Guidance for Industry
Developing Medical Imaging Drug and
Biological Products
Part 2:  Clinical Indications
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)
June 2004
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)
June 2004
Clinical Medical  
Table of Contents
I. INTRODUCTION.................................................................................................................2
II. SCOPE  TYPES OF MEDICAL IMAGING AGENTS................................................3
A. Contrast Agents..............................................................................................................................3
B. Diagnostic Radiopharmaceuticals................................................................................................4
III. INDICATIONS FOR MEDICAL IMAGING AGENTS..................................................4
A. Structure Delineation.....................................................................................................................5
1. Locating and Outlining Normal Anatomic Structures.....................................................................6
2. Distinguishing Between Normal and Abnormal Anatomy...............................................................6
B. Disease or Pathology Detection or Assessment............................................................................7
C. Functional, Physiological, or Biochemical Assessment...............................................................8
D. Diagnostic or Therapeutic Patient Management........................................................................8
E. Multiple or Other Indications.....................................................................................................10
IV. CLINICAL TRIALS TO DETERMINE EFFECTIVENESS OF MEDICAL
IMAGING AGENTS..................................................................................................................10
A. General Considerations for Establishing Accuracy and Validity of a Test............................11
B. Clinical Usefulness.......................................................................................................................12
C. Defined Clinical Settings.............................................................................................................14
APPENDIX:  MEDICAL LITERATURE................................................................................16
GLOSSARY.................................................................................................................................18 Contains Nonbinding Recommendations
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1
Guidance for Industry
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3
Developing Medical Imaging Drug and Biological Products 
4
Part: 2  Clinical Indications
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7
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9
10 This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It
11 does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 
12 An alternative approach may be used if such approach satisfies the requirements of the applicable statutes
13 and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for
14 implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate
15 number listed on the title page of this guidance.
16
17
18
19
20 I. INTRODUCTION
21
22 This guidance is one of three guidances intended to assist developers of medical imaging drug
23 and biological products (medical imaging agents) in planning and coordinating their clinical
24 investigations and preparing and submitting investigational new drug applications (INDs), new
25 drug applications (NDAs), biologics license applications (BLAs), abbreviated NDAs (ANDAs),
26 and supplements to NDAs or BLAs.  The three guidances are:  Part 1: Conducting Safety
27 Assessments; Part 2:  Clinical Indications; and Part 3: Design, Analysis, and Interpretation of
28 Clinical Studies.
29
30 Medical imaging agents generally are governed by the same regulations as other drugs or
31 biological products.  However, because medical imaging agents are used solely to diagnose and
32 monitor diseases or conditions as opposed to treat them, development programs for medical
33 imaging agents can be tailored to reflect these particular uses.  Specifically, this guidance
34 discusses our recommendations on selecting and studying clinical indications for medical
35 imaging agents administered in vivo.2 
                                                
1 This guidance has been prepared by the Division of Medical Imaging and Radiopharmaceutical Drug Products and
the Office of Therapeutics Research and Review in the Center for Drug Evaluation and Research (CDER) at the
Food and Drug Administration.  
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) by adding provisions for the evaluation and approval of in
vivo radiopharmaceuticals used in the diagnosis or monitoring of diseases (64 FR 26657, May 17, 1999).  This
guidance elaborates on the provisions contained in that regulation.
2 Contains Nonbinding Recommendations
36
37 FDA's guidance documents, including this guidance, do not establish legally enforceable
38 responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should
39 be viewed only as recommendations, unless specific regulatory or statutory requirements are
40 cited.  The use of the word should in Agency guidances means that something is suggested or
41 recommended, but not required.
42
43 A glossary of common terms used in diagnostic medical imaging is provided at the end of this
44 document.
45
46
47 II. SCOPE  TYPES OF MEDICAL IMAGING AGENTS 
48
49 This guidance discusses medical imaging agents that are administered in vivo and are used for
50 diagnosis or monitoring with a variety of modalities, such as radiography, computed tomography
51 (CT), ultrasonography, magnetic resonance imaging (MRI), and radionuclide imaging.  The
52 guidance is not intended to apply to the development of in vitro diagnostic or therapeutic uses of
53 these agents.3
54
55 Medical imaging agents can be classified into at least two general categories, contrast agents and
56 diagnostic radiopharmaceuticals.
57
58 A. Contrast Agents
59
60 As used in this guidance, a contrast agent is a medical imaging agent used to improve the
61 visualization of tissues, organs, and physiologic processes by increasing the relative difference of
62 imaging signal intensities in adjacent regions of the body.  Products include, but are not limited
63 to (1) iodinated compounds used in radiography and CT; (2) paramagnetic metallic ions (such as
64 ions of gadolinium, iron, and manganese) linked to a variety of molecules and used in MRI; and
65 (3) microbubbles, microaerosomes, and related microparticles used in diagnostic
66 ultrasonography. 
                                                
3
 The guidance is not intended to apply to the development of research drugs that do not provide direct patient
benefit with respect to diagnosis, therapy, prevention, or prognosis, or other clinically useful information.  These
include radioactive drugs for research that are used in accordance with 21 CFR 361.1.  Section 361.1(a) states that
radioactive drugs (defined in 21 CFR 310.3(n)) are generally recognized as safe and effective when administered
under specified conditions to human research subjects in the course of a project intended to obtain basic information
about the metabolism of a radioactively labeled drug or about human physiology, pathophysiology, or biochemistry.
 However, if a radioactive drug is used for immediate therapeutic, diagnostic, or similar purposes or to determine the
safety and effectiveness of the drug in humans, or if the radioactive drug has a pharmacological effect in the human
body, an IND is required.  FDA is developing a guidance on determining when research with radioactive drugs may
be conducted under  361.1.
The Agency recognizes the potential of imaging agents as research tools for aiding the development of therapeutic
drugs, and some of the principles in the guidance may be applicable to such research.  Sponsors of such imaging
research agents are urged to contact the Division of Medical Imaging and Radiopharmaceutical Drug Products for
advice on development of the imaging research agent.
3 Contains Nonbinding Recommendations
67
68 B. Diagnostic Radiopharmaceuticals
69
70 As used in this guidance, a diagnostic radiopharmaceutical is (1) an article that is intended for
71 use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that
72 exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or
73 photons or (2) any nonradioactive reagent kit or nuclide generator that is intended to be used in
74 the preparation of such an article.4  The FDA interprets this definition to include articles that
75 exhibit spontaneous disintegration leading to the reconstruction of unstable nuclei and the
76 subsequent emission of nuclear particles or photons.
77
78 Diagnostic radiopharmaceuticals are generally radioactive drugs or biological products that
79 contain a radionuclide that typically is linked to a ligand or carrier.5  These products are used
80 with planar imaging, single photon emission computed tomography (SPECT), positron emission
81 tomography (PET), or with other radiation detection probes.
82
83 Diagnostic radiopharmaceuticals used for imaging typically have two distinct components.
84
85   A radionuclide that can be detected in vivo (e.g., technetium-99m, iodine-123,
86 indium-111).  
87 The radionuclide typically is a radioactive molecule with a relatively short physical half-life
88 that emits radioactive decay photons having sufficient energy to penetrate the tissue mass of
89 the patient.  These photons can then be detected with imaging devices or other detectors. 
90   A nonradioactive component to which the radionuclide is bound that delivers the
91 radionuclide to specific areas within the body. 
92 This nonradionuclidic portion of the diagnostic radiopharmaceutical often is an organic
93 molecule such as a carbohydrate, lipid, nucleic acid, peptide, small protein, or antibody. 
94
95 As technology advances, new products may emerge that do not fit into the traditional categories
96 of contrast agents and radiopharmaceuticals (e.g., agents for optical imaging, magnetic
97 resonance spectroscopy, combined contrast and functional imaging).  It is anticipated, however,
98 that the general principles discussed here could apply to these new diagnostic products. 
99 Developers of these products should contact the appropriate reviewing division for advice on
100 product development.
101
102
103
104 III. INDICATIONS FOR MEDICAL IMAGING AGENTS
105
                                                
4 21 CFR 315.2 and 601.31.
5 In this guidance, the terms ligand and carrier refer to the entire nonradionuclidic portion of the diagnostic
radiopharmaceutical.
4 Contains Nonbinding Recommendations
106 The labeled indications for medical imaging agents fall within the following general categories:
107
108   Structure delineation
109   Disease or pathology detection or assessment
110   Functional, physiological, or biochemical assessment
111   Diagnostic or therapeutic patient management
112
113 The above categories do not represent a hierarchy or progression (e.g., a structure delineation
114 indication does not need to precede a disease assessment indication).  In addition, indications
115 from different categories could be granted for the same imaging agent.  Approval also may be
116 possible for categories of indications not listed above.  
117
118 Under section 505(d) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(d)),
119 FDA cannot approve a new drug application (NDA) unless it contains adequate tests
120 demonstrating whether the proposed drug product is safe for use under the conditions prescribed,
121 recommended, or suggested in its proposed labeling.6  All drugs have risks, including risks
122 related to the intrinsic properties of the drug, the administration process, the reactions of the
123 patient, and incorrect diagnostic information.  Incorrect diagnostic information includes
124 inaccurate structural, functional, physiological, or biochemical information; false positive or
125 false negative diagnostic determinations; and information leading to inappropriate decisions in
126 diagnostic or therapeutic management.  Even if risks are found to be small, all drug development
127 programs must obtain evidence of drug effectiveness under section 505 of the Act.  Simply
128 generating an image, for which the implications to the patient are not understood, does not
129 confer benefits to the patient.  
130
131 In determining the most appropriate indication for a medical imaging agent, special
132 considerations may apply to agents that may pose significant patient risk, for example, biological
133 medical imaging agents that are frequently immunogenic.  The development of antibodies after
134 intermittent, repeated administration can alter the pharmacokinetics, biodistribution, safety,
135 and/or imaging properties of such agents and, potentially, of immunologically related agents. For
136 agents that pose significant risk and where the clinical benefit is generally not readily apparent,
137 an indication of disease or pathology detection or assessment or diagnostic or therapeutic
138 patient management is more appropriate.  If one of the other indications (i.e., structure
139 delineation or functional, physical or biochemical assessment) will be sought for an agent that
140 may pose significant patient risk, we recommend that the development plan be discussed with
141 the review division.  
142
143 A. Structure Delineation
144
145 As described in the following sub-sections, at least two types of labeled indications for structure
146 delineation are possible: (1) locating and outlining normal (or variants of normal) anatomic
147 structures and (2) distinguishing between normal and abnormal anatomy in a defined clinical
148 setting.  Ordinarily, the ability to locate and outline normal structures or distinguish between
                                                
6 For approval of a biological license application, the safety of the proposed product must be demonstrated under
section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)).
5 Contains Nonbinding Recommendations
149 normal and abnormal anatomy can speak for itself with respect to the clinical value of the
150 information and will not require additional information substantiating clinical usefulness.
151
152 1. Locating and Outlining Normal Anatomic Structures
153
154 We recommend that a medical imaging agent intended for this type of indication be able
155 to locate and outline normal (or variants of normal) anatomic structures.  We recommend
156 that the product clarify the spatial relationship of the visualized normal structure with
157 respect to other body parts or structures. Such a medical imaging agent could distinguish
158 normal structures that cannot be seen well with other imaging agents or modalities.  For
159 example, a contrast agent developed to image the normal parathyroid glands could be
160 clinically useful because it could help surgeons plan and perform thyroid surgery.
161
162 2. Distinguishing Between Normal and Abnormal Anatomy
163
164 We recommend that a medical imaging agent intended for this type of indication be able
165 to locate and outline both normal and abnormal anatomic structures.  We recommend that
166 the agent also clarify the spatial relationships of the normal and abnormal anatomic
167 structure(s) with respect to other body parts or structures.  Imaging agents that identify
168 abnormalities common to one or more disease entities (and therefore not specific to a
169 particular disease) could be eligible for a structural indication.  Examples of this type of
170 agent include:
171
172   An agent that nonspecifically enhances the airway lumen to distinguish dilated
173 bronchi from normal bronchi and categorizes the bronchiectasis anatomically
174 (e.g., as cylindric, sacculated, or fusiform) 
175   An agent that nonspecifically enhances the joint cavity to evaluate and describe
176 meniscal or ligamentous injuries of the knee
177   An agent that outlines the vascular system to identify structural narrowing,
178 dissections, aneurysms, and relationships to normal vasculature
179   A contrast agent that localizes or outlines masses 
180  
181 In the preceding examples, the agents ability to outline abnormal anatomy may also be
182 supportive of a disease detection indication in a specific population (section III.B).  If the
183 sponsor can demonstrate that use of the agent provides clinical benefit in this population,
184 a disease detection indication might be appropriate. 
185
6 Contains Nonbinding Recommendations
186 B. Disease or Pathology Detection or Assessment
187
188 We recommend that a medical imaging agent intended for disease or pathology detection be able
189 to detect and locate a specific disease or pathological state in at least one defined clinical
190 setting.7 The medical imaging agent could be used alone or in combination with other diagnostic
191 procedures to achieve this labeled indication.  
192
193 Examples of medical imaging agents for which this type of indication may be appropriate
194 include:
195
196   An agent that can bind to multiple regions of the brain but is intended to detect or assess
197 the extent of a specific neurological disease, such as Parkinsons disease
198   A radiolabeled monoclonal antibody that can attach to a unique tumor antigen to detect
199 the presence of, or extent of, a mass with this tumor antigen (e.g., breast cancer)
200
201 We recommend that efficacy trials for these indications be conducted in subjects presenting for
202 diagnostic evaluation of a specific disease or condition in a defined clinical setting.  This is
203 because the likelihood of disease or the spectrum of disease (e.g., severity or stage) is dependent
204 on the clinical setting.  Examples of two common clinical settings are (1) providing a diagnosis
205 in patients with suspected disease and (2) monitoring and assessing the extent, rate of
206 progression, or other aspects of the specific disease in patients previously diagnosed with the
207 disease.  An indication of detection of disease or pathology in an asymptomatic population (a
208 screening indication) may be appropriate if the sensitivity of the imaging modality is high
209 enough and the rate of false positives is low enough (see also diagnostic or therapeutic patient
210 management, section III.D). 
211
212 It is likely that the clinical usefulness and the diagnostic performance of the medical imaging
213 agent will differ in each clinical setting.8  We recommend that if a medical imaging agent is
214 being developed to diagnose a particular disease, efficacy trials generally enroll subjects in
215 whom the disease status is unknown, but in whom specific aspects of the clinical presentation
216 have led to the desire for more diagnostic information.  That is, we recommend that the trials
217 include the intended population in the appropriate clinical setting.  Data from subjects known
218 definitely to have (or to not have) the disease of interest may be of limited value because
219 estimates of diagnostic performance derived from a known disease population may not apply to
220 performance in the intended population.
221
222
223
                                                
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.
7 Contains Nonbinding Recommendations
224 C. Functional, Physiological, or Biochemical Assessment
225
226 We recommend that a medical imaging agent intended to provide functional, physiological, or
227 biochemical assessment be able to evaluate the function, physiology, or biochemistry of a tissue,
228 organ system, or body region.  This type of indication could apply to agents used to detect either
229 a reduction or an increase of a normal functional, physiological, or biochemical process.  The
230 indication functional, physiological, or biochemical assessment could be limited to assessment
231 of functional, physiological, or biochemical processes when disturbances of these processes are
232 common to several diseases or conditions and they are not diagnostic for any particular disease
233 or condition. 
234
235 The indication functional, physiological, or biochemical assessment is appropriate for patients
236 when evaluations of functional, physiological, or biochemical aspects of a tissue, organ, or body
237 region would provide clinically useful information. 
238
239 Examples of medical imaging agents with functional, physiological, or biochemical assessment
240 indications include:
241
242   A contrast agent to assess cardiac ejection fraction or myocardial wall motion
243   A radiopharmaceutical that assesses metabolism of a substrate where the normal pattern
244 of metabolism in that organ or tissue is well known
245
246 To establish efficacy in clinical studies, we recommend that the functional, physiological, or
247 biochemical measurements of the medical imaging agent be compared with those of a reference
248 product or a procedure of known high validity (i.e., a truth standard).  Ideally, we recommend
249 that the high validity of this reference product or truth standard be documented thoroughly and
250 critically before its use in clinical studies intended to demonstrate effectiveness of the test-
251 imaging agent.  We recommend that a functional indication be studied in the wide spectrum of
252 diseases and disease severity states that affect the functional endpoint.  For example, a sponsor
253 might seek an indication of measuring myocardial left ventricular function.  To ensure that the
254 test is valid in the patient population most likely to be referred for testing, the sponsor might
255 design studies that include subjects with different cardiac diseases, such as dilated
256 cardiomyopathy, valvulopathy, hypertrophic cardiomyopathy, and myocardial infarction,
257 including subjects with normal function as well as those with mild, moderate, and severe
258 dysfunction.  In that case, separate studies for each disease would not be needed.  
259
260 If no standard of truth applies to the proposed use of a medical imaging agent for functional,
261 physiological, or biochemical assessment, we recommend that a clinical trial be conducted to
262 determine that the findings are clinically useful (see section IV.B). 
263
264 D. Diagnostic or Therapeutic Patient Management
265
266 We recommend that a medical imaging agent intended for the indication diagnostic or
267 therapeutic patient management be able to improve patient management decisions (e.g., the need
268 for further diagnostic testing or the use of specific therapeutic interventions) or improve patient
8 Contains Nonbinding Recommendations
269 outcomes when used in a defined clinical setting.9  Included in this indication is the ability to
270 provide information (such as the presence of a certain receptor in a type of cancer patient) that
271 can predict survival or patient response to a particular type of therapeutic drug. 
272
273 To obtain approval for a diagnostic or therapeutic patient management indication, we
274 recommend that adequate and well-controlled investigations demonstrate that patient
275 management decisions or outcomes are, in fact, improved by use of the medical imaging agent. 
276 The medical imaging agent can be used alone or in combination with other diagnostic procedures
277 to achieve this labeled indication.  Studies might involve randomization into one arm with
278 testing and patient management based on the testing results in accordance with a prespecified
279 algorithm compared to a nontesting arm that proceeded to treatment as defined by current
280 standards.  Patient outcomes such as recovery, survival, and response rates that are based on the
281 treatment standard could be collected and compared.
282
283 Examples of medical imaging agents for which this type of indication may be appropriate are:
284
285   Products shown to provide improved clinical decisions about whether suspected cardiac
286 patients should undergo further invasive, diagnostic testing, such as with coronary
287 angiography (i.e., use for diagnostic patient management) 
288   Products that predict whether a patient has a better prognosis with tumor resection
289 instead of with chemotherapy (i.e., use for therapeutic patient management)
290
291 We recommend that the trials demonstrate that diagnostic or therapeutic management is
292 improved when using the medical imaging agent compared to management without use of the
293 medical imaging agent.  The medical imaging agent can be used in conjunction with other tests
294 to influence a patient diagnostic or therapeutic management decision.  We suggest that it would
295 not be sufficient simply to demonstrate that the results of the test drug were used to direct a
296 change in patient management, even to an intervention that is well established.  Rather, we
297 recommend that the sponsor establish whether the change was better or worse for the patient. 
298 For example, when using a new imaging agent in determining whether to perform breast biopsy
299 versus repeat clinical breast examination followed by mammography, the sponsor should show
300 whether use of the test drug results in fewer or greater numbers of unnecessary biopsies or
301 undiagnosed cancers than use of a comparator.  We recommend that this principle also be
302 applied to studies to demonstrate a therapeutic patient management claim:  the sponsor should
303 show that use of the new imaging agent leads to better patient therapy choices than result from
304 the use of existing methods of managing therapy.  If sponsors do not wish to perform such
305 follow up, we recommend that they instead seek an indication for disease or pathology detection
306 or assessment.
307
308 To obtain the indication diagnostic or therapeutic patient management for a medical imaging
309 agent that identifies unrecognized disease in asymptomatic individuals (e.g., used in a screening
310 setting), we recommend that a sponsor show that use of the test decreases morbidity or mortality,
                                                
9 See section IV.C for a definition of defined clinical setting.
9 Contains Nonbinding Recommendations
311 or provide existing data that show that early detection and treatment of the disease decreases
312 morbidity or mortality. 
313
314 E. Multiple or Other Indications
315
316 The indication categories outlined above are flexible, and indications for medical imaging agents
317 need not be mutually exclusive.  A labeled indication can include several indication categories. 
318 For example, a diagnostic radiopharmaceutical could be developed as an aid in the diagnosis of
319 lung cancer for the labeled indication disease or pathology detection or assessment.  This
320 diagnostic radiopharmaceutical could also be evaluated in subpopulations of patients with lung
321 cancer for its ability to provide information that leads directly to appropriate therapeutic
322 management decisions (e.g., using test results to determine what combination of surgery,
323 radiotherapy, and chemotherapy is most appropriate).
324
325 Structural and functional aspects of diseases or conditions sometimes are evaluated together with
326 imaging in clinical practice (e.g., use of a contrast agent to evaluate cardiac anatomy and
327 segmental wall motion).  In such cases, we recommend that clinical studies evaluate the effect of
328 the imaging agent on assessments of both structure and function. 
329
330 Functional evaluations of diseases or conditions may be accomplished for various purposes.  For
331 example, a drug may have a functional indication for the evaluation of cardiac ejection fraction. 
332 Subsequently, the drug may be developed for a therapeutic management indication for the
333 evaluation of perfusion or wall motion abnormalities to predict response to surgical intervention. 
334
335 For indications that do not fall within the categories identified above (e.g., providing prognostic
336 information based on imaged gene expression), we recommend that the applicant or sponsor
337 consult FDA on the nature of the desired labeled indication and how to establish effectiveness
338 for it.
339
340
341 IV. CLINICAL TRIALS TO DETERMINE EFFECTIVENESS OF MEDICAL
342 IMAGING AGENTS
343
344 In general, establishing effectiveness has two components:  (1) establishing the accuracy of the
345 test and (2) establishing the clinical value of the test.  In some cases, a test that provides accurate
346 information in describing a clinical condition is of well-established value.  Generally, this is true
347 for proposed indications for structure delineation and disease or pathology detection or
348 assessment.  When there are established methods of seeking similar information and the only
349 issue is comparing the accuracy of the new and old methods, the clinical usefulness of the
350 indication need not be reestablished.  Many functional, physiological, or biochemical
351 assessments are similarly well established as useful (ejection fraction, renal function, myocardial
352 wall motion) but others (glucose utilization by various parts of the body, presence of serotonin
353 receptors, cerebral blood flow, palmitate metabolism) may not be.  Where the clinical value of
354 valid information is not established, we recommend that additional information establishing its
355 value be developed.  This recommendation applies to all drugs, including therapeutic drugs, for
356 which the indication or mechanism of action for an indication is not accepted or well understood
10 Contains Nonbinding Recommendations
357 in the medical community.  
358
359 Demonstration of improved patient management means more than assessment of the accuracy of
360 the test.  Either by reference to prior data or through new trials, we recommend that this claim
361 show that the test really makes a difference in outcome or management.  Of course, the impact of
362 a test may be considered obvious (e.g., staging of breast cancer is disease or pathology detection
363 or assessment indication).  In some cases, the test will have plain therapeutic implications, as
364 would be the case for effective staging of some other malignancies, although, in many cases, trial
365 data should be collected.
366
367 We recommend that investigations establish the validity  (generally assessed by describing the
368 sensitivity, specificity, positive predictable value and negative predictive value in relevant
369 settings) and reliability (how reproducible the test results are) of the imaging agent.  These test
370 characteristics can provide information on risk-benefit as well, including estimates of risk of
371 incorrect diagnosis.  Safety information obtained in studies (see the companion guidance Part 3:
372 Design, Analysis, and Interpretation of Clinical Studies) will also contribute to an Agency risk-
373 benefit assessment.  The clinical usefulness of an imaging agent may be obvious from a
374 description of what it can demonstrate (or supportable by evaluation of the literature), or it may
375 be appropriate to demonstrate the agent's usefulness.  We recommend that clinical studies and
376 related methods for establishing effectiveness be performed in defined clinical settings that
377 reflect the proposed indications.
378  
379 A. General Considerations for Establishing Accuracy and Validity of a Test 
380
381 To establish efficacy in clinical studies, we recommend that the accuracy and/or validity of the
382 structural delineation, functional, physiological, or biochemical assessment and disease or
383 pathology detection generally be demonstrated by comparing the performance of the medical
384 imaging agent with that of a reference product or a truth standard in a relevant clinical setting.  
385
386 To provide adequate estimates of the validity and reliability of the medical imaging agent over
387 the full range of conditions for which it is intended to be used, we recommend that medical
388 imaging agents be evaluated in studies with appropriate representation of sufficient numbers of
389 subjects (1) with and without the abnormalities or diseases in question (over the full spectrum of
390 the condition or disease presentation) and (2) with other conditions, processes, or diseases that
391 could affect the interpretation of the imaging results (e.g., inflammation, neoplasm, infection,
392 trauma).  We recommend that sponsors justify the inclusion or exclusion of selected
393 subpopulations during clinical development.  We recommend that studies of agents for
394 functional, physiological, or biochemical assessment indications provide a quantitative or
395 qualitative understanding of how the measurement varies in normal and abnormal subjects or
396 tissues, including the variable's normal range, distribution, and confidence intervals in these
397 subjects or tissues.  We believe it is critical to identify the range that is normal and the values
398 that indicate an abnormality.  When possible, we recommend that the minimum detectable limits
399 and reproducibility of the measurement be assessed.
400
11 Contains Nonbinding Recommendations
401 Reproducibility assessments are most meaningful when performed within the same subject. 
402 However, under some circumstances this practice might be unethical, in which case the sponsor
403 should consider alternative approaches to testing reproducibility (e.g., in animals).
404
405 In cases when a valid reference product or a truth standard is unavailable or infeasible, the
406 validity of the information obtained can be demonstrated in clinical studies showing a beneficial
407 clinical outcome.  We recommend that the sponsor discuss these issues with the Agency prior to
408 initiation of phase 3 studies.
409
410 B. Clinical Usefulness
411   
412 Under section 505 of the Act (or, for a biologic, section 351 of the PHS Act) and its
413 implementing regulations, FDA cannot approve a drug without evidence that the drugs benefit
414 to patients outweighs its risks:
415
416  Sponsors are not asked to re-demonstrate the benefits already shown by diagnosing a
417 patients specific disease or defining anatomy or functional status.  However, under
418 section 505 of the Act or section 351 of the PHS Act, the sponsor must demonstrate that
419 the agents benefits justify the risks.
420  For an indication for which the benefits of an imaging agent have not yet been shown,
421 such as imaging a new biochemical process, a sponsor should conduct clinical trials to
422 demonstrate the agents clinical prognostic value, the diagnostic performance
423 characteristics of the test agent compared to existing testing, the tests ability to predict
424 appropriate therapy, or the tests ability to help select appropriate further diagnostic
425 testing over existing testing.
426
427 The use of medical imaging agents without defined benefits and without an understanding of
428 how the imaging results can be used for patient management might cause harm to patients even
429 if the agent has low toxicity.  Such harm might include (1) conducting unnecessary diagnostic
430 testing based on the results of the agent, (2) directing patients to invasive procedures or
431 inappropriate or unnecessary therapy, and (3) creating unnecessary patient anxiety from
432 abnormal test results.
433
434 Medical imaging results may have clinical usefulness in some settings but not in others; it is,
435 therefore, important to prospectively define and study the imaging agent in the clinical setting of
436 intended use.  We recommend that a medical imaging agent be able to provide accurate and
437 reliable information that, in one of a number of ways, facilitates clinical management, including
438 (1) helping make an accurate diagnosis, (2) contributing to beneficial clinical outcome (e.g., by
439 helping choose the right therapy), or (3) providing accurate prognostic information. All
440 indications under section III should reflect these benefits, which are then weighed by FDA
441 against the agents risks as part of an approval decision.  Once clinical usefulness is established,
442 other benefits of imaging agents, such as safety advantages and enhanced convenience to
443 patients over existing marketed products, can be considered. 
444  
12 Contains Nonbinding Recommendations
445 Depending on the specific indication, clinical usefulness can generally be established in two
446 ways:  (1) by direct demonstration in studies carried out during clinical development and (2) by
447 reference to historical data.  In circumstances when the measure is well established as useful in
448 the medical literature, the clinical benefit of the measure does not need to be re-established (e.g.,
449 ejection fraction or myocardial wall motion are widely used measures of cardiac function with
450 known prognostic and therapeutic implications).  Even if the new measure has not been used
451 before, we suggest that clinical usefulness can be established historically when the information
452 being obtained has been shown to be useful when obtained by other means.  For example, if a
453 product is able to establish the early detection of colon polyps without the need for colonoscopy,
454 the clinical benefit of the use of this product can be inferred because treatment is available for
455 this disease (polypectomy), and the test would allow people to avoid unnecessary colonoscopy
456 (i.e., clinical usefulness has been established indirectly).  In such situations, clinical usefulness
457 can be documented by a critical and thorough analysis of the medical literature and any historical
458 precedents. 
459
460 For indications in which it cannot be established from prior knowledge, we recommend that
461 clinical usefulness be established through new trials during development.  For example, we
462 recommend that clinical usefulness be established directly for a medical imaging agent that has
463 been shown in a research setting to bind specifically to particular receptors, but where it has not
464 yet been established that assessment of such binding adds to the accuracy of diagnosis,
465 contributes to beneficial clinical outcome, or provides accurate prognostic information.  For
466 novel technologies relying on mechanisms for imaging never approved before, we recommend
467 that a plan for establishing clinical usefulness be incorporated into the development plan of a
468 medical imaging agent.  In general, we recommend that clinical usefulness be evaluated
469 prospectively in the principal clinical studies of efficacy.  We recommend that sponsors assess
470 how the novel technology imaging results are used and how usefulness to the patient is
471 confirmed.  
472
473 For a contrast agent to be considered clinically useful, we recommend that, when used in
474 combination with an imaging device, the agent be able to provide useful information or other
475 advantages (such as improved imaging time or convenience) beyond that obtained by the
476 imaging device alone.  That is, we recommend that imaging with the contrast agent have added
477 benefit when compared to imaging without the contrast agent.
478
479 To illustrate how effectiveness could be evaluated, consider the following possible approaches:
480
481 1. Compare the new test and the established (comparator) test, which could be either
482 another test or a truth standard, such as pathology.  Ideally, both a comparator and
483 a truth standard are employed so that the diagnostic performance measures of the
484 new test can be compared to those of the comparator.  We recommend that the
485 population studied include the spectrum of presenting patients that would be
486 expected to undergo the new test, and that standard analyses be performed on
487 sensitivity and specificity, positive predictive value, and negative predicative
488 value.  If the comparator test is established as clinically useful through controlled
489 clinical trials or literature and is considered the standard of care by the practicing
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490 community, comparing the new test to the comparator could be sufficient to
491 demonstrate the usefulness of the new test. 
492
493 2. Compare the new test added to the current standard test battery to a truth standard
494 (such as pathology).  If the new test added to the standard battery shows greater
495 sensitivity and specificity than the standard test battery without the new test, that
496 result alone could be sufficient.  Or, if the new test detects some lesions that the
497 standard tests miss (greater sensitivity) and the result is of accepted clinical value
498 (i.e., leads to improved patient management and has a very low false positive
499 rate), that result alone could be sufficient.
500
501 Note:  Situation 2 would be similar to imaging with and without the new test to determine
502 the contribution of the new imaging test. 
503
504 For 1 and 2, the results of the new test would be presumed to be of prognostic,
505 therapeutic, or diagnostic value, and the new imaging drug would be presumed to
506 improve these aspects.  If that is not the case, we recommend that the value be
507 documented through a randomized clinical trial. The new test (or the new test added to
508 the standard testing battery) could be compared to standard testing without the new test to
509 determine if the new test improves clinical outcomes or prognosis.  Refer to Part 3 of the
510 medical imaging guidances, section IV.D.1, for additional discussion.
511
512 C. Defined Clinical Settings
513
514 We recommend that a defined clinical setting reflect the circumstances and conditions under
515 which the medical imaging agent is intended to be used.10  Generally, the choice of anticipated
516 labeled indications will determine the clinical setting for the trials.  In some cases, an
517 appropriately designed trial may contain several clinical settings.
518
519 For example, a medical imaging agent intended to detect prostate cancer (a disease specific
520 indication) could be developed for use in different defined clinical settings such as:
521
522   For asymptomatic, healthy men for early detection screening
523   For use in men presenting with a high clinical index of suspicion for prostate cancer
524 either by physical examination or abnormal prostate specific antigen testing 
525   For use in men with existing diagnosis of prostate cancer to evaluate recurrence
                                                
 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.   
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526 We recommend that the circumstances and conditions under which the medical imaging agent is
527 intended for use be evaluated in clinical trials and be described in the labeling using the
528 following mechanisms:
529
530 1.  Specify aspects of the medical history and physical examination that are pertinent for
531 determining the likelihood of the disease or condition that is in question.  For example:
532
533   A medical imaging agent intended to detect breast cancer might be evaluated for use
534 in the assessment of (1) otherwise healthy women over 40 years of age, (2) women
535 with a family history of breast cancer, or (3) women presenting with palpable breast
536 masses or abnormal mammograms.
537
538 2. Specify a patient population that is at a particular step in the diagnostic or patient
539 surveillance sequence.  For example:
540
541   A diagnostic radiopharmaceutical may be intended to evaluate patients in an
542 emergency room with equivocal clinical and laboratory findings of a myocardial
543 infarction, or to evaluate the location and extent of a myocardial infarction in patients
544 with definitive findings.  
545   An agent may be intended for use in an outpatient office setting to monitor disease
546 progression.  Typically, we recommend that such an imaging agent be studied using
547 repeated, periodic surveillance imaging of ambulatory patients in an outpatient
548 setting. 
549  
550 3. Specify any other diagnostic assessments that are to be performed in the evaluation of
551 this patient population.  We recommend that this delineation include describing how the
552 medical imaging agent should be used with respect to other diagnostic tests or
553 evaluations, including (1) whether the medical imaging agent is intended to be used
554 together with, or as a replacement for, other diagnostic tests or modalities and (2) how
555 the use of the medical imaging agent is influenced by the results of other diagnostic
556 evaluations.  
557
558 Pooling efficacy data (additive derivation of summary statistics) across defined clinical settings
559 may only be of limited value because differences in disease prevalence and in pathophysiology
560 may result in different diagnostic performance (sensitivity, specificity, positive and negative
561 predictive value) in different settings.  Pooled results may suggest that the product is useful in all
562 the evaluated clinical settings and may obscure the evidence of differential usefulness in each
563 one of the settings.  Of course, data from independent trials in different clinical settings may be
564 useful in determining the overall labeling in one or more clinical settings.  The number and type
565 of populations to be studied depends on the type of the indication and clinical uses sought by the
566 sponsor.  If there are data showing that the benefits from use of a medical imaging agent in a
567 particular clinical setting exceed the risks, that can be reflected on the labeling.
568
569
570
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571
572 APPENDIX:  MEDICAL LITERATURE
573
574 On occasion, the medical literature may provide critical information on various aspects of the
575 safety or efficacy of a product.  Considerations in the use of the medical literature are described
576 in the FDA guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug
577 and Biological Products.  In applying these fundamental principles to imaging trials, we
578 recommend that sponsors consider whether the methods section in a relevant literature article
579 describes a prospective protocol in sufficient detail to assess the strengths and weaknesses of the
580 protocol design features discussed in this medical imaging guidance.  For example, the design
581 features that are critical include selection of the patient population, clinical setting, image
582 handling, image reading plan for the test product and the standard of truth, use of an accepted
583 standard of truth, the statistical plan, and use of appropriate steps to eliminate bias.  As literature
584 studies are often completed for purposes other than drug approval, the relevance of the selected
585 endpoints to the proposed indication should be justified.
586
587 We recommend that a critical review of the literature present the method used for the literature
588 search, the criteria used to review the data, and the criteria used to determine the applicability of
589 the results.  Although we recommend that each article be reviewed and summarized, we also
590 recommend that the key articles be discussed more extensively.  
591
592 Typically, articles in the imaging literature provide limited data on safety, so that additional
593 safety studies may be called for.  Other information that can be supplied either fully or partially
594 by the literature include:
595
596   Information on human drug safety: population exposed, types of adverse events and how they
597 were monitored and reported, reliability of data collection
598   Pharmacology
599   Toxicology studies
600   Biopharmaceutical information
601
602 In the FDA guidance for industry, Providing Clinical Evidence of Effectiveness for Human Drug
603 and Biological Products, the Agency discusses the use of the medical literature by sponsors.  We
604 recommend:
605
606   Independent substantiation of experimental results.  Multiple studies from different authors
607 provide greater support.
608 Replication of findings in usually two or more adequate and well-controlled human
609 investigations 
610 Similar study questions, populations, diseases or conditions or indications being
611 studied with the same imaging agent 
612 Studies from more than a single center (or from more than a single investigator) for
613 independence of finding
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614   A showing that studies were conducted by groups with properly documented operating
615 procedures and a history of implementing such procedures effectively 
616   Prospective design to minimize bias
617   A showing that a sufficient number of patients were enrolled in the studies to provide results
618 that are valid (we recommend this be documented by a sample size discussion in the article)
619   A showing that there is a sufficient level of detail of information in the studies to assess:
620 Mass dose(s) and radiation dose(s) used and regimen(s) used for dosage administration 
621 Image acquisition, including device settings, timing and interval of imaging, and views
622 obtained
623 Image blinding method used, how images were handled and presented to the blinded
624 reader, details on sequential unblinding if used, methods used by the core laboratory before
625 images were presented to the blinded reader, and how multiple lesions were tracked
626 Details of how the imaging agent is made so that FDA can assess the identity of an agent
627 used in multiple studies if that agent is made locally
628 --Use and description of controls to minimize bias:  for example, randomization,
629 blinding, central reading versus local reading 
630 --Statistical plans, prespecified analytic methods, prospectively defined study endpoints,
631 and a full accounting of the study population enrolled
632 --Study endpoints that are objective and not dependent on investigator judgment. 
633 Description of imaging features used by the blinded readers to reach their decision.  For
634 diagnostic tests where endpoints are interpretive, we recommend use of a well-accepted
635 truth standard, such as pathology.  If study endpoints are also compared to an active
636 imaging control drug or modality, that imaging approach must be approved for the
637 indication being studied.  We recommend the endpoint be clinically useful. 
638 Robust results that yield a conclusion of efficacy that is consistent with the prospective
639 protocol design and that do not require post-hoc analyses
640
641
642
643
644
645
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646 GLOSSARY
647
648 Note:  Subjects in trials of medical imaging agents are often classified into one of four groups
649 depending on (1) whether disease is present (often determined with a truth standard or gold
650 standard) and (2) the results of the diagnostic test of interest (positive or negative).  The
651 following table identifies the variables that are used to estimate the parameters defined below.
652
                             Test Result: Disease:
Present (+) Absent (-)
Positive (+) TP (a) FP (b)    m1 =a+b =
  TP+FP
true positive=TP  false positive=FP total with positive test
Negative (-) FN (c) TN (d)    m2 = c+d =
FN+TN
false negative=FN true negative=TN total with negative test
n1 = a + c = TP+FN n2 = b +d=FP+TN N = a+b+c+d 
=TP+FP+FN+TN
total with disease total without disease total in study
653
654
655 Accuracy:  (1) In common usage, accuracy is the quality of being true or correct.  (2) As a
656 measure of diagnostic performance, accuracy is a measure of how faithfully the information
657 obtained using a medical imaging agent reflects reality or truth as measured by a truth standard
658 or gold standard.  Accuracy is the proportion of cases, considering both positive and negative
659 test results, for which the test results are correct (i.e., concordant with the truth standard or gold
660 standard.)  Accuracy = (a+d)/N  = (TP+TN)/(TP+FP+FN+TN). 
661
662 Comparator:  An established test against which a proposed test is compared to evaluate the
663 effectiveness of the proposed test.  A comparator usually means an agent or modality approved
664 for a similar indication.  (See also definition for reference product.)
665
666 Negative predictive value:  The probability that a subject does not have the disease when the
667 test result is negative.  Synonyms include predictive value negative.  Negative predictive value =
668  d/m2 = TN/(TN+FN).  By application of Bayes Rule, the negative predictive value also can be
669 defined as a function of the pretest probability of disease (p), sensitivity, and specificity: 
670 negative predictive value = [(1-p)  specificity]/[(1-p)  specificity + p  (1- sensitivity)].
671
672 Positive predictive value:  The probability that a subject has the disease when the test result is
673 positive.  Synonyms include predictive value positive.  Positive predictive value = a/m1 =
674 TP/(TP+FP).  By application of Bayes Rule, the positive predictive value also can be defined as
675 a function of pretest probability of disease (p), sensitivity, and specificity:  positive predictive
676 value = [(p  sensitivity)/[p  sensitivity + (1-p)  (1- specificity)].
677
678 Precision:  A measure of the reproducibility of a test, including reproducibility within and
679 across doses, rates of administration, routes of administration, timings of imaging after product
680 administration, instruments, instrument operators, patients, and image interpreters, and possibly
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681 other variables.  Precision is usually expressed in terms of variability, using such measures as
682 confidence intervals and/or standard deviations.  Precise tests have relatively narrow confidence
683 intervals (or relatively small standard deviations).
684
685 Reference product:  An FDA-approved drug product having an indication similar to that of an
686 investigational drug or biological product to which it is being compared for the purpose of
687 evaluating the effectiveness of the investigational drug or biological product.
688
689 Sensitivity:  The probability that a test result is positive when the subject has the disease. 
690 Synonyms include true positive rate.  Sensitivity = a/n1 = TP/(TP+FN). 
691
692 Specificity:  The probability that a test result is negative when the subject does not have the
693 disease.  Synonyms include true negative rate.  Specificity = d/n2 = TN/(TN+FP).
694
695 Truth standard (gold standard):  An independent method of measuring the same variable
696 being measured by the investigational drug or biological product that is known or believed to
697 give the true value of a measurement.
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