**Guidance for Industry**

**Developing Medical Imaging Drug** **and Biological Products**

####### **Part 2: Clinical Indications**

***Draft Guidance***

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 30 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit
comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane., rm. 1061, Rockville, MD 20852. All
comments should be identified with the docket number listed in the
notice of availability published in the *Federal Register*.

For questions regarding this draft document contact (CDER) Kyong Kang,
301-827-7510 or (CBER) George Mills, 301-827-5097.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**May 2003**

**Clinical Medical**

**Guidance for Industry**

**Developing Medical Imaging Drug** **and Biological Products**

####### **Part 2: Clinical Indications**

*Additional copies of this Guidance are available from:*

*Division of Drug Information HFD-240*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane, Rockville, MD 20857*

*(Phone 301-827-4573)*

*Internet: http://www.fda.gov/cder/guidance/index.htm.*

*or*

*Office of Communication, Training and*

*Manufacturers Assistance, HFM-40*

*Center for Biologics Evaluation and Research*

*Food and Drug Administration*

*1401 Rockville Pike, Rockville, MD 20852-1448*

*Internet: http://www.fda.gov/cber/guidelines.htm.*

*Mail: the Voice Information System at 800-835-4709 or 301-827-1800.*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**May 2003**

**Clinical Medical**

**Table of Contents**

# I. INTRODUCTION [1](#i.-introduction) {#i.-introduction-1 .TOC-1}

# II. SCOPE --- TYPES OF MEDICAL IMAGING agents [2](#ii.-scope-types-of-medical-imaging-agents) {#ii.-scope-types-of-medical-imaging-agents-2 .TOC-1}

## A. Contrast Agents [2](#a.-contrast-agents) {#a.-contrast-agents-2 .TOC-2}

## B. Diagnostic Radiopharmaceuticals [2](#b.-diagnostic-radiopharmaceuticals) {#b.-diagnostic-radiopharmaceuticals-2 .TOC-2}

# III. INDICATIONS FOR MEDICAL IMAGING AGENTS [3](#iii.-indications-for-medical-imaging-agents) {#iii.-indications-for-medical-imaging-agents-3 .TOC-1}

## A. Structure Delineation [4](#a.-structure-delineation) {#a.-structure-delineation-4 .TOC-2}

### 1. Locating and Outlining Normal Anatomic Structures [4](#locating-and-outlining-normal-anatomic-structures) {#locating-and-outlining-normal-anatomic-structures-4 .TOC-3}

### 2. Distinguishing Between Normal and Abnormal Anatomy [4](#distinguishing-between-normal-and-abnormal-anatomy) {#distinguishing-between-normal-and-abnormal-anatomy-4 .TOC-3}

## B. Disease or Pathology Detection or Assessment [5](#b.-disease-or-pathology-detection-or-assessment) {#b.-disease-or-pathology-detection-or-assessment-5 .TOC-2}

## C. Functional, Physiological, or Biochemical Assessment [6](#c.-functional-physiological-or-biochemical-assessment) {#c.-functional-physiological-or-biochemical-assessment-6 .TOC-2}

## D. Diagnostic or Therapeutic Patient Management [7](#d.-diagnostic-or-therapeutic-patient-management) {#d.-diagnostic-or-therapeutic-patient-management-7 .TOC-2}

## E. Multiple or Other Indications [7](#e.-multiple-or-other-indications) {#e.-multiple-or-other-indications-7 .TOC-2}

# IV. CLINICAL TRIALS TO DeterminE effectiveness of MEDICAL IMAGING AGENTS [8](#iv.-clinical-trials-to-determine-effectiveness-of-medical-imaging-agents) {#iv.-clinical-trials-to-determine-effectiveness-of-medical-imaging-agents-8 .TOC-1}

## A. General Considerations for Establishing Accuracy and Validity of a Test [9](#a.-general-considerations-for-establishing-accuracy-and-validity-of-a-test) {#a.-general-considerations-for-establishing-accuracy-and-validity-of-a-test-9 .TOC-2}

## B. Clinical Usefulness [10](#b.-clinical-usefulness) {#b.-clinical-usefulness-10 .TOC-2}

## C. Defined Clinical Settings [11](#c.-defined-clinical-settings) {#c.-defined-clinical-settings-11 .TOC-2}

# APPENDIX: MEDICAL LITERATURE [14](#appendix-medical-literature) {#appendix-medical-literature-14 .TOC-1}

# GLOSSARY [16](#glossary) {#glossary-16 .TOC-1}

**Guidance for Industry**[^1]

**Developing Medical Imaging Drug and Biological Products**

**Part: 2 Clinical Indications**

This draft guidance, when finalized, will represent 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. An alternative approach may be used if such
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.

# I. INTRODUCTION

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 of Medical Imaging Agents*; *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 drugs or biological products.[^2] In response to the requirements
of the Food and Drug Administration Modernization Act of 1997, FDA
amended the drug and biologics regulations (21 CFR 315 and 601) for one
category of medical imaging agents by adding provisions for the
evaluation and approval of in vivo radiopharmaceuticals used in the
diagnosis or monitoring of diseases.[^3] This guidance elaborates on the
concepts contained in that final regulation on radiopharmaceutical
diagnostic product indications.

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.

# II. SCOPE --- TYPES OF MEDICAL IMAGING agents 

This guidance discusses medical imaging agents that are administered in
vivo and are used for diagnosis or monitoring. Included are medical
imaging agents used with medical imaging techniques such as radiography,
computed tomography (CT), ultrasonography, magnetic resonance imaging
(MRI), and radionuclide imaging. This guidance is not intended to cover
the development of in vitro diagnostic uses, or to therapeutic uses of
these agents.[^4]

Medical imaging agents can be classified into at least two general
categories:

## A. Contrast Agents

Contrast agents improve the visualization of tissues, organs, and
physiologic processes by increasing the relative difference of imaging
signal intensities in adjacent regions of the body. Products 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 used in MRI; and (3)
microbubbles, microaerosomes, and related microparticles used in
diagnostic ultrasonography.

## B. Diagnostic Radiopharmaceuticals

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.[^5] The FDA 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.

Diagnostic radiopharmaceuticals are generally radioactive drugs or
biological products that contain a radionuclide that may be linked to a
ligand or carrier.[^6] These products are used with planar imaging,
single photon emission computed tomography (SPECT), positron emission
tomography (PET), or 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
    molecule 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 that delivers the molecule 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, it is recognized that new products may emerge
that do not fit into the traditional categories of contrast agents and
radiopharmaceuticals (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.

# III. INDICATIONS FOR MEDICAL IMAGING AGENTS

The labeled indications for medical imaging agents fall within the
following general categories:

-   Structure delineation

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-   Disease or pathology detection or assessment

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-   Functional, physiological, or biochemical assessment

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-   Diagnostic or therapeutic patient management

We recommend that effectiveness be defined for all indications as the
ability to provide clinically useful information. The methods used to
demonstrate effectiveness may differ depending on the category of
indication sought, as discussed below. The above categories do not
represent a hierarchy or progression (e.g., a \"structure delineation\"
indication does not need to precede a \"disease assessment\"
indication). In addition, indications from different categories could be
granted for the same imaging agent. Approval also may be possible for
categories of indications not listed above.

Benefits of the use of the medical imaging agent must outweigh the risks
to the patient. In determining the most appropriate indication, special
considerations may apply to agents that may pose significant patient
risk, for example, biological medical imaging agents that are frequently
immunogenic. 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. For agents that pose significant risk
and where the clinical benefit is generally not readily apparent, an
indication of disease or pathology detection or assessment or diagnostic
or therapeutic patient management is more appropriate. If one of the
other indications (i.e*., structure delineation* or *functional,
physical or biochemical assessment*) will be sought for an agent that
may pose significant patient risk, we recommend that the development
plan be discussed with the review division.

## A. Structure Delineation

As described in the following sub-sections, at least two types of
labeled indications for structure delineation are possible: (1) locating
and outlining normal (or variants of normal) anatomic structures and (2)
distinguishing between normal and abnormal anatomy in a defined clinical
setting. Ordinarily, the ability to locate and outline normal structures
or distinguish between normal and abnormal anatomy can *speak for
itself* with respect to the clinical value of the information and will
not require additional information substantiating clinical usefulness.

### 1. Locating and Outlining Normal Anatomic Structures

> We recommend that a medical imaging agent approved for this type of
> indication be able to locate and outline normal (or variants of
> normal) anatomic structures. We recommend that the product clarify the
> spatial relationship of the visualized normal structure(s) with
> respect to other body parts or structures. Such a medical imaging
> agent could distinguish normal structures that cannot be seen well
> with other imaging agents or modalities. For example, a contrast agent
> developed to image the normal parathyroid glands would be clinically
> useful because it could help surgeons plan and perform thyroid
> surgery.

### 2. Distinguishing Between Normal and Abnormal Anatomy

> We recommend that a medical imaging agent approved for this type of
> indication be able to locate and outline both normal and abnormal
> anatomic structures. We recommend that the agent also clarify the
> spatial relationships of the normal and abnormal anatomic structure(s)
> with respect to other body parts or structures. Examples of this type
> of agent include:

-   An agent that nonspecifically enhances the airway lumen to
    distinguish dilated bronchi from normal bronchi and categorizes the
    bronchiectasis anatomically (e.g., as cylindric, sacculated, or
    fusiform)

-   An agent that nonspecifically enhances the joint cavity to evaluate
    and describe meniscal or ligamentous injuries of the knee

-   An agent that outlines the vascular system to identify structural
    narrowing, dissections, aneurysms, and relationships to normal
    vasculature

-   A contrast agent that localizes or outlines masses

In the preceding examples, the agent's ability to outline abnormal
anatomy approaches a disease detection indication (Section III.B.). If
that is the goal of the clinical use, a disease detection indication
should be sought.

## B. Disease or Pathology Detection or Assessment

We recommend that a medical imaging agent intended for disease or
pathology detection be able to detect and locate a specific disease or
pathological state in at least one defined clinical setting.[^7] The
medical imaging agent could be used alone or in combination with other
diagnostic procedures to achieve this labeled indication.

Examples of medical imaging agents for which this type of indication may
be appropriate include:

-   An agent that can bind to a brain receptor and is intended to detect
    or assess the extent of a specific neurological disease, such as
    Parkinson's disease

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-   A radiolabeled monoclonal antibody that can attach to a unique tumor
    antigen to detect the presence of, or extent of, a mass with this
    tumor antigen (e.g. breast cancer)

We recommend that efficacy trials for these indications be conducted in
subjects presenting for diagnostic evaluation of a specific disease or
condition in a defined clinical setting. This is because the likelihood
of disease or the spectrum of disease (e.g., severity or stage) is
dependent on the clinical setting. Examples of two common clinical
settings are (1) providing a diagnosis in patients with suspected
disease and (2) monitoring and assessing the extent, rate of
progression, or other aspects of the specific disease in patients
previously diagnosed with the disease. An indication of detection of
disease or pathology in an asymptomatic population (a screening
indication) may be appropriate if the sensitivity of the imaging
modality is high enough and the rate of false positives is low enough.
See also, diagnostic or therapeutic patient management, Section III.D.

It is likely that the clinical usefulness and the diagnostic performance
of the medical imaging agent will differ in each clinical setting.[^8]
We recommend that if a medical imaging agent is being developed to
diagnose a particular disease, efficacy trials generally enroll subjects
in whom the disease status is unknown, but in whom specific aspects of
the clinical presentation have led to the desire for more diagnostic
information. That is, we recommend that the trials include the intended
population in the appropriate clinical setting. Data from subjects known
definitely to have (or to not have) the disease of interest may be of
limited value because estimates of diagnostic performance derived from a
known disease population may not apply to performance in the intended
population.

## 

## C. Functional, Physiological, or Biochemical Assessment

We recommend that a medical imaging agent intended to provide
functional, physiological, or biochemical assessment be able to evaluate
the function, physiology, or biochemistry of a tissue, organ system, or
body region. This type of indication could apply to agents used to
detect either a reduction or an increase of a normal functional,
physiological, or biochemical process. The indication *functional,
physiological, or biochemical assessment* (would) could be limited to
assessment of functional, physiological, or biochemical processes when
disturbances of these processes are common to several diseases or
conditions and they are not diagnostic for any particular disease or
condition.

The indication *functional, biochemical, or biological assessment* is
appropriate for patients in whom the diagnosis is already established
and when evaluations of functional, physiological, or biochemical
aspects of a tissue, organ, or body region would provide new information
that has a clinically useful effect on management.

Examples of medical imaging agents with *functional, physiological, or*
*biochemical assessment* indications include:

-   A contrast agent to assess cardiac ejection fraction or myocardial
    wall motion

-   A radiopharmaceutical that assesses metabolism of a substrate where
    the normal pattern of metabolism in that organ or tissue is well
    known

To establish efficacy in clinical studies, we recommend that the
functional, physiological, or biochemical measurements of the medical
imaging agent be compared with those of a reference product or procedure
of known high validity (i.e., a truth standard). Ideally, we recommend
that the high validity of this reference product or procedure be
documented thoroughly and critically before its use in clinical studies
intended to demonstrate effectiveness of the test-imaging agent. We
recommend that a functional indication be studied in the wide spectrum
of diseases and disease severity states that impact on the functional
endpoint. If no standard of truth applies, we recommend that a clinical
trial be conducted to determine that the findings are clinically useful
(see Section IV.B).

## 

## D. Diagnostic or Therapeutic Patient Management

We recommend that a medical imaging agent intended for the indication
*diagnostic or therapeutic patient management* improve patient
management decisions (e.g., the need for further diagnostic testing or
the use of specific therapeutic interventions) or improve patient
outcomes when used in a defined clinical setting.[^9] To obtain this
indication, we recommend that adequate and well-controlled
investigations demonstrate that patient management decisions or outcomes
are, in fact, improved by use of the medical imaging agent. The medical
imaging agent can be used alone or in combination with other diagnostic
procedures to achieve this labeled indication.

Examples of medical imaging agents for which this type of indication may
be appropriate are:

-   Products shown to provide improved clinical decisions about whether
    suspected cardiac patients should undergo further invasive,
    diagnostic testing, such as with coronary angiography (i.e., use for
    diagnostic patient management)

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-   Products that predict whether a patient has a better prognosis with
    tumor resection instead of with chemotherapy (i.e., use for
    therapeutic patient management)

We recommend that the trials demonstrate that diagnostic or therapeutic
management based on findings using the medical imaging agent is improved
compared to management without use of the medical imaging agent. The
medical imaging agent can be used in conjunction with other tests to
influence a patient diagnostic or therapeutic management decision.

A medical imaging agent that identifies unrecognized disease in
asymptomatic individuals (e.g., used in a screening setting) can obtain
the indication *diagnostic or therapeutic patient management* if it can
be demonstrated that use of the test decreases irreversible morbidity or
mortality, or by providing existing data that show that early detection
and treatment of the disease decreases morbidity or mortality.

## E. Multiple or Other Indications

The indication categories outlined above are flexible, and indications
for medical imaging agents need not be mutually exclusive. A labeled
indication can include several indication categories. For example, a
diagnostic radiopharmaceutical could be developed as an aid in the
diagnosis of lung cancer for the labeled indication *disease or
pathology detection or assessment*. This diagnostic radiopharmaceutical
could also be evaluated in subpopulations of patients with lung cancer
for its ability to provide information that leads directly to
appropriate therapeutic management decisions (e.g., using test results
to determine what combination of surgery, radiotherapy, and chemotherapy
is most appropriate).

Structural and functional aspects of diseases or conditions sometimes
are evaluated together with imaging in clinical practice (e.g., use of a
contrast agent to evaluate cardiac anatomy and segmental wall motion).
In such cases, we recommend that clinical studies evaluate the effect of
the imaging agent on assessments of both structure and function.

Functional evaluations of diseases or conditions may be accomplished for
various purposes. For example, a drug may have a functional indication
for the evaluation of cardiac ejection fraction. Subsequently, the drug
may be developed for a therapeutic management indication for the
evaluation of perfusion or wall motion abnormalities to predict response
to surgical intervention.

For indications that do not fall within the categories identified above
(e.g., providing prognostic information based on imaged gene
expression), we recommend that the applicant or sponsor consult FDA on
the nature of the desired labeled indication and how to establish
effectiveness for it.

# IV. CLINICAL TRIALS TO DeterminE effectiveness of MEDICAL IMAGING AGENTS

In general, establishing effectiveness has two components: (1)
establishing the accuracy of the test and (2) establishing the clinical
value of the test. In some cases, a test that provides accurate
information in describing a clinical condition is of well-established
value. Generally, this is true for indications for structure delineation
and disease or pathology detection or assessment. In many cases, there
will be established methods of seeking similar information and the only
issue is comparing the accuracy of the new and old method. Many
functional, physiological, or biochemical assessments are similarly
well-established as useful (ejection fraction, renal function,
myocardial wall motion) but others (glucose utilization by various parts
of the body, presence of serotonin receptors, palmitate metabolism) may
not be. Where the clinical value of valid information is not
established, we recommend that additional information establishing this
value be developed. Demonstration of improved patient management means
more than assessment of the accuracy of the test. Either by reference to
prior data or through new trials, we recommend that this claim show that
the test really makes a difference in outcome or management. Even in
this case, the impact of a test may be considered obvious (e.g., staging
of breast cancer is disease or pathology detection or assessment
indication). In some cases, the test will have plain therapeutic
implications, as would be the case for effective staging of some other
malignancies, although, in many cases, trial data should be collected.

We recommend that investigations establish the validity (generally
assessed by describing the sensitivity, specificity, positive
predictable value and negative predictive value in relevant settings)
and reliability (how reproducible the test results are) of the imaging
agent. These test characteristics can provide information on
risk-benefit as well, including estimates of risk of incorrect
diagnosis. Safety information obtained in studies (see the companion
guidance *Part 3: Design, Analysis, and Interpretation of Clinical
Studies*) will also contribute to an Agency risk-benefit assessment. The
clinical usefulness of an imaging agent may be obvious from a
description of what it can demonstrate (or supportable by evaluation of
the literature), or it may be appropriate to demonstrate the agent\'s
usefulness. We recommend that clinical studies and related methods for
establishing effectiveness be performed in defined clinical settings
that reflect the proposed indications.

## A. General Considerations for Establishing Accuracy and Validity of a Test 

To establish efficacy in clinical studies, we recommend that the
accuracy and/or validity of the structural delineation, functional,
physiological, or biochemical assessment and disease or pathology
detection generally be demonstrated by comparing the performance of the
medical imaging agent with that of a reference product or procedure of
known high validity (i.e., a truth standard) in a relevant clinical
setting.

To provide adequate estimates of the validity and reliability of the
medical imaging agent over the full range of conditions for which it is
intended to be used, we recommend that medical imaging agents be
evaluated in studies with appropriate representation of sufficient
numbers of subjects (1) with and without abnormalities or diseases of
question (over the full spectrum of the condition or disease
presentation) and (2), with other conditions, processes, or diseases
that could affect the interpretation of the imaging results (e.g.,
inflammation, neoplasm, infection, trauma). We recommend that sponsors
justify the inclusion or exclusion of selected subpopulations during
clinical development. We recommend that studies of agents for
functional, physiological, or biochemical assessment indications provide
a quantitative or qualitative understanding of how the measurement
varies in normal and abnormal subjects or tissues, including the
variable\'s normal range, distribution, and confidence intervals in
these subjects or tissues. We believe it is critical to identify the
range that is normal and the values that indicate an abnormality. When
possible, we recommend that the minimum detectable limits and
reproducibility of the measurement be assessed.

In cases when valid reference products or procedures are not available
or cannot be used feasibly, the validity of the information obtained can
be demonstrated in clinical studies that show how the product provides
information that is consistent with known and accepted medical science
or with clinical outcomes. We recommend that the sponsor discuss these
facts with the Agency and carefully delineate and document them prior to
initiation of phase 3 studies.

Appropriate nonclinical studies in relevant animal models, if available,
could provide additional information to support indications for
*structure delineation* and *functional, physiological, or biochemical
assessment*.

## 

## B. Clinical Usefulness

Defining clinical usefulness is important for medical imaging agents,
even for agents with anticipated low toxicity rates (low radiation
exposure and/or limited pharmacologic toxicity). Sponsors of products
with known toxicity, e.g., an immunogenic imaging agent, should
establish through clinical studies, that use of the agent justifies the
potential risk to patients. The use of a medical imaging result without
established clinical benefit can cause harm to the patient. For example,
there can be unintended, negative consequences when imaging results lead
to unnecessary diagnostic testing, invasive procedures, initiation of
inappropriate therapy, or in the case of false negatives, failure to
initiate appropriate therapy. Medical imaging results may have clinical
usefulness in some settings but not in others; it is, therefore,
important to prospectively define and study the imaging agent in the
clinical setting of intended use.

We recommend that a medical imaging agent provide accurate and reliable
information that, in one of a number of ways, facilitates clinical
management, including (1) helping make an accurate diagnosis, (2)
contributing to beneficial clinical outcome (e.g., by helping choose the
right therapy, or (3) providing accurate prognostic information. All
indications under Section III should reflect these benefits, which are
then weighed by FDA against the agent's risks as part of an approval
decision about marketing. Once clinical usefulness is established, other
benefits of imaging agents, such as safety advantages and enhanced
convenience to patients over existing marketed products, can be
considered.

Depending on the specific indication, clinical usefulness can generally
be established in two ways: (1) by direct demonstration in studies
carried out during clinical development, and (2) by reference to
historical data. In circumstances where the measure is well established
as useful in the medical literature, the clinical benefit of the measure
does not need to be re-established; (e.g., ejection fraction or
myocardial wall motion are widely used measures of cardiac function with
prognostic and therapeutic implications. Even if the new measure has not
been used before, clinical usefulness can be established historically
when the information being obtained has been shown to be useful when
obtained by other means. For example, if a product is able to establish
the diagnosis of early colonic polyps without the need for colonoscopy,
the clinical benefit of the use of this product can be inferred because
treatment is available for this disease (polypectomy), and the test
would allow people to avoid unnecessary colonoscopy (i.e., clinical
usefulness has been established indirectly). In such situations,
clinical usefulness can be documented by a critical and thorough
analysis of the medical literature and any historical precedents.

For indications in which it cannot be established from prior knowledge,
we recommend that clinical usefulness be established through new trials
during development. For example, we recommend that clinical usefulness
be established directly for a medical imaging agent that has been shown
in a research setting to bind specifically to particular receptors, but
where it has not yet been established that assessment of such binding
adds to the accuracy of diagnosis, contributes to beneficial clinical
outcome, or provides accurate prognostic information. For novel
technologies relying on mechanisms for imaging never approved before, we
recommend that a plan for establishing clinical usefulness be
incorporated into the development plan of a medical imaging agent. In
general, we recommend that clinical usefulness be evaluated
prospectively in the principal clinical studies of efficacy. We
recommend that sponsors assess how the novel technology imaging results
are used and how usefulness to the patient is confirmed.

For a contrast agent to be considered clinically useful, we recommend
that the product used in combination with an imaging device provide
useful information or other advantages (such as improved imaging time or
convenience) beyond that obtained by the imaging device alone. That is,
we recommend that imaging with the contrast agent add value when
compared to imaging without the contrast agent.

To illustrate how both aspects of effectiveness could be evaluated,
consider the following possible approaches:

> 1\. Compare the new test and the established (comparator) test, which
> could be either another test or a truth standard, such as pathology.
> We recommend that the population studied include the spectrum of
> presenting patients that would be expected to undergo the new test.
> Perform standard analyses of sensitivity and specificity, positive
> predictive value, and negative predicative value. If the comparator
> test is well established as clinically useful (such as ejection
> fraction), we think it could be sufficient to demonstrate the value of
> the new test.
>
> 2\. Compare the new test added to the current standard test battery to
> a truth standard (such as pathology). If the new test added to the
> standard battery shows greater sensitivity and specificity than the
> standard test battery without the new test, we think that result alone
> could be sufficient. Or, if the new test detects some lesions that the
> standard tests misses (greater sensitivity) and the result is of
> accepted clinical value i.e., leads to improved patient management and
> has a very low false positive rate, we think that result alone could
> be sufficient.
>
> Note: Situation 2 would be similar to imaging with and without the new
> test to determine the contribution of the new imaging test.
>
> For 1 and 2, the results of the new test would be presumed to be of
> prognostic, therapeutic, or diagnostic value, and the new imaging drug
> would improve these aspects. If that is not the case, we recommend
> that the value be documented through a randomized clinical trial. The
> new test (or the new test added to the standard testing battery) could
> be compared to standard testing without the new test to determine if
> the new test improves clinical outcomes or prognosis.

## C. Defined Clinical Settings

We recommend that a *defined clinical setting* reflect the circumstances
and conditions under which the medical imaging agent is intended to be
used.[^10] Generally, the choice of anticipated labeled indications will
determine the clinical setting for the trials. In some cases, an
appropriately designed trial may contain several clinical settings.

For example, a medical imaging agent that detects prostate cancer
(disease specific indication) could be developed for use in different
defined clinical settings such as:

-   For asymptomatic, healthy men for early detection screening

-   For use in men presenting with a high clinical index of suspicion
    for prostate cancer either by physical examination or abnormal
    prostate specific antigen testing

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-   For use in men with existing diagnosis of prostate cancer to
    evaluate recurrence

We recommend that the circumstances and conditions under which the
medical imaging agent is intended for use be evaluated in clinical
trials and be described in the labeling using the following mechanisms.

1.  Specifying aspects of the medical history and physical examination
    that are pertinent for determining the likelihood of the disease or
    condition that is in question.

For example:

-   A medical imaging agent intended to detect breast cancer might be
    evaluated for use in the assessment of (1) otherwise healthy women
    over 40 years of age, (2) women with a family history of breast
    cancer, or (3) women presenting with palpable breast masses.

2\. Specifying a patient population that is at a particular step in the
diagnostic or patient surveillance sequence. For example:

-   A diagnostic radiopharmaceutical may be intended to evaluate
    patients in an emergency room with equivocal clinical and laboratory
    findings of a myocardial infarction, or to evaluate the location and
    extent of a myocardial infarction in patients with definitive
    findings.

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-   An agent may be intended for use in an outpatient office setting to
    monitor disease progression. Typically, we recommend that such an
    imaging agent be studied using repeated, periodic surveillance
    imaging of ambulatory patients in an outpatient setting.

3\. Specifying any other diagnostic assessments that are to be performed
in the evaluation of this patient population. We recommend that this
delineation include describing how the medical imaging agent should be
used with respect to other diagnostic tests or evaluations, including
(1) whether the medical imaging agent is intended to be used together
with, or as a replacement for, other diagnostic tests or modalities and
(2) how the use of the medical imaging agent is influenced by the
results of other diagnostic evaluations.

Pooling efficacy data (additive derivation of summary statistics) across
defined clinical settings may be of limited value because differences in
disease prevalence and in pathophysiology may result in different
diagnostic performance (sensitivity, specificity, positive and negative
predictive value) in different settings. Pooled results may suggest that
the product is useful in all the evaluated clinical settings, and may
obscure the evidence of differential usefulness in each one of the
settings. Of course, data from independent trials in different clinical
settings may be useful in determining the overall labeling in one or
more clinical settings. The number and type of populations to be studied
depends upon the type of the indication and clinical uses sought by the
sponsor.

## 

# APPENDIX: MEDICAL LITERATURE

On occasion, the medial literature may provide critical information on
various aspects of the safety or efficacy of a product. Considerations
in the use of the medical literature are described in the FDA guidance
for industry *Providing Clinical Evidence of Effectiveness for Human
Drug and Biological Products*. In applying these fundamental principles
to imaging trials, we recommend that sponsors consider whether the
literature article methods section describes a prospective protocol in
sufficient detail to assess the strengths and weaknesses of the protocol
design features discussed in the imaging guidance. For example, the
design features that are critical include selection of the patient
population, clinical setting, image handling, image reading plan for the
test product and the standard of truth, use of an accepted standard of
truth, the statistical plan, and use of appropriate steps to eliminate
bias. As literature studies are often completed for purposes other than
drug approval, the relevance of the selected endpoints to the proposed
indication should be justified.

We recommend that a critical review of the literature present the method
used for the literature search, the criteria used to review the data,
and the criteria used to determine the applicability of the results.
Although we recommend that each article be reviewed and summarized, we
also recommend that the key articles have an extensive discussion.

Typically, articles in the imaging literature provide limited data on
safety, so that additional safety studies may be called for. Other
information that can be supplied either fully or partially by the
literature include:

-   Information on human drug safety: population exposed, types of
    adverse events and how these were monitored and reported,
    reliability of data collection

-   Pharmacology

-   Toxicology studies

-   Biopharmaceutical information

A discussion of use of medical literature based on the FDA guidance to
industry, *Providing Clinical Evidence of Effectiveness for Human Drug
and Biological Products* follows. We recommend:

-   Independent substantiation of experimental results. Multiple studies
    from different authors provide greater support.

> ---Replication of findings in usually two or more adequate and
> well-controlled human investigations
>
> ---Similar study questions, populations, diseases or conditions or
> indications being studied by the same imaging agent
>
> ---Studies from more than a single center (or from more than a single
> investigator) for independence of finding

-   Conduct of studies by groups with properly documented operating
    procedures and a history of implementing such procedures effectively

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-   Prospective design to minimize bias

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-   Studies in sufficient numbers of patients to provide results that
    are valid (we recommend this be documented by a sample size
    discussion in the article)

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-   Level of detail of information in studies to assess:

> ---Dose(s) used and regimen(s) used for dosage administration
>
> ---Image acquisition, including device settings, timing and interval
> of imaging, and views obtained
>
> ---Image blinding method used, how images were handled and presented
> to the blinded reader, details on sequential unblinding if used,
> methods used by the core laboratory before images were presented to
> the blinded reader, how multiple lesions are tracked
>
> ---Details of how the imaging agent is made to assess identity of
> agent in multiple studies if the agent is made locally
>
> \--Use and description of controls to minimize bias: randomization,
> blinding, central reading versus local reading, etc.
>
> \--Statistical plans, prespecified analytic methods, prospectively
> defined study endpoints, full accounting of the study population
> enrolled
>
> \--Study endpoints that are objective and not dependent on
> investigator judgment. Description of imaging features used by the
> blinded readers to reach their decision. For diagnostic tests where
> endpoints are interpretive, we recommend use of a well-accepted truth
> standard, such as pathology. If study endpoints are also compared to
> an active imaging control drug or modality, that imaging approach must
> be approved for the indication being studied. We recommend the
> endpoint be clinically useful.
>
> ---Robust results that yield a conclusion of efficacy that is
> consistent with the prospective protocol design and that do not
> require post-hoc analyses

#  

# GLOSSARY

*Note*: Subjects in trials of medical imaging agents are often
classified into one of four groups depending on (1) whether disease is
present (often determined with a truth standard or *gold standard*) and
(2) the results of the diagnostic test of interest (positive or
negative). The following table identifies the variables that are used to
estimate the parameters defined below.

These results may then be used to classify the major parameters by which
the ability of a test to produce useful results is judged: sensitivity,
specificity, positive predicative value, and negative predicative value.
Note that the specific cut-off point at which a test is considered
positive will affect all of those parameters and the cut-off point will
be chosen with the parameters in mind. Thus a higher test value might
decrease sensitivity but improve specificity.

+-------------+----------+--------------+-------------+--------------+
| **Test      |          | **Disease:** |             |              |
| Result:**   |          |              |             |              |
+-------------+----------+--------------+-------------+--------------+
|             |          | **Present    | **Absent    |              |
|             |          | (+)**        | (-)**       |              |
+-------------+----------+--------------+-------------+--------------+
|             | **       | **TP**       | **FP**      | **m1 = a+b = |
|             | Positive |              |             | TP+FP**      |
|             | (+)**    | **true       | **false     |              |
|             |          | p            | po          | **total with |
|             |          | ositive=TP** | sitive=FP** | positive     |
|             |          |              |             | test**       |
+-------------+----------+--------------+-------------+--------------+
|             | **       | **FN**       | **TN**      | m2 = c+d =   |
|             | Negative |              |             | FN+TN        |
|             | (-)**    | **false      | **true      |              |
|             |          | n            | ne          | **total with |
|             |          | egative=FN** | gative=TN** | negative     |
|             |          |              |             | test**       |
+-------------+----------+--------------+-------------+--------------+
|             |          | **n1 = a+c = | **n2 = b+d  | **N =        |
|             |          | TP+FN**      | = FP+TN**   | a+b+c+d**    |
|             |          |              |             |              |
|             |          | **total with | **total     | **=          |
|             |          | disease**    | without     | T            |
|             |          |              | disease**   | P+FP+FN+TN** |
|             |          |              |             |              |
|             |          |              |             | **total in   |
|             |          |              |             | study**      |
+-------------+----------+--------------+-------------+--------------+

**Accuracy**: (1) *Accuracy* of a test is a measure of how faithfully
the information obtained using a medical imaging agent reflects reality
or *truth* as measured by a truth standard or *gold standard*. Accuracy
is the proportion of cases, considering both positive and negative test
results, for which the test results are correct (i.e., concordant with
the truth standard or *gold standard*). Accuracy
= (TP+TN)/(TP+FP+FN+TN).

**False positive rate:** The probability that a patient does not have
the disease given that the test result is positive.

**Negative predictive value:** The accuracy of a negative result; i.e.,
the probability that a subject does not have the disease given that the
test result is negative. The negative predictive value = TN/(TN+FN).

**Positive predictive value:** The accuracy of a positive result; i.e.,
the probability that a subject has disease given that the test result is
positive. The positive predictive value = TP/(TP+FP)

**Precision:** A measure of the reproducibility of a test, including
reproducibility within and across doses, rates of administration, routes
of administration, timings of imaging after product administration,
instruments, instrument operators, patients, and image interpreters, and
possibly other variables. Precision is usually expressed in terms of
variability, using such measures as confidence intervals and/or standard
deviations. Precise tests have relatively narrow confidence intervals
(or relatively small standard deviations).

**Receiver operating characteristic (ROC) curve:** A graphical
representation of the test results attained in relation to the threshold
used to classify the test as positive or negative. The results plotted
are usually the *true positive rate* (or sensitivity) and the
corresponding *false positive rate* (or 1‑specificity) for the test.
Each result is established by classifying the test result as *positive*
when the test outcome equals or exceeds the value set by a given
threshold, and *negative* when the test outcome is less than this
threshold value. For example, if a five-point ordinal scale is used to
rate the likelihood of malignancy for a tumor (e.g., definitely benign,
probably benign, equivocal, probably malignant, definitely malignant),
setting the threshold at *equivocal* will classify tumors as malignant
(i.e., a *positive* test result) when the test outcome is at this level
or higher and will classify tumors as nonmalignant (i.e., a *negative*
test result) when the test outcome is less than this level. To generate
an ROC curve, the sensitivity and specificity of the diagnostic test are
calculated for several thresholds (e.g., all values of the rating scale)
and values for *true positive rate* (or sensitivity) plotted on the
vertical axis, with corresponding values for *false positive rate* (or
1‑specificity) plotted on the horizontal axis.

**Sensitivity:** The probability that a test result is positive given
the subject has the disease. A synonym is *true positive rate*.
Sensitivity = TP/(TP+FN).

**Specificity:** The probability that a test result is negative given
that the subject does not have the disease. Synonyms include *true
negative rate*. Specificity = d/n2 = TN/(TN+FP).

**Truth standard (gold standard):** An independent method of measuring
the same variable being measured by the investigational drug or
biological product that is known or believed to give the *true* value
measurement

[^1]: This guidance has been prepared by the Division of Medical Imaging
    and Radiopharmaceutical Drug Products in the Center for Drug
    Evaluation and Research (CDER) and the Office of Therapeutics
    Research and Review in the Center for Biologics Evaluation and
    Research (CBER) at the Food and Drug Administration.

[^2]: Sponsors developing medical imaging agents should be familiar with
    Agency regulations and guidances pertaining to the development of
    these products.

[^3]: See the *Federal Register*, Vol. 64, p. 26657, May 17 1999.

[^4]: The guidance is not intended to apply to the development of
    research drugs that do not have clinical usefulness. The Agency
    recognizes the potential of imaging as a research tool, and some of
    the principles in the guidance may be applicable. Sponsors of such
    products are urged to contact the appropriate review division for
    advice on product development.

[^5]: 21 CFR 315.2 and 601.31.

[^6]: In this guidance, the terms *ligand* and *carrier* refer to the
    entire nonradionuclidic portion of the diagnostic
    radiopharmaceutical.

[^7]: See Section IV.C for a definition of *defined clinical setting*.

[^8]: Studying patients with known disease provides information useful
    in developing a hypothesis for testing in subsequent clinical
    trials. Typically, such clinical settings are not used to establish
    efficacy in disease or pathology detection.

[^9]: See Section IV.C for a definition of *defined clinical setting*.

[^10]: ^?^ Note that use of a *defined clinical setting* in studies of
    medical imaging agents also tends to anchor both the *pretest
    probability* and the *spectrum* (e.g., severity or stage) of the
    disease or condition under study. Thus, when evaluated in a defined
    clinical setting, diagnostic performance measures that vary with the
    pretest probability of the disease or condition (e.g., positive and
    negative predictive values, accuracy), or that can vary with the
    spectrum of the disease or condition (e.g., sensitivity,
    specificity, positive and negative predictive values, accuracy) tend
    to take on values that are relatively constant for that defined
    clinical setting. See Section III B.