Guidance for Industry
Developing Medical Imaging Drug and
Biological Products
Part 1:  Conducting Safety Assessments
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
June 2004
Clinical Medical Guidance for Industry
Developing Medical Imaging Drug and
Biological Products
Part 1:  Conducting Safety Assessments
Additional copies of this Guidance are available from:
 
Division of Drug Information HFD-240
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Food and Drug Administration
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(Phone 301-827-4573)
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or
 Office of Communication, Training and 
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 Food and Drug Administration
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Internet:   http://www.fda.gov/cber/guidelines.htm.  
Mail: the Voice Information System at 800-835-4709 or 301-827-1800.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
June 2004
Clinical Medical  
Table of Contents
I. INTRODUCTION.................................................................................................................1
II. SCOPE  TYPES OF MEDICAL IMAGING AGENTS................................................2
A. Contrast Agents..............................................................................................................................2
B. Diagnostic Radiopharmaceuticals................................................................................................2
III. GENERAL CONSIDERATIONS FOR SAFETY ASSESSMENTS OF MEDICAL
IMAGING AGENTS....................................................................................................................3
A. Medical Imaging Agent Characteristics Relevant to Safety......................................................3
1.  Mass Dose.......................................................................................................................................4
2. Route of Administration...................................................................................................................4
3. Frequency of Use.............................................................................................................................4
4. Biological, Physical, and Effective Half-Lives................................................................................5
B. Performance of Nonclinical Safety Assessments.........................................................................5
1. Nonclinical Safety Assessments for Nonbiological Drug Products.................................................5
a. Timing of Nonclinical Studies Submitted to an IND Application...............................................5
b. Contrast Agents...........................................................................................................................6
c. Diagnostic Radiopharmaceuticals (Nonbiological Products)......................................................8
2. Nonclinical Safety Assessments for Biological Products.................................................................8
IV. CLINICAL SAFETY ASSESSMENTS..............................................................................9
A. Group 1 and 2 Medical Imaging Agents......................................................................................9
1. Group 1 Medical Imaging Agents....................................................................................................9
2. Group 2 Medical Imaging Agents..................................................................................................10
B. Considerations For Groups 1 or 2..............................................................................................11
1. Safety-Margin Considerations.......................................................................................................11
a. Results of nonclinical studies.....................................................................................................11
b. Results of initial human experience...........................................................................................13
2. Clinical Use Considerations..........................................................................................................14
C.  Radiation Safety Assessment for All Diagnostic Radiopharmaceuticals................................14
1. General Considerations.................................................................................................................14
2. Calculation of Radiation Absorbed Dose to the Target Organs or Tissues..................................15
3. Maximum Radiation Absorbed Dose.............................................................................................16 Contains Nonbinding Recommendations
1
1
Guidance for Industry
2
Developing Medical Imaging Drug and Biological Products
3
Part 1:  Conducting Safety Assessments
4
5
6
7
8
9 This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It
10 does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
11 You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
12 and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for
13 implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate
14 number listed on the title page of this guidance.
15
16
17
18
19 I. INTRODUCTION
20
21 This guidance is one of three guidances intended to assist developers of medical imaging drug
22 and biological products (medical imaging agents) in planning and coordinating their clinical
23 investigations and preparing and submitting investigational new drug applications (INDs), new
24 drug applications (NDAs), biologics license applications (BLAs), abbreviated NDAs (ANDAs),
25 and supplements to NDAs or BLAs.  The three guidances are:  Part 1: Conducting Safety
26 Assessments; Part 2:  Clinical Indications; and Part 3: Design, Analysis, and Interpretation of
27 Clinical Studies.
28
29 Medical imaging agents generally are governed by the same regulations as other drug and
30 biological products.  However, because medical imaging agents are used solely to diagnose and
31 monitor diseases or conditions as opposed to treat them, development programs for medical
32 imaging agents can be tailored to reflect these particular uses.  Specifically, this guidance
33 discusses our recommendations on conducting safety assessments of medical imaging agents. 
34
35 FDA's guidance documents, including this guidance, do not establish legally enforceable
36 responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should
37 be viewed only as recommendations, unless specific regulatory or statutory requirements are
38 cited.  The use of the word should in Agency guidances means that something is suggested or
39 recommended, but not required.
40
                                                
1 This guidance has been prepared by the Division of Medical Imaging and Radiopharmaceutical Drug Products and
the Office of Therapeutics Research and Review in the Center for Drug Evaluation and Research (CDER) at the
Food and Drug Administration.  
1 Contains Nonbinding Recommendations
41 A glossary of common terms used in diagnostic medical imaging is provided at the end of this
42 document.
43
44
45 II. SCOPE  TYPES OF MEDICAL IMAGING AGENTS 
46
47 This guidance discusses medical imaging agents that are administered in vivo and are used for
48 diagnosis or monitoring with a variety of different modalities, such as radiography, computed
49 tomography (CT), ultrasonography, magnetic resonance imaging (MRI), and radionuclide
50 imaging.  The guidance is not intended to apply to the development of in vitro diagnostic or
51 therapeutic uses of these agents.2
52
53 Medical imaging agents can be classified into at least two general categories, contrast agents and
54 diagnostic radiopharmaceuticals.
55
56 A. Contrast Agents
57
58 As used in this guidance, a contrast agent is a medical imaging agent used to improve the
59 visualization of tissues, organs, and physiologic processes by increasing the relative difference of
60 imaging signal intensities in adjacent regions of the body.  Types of contrast agents include, but
61 are not limited to, (1) iodinated compounds used in radiography and CT; (2) paramagnetic
62 metallic ions (such as ions of gadolinium, iron, and manganese) linked to a variety of molecules
63 and microparticles (such as superparamagnetic iron oxide) used in MRI; and (3) microbubbles,
64 microaerosomes, and related microparticles used in diagnostic ultrasonography. 
65
66 B. Diagnostic Radiopharmaceuticals
67
68 As used in this guidance, a diagnostic radiopharmaceutical is (1) an article that is intended for
69 use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that
70 exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or
71 photons or (2) any nonradioactive reagent kit or nuclide generator that is intended to be used in
                                                
2 The guidance is not intended to apply to the development of research drugs that do not provide direct patient
benefit with respect to diagnosis, therapy, prevention, or prognosis, or other clinically useful information.  These
include radioactive drugs for research that are used in accordance with 21 CFR 361.1.  Section 361.1(a) states that
radioactive drugs (defined in 21 CFR 310.3(n)) are generally recognized as safe and effective when administered
under specified conditions to human research subjects in the course of a project intended to obtain basic information
about the metabolism of a radioactively labeled drug or about human physiology, pathophysiology, or biochemistry.
However, if a radioactive drug is used for immediate therapeutic, diagnostic, or similar purposes or to determine the
safety and effectiveness of the drug in humans, or if the radioactive drug has a pharmacological effect in the human
body, an IND is required.  FDA is developing a guidance on determining when research with radioactive drugs may
be conducted under  361.1.
The Agency recognizes the potential of imaging agents as research tools for aiding the development of therapeutic
drugs, and some of the principles of the guidance may be applicable to such research.  Sponsors of such imaging
research agents are urged to contact the Division of Medical Imaging and Radiopharmaceutical Drug Products for
advice on development of the imaging research agent.
2 Contains Nonbinding Recommendations
72 the preparation of such an article.3  As stated in the preamble to FDA's proposed rule on
73 Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis and Monitoring, the Agency
74 interprets this definition to include articles that exhibit spontaneous disintegration leading to the
75 reconstruction of unstable nuclei and the subsequent emission of nuclear particles or photons
76 (63 FR 28301 at 28303; May 22, 1998).
77
78 Diagnostic radiopharmaceuticals are generally radioactive drug or biological products that
79 contain a radionuclide that typically is linked to a ligand or carrier.4  These products are used in
80 nuclear medicine procedures, including planar imaging, single photon emission computed
81 tomography (SPECT), positron emission tomography (PET), or in combination with other
82 radiation detection probes.
83
84 Diagnostic radiopharmaceuticals used for imaging typically have two distinct components.
85
86   A radionuclide that can be detected in vivo (e.g., technetium-99m, iodine-123, indium-
87 111).
88
89 The radionuclide typically is a radioactive atom with a relatively short physical half-life
90 that emits radioactive decay photons having sufficient energy to penetrate the tissue mass
91 of the patient.  These photons can then be detected with imaging devices or other
92 detectors
93  
94   A nonradioactive component to which the radionuclide is bound that delivers the
95 radionuclide to specific areas within the body.  
96
97 This nonradionuclidic portion of the diagnostic radiopharmaceutical often is an organic
98 molecule such as a carbohydrate, lipid, nucleic acid, peptide, small protein, or antibody.  
99
100 As technology advances, new products may emerge that do not fit into these traditional
101 categories (e.g., agents for optical imaging, magnetic resonance spectroscopy, combined contrast
102 and functional imaging).  It is anticipated, however, that the general principles discussed here
103 could apply to these new diagnostic products.  Developers of these products should contact the
104 appropriate reviewing division for advice on product development.
105
106
107 III. GENERAL CONSIDERATIONS FOR SAFETY ASSESSMENTS OF MEDICAL
108 IMAGING AGENTS
109
110 A. Medical Imaging Agent Characteristics Relevant to Safety
111
                                                
3 21 CFR 315.2 and 601.31.
4 In this guidance, the terms ligand and carrier refer to the entire nonradionuclidic portion of the diagnostic
radiopharmaceutical.
3 Contains Nonbinding Recommendations
112 The following sections discuss the special characteristics of a medical imaging agent that can
113 lead to a more focused safety evaluation.  Characteristics include its radiation absorbed dose,
114 mass dose, route of administration, frequency of use, biodistribution, and biological, physical,
115 and effective half-lives in the serum, the whole body, and critical organs.5  
116
117 1.  Mass Dose
118
119 Some medical imaging agents can be administered at low mass doses.  For example, the mass
120 dose of a single administration of a diagnostic radiopharmaceutical can be small because device
121 technologies can typically detect relatively small amounts of a radionuclide (e.g.,
122 radiopharmaceuticals for myocardial perfusion imaging).   When a medical imaging agent is
123 administered at a mass dose that is at the low end of the dose-response curve, dose-related
124 adverse events are less likely to occur.
125
126 2. Route of Administration
127
128 Some medical imaging agents are administered by routes that decrease the likelihood of systemic
129 adverse events.  For example, medical imaging agents that are administered as contrast media for
130 radiographic examination of the gastrointestinal tract (e.g., barium sulfate) can be administered
131 orally, through an oral tube, or rectally.  In patients with normal gastrointestinal tracts, many of
132 these products are not absorbed, so systemic adverse events are less likely to occur.  In general,
133 nonradiolabeled contrast agents pose safety issues similar to therapeutic drugs because of the
134 inherently large amounts needed for administration.  Therefore, nonradiolabeled drugs generally
135 should be treated like therapeutic agents for the purpose of conducting clinical safety
136 assessments.
137
138 3. Frequency of Use
139
140 Many medical imaging agents, including both contrast agents and diagnostic
141 radiopharmaceuticals, are administered infrequently or as single doses.  Accordingly, adverse
142 events that are related to long-term use or to accumulation are less likely to occur with these
143 agents than with agents that are administered repeatedly to the same patient.  Therefore, the
144 nonclinical development programs for such single-use products usually can omit long-term (i.e.,
145 3 months duration or longer), repeat-dose safety studies.  In clinical settings where it is possible
146 that the medical imaging agent will be administered to a single patient repeatedly (e.g., to
147 monitor disease progression), we recommend that repeat-dose studies (of 14 to 28 days
148 duration) be performed to assess safety.   
149
150 Biological medical imaging agents are frequently immunogenic, and the development of
151 antibodies after intermittent, repeated administration can alter the pharmacokinetics,
152 biodistribution, safety, and/or imaging properties of such agents and, potentially, of
153 immunologically related agents.  We recommend that studies in which repeat dosing of a
154 biological imaging agent is planned incorporate pharmacokinetic data, human anti-mouse
                                                
5
 See also 21 CFR 315.6 on evaluation of safety.  When a medical imaging agent does not possess any of these
special characteristics, as described in section III.A.1-4, complete standard safety assessments should be performed. 
4 Contains Nonbinding Recommendations
155 antibody (HAMA), human anti-humanized antibody (HAHA), or human anti-chimeric antibody
156 (HACA) levels as well as whole body biodistribution imaging to assess for alterations in the
157 biodistribution of the imaging agent following repeat dosing.  Studies of immunogenicity in
158 animal models are generally of limited value.  Therefore, we recommend that human clinical
159 data assessing the repeat use of a biological imaging agent be obtained prior to application for
160 licensure of such an agent.
161
162 4. Biological, Physical, and Effective Half-Lives
163
164 Diagnostic radiopharmaceuticals often use radionuclides with short physical half-lives or that are
165 excreted rapidly.  The biological, physical, and effective half-lives of diagnostic
166 radiopharmaceuticals are incorporated into radiation dosimetry evaluations6 that require an
167 understanding of the kinetics of the distribution and excretion of the radionuclide and its mode of
168 decay.  We recommend that biological, physical, and effective half-lives be considered in
169 planning appropriate safety and dosimetry evaluations of diagnostic radiopharmaceuticals.
170
171 B. Performance of Nonclinical Safety Assessments
172
173 We recommend that the nonclinical development strategy for an agent be based on sound
174 scientific principles, the agent's unique chemistry (including, for example, those of its
175 components, metabolites, and impurities), and the agents intended use.  Because each product is
176 unique, we encourage sponsors to consult with us before submitting an IND application and
177 during product development.  The number and types of nonclinical studies recommended would
178 depend in part on the phase of development, what is known about the agent or its pharmacologic
179 class, its proposed use, and the indicated patient population.  If you determine that nonclinical
180 pharmacology or toxicology studies are not needed, we are prepared to grant a waiver under
181 21 CFR 312.10 if you provide adequate justification.
182
183 In the discussion that follows, a distinction is made between drug products and biological
184 products.  Existing specific guidance for biological products is referenced but not repeated here
185 (see section III.B.2). 
186
187 1. Nonclinical Safety Assessments for Nonbiological Drug Products 
188
189 a. Timing of Nonclinical Studies Submitted to an IND Application
190
191 We recommend that nonclinical studies be timed so that they help facilitate the
192 timely conduct of clinical trials (including appropriate safety monitoring based on
193 findings in nonclinical studies) and to reduce the unnecessary use of animals and
                                                
6 Biological half-life is the time needed for a human or animal to remove, by biological elimination, half of the
amount of a substance that has been administered.  Effective half-life is the time needed for a radionuclide in a
human or animal to decrease its activity by half as a combined result of biological elimination and radioactive decay.
Physical half-life is the time needed for half of the population of atoms of a particular radioactive substance to
disintegrate to another nuclear form.
5 Contains Nonbinding Recommendations
194 other resources.7  The recommended timing of nonclinical studies for medical
195 imaging drugs is summarized in Table 1.
196
197 b. Contrast Agents  
198
199 Because of the characteristics of contrast drug products (e.g., variable biologic
200 half-life) and the way they are used, we recommend that nonclinical safety
201 evaluations of such drug products be made more efficient with the following
202 modifications:
203
204   Long-term (i.e., greater than 3 months), repeat-dose toxicity studies in animals
205 usually can be omitted.  (Exceptions are products with long residence time,
206 e.g., > 90 days.)
207
208   Long-term rodent carcinogenicity studies usually can be omitted.8   
209
210   Reproductive toxicology studies required under  312.23(a)(8)(ii)(a) often can
211 be limited to an evaluation of embryonic and fetal toxicities in rats and rabbits
212 and to evaluations of reproductive organs in other short-term toxicity studies.9
213 If you determine that such reproductive studies are not needed, we are
214 prepared to grant a waiver under  312.10 if you provide adequate
215 justification.
216
217 We recommend that studies be conducted to address the effects of large mass
218 dose and volume (especially for iodinated contrast materials administered
219 intravenously); osmolality effects; potential transmetalation of complexes of
220 gadolinium, manganese, or iron (generally MRI drugs); potential effects of tissue
221 or cellular accumulation on organ function (particularly if the drug is intended to
222 image a diseased organ system); and the chemical, physiological, and physical
223 effects of ultrasound microbubble drugs (e.g., coalescence, aggregation,
224 margination, and cavitation). 
                                                
7 See the guidance M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals.
This and all other guidances cited in this document are available at FDAs Web site at
http://www.fda.gov/cder/guidance/index.htm.
8
 Circumstances in which carcinogenicity testing may be recommended are summarized in the guidance S1A The
Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals.
9
 See the guidance S5A Detection of Toxicity to Reproduction for Medicinal Products and S5B Detection of Toxicity
to Reproduction for Medicinal Products:  Addendum on Toxicity to Male Fertility.
6 Contains Nonbinding Recommendations
225 Table 1:  Timing of Nonclinical Studies for Nonbiological Products Submitted to an IND 
226
Study Type Before Phase 1 Before Phase 2 Before Phase 3 Before NDA
Safety Major organs,(a) and
pharmacology organ systems the drug
is intended to visualize
Toxicokinetic See ICH guidances
pharmacokinetic 
Expanded single- Expanded acute single
dose toxicity  dose (b) 
Short-term (2 to 4 Repeat-dose toxicity
weeks) multiple
dose toxicity
Special toxicology Conduct as necessary
based on route-
irritancy, blood
compatibility, protein
flocculation,
misadministration,
extravasation 
Radiation If applicable
dosimetry
Genotoxicity In vitro (d) Complete standard
battery
Immunotoxicity May be needed based
on molecular
structure,
biodistribution
pattern, class
concern, or clinical or
nonclinical signal
Reproductive and Needed or waiver 
developmental obtained (d)
toxicity
Drug interaction As needed
Other based on As needed
data results 
227 (a) See the guidances S7A Safety Pharmacology Studies for Human Pharmaceutical and S7B Safety Pharmacology
228 Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human
229 Pharmaceuticals (note that S7B allows for phase evaluation of the required studies).
230 (b) See the guidance Single Dose Acute Testing for Pharmaceuticals.
231 (c) When repeat-dose toxicity studies have been performed, but single-dose toxicology studies have not, dose
232 selection for initial human studies will likely be based on the results of the no-adverse-effect level (NOAEL)
233 obtained in the repeat-dose study.  The likely result will be a mass dose selection for initial human administration
234 that is lower than if the dose selection had been based on the results of acute, single-dose toxicity studies.
235 (d) See radiopharmaceutical discussion in section III.B.1.c of this document.
236
7 Contains Nonbinding Recommendations
237 c. Diagnostic Radiopharmaceuticals (Nonbiological Products)
238
239 Because of the characteristics of diagnostic radiopharmaceuticals and the way
240 they are used, we recommend that nonclinical safety evaluations of these drugs be
241 made more efficient by the following modifications:
242
243   Long-term, repeat-dose toxicity studies in animals typically can be omitted.
244
245   Long-term rodent carcinogenicity studies typically can be omitted.
246
247   Reproductive toxicology studies can be waived when adequate scientific
248 justification is provided.10
249
250   Genotoxicity studies should be conducted on the nonradioactive component
251 because the genotoxicity of the nonradioactive component should be
252 identified separately from that of the radionuclide.  Genotoxicity studies can
253 be waived if adequate scientific justification is provided.11  
254
255 We recommend that special safety considerations for diagnostic
256 radiopharmaceuticals include verification of the mass dose of the radiolabeled
257 and unlabeled moiety; assessment of the mass, toxic potency, and receptor
258 interactions for any unlabeled moiety; assessment of potential pharmacologic
259 or physiologic effects due to molecules that bind with receptors or enzymes;
260 and evaluation of all components in the final formulation for toxicity (e.g.,
261 excipients, reducing drugs, stabilizers, anti-oxidants, chelators, impurities, and
262 residual solvents).  We recommend that the special safety considerations
263 include an analysis of particle size (for products containing particles) and an
264 assessment of instability manifested by aggregation or precipitation.  We also
265 recommend that an individual component be tested if specific toxicological
266 concerns are identified or if toxicological data for that component are lacking.
267 However, if toxicological studies are performed on the combined components
268 of a radiopharmaceutical and no significant toxicity is found, toxicological
269 studies of individual components are seldom required.
270
271 2. Nonclinical Safety Assessments for Biological Products
272
273 Many biological products raise relatively distinct nonclinical issues such as immunogenicity and
274 species specificity.  We recommend the following Agency documents be reviewed for guidance
275 on the preclinical evaluation of biological medical imaging agents:
276
277   S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
                                                
10 
See footnote 11.
11
 See guidances S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals and S2B Genotoxicity:
A Standard Battery for Genotoxicity Testing of Pharmaceuticals.
8 Contains Nonbinding Recommendations
278
279   Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products
280 for Human Use
281
282 Sponsors are encouraged to consult with the appropriate reviewing division for additional
283 information when needed.
284
285
286 IV. CLINICAL SAFETY ASSESSMENTS
287
288 Under section 505(d) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(d)),
289 FDA cannot approve a new drug application (NDA) unless it contains adequate tests
290 demonstrating whether the proposed drug product is safe for use under the conditions prescribed,
291 recommended, or suggested in its proposed labeling.12  All drugs have risks, including risks
292 related to the intrinsic properties of the drug, the administration process, the reactions of the
293 patient, and incorrect diagnostic information.  Incorrect diagnostic information includes
294 inaccurate structural, functional, physiological, or biochemical information; false positive or
295 false negative diagnostic determinations; and information leading to inappropriate decisions in
296 diagnostic or therapeutic management.  Even if risks are found to be small, all drug development
297 programs must also obtain evidence of drug effectiveness under section 505 of the Act.
298 Although it has been suggested that a demonstration of effectiveness not be required for safer
299 drugs, this statutory requirement cannot be waived.   FDA weighs the benefits and risks of each
300 proposed drug product when making its decision about whether to approve a marketing
301 application (e.g., an NDA or BLA).
302
303 A. Group 1 and 2 Medical Imaging Agents 
304
305 The special characteristics of medical imaging agents may allow for a more efficient clinical
306 safety program.  This guidance describes two general categories for medical imaging agents:
307 Group 1 and Group 2.  The extent of clinical safety monitoring and evaluation that we
308 recommend differs for these two categories.  Generally, a less extensive clinical safety
309 evaluation is appropriate for Group 1 agents.  Conversely, we recommend that Group 2 agents
310 undergo standard clinical safety evaluations in clinical trials throughout their development.
311 These different groups have been conceived to help drug sponsors identify and differentiate
312 those characteristics that are of greatest interest to the Agency in assessing the potential safety of
313 a medical imaging agent.  
314
315 FDA anticipates that it can assess which agents are Group 1 agents based on the safety-margin
316 criteria from animal studies and initial human trials completed at the end of Phase 1.
317
318 1. Group 1 Medical Imaging Agents
319
320 For purposes of this guidance, a Group 1 medical imaging agent generally exhibits the following
321 three characteristics.
                                                
12 For approval of a biological license application, the safety of the proposed product must be demonstrated under
section 351 of the Public Health Service Act (42 U.S.C. 262).
9 Contains Nonbinding Recommendations
322
323   The medical imaging agent meets either the safety-margin considerations or the clinical-
324 use considerations described below (see sections B.1 and B.2, respectively).
325   The medical imaging agent is not a biological product13, 14 
326   The medical imaging agent does not predominantly emit alpha or beta particles 
327 Note that under the safety margin criteria (see section IV.B), medical imaging agents that are
328 administered in low mass doses to humans (e.g., diagnostic radiopharmaceuticals) usually are
329 more likely to be considered Group 1 than those administered in higher mass doses.15  There
330 are important exceptions, including cases where the medical imaging agents are likely to be
331 immunogenic (e.g., biological products) when the pharmacologic response exists at a low
332 mass dose, or when the medical imaging agents cause adverse reactions that are not dose-
333 related (e.g., idiosyncratic drug reactions).
334 We recommend that standard clinical safety evaluations be performed in all clinical
335 investigations of medical imaging agents, but we suggest that, for Group 1 agents, reduced
336 human safety monitoring may be appropriate in subsequent human trials. 
337
338   For example, human safety monitoring may be limited to recording adverse events and
339 monitoring only particular organs or tissues of interest for toxicity (such as organs that
340 showed toxicity in the animal studies, or the organs and tissues in which the medical
341 imaging agent localizes, which usually would include the liver and kidneys).
342
343 Persons having questions about whether a medical imaging agent is a Group 1 agent are
344 encouraged to contact FDA to discuss.  Whether a medical imaging agent should be considered a
345 Group 1 or Group 2 agent may change during the course of a products development.  For
346 example, even if an agent is initially thought to be Group 1, the subsequent identification of
347 safety concerns could be reason to treat that agent as a Group 2 agent for the remainder of the
348 products development.
349
350 2. Group 2 Medical Imaging Agents
351
352 For purposes of this guidance, Group 2 medical imaging agents are generally medical imaging
353 drugs or biological products that do not fall under the considerations for Group 1 medical
354 imaging agents.  All biological products are assumed to be Group 2 agents unless the sponsor
355 demonstrates that its product lacks immunogenicity.  Medical imaging agents that are
                                                
13
 Biological medical imaging products (e.g..,  radiolabeled cells, monoclonal antibodies, monoclonal antibody
fragments; see 21 CFR 600.3(h) for definition of a biological product) have the potential to elicit an immunogenic
response.  Because the development of antibodies following repeat or intermittent administration can alter the safety,
pharmacokinetics, and biodistribution of such agents, we regard biological medical imaging products as Group 2
agents.
14 See also the final regulation Adverse Experience Reporting Requirements for Licensed Biological Products
(59 FR 54042; October 27, 1994). 
15 For example, the approved PET drug products meet the Group 1 criteria.
10 Contains Nonbinding Recommendations
356 biologically active in animal studies or in human studies when administered at dosages that are
357 similar to those intended for clinical use should also be considered Group 2 agents.16 
358
359 For Group 2 medical imaging agents, standard clinical safety evaluations should include serial
360 assessments of patient symptoms, physical signs, clinical laboratory tests (e.g., blood chemistry,
361 hematology, coagulation profiles, urinalyses), other tests (e.g., electrocardiograms as
362 appropriate), and adverse events.  We recommend that additional specialized evaluations be
363 performed when appropriate (e.g., immunological evaluations, creatine kinase isoenzymes), or if
364 a particular toxicity is deemed possible based on animal studies or the known chemical or
365 pharmacological properties of the medical imaging agent.  Although the extent of clinical
366 monitoring cannot be predetermined, we recommend that it be of sufficient duration to identify
367 possible effects that may lag behind those predicted by pharmacokinetic analyses.  If some of
368 these standard clinical safety evaluations are felt to be unnecessary, this should be discussed with
369 the reviewing division.  We recommend that sponsors seek FDA comment on the clinical safety
370 monitoring plans in clinical studies before such studies are initiated.
371
372 B. Considerations For Groups 1 or 2
373
374 1. Safety-Margin Considerations
375
376 Under the safety-margin considerations, medical imaging agents can be considered Group 1 if
377 the results of nonclinical studies and initial human experience are consistent with the conditions
378 outlined below:
379
380 a. Results of nonclinical studies
381
382 To be considered a Group 1 agent under the safety-margin considerations, we
383 recommend that a medical imaging agent have an adequately documented margin
384 of safety as assessed in the nonclinical studies outlined in the following list.17 
385
386  We recommend that the no-observed-adverse-effect level (NOAEL)18 in
387 expanded-acute, single-dose toxicity studies in suitable animal species be at
388 least one hundred times (100x) greater than the maximal mass dose to be used
389 in human studies.  We further recommend that such expanded, acute, single-
390 dose toxicity studies be completed before the medical imaging agent is
391 introduced into humans (see section III.B.1).
                                                
16 Group 2 diagnostic radiopharmaceuticals can also include radionuclides and carriers that are known to be
biologically active.  This group includes radionuclides and carriers used at radiation doses or mass dosages that are
higher than those used previously, including radionuclides and carriers that have been documented to produce
adverse reactions.
17 In addition, the medical imaging agent should meet the conditions described for the results of initial human
experience (see section IV.B.1.b).
18 For purposes of Groups 1 and 2 in this section of this guidance, the  term no-observed-adverse-effect-level
(NOAEL) is defined as the highest mass dose tested in animals with no adverse effects. (See guidance A Harmonized
Approach to Estimating the Safe Starting Dose for Clinical Trials of Therapeutics in Healthy Volunteers.)
11 Contains Nonbinding Recommendations
392
393   We recommend that the NOAEL in safety pharmacology studies in suitable
394 animal species be at least one hundred times (100x) greater than the maximal
395 mass dose to be used in human studies.  We further recommend that such
396 safety pharmacology studies be completed before the medical imaging agent
397 is introduced into humans (see section III.B.1).
398
399   We recommend that the NOAEL in short-term, repeat-dose toxicity studies in
400 suitable animal species be at least twenty-five times (25x) greater than the
401 maximal mass dose to be used in human studies.19  Short-term, repeat-dose
402 toxicity studies are conducted to evaluate the effects of exaggerated dose
403 regimens.  Such regimens can reveal effects not detected in studies of small
404 numbers of patients, suggest effects to be monitored in clinical studies, and
405 reveal effects that might occur in sensitive individuals.  Short-term, repeat-
406 dose toxicity studies can be performed either before the medical imaging
407 agent is introduced into humans, or concurrently with early human studies, but
408 we recommend that they be completed before phase 2 (see section III.B.1).
409
410 To establish these margins of safety, we recommend that the NOAELs be
411 assessed in properly designed and conducted studies and be appropriately
412 adjusted.  Appropriately adjusted means that mass dose comparisons between
413 animals and humans should be suitably modified for factors such as body size
414 (e.g., body surface area) and otherwise adjusted for possible pharmacokinetic and
415 toxicokinetic differences between animals and humans (e.g., differences in
416 absorption for products that are administered orally).20
417
418 We recommend that Group 1 medical imaging agents also undergo other
419 nonclinical toxicological studies as described in section III.B.1, such as
420 genotoxicity, reproductive toxicity, irritancy studies, and drug-drug interaction
421 studies.  See section III.B.1 for details and timing sequence.
422
423 i. Additional considerations
424
425 FDA may still consider a medical imaging agent Group 1 even if its NOAELs are
426 slightly less than the multiples specified above.  For example, FDA will also take
427 into consideration, among other things, how close the NOAELs are to the
428 multiples specified above, the amount of safety information known about
429 chemically similar and pharmacologically related medical imaging agents, the
                                                
19 Short-term, repeated-dose toxicity studies may identify toxicities associated with accumulation of a medical
imaging agent or its metabolites.  In addition, even if such accumulation is not anticipated (e.g., non-metabolized
medical imaging agents with short half-lives), short-term repeated-dose toxicity studies may identify toxicities
caused by repeated toxic insults, each of which may be below the threshold of detection in expanded-acute, single-
dose toxicity studies.
20 For example, if drug elimination is based on a physiologic function that reflects blood flow, we then recommend
that scaling on body surface area be used.
12 Contains Nonbinding Recommendations
430 nature of observed animal toxicities, and whether adverse events have occurred
431 during initial human experience, including the nature of such adverse events (see
432 section IV.B.1.b).
433
434 ii. Formulations used in nonclinical studies
435
436 We recommend that the formulation used to establish safety margins in
437 nonclinical studies be identical to the formulation that will be used in clinical
438 trials and that is intended for marketing.  We also recommend that any differences
439 in the formulations used in the clinical trials and nonclinical studies be specified
440 so that any effect on the adequacy of the nonclinical studies can be determined.
441 Bridging studies may be helpful when changes in the formulation are apt to
442 change the pharmacokinetics, the pharmacodynamics, or safety characteristics of
443 the drug.21
444
445 In some cases, it may be infeasible or impractical to administer the intended
446 clinical formulation to animals in multiples of the maximal human mass dose
447 specified above (e.g., the volume of such an animal mass dose may be excessive).
448 We recommend that sponsors discuss their plans with FDA before studies are
449 initiated.  In these cases, alternative strategies can be employed, such as dividing
450 the daily mass dose (e.g., into a morning and evening dose), or by using a more
451 concentrated formulation of the medical imaging agent, or the maximal feasible
452 daily mass dose can be administered. 
453
454 b. Results of initial human experience
455
456 In addition to those considerations described above for nonclinical studies, FDA
457 also intends to consider the following when evaluating whether a medical imaging
458 agent is a Group 1 agent. 
459
460   Whether safety issues were identified during initial human use of the medical
461 imaging agent in appropriately designed studies that include adequate and
462 documented standard clinical safety evaluations.  Identification of any adverse
463 events during initial human use that were not predicted from effects observed
464 in animals could be considered significant, regardless of severity.  If adverse
465 events occur at any time during human studies, we intend to conduct a risk
466 assessment to determine whether the medical imaging agent should be
467 reconsidered as a Group 2 medical imaging agent.  This risk assessment will
468 examine the type, frequency, severity, and potential attribution of the adverse
469 events with respect to what is known about the pharmacology of the drug.  For
470 example, the safety profile of a specific drug class may be well known, so that
471 the occurrence of a common, nonserious adverse event, such as headache,
472 would not be of particular concern.  However, in a drug class in which
473 microparticles of varying sizes are administered, the occurrence of the same
474 adverse event might be a signal of microcirculatory compromise.
                                                
21 See guidance S7A Safety pharmacology studies for human pharmaceuticals.
13 Contains Nonbinding Recommendations
475
476   We recommend that human pharmacokinetic studies of the
477 radiopharmaceutical be performed during phase 1 to collect information about
478 the disposition of the radioactivity in humans.  Such data help facilitate
479 adequate comparisons of exposure between humans and the species used in
480 the nonclinical studies and allow a more meaningful assessment of the
481 relevance of the animal safety data (e.g., toxicokinetics).
482
483 2. Clinical Use Considerations
484
485 Another way to be considered a Group 1 agent is by adequately documenting extensive
486 prior clinical use without development of a safety signal.  This means showing that there
487 were no human toxicity or adverse events with clinical mass doses (and activities, if
488 applicable) of the agent, under conditions of adequate safety monitoring, and that the lack
489 of human toxicity was adequately documented.  We recommend that the methods used to
490 monitor for adverse events be documented.  Literature may be of limited value in
491 establishing the clinical safety of a drug because most published studies focus on
492 efficacy, with little or no description of any safety assessments.
493
494 An agent can be identified as Group 1 based on the clinical-use considerations at any
495 time during drug development (e.g., after the conditions specified in this section have all
496 been met).
497
498 C.  Radiation Safety Assessment for All Diagnostic Radiopharmaceuticals
499
500 1. General Considerations
501
502 We recommend that an IND sponsor submit sufficient data from animal or human studies
503 to allow a reasonable calculation of the radiation absorbed dose to the whole body and to
504 critical organs upon administration to a human subject (21 CFR 312.23(a)(10)(ii)).  At a
505 minimum, we recommend that radiation absorbed dose estimates be provided for all
506 organs and tissues in the standardized anthropomorphic phantoms established in the
507 literature (e.g., by the Medical Internal Radiation Dose (MIRD) Committee of the Society
508 of Nuclear Medicine).  For diagnostic radiopharmaceuticals, we also recommend
509 calculation of the effective dose as defined by the International Commission on
510 Radiological Protection (ICRP) in its ICRP Publication 60 (this quantity is not
511 meaningful for therapeutic radiopharmaceuticals).
512
513 When a diagnostic radiopharmaceutical is being developed for pediatric use, the radiation
514 absorbed dose should be provided for all age groups in which the agent is intended to be
515 used, as provided by standard anthropomorphic phantoms established in the literature
516 (i.e., newborn, 1-year-old, 5-year-old, 10-year-old, and 15-year-old).  
517
518 We recommend that the amount of the radiation absorbed dose delivered by internal
519 administration of diagnostic radiopharmaceuticals be calculated by standardized methods,
520 such as the absorbed fraction method described by the MIRD Committee and the ICRP.
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521
522 We also recommend that the methodology used to assess radiation safety be specified
523 including reference to the body models that were used.  We recommend that the
524 mathematical equations used to derive the time activity curves and the radiation absorbed
525 dose estimates be provided along with a full description of assumptions that were made.
526 We further recommend that sample calculations and all pertinent assumptions be listed
527 and submitted.  We recommend that the reference to the body, organ, or tissue model
528 used in the dosimetry calculations be specified, particularly for new models being tested.
529 If a software program was used to calculate the radiation doses, we recommend that you
530 provide (1) a full description of the code, including official name, version number, and
531 computing platform; (2) a literature citation for the code; and (3) photocopies of the
532 codes output, preferably showing all of the user input data and model choices.
533
534 We recommend that safety hazards for patients and health care workers during and after
535 administration of the radiolabeled product be identified, evaluated, and managed
536 appropriately.
537
538 2. Calculation of Radiation Absorbed Dose to the Target Organs or Tissues
539
540 For established radionuclides used with a diagnostic agent (e.g., Tc-99m, In-111), we
541 recommend that the following items be determined based on the average patient as
542 defined by the MIRD phantom:
543
544   The tissue or organ in which a significant accumulation of radioactivity occurs (i.e.,
545 source organ)
546   The amount of radioactivity that accumulates in these tissues, expressed as a
547 percentage of the administered activity
548   The times at which radioactivity accumulation was observed in these tissues.  We
549 recommend that observations be made at two or more times during each phase of
550 radioactivity accumulation or clearance from the source regions.  If there is rapid
551 accumulation in a region and nonexponential clearance, two to three time points may
552 be sufficient to characterize the kinetic behavior.  If there are two phases of clearance,
553 we recommend at least two points of observation during each phase to adequately
554 characterize the biokinetics.  A description of the kinetic behavior of the activity
555 accumulation and clearance from these tissues.  This is most typically shown as
556 biological half-times for accumulation and clearance, although other representations
557 may be used.
558   The time-integral of activity for the accumulation of radiopharmaceutical in these
559 source tissues or organs.  For purposes of this guidance, this time-integral is defined
560 as the cumulated activity or residence time by the MIRD Committee in various
561 publications.
562   A description of how this time-integral was calculated.  This should be based
563 primarily on the accumulation and kinetic behavior in the source organs.  We
564 recommend that you specify the method used to calculate the time-integrals (e.g.,
15 Contains Nonbinding Recommendations
565 numerical integration, regression analysis, or compartment model analysis).  We also
566 recommend that you provide a description of how the terminal portion of the time-
567 activity curve for a given source region was integrated (e.g., assuming only physical
568 decay after the last data point, some rate of biological elimination estimated by two or
569 more of the later data points, or a fitted function continued to infinite time).
570   A description of how these time-integrals for source regions were combined with
571 dose conversion factors to calculate the radiation absorbed dose to all target regions.
572 If hand calculations were performed, we recommend that you specify the source of
573 dose conversion factors and provide copies of all calculations.  If an electronic
574 spreadsheet was used, we recommend that you provide printouts and electronic copies
575 of the spreadsheets to verify the formulas used.  If a computer program was used, we
576 recommend that you provide a complete description of the code and version number
577 as well as documentation of the code input and output.
578 For new radionuclides used with diagnostic agents, the same principles apply and we
579 recommend that you provide the same information.  If you want guidance on these
580 calculations, we recommend that you consult the appropriate review division. 
581 3. Maximum Radiation Absorbed Dose
582
583 We recommend that the amount of radioactive material administered to human subjects
584 be the smallest radiation absorbed dose practical to perform the procedure while
585 providing an adequate diagnostic examination for evaluation by the physician.
586
587 We recommend that calculations include the radiation absorbed dose contributions made
588 by all potential radionuclide contaminants that may be present in the product.
589
590 We recommend that you perform calculations to anticipate possible changes in dosimetry
591 that might occur in the presence of diseases in organs that are critical in metabolism or
592 excretion of the diagnostic radiopharmaceutical. For example, renal dysfunction may
593 cause significant, slow-clearing accumulation in one or both kidneys (and thus a high
594 dose to kidneys and adjacent tissues) and/or a larger fraction of the administered activity
595 to be cleared by the hepatobiliary system (or vice versa).
596
597 We recommend that possible changes in dosimetry resulting from patient-to-patient
598 variations in antigen or receptor mass be considered in dosimetry calculations.  For
599 example, a large tumor mass may result in a larger-than-expected radiation absorbed dose
600 to a target organ from a diagnostic radiopharmaceutical that has specificity for a tumor
601 antigen.  (For the purposes of dose calculation, a primary tumor, without metastases, can
602 be regarded as part of the organ in which it arises and its activity can be added to that of
603 the organ.)
604
605 We recommend that the mathematical equations used to derive the estimates of the
606 individual organ time activity curves and the radiation absorbed doses be provided along
607 with a full description of assumptions that were made.  We recommend that sample
608 calculations and all pertinent assumptions be listed.
609
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610 We recommend that calculations of radiation absorbed dose estimates be performed
611 assuming freshly labeled material (to account for the maximum amount of radioactivity)
612 as well as the maximum shelf life of the diagnostic radiopharmaceutical (to allow for the
613 upper limit of accumulation of radioactive decay contaminants).  We recommend that
614 these calculations:
615
616   Include radiation absorbed doses from x-ray procedures that are part of the study (i.e.,
617 would not have occurred but for the study).  The possibility of follow-up studies
618 should be considered for inclusion in the dose calculations. 
619   Be expressed as milligray (mGy) per megabecquerel (MBq) and as rad per millicurie
620 (mCi) of the administered radiopharmaceutical
621   Be expressed as mGy and rad for a typical administered quantity of the
622 radiopharmaceutical
623   Be presented in a tabular format and include individual radiation absorbed doses for
624 the target tissues or organs and the organs listed above in section IV.D.1 
625  
17 Contains Nonbinding Recommendations
626 GLOSSARY
627
628 Effective dose:  The sum of the weighted equivalent doses in all the tissues and organs of the
629 body, given by the expression E = WTHT,R, where WT is the weighting.  Effective dose,
630 defined in 1990 by the International Commission on Radiological Protection, allows the
631 conversion of the risk from partial body irradiations to those of whole body irradiations.
632
633 Mass dose:  The mass or weight of the ligand or carrier, including the radionuclide, administered
634 to the subject.  
635
636 No observed adverse effect level (NOAEL):  The highest radiation absorbed dose tested in an
637 animal species without adverse effects detected.
638
639 No observed effect level (NOEL):  The highest radiation absorbed dose tested in an animal
640 species with no detected effects.
641
642 Radiation absorbed dose:  The energy absorbed per unit mass.  This is the fundamental
643 dosimetric quantity in radiological protection.  Its unit is the joule per kilogram, which is given
644 the special name gray (Gy).  The older quantity was the rad, where 1 Gy = 100 rads.
645
646 Repeat-dose toxicity study:  A study that investigates the toxicities produced when a
647 pharmaceutical is administered repeatedly during a given period of more than 24 hours.  A
648 repeat-dose toxicity study evaluates the effects of exaggerated dose regimens.  Usually all
649 animals in a repeat-dose toxicity study are terminated the day after the final dose; however, a
650 recovery period may be included in the design to test the reversibility of effects.  An interim
651 sacrifice is sometimes included to detect effects that may occur after a few doses.
652
653 Safety pharmacology study:  A study that investigates the potential undesirable
654 pharmacodynamic effects of a substance on physiologic functions in relation to exposure levels.
655
656 Special toxicology study:  A study conducted when something about the nature of the drug or
657 how it is used raises a concern, or when previous nonclinical or clinical findings on the product
658 or a related product have indicated special toxicological concerns.  Examples include a local
659 irritation study conducted to test the effects of potential misadministration or extravasation.
660
661 Standard/expanded acute toxicity study:  A study that investigates toxicities produced by a
662 pharmaceutical when it is administered in one dose.  During a period not exceeding 24 hours,
663 doses may be split due to large volumes or high concentrations.  An expanded acute toxicity
664 study includes more measures of toxicities than a standard acute toxicity study.
665
666
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