Guidance for Industry 
Internal Radioactive Contamination 
Development of Decorporation Agents  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2006 
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) 
 
March 2006 
Clinical Medical
   
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................1 
A.  Radiation Contamination Scenarios.............................................................................................2 
B.  Uptake and Clearance of Radioactive Contaminants.................................................................3 
C.  Management of External Radioactive Contamination...............................................................4 
D.  Treatment of Internal Radioactive Contamination....................................................................4 
1. General Principles...........................................................................................................................4 
2. The Gastrointestinal (GI) Tract as a Route of Elimination.............................................................5 
3. Prevention or Reversal of Radiocontaminant Interaction with Tissues...........................................6 
4. Potential Radioactive Contaminants and Possible Treatments.......................................................8 
E.  Animal Efficacy Rule.....................................................................................................................9 
1. Applying the Animal Efficacy Rule to Decorporation Agents........................................................10 
2. Three Requirements for Approval under the Animal Efficacy Rule...............................................10 
III.  PRODUCT DEVELOPMENT PLAN FOR AN NDA EFFICACY SUPPLEMENT11 
A.  Study Sequence............................................................................................................................11 
B.  Chemistry, Manufacturing, and Controls.................................................................................12 
C.  Animal Efficacy Studies..............................................................................................................13 
1. Considerations Regarding Efficacy Studies Supporting Approval................................................13 
2. Good Laboratory Practice (GLP) Compliance.............................................................................14 
D.  Animal Safety Pharmacology and Toxicology Studies.............................................................14 
1. Safety Pharmacology Studies.........................................................................................................14 
2. Toxicokinetic and Pharmacokinetic Studies..................................................................................15 
3. Toxicology Studies.........................................................................................................................15 
E.   Clinical Pharmacology and Biopharmaceutics Studies............................................................16 
F.  Safety Assessment in Humans.....................................................................................................17 
G.  Benefit-Risk Assessment..............................................................................................................19 
IV.  POSTAPPROVAL COMMITMENTS FOR PRODUCTS APPROVED UNDER 
THE ANIMAL EFFICACY RULE...............................................................................20 
GLOSSARY.................................................................................................................................22 
  Contains Nonbinding Recommendations 
1
Guidance for Industry  
 
Internal Radioactive Contamination  
Development of Decorporation Agents  
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 CFR part 314 subpart I, 
may be invoked to approve new decorporation agents not previously marketed or new 
indications for previously marketed drug 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 drug products. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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 these accidents has been present for many years.  
Recent events also have highlighted the potential for nonaccidental radioactive contamination as 
a result of criminal or terrorist actions.  Internal contamination occurs when radioactive material 
is ingested, inhaled, or absorbed from a contaminated wound.  As long as these radioactive 
                                                 
1 This guidance has been prepared by the Radioeliminators Working Group in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration. 
  1 Contains Nonbinding Recommendations 
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 drug products3 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 
                                                 
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 This guidance does not apply to biological products because FDA does not expect many products developed as 
decorporation agents to be biologics.  Sponsors interested in developing a biological product for use as a 
decorporation agent should contact the appropriate review division.   
  2 Contains Nonbinding Recommendations 
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.2,4,5  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.2,4,5 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.4,6  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.2  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.2,5   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 because of acidic or 
caustic properties that fix them to tissue proteins.2 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).2   The gastrointestinal tract is the critical target organ for the many insoluble radioactive 
contaminants that travel its length almost unabsorbed.  
 
                                                 
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. 
  3 Contains Nonbinding Recommendations 
Wounds contaminated by fallout and shrapnel may provide continuous irradiation of surrounding 
tissues and increase the likelihood of systemic incorporation.2,5,6  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.2  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.2 
 
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.  After careful 
retrospective review of clinical data from human exposures resulting from nuclear detonations or 
nuclear reactor accidents, Prussian blue, potassium iodide (KI), and calcium- 
diethylenetriaminepentacetate (Ca-DTPA) and zinc-diethylenetriaminepentacetate (Zn-DTPA), 
when manufactured under conditions specified in an approved new drug application (NDA), 
were found safe and effective for the treatment of internal contamination with radioactive 
cesium; iodine; and plutonium, americium, or curium, respectively.  Currently, there are 
approved Prussian blue, KI, and Ca- and Zn-DTPA 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 probably 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  
  4 Contains Nonbinding Recommendations 
contamination,2,4,5,7,8  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.2,4,5,7
  
 
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.2,4,5  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 (see Subsection 
II.D.4), with descriptions of their properties, target organs, and treatment (either with an FDA-
approved product or as suggested in the literature).  
 
2.  The Gastrointestinal (GI) 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.  However, use of emetics 
and purgatives is not always feasible.  Emetics are contraindicated in unconscious individuals or 
following ingestion of corrosive agents, and purgatives should not be used in individuals with 
abdominal pain of undetermined etiology, ileus, or acute surgical abdomen.2    
 
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 Goiania9,10 and has been well tolerated 
                                                 
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. Radiation Protection 
Dosimetry 87:1-57. 
 
8 See Waller EA, Stodilka RZ, Leach K, and Prudhomme-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 137Cs Decorporation: The Goiania 
Radiological Accident.  Health Physics 60:63-66. 
 
  5 Contains Nonbinding Recommendations 
in humans. 2,4,11,12  In Goiania, contamination occurred primarily via the oral route.  In some 
individuals, Prussian blue reduced the cesium-137 uptake in target tissues, thereby reducing the 
whole body radiation dose by up to a factor of 2.  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 Goiania casualties.   
 
After review of human data from the Goiania incident and published literature on human 
exposures in other incidents, FDA concluded in 2003 that Prussian blue, when produced under 
conditions specified in approved 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, 14 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.2  Sodium polystyrene sulfonate is approved in the United States under the name 
Kayexalate 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.2,4  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. 2,4  However, the efficacy of these 
products as potential decorporation agents has not been established, 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 
________________________ 
10 See Melo DR, Lipzstein, JL, de Oliveira, CAN, and Bertelli, L (1994), 137Cs 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 241Am Under DTPA Therapy, 
Health Physics 21:523-529. 
 
13 See the Federal Register, Vol. 68, p. 5645, February 4, 2003. 
 
14 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the 
CDER guidance page at http://www.fda.gov/cder/guidance/index.htm.  
  6 Contains Nonbinding Recommendations 
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.15  In 1982, FDA announced its final recommendations on the 
administration of KI to the general public in a radiation emergency.16  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 suppressing radioiodine-induced thyroid cancer outweighed the 
risks of short-term use of small quantities of KI.   
 
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.17  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.18 
 
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.2  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 propylthiouracil, ammonium chloride, diuretics, expectorants and 
inhalants, parathyroid extract, and corticosteroids.2,7,9  These agents require experienced 
consultation, treatment, and management and are not currently FDA approved as 
decorporation agents.
 
 
c.  Chelating Agents   
 
                                                 
15 See the Federal Register, Vol. 43, p. 58798, December 15, 1978. 
   
16 See the Federal Register, Vol. 47, p. 28158, June 29, 1982. 
 
17 See the Federal Register, Vol. 66, p. 64066, December 11, 2001. 
 
18 See FDA guidance Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies, available at 
http://www.fda.gov/cder/guidance/index.htm. 
 
  7 Contains Nonbinding Recommendations 
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 in this way 
as an investigational agent for many years.7,9,10,11,12,19 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 maintenance therapy, as necessary.  Based on a review of 
clinical data maintained by REAC/TS on acute occupational exposures, 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.20  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.  
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.2  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. 
 
                                                 
19 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 
20 See the Federal Register, Vol. 68, p. 53984, September 15, 2003. 
 
  8 Contains Nonbinding Recommendations 
 
TABLE  1. RADIOACTIVE CONTAMINANTS WITH MEDICAL SIGNIFICANCE AND 
POSSIBLE TREATMENTS 21 
 
Radioactive  Radiation  Target Organ  Contamination  Treatment 
Contaminant  Type22  Mode* 
Americium-241  ,    Bone   I/W   Ca-DTPA, Zn-DTPA  
Californium-252   , ,    Bone   I/W   Ca-DTPA, Zn-DTPA  
Cerium-141, 144   ,    GI, lung   I/GI   Ca-DTPA, Zn-DTPA 
Cesium-137   ,    Total body   I/S/GI   Prussian blue  
Curium-244   , ,    Bone   I/GI   Ca-DTPA, Zn-DTPA 
Iodine-131, 132, 134, 135   ,    Thyroid   I/GI/S   KI   
Plutonium-239, 238  ,    Bone   I/W   Ca-DTPA, Zn-DTPA 
Polonium-210      Lung   I   Dimercaprol  
Strontium-89, 90      Bone   I/GI   AlPO4**  
Tritium (3H)     Total body   I/S/GI   Forced H2O  
Uranium-238, 235, 239  , ,    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 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 
                                                 
21 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. 
 
22 The various types of radiation are described in the glossary. 
  9 Contains Nonbinding Recommendations 
feasible before approval.  The intent of the Animal Efficacy Rule23 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 
section 564 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 360bbb-3).  
 
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 pathophysiologic 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 Subsection III.D 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). 
 
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).  Products evaluated for effectiveness under the Animal Efficacy Rule 
must be evaluated for safety under preexisting requirements for establishing the safety of new 
drug products (21 CFR 314.600).  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 
 
                                                 
23 The Animal Efficacy Rule is codified in 21 CFR part 314, subpart I for human drug products.  
 
  10 Contains Nonbinding Recommendations 
Approval of a decorporation agent under 21 CFR part 314 subpart I 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 before product 
administration or dispensing, advising, among other things, that the products approval was 
based on efficacy studies conducted in animals alone. 
 
 
III.  PRODUCT DEVELOPMENT PLAN FOR AN NDA OR AN EFFICACY 
SUPPLEMENT 
 
We recommend that a sponsor planning to develop a decorporation agent for submission as a 
new drug application (NDA) or 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 Hematology Products and the Office of Counter-Terrorism and Pediatric Drug Development 
in CDER regarding the specifics of a products 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 products 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.24  We believe a well-planned and executed development program to 
prospectively assess product efficacy in animals and safety in humans is preferable to the post-
event collection and analysis of data that has characterized the data supporting prior product 
approvals.   
 
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. 
 
                                                 
24 See 21 CFR 314.54 and FDAs Citizen Petition Response (Dockets Nos. 2001P-0323/CPI & C5, 2002P-
0447/CP1, and 2003P-0408/CP1), dated October 14, 2003, for a description of FDAs drug approval process under 
section 505(b)(2) of the Act (21 U.S.C. 355(b)(2)).  An applicant may rely on the literature and/or the Agencys 
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. 
  11 Contains Nonbinding Recommendations 
  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 efficacy studies supporting 
approval; 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 (Subsection III.C).  
 
  Efficacy studies supporting approval, conducted in the most appropriate animal species 
(Subsection III.C). 
 
  Safety studies in humans; these studies should be conducted at the highest dose 
anticipated to be marketed and be performed in parallel with the animal efficacy study or 
studies intended to support approval, assuming the product is reasonably likely to 
produce clinical benefits in humans (Subsection III.F). 
 
B.  Chemistry, Manufacturing, and Controls  
        
The same standards for chemistry, manufacturing, and controls (CMC) apply to decorporation 
agents as with other pharmaceuticals.  Sponsors should consult the appropriate FDA guidances 
for drug substances and drug 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 products should be adequate for the intended dosage 
form and route of administration to ensure identity, strength, quality, purity, and potency.25  
 
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 
                                                 
25 See International Conference on Harmonisation (ICH) guidance Q6A Specifications: Test Procedures and 
Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (available at 
http://www.fda.gov/cder/guidance/index.htm).  
 
  12 Contains Nonbinding Recommendations 
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 FDAs experience, it was important 
to consider the effects of all these factors on Prussian blues 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 products intended to reduce or prevent the toxicity 
of chemical, biological, radiological, or nuclear substances.  Under  314.610(a)(2), one of the 
requirements for approval based on effectiveness data from animals alone is that the effect be 
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 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 express 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 nonrodent, animal 
species.  
 
1.  Considerations Regarding Efficacy Studies Supporting Approval   
 
The following considerations and study characteristics are important in designing and 
interpreting the animal studies that will be used to support product approval (this list is not 
comprehensive):  
 
1.  Evaluation of efficacy 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).  
 
  13 Contains Nonbinding Recommendations 
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, the residual body 
burden may be measured.  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 animal 
efficacy study or studies intended to support approval is clearly related to the desired 
benefit in humans, generally the enhancement of survival or prevention of major 
morbidity (21 CFR 314.610(a)(3)).26   
 
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 
statistically significant and clinically meaningful reduction in whole-body committed 
radiation dose compared to the 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, efficacy studies supporting approval must be conducted in compliance with 
GLPs (see 21 CFR part 58).   
 
D.  Animal Safety Pharmacology and Toxicology Studies 
 
Sponsors must conduct animal safety studies to define pharmacological and toxicological effects 
before initiation of first-in-human clinical trials to establish a safe starting dose for decorporation 
agents that are new molecular entities (see 21 CFR 312.23(a)(8)).  The product used for 
definitive animal safety pharmacology and toxicology studies should 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 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 
                                                 
26 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. 
 
  14 Contains Nonbinding Recommendations 
cardiovascular, central nervous, pulmonary, and renal systems before first administration in 
humans.27,28  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. 27  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).  Sponsors should thoroughly evaluate 
local gastrointestinal toxicity for such products. 
 
2.  Toxicokinetic and Pharmacokinetic Studies   
 
FDA recommends that exposure in animals be evaluated before human safety studies.29  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  
 
Toxicology studies should include the following: 
  
  Expanded single- and repeat-dose toxicity studies in two mammalian species (one 
nonrodent).  The duration of the repeat-dose toxicity studies should be equal to or exceed 
the duration of the intended treatment in humans.30 
 
  Genotoxicity studies in vitro and in vivo31,32 
 
  Reproductive toxicity studies (Segment I & II).33,34  For oral decorporation agents that are 
not systemically absorbed, reproductive studies may not be needed.  
 
                                                 
27 See ICH guidance S7A Safety Pharmacology Studies for Human Pharmaceuticals, for further discussion of safety 
pharmacology study designs. 
 
28 In September 2004 (69 FR 55164), the Agency issued a revised, draft ICH guidance S7B Nonclinical Evaluation 
of  the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. 
 
29 See ICH guidance S3A Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies. 
 
30 See ICH guidance S4A Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing). 
 
31 See ICH guidance S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals. 
 
32 See ICH guidance S2B Genotoxicity: A Standard Battery of Genotoxicity Tests of Pharmaceuticals. 
 
33 See ICH guidance S5A Detection of Toxicity to Reproduction for Medicinal Products. 
 
34 See ICH guidance S5B Detection of Toxicity to Reproduction for Medicinal Products: Addendum on Toxicity to 
Male Fertility. 
 
  15 Contains Nonbinding Recommendations 
  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 if the decorporation agents are likely to be used in 
pediatric populations.35 
 
  Carcinogenicity studies, but 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. 
 
Sponsors should 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.36   
 
E.   Clinical Pharmacology and Biopharmaceutics Studies  
 
Under  314.610(a)(4), 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.  Sponsors should 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 should consider the following issues relating to 
these topics: 
 
General attributes, including the physicochemical 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.  The pharmacologic 
assessment should address the following in detail: 
 
                                                 
35 In 2003, the Agency issued the draft guidance for industry Nonclinical Safety Evaluation of Pediatric Drug 
Products.   
 
36 See FDA guidance entitled Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics 
in Adult Healthy Volunteers.  
  16 Contains Nonbinding Recommendations 
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. 
  The change in pharmacokinetic parameters with time following multiple dosing, if 
multiple dosing is indicated.  
  The metabolic profile, pharmacokinetic parameters, and plasma protein binding in 
humans as compared to animals. 
  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, 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).   Sponsors should 
provide the rationale for selecting metabolites for analysis and describe the range of the standard 
curve and curve fitting techniques.  They should also identify the upper and lower limits of 
quantification (ULOQ/LLOQ) and describe the accuracy, precision, and selectivity of analytical 
methods at these limits.  In addition, sponsors should 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, sponsors should 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? 
 
  17 Contains Nonbinding Recommendations 
2.  What safety information reasonably may be delayed to postmarketing studies? 
 
Considerations for Safety Studies Supporting Approval.  At a minimum, sponsors should 
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 should consider the following factors in the design and interpretation of human safety 
studies that will support product approval (this list is not comprehensive):  
 
1.  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. 
 
2.  Focused evaluation of the planned human dose; evaluation of a range of doses and 
establishment of a dose-response relationship for any observed adverse events would also 
be useful. 
 
3.  Inclusion of complete physical examinations with vital signs, ECGs, 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.  
 
4.  Incorporation of population PK/PD studies using sparse sampling techniques.  Such 
studies may be useful in identifying factors causing intersubject variability and in relating 
individual drug exposure to safety outcomes.  
 
5.  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).   
 
Sponsors should refer to the FDA guidance, Premarketing Risk Assessment, for more 
information on preapproval risk assessment, including generation, analysis, and presentation of 
human safety data in an application for approval.   
 
Size of the NDA Safety Database.  We recommend that a sponsor planning to submit an NDA 
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 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 
 
  18 Contains Nonbinding Recommendations 
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)37  
 
6.  Whether the product is already marketed and known to have an acceptable safety profile 
for the populations that would be given it as a decorporation agent 
 
7.  Whether the product is first in its class or relatively similar to other products on the 
market  
 
An NDA 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 will vary 
across applications for the reasons cited above, for products that (1) are intended to treat 
conditions for which there are no available therapies, (2) meet an unmet medical need, (3) are 
intended for short-term use, or (4) have a well-defined and acceptable toxicity profile in animals, 
200 to 300 subjects may be sufficient to support approval, if those subjects have been exposed to 
the decorporation agent at doses and durations comparable to those anticipated in marketed use 
and have had an adequate battery of safety testing.   
 
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 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, before 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. 
 
 
                                                 
37 See FDA guidance for industry Available Therapy. 
 
  19 Contains Nonbinding Recommendations 
IV.  POSTAPPROVAL COMMITMENTS FOR PRODUCTS APPROVED UNDER 
THE ANIMAL EFFICACY RULE 
 
Sponsors planning to submit an NDA 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 Rule23 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 in  314.610(b). 
 
One of the requirements for approval under the Animal Efficacy Rule is that sponsors must 
conduct postmarketing studies to verify and describe a decorporation agents clinical benefit and 
to assess its safety when used as indicated when such studies are feasible and ethical (see  
314.610(b)(1)).  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 or efficacy supplement a plan for conducting postmarketing studies.  Such studies 
could include field studies of subjects with radioactive contamination.  Sponsors should 
anticipate and plan for data collection under emergency use conditions and develop methods for 
maximizing information collection.   
 
At a minimum, sponsors should design postmarketing studies to collect the following information on 
subjects with radioactive internal contamination: 38  
 
  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) 
                                                 
38 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.  
   
  20 Contains Nonbinding Recommendations 
  Any adverse events, not just those deemed product-related 
  Any short- and long-term serious outcomes observed (e.g., death, hospitalization, cancer diagnosis) 
  21  
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.  Blocking agents are medical products that reduce 
radiocontaminant uptake in the tissues (e.g., potassium iodide prevents the uptake of radioiodine 
in the thyroid).  Isotopic dilution is achieved by administration of large quantities of the stable, 
nonradioactive isotope to minimize incorporation of the radioactive contaminant (e.g., use of 
water to increase the excretion of tritium). 
 
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, such as cesium-137 
and radioiodine.  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.  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. At equivalent absorbed doses, neutrons 
can cause more severe damage to the body than gamma rays.  
22  Contains Nonbinding Recommendations 
 
Rad.  Acronym for radiation absorbed dose.  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. 
 
  23