Guidance for Industry
Developing Medical Imaging Drug
and Biological Products
Part 1: Conducting Safety
Assessments
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or
confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative
approach if the approach satisfies the requirements of the
applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
This guidance is one of three guidances
intended to assist developers of medical imaging drug and
biological products (medical imaging agents) in planning
and coordinating their clinical investigations and preparing and
submitting investigational new drug applications (INDs), new drug
applications (NDAs), biologics license applications (BLAs),
abbreviated NDAs (ANDAs), and supplements to NDAs or BLAs.
The three guidances are: Part 1: Conducting Safety
Assessments; Part 2: Clinical Indications; and
Part 3: Design, Analysis, and Interpretation of Clinical Studies.
Medical imaging agents generally are governed
by the same regulations as other drug and biological
products. However, because medical imaging agents are used
solely to diagnose and monitor diseases or conditions as opposed
to treat them, development programs for medical imaging agents can
be tailored to reflect these particular uses. Specifically,
this guidance discusses our recommendations on conducting safety
assessments of medical imaging agents.
FDA's guidance documents, including this
guidance, 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.
A glossary of common terms used in diagnostic
medical imaging is provided at the end of this document.
This guidance discusses medical imaging
agents that are administered in vivo and are used for diagnosis or
monitoring with a variety of different modalities, such as
radiography, computed tomography (CT), ultrasonography, magnetic
resonance imaging (MRI), and radionuclide imaging. The
guidance is not intended to apply to the development of in vitro
diagnostic or therapeutic uses of these agents.
Medical imaging agents can be classified into
at least two general categories, contrast agents and diagnostic
radiopharmaceuticals.
As used in this guidance, a contrast
agent is a medical imaging agent used to improve the
visualization of tissues, organs, and physiologic processes by
increasing the relative difference of imaging signal intensities
in adjacent regions of the body. Types of contrast agents
include, but are not limited to, (1) iodinated compounds used in
radiography and CT; (2) paramagnetic metallic ions (such as ions
of gadolinium, iron, and manganese) linked to a variety of
molecules and microparticles (such as superparamagnetic iron
oxide) used in MRI; and (3) microbubbles, microaerosomes, and
related microparticles used in diagnostic ultrasonography.
As used in this guidance, a diagnostic
radiopharmaceutical is (1) an article 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 reagent kit or nuclide generator
that is intended to be used in the preparation of such an article.
As stated in the preamble to FDA's proposed rule on Regulations
for In Vivo Radiopharmaceuticals Used for Diagnosis and
Monitoring, the Agency interprets this definition to include
articles that exhibit spontaneous disintegration leading to the
reconstruction of unstable nuclei and the subsequent emission of
nuclear particles or photons (63 FR 28301 at 28303; May 22, 1998).
Diagnostic radiopharmaceuticals are generally
radioactive drug or biological products that contain a
radionuclide that typically is linked to a ligand or carrier.
These products are used in nuclear medicine procedures, including
planar imaging, single photon emission computed tomography (SPECT),
positron emission tomography (PET), or in combination with other
radiation detection probes.
Diagnostic radiopharmaceuticals used for
imaging typically have two distinct components.
·
A radionuclide that can be detected in vivo (e.g.,
technetium-99m, iodine-123, indium-111).
The radionuclide
typically is a radioactive atom with a relatively short physical
half-life that emits radioactive decay photons having sufficient
energy to penetrate the tissue mass of the patient. These
photons can then be detected with imaging devices or other
detectors
·
A nonradioactive component to which the radionuclide
is bound that delivers the radionuclide to specific areas within
the body.
This
nonradionuclidic portion of the diagnostic radiopharmaceutical
often is an organic molecule such as a carbohydrate, lipid,
nucleic acid, peptide, small protein, or antibody.
As technology advances, new products may
emerge that do not fit into these traditional categories (e.g.,
agents for optical imaging, magnetic resonance spectroscopy,
combined contrast and functional imaging).
It is anticipated, however, that
the general principles discussed here could apply to these new
diagnostic products. Developers of these products
should contact the appropriate reviewing division for advice on
product development.
The following sections discuss the special
characteristics of a medical imaging agent that can lead to a more
focused safety evaluation. Characteristics include its
radiation absorbed dose, mass dose, route of administration,
frequency of use, biodistribution, and biological, physical, and
effective half-lives in the serum, the whole body, and critical
organs.
Some medical
imaging agents can be administered at low mass doses. For
example, the mass dose of a single administration of a diagnostic
radiopharmaceutical can be small because device technologies can
typically detect relatively small amounts of a radionuclide (e.g.,
radiopharmaceuticals for myocardial perfusion imaging).
When a medical imaging agent is administered at a mass dose that
is at the low end of the dose-response curve, dose-related adverse
events are less likely to occur.
Some medical imaging agents are administered
by routes that decrease the likelihood of systemic adverse events.
For example, medical imaging agents that are administered as
contrast media for radiographic examination of the
gastrointestinal tract (e.g., barium sulfate) can be administered
orally, through an oral tube, or rectally. In patients with
normal gastrointestinal tracts, many of these products are not
absorbed, so systemic adverse events are less likely to occur.
In general, nonradiolabeled contrast agents pose safety issues
similar to therapeutic drugs because of the inherently large
amounts needed for administration. Therefore,
nonradiolabeled drugs generally should be treated like therapeutic
agents for the purpose of conducting clinical safety assessments.
Many medical imaging agents, including both
contrast agents and diagnostic radiopharmaceuticals, are
administered infrequently or as single doses. Accordingly,
adverse events that are related to long-term use or to
accumulation are less likely to occur with these agents than with
agents that are administered repeatedly to the same patient.
Therefore, the nonclinical development programs for such
single-use products usually can omit long-term (i.e., 3 months’
duration or longer), repeat-dose safety studies. In clinical
settings where it is possible that the medical imaging agent will
be administered to a single patient repeatedly (e.g., to monitor
disease progression), we recommend that repeat-dose studies (of 14
to 28 days’ duration) be performed to assess safety.
Biological medical imaging agents are
frequently immunogenic, and the development of antibodies after
intermittent, repeated administration can alter the
pharmacokinetics, biodistribution, safety, and/or imaging
properties of such agents and, potentially, of immunologically
related agents. We recommend that studies in which repeat
dosing of a biological imaging agent is planned incorporate
pharmacokinetic data, human anti-mouse antibody (HAMA), human
anti-humanized antibody (HAHA), or human anti-chimeric antibody (HACA)
levels as well as whole body biodistribution imaging to assess for
alterations in the biodistribution of the imaging agent following
repeat dosing. Studies of immunogenicity in animal models
are generally of limited value. Therefore, we recommend that
human clinical data assessing the repeat use of a biological
imaging agent be obtained prior to application for licensure of
such an agent.
Diagnostic radiopharmaceuticals often use
radionuclides with short physical half-lives or that are excreted
rapidly. The biological, physical, and effective half-lives
of diagnostic radiopharmaceuticals are incorporated into radiation
dosimetry evaluations
that require an understanding of the kinetics of the distribution
and excretion of the radionuclide and its mode of decay. We
recommend that biological, physical, and effective half-lives be
considered in planning appropriate safety and dosimetry
evaluations of diagnostic radiopharmaceuticals.
We recommend that the nonclinical development
strategy for an agent be based on sound scientific principles, the
agent's unique chemistry (including, for example, those of its
components, metabolites, and impurities), and the agent’s intended
use. Because each product is unique, we encourage sponsors
to consult with us before submitting an IND application and during
product development. The number and types of nonclinical
studies recommended would depend in part on the phase of
development, what is known about the agent or its pharmacologic
class, its proposed use, and the indicated patient population.
If you determine that nonclinical pharmacology or toxicology
studies are not needed, we are prepared to grant a waiver under
21 CFR 312.10 if you provide adequate justification.
In the discussion that follows, a distinction
is made between drug products and biological products.
Existing specific guidance for biological products is referenced
but not repeated here (see section III.B.2).
We recommend that
nonclinical studies be timed so that they help facilitate the
timely conduct of clinical trials (including appropriate safety
monitoring based on findings in nonclinical studies) and to reduce
the unnecessary use of animals and other resources.
The recommended timing of nonclinical studies for medical imaging
drugs is summarized in Table 1.
Because of the
characteristics of contrast drug products (e.g., variable biologic
half-life) and the way they are used, we recommend that
nonclinical safety evaluations of such drug products be made more
efficient with the following modifications:
·
Long-term (i.e., greater than 3 months), repeat-dose
toxicity studies in animals usually can be omitted.
(Exceptions are products with long residence time, e.g., > 90
days.)
·
Long-term rodent carcinogenicity studies usually can
be omitted.
·
Reproductive toxicology studies required under
§ 312.23(a)(8)(ii)(a) often can be limited to an evaluation
of embryonic and fetal toxicities in rats and rabbits and to
evaluations of reproductive organs in other short-term toxicity
studies.
If you determine that such reproductive studies are not needed, we
are prepared to grant a waiver under § 312.10 if you provide
adequate justification.
We recommend that
studies be conducted to address the effects of large mass dose and
volume (especially for iodinated contrast materials administered
intravenously); osmolality effects; potential transmetalation of
complexes of gadolinium, manganese, or iron (generally MRI drugs);
potential effects of tissue or cellular accumulation on organ
function (particularly if the drug is intended to image a diseased
organ system); and the chemical, physiological, and physical
effects of ultrasound microbubble drugs (e.g., coalescence,
aggregation, margination, and cavitation).
Table 1: Timing of Nonclinical
Studies for Nonbiological Products Submitted to an IND
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 Pharmaceutical
and
S7B Safety Pharmacology Studies for Assessing the Potential for
Delayed Ventricular Repolarization (QT Interval Prolongation) by
Human Pharmaceuticals (note that S7B allows for phase
evaluation of the required studies).
(c)
When repeat-dose toxicity studies
have been performed, but single-dose toxicology studies have not,
dose selection for initial human studies will likely be based on
the results of the no-adverse-effect level (NOAEL) obtained in the
repeat-dose study. The likely result will be a mass dose
selection for initial human administration that is lower than if
the dose selection had been based on the results of acute,
single-dose toxicity studies.
(d) See radiopharmaceutical
discussion in section III.B.1.c of this document.
Because of the
characteristics of diagnostic radiopharmaceuticals and the way
they are used, we recommend that nonclinical safety evaluations of
these drugs be made more efficient by the following modifications:
·
Long-term, repeat-dose toxicity studies in animals
typically can be omitted.
·
Long-term rodent carcinogenicity studies typically
can be omitted.
·
Reproductive toxicology studies can be waived when
adequate scientific justification is provided.
·
Genotoxicity studies should be conducted on
the nonradioactive component because the genotoxicity of the
nonradioactive component should be identified separately from that
of the radionuclide. Genotoxicity studies can be waived if
adequate scientific justification is provided.
We recommend that
special safety considerations for diagnostic radiopharmaceuticals
include verification of the mass dose of the radiolabeled and
unlabeled moiety; assessment of the mass, toxic potency, and
receptor interactions for any unlabeled moiety; assessment of
potential pharmacologic or physiologic effects due to molecules
that bind with receptors or enzymes; and evaluation of all
components in the final formulation for toxicity (e.g., excipients,
reducing drugs, stabilizers, anti-oxidants, chelators, impurities,
and residual solvents). We recommend that the special safety
considerations include an analysis of particle size (for products
containing particles) and an assessment of instability manifested
by aggregation or precipitation. We also recommend that an
individual component be tested if specific toxicological concerns
are identified or if toxicological data for that component are
lacking. However, if toxicological studies are performed on
the combined components of a radiopharmaceutical and no
significant toxicity is found, toxicological studies of individual
components are seldom required.
Many biological products raise relatively
distinct nonclinical issues such as immunogenicity and species
specificity. We recommend the following Agency documents be
reviewed for guidance on the preclinical evaluation of biological
medical imaging agents:
·
S6 Preclinical Safety Evaluation of
Biotechnology‑Derived Pharmaceuticals
·
Points to Consider in the Manufacture and Testing
of Monoclonal Antibody Products for Human Use
Sponsors are encouraged to consult with the
appropriate reviewing division for additional information when
needed.
Under section 505(d) of the Federal Food,
Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(d)), FDA cannot
approve a new drug application (NDA) unless it contains adequate
tests demonstrating whether the proposed drug product is safe for
use under the conditions prescribed, recommended, or suggested in
its proposed labeling.
All drugs have risks, including risks related to the intrinsic
properties of the drug, the administration process, the reactions
of the patient, and incorrect diagnostic information.
Incorrect diagnostic information includes inaccurate structural,
functional, physiological, or biochemical information; false
positive or false negative diagnostic determinations; and
information leading to inappropriate decisions in diagnostic or
therapeutic management. Even if risks are found to be small,
all drug development programs must also obtain evidence of drug
effectiveness under section 505 of the Act. Although it has
been suggested that a demonstration of effectiveness not be
required for safer drugs, this statutory requirement cannot
be waived. FDA weighs the benefits and risks of each
proposed drug product when making its decision about whether to
approve a marketing application (e.g., an NDA or BLA).
The special characteristics of medical
imaging agents may allow for a more efficient clinical safety
program. This guidance describes two general categories for
medical imaging agents: Group 1 and Group 2. The extent of
clinical safety monitoring and evaluation that we recommend
differs for these two categories. Generally, a less
extensive clinical safety evaluation is appropriate for Group 1
agents. Conversely, we recommend that Group 2 agents undergo
standard clinical safety evaluations in clinical trials throughout
their development. These different groups have been
conceived to help drug sponsors identify and differentiate those
characteristics that are of greatest interest to the Agency in
assessing the potential safety of a medical imaging agent.
FDA anticipates that it can assess which
agents are Group 1 agents based on the safety-margin criteria from
animal studies and initial human trials completed at the end of
Phase 1.
For purposes
of this guidance, a Group 1 medical imaging agent generally
exhibits the following three characteristics.
·
The medical imaging agent meets either the
safety-margin considerations or the clinical-use
considerations described below (see sections B.1 and B.2,
respectively).
·
The medical imaging agent is not a biological
product,
·
The medical imaging agent does not predominantly
emit alpha or beta particles
Note that under the safety margin criteria (see section IV.B),
medical imaging agents that are administered in low mass doses to
humans (e.g., diagnostic radiopharmaceuticals) usually are more
likely to be considered Group 1 than those administered in higher
mass doses.
There are important exceptions, including cases where the medical
imaging agents are likely to be immunogenic (e.g., biological
products) when the pharmacologic response exists at a
low mass dose, or when the medical imaging agents cause
adverse reactions that are not dose-related (e.g., idiosyncratic
drug reactions).
We recommend that standard clinical safety
evaluations be performed in all clinical investigations of medical
imaging agents, but we suggest that, for Group 1 agents, reduced
human safety monitoring may be appropriate in subsequent human
trials.
·
For example, human safety monitoring may be limited
to recording adverse events and monitoring only particular organs
or tissues of interest for toxicity (such as organs that showed
toxicity in the animal studies, or the organs and tissues in which
the medical imaging agent localizes, which usually would include
the liver and kidneys).
Persons having questions about whether a
medical imaging agent is a Group 1 agent are encouraged to contact
FDA to discuss. Whether a medical imaging agent should be
considered a Group 1 or Group 2 agent may change during the course
of a product’s development. For example, even if an agent is
initially thought to be Group 1, the subsequent identification of
safety concerns could be reason to treat that agent as a Group 2
agent for the remainder of the product’s development.
For purposes of this guidance, Group 2
medical imaging agents are generally medical imaging drugs or
biological products that do not fall under the considerations for
Group 1 medical imaging agents. All biological products are
assumed to be Group 2 agents unless the sponsor demonstrates that
its product lacks immunogenicity. Medical imaging agents
that are biologically active in animal studies or in human studies
when administered at dosages that are similar to those intended
for clinical use should also be considered Group 2 agents.
For Group 2 medical imaging agents,
standard clinical safety evaluations should include serial
assessments of patient symptoms, physical signs, clinical
laboratory tests (e.g., blood chemistry, hematology, coagulation
profiles, urinalyses), other tests (e.g., electrocardiograms as
appropriate), and adverse events. We recommend that
additional specialized evaluations be performed when appropriate
(e.g., immunological evaluations, creatine kinase isoenzymes), or
if a particular toxicity is deemed possible based on animal
studies or the known chemical or pharmacological properties of the
medical imaging agent. Although the extent of clinical
monitoring cannot be predetermined, we recommend that it be of
sufficient duration to identify possible effects that may lag
behind those predicted by pharmacokinetic analyses. If some
of these standard clinical safety evaluations are felt to be
unnecessary, this should be discussed with the reviewing division.
We recommend that sponsors seek FDA comment on the clinical safety
monitoring plans in clinical studies before such studies are
initiated.
Under the safety-margin considerations,
medical imaging agents can be considered Group 1 if the results of
nonclinical studies and initial human experience are
consistent with the conditions outlined below:
To be considered a
Group 1 agent under the safety-margin considerations, we recommend
that a medical imaging agent have an adequately documented margin
of safety as assessed in the nonclinical studies outlined in the
following list.
• We recommend that the
no-observed-adverse-effect level (NOAEL)
in expanded-acute, single-dose toxicity studies in suitable animal
species be at least one hundred times (100x) greater than the
maximal mass dose to be used in human studies. We further
recommend that such expanded, acute, single-dose toxicity studies
be completed before the medical imaging agent is introduced into
humans (see section III.B.1).
·
We recommend that the NOAEL in safety pharmacology
studies in suitable animal species be at least one hundred times
(100x) greater than the maximal mass dose to be used in human
studies. We further recommend that such safety pharmacology
studies be completed before the medical imaging agent is
introduced into humans (see section III.B.1).
·
We recommend that the NOAEL in short-term,
repeat-dose toxicity studies in suitable animal species be at
least twenty-five times (25x) greater than the maximal mass dose
to be used in human studies.
Short-term, repeat-dose toxicity studies are conducted to evaluate
the effects of exaggerated dose regimens. Such regimens can
reveal effects not detected in studies of small numbers of
patients, suggest effects to be monitored in clinical studies, and
reveal effects that might occur in sensitive individuals.
Short-term, repeat-dose toxicity studies can be performed either
before the medical imaging agent is introduced into humans, or
concurrently with early human studies, but we recommend that they
be completed before phase 2 (see section III.B.1).
To establish these
margins of safety, we recommend that the NOAELs be assessed in
properly designed and conducted studies and be appropriately
adjusted. Appropriately adjusted means that mass dose
comparisons between animals and humans should be suitably modified
for factors such as body size (e.g., body surface area) and
otherwise adjusted for possible pharmacokinetic and toxicokinetic
differences between animals and humans (e.g., differences in
absorption for products that are administered orally).
We recommend that
Group 1 medical imaging agents also undergo other nonclinical
toxicological studies as described in section III.B.1, such as
genotoxicity, reproductive toxicity, irritancy studies, and
drug-drug interaction studies. See section III.B.1 for
details and timing sequence.
i.
Additional considerations
FDA may still
consider a medical imaging agent Group 1 even if its NOAELs are
slightly less than the multiples specified above. For
example, FDA will also take into consideration, among other
things, how close the NOAELs are to the multiples specified above,
the amount of safety information known about chemically similar
and pharmacologically related medical imaging agents, the nature
of observed animal toxicities, and whether adverse events have
occurred during initial human experience, including the nature of
such adverse events (see section IV.B.1.b).
ii.
Formulations used in nonclinical studies
We recommend that
the formulation used to establish safety margins in nonclinical
studies be identical to the formulation that will be used in
clinical trials and that is intended for marketing. We also
recommend that any differences in the formulations used in the
clinical trials and nonclinical studies be specified so that any
effect on the adequacy of the nonclinical studies can be
determined. Bridging studies may be helpful when
changes in the formulation are apt to change the pharmacokinetics,
the pharmacodynamics, or safety characteristics of the drug.
In some cases, it
may be infeasible or impractical to administer the intended
clinical formulation to animals in multiples of the maximal human
mass dose specified above (e.g., the volume of such an animal mass
dose may be excessive). We recommend that sponsors discuss
their plans with FDA before studies are initiated. In these
cases, alternative strategies can be employed, such as dividing
the daily mass dose (e.g., into a morning and evening dose), or by
using a more concentrated formulation of the medical imaging
agent, or the maximal feasible daily mass dose can be
administered.
In addition to
those considerations described above for nonclinical studies, FDA
also intends to consider the following when evaluating whether a
medical imaging agent is a Group 1 agent.
·
Whether safety issues were identified during initial
human use of the medical imaging agent in appropriately designed
studies that include adequate and documented standard clinical
safety evaluations. Identification of any adverse events
during initial human use that were not predicted from effects
observed in animals could be considered significant, regardless of
severity. If adverse events occur at any time during human
studies, we intend to conduct a risk assessment to determine
whether the medical imaging agent should be reconsidered as a
Group 2 medical imaging agent. This risk assessment will
examine the type, frequency, severity, and potential attribution
of the adverse events with respect to what is known about the
pharmacology of the drug. For example, the safety profile of
a specific drug class may be well known, so that the occurrence of
a common, nonserious adverse event, such as headache, would not be
of particular concern. However, in a drug class in which
microparticles of varying sizes are administered, the occurrence
of the same adverse event might be a signal of microcirculatory
compromise.
·
We recommend that human pharmacokinetic studies of
the radiopharmaceutical be performed during phase 1 to collect
information about the disposition of the radioactivity in humans.
Such data help facilitate adequate comparisons of exposure between
humans and the species used in the nonclinical studies and allow a
more meaningful assessment of the relevance of the animal safety
data (e.g., toxicokinetics).
Another way to be
considered a Group 1 agent is by adequately documenting extensive
prior clinical use without development of a safety signal.
This means showing that there were no human toxicity or adverse
events with clinical mass doses (and activities, if applicable) of
the agent, under conditions of adequate safety monitoring, and
that the lack of human toxicity was adequately documented.
We recommend that the methods used to monitor for adverse events
be documented. Literature may be of limited value in
establishing the clinical safety of a drug because most published
studies focus on efficacy, with little or no description of any
safety assessments.
An agent can be identified as Group
1 based on the clinical-use considerations at any time during drug
development (e.g., after the conditions specified in this section
have all been met).
We recommend that an
IND sponsor submit sufficient data from animal or human studies to
allow a reasonable calculation of the radiation absorbed dose to
the whole body and to critical organs upon administration to a
human subject (21 CFR 312.23(a)(10)(ii)). At a minimum, we
recommend that radiation absorbed dose estimates be provided for
all organs and tissues in the standardized anthropomorphic
phantoms established in the literature (e.g., by the Medical
Internal Radiation Dose (MIRD) Committee of the Society of Nuclear
Medicine). For diagnostic radiopharmaceuticals, we also
recommend calculation of the effective dose as defined by
the International Commission on Radiological Protection (ICRP) in
its ICRP Publication 60 (this quantity is not meaningful for
therapeutic radiopharmaceuticals).
When a diagnostic
radiopharmaceutical is being developed for pediatric use, the
radiation absorbed dose should be provided for all age groups in
which the agent is intended to be used, as provided by standard
anthropomorphic phantoms established in the literature (i.e.,
newborn, 1-year-old, 5-year-old, 10-year-old, and 15-year-old).
We recommend that
the amount of the radiation absorbed dose delivered by internal
administration of diagnostic radiopharmaceuticals be calculated by
standardized methods, such as the absorbed fraction method
described by the MIRD Committee and the ICRP.
We also recommend
that the methodology used to assess radiation safety be specified
including reference to the body models that were used. We
recommend that the mathematical equations used to derive the time
activity curves and the radiation absorbed dose estimates be
provided along with a full description of assumptions that were
made. We further recommend that sample calculations and all
pertinent assumptions be listed and submitted. We recommend
that the reference to the body, organ, or tissue model used in the
dosimetry calculations be specified, particularly for new models
being tested. If a software program was used to calculate
the radiation doses, we recommend that you provide (1) a full
description of the code, including official name, version number,
and computing platform; (2) a literature citation for the code;
and (3) photocopies of the code’s output, preferably showing all
of the user input data and model choices.
We recommend that
safety hazards for patients and health care workers during and
after administration of the radiolabeled product be identified,
evaluated, and managed appropriately.
For established
radionuclides used with a diagnostic agent (e.g., Tc-99m, In-111),
we recommend that the following items be determined based on the
average patient as defined by the MIRD phantom:
·
The tissue or organ in which a significant
accumulation of radioactivity occurs (i.e., source organ)
·
The amount of radioactivity that accumulates in
these tissues, expressed as a percentage of the administered
activity
·
The times at which radioactivity accumulation was
observed in these tissues. We recommend that observations be
made at two or more times during each phase of radioactivity
accumulation or clearance from the source regions. If there
is rapid accumulation in a region and nonexponential clearance,
two to three time points may be sufficient to characterize the
kinetic behavior. If there are two phases of clearance, we
recommend at least two points of observation during each phase to
adequately characterize the biokinetics. A description of
the kinetic behavior of the activity accumulation and clearance
from these tissues. This is most typically shown as
biological half-times for accumulation and clearance, although
other representations may be used.
·
The time-integral of activity for the accumulation
of radiopharmaceutical in these source tissues or organs. For
purposes of this guidance, this time-integral is defined as
the “cumulated activity” or “residence time” by the MIRD Committee
in various publications.
·
A description of how this time-integral was
calculated. This should be based primarily on the
accumulation and kinetic behavior in the source organs. We
recommend that you specify the method used to calculate the
time-integrals (e.g., numerical integration, regression analysis,
or compartment model analysis). We also recommend that you
provide a description of how the terminal portion of the
time-activity curve for a given source region was integrated
(e.g., assuming only physical decay after the last data point,
some rate of biological elimination estimated by two or more of
the later data points, or a fitted function continued to infinite
time).
·
A description of how these time-integrals for source
regions were combined with dose conversion factors to calculate
the radiation absorbed dose to all target regions. If hand
calculations were performed, we recommend that you specify the
source of dose conversion factors and provide copies of all
calculations. If an electronic spreadsheet was used, we
recommend that you provide printouts and electronic copies of the
spreadsheets to verify the formulas used. If a computer
program was used, we recommend that you provide a complete
description of the code and version number as well as
documentation of the code input and output.
For new radionuclides used with diagnostic agents, the same
principles apply and we recommend that you provide the same
information. If you want guidance on these calculations, we
recommend that you consult the appropriate review division.
We recommend that
the amount of radioactive material administered to human subjects
be the smallest radiation absorbed dose practical to perform the
procedure while providing an adequate diagnostic examination for
evaluation by the physician.
We recommend that
calculations include the radiation absorbed dose contributions
made by all potential radionuclide contaminants that may be
present in the product.
We recommend that
you perform calculations to anticipate possible changes in
dosimetry that might occur in the presence of diseases in organs
that are critical in metabolism or excretion of the diagnostic
radiopharmaceutical. For example, renal dysfunction may cause
significant, slow-clearing accumulation in one or both kidneys
(and thus a high dose to kidneys and adjacent tissues) and/or a
larger fraction of the administered activity to be cleared by the
hepatobiliary system (or vice versa).
We recommend that
possible changes in dosimetry resulting from patient-to-patient
variations in antigen or receptor mass be considered in dosimetry
calculations. For example, a large tumor mass may result in
a larger-than-expected radiation absorbed dose to a target organ
from a diagnostic radiopharmaceutical that has specificity for a
tumor antigen. (For the purposes of dose calculation, a
primary tumor, without metastases, can be regarded as part of the
organ in which it arises and its activity can be added to that of
the organ.)
We recommend that
the mathematical equations used to derive the estimates of the
individual organ time activity curves and the radiation absorbed
doses be provided along with a full description of assumptions
that were made. We recommend that sample calculations and
all pertinent assumptions be listed.
We recommend that
calculations of radiation absorbed dose estimates be performed
assuming freshly labeled material (to account for the maximum
amount of radioactivity) as well as the maximum shelf life of the
diagnostic radiopharmaceutical (to allow for the upper limit of
accumulation of radioactive decay contaminants). We
recommend that these calculations:
Include radiation absorbed doses from x-ray
procedures that are part of the study (i.e., would not have
occurred but for the study). The possibility of follow-up
studies should be considered for inclusion in the dose
calculations.
·
Be expressed as milligray (mGy) per megabecquerel (MBq)
and as rad per millicurie (mCi) of the administered
radiopharmaceutical
·
Be expressed as mGy and rad for a typical
administered quantity of the radiopharmaceutical
·
Be presented in a tabular format and include
individual radiation absorbed doses for the target tissues or
organs and the organs listed above in section IV.D.1
GLOSSARY
Effective dose: The sum of the
weighted equivalent doses in all the tissues and organs of the
body, given by the expression E = ∑WTHT,R,
where WT is the weighting. Effective dose, defined in 1990
by the International Commission on Radiological Protection, allows
the conversion of the risk from partial body irradiations to those
of whole body irradiations.
Mass dose: The mass or weight of
the ligand or carrier, including the radionuclide, administered to
the subject.
No observed adverse effect level (NOAEL):
The highest radiation absorbed dose tested in an animal species
without adverse effects detected.
No observed effect level (NOEL):
The highest radiation absorbed dose tested in an animal species
with no detected effects.
Radiation absorbed dose: The energy
absorbed per unit mass. This is the fundamental dosimetric
quantity in radiological protection. Its unit is the joule
per kilogram, which is given the special name gray (Gy). The
older quantity was the rad, where 1 Gy = 100 rads.
Repeat-dose toxicity study: A
study that investigates the toxicities produced when a
pharmaceutical is administered repeatedly during a given period of
more than 24 hours. A repeat-dose toxicity study evaluates
the effects of exaggerated dose regimens. Usually all
animals in a repeat-dose toxicity study are terminated the day
after the final dose; however, a recovery period may be included
in the design to test the reversibility of effects. An
interim sacrifice is sometimes included to detect effects that may
occur after a few doses.
Safety pharmacology study: A
study that investigates the potential undesirable pharmacodynamic
effects of a substance on physiologic functions in relation to
exposure levels.
Special toxicology study: A
study conducted when something about the nature of the drug or how
it is used raises a concern, or when previous nonclinical or
clinical findings on the product or a related product have
indicated special toxicological concerns. Examples include a
local irritation study conducted to test the effects of potential
misadministration or extravasation.
Standard/expanded acute toxicity study:
A study that investigates toxicities produced by a pharmaceutical
when it is administered in one dose. During a period not
exceeding 24 hours, doses may be split due to large volumes or
high concentrations. An expanded acute toxicity study
includes more measures of toxicities than a standard acute
toxicity study.