Developing Medical Imaging Drug and Biological Products Part 1: Conducting Safety Assessments

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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
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
(Phone 301-827-4573)
Internet: http://www.fda.gov/cder/guidance/index.htm.
or
Office of Communication, Training and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
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 Industry1
2
Developing Medical Imaging Drug and Biological Products	3
Part 1: Conducting Safety Assessments	4
5
6
7
8
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It	9
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.	10
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes	11
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for	12
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate	13
number listed on the title page of this guidance.	14
15
16
17
18
I. 	INTRODUCTION	19
20
This guidance is one of three guidances intended to assist developers of medical imaging drug	21
and biological products (medical imaging agents) in planning and coordinating their clinical	22
investigations and preparing and submitting investigational new drug applications (INDs), new	23
drug applications (NDAs), biologics license applications (BLAs), abbreviated NDAs (ANDAs),	24
and supplements to NDAs or BLAs. The three guidances are: Part 1: Conducting Safety	25
Assessments; Part 2: Clinical Indications; and Part 3: Design, Analysis, and Interpretation of	26
Clinical Studies.	27
28
Medical imaging agents generally are governed by the same regulations as other drug and	29
biological products. However, because medical imaging agents are used solely to diagnose and	30
monitor diseases or conditions as opposed to treat them, development programs for medical	31
imaging agents can be tailored to reflect these particular uses. Specifically, this guidance	32
discusses our recommendations on conducting safety assessments of medical imaging agents.	33
34
FDA's guidance documents, including this guidance, do not establish legally enforceable	35
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should	36
be viewed only as recommendations, unless specific regulatory or statutory requirements are	37
cited. The use of the word should in Agency guidances means that something is suggested or	38
recommended, but not required.	39
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.

Contains Nonbinding Recommendations
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A glossary of common terms used in diagnostic medical imaging is provided at the end of this	41
document.	42
43
44
II. 	SCOPE — TYPES OF MEDICAL IMAGING AGENTS	45
46
This guidance discusses medical imaging agents that are administered in vivo and are used for	47
diagnosis or monitoring with a variety of different modalities, such as radiography, computed	48
tomography (CT), ultrasonography, magnetic resonance imaging (MRI), and radionuclide	49
imaging. The guidance is not intended to apply to the development of in vitro diagnostic or	50
therapeutic uses of these agents.2
51
52
Medical imaging agents can be classified into at least two general categories, contrast agents and	53
diagnostic radiopharmaceuticals.	54
55
A. 	Contrast Agents	56
57
As used in this guidance, a contrast agent is a medical imaging agent used to improve the	58
visualization of tissues, organs, and physiologic processes by increasing the relative difference of	59
imaging signal intensities in adjacent regions of the body. Types of contrast agents include, but	60
are not limited to, (1) iodinated compounds used in radiography and CT; (2) paramagnetic	61
metallic ions (such as ions of gadolinium, iron, and manganese) linked to a variety of molecules	62
and microparticles (such as superparamagnetic iron oxide) used in MRI; and (3) microbubbles,	63
microaerosomes, and related microparticles used in diagnostic ultrasonography.	64
65
B. 	Diagnostic Radiopharmaceuticals	66
67
As used in this guidance, a diagnostic radiopharmaceutical is (1) an article that is intended for	68
use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that	69
exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or	70
photons or (2) any nonradioactive reagent kit or nuclide generator that is intended to be used in	71
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.

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the preparation of such an article.3 As stated in the preamble to FDA's proposed rule on	72
Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis and Monitoring, the Agency	73
interprets this definition to include articles that exhibit spontaneous disintegration leading to the	74
reconstruction of unstable nuclei and the subsequent emission of nuclear particles or photons	75
(63 FR 28301 at 28303; May 22, 1998).	76
77
Diagnostic radiopharmaceuticals are generally radioactive drug or biological products that	78
contain a radionuclide that typically is linked to a ligand or carrier.4 These products are used in	79
nuclear medicine procedures, including planar imaging, single photon emission computed	80
tomography (SPECT), positron emission tomography (PET), or in combination with other	81
radiation detection probes.	82
83
Diagnostic radiopharmaceuticals used for imaging typically have two distinct components.	84
85
• 	A radionuclide that can be detected in vivo (e.g., technetium-99m, iodine-123, indium-	86
111).	87
88
The radionuclide typically is a radioactive atom with a relatively short physical half-life	89
that emits radioactive decay photons having sufficient energy to penetrate the tissue mass	90
of the patient. These photons can then be detected with imaging devices or other	91
detectors	92
93
• 	A nonradioactive component to which the radionuclide is bound that delivers the	94
radionuclide to specific areas within the body.	95
96
This nonradionuclidic portion of the diagnostic radiopharmaceutical often is an organic	97
molecule such as a carbohydrate, lipid, nucleic acid, peptide, small protein, or antibody.	98
99
As technology advances, new products may emerge that do not fit into these traditional	100
categories (e.g., agents for optical imaging, magnetic resonance spectroscopy, combined contrast	101
and functional imaging). It is anticipated, however, that the general principles discussed here	102
could apply to these new diagnostic products. Developers of these products should contact the	103
appropriate reviewing division for advice on product development.	104
105
106
III. 	GENERAL CONSIDERATIONS FOR SAFETY ASSESSMENTS OF MEDICAL	107
IMAGING AGENTS	108
109
A. 	Medical Imaging Agent Characteristics Relevant to Safety	110
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.

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The following sections discuss the special characteristics of a medical imaging agent that can	112
lead to a more focused safety evaluation. Characteristics include its radiation absorbed dose,	113
mass dose, route of administration, frequency of use, biodistribution, and biological, physical,	114
and effective half-lives in the serum, the whole body, and critical organs.5
115
116
1. 	Mass Dose	117
118
Some medical imaging agents can be administered at low mass doses. For example, the mass	119
dose of a single administration of a diagnostic radiopharmaceutical can be small because device	120
technologies can typically detect relatively small amounts of a radionuclide (e.g.,	121
radiopharmaceuticals for myocardial perfusion imaging). 	When a medical imaging agent is	122
administered at a mass dose that is at the low end of the dose-response curve, dose-related	123
adverse events are less likely to occur.	124
125
2. 	Route of Administration	126
127
Some medical imaging agents are administered by routes that decrease the likelihood of systemic	128
adverse events. For example, medical imaging agents that are administered as contrast media for	129
radiographic examination of the gastrointestinal tract (e.g., barium sulfate) can be administered	130
orally, through an oral tube, or rectally. In patients with normal gastrointestinal tracts, many of	131
these products are not absorbed, so systemic adverse events are less likely to occur. In general,	132
nonradiolabeled contrast agents pose safety issues similar to therapeutic drugs because of the	133
inherently large amounts needed for administration. Therefore, nonradiolabeled drugs generally	134
should be treated like therapeutic agents for the purpose of conducting clinical safety	135
assessments.	136
137
3. 	Frequency of Use	138
139
Many medical imaging agents, including both contrast agents and diagnostic	140
radiopharmaceuticals, are administered infrequently or as single doses. Accordingly, adverse	141
events that are related to long-term use or to accumulation are less likely to occur with these	142
agents than with agents that are administered repeatedly to the same patient. Therefore, the	143
nonclinical development programs for such single-use products usually can omit long-term (i.e.,	144
3 months’ duration or longer), repeat-dose safety studies. In clinical settings where it is possible	145
that the medical imaging agent will be administered to a single patient repeatedly (e.g., to	146
monitor disease progression), we recommend that repeat-dose studies (of 14 to 28 days’	147
duration) be performed to assess safety.	148
149
Biological medical imaging agents are frequently immunogenic, and the development of	150
antibodies after intermittent, repeated administration can alter the pharmacokinetics,	151
biodistribution, safety, and/or imaging properties of such agents and, potentially, of	152
immunologically related agents. We recommend that studies in which repeat dosing of a	153
biological imaging agent is planned incorporate pharmacokinetic data, human anti-mouse	154
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.

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antibody (HAMA), human anti-humanized antibody (HAHA), or human anti-chimeric antibody	155
(HACA) levels as well as whole body biodistribution imaging to assess for alterations in the	156
biodistribution of the imaging agent following repeat dosing. Studies of immunogenicity in	157
animal models are generally of limited value. Therefore, we recommend that human clinical	158
data assessing the repeat use of a biological imaging agent be obtained prior to application for	159
licensure of such an agent.	160
161
4. 	Biological, Physical, and Effective Half-Lives	162
163
Diagnostic radiopharmaceuticals often use radionuclides with short physical half-lives or that are	164
excreted rapidly. The biological, physical, and effective half-lives of diagnostic	165
radiopharmaceuticals are incorporated into radiation dosimetry evaluations6 that require an	166
understanding of the kinetics of the distribution and excretion of the radionuclide and its mode of	167
decay. We recommend that biological, physical, and effective half-lives be considered in	168
planning appropriate safety and dosimetry evaluations of diagnostic radiopharmaceuticals.	169
170
B. 	Performance of Nonclinical Safety Assessments	171
172
We recommend that the nonclinical development strategy for an agent be based on sound	173
scientific principles, the agent's unique chemistry (including, for example, those of its	174
components, metabolites, and impurities), and the agent’s intended use. Because each product is	175
unique, we encourage sponsors to consult with us before submitting an IND application and	176
during product development. The number and types of nonclinical studies recommended would	177
depend in part on the phase of development, what is known about the agent or its pharmacologic	178
class, its proposed use, and the indicated patient population. If you determine that nonclinical	179
pharmacology or toxicology studies are not needed, we are prepared to grant a waiver under	180
21 CFR 312.10 if you provide adequate justification.	181
182
In the discussion that follows, a distinction is made between drug products and biological	183
products. Existing specific guidance for biological products is referenced but not repeated here	184
(see section III.B.2).	185
186
1. 	Nonclinical Safety Assessments for Nonbiological Drug Products	187
188
a. 	Timing of Nonclinical Studies Submitted to an IND Application	189
190
We recommend that nonclinical studies be timed so that they help facilitate the	191
timely conduct of clinical trials (including appropriate safety monitoring based on	192
findings in nonclinical studies) and to reduce the unnecessary use of animals and	193
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.

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other resources.7 The recommended timing of nonclinical studies for medical	194
imaging drugs is summarized in Table 1.	195
196
b. 	Contrast Agents	197
198
Because of the characteristics of contrast drug products (e.g., variable biologic	199
half-life) and the way they are used, we recommend that nonclinical safety	200
evaluations of such drug products be made more efficient with the following	201
modifications:	202
203
• 	Long-term (i.e., greater than 3 months), repeat-dose toxicity studies in animals	204
usually can be omitted. (Exceptions are products with long residence time,	205
e.g., > 90 days.)	206
207
• 	Long-term rodent carcinogenicity studies usually can be omitted.8
208
209
• 	Reproductive toxicology studies required under § 312.23(a)(8)(ii)(a) often can	210
be limited to an evaluation of embryonic and fetal toxicities in rats and rabbits	211
and to evaluations of reproductive organs in other short-term toxicity studies.9
212
If you determine that such reproductive studies are not needed, we are	213
prepared to grant a waiver under § 312.10 if you provide adequate	214
justification.	215
216
We recommend that studies be conducted to address the effects of large mass	217
dose and volume (especially for iodinated contrast materials administered	218
intravenously); osmolality effects; potential transmetalation of complexes of	219
gadolinium, manganese, or iron (generally MRI drugs); potential effects of tissue	220
or cellular accumulation on organ function (particularly if the drug is intended to	221
image a diseased organ system); and the chemical, physiological, and physical	222
effects of ultrasound microbubble drugs (e.g., coalescence, aggregation,	223
margination, and cavitation).	224
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 FDA’s 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.

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Table 1: Timing of Nonclinical Studies for Nonbiological Products Submitted to an IND	225
226
Study Type 	Before Phase 1 	Before Phase 2 	Before Phase 3 	Before NDA
Safety
pharmacology
Major organs, (a) and
organ systems the drug
is intended to visualize
Toxicokinetic
pharmacokinetic
See ICH guidances
Expanded single-
dose toxicity
Expanded acute single
dose (b)
Short-term (2 to 4
weeks) multiple
dose toxicity
Repeat-dose toxicity
Special toxicology 	Conduct as necessary
based on route-
irritancy, blood
compatibility, protein
flocculation,
misadministration,
extravasation
Radiation
dosimetry
If applicable
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
developmental
toxicity
Needed or waiver
obtained (d)
Drug interaction 	As needed
Other based on
data results
As needed
(a) See the guidances S7A Safety Pharmacology Studies for Human Pharmaceutica l and S7B Safety Pharmacology	227 Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human	228 Pharmaceuticals (note that S7B allows for phase evaluation of the required studies).	229 (b) See the guidance Single Dose Acute Testing for Pharmaceuticals.	230 (c) When repeat-dose toxicity studies have been performed, but single-dose toxicology studies have not, dose	231 selection for initial human studies will likely be based on the results of the no-adverse-effect level (NOAEL)	232 obtained in the repeat-dose study. The likely result will be a mass dose selection for initial human administration	233 that is lower than if the dose selection had been based on the results of acute, single-dose toxicity studies.	234 (d) See radiopharmaceutical discussion in section III.B.1.c of this document.	235
236

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c. 	Diagnostic Radiopharmaceuticals (Nonbiological Products)	237
238
Because of the characteristics of diagnostic radiopharmaceuticals and the way	239
they are used, we recommend that nonclinical safety evaluations of these drugs be	240
made more efficient by the following modifications:	241
242
• 	Long-term, repeat-dose toxicity studies in animals typically can be omitted.	243
244
• 	Long-term rodent carcinogenicity studies typically can be omitted.	245
246
• 	Reproductive toxicology studies can be waived when adequate scientific	247
justification is provided.10
248
249
• 	Genotoxicity studies should be conducted on the nonradioactive component	250
because the genotoxicity of the nonradioactive component should be	251
identified separately from that of the radionuclide. Genotoxicity studies can	252
be waived if adequate scientific justification is provided.11
253
254
We recommend that special safety considerations for diagnostic	255
radiopharmaceuticals include verification of the mass dose of the radiolabeled	256
and unlabeled moiety; assessment of the mass, toxic potency, and receptor	257
interactions for any unlabeled moiety; assessment of potential pharmacologic	258
or physiologic effects due to molecules that bind with receptors or enzymes;	259
and evaluation of all components in the final formulation for toxicity (e.g.,	260
excipients, reducing drugs, stabilizers, anti-oxidants, chelators, impurities, and	261
residual solvents). We recommend that the special safety considerations	262
include an analysis of particle size (for products containing particles) and an	263
assessment of instability manifested by aggregation or precipitation. We also	264
recommend that an individual component be tested if specific toxicological	265
concerns are identified or if toxicological data for that component are lacking.	266
However, if toxicological studies are performed on the combined components	267
of a radiopharmaceutical and no significant toxicity is found, toxicological	268
studies of individual components are seldom required.	269
270
2. 	Nonclinical Safety Assessments for Biological Products	271
272
Many biological products raise relatively distinct nonclinical issues such as immunogenicity and	273
species specificity. We recommend the following Agency documents be reviewed for guidance	274
on the preclinical evaluation of biological medical imaging agents:	275
276
• 	S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals	277
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.

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278
• 	Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products	279
for Human Use	280
281
Sponsors are encouraged to consult with the appropriate reviewing division for additional	282
information when needed.	283
284
285
IV. 	CLINICAL SAFETY ASSESSMENTS	286
287
Under section 505(d) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(d)),	288
FDA cannot approve a new drug application (NDA) unless it contains adequate tests	289
demonstrating whether the proposed drug product is safe for use under the conditions prescribed,	290
recommended, or suggested in its proposed labeling. 12 All drugs have risks, including risks	291
related to the intrinsic properties of the drug, the administration process, the reactions of the	292
patient, and incorrect diagnostic information. Incorrect diagnostic information includes	293
inaccurate structural, functional, physiological, or biochemical information; false positive or	294
false negative diagnostic determinations; and information leading to inappropriate decisions in	295
diagnostic or therapeutic management. Even if risks are found to be small, all drug development	296
programs must also obtain evidence of drug effectiveness under section 505 of the Act.	297
Although it has been suggested that a demonstration of effectiveness not be required for safer	298
drugs, this statutory requirement cannot be waived. 	FDA weighs the benefits and risks of each	299
proposed drug product when making its decision about whether to approve a marketing	300
application (e.g., an NDA or BLA).	301
302
A. 	Group 1 and 2 Medical Imaging Agents	303
304
The special characteristics of medical imaging agents may allow for a more efficient clinical	305
safety program. This guidance describes two general categories for medical imaging agents:	306
Group 1 and Group 2. The extent of clinical safety monitoring and evaluation that we	307
recommend differs for these two categories. Generally, a less extensive clinical safety	308
evaluation is appropriate for Group 1 agents. Conversely, we recommend that Group 2 agents	309
undergo standard clinical safety evaluations in clinical trials throughout their development.	310
These different groups have been conceived to help drug sponsors identify and differentiate	311
those characteristics that are of greatest interest to the Agency in assessing the potential safety of	312
a medical imaging agent.	313
314
FDA anticipates that it can assess which agents are Group 1 agents based on the safety-margin	315
criteria from animal studies and initial human trials completed at the end of Phase 1.	316
317
1. 	Group 1 Medical Imaging Agents	318
319
For purposes of this guidance, a Group 1 medical imaging agent generally exhibits the following	320
three characteristics.	321
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).

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322
• 	The medical imaging agent meets either the safety-margin considerations or the clinical-	323
use considerations described below (see sections B.1 and B.2, respectively).	324
• 	The medical imaging agent is not a biological product13, 14
325
• 	The medical imaging agent does not predominantly emit alpha or beta particles	326
Note that under the safety margin criteria (see section IV.B), medical imaging agents that are	327
administered in low mass doses to humans (e.g., diagnostic radiopharmaceuticals) usually are	328
more likely to be considered Group 1 than those administered in higher mass doses.15 There	329
are important exceptions, including cases where the medical imaging agents are likely to be	330
immunogenic (e.g., biological products) when the pharmacologic response exists at a low	331
mass dose, or when the medical imaging agents cause adverse reactions that are not dose-	332
related (e.g., idiosyncratic drug reactions).	333
We recommend that standard clinical safety evaluations be performed in all clinical	334
investigations of medical imaging agents, but we suggest that, for Group 1 agents, reduced	335
human safety monitoring may be appropriate in subsequent human trials.	336
337
• 	For example, human safety monitoring may be limited to recording adverse events and	338
monitoring only particular organs or tissues of interest for toxicity (such as organs that	339
showed toxicity in the animal studies, or the organs and tissues in which the medical	340
imaging agent localizes, which usually would include the liver and kidneys).	341
342
Persons having questions about whether a medical imaging agent is a Group 1 agent are	343
encouraged to contact FDA to discuss. Whether a medical imaging agent should be considered a	344
Group 1 or Group 2 agent may change during the course of a product’s development. For	345
example, even if an agent is initially thought to be Group 1, the subsequent identification of	346
safety concerns could be reason to treat that agent as a Group 2 agent for the remainder of the	347
product’s development.	348
349
2. 	Group 2 Medical Imaging Agents	350
351
For purposes of this guidance, Group 2 medical imaging agents are generally medical imaging	352
drugs or biological products that do not fall under the considerations for Group 1 medical	353
imaging agents. All biological products are assumed to be Group 2 agents unless the sponsor	354
demonstrates that its product lacks immunogenicity. Medical imaging agents that are	355
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.

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biologically active in animal studies or in human studies when administered at dosages that are	356
similar to those intended for clinical use should also be considered Group 2 agents.16
357
358
For Group 2 medical imaging agents, standard clinical safety evaluations should include serial	359
assessments of patient symptoms, physical signs, clinical laboratory tests (e.g., blood chemistry,	360
hematology, coagulation profiles, urinalyses), other tests (e.g., electrocardiograms as	361
appropriate), and adverse events. We recommend that additional specialized evaluations be	362
performed when appropriate (e.g., immunological evaluations, creatine kinase isoenzymes), or if	363
a particular toxicity is deemed possible based on animal studies or the known chemical or	364
pharmacological properties of the medical imaging agent. Although the extent of clinical	365
monitoring cannot be predetermined, we recommend that it be of sufficient duration to identify	366
possible effects that may lag behind those predicted by pharmacokinetic analyses. If some of	367
these standard clinical safety evaluations are felt to be unnecessary, this should be discussed with	368
the reviewing division. We recommend that sponsors seek FDA comment on the clinical safety	369
monitoring plans in clinical studies before such studies are initiated.	370
371
B. 	Considerations For Groups 1 or 2	372
373
1. 	Safety-Margin Considerations	374
375
Under the safety-margin considerations, medical imaging agents can be considered Group 1 if	376
the results of nonclinical studies and initial human experience are consistent with the conditions	377
outlined below:	378
379
a. 	Results of nonclinical studies	380
381
To be considered a Group 1 agent under the safety-margin considerations, we	382
recommend that a medical imaging agent have an adequately documented margin	383
of safety as assessed in the nonclinical studies outlined in the following list.17
384
385
• 	We recommend that the no-observed-adverse-effect level (NOAEL)18 in	386
expanded-acute, single-dose toxicity studies in suitable animal species be at	387
least one hundred times (100x) greater than the maximal mass dose to be used	388
in human studies. We further recommend that such expanded, acute, single-	389
dose toxicity studies be completed before the medical imaging agent is	390
introduced into humans (see section III.B.1).	391
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.)

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392
• 	We recommend that the NOAEL in safety pharmacology studies in suitable	393
animal species be at least one hundred times (100x) greater than the maximal	394
mass dose to be used in human studies. We further recommend that such	395
safety pharmacology studies be completed before the medical imaging agent	396
is introduced into humans (see section III.B.1).	397
398
• 	We recommend that the NOAEL in short-term, repeat-dose toxicity studies in	399
suitable animal species be at least twenty-five times (25x) greater than the	400
maximal mass dose to be used in human studies.19 Short-term, repeat-dose	401
toxicity studies are conducted to evaluate the effects of exaggerated dose	402
regimens. Such regimens can reveal effects not detected in studies of small	403
numbers of patients, suggest effects to be monitored in clinical studies, and	404
reveal effects that might occur in sensitive individuals. Short-term, repeat-	405
dose toxicity studies can be performed either before the medical imaging	406
agent is introduced into humans, or concurrently with early human studies, but	407
we recommend that they be completed before phase 2 (see section III.B.1).	408
409
To establish these margins of safety, we recommend that the NOAELs be	410
assessed in properly designed and conducted studies and be appropriately	411
adjusted. Appropriately adjusted means that mass dose comparisons between	412
animals and humans should be suitably modified for factors such as body size	413
(e.g., body surface area) and otherwise adjusted for possible pharmacokinetic and	414
toxicokinetic differences between animals and humans (e.g., differences in	415
absorption for products that are administered orally).20
416
417
We recommend that Group 1 medical imaging agents also undergo other	418
nonclinical toxicological studies as described in section III.B.1, such as	419
genotoxicity, reproductive toxicity, irritancy studies, and drug-drug interaction	420
studies. See section III.B.1 for details and timing sequence.	421
422
i. 	Additional considerations	423
424
FDA may still consider a medical imaging agent Group 1 even if its NOAELs are	425
slightly less than the multiples specified above. For example, FDA will also take	426
into consideration, among other things, how close the NOAELs are to the	427
multiples specified above, the amount of safety information known about	428
chemically similar and pharmacologically related medical imaging agents, the	429
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.

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13
nature of observed animal toxicities, and whether adverse events have occurred	430
during initial human experience, including the nature of such adverse events (see	431
section IV.B.1.b).	432
433
ii. 	Formulations used in nonclinical studies	434
435
We recommend that the formulation used to establish safety margins in	436
nonclinical studies be identical to the formulation that will be used in clinical	437
trials and that is intended for marketing. We also recommend that any differences	438
in the formulations used in the clinical trials and nonclinical studies be specified	439
so that any effect on the adequacy of the nonclinical studies can be determined.	440
Bridging studies may be helpful when changes in the formulation are apt to	441
change the pharmacokinetics, the pharmacodynamics, or safety characteristics of	442
the drug.21
443
444
In some cases, it may be infeasible or impractical to administer the intended	445
clinical formulation to animals in multiples of the maximal human mass dose	446
specified above (e.g., the volume of such an animal mass dose may be excessive).	447
We recommend that sponsors discuss their plans with FDA before studies are	448
initiated. In these cases, alternative strategies can be employed, such as dividing	449
the daily mass dose (e.g., into a morning and evening dose), or by using a more	450
concentrated formulation of the medical imaging agent, or the maximal feasible	451
daily mass dose can be administered.	452
453
b. 	Results of initial human experience	454
455
In addition to those considerations described above for nonclinical studies, FDA	456
also intends to consider the following when evaluating whether a medical imaging	457
agent is a Group 1 agent.	458
459
• 	Whether safety issues were identified during initial human use of the medical	460
imaging agent in appropriately designed studies that include adequate and	461
documented standard clinical safety evaluations. Identification of any adverse	462
events during initial human use that were not predicted from effects observed	463
in animals could be considered significant, regardless of severity. If adverse	464
events occur at any time during human studies, we intend to conduct a risk	465
assessment to determine whether the medical imaging agent should be	466
reconsidered as a Group 2 medical imaging agent. This risk assessment will	467
examine the type, frequency, severity, and potential attribution of the adverse	468
events with respect to what is known about the pharmacology of the drug. For	469
example, the safety profile of a specific drug class may be well known, so that	470
the occurrence of a common, nonserious adverse event, such as headache,	471
would not be of particular concern. However, in a drug class in which	472
microparticles of varying sizes are administered, the occurrence of the same	473
adverse event might be a signal of microcirculatory compromise.	474
21 See guidance S7A Safety pharmacology studies for human pharmaceuticals.

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14
475
• 	We recommend that human pharmacokinetic studies of the	476
radiopharmaceutical be performed during phase 1 to collect information about	477
the disposition of the radioactivity in humans. Such data help facilitate	478
adequate comparisons of exposure between humans and the species used in	479
the nonclinical studies and allow a more meaningful assessment of the	480
relevance of the animal safety data (e.g., toxicokinetics).	481
482
2. 	Clinical Use Considerations	483
484
Another way to be considered a Group 1 agent is by adequately documenting extensive	485
prior clinical use without development of a safety signal. This means showing that there	486
were no human toxicity or adverse events with clinical mass doses (and activities, if	487
applicable) of the agent, under conditions of adequate safety monitoring, and that the lack	488
of human toxicity was adequately documented. We recommend that the methods used to	489
monitor for adverse events be documented. Literature may be of limited value in	490
establishing the clinical safety of a drug because most published studies focus on	491
efficacy, with little or no description of any safety assessments.	492
493
An agent can be identified as Group 1 based on the clinical-use considerations at any	494
time during drug development (e.g., after the conditions specified in this section have all	495
been met).	496
497
C. 	Radiation Safety Assessment for All Diagnostic Radiopharmaceuticals	498
499
1. 	General Considerations	500
501
We recommend that an IND sponsor submit sufficient data from animal or human studies	502
to allow a reasonable calculation of the radiation absorbed dose to the whole body and to	503
critical organs upon administration to a human subject (21 CFR 312.23(a)(10)(ii)). At a	504
minimum, we recommend that radiation absorbed dose estimates be provided for all	505
organs and tissues in the standardized anthropomorphic phantoms established in the	506
literature (e.g., by the Medical Internal Radiation Dose (MIRD) Committee of the Society	507
of Nuclear Medicine). For diagnostic radiopharmaceuticals, we also recommend	508
calculation of the effective dose as defined by the International Commission on	509
Radiological Protection (ICRP) in its ICRP Publication 60 (this quantity is not	510
meaningful for therapeutic radiopharmaceuticals).	511
512
When a diagnostic radiopharmaceutical is being developed for pediatric use, the radiation	513
absorbed dose should be provided for all age groups in which the agent is intended to be	514
used, as provided by standard anthropomorphic phantoms established in the literature	515
(i.e., newborn, 1-year-old, 5-year-old, 10-year-old, and 15-year-old).	516
517
We recommend that the amount of the radiation absorbed dose delivered by internal	518
administration of diagnostic radiopharmaceuticals be calculated by standardized methods,	519
such as the absorbed fraction method described by the MIRD Committee and the ICRP.	520

Contains Nonbinding Recommendations
15
521
We also recommend that the methodology used to assess radiation safety be specified	522
including reference to the body models that were used. We recommend that the	523
mathematical equations used to derive the time activity curves and the radiation absorbed	524
dose estimates be provided along with a full description of assumptions that were made.	525
We further recommend that sample calculations and all pertinent assumptions be listed	526
and submitted. We recommend that the reference to the body, organ, or tissue model	527
used in the dosimetry calculations be specified, particularly for new models being tested.	528
If a software program was used to calculate the radiation doses, we recommend that you	529
provide (1) a full description of the code, including official name, version number, and	530
computing platform; (2) a literature citation for the code; and (3) photocopies of the	531
code’s output, preferably showing all of the user input data and model choices.	532
533
We recommend that safety hazards for patients and health care workers during and after	534
administration of the radiolabeled product be identified, evaluated, and managed	535
appropriately.	536
537
2. 	Calculation of Radiation Absorbed Dose to the Target Organs or Tissues	538
539
For established radionuclides used with a diagnostic agent (e.g., Tc-99m, In-111), we	540
recommend that the following items be determined based on the average patient as	541
defined by the MIRD phantom:	542
543
• 	The tissue or organ in which a significant accumulation of radioactivity occurs (i.e.,	544
source organ)	545
• 	The amount of radioactivity that accumulates in these tissues, expressed as a	546
percentage of the administered activity	547
• 	The times at which radioactivity accumulation was observed in these tissues. We	548
recommend that observations be made at two or more times during each phase of	549
radioactivity accumulation or clearance from the source regions. If there is rapid	550
accumulation in a region and nonexponential clearance, two to three time points may	551
be sufficient to characterize the kinetic behavior. If there are two phases of clearance,	552
we recommend at least two points of observation during each phase to adequately	553
characterize the biokinetics. A description of the kinetic behavior of the activity	554
accumulation and clearance from these tissues. This is most typically shown as	555
biological half-times for accumulation and clearance, although other representations	556
may be used.	557
• 	The time-integral of activity for the accumulation of radiopharmaceutical in these	558
source tissues or organs. For purposes of this guidance, this time-integral is defined	559
as the “cumulated activity” or “residence time” by the MIRD Committee in various	560
publications.	561
• 	A description of how this time-integral was calculated. This should be based	562
primarily on the accumulation and kinetic behavior in the source organs. We	563
recommend that you specify the method used to calculate the time-integrals (e.g.,	564

Contains Nonbinding Recommendations
16
numerical integration, regression analysis, or compartment model analysis). We also	565
recommend that you provide a description of how the terminal portion of the time-	566
activity curve for a given source region was integrated (e.g., assuming only physical	567
decay after the last data point, some rate of biological elimination estimated by two or	568
more of the later data points, or a fitted function continued to infinite time).	569
• 	A description of how these time-integrals for source regions were combined with	570
dose conversion factors to calculate the radiation absorbed dose to all target regions.	571
If hand calculations were performed, we recommend that you specify the source of	572
dose conversion factors and provide copies of all calculations. If an electronic	573
spreadsheet was used, we recommend that you provide printouts and electronic copies	574
of the spreadsheets to verify the formulas used. If a computer program was used, we	575
recommend that you provide a complete description of the code and version number	576
as well as documentation of the code input and output.	577
For new radionuclides used with diagnostic agents, the same principles apply and we	578
recommend that you provide the same information. If you want guidance on these	579
calculations, we recommend that you consult the appropriate review division.	580
3. 	Maximum Radiation Absorbed Dose	581
582
We recommend that the amount of radioactive material administered to human subjects	583
be the smallest radiation absorbed dose practical to perform the procedure while	584
providing an adequate diagnostic examination for evaluation by the physician.	585
586
We recommend that calculations include the radiation absorbed dose contributions made	587
by all potential radionuclide contaminants that may be present in the product.	588
589
We recommend that you perform calculations to anticipate possible changes in dosimetry	590
that might occur in the presence of diseases in organs that are critical in metabolism or	591
excretion of the diagnostic radiopharmaceutical. For example, renal dysfunction may	592
cause significant, slow-clearing accumulation in one or both kidneys (and thus a high	593
dose to kidneys and adjacent tissues) and/or a larger fraction of the administered activity	594
to be cleared by the hepatobiliary system (or vice versa).	595
596
We recommend that possible changes in dosimetry resulting from patient-to-patient	597
variations in antigen or receptor mass be considered in dosimetry calculations. For	598
example, a large tumor mass may result in a larger-than-expected radiation absorbed dose	599
to a target organ from a diagnostic radiopharmaceutical that has specificity for a tumor	600
antigen. (For the purposes of dose calculation, a primary tumor, without metastases, can	601
be regarded as part of the organ in which it arises and its activity can be added to that of	602
the organ.)	603
604
We recommend that the mathematical equations used to derive the estimates of the	605
individual organ time activity curves and the radiation absorbed doses be provided along	606
with a full description of assumptions that were made. We recommend that sample	607
calculations and all pertinent assumptions be listed.	608
609

Contains Nonbinding Recommendations
17
We recommend that calculations of radiation absorbed dose estimates be performed	610
assuming freshly labeled material (to account for the maximum amount of radioactivity)	611
as well as the maximum shelf life of the diagnostic radiopharmaceutical (to allow for the	612
upper limit of accumulation of radioactive decay contaminants). We recommend that	613
these calculations:	614
615
• 	Include radiation absorbed doses from x-ray procedures that are part of the study (i.e.,	616
would not have occurred but for the study). The possibility of follow-up studies	617
should be considered for inclusion in the dose calculations.	618
• 	Be expressed as milligray (mGy) per megabecquerel (MBq) and as rad per millicurie	619
(mCi) of the administered radiopharmaceutical	620
• 	Be expressed as mGy and rad for a typical administered quantity of the	621
radiopharmaceutical	622
• 	Be presented in a tabular format and include individual radiation absorbed doses for	623
the target tissues or organs and the organs listed above in section IV.D.1	624
625

Contains Nonbinding Recommendations
18
GLOSSARY	626
627
Effective dose: The sum of the weighted equivalent doses in all the tissues and organs of the	628
body, given by the expression E = ∑WTHT,R, where WT is the weighting. Effective dose,	629
defined in 1990 by the International Commission on Radiological Protection, allows the	630
conversion of the risk from partial body irradiations to those of whole body irradiations.	631
632
Mass dose: The mass or weight of the ligand or carrier, including the radionuclide, administered	633
to the subject.	634
635
No observed adverse effect level (NOAEL): The highest radiation absorbed dose tested in an	636
animal species without adverse effects detected.	637
638
No observed effect level (NOEL): The highest radiation absorbed dose tested in an animal	639
species with no detected effects.	640
641
Radiation absorbed dose: The energy absorbed per unit mass. This is the fundamental	642
dosimetric quantity in radiological protection. Its unit is the joule per kilogram, which is given	643
the special name gray (Gy). The older quantity was the rad, where 1 Gy = 100 rads.	644
645
Repeat-dose toxicity study: A study that investigates the toxicities produced when a	646
pharmaceutical is administered repeatedly during a given period of more than 24 hours. A	647
repeat-dose toxicity study evaluates the effects of exaggerated dose regimens. Usually all	648
animals in a repeat-dose toxicity study are terminated the day after the final dose; however, a	649
recovery period may be included in the design to test the reversibility of effects. An interim	650
sacrifice is sometimes included to detect effects that may occur after a few doses.	651
652
Safety pharmacology study: A study that investigates the potential undesirable	653
pharmacodynamic effects of a substance on physiologic functions in relation to exposure levels.	654
655
Special toxicology study: A study conducted when something about the nature of the drug or	656
how it is used raises a concern, or when previous nonclinical or clinical findings on the product	657
or a related product have indicated special toxicological concerns. Examples include a local	658
irritation study conducted to test the effects of potential misadministration or extravasation.	659
660
Standard/expanded acute toxicity study: A study that investigates toxicities produced by a	661
pharmaceutical when it is administered in one dose. During a period not exceeding 24 hours,	662
doses may be split due to large volumes or high concentrations. An expanded acute toxicity	663
study includes more measures of toxicities than a standard acute toxicity study.	664
665
666