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

II.        background

A.    Radiation Contamination Scenarios

B.    Uptake and Clearance of Radioactive Contaminants

C.    Management of External Radioactive Contamination

D.    Treatment of Internal Radioactive Contamination

1. General Principles

2. The Gastrointestinal (GI) Tract as a Route of Elimination

3. Prevention or Reversal of Radiocontaminant Interaction with Tissues

4. Potential Radioactive Contaminants and Possible Treatments

E.     Animal Efficacy Rule

1. Applying the Animal Efficacy Rule to Decorporation Agents

2. Three Requirements for Approval under the Animal Efficacy Rule

III.       PRODUCT DEVELOPMENT PLAN FOR AN NDA EFFICACY SUPPLEMENT...

A.    Study Sequence

B.    Chemistry, Manufacturing, and Controls

C.    Animal Efficacy Studies

1. Considerations Regarding Efficacy Studies Supporting Approval

2. Good Laboratory Practice (GLP) Compliance

D.    Animal Safety Pharmacology and Toxicology Studies

1. Safety Pharmacology Studies

2. Toxicokinetic and Pharmacokinetic Studies

3. Toxicology Studies

E.     Clinical Pharmacology and Biopharmaceutics Studies

F.     Safety Assessment in Humans

G.    Benefit-Risk Assessment

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

GLOSSARY

Guidance for Industry[1]
Internal Radioactive Contamination —
Development of Decorporation Agents  

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. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities.  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  The use of the word should in Agency guidances means that something is suggested or recommended, but not required.  

II.        background 

Internal radioactive contamination can arise from accidents involving nuclear reactors, industrial sources, or medical sources.  The potential for 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.[2] 

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

A.        Radiation Contamination Scenarios 

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

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

B.        Uptake and Clearance of Radioactive Contaminants 

The uptake and retention of a radioactive contaminant is influenced by its portal of entry, chemistry, solubility, metabolism, and particle size.[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. [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.  

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 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 Goiânia[9]^,[10] and has been well tolerated in humans.[2] [4]^,[11]^,[12]  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.[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 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]^,    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.[7]^,[9]^,[10], [11], [12] 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.[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. 

TABLE  1. RADIOACTIVE CONTAMINANTS WITH MEDICAL SIGNIFICANCE AND POSSIBLE TREATMENTS [21] 

Radioactive Contaminant	Radiation Type[22]	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

 

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 feasible before approval.  The intent of the Animal Efficacy Rule[23] 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 

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 product’s 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 product’s development plans.  This is particularly important if the sponsor intends to seek approval under the Animal Efficacy Rule.  

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

·     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 also the kinetics of the solution to solid (heterogeneous) exchange reaction.  The synthetic procedure for manufacturing Prussian blue can produce insoluble solids of highly variable particle size, porosity, hydration, and defect impurities.  In FDA’s experience, it was important to consider the effects of all these factors on Prussian blue’s cesium exchange properties.

 

C.        Animal Efficacy Studies 

Under the Animal Efficacy Rule, a sponsor can rely on animal studies to provide substantial evidence of effectiveness for certain new drug 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).  

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 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 vivo[31]^,[32] 

·        Reproductive toxicity studies (Segment I & II).[33]^,[34]  For oral decorporation agents that are not systemically absorbed, reproductive studies may not be needed.  

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

·        Safety studies in juvenile animals 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: 

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? 

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 

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. 
 

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 agent’s 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)
• Any adverse events, not just those deemed product-related
• Any short- and long-term serious outcomes observed (e.g., death, hospitalization, cancer diagnosis)