This
guidance represents the Food and Drug Administration’s (FDA’s)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of
this guidance.
This 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.
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.
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 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.
For the purposes of this guidance, the term
decorporation agents refers to drug products
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
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.
The uptake and retention of a radioactive
contaminant is influenced by its portal of entry, chemistry,
solubility, metabolism, and particle size.,,
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.,
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.
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. 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.,
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.
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).
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., This
hazard remains until the contaminant is removed by irrigation,
surgical debridement, or decay.
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.
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.
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
contamination,,,
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.,
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.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).
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
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,
and has been well tolerated in humans.,,
In Goiânia, 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 Goiânia
casualties.
After review of human data from the Goiânia
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.
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., 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. , 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.
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.
In 1982, FDA announced its final recommendations on the
administration of KI to the general public in a radiation
emergency.
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.
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.
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.
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.
, 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 in this way as an investigational agent for
many years.,, 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. 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. 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
|
Radioactive
Contaminant |
Radiation
Type |
Target Organ |
Contamination Mode* |
Treatment |
|
Americium-241 |
α, γ |
Bone |
I/W |
Ca-DTPA, Zn-DTPA†
|
|
Californium-252 |
γ, α, η |
Bone |
I/W |
Ca-DTPA, Zn-DTPA† |
|
Cerium-141, 144 |
β, γ |
GI, lung |
I/GI |
Ca-DTPA, Zn-DTPA† |
|
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 |
Ca-DTPA, Zn-DTPA† |
|
Polonium-210 |
α |
Lung |
I |
Dimercaprol‡
|
|
Strontium-89, 90 |
γ |
Bone |
I/GI |
AlPO4** |
|
Tritium (3H) |
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 |
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 feasible before approval. The intent of the
Animal Efficacy Rule
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).
