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 
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. 
1  Contains Nonbinding Recommendations 
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, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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. 
2  Contains Nonbinding Recommendations 
 
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 pharmaceuticals 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 
3  Contains Nonbinding Recommendations 
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 
4  Contains Nonbinding Recommendations 
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 
5  Contains Nonbinding Recommendations 
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 
6  Contains Nonbinding Recommendations 
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. 
 
 
7  Contains Nonbinding Recommendations 
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 FDAs 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. 
8  Contains Nonbinding Recommendations 
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. 
 
9  Contains Nonbinding Recommendations 
1  GLOSSARY 
2   
3  Activity:  Activity of a given amount of radioactive material is the number of transitions or 
4  decays per unit of time.  The SI unit of activity is Bq, which is one transition per second.  The 
5  legacy unit of activity is denoted Ci. 
6   
7  1 MBq = 27 Ci; 1 mCi = 37 MBq 
8   
9  Cold pharmaceutical:  The nonradioactive or decayed form of the product.  For the purpose of 
10  this guidance, this terminology is used when the product contains a ligand. 
11   
12  Dose 
13  Mass Dose:  The dose (mass unit) of the cold pharmaceutical administered per BW or per 
14  body surface area. 
15   
16  Radiation Dose 
17  Administered dose:  The amount of radioactivity administered to animals or to patients 
18  and expressed as the unit of activity (e.g., in units of MBq or mCi). 
19   
20  Absorbed dose (D):  The ionizing-radiation energy deposited per unit mass of an organ or 
21  tissue.  The SI unit of absorbed dose is Gy, where 1 Gy = 1 J/kg (International 
22  Commission on Radiation Units and Measurements (ICRU) 2011).  The legacy unit of 
23  absorbed dose is denoted rad. 
24   
25  1 Gy = 100 rad; 1 cGy = 1 rad 
26   
27  Equivalent dose (H):  A measure of biological effect of the radioactive dose that takes 
28  into account both the absorbed dose and the biological effectiveness of the radiation, and 
29  hence, the radiation type.  The SI unit is Sievert (Sv) and the legacy unit is rem. 
30   
31  1 Sv = 100 rem 
32   
33  The equivalent dose is dependent on the RBE.  RBE can be defined as the ratio of 
34  biological effectiveness of one type of ionizing radiation to another radiation of interest 
35  (e.g., alpha particles to gamma rays or beta particles).  The RBE of alpha particles is 
36  higher compared with beta particles and gamma and X-rays.  For oncology 
37  pharmaceuticals, an RBE of 5 can be assigned to alpha particles, signifying that there is a 
38  fivefold higher toxicity associated with alpha irradiation than there would be for beta 
39  particles, gamma, or X-rays delivering the same absorbed dose (Gy).  RBE has no unit. 
40   
41  H (Sv) = RBE. D (Gy) 
42   
43  Dosimetry:  For the purpose of this guidance, refers to measuring and characterizing the effects 
44  of radiation in organs  including activity and/or absorbed radiation dose in an organ and its 
45  biological effects  after administration of a radiopharmaceutical. 
46   
10  Contains Nonbinding Recommendations 
47  Half-life 
48  Biological half-life:  Half-life of the cold pharmaceutical in the living system. 
49   
50  Physical half-life:  Half-life of the radionuclide itself, not affected by surrounding conditions, 
51  independent of the living system. 
52   
53  Effective half-life:  Half-life of radionuclide in a living system that takes into consideration 
54  both the physical half-life and the biological half-life. 
55   
56  The effective half-life can be calculated mathematically (see below) or obtained 
57  experimentally.  T  is the physical half-life, T  is the biological half-life, and T  is the 
p b e
58  effective half-life. 
59   
60  1/T  + 1/T  = 1/T  
p b e
61   
62  Ligand:  For the purpose of this guidance, refers to any moiety used to chelate the radionuclide 
63  or to deliver/target the radionuclide to an organ or tissue. 
64   
65  Neat radionuclide:  For the purpose of this guidance, refers to a radionuclide administered 
66  without any ligand. 
67   
68  Organ 
69  Source organ:  The organ that takes up the radiopharmaceutical and hence contains 
70  significant levels of radioactivity. 
71   
72  Target organ:  The organ in which energy is deposited from the source organ; for example, 
73  an organ adjacent to the source organ.  All source organs are also target organs. 
74   
75  Parameters from animal biodistribution and dosimetry and extrapolation to human 
76  Cumulated activity or time-integrated activity (A):  The activity as a function of time in each 
77  organ (Ci-h or MBq-s).  Activity time curves can be obtained by measurements of activity 
78  over time and it is a function of the initial activity A  (Ci or Bq unit) and the residence time   
0
79  (hour). 
80    
81  A = A .  
0
82   
83  Estimation  of human values of activity and residence time in source organs  
84  Values in humans can be based on data obtained from animals.  One method for 
85  extrapolating animal data to humans is using animal and human organ/BW ratios, based on 
86  Kirshner et al. 1975, as shown below.   
87   
88   
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89   (huuuuuuuu)= (uuuuaauuuuaa).  
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90   
91   
OOOOOOuuuu wwwwaaOOhtt (huuuuuuuu) BBBB(uuuuaauuuuaa)
%IIII (huuuuuuuu)=%IIII (uuuuaauuuuaa).  
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11  Contains Nonbinding Recommendations 
92   
93  Or: 
94   
95   
%IIII (huuuuuuuu) %IIII (uuuuaauuuuaa)
96    .kkOO oooo BBBB (huuuuuuuu)= .kkOO oooo BBBB (uuuuaauuuuaa)   
OO oooo ooOOOOuuuu (huuuuuuuu) OO oooo ooOOOOuuuu (uuuuaauuuuaa)
97  %ID (human):  the fraction of the total administered activity in human organ. 
98  %ID (animal):  the fraction of the total administered activity in animal organ. 
99   
100  The values extrapolated from animals to humans can then be used to estimate the radiation 
101  absorbed dose in target organs of humans and to support a human dosimetry. 
102   
12  Contains Nonbinding Recommendations 
103  REFERENCES 
104   
105  American Society for Radiation Oncology, 2010, Quantitative Analyses of Normal Tissue 
106  Effects in the Clinic, Int J Radiat Oncol Biol Phys, 76(3 Suppl): S1S160. 
107   
108  Emami B, 2013, Tolerance of Normal Tissue to Therapeutic Radiation, Reports of Radiotherapy 
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