Microdose 
Radiopharmaceutical 
Diagnostic Drugs:  Nonclinical 
Study Recommendations 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2018 
Pharmacology/Toxicology 
 
   
Microdose 
Radiopharmaceutical 
Diagnostic Drugs:  Nonclinical 
Study 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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2018 
Pharmacology/Toxicology 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  RECOMMENDATIONS FOR NONCLINICAL STUDIES ........................................ 3 
IV.  CONCLUSION ................................................................................................................. 4 
  Contains Nonbinding Recommendations 
 
Microdose Radiopharmaceutical Diagnostic Drugs:   
Nonclinical Study 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 
 
This guidance is intended to assist sponsors of microdose radiopharmaceutical diagnostic drugs 
on the nonclinical studies recommended to support human clinical trials and marketing 
applications.2  This guidance addresses the Food and Drug Administrations (FDAs) current 
thinking regarding regulation of this class of drugs and provides complementary 
recommendations to the guidance for industry, investigators, and reviewers Exploratory IND 
(Investigational New Drug Application) Studies (exploratory IND guidance) and the ICH 
guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals (ICH M3(R2)).   
 
This guidance discusses how to refine nonclinical study recommendations for this class of drug 
given its unique characteristics (e.g., microdose, radiolabeled, single (or infrequent) use, clinical 
use setting, the Agencys nonclinical and clinical safety experience with these drugs).   
 
This guidance also is intended to help sponsors facilitate the timely conduct of clinical trials, 
reduce the use of animals with the 3R (reduce/refine/replace) principles, and reduce the use of 
drug development resources.  While both the exploratory IND and the ICH M3(R2) guidances 
                                                 
1 This guidance has been prepared by the Division of Medical Imaging Products in the Center for Drug Evaluation 
and Research at the Food and Drug Administration. 
 
2 As defined by the guidance for industry, investigators, and reviewers Exploratory IND (Investigational New Drug 
Application) Studies, a microdose is less than 1/100 of the dose of a test substance calculated (based on animal data) 
to yield a pharmacologic effect of the test substance with a maximum dose of less than or equal to 100 micrograms 
(g).  The maximum dose for protein products is less than or equal to 30 nanomoles (nmol).  This definition 
corresponds to approach 1 in Table 3:  Recommended Nonclinical Studies to Support Exploratory Clinical Trials in 
the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals.  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/RegulatoryInformation/Guidances/default.htm.  
  1  Contains Nonbinding Recommendations 
 
describe recommended nonclinical studies intended to be conducted early in phase 1 exploratory 
studies of microdose radiopharmaceutical diagnostic drugs, the guidances do not address what 
additional nonclinical studies are recommended for marketing approval.  This guidance is 
intended to provide recommendations for a pathway to full drug development (marketing 
authorization) for microdose radiopharmaceutical diagnostic drugs.  
 
As used in this guidance, a diagnostic radiopharmaceutical drug is (1) a drug that is intended for 
use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that 
exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or 
photons or (2) any nonradioactive kit or nuclide generator that is intended to be used in the 
preparation of such a drug.3  These drugs are used in nuclear medicine procedures, including 
planar imaging, single photon emission computed tomography, positron emission tomography, 
and in combination with other radiation detection probes.  As technology advances, microdose 
drugs that use new modalities may emerge.  Although this guidance describes recommendations 
for current radiopharmaceutical diagnostic drugs, the general principles discussed could apply to 
new diagnostic drugs. 
 
This guidance does not apply to radioactive drugs for research that are used in accordance with 
21 CFR 361.1.4  These issues are addressed in the guidance for industry and researchers The 
Radioactive Drug Research Committee:  Human Research Without an Investigational New Drug 
Application. 
 
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 
 
For radiopharmaceutical diagnostic drugs, the microdose evaluated during early clinical trials 
does not differ significantly from the microdose intended for marketing approval and is less than 
or equal to 100 micrograms (g).  Because these diagnostic drugs are administered using a dose 
at the low end of the dose-response curve, dose-related adverse events are unlikely to occur.  The 
Agency recommends that sponsors tailor the amount and type of nonclinical supporting data to 
account for the low potential for adverse events.  
 
Because each drug is unique, the Agency encourages sponsors to consult the Division of Medical 
Imaging Products in the Center for Drug Evaluation and Research before submitting an IND and 
                                                 
3 21 CFR 315 and 601.31. 
 
4 A radiolabeled compound without an IND can be administered at doses that are known to have no pharmacologic 
effect in humans when the compound has been studied in humans and the results of the studies have been published 
in the literature.  These basic research studies should be conducted under the oversight of an institutional review 
board and a radioactive research committee (21 CFR 361.1). 
  2  Contains Nonbinding Recommendations 
 
during drug development.  If, at any stage of development, a sponsor determines that particular 
nonclinical pharmacology or toxicology studies are not needed and provides adequate 
justification in a waiver request, the Agency may grant a waiver for specific studies.5  
 
 
III.  RECOMMENDATIONS FOR NONCLINICAL STUDIES 
 
The Agency recommends that the sponsor schedule the nonclinical studies to facilitate the timely 
conduct of clinical trials (including appropriate safety monitoring based on findings in 
nonclinical studies) and to reduce unnecessary use of animals and other resources.  Nonclinical 
recommendations for microdose diagnostic radiopharmaceutical diagnostic drugs are listed in 
Table 1 below. 
 
Table 1:  Recommendations for Nonclinical Studies for Microdose ( 100 g) 
Radiopharmaceutical Diagnostic Drugs 
Study Type  Phase  Comments 
Pharmacology  Before  These studies can include in vivo and in vitro pharmacologic 
phase 1  characterizations (e.g., receptor/target/off-target profiling, 
  imaging/radiation dosimetry studies).  These studies should 
provide evidence that radiolabeling of an unlabeled moiety 
does not significantly alter pharmacologic characterizations.  
The studies should be of sufficient sensitivity to rule out 
pharmacologic effects at the anticipated clinical dose. 
Extended single-dose  Before  FDA accepts the use of extended single-dose toxicity studies 
toxicity in one species  phase 1   in animals to support single-dose clinical trials in humans.  
(usually a rodent)  When a toxicity study is recommended, a sponsor can use a 
single mammalian species (both sexes).  The route of 
exposure in animals should be the intended clinical route.*  
To establish safety margins, the sponsor should use a 
formulation that is as similar as possible to the formulation 
intended for use in clinical trials for marketing approval.** 
continued 
* In extended single-dose studies, animals should be observed for 14 days after dosing with an interim necropsy, 
typically on day 2, and evaluated endpoints should include body weights, clinical signs, clinical chemistries, 
hematology, and histopathology (high dose and control only if no pathology is seen at the high dose).  The sponsor 
should design the study to establish a dose inducing a minimal toxic effect or, alternatively, establishing a margin of 
safety.  To establish a margin of safety, the sponsor should demonstrate that a large multiple of the proposed human 
dose (e.g., 100 times the human dose) does not induce adverse effects in the experimental animals.  Scaling from 
animals to humans based on milligram per kilogram for IV or milligram per square meter for oral administration can 
be used to select the dose for use in the clinical trial.  Scaling based on pharmacokinetic/pharmacodynamic 
modeling would also be appropriate if such data are available and the suggested dose does not exceed the dose 
determined from milligram per kilogram or milligram per square meter scaling. 
 
** Bridging studies may be needed if changes in the formulation are apt to change the pharmacokinetics, the 
pharmacodynamics, or safety characteristics of the drug.  A sponsor could use the cold compound or the decayed 
moiety of the labeled compound for these studies, when applicable. 
                                                 
5 21 CFR 312.10. 
  3  Contains Nonbinding Recommendations 
 
 
Table 1, continued 
Study Type  Phase  Comments 
Genotoxicity  Not needed  The exploratory IND guidance states, Because 
microdose studies involve only single exposures to 
microgram quantities of test materials and because such 
exposures are comparable to routine environmental 
exposures, routine genetic toxicology testing is not 
needed.  
 
This applies to any phase of clinical development when 
considering that the mass dose remains the same through 
marketing approval.  Genotoxicity risk could be, by 
default, incorporated in labeling language regarding 
radiation exposure risk. 
Safety pharmacology  Not needed  Safety pharmacology studies are not recommended 
because of the low subpharmacologic dose. 
Repeat dose toxicity   Not needed   
Pharmacokinetic  Before  Information on pharmacokinetics (e.g., absorption, 
phase 3  distribution, metabolism, excretion) in test species and in 
vitro biochemical information relevant to potential drug 
interactions should be available before exposing large 
numbers of human subjects to the investigational drug. 
Developmental and  Waiver  With a waiver, these studies are not necessary because of 
reproductive toxicity  obtained as  the inherent radiation risk to the fetus from the 
per   radiopharmaceutical drug, which would be reflected in 
312.10  labeling. 
Special toxicity  As per ICH  FDA does not recommend investigating IV local 
M3(R2)  tolerance of a drug substance for microdose studies.  The 
use of novel vehicles or excipients should be governed by 
applicable ICH and FDA guidances for industry. 
 
 
IV.  CONCLUSION 
 
The recommendations in this guidance are intended to reduce the time and resources expended in 
microdose radiopharmaceutical diagnostic drug development without compromising patient 
safety.  The clinical and nonclinical safety profiles of microdose radiopharmaceutical diagnostic 
drugs are critically important in the Agencys decision to tailor nonclinical recommendations for 
the safety profile of these diagnostic drugs.  The Agency strongly recommends that the sponsor 
schedule a pre-IND meeting for evaluating the drug development recommendations for a specific 
drug.  
 
  4