Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Oncology Therapeutic
Radiopharmaceuticals:
Nonclinical Studies and
Labeling Recommendations
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2019
Pharmacology/Toxicology

Oncology Therapeutic
Radiopharmaceuticals:
Nonclinical Studies and
Labeling Recommendations
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2019
Pharmacology/Toxicology

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	PHARMACOLOGY ......................................................................................................... 3
A. 	Primary Pharmacology ................................................................................................................. 3
B. 	Safety Pharmacology ..................................................................................................................... 3
IV. 	ANIMAL BIODISTRIBUTION AND DOSIMETRY................................................... 3
V. 	TOXICOLOGY ................................................................................................................ 5
A. 	General Toxicology ........................................................................................................................ 5
1. Toxicology Studies to Support the FIH Therapeutic Phase ............................................................. 5
2. Long-Term Toxicity Assessments to Support Marketing.................................................................. 5
B. 	Genotoxicity, Reproductive Toxicology, and Carcinogenicity Studies ..................................... 6
VI. 	FIH DOSE SELECTION ................................................................................................. 6
A. 	Radiation Administered Dose ....................................................................................................... 6
B. 	Mass Dose ....................................................................................................................................... 7
VII. 	LABELING RECOMMENDATIONS............................................................................ 7
A. 	Genotoxicity, Reproductive Toxicology, and Carcinogenicity ................................................... 7
B. 	Lactation ......................................................................................................................................... 8
GLOSSARY................................................................................................................................. 10
REFERENCES............................................................................................................................ 13

Contains Nonbinding Recommendations
1
Oncology Therapeutic Radiopharmaceuticals:
Nonclinical Studies and Labeling Recommendations
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
The purpose of this guidance is to provide information to assist sponsors in the design of an
appropriate nonclinical program for the development of radiopharmaceuticals to treat cancer —
also known as oncology therapeutic radiopharmaceuticals — and to provide recommendations
for certain aspects of product labeling. For the purpose of this guidance, a therapeutic
radiopharmaceutical is a product that contains a radionuclide and is used in patients with cancer
to treat the disease or palliate tumor-related symptoms (e.g., pain). Recommendations in this
guidance are applicable to products that are administered systemically and undergo alpha, beta,
and/or gamma decay.
This guidance is specific to therapeutic radiopharmaceuticals for oncology indications and
covers topics that are not addressed in current FDA or International Council for Harmonisation
(ICH) guidance, such as nonclinical studies in support of first-in-human (FIH) trials and
approval. This complementary guidance provides additional information that supplements the
guidance for industry Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic
Radiopharmaceuticals (November 2011) for the design of late radiation toxicity studies.2
The recommendations in this guidance generally apply to new products with no previous clinical
experience. Often, there is clinical experience with the ligand (e.g., an antibody previously
evaluated for its safety and efficacy in the treatment of cancer).3 When there is experience with
the radionuclide or the ligand components of the radiopharmaceutical being developed, the
1 This guidance has been prepared by the Division of Hematology, Oncology, Toxicology in the Center for Drug
Evaluation and Research at the Food and Drug Administration.
2 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
3 Words bolded at first use are described in the Glossary.

Contains Nonbinding Recommendations
2
nonclinical program can be abbreviated as needed, and the FIH dose can be based on clinical
data, as appropriate.
This guidance discusses the following concepts:
• 	Evaluation of toxicities from the ligand
• 	Evaluation of radiation toxicities
• 	Information for product labeling as related to reproductive toxicity, genotoxicity,
carcinogenicity, contraception, and use in lactating women
This guidance is not applicable to therapeutic radiopharmaceuticals with a local route of
administration, such as intratumoral, intrathecal, or inhalation route of administration, because
the nonclinical study designs and the approach to FIH dose selection discussed in this guidance
may not apply. In addition, this guidance is not applicable to external beam radiation therapy,
radiolabeled vaccine products, diagnostic radiopharmaceuticals, or radioactive drugs for research
use as described in 21 CFR 361.1. Although this guidance does not apply to diagnostic
radiopharmaceuticals as described in the FDA guidance for industry Microdose
Radiopharmaceutical Diagnostic Drugs: Nonclinical Study Recommendations (August 2018),
nonclinical studies conducted in support of product development for a diagnostic
radiopharmaceutical may in part satisfy the nonclinical studies for a therapeutic
radiopharmaceutical, as applicable based on product characteristics and clinical trial design.
Topics related to the product quality (such as impurity level and specification), product stability,
or labeling kit (used to produce a radiopharmaceutical before human use) are not discussed in
this guidance. However, the entire radioactive decay cascade, also known as daughter decays,
should be considered in the biodistribution and dosimetry studies for estimation of radiation
activity in organs and absorbed radiation doses.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
Radiation therapy may be delivered through an external source or by systemic administration of
a radioactive compound. Therapeutic radiopharmaceuticals are generally administered
intravenously and are intended to deliver cytotoxic levels of radiation selectively to tumor sites.
Targeted delivery is generally achieved with the use of a targeting moiety, such as a peptide or
an antibody. Some radionuclides (known as organ seekers) are naturally directed to a particular
organ, reaching a desired organ without a ligand. Examples include radium, which is a bone
seeker, and iodine, which is a thyroid seeker.

Contains Nonbinding Recommendations
3
The Agency supports the principles of the 3Rs, to reduce, refine, and replace animal use in
testing when feasible. Sponsors can consult with the Agency if they wish to use other testing
methods or strategies not described in this guidance. The Agency will consider whether the
alternative method is adequate to meet a nonclinical regulatory need.
III. 	PHARMACOLOGY
A. 	Primary Pharmacology
The sponsor should conduct proof-of-concept studies before initiating a FIH study to show
uptake by the tumor and antitumor activity. Preliminary characterization of the mechanism of
action can be through in vitro (such as target binding and antitumor activity) and animal studies
and should include appropriate endpoints. These studies may inform species selection for
biodistribution and toxicology studies. When needed, pharmacology studies could also be used to
determine the maximum tolerated radiation dose in animals.
B. 	Safety Pharmacology
Stand-alone studies to assess the pharmaceutical’s effect on vital organ functions
(cardiovascular, respiratory, and central nervous systems) generally are not warranted to initiate
a study in patients with cancer or for approval. These safety endpoints can be incorporated into
the design of toxicology and/or animal biodistribution studies. Detailed clinical observations
following dosing in rodents and nonrodents, and appropriate electrocardiographic measurements
in nonrodents, are generally considered sufficient safety assessments. In addition, the results of a
biodistribution study can provide further evidence of the potential for adverse effects on these
organ systems. For instance, distribution of radioactivity into the central nervous system (CNS)
can indicate the potential for anatomic and functional neurological deficits resulting from
radiation-induced vascular abnormalities, demyelination, and necrosis in the CNS (Greene-
Schloesser et al. 2012).
IV. 	ANIMAL BIODISTRIBUTION AND DOSIMETRY
The sponsor should conduct a biodistribution and dosimetry study in animals (typically a single
dose administration) to guide dose selection for the human biodistribution and dosimetry study
(typically a single dose of the radiopharmaceutical or its theranostic pair in patients). A single
animal species, that is scientifically justified, is usually sufficient. All relevant information
should be considered for selection of the animal species, including pharmacology data and tissue
cross reactivity for biological products, as applicable, to compare distribution in animal and
human tissues.
The sponsor should evaluate radioactivity in organs over time post-administration, using
sufficient duration of sampling (e.g., 5 x effective half-lives) to generate the time-integrated
activity curves, also referred to as cumulated activity (Siegel et al. 1999). The sampling

Contains Nonbinding Recommendations
4
interval should be scientifically justified. Pharmacokinetic parameters should be collected. The
sponsor should consider daughter decays and their half-lives when designing the animal
biodistribution study. Duration of data collection can be adjusted as needed (e.g., when a long
effective half-life or a multiexponential time-integrated activity curve may necessitate many
sampling time points and a substantial increase in the number of animals). In such cases,
alternative approaches and modeling can be considered to integrate the terminal portion of the
activity time curve. If alternative approaches and modeling are used, the sponsor should describe
them in the investigational new drug application (IND).
The design of an animal biodistribution study should incorporate aspects of the planned clinical
biodistribution and dosimetry study that might affect distribution of the product. For instance, if
the planned clinical study includes patients being pretreated with thyroid-protecting agents to
reduce radioiodine uptake by the thyroid, then this same design should be considered in the
animal biodistribution study. Additionally, because the amount of radioactive and
nonradioactive materials in the dosing mixture can affect the biodistribution, the ratio used in
animal studies should be comparable to that proposed in patients or be justified. Multiple dose
levels in biodistribution studies can provide useful information on the amount of radioactive and
nonradioactive materials needed for an optimal distribution in organs.
Organs assessed for distribution of time-integrated activity generally include the adrenals, bone
and bone marrow, brain, small and large intestine walls, stomach, heart, kidneys, liver, lungs,
muscles, ovaries, pancreas, spleen, testes, thymus, thyroid, urinary bladder, uterus, and total
body. Additional organs can be included as appropriate based on the potential distribution
specific to the particular radiopharmaceutical (e.g., eyes and skin for melanin-binding
compounds). Excretion data in urine and feces should be collected. The number of organs
assessed can be abbreviated if adequately justified. The abbreviated organ list should generally
include bone marrow and organs of excretion, such as kidneys and liver, because these organs
are generally affected, regardless of target binding. An example of using a limited number of
organs in a biodistribution study is when the intention is to show comparability of two related
radiopharmaceuticals (bridging study) such that the clinical data with one radiopharmaceutical
may be used to select the starting dose of the other radiopharmaceutical for a human dosimetry
study.
Both male and female animals should be included in the study for uptake of radioactivity by
male- and female-specific organs, unless the indication is sex-specific. Biodistribution and
dosimetry in large animals (e.g., monkeys) are usually done with imaging techniques; hence, a
small number of animals (e.g., three males and three females) may be sufficient to assess activity
levels and distribution over time. For small animals, such as mice and rats, there should be a
sufficient number of animals per time point when a method requiring animal sacrifice is used
(e.g., autoradiography).
The activity time curve in organs of animals can be used to estimate the percent administered
activity (%ID), residence time, and time-integrated activity in human organs. See the Glossary
(Estimation of human values of activity and residence time in source organs) for examples
of methods used for animal-to-human extrapolations; other methods can be used and should be
described in the IND. The estimated human values should be used to generate the radiation

Contains Nonbinding Recommendations
5
absorbed doses in human organs, through mathematical calculations or appropriate software
programs (Stabin and Xu 2014). The sponsor should describe dosimetry methodology and
associated software, including version identification, in the IND.
V. 	TOXICOLOGY
A. 	General Toxicology
1. 	Toxicology Studies to Support the FIH Therapeutic Phase
The sponsor should evaluate both radiation- and ligand-related toxicities. Such evaluations can
be through toxicology studies or biodistribution studies, as appropriate. Generally, no toxicity
studies are warranted before a FIH study when the radiopharmaceutical is a neat radionuclide
(i.e., contains no ligand). Toxicities of the radiopharmaceutical are from the radionuclide decay;
thus, the results of the animal biodistribution study with added safety endpoints can be used to
determine short-term radiation-related toxicities. Below are recommendations for radiation- and
ligand-related safety assessment.
• 	Evaluation of radiation-induced toxicity: A general toxicology study with the
radiopharmaceutical usually is not warranted. The animal biodistribution study, together
with the general knowledge of organ-specific radiation-induced toxicities, is usually
sufficient to address toxicities from the radiation. Published articles on organ-specific,
radiation-induced toxicities should be included in the submission. The sponsor should
consider adding safety endpoints, such as clinical signs, body weight (BW), hematology,
and serum chemistry, to the design of the biodistribution study.
• 	Evaluation of ligand-induced toxicity: To identify any ligand-related toxicities, the
sponsor should conduct a general toxicology study with the cold pharmaceutical in a
relevant species before initiation of a FIH study. Ligand-related toxicities have been
observed but are usually minor compared with radiation-induced toxicities; hence, a
study in one species is generally considered sufficient. Unless otherwise justified, the
species selected for toxicology study should be the same as the species used for animal
biodistribution and dosimetry study. Frequency of administration in the toxicology study
should follow recommendations in the ICH guidance for industry S9 Nonclinical
Evaluation for Anticancer Pharmaceuticals (March 2010) and should take into account
the frequency of administration in the FIH trial (both the human biodistribution and
dosimetry and the therapeutic phase that follows it).
2. 	Long-Term Toxicity Assessments to Support Marketing
In general, the nonclinical data generated in support of the FIH study and the clinical phase 1
data should be sufficient for moving to phase 2. The sponsor should conduct long-term toxicity
assessment studies and should submit the results with the marketing application. These studies
should assess both ligand- and radiation-related toxicities. The dosing period in animals can
follow ICH S9. For most pharmaceuticals intended for the treatment of patients with advanced

Contains Nonbinding Recommendations
6
cancer, nonclinical studies of 3 months’ duration are considered sufficient to support marketing.
Below are recommendations for study design and circumstances when studies may not be
needed.
• 	Evaluation of ligand-induced toxicity: Chronic toxicity studies of the cold
pharmaceutical may not be needed in several circumstances: when a limited number of
doses are administered to patients (e.g., two or three doses), when the ligand is for
delivery purposes only and administration will result in a small dose (e.g., in microgram
ranges), or when the cold pharmaceutical has a short half-life and dosing frequency is
low (e.g., every 4 to 8 weeks). When a chronic (i.e., 3-month) study is needed, a study in
a single species is generally considered sufficient. This study can be combined with the
late radiation toxicity study when a late radiation toxicity study is being conducted.
• 	Evaluation of late radiation toxicity: An assessment of late radiation toxicities is
warranted when patients have a long life expectancy that could be affected by late
radiation adverse effects. The assessment could be based on an integrated summary that
takes into consideration the distribution of radiation (from animal biodistribution and
human dosimetry studies) and publications describing late radiation effects.
Alternatively, an animal study can be conducted. For recommendations on animal study
design and endpoints, see the guidance for industry Nonclinical Evaluation of Late
Radiation Toxicity of Therapeutic Radiopharmaceuticals. Identification of a no-
observed-adverse-effect level is not needed. The study in a single species is generally
considered sufficient. When a limited number of organs is examined by histopathology,
the organs selected should be justified. Any organs with gross pathology findings should
be examined microscopically.
B. 	Genotoxicity, Reproductive Toxicology, and Carcinogenicity Studies
No genetic or reproductive toxicity or carcinogenicity study with the radiopharmaceutical or the
cold pharmaceutical is warranted during drug development or for approval. Alpha, beta, and
gamma radiation cause deoxyribonucleic acid damage and are inherently genotoxic and
carcinogenic and damage male and female germ cells and a developing conceptus. These risks
should be communicated in product labeling (see section VII., Labeling Recommendations).
VI. 	FIH DOSE SELECTION
FIH dose estimation should be based on two factors: the radioactive administered dose (i.e.,
administered activity) of the radiopharmaceutical and the mass dose of the pharmaceutical. The
sponsor should consider the following recommendations.
A. 	Radiation Administered Dose
Selection of the activity to be administered (becquerel (Bq) or curie (Ci) per BW or body surface
area) for patient dosimetry should be based on the animal biodistribution and dosimetry data, the
estimated absorbed radiation doses in human organs, and tolerance of normal human organs to

Contains Nonbinding Recommendations
7
radiation. As described in the Glossary and section IV., Animal Biodistribution and Dosimetry,
activity over time in each source organ is extrapolated from animals to humans to obtain the
estimated absorbed doses in human target organs. The radiation dose administered in patients
should be adjusted on the basis of tolerated absorbed radiation doses in human organs (e.g., using
threshold from external radiation therapy as a starting point), not to exceed prespecified limits.
As described in the guidance for industry Nonclinical Evaluation of Late Radiation Toxicity of
Therapeutic Radiopharmaceuticals, organ tolerance doses for systemically administered
radiopharmaceuticals can differ from the tolerance doses for external radiation beam. However,
because there currently are no accepted criteria for determination of organ tolerance for internal
radiation from radiopharmaceuticals, the sponsor should use published literature on external
radiation therapy as a starting point for radiopharmaceuticals (e.g., American Society for
Radiation Oncology 2010; Emami et al. 1991; Emami 2013; Stewart et al. 2012). Further
adjustment to a radiation administered dose can be made based on data.
Because the normal organ tolerance described in the published articles is for external beam,
caution should be exercised in extrapolating the data to acceptable organ doses for alpha decay.
For estimating the equivalent dose of alpha-emitting therapeutic radiopharmaceuticals, the
absorbed dose with an appropriate value (e.g., 5; Sgouros 2015) of relative biological
effectiveness (RBE) can be used. An RBE of 5 means that there is a fivefold higher toxicity
associated with alpha irradiation than there would be for X-ray irradiation delivering the same
absorbed dose (gray (Gy)). An RBE of 5 is recommended for alpha-emitting
radiopharmaceuticals when using organ tolerance data generated with external beam radiation.
An RBE of 1 is assigned to gamma and beta decays. Results of dosimetry in patients can then
guide selection of a reasonably safe therapeutic radiation administered dose.
B. 	Mass Dose
The total dose of the cold pharmaceutical should be considered for the FIH dose selection unless
the dose of the cold pharmaceutical is low (e.g., microgram doses). Results from general
toxicology studies or other nonclinical studies conducted with the cold pharmaceutical can be
used to define the appropriate FIH mass dose, according to principles described in ICH S9 and
ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Questions
and Answers (June 2018).
VII. 	LABELING RECOMMENDATIONS
A. 	Genotoxicity, Reproductive Toxicology, and Carcinogenicity
Product labeling must describe the potential for adverse reproductive toxicity, genotoxicity, and
carcinogenicity.4 Nonclinical studies specifically designed to evaluate these effects are not
warranted for radiopharmaceuticals (see section V. B., Genotoxicity, Reproductive Toxicology,
and Carcinogenicity Studies). However, the sponsor should discuss any available animal data or
4 21 CFR 201.57.

Contains Nonbinding Recommendations
8
anticipated effects that suggest carcinogenicity, genotoxicity, or impairment of fertility in the
Carcinogenesis, Mutagenesis, Impairment of Fertility subsection,5 whereas animal data or
anticipated effects that suggest adverse developmental effects should be discussed in the
Pregnancy subsection.6
Radiopharmaceuticals are genotoxic (see section V. B., Genotoxicity, Reproductive Toxicology,
and Carcinogenicity Studies), and a period of contraception during and after completion of
treatment is necessary to minimize adverse developmental effects. The effects of genotoxic
pharmaceuticals on embryo-fetal development have been described in the FDA guidance
Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations
(May 2019). The information on contraception use during and after treatment should be
communicated in the Females and Males of Reproductive Potential subsection.7
• 	Female patients should be advised to use contraception during treatment and then for at
least a period of time that equals five effective half-lives and an additional 6 months after
the last dose of the radiopharmaceutical. The half-life of daughter decays also should be
considered. The recommended period of contraception will ensure that most of the
radiopharmaceutical and damaged follicles and oocytes are released before fertilization.
• 	Male patients with female partners of reproductive potential should be advised to use
contraception during treatment and then for at least a period of time that equals five
effective half-lives and an additional 3 months after the last dose of the
radiopharmaceutical. The recommended period of contraception will allow elimination
of most of the radiopharmaceutical and damaged sperm before fertilization.
B. 	Lactation
When applicable, methods to minimize drug exposure to the breastfed child should be included
in the Lactation subsection.8 Because of high sensitivity of infants to radiation and risk of
toxicities, the following concepts are provided to calculate a period when breastfeeding is not
recommended to avoid or minimize exposure to radiopharmaceuticals in a nursing child.
Lactating women should be advised not to breastfeed during treatment with a therapeutic
radiopharmaceutical and if applicable for a specific period of time after the last dose. The period
5 See 21 CFR 201.57(c)(14)(i).
6 See 21 CFR 201.57(c)(9)(i) and the draft guidance for industry Pregnancy, Lactation, and Reproductive Potential:
Labeling for Human Prescription Drug and Biological Products — Content and Format (December 2014). When
final, this guidance will represent the FDA’s current thinking on this topic.
7 See 21 CFR 201.57(c)(9)(iii) and the guidance for industry Oncology Pharmaceuticals: Reproductive Toxicity
Testing and Labeling Recommendations.
8 See 21 CFR 201.57(c)(9)(ii) and the draft guidance for industry Pregnancy, Lactation, and Reproductive Potential:
Labeling for Human Prescription Drug and Biological Products — Content and Format.

Contains Nonbinding Recommendations
9
during which a woman should not breastfeed should be long enough to limit the radiation
effective dose to the nursing child to no more than one millisievert (1 mSv; Nuclear Regulatory
Commission 2008). An actual duration for advising against breastfeeding post-treatment should
be proposed and should be supported by estimation of radioactivity present in the breast milk at
the end of this period and an assumption of complete absorption by the nursing child. During this
period, a woman who plans to resume breastfeeding may pump and discard breast milk to
maintain her milk supply. When the radiopharmaceutical contains a ligand with a long half-life,
the recommendation should also address any safety issue related to the transfer of the ligand to a
nursing child.

Contains Nonbinding Recommendations
10
GLOSSARY	1
2
Activity: Activity of a given amount of radioactive material is the number of transitions or	3
decays per unit of time. The SI unit of activity is Bq, which is one transition per second. The	4
legacy unit of activity is denoted Ci.	5
6
1 MBq = 27 μCi; 1 mCi = 37 MBq	7
8
Cold pharmaceutical: The nonradioactive or decayed form of the product. For the purpose of	9
this guidance, this terminology is used when the product contains a ligand.	10
11
Dose	12
Mass Dose: The dose (mass unit) of the cold pharmaceutical administered per BW or per	13
body surface area.	14
15
Radiation Dose	16
Administered dose: The amount of radioactivity administered to animals or to patients	17
and expressed as the unit of activity (e.g., in units of MBq or mCi).	18
19
Absorbed dose (D): The ionizing-radiation energy deposited per unit mass of an organ or	20
tissue. The SI unit of absorbed dose is Gy, where 1 Gy = 1 J/kg (International	21
Commission on Radiation Units and Measurements (ICRU) 2011). The legacy unit of	22
absorbed dose is denoted rad.	23
24
1 Gy = 100 rad; 1 cGy = 1 rad	25
26
Equivalent dose (H): A measure of biological effect of the radioactive dose that takes	27
into account both the absorbed dose and the biological effectiveness of the radiation, and	28
hence, the radiation type. The SI unit is Sievert (Sv) and the legacy unit is rem.	29
30
1 Sv = 100 rem	31
32
The equivalent dose is dependent on the RBE. RBE can be defined as the ratio of	33
biological effectiveness of one type of ionizing radiation to another radiation of interest	34
(e.g., alpha particles to gamma rays or beta particles). The RBE of alpha particles is	35
higher compared with beta particles and gamma and X-rays. For oncology	36
pharmaceuticals, an RBE of 5 can be assigned to alpha particles, signifying that there is a	37
fivefold higher toxicity associated with alpha irradiation than there would be for beta	38
particles, gamma, or X-rays delivering the same absorbed dose (Gy). RBE has no unit.	39
40
H (Sv) = RBE. D (Gy)	41
42
Dosimetry: For the purpose of this guidance, refers to measuring and characterizing the effects	43
of radiation in organs — including activity and/or absorbed radiation dose in an organ and its	44
biological effects — after administration of a radiopharmaceutical.	45
46

Contains Nonbinding Recommendations
11
Half-life	47
Biological half-life: Half-life of the cold pharmaceutical in the living system.	48
49
Physical half-life: Half-life of the radionuclide itself, not affected by surrounding conditions,	50
independent of the living system.	51
52
Effective half-life: Half-life of radionuclide in a living system that takes into consideration	53
both the physical half-life and the biological half-life.	54
55
The effective half-life can be calculated mathematically (see below) or obtained	56
experimentally. Tp is the physical half-life, Tb is the biological half-life, and Te is the	57
effective half-life.	58
59
1/Tp + 1/Tb = 1/Te	60
61
Ligand: For the purpose of this guidance, refers to any moiety used to chelate the radionuclide	62
or to deliver/target the radionuclide to an organ or tissue.	63
64
Neat radionuclide: For the purpose of this guidance, refers to a radionuclide administered	65
without any ligand.	66
67
Organ	68
Source organ: The organ that takes up the radiopharmaceutical and hence contains	69
significant levels of radioactivity.	70
71
Target organ: The organ in which energy is deposited from the source organ; for example,	72
an organ adjacent to the source organ. All source organs are also target organs.	73
74
Parameters from animal biodistribution and dosimetry and extrapolation to human	75
Cumulated activity or time-integrated activity (Ã): The activity as a function of time in each	76
organ (μCi-h or MBq-s). Activity time curves can be obtained by measurements of activity	77
over time and it is a function of the initial activity A0 (Ci or Bq unit) and the residence time τ	78
(hour).	79
80
à = A0 . τ	81
82
Estimation of human values of activity and residence time in source organs	83
Values in humans can be based on data obtained from animals. One method for	84
extrapolating animal data to humans is using animal and human organ/BW ratios, based on	85
Kirshner et al. 1975, as shown below.	86
87
𝜏𝜏(ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢) = 𝜏𝜏 (𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎). 𝑂𝑂𝑂𝑂𝑂𝑂𝑢𝑢𝑢𝑢 𝑤𝑤𝑤𝑤𝑎𝑎𝑂𝑂ℎ𝑡𝑡 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢)
𝑂𝑂𝑂𝑂𝑂𝑂𝑢𝑢𝑢𝑢 𝑤𝑤𝑤𝑤𝑎𝑎𝑂𝑂ℎ𝑡𝑡 (𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎)
𝐵𝐵𝐵𝐵(𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎)
𝐵𝐵𝐵𝐵 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢)
88
89
90
%𝐼𝐼𝐼𝐼 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢) = %𝐼𝐼𝐼𝐼 (𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎). 𝑂𝑂𝑂𝑂𝑂𝑂𝑢𝑢𝑢𝑢 𝑤𝑤𝑤𝑤𝑎𝑎𝑂𝑂ℎ𝑡𝑡 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢)
𝑂𝑂𝑂𝑂𝑂𝑂𝑢𝑢𝑢𝑢 𝑤𝑤𝑤𝑤𝑎𝑎𝑂𝑂ℎ𝑡𝑡 (𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎)
𝐵𝐵𝐵𝐵(𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎)
𝐵𝐵𝐵𝐵 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢)
91

Contains Nonbinding Recommendations
12
92 Or:	93
94 %𝐼𝐼𝐼𝐼 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢)
𝑂𝑂 𝑜𝑜𝑜𝑜 𝑜𝑜𝑂𝑂𝑂𝑂𝑢𝑢𝑢𝑢 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢) . 𝑘𝑘𝑂𝑂 𝑜𝑜𝑜𝑜 𝐵𝐵𝐵𝐵 (ℎ𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢) = %𝐼𝐼𝐼𝐼 (𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎)
𝑂𝑂 𝑜𝑜𝑜𝑜 𝑜𝑜𝑂𝑂𝑂𝑂𝑢𝑢𝑢𝑢 (𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎) . 𝑘𝑘𝑂𝑂 𝑜𝑜𝑜𝑜 𝐵𝐵𝐵𝐵 (𝑢𝑢𝑢𝑢𝑎𝑎𝑢𝑢𝑢𝑢𝑎𝑎)	95
96
%ID (human): the fraction of the total administered activity in human organ.	97
%ID (animal): the fraction of the total administered activity in animal organ.	98
99
The values extrapolated from animals to humans can then be used to estimate the radiation	100
absorbed dose in target organs of humans and to support a human dosimetry.	101
102

Contains Nonbinding Recommendations
13
REFERENCES	103
104
American Society for Radiation Oncology, 2010, Quantitative Analyses of Normal Tissue	105
Effects in the Clinic, Int J Radiat Oncol Biol Phys, 76(3 Suppl): S1–S160.	106
107
Emami B, 2013, Tolerance of Normal Tissue to Therapeutic Radiation, Reports of Radiotherapy	108
and Oncology, 1(1):35–48.	109
110
Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, and	111
Wesson M, 1991, Tolerance of Normal Tissue to Therapeutic Irradiation, Int J Radiat Oncol Biol	112
Phys, 21(1):109–122.	113
114
Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, and Chan MD, 2012,	115
Radiation-Induced Brain Injury: A Review, Frontiers in Oncology, 2:1–18.	116
117
ICRU, 2011, Fundamental Quantities and Units for Ionizing Radiation (ICRU Report No. 85a-	118
Revised), originally published as ICRU Report No. 85 in the Journal of the ICRU, 11(1), Oxford	119
University Press.	120
121
Kirshner A, Ice R, and Beierwaltes W, 1975, Radiation Dosimetry of 131-I-19-Iodocholesterol:	122
The Pitfalls of Using Tissue Concentration Data, The Author’s Reply, J Nucl Med, 16(3):248–	123
249.	124
125
Nuclear Regulatory Commission, 2008, NUREG-1556, Vol. 9, Rev. 2, Appendix U, Section	126
U.2.2, Additional Instructions for Release of Patients Who Could Be Breast-Feeding After	127
Release, and Section U.2.3, Content of Instructions, January.	128
129
Sgouros G, editor, and SNMMI MIRD Committee, 2015, Radiobiology and Dosimetry for	130
Radiopharmaceutical Therapy with Alpha-Particle Emitters, Society of Nuclear Medicine and	131
Molecular Imaging, Inc., Reston, Virginia.	132
133
Siegel J, Thomas S, Stubbs J, Stabin MG, Hays M, Koral K, Robertson J, Howell R, Wessels B,	134
Fisher D, Weber D, and Brill A, 1999, MIRD Pamphlet No. 16: Techniques for Quantitative	135
Radiopharmaceutical Biodistribution Data Acquisition and Analysis for Use in Human Radiation	136
Dose Estimates, J Nucl Med, 40(2 Suppl): S37–S61.	137
138
Stabin M and Xu XG, 2014, Basic Principles in the Radiation Dosimetry of Nuclear Medicine,	139
Semin Nucl Med, 44(3):162–171.	140
141
Stewart FA, Akleyev AV, Hauer-Jensen M, Hendry JH, Kleiman NJ, MacVittie TJ, Aleman BM,	142
Edgar AB, Mabuchi K, Muirhead CR, Shore, RE, and Wallace WH, 2012, ICRP Statement on	143
Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs —	144
Threshold Doses for Tissue Reactions in a Radiation Protection Context, ICRP Publication 118,	145
Clement, CH, editor, Annals of the ICRP, 41(1–2), Published for The International Commission	146
on Radiological Protection by Elsevier.	147