vol. 43, p. 58798, December 15, 1978.

[^15]: See the *Federal Register*, Vol. 47, p. 28158 June 29, 1982.

[^16]: See the *Federal Register*, Vol. 66, p. 64066, (December 11,
    2001.

[^17]: See FDA guidance *Potassium Iodide as a Thyroid Blocking Agent in
    Radiation Emergencies*, available at
    [www.fda.gov/cder/guidance/4825fnl.htm](http://www.fda.gov/cder/guidance/4825fnl.htm).

[^18]: See Breitenstein BD, Fry SA, and Lushbaugh CC (1990), DTPA
    Therapy: The US Experience 1958-1987. In *The Medical Basis for
    Radiation Accident Preparedness*, edited by RC Ricks and SA Fry,
    Amsterdam, Elsevier Science Publishing Co

[^19]: See the *Federal Register*, Vol. 68, p. 53984, September15, 2003.

[^20]: Based on Cerveny, TJ (1989), Treatment of Internal Radionuclide
    Contamination. In *Textbook of Military Medicine, Part I, Medical
    Consequences of Nuclear Warfare; Warfare, Weaponry, and the
    Casualty*, Office of the Surgeon General, Department of the Army.

[^21]: The various types of radiation are described in the glossary.

[^22]: The Animal Efficacy Rule is codified in 21 CFR part 314, subpart
    I for human drug products and 21 CFR part 601, subpart H for human
    biological products.

[^23]: See 21 CFR 314.54 and FDA's Citizen Petition Response (Dockets
    Nos. 2001P-0323/CPI & C5, 2002P-0447/CP1, and 2003P-0408/CP1), dated
    October 14, 2003, for a description of FDA's drug approval process
    under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act.
    An applicant may rely on the literature and/or the Agency's previous
    finding of safety and effectiveness for a listed drug. Such reliance
    will be appropriate only to the extent that the proposed product in
    the 505(b)(2) application shares characteristics (active ingredient,
    dosage form, strength, route of administration, indications, and
    conditions of use) in common with the listed drug. The safety and
    effectiveness of any differences between the listed drug and the
    drug proposed in the 505(b)(2) application must be supported by
    additional data, including clinical or animal data as appropriate.

[^24]: See International Conference on Harmonisation (ICH) guidance *Q6A
    Specifications: Test Procedures and Acceptance Criteria for New Drug
    Substances and New Drug Products: Chemical Substances*; and ICH *Q6B
    Specifications: Test Procedures and Acceptance Criteria for
    Biotechnological/ Biological Products.*

[^25]: Studies evaluating long-term cancer risk or survival following
    radioactive contamination may not be feasible or ethical and would
    generally not be required to support approval of a new decorporation
    agent or a new indication for a previously approved product.

[^26]: See ICH guidance *S7A Safety Pharmacology Studies for Human
    Pharmaceuticals*, for further discussion of safety pharmacology
    study designs.

[^27]: See ICH guidance *S7B Safety Pharmacology Studies for Assessing
    the Potential for Delayed Ventricular Repolarization (QT Interval
    Prolongation) by Human Pharmaceuticals.*

[^28]: See ICH guidance *S3A Toxicokinetics: The Assessment of Systemic
    Exposure in Toxicity Studies.*

[^29]: See ICH guidance *S4A Duration of Chronic Toxicity Testing in
    Animals (Rodent and Nonrodent Toxicity Testing).*

[^30]: See ICH guidance *S2A Specific Aspects of Regulatory Genotoxicity
    Tests for Pharmaceuticals.*

[^31]: See ICH guidance *S2B Genotoxicity: A Standard Battery of
    Genotoxic Tests for Pharmaceuticals.*

[^32]: See ICH guidance *S5A Detection of Toxicity to Reproduction for
    Medicinal Products.*

[^33]: See ICH guidance *S5A Detection of Toxicity to Reproduction for
    Medicinal Products: Addendum on Toxicity to Male Fertility.*

[^34]: In 2003, the Agency issued the draft guidance for industry
    *Nonclinical Safety Evaluation of Pediatric Drug Products.*

[^35]: In 2002, FDA issued a draft guidance entitled *Estimating the
    Safe Starting Dose in Clinical Trials for Therapeutics in Adult
    Healthy Volunteers*. Once finalized, it will represent the Agency\'s
    thinking on this issue.

[^36]: See FDA guidance for industry *Available Therapy.*

[^37]: See e.g., the "Prussian Blue Patient Treatment Data Form"
    included in the professional labeling for Radiogardase (Insoluble
    Prussian Blue capsules) for the kinds of information that may be
    collected in the event of a radiation accident or terrorist attack.
    The professional labeling for Radiogardase is available at
    http://www.fda.gov/cder/foi/label/2003/021626lbl.pdf