Contains Nonbinding Recommendations 
 
Draft  Not for Implementation 
 
Investigational IVDs Used in Clinical 
Investigations of Therapeutic 
Products 
 
 
Draft Guidance for Industry, Food 
and Drug Administration Staff, 
Sponsors, and Institutional Review 
Boards 
 
DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.  
 
Document issued on: December 18, 2017 
 
You should submit comments and suggestions regarding this draft document within 90 days 
of publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  Identify all comments with the docket 
number listed in the notice of availability that publishes in the Federal Register. 
 
For questions about this document regarding CDRH-regulated devices, contact CDRHs 
Office of In Vitro Diagnostics and Radiological Health at 301-796-5711, or David Litwack at 
301-796-6697 or Ernest.Litwack@fda.hhs.gov.  For questions about this document regarding 
CBER-regulated devices, contact the Office of Communication, Outreach, and Development 
(OCOD) at 1-800-835-4709 or 240-402-8010. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
Center for Biologics Evaluation and Research 
 
 
  Contains Nonbinding Recommendations 
 
Draft  Not for Implementation 
 
 
Preface 
 
 
Additional Copies 
 
CDRH 
 
Additional copies are available from the Internet.  You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document 
number 1400025 to identify the guidance you are requesting. 
 
CBER 
Additional copies are available from the Center for Biologics Evaluation and Research 
(CBER), Office of Communication, Outreach, and Development (OCOD), 10903 New 
Hampshire Ave., Bldg. 71, Room 3128, Silver Spring, MD 20993-0002, or by calling 1-800-
835-4709 or 240-402-8010, by email, ocod@fda.hhs.gov or from the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/default.htm. 
  Contains Nonbinding Recommendations 
 
Draft  Not for Implementation 
 
Table of Contents 
I.  Introduction ................................................................................................................... 1 
II.  Background ................................................................................................................... 2 
III.  Policy ............................................................................................................................ 3 
A.  What is an Investigational IVD? ............................................................................... 3 
B.  IDE Regulation and Investigational IVD Risk in Investigations .............................. 4 
1) Significant Risk (SR) Devices .................................................................................. 5 
2) Non-Significant Risk (NSR) Devices ....................................................................... 6 
3) IDE Exempt Investigations ....................................................................................... 7 
C.  Evaluating Whether an Investigational IVD Used in a Clinical Investigation of a 
Therapeutic Product is Significant Risk ............................................................................. 7 
1) Factors to Consider in Making a Risk Determination .............................................. 8 
2) Investigational IVD Risk and the Design of Clinical Investigations for Therapeutic 
Products......................................................................................................................... 9 
3) How Investigational IVD Risk May Change During the Course of a Clinical 
Investigation ................................................................................................................ 12 
D.  Recommendations for IRBs and Sponsors in Evaluating Investigational IVDs in the 
Context of Clinical Investigations for Therapeutic Products ............................................ 12 
1) Information the Sponsor Should Include in Its Submission to the IRB .................. 13 
2) Recommendations for Review Questions for IRBs ................................................ 14 
3) When Can a Sponsor Begin a Therapeutic Product Trial Involving Use of an 
Investigational IVD? ................................................................................................... 16 
E.  Common Questions about Investigational IVD Use in Clinical Investigations of 
Therapeutic Products and Compliance with the IDE Regulation ..................................... 16 
F.  Inclusion of Investigational IVD Information in an IND ....................................... 17 
G.  Managing IDEs and INDs for the Same Study ....................................................... 18 
H.  Q-Submission Meetings .......................................................................................... 19 
APPENDIX. Important Considerations for Sponsors ............................................................. 20 
A.  Contents of an IDE Application .............................................................................. 20 
B.  FDA Review of IDE Applications .......................................................................... 23 
 
 
  Contains Nonbinding Recommendations 
 
Draft  Not for Implementation 
 
Investigational IVD Used in Clinical 
1 
Investigations of Therapeutic Products
2   
3 
 
4   
Draft Guidance for Industry, Food and 
5 
Drug Administration Staff, Sponsors, and 
6 
Institutional Review Boards 
7 
8   
9  This draft guidance, when finalized, will represent the current thinking of the Food and 
10  Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for 
11  any person and is not binding on FDA or the public.  You can use an alternative approach 
12  if it satisfies the requirements of the applicable statutes and regulations.  To discuss an 
13  alternative approach, contact the FDA staff or Office responsible for this guidance as 
14  listed on the title page.   
15   
I.  Introduction 
16 
17  Personalized medicine (also referred to as precision medicine) relies on the use of in 
18  vitro diagnostic (IVD) devices1 to detect and measure biomarkers and other individual 
19  characteristics of disease or other conditions with the goal of better directing patient 
20  treatment.  With the continued growth of personalized medicine, an increasing number of 
21  clinical investigations of therapeutic products (also referred to here as therapeutic product 
22  trials or studies) are using investigational IVDs to guide the management of subjects in 
23  such investigations.2  In some cases this has led to the development of an in vitro 
24  companion diagnostic device that is essential to the safe and effective use of the 
25  therapeutic product, once approved.3  The information generated by the use of 
26  investigational IVDs in therapeutic product trials may affect important aspects of 
27  treatment for the enrolled subjects and, by doing so, directly influence the types of 
28  therapeutic products or therapeutic management strategies the subjects may be exposed to 
29  during the study. Therefore, use of an investigational IVD in a therapeutic product trial 
30  may pose significant risk to subjects. FDA is concerned that sponsors (including sponsor-
                                                 
1 See 21 CFR 809.3(a) for the complete definition of in vitro diagnostic products. 
2 For purposes of this guidance, the terms investigation, study, and trial are used interchangeably and have the 
same meaning. 
3 See the guidance entitled In Vitro Companion Diagnostic Devices 
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm262327.
pdf) which provides information about FDAs policies regarding such devices.  
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31  investigators) and IRBs may not understand that many IVDs used as a critical part of 
32  therapeutic product trials are investigational. This guidance document is intended to 
33  inform stakeholders, including institutional review boards or institutional review 
34  committees (referred to hereafter as IRBs) reviewing clinical investigations, and sponsors 
35  that therapeutic product4 trials that include investigational IVDs are subject to FDAs 
36  Investigational Device Exemption (IDE) regulation (21 CFR Part 812), regardless of the 
37  source or manufacturer of the device, in addition to the Investigational New Drug (IND) 
38  regulation (21 CFR Part 312).   
39   
40  In addition, this guidance is intended to aid sponsors and IRBs in making determinations 
41  about the nature of risks of investigational IVDs used in therapeutic product studies to 
42  streamline the decision-making process, and provides information about: (i) definitions and 
43  concepts that are important in assessing investigational IVD risks (see sections III.A - III.C), 
44  (ii) the roles and responsibilities of sponsors and IRBs in complying with IDE requirements 
45  (sections III.D - III.G), and (iii) FDAs recommendations and requirements for submitting 
46  significant risk investigational IVD information in an IDE application (Appendix). The 
47  information presented in this document is consistent with FDA regulation of investigational 
48  use of IVDs in general. 
49   
50  FDA's guidance documents, including this draft guidance, do not establish legally 
51  enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a 
52  topic and should be viewed only as recommendations, unless specific regulatory or statutory 
53  requirements are cited. The use of the word should in Agency guidance documents means 
54  that something is suggested or recommended, but not required. 
II.  Background 
55 
56  In contrast to other types of devices that act on or in a patient, IVDs are usually used on 
57  samples that are removed from or originate in the patients body.5 Despite their use ex 
58  vivo, IVDs may pose risk to patients, e.g., when they provide inaccurate test results that 
59  misinform patients healthcare management decisions. This risk extends to the use of 
60  investigational IVDs when their results are used to guide the management of subjects in 
61  therapeutic product trials, e.g., to select or classify subjects, assign subjects to therapeutic 
62  product arms or doses, or monitor responses to treatment. Such uses have become more 
63  common given the increasing number of targeted therapeutic product development 
64  programs and potential response biomarkers.  
65   
                                                 
4 As used in this guidance, therapeutic product includes therapeutic, preventive, and prophylactic drugs and 
biological products.  Although this guidance does not expressly address therapeutic devices as therapeutic 
products intended for use with in vitro diagnostics, the principles discussed in this guidance may also be 
relevant to such devices. 
5 Note, however, that specimen collection devices are also considered IVD devices. 
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66  An investigational IVD is an IVD (i.e., a reagent, instrument, or system intended for use in 
67  the diagnosis of disease or other conditions6) that is the object of an investigation,7 and thus 
68  is subject to the IDE regulation (21 CFR Part 812).  Compliance with the IDE regulation 
69  allows the shipment of investigational IVDs and their use in investigations while at the same 
70  time providing measures to protect the safety of study subjects.  Under the IDE regulation, an 
71  approved IDE is required for an investigational device unless it is exempted under 21 CFR 
72  812.2(c). Investigational IVDs are often exempt under 21 CFR 812.2(c) from most of the 
73  IDE regulation.  
74   
75  As specified in 21 CFR 812.40, the sponsor is responsible for ensuring IRB review and 
76  approval of an investigation.8 Sponsor-investigators,9 who serve as both sponsors and 
77  investigators10 in an investigation, also assume the responsibility for ensuring IRB review 
78  and approval. Sponsors may fail to appropriately recognize and identify to their IRBs the 
79  investigational status of IVDs used in therapeutic product trials.  FDA is also concerned 
80  that sponsors and/or IRBs may not adequately assess and/or describe the risks associated 
81  with investigational IVDs. The following sections are intended to provide additional 
82  information to sponsors and IRBs to clarify issues relating to the investigational status of 
83  IVDs, risk assessment(s) that should be undertaken, and the requirements applicable to 
84  investigational IVDs in 21 CFR Parts 50, 56, and 812. 
III.  Policy11 
85 
A.  What is an Investigational IVD? 
86 
87  An investigational IVD is an IVD that is the object of an investigation (21 CFR 812.3(g)). 
88  An investigation is defined as a clinical investigation or research involving one or more 
89  subjects to determine the safety or effectiveness of a device (21 CFR 812.3(h)).12 When an  
90  investigational IVD is used to guide the therapeutic management of subjects in a therapeutic 
                                                 
6 See 21 CFR 809.3(a) for the complete definition of in vitro diagnostic product. 
7 See 21 CFR 812.3(g) for the complete definition of an investigational device and see 21 CFR 812.3(h) for the 
definition of investigation. 
8 Sponsor means a person who initiates, but who does not actually conduct, the investigation, that is, the 
investigational device is administered, dispensed, or used under the immediate direction of another individual. 
A person other than an individual that uses one or more of its own employees to conduct an investigation that it 
has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators (21 CFR 812.3(n)). 
9 Sponsor-investigator means an individual who both initiates and actually conducts, alone or with others, an 
investigation (i.e., an individual under whose immediate direction the investigational device is administered, 
dispensed, or used). The term does not include any person other than an individual. The obligations of a 
sponsor-investigator under 21 CFR Part 812 include those of an investigator and those of a sponsor (21 CFR 
812.3(o)). 
10 Investigator means an individual who actually conducts a clinical investigation, i.e., under whose immediate 
direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an 
investigation conducted by a team of individuals, is the responsible leader of that team (21 CFR 812.3(i)). 
11 This guidance is not intended to address investigations of combination products as defined in 21 CFR 3.2(e). 
12 For determining the applicability of the IDE regulation, the relevant definition of investigation is the one 
found in 21 CFR 812.3(h), not the one found in 21 CFR 56.102(c). 
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91  product trial, and trial results provide information on the safety and effectiveness of the  
92  investigational IVD in addition to the safety and effectiveness of the investigational 
93  therapeutic product, FDA believes that the trial falls within the definition in 21 CFR 
94  812.3(h). An investigational IVD used in a therapeutic product study might be, for example, 
95  a novel IVD, an IVD that is legally marketed13 in the U.S. for a different intended use14, or a 
96  legally marketed IVD that has been significantly modified with respect to its technological 
97  characteristics. It is important that sponsors and IRBs consider whether changes made to a 
98  legally marketed IVD, including changes to IVD labeling, result in it being investigational 
99  and, if so, subject to the IDE regulation. For example, changes to a cleared or approved IVD 
100  that would identify a new patient population, new specimen type, or both, would render the 
101  IVD investigational for the new intended use.  An illustration of this would be a test 
102  approved for measuring HER2 levels in breast cancer patients for the purposes of 
103  determining if the patient should receive treatment with trastuzumab would be considered 
104  investigational in a clinical trial when used for measuring HER2 levels in lung cancer 
105  patients for the purposes of determining if the patient should receive treatment with 
106  trastuzumab).15  Legally marketed IVDs that are used in therapeutic product trials in 
107  accordance with the intended use and indications for use for which they were cleared or 
108  approved (and that have not been modified) are not considered to be investigational, and 
109  hence are not subject to the IDE regulation. 
B.  IDE Regulation and Investigational IVD Risk in 
110 
Investigations 
111 
112  Investigational devices are subject to the IDE regulation. The regulatory requirements for 
113  an investigational IVD are determined by the risk posed to subjects by use of that IVD. 
114  The IDE regulation describes three categories of device studies: significant risk (SR) 
115  studies, non-significant risk (NSR) studies, and exempt studies. It is important for 
116  sponsors and IRBs to understand the differences between these categories and 
117  appropriately evaluate the risks associated with the use of investigational IVDs in 
118  therapeutic product trials. Each investigational IVD (including those that are legally 
119  marketed for a different intended use and those that are legally marketed but significantly 
120  modified) should be assessed to determine if it is SR, NSR, or exempt.   
121  The intended use of an investigational IVD in a therapeutic product trial, which is needed 
122  to determine if the IVD is SR, NSR, or exempt, depends upon how that IVD is 
123  incorporated in the clinical protocol, including how test results will drive treatment 
124  assignment or otherwise influence the clinical management of study subjects. When 
125  describing the intended use of an investigational IVD in a study risk determination Q-
126  submission (see section III.H for additional information on submitting a study risk 
                                                 
13 For purposes of this document, a legally marketed IVD is one that is approved, cleared, or Class I or Class II 
exempt. For purposes of this document, cleared or approved IVDs include those that were granted de novo 
classification. 
14 See Appendix for a description of intended use. 
15 Another example of an investigational use is modifying the use of the device such that quantitative results can 
be obtained rather than qualitative results, e.g., use in titration studies. 
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127  determination Q-submission utilizing the Q-Submission process) or an investigational 
128  plan contained in an IDE submission (21 CFR 812.25(a)), the types of information 
129  discussed in the Intended Use section of this guidances Appendix should be addressed.   
130  The following discussion of the nature of risks is specific to device studies under the IDE 
131  regulation and is not intended to inform FDAs risk evaluation in other contexts, 
132  including FDAs assessment of potential risk during FDAs classification of IVDs. 
133  Furthermore, the evaluation of risk, or the determination of exemption under the IDE 
134  regulation, for investigational IVDs in therapeutic product trials is independent of the 
135  determination of whether an IND is required for that same trial. For a general discussion 
136  of this topic, please refer to the guidance entitled "Significant Risk and Nonsignificant 
137  Risk Medical Device Studies" 
138  (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf).   
139   
140  1) Significant Risk (SR) Devices 
141  As defined in 21 CFR 812.3(m), a significant risk (SR) device means an investigational 
142  device that: 
143  (1) Is intended as an implant and presents a potential for serious risk to the health, 
144  safety, or welfare of a subject; 
145  (2) Is purported or represented to be for a use in supporting or sustaining human life 
146  and presents a potential for serious risk to the health, safety, or welfare of a subject; 
147  (3) Is for a use of substantial importance in diagnosing, curing, mitigating, or treating 
148  disease, or otherwise preventing impairment of human health and presents a potential 
149  for serious risk to the health, safety, or welfare of a subject; or 
150  (4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a 
151  subject. 
152  Sections 812.3(m)(3) and (4) are especially relevant to the use of investigational IVDs in 
153  therapeutic product trials as described in this guidance. Incorrect test results can present 
154  significant risk when they lead to misdiagnosis and/or mismanagement of subjects care. For 
155  example, if the treatment is a drug that has significant toxicity and efficacy is expected only 
156  in the marker-positive population, false positive test results may lead subjects without the 
157  marker to be treated with the drug, and therefore risk experiencing serious adverse events 
158  without any expectation of benefit. Note that under 21 CFR 812.3(m), the relevant 
159  consideration is whether there is a potential for serious risk, but not the likelihood for serious 
160  harm occurring. Invasive sampling16 (e.g., certain biopsies or sampling procedures) may also 
161  introduce significant risk, even if the selection of therapy is not guided by results from the 
162  investigational IVD. 
                                                 
16 See 21 CFR 812.2(c)(3)(ii); see also 21 CFR 812.3(k) for a definition of noninvasive. 
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163   
164  For a more detailed discussion on the subject of risk assessment, see section III.C in this 
165  guidance. 
166   
167  2) Non-Significant Risk (NSR) Devices 
168  FDA may consider certain non-exempt investigational IVDs in a therapeutic product trial to 
169  present risks that are not considered significant (21 CFR 812.3(m)). In such cases, the 
170  investigational IVD is considered to be non-significant risk (NSR). 
171   
172  If an investigational IVD in a therapeutic product trial is considered to be NSR, the trial is 
173  considered to have an approved IDE, i.e., the sponsor does not need to submit an IDE 
174  application and obtain FDA approval before starting the trial, if the sponsor complies with 
175  the abbreviated IDE requirements described in 21 CFR 812.2(b), including obtaining IRB 
176  approval of the trial and complying with the informed consent requirements under 21 CFR 
177  part 50.17     
178   
179  There is no requirement to inform the relevant FDA device review Center (whether the 
180  Center for Devices and Radiological Health (CDRH) or the Center for Biologics Evaluation 
181  and Research (CBER)) of NSR studies, even when the device is used in a therapeutic product 
182  study.18 When the sponsor determines that an investigational IVD used in a therapeutic 
183  product trial is NSR and submits the investigation to the IRB, the IRB provides initial 
184  review, approval if appropriate, and continuing review of the trial (see Section III.D of this 
185  guidance).  If information becomes available that the investigational IVD represents an 
186  unreasonable risk to the safety of the subjects (for example, the information indicates that 
187  significant harm has been incurred as a result of using an investigational IVD that was 
188  considered NSR in a therapeutic product trial, even if the IRB concurred with the sponsor 
189  that the device in question was NSR), FDA may place a clinical hold on the trial,19 and may 
190  require submission and approval of an IDE prior to continuation of the trial (21 CFR 
191  812.20(a)). 
192   
                                                 
17 However, if FDA notifies the sponsor that the investigational IVD is significant risk, the sponsor must submit 
an IDE application to FDA and obtain approval before starting the investigation (21 CFR 812.2(b) and 
812.20(a)).  
18 However, the sponsor must notify the applicable FDA device review Center (CDRH or CBER) of any 
unanticipated adverse device effect, withdrawal of IRB approval, device recall or disposition, failure to obtain 
informed consent, or when otherwise directed by the IRB or FDA (21 CFR 812.150).  All records associated 
with an NSR study are subject to inspection by FDA, particularly if the data collected in the investigation are 
used to support a subsequent U.S. device marketing application (21 CFR 812.145).  
19 The Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. No. 112-144, 126 Stat. 
1054), enacted in 2012, amended section 520(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) by 
adding a new paragraph (8) that gave FDA explicit authority to place a study on clinical hold when the device 
involved represents an unreasonable risk to the safety of the persons who are the subjects of the clinical 
investigation and for such other reasons as FDA may by regulation establish. 
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193  3) IDE Exempt Investigations 
194  Trials involving investigational IVDs are exempt from most requirements found under the 
195  IDE regulation if they meet the criteria outlined in 21 CFR 812.2(c).20 These trials are 
196  considered exempted investigations.  Most pertinent to this guidance, to be an exempted 
197  investigation under 21 CFR 812.2(c)(3), the investigational IVD used in the study must be 
198  labeled in accordance with 21 CFR 809.10(c) and the testing (i) must be noninvasive, (ii) 
199  must not require an invasive sampling procedure that presents significant risk, (iii) must not 
200  by design or intention introduce energy into a subject, and (iv) must not be used as a 
201  diagnostic procedure without confirmation of the diagnosis by another, medically established 
202  diagnostic product or procedure.21  Under 21 CFR 809.10(c)(2)(ii), for such a device, when 
203  being shipped or delivered for product testing prior to full commercial marketing, all labeling 
204  must bear the following statement, prominently placed: "For Investigational Use Only. The 
205  performance characteristics of this product have not been established." 
206   
207  Even if a device investigation is exempt under 21 CFR 812.2(c) from most requirements of 
208  the IDE regulation, such studies are subject to applicable requirements under 21 CFR 
209  812.119 (disqualification of a clinical investigator), 21 CFR Part 50 (informed consent) and 
210  21 CFR Part 56 (IRB).22,23 For more information on exempted investigational IVD 
211  investigations, see the guidance entitled In Vitro Diagnostic Device Studies  Frequently 
212  Asked Questions 
213  (https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidance
214  Documents/UCM071230.pdf). 
C.  Evaluating Whether an Investigational IVD Used in a 
215 
Clinical Investigation of a Therapeutic Product is 
216 
Significant Risk 
217 
218  Because the regulatory requirements for use of a non-exempt investigational IVD differ 
219  based on the risk of its use, sponsors should assess IVD risk during the planning phase of a 
220  clinical investigation. In large part, the risk will depend on the clinical consequences of 
221  erroneous or inaccurate results from the IVD (e.g., false positives or false negatives). Risk 
222  determinations should take into consideration factors that may be unique to each trial and the 
223  investigational therapeutic product and investigational IVD used.   
                                                 
20 Sponsors of investigational IVDs that are exempt under 21 CFR 812.2(c) must comply with applicable 
requirements under 21 CFR 809.10(c), 812.119, Part 50, and Part 56. 
21 We consider diagnosis here to mean diagnosis of a disease or other conditions, including a determination of 
the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae (21 CFR 809.3(a)). 
22 Sponsors and IRBs who have questions about these requirements may contact Elaine Katrivanos 
(Elaine.Katrivanos@fda.hhs.gov), Division of Program Operations and Management, Office of In Vitro 
Diagnostics and Radiological Health. 
23 For questions related to a CBER-regulated IVD, please contact the Regulatory Project Manager (RPM) in the 
CBER Office where your product will be reviewed. If you dont know or are unsure of whom to contact, please 
contact CBERs Office of Communication, Outreach and Development (OCOD) as listed on the title page of 
this guidance.   
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224   
225  The sections below present questions to help sponsors and IRBs evaluate critical factors 
226  when making risk determinations for investigational IVDs in therapeutic product trials and 
227  describe how clinical trial designs generally affect the risk of investigational IVD use. 
228   
229  1) Factors to Consider in Making a Risk Determination 
230  This section presents key questions that sponsors and IRBs should consider when assessing 
231  the risk of investigational IVD use in a therapeutic product study. These questions are 
232  focused on considerations regarding how results from the IVD will be used, the potential 
233  consequences of such use, and a number of other factors pertaining to the specific 
234  circumstances of the study. Answers to these questions will assist sponsors and IRBs in 
235  assessing whether the trial involves a significant risk device as defined in 21 CFR 812.3(m). 
236  a. Will use of the results from an investigational IVD lead to some 
237  study subjects foregoing or delaying a treatment that is known to 
238  be effective? 
239   
240  When the result from an investigational IVD directs subjects to an 
241  investigational therapeutic product, the availability of alternative therapies and 
242  the nature of those alternatives may influence the level of risk to the subject from 
243  an erroneous result. For example, in an investigation for a population that has no 
244  other treatment options, has exhausted all other treatment options, or for which 
245  standard of care provides only marginal benefit, the potential harm caused by an 
246  erroneous result from the investigational IVD use may be lower, because the 
247  investigational therapeutic product may not present greater risks than the 
248  alternatives available to the subject. Likewise, if treatment with the 
249  investigational therapeutic product will not interfere with the likely effectiveness 
250  of later treatment with a known effective therapy (i.e., a delay in receiving the 
251  known effective therapy will not irreversibly degrade the condition of the 
252  subject), the risk of an erroneous investigational IVD result may be lower. If, 
253  however, the standard of care or other alternatives are reasonably effective, or a 
254  delay in receiving known effective therapy would irreversibly degrade the 
255  condition of the subject, then the potential harm caused by an erroneous 
256  investigational IVD result may be greater. 
257   
258  b. Will use of the results from an investigational IVD expose study 
259  subjects to safety risks (e.g., adverse events from the 
260  investigational therapeutic product) that exceed the risks 
261  encountered with the control arm therapy or non-trial standard of 
262  care? 
263   
264  The risk(s) of the investigational therapeutic product should be considered in 
265  assessing the risk of investigational IVD use. When a drug has minimal side 
266  effects, for instance, the risk associated with use of the investigational IVD for 
267  enrollment or assignment to treatment arms will generally be lower because an 
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268  erroneous test result would not be expected to cause serious harm. However, in a 
269  study of an investigational therapeutic product with significant toxicity, the risk 
270  associated with investigational IVD use will generally be greater because an 
271  erroneous test result could unnecessarily expose a subject to the therapeutic 
272  products toxicity. 
273   
274  c. Is it likely, based on existing knowledge about the relationship 
275  between the biomarker and the investigational therapeutic 
276  product, that incorrect results from the investigational IVD would 
277  present a potential for serious risk to study subjects? 
278   
279  Existing knowledge about the relationship of the result obtained from the 
280  investigational IVD and the potential safety and efficacy of the investigational 
281  therapeutic product should be considered independently of the answers to 
282  questions posed in sections III.C.1.a and b.  For instance, if there is strong (e.g., 
283  clinical) evidence that an investigational therapeutic product with serious side 
284  effects may be effective only in a marker-positive population, then an 
285  investigational IVD used to identify marker-positive subjects is likely to be of 
286  higher risk, regardless of the relative safety and efficacy of the standard of care 
287  or alternative therapies. 
288   
289  A determination that the investigational therapeutic product should be restricted 
290  to a test-defined population may rely on preclinical studies.  However, evidence 
291  needed to define a biomarker-positive or negative population is oftentimes 
292  obtained during early clinical trials or in the course of an ongoing trial. For this 
293  reason, an investigational IVD that is initially NSR (e.g., used for stratification) 
294  could become SR in a later phase investigation of the same therapeutic product, 
295  or even in the middle of a particular trial.  Surveillance and changing risk is 
296  discussed in section III.C.3 below. 
297   
298  d. Does use of the investigational IVD require invasive sampling 
299  that is not part of standard of care? 
300   
301  If invasive sampling is used to collect samples for testing with the investigational 
302  IVD, and that sampling is not part of the standard of care (for example, if extra 
303  biopsies of a tumor or an additional surgical procedure to obtain a specimen for 
304  testing is required), then the IVD may be SR, regardless of the risks associated 
305  with erroneous results. 
306   
307  2) Investigational IVD Risk and the Design of Clinical 
308  Investigations for Therapeutic Products 
309  This section describes some intended uses for investigational IVDs in the context of some 
310  commonly used therapeutic product trial designs. To assess risk, it is important to understand 
311  how the intended use of the investigational IVD affects trial subjects medical treatment. 
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312   
313  Note that the risks associated with the trial designs and other uses described in the examples 
314  below are presented without reference to other information that may affect the overall risk 
315  from an erroneous result. As discussed in the previous section (section III.C.1), predicted 
316  side effects of the investigational therapeutic product and other factors should also be taken 
317  into account when making a final risk determination. 
318   
319    Study enrollment. Investigational IVDs can be used to identify subjects for enrollment 
320  eligibility. The goal is usually to identify for inclusion those subjects most likely to 
321  benefit from therapy (efficacy), or to identify for exclusion those subjects most likely to 
322  suffer toxicity without significant benefit. Misclassification of subjects due to erroneous 
323  investigational IVD results can lead to treatment that might unnecessarily expose them to 
324  toxicities or suboptimal treatment. 
325   
326    Predicting serious adverse reactions. An investigational IVD can be used to identify 
327  study subjects likely to be at increased risk for serious adverse reactions as a result of 
328  treatment with an investigational therapeutic product, and who, thus, should be subjected 
329  to additional or different monitoring or therapeutic procedures. Similarly, the 
330  investigational IVD may be used to identify subjects at decreased risk for adverse 
331  reactions, and thus results from that IVD may justify reduced monitoring. This use of the 
332  IVD, given its role in predicting risk for serious adverse reactions to the investigational 
333  therapeutic product, is potentially of higher risk due to the probable harm that may be 
334  incurred from acting on incorrect test results. The potential use of an investigational IVD 
335  to predict the risk of serious adverse reactions may be identified while the trial of an 
336  investigational therapeutic product is already underway. This may lead to a change in the 
337  use of the investigational IVD and its associated risk from lower risk at the start of the 
338  trial to higher risk during the course of the trial (see section III.C.3 below). 
339   
340    Dosing. Safety and efficacy of a therapeutic product is often closely related to the dose 
341  administered if that product has a narrow therapeutic window and/or has harmful effects 
342  outside of the efficacy window. When over- or under-dosing may pose serious risks and 
343  an investigational IVD is used to determine the dose a study subject should receive, that 
344  use is likely to be of higher risk. 
345    
346    Monitoring. An investigational IVD generally has higher risk when it is used to 
347  determine response to an investigational therapeutic product for the purpose of adjusting 
348  that treatment (e.g., schedule, dose, discontinuation) to maintain an appropriate 
349  therapeutic or safety margin.  
350   
351    Assigning subjects to study arms. An investigational IVD can be used to assign 
352  enrolled subjects to a particular study arm. The risks associated with assignment depend 
353  on the study design (some examples noted below). However, if a study design involves a 
354  combination of different trial designs, the investigational IVD will be of higher risk if its 
355  use is of high risk within any particular component of the trial. 
356   
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357  o  A stratification study design utilizes an investigational IVD result to classify 
358  subjects into test-positive or test-negative subgroups, followed by 
359  randomization to the investigational therapeutic product or control group within 
360  each of the subgroups. When each subject has an equal chance of being in the 
361  investigational therapeutic product or control group, the investigational IVD is 
362  generally of lower risk because its use does not determine treatment selection. 
363  In some cases, the result contributes to a probability of being assigned to a 
364  particular treatment, but is not the sole determinant. In such cases, the degree of 
365  risk related to investigational IVD use will depend on the degree to which the 
366  result contributes to that probability. 
367   
368  o  Adaptive study designs typically advance in stages, with inclusion/exclusion 
369  criteria or methodologies for assigning study subjects to treatment arms in later 
370  stages based on the outcome of earlier stages.24 In such trials, early use of the 
371  investigational IVD may be NSR; however, use of the IVD in subsequent 
372  phases may be different and may present additional risk. When investigational 
373  IVD use becomes SR in a later stage of an adaptive trial, FDA approval of an 
374  IDE application will be required for continued use of the investigational IVD in 
375  the trial (see section III.C.3 below). 
376   
377    Retrospective studies. Retrospective studies involve the analysis of specimens after 
378  subjects are enrolled in the trial or the trial is complete. In most cases, if the 
379  investigational IVD result does not influence treatment, that IVD would be considered 
380  lower risk and may be exempt from most IDE regulation requirements if the criteria in 21 
381  CFR 812.2(c)(3) are met (see section III.B.3 above). Prospective retrospective studies, 
382  where specimens are collected expressly for the purpose of retrospective analysis, would 
383  carry the risk associated with specimen collection occurring outside of standard patient 
384  care. 
385   
386  Note that certain trial features do not inherently influence an investigational IVD risk 
387  determination. Among these are the size and the phase of the trial, the line of therapy 
388  proposed for the investigational therapeutic product, and the potential access of patients to 
389  other trials. 
390   
                                                 
24 For more discussion of adaptive study designs, see the guidance entitled  
Adaptive Designs for Medical Device Clinical Studies 
(https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM44
6729.pdf) and the draft guidance entitled Adaptive Design Clinical Trials for Drugs and Biologics 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pd
f) (This draft guidance represents FDAs proposed approach on this topic. When final, this guidance will 
represent FDAs current thinking on this topic.).   
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391  3) How Investigational IVD Risk May Change During the Course 
392  of a Clinical Investigation 
393  When an investigational IVD is NSR at the beginning of a clinical investigation but becomes 
394  SR at a later stage, or when a SR investigational IVD is introduced into a clinical 
395  investigation, FDA approval of an IDE application, in accordance with 21 CFR 812.20(a)(2) 
396  and 21 CFR 812.30(a), is required prior to use of the SR investigational IVD in the clinical 
397  investigation. There are several ways in which an investigational IVD may be introduced into 
398  a clinical investigation or an investigational IVDs use may change during the course of a 
399  clinical trial. 
400   
401    Safety and outcomes data, and other information gathered during the trial may change 
402  the risk of the investigational IVD. For example, if results from early subjects in the 
403  trial indicate more severe side effects or less improvement in a biomarker-positive 
404  population than expected, the assessment of risk from use of an investigational IVD 
405  to detect that biomarker may change. 
406     
407    Adaptive clinical trial designs that incorporate pre-planned and conditional alterations 
408  in trial conduct may change the use of an investigational IVD as the trial progresses. 
409  Risk posed by altered use of the IVD should be considered. 
410   
411    A new or amended study protocol for an existing investigational new drug application 
412  (IND) may introduce or alter the risk of an investigational IVD. For instance, a Phase 
413  1 trial may not include an IVD or it may include an IDE exempt or a NSR IVD. 
414  However, a later Phase 2 trial conducted under the same IND may add a SR device or 
415  may change the  use of an investigational IVD in such a way as to make the IVD SR. 
416  In such a case, the sponsor would be required to submit an IDE application to FDA in 
417  accordance with 21 CFR 812.20; the investigational IVD could not be used in the 
418  Phase 2 trial until FDA approves the IDE application (21 CFR 812.20(a)(2) and 
419  812.30(a)). 
420   
421  Ongoing surveillance during a clinical investigation is recommended to monitor the risk  of 
422  the investigational IVD. For a SR investigation, the timing of an IDE application is at the 
423  sponsors discretion and should be planned to allow sufficient time for FDA review before 
424  the use of the SR investigational IVD in the clinical investigation. FDA recommends 
425  interacting with the applicable Center (CDRH or CBER) via the Q-Submission process (see 
426  section III.H) prior to initiating the first stage of the trial. This interaction may facilitate FDA 
427  review of a future IDE application if required and may provide the sponsor with greater 
428  predictability in regard to the IDE process. 
D.  Recommendations for IRBs and Sponsors in 
429 
Evaluating Investigational IVDs in the Context of Clinical 
430 
Investigations for Therapeutic Products 
431 
432   
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433  Each U.S. site that performs testing using the investigational IVD is considered a study site. 
434  Whether a trial involves only one site or many sites, it is the responsibility of the trial sponsor 
435  to ensure that IRB review and approval are obtained (21 CFR 812.40). 
436   
437  Each reviewing IRB must, as part of its review of the clinical investigation, consider the 
438  sponsors risk determination of the investigational IVD (21 CFR 56.108, 56.111, 
439  812.2(b)(1)(ii), 812.62, and 812.66). If a sponsor and its IRB cannot agree on the level of risk 
440  presented by the investigational IVD, the sponsor may request a study risk determination 
441  from FDA through the Q-Submission process (see section III.H).   
442  If the IRB concurs with a sponsors NSR determination and approves the investigation, and 
443  the sponsor complies with the abbreviated requirements in 21 CFR 812.2(b)(1), the sponsor 
444  is considered to have an approved IDE for use of the investigational  IVD in the therapeutic 
445  product trial, unless FDA has notified the sponsor under 21 CFR 812.20(a) that approval of 
446  an IDE application is required. Failure of a sponsor and an IRB to recognize or correctly 
447  assess the risks of use of an investigational IVD in a therapeutic product trial may deprive the 
448  study subjects of the additional protections associated with significant risk device 
449  investigations. In addition to other IDE requirements, a significant risk device study entails 
450  FDA evaluation of the investigational IVD to determine, among other things, whether the 
451  IVD has been adequately validated for its use in the study. For this reason, it is important for 
452  IRBs to be aware of how investigational IVDs are used and the risks associated with their use 
453  in the context of therapeutic product trials.  
454  The information described below is intended to provide assistance to sponsors and IRBs in 
455  understanding FDAs regulations, and to aid in the development of a risk assessment process 
456  for investigational IVDs intended for use in therapeutic product trials. 
457   
458  1) Information the Sponsor Should Include in Its Submission to 
459  the IRB 
460   
461  The sponsor should provide an assessment of whether or not any IVD being used in a study 
462  is an investigational IVD, along with supporting information. The sponsor should also 
463  provide its assessment of the investigational IVD as SR, NSR, or exempt from most 
464  requirements of the IDE regulation, and provide a rationale for the assessment.25  Note that 
465  this should be done even if the forms provided by the IRB to the sponsor do not specifically 
466  request such information. If the IRB determines that the investigational IVD is SR and 
467  notifies the sponsor of such determination, then the sponsor may either seek a study risk 
468  determination from FDA (if the sponsor disagrees with the IRBs determination) or submit 
469  an IDE application to FDA and comply with other applicable regulatory requirements in the 
470  IDE regulation.26 
                                                 
25 Under 21 CFR 812.2(b)(1)(ii), if the sponsor believes its investigational device is NSR, the sponsor must 
present the IRB with a brief explanation of why the device is NSR. 
26 Under 21 CFR 812.150(b)(9), if the IRB disagrees with an NSR determination by the sponsor and determines 
that the device poses a significant risk, the sponsor must report this finding to the FDA within five working 
days. 
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471   
472  In reviewing a clinical investigation, an IRB considers whether the criteria in 21 CFR 56.111 
473  are met, including that the risks to subjects are minimized and are reasonable in relation to 
474  the anticipated benefits, if any, to subjects, and the importance of the knowledge that may be 
475  expected to result. So that IRBs may make such a determination, in the submission of a 
476  therapeutic product trial to an IRB, a sponsor should identify each investigational IVD and its 
477  use in the trial.27 
478   
479  2) Recommendations for Review Questions for IRBs 
480  In order to carry out its obligations under 21 CFR Part 56, including that information given to 
481  subjects as part of informed consent is in accordance with 21 CFR 50.25 (as required by 21 
482  CFR 56.109(b)) and that a clinical investigation meets the criteria for approval in 21 CFR 
483  56.111, IRBs should assess the risks of use of proposed investigational IVDs in all 
484  therapeutic product trials. IRBs should request follow-up information if they believe that the 
485  sponsor did not identify or adequately describe the use of an investigational IVD and its 
486  associated risks in such trials. 
487   
488  To correctly identify whether an investigational IVD is used in a study, and to assess the 
489  risks of use of an investigational IVD in such study, FDA recommends that IRBs consider 
490  the following questions when reviewing applications for therapeutic product trials: 
491   
492  1)  Are one or more IVDs being used in this study? If so, the answers to the following 
493  questions should be assessed separately for each IVD. 
494  2)  Is the IVD investigational? 
495  a.       Is the IVD legally marketed (see footnote 13)? If not, its use in the clinical trial 
496  should be considered investigational.   
497  b.  If the IVD is legally marketed, does the use of the IVD in the therapeutic product 
498  study represent a new use (see section III.A.)?   A new use for a cleared or 
499  approved IVD will make that device investigational and subject to the IDE 
500  regulation. New uses may involve use of the IVD on patient populations for which 
501  it was not cleared or approved, or use in the same patient population but with a 
502  different specimen type or with a different therapeutic product than for which it 
503  was cleared or approved. Other modifications to a cleared or approved IVD, 
504  including changes to the instructions for use, may also render it investigational and 
505  subject to the IDE regulation. 
506  If the IVD is investigational: 
                                                 
27 Under 21 CFR 50.25(a), the informed consent form must include, among other things, a description of any 
experimental procedures and of any reasonably foreseeable risks or discomforts to the subject.  Therefore, the 
informed consent form must identify investigational IVD use and the risks associated with that use in the 
clinical investigation. Description and acceptance of investigational IVD risk does not constitute mitigation of 
that risk. 
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507  3)  Does it meet the exemption criteria under 21 CFR 812.2(c)?  For example, does it meet 
508  the criteria in 21 CFR 812.2(c)(3), which are specific to diagnostic devices?  Note that 
509  even if it is exempt under 21 CFR 812.2(c), sponsors must comply with applicable 
510  requirements under 21 CFR 809.10(c), 812.119, Part 50, and Part 56.. 
511  4)  If not exempt under 21 CFR 812.2(c), what are the risks of investigational IVD use in 
512  this investigation (see section III.C)? In particular: 
513  a.       Would inaccurate results from use of the investigational IVD present a potential 
514  for serious risk to the health, safety, or welfare of a subject? Consideration of the 
515  trials design (see section III.C.2 above) may help in addressing the key questions 
516  about significant risk that are set forth in section III.C.1. Examples of specific 
517  questions to consider are: 
518  1.  Does the investigational IVD determine whether a subject is enrolled in a 
519  study, or to which treatment arm within that study a subject will be assigned? If 
520  so, what are the consequences of an incorrect investigational IVD result?  
521  2.  Will the investigational IVD be used for subject monitoring or adjusting 
522  dosage?  Again, the risk associated with erroneous investigational IVD results 
523  should be considered. 
524  b.  Does specimen collection for use of the investigational IVD present a potential for 
525  serious risk to the health, safety, or welfare of a subject? If use of the 
526  investigational IVD involves invasive procedures for the subject that would not 
527  normally be performed as part of standard of care or patient management, then it 
528  may be considered SR. 
529  5)  Is an IDE application required for the investigation? It is important to understand that 
530  compliance with the IND regulation does not exempt the investigation from the IDE 
531  regulation (see sections III.E - III.G). 
532  6)  If an IDE application is required, what is the status of the IDE application? While an 
533  IRB is not involved in the review of an IDE application, the IRB may wish to be made 
534  aware of FDAs comments and decision on the IDE application. 
535  7)  Do informed consent documents clearly explain the investigational nature of the IVD 
536  and its risks (e.g., the risks of inaccurate test results)? In accordance with 21 CFR 
537  50.25(a)(1) and (2), informed consent documents must identify any procedures which 
538  are experimental and provide a description of any reasonably foreseeable risks or 
539  discomforts to the subjects. Thus, the informed consent documents for the types of 
540  investigations discussed in this guidance must describe any reasonably foreseeable risks 
541  or discomforts associated with the investigational therapeutic product and the fact that 
542  an investigational IVD would be used along with any reasonably foreseeable risks or 
543  discomforts associated with that use. For the investigational IVD, these risks include 
544  the risks associated with inaccurate results (in the context of IVD use in the study), and 
545  the risks associated with specimen collection and use as part of the study. 
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546  3) When Can a Sponsor Begin a Therapeutic Product Trial 
547  Involving Use of an Investigational IVD? 
548  In addition to IRB approval, it is important for sponsors to understand that even if a 
549  therapeutic product trial is permitted under the IND regulation, or is exempt from the 
550  requirements of the IND regulation under 21 CFR 312.2(b), the sponsor must still have an 
551  IDE that is approved or approved with conditions by the FDA if the trial includes a SR 
552  investigational IVD. 
553   
554  As explained in FDAs guidance entitled FDA Decisions for Investigational Device 
555  Exemption Clinical Investigations 
556  (www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/
557  ucm279107.pdf), approval with conditions for an IDE indicates that: (i) FDA believes the 
558  sponsor has provided sufficient data to support initiation of subject enrollment in a clinical 
559  investigation; (ii) there are no subject protection concerns that preclude initiation of subject 
560  enrollment; (iii) there are additional conditions that must be met to address certain 
561  outstanding issues; and (iv) the investigation may proceed, but the additional conditions are 
562  to be fulfilled within 45 days of the date of FDAs decision letter. FDA recommends that 
563  IRBs ensure that any investigation incorporating an SR investigational IVD has an FDA-
564  approved or conditionally approved IDE by obtaining a copy of FDAs IDE approval letter 
565  from the sponsor of the investigation. 
566   
567  Sponsors and IRBs should be aware of protocol amendments that may change subject 
568  monitoring as outlined in 21 CFR 312.30(b)(1)(iii).28 They should also be aware of other 
569  modifications to the protocol that alter the investigational IVD risk from NSR to SR, or that 
570  add the use of an SR investigational IVD to a therapeutic product trial which originally did 
571  not involve any investigational IVD, or involved the use of an investigational IVD that met 
572  the criteria for exemption under 21 CFR 812.2(c)(3), or involved the use of an NSR 
573  investigational device. Attention to such protocol amendments by IRBs is critical in 
574  protecting study subjects (see section III.C.3) Changes that introduce a SR investigational 
575  IVD to the trial will require FDA approval of a new IDE or approval of a supplement to an 
576  existing IDE independent of any amendments to an existing IND (21 CFR 812.20). 
E.  Common Questions about Investigational IVD Use in 
577 
Clinical Investigations of Therapeutic Products and 
578 
Compliance with the IDE Regulation 
579 
580  The IDE regulation applies to all clinical investigations of devices to determine safety and 
581  effectiveness (see section III.A) except as provided in 21 CFR 812.2(c) (21 CFR 812.2(a)). 
582  FDA has identified several situations in which sponsors and IRBs had questions as to 
583  whether an IDE was required. These include: 
                                                 
28 21 CFR 312.30(b)(1)(iii) requires the submission of a protocol amendment for [t]he addition of a new test or 
procedure that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the 
dropping of a test intended to monitor safety. 
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584    Use of an investigational IVD in a therapeutic product trial that was exempt from the 
585  IND regulation. Even if the therapeutic product(s) in the trial is/are exempt from the 
586  requirements of 21 CFR Part 312 under 21 CFR 312.2(b), the investigational IVD in 
587  the trial is subject to the IDE regulation (21 CFR Part 812). If the investigational IVD 
588  does not meet the exemption criteria under 21 CFR 812.2(c), then a risk assessment 
589  should be conducted to determine whether the IVD is NSR or SR. If the 
590  investigational IVD is SR, then in accordance with 21 CFR 812.42, a sponsor shall 
591  not begin an investigation or part of an investigation involving the IVD until FDA has 
592  approved an IDE application.   
593    Use of an investigational IVD without intent to commercialize. If the investigation 
594  uses an investigational IVD for directing the management of subjects but the IVD 
595  manufacturer does not intend to seek FDA clearance or approval for the commercial 
596  distribution of the IVD, the IDE regulation may still apply, as 21 CFR 812.2(a) states 
597  that Part 812 applies to all clinical investigations of devices to determine safety and 
598  effectiveness29 except as provided in 21 CFR 812.2(c), which addresses investigations 
599  exempted from most of the IDE regulation.    
F.  Inclusion of Investigational IVD Information in an 
600 
IND 
601 
602  Increasingly, the use of diagnostic tests for markers of interest in therapeutic treatment 
603  selection in protocols submitted to therapeutic product INDs has necessitated consultation 
604  between the device review Center (CDRH or CBER) and the therapeutic product review 
605  Center (CDER or CBER). Sponsors should be aware that all investigational IVDs used in 
606  therapeutic product trials are also subject to the IDE regulation (21 CFR Part 812), and may 
607  also require the submission of a separate IDE application if determined to be SR. A 
608  therapeutic product trial that also incorporates the use of an SR investigational IVD may not 
609  be initiated without an approved IDE application.30 Parts of the therapeutic product trial 
610  unrelated to the investigational IVD may still proceed, however, unless the trial is placed on 
611  clinical hold by the therapeutic product review Center. 
612   
613  Although studies with NSR investigational IVDs do not require the submission of an IDE, 
614  they must still comply with the abbreviated IDE requirements described in 21 CFR 812.2(b). 
                                                 
29 See section III.A for further discussion.    
30 When an approved IVD is used to guide the therapeutic management of subjects in a clinical trial of a new 
therapeutic product (e.g., a HER2 test that is approved for use with trastuzumab is used to guide the therapeutic 
management of subjects in a clinical trial of a new breast cancer drug), generally the use of the IVD would be 
considered investigational (see section III.A).  However, for such IVDs, FDA does not intend to examine 
whether they comply with the requirement for IDE approval under the FD&C Act and 21 CFR Part 812 when 
IRB approval is obtained and maintained for the investigation using such IVD, the investigation meets the 
abbreviated requirements under 21 CFR 812.2(b)(1)(i), (iii)-(vii), and assurance is provided to the IND that the 
IVD is used with the new therapeutic product in accordance with the instructions for use (IFU) that are provided 
in the devices approved labeling. Assurance of adherence to the IFU should minimally address the intent-to-
test criteria (e.g., disease type [such as lung cancer, colon cancer], specimen type [such as plasma, serum, 
tissue], and specimen adequacy), the test methodology, and the classification criteria (i.e., cutoff, if used). 
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615  In addition, under the IND regulation, clinical protocols for INDs must contain a description 
616  of laboratory tests used to monitor the effects of the drug in human subjects and to minimize 
617  risk (21 CFR 312.23(a)(6)(iii)(g)). Further, FDA may request that the sponsor submit in the 
618  IND other relevant information concerning the IVD(s) used in the trial as needed (21 CFR 
619  312.23(a)(10)(iv),(11)). For instance, the therapeutic product review Center (CDER or 
620  CBER) may request submission of IVD data, including performance data, to an IND should 
621  such information be needed to assess the clinical trial as a part of the IND review.   
G.  Managing IDEs and INDs for the Same Study 
622 
623  To simplify the application process, the IDE submission for a therapeutic product trial that is 
624  under an IND should cite the corresponding IND number. IDEs and INDs may also cross-
625  reference each other through a letter of authorization (LOA) or, in cases where either an IND 
626  or IDE is not required, information about the non-submitted investigational product may be 
627  provided through use of a master file.31 Master files allow one party to submit information 
628  for confidential review by FDA without granting access to other parties. For instance, if the 
629  manufacturer of the investigational IVD wishes to refer to confidential information about an 
630  investigational drug product to which it does not have access, the therapeutic product 
631  manufacturer can submit a master file containing that information and authorize the IVD 
632  manufacturer to reference it. FDA will then review the information in the master file as part 
633  of its review of the IDE for the investigational IVD. Similarly, an IVD manufacturer may 
634  submit a master file and authorize a therapeutic product manufacturer to reference that file, 
635  so that the confidential information about the investigational IVD can be included in FDAs 
636  review of the therapeutic product IND. In cases in which the relevant confidential 
637  information has been submitted in another regulatory submission, such as an IND or an IDE, 
638  the owner of the submission may simply provide the third party an LOA to reference specific 
639  sections of the regulatory submission. The LOA may grant the FDA either the right to 
640  reference or the right to reference and discuss the information in the regulatory submission 
641  with the third party.    
642   
643  An IND and IDE may be held by the same sponsor or each may be held by different sponsors 
644  representing different entities (e.g., a pharmaceutical company and an IVD company). The 
645  investigation conducted under the IND is subject to clinical hold under 21 CFR 312.42.32 For 
646  example, CDER may place an investigation on clinical hold under 21 CFR 312.42(b)(1)(i) or 
647  (b)(2)(i) if the agency determines that the investigation places subjects at an unreasonable 
648  and significant risk of illness or injury. For example, this determination could be made 
649  because an investigational IVD used to identify subjects for inclusion in the clinical trial of 
                                                 
31 For more information, see Introduction to Master Files for Devices (MAFs) 
(http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissio
ns/premarketapprovalpma/ucm142714.htm) and Guideline for Drug Master Files (DMF) 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesD
MFs/ucm073164.htm).  For information on master files relating to biologics license applications, contact the 
Center responsible for review of that biological product. 
32 This is in addition to the authority granted under FDASIA to place investigations subject to the IDE 
regulation on clinical hold. See footnote 19, above. 
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650  an investigational therapeutic product with significant toxicity was deficient and therefore 
651  might not reliably select subjects. Regardless of whether the IND and IDE are held by the 
652  same or different sponsors, sponsors should understand the regulatory requirements 
653  applicable to investigations involving both an investigational therapeutic product and an 
654  investigational IVD. 
655   
656  An approved IDE for an investigational IVD used in a therapeutic product trial may make it 
657  easier for sponsors to use that same investigational IVD for a separate therapeutic product 
658  trial, as only an approved supplement to the IDE (in addition to IRB approval) may be 
659  needed to commence the new trial if the IVD indication is the same or very similar (21 CFR 
660  812.35).33 
H.  Q-Submission Meetings 
661 
662  FDA recognizes that many factors must be considered in designing therapeutic product trials 
663  that involve the use of investigational IVDs for subject selection or other purposes. As the 
664  testing and therapeutic strategy is being developed, sponsors and sponsor-investigators are 
665  encouraged to meet with FDA in a Q-submission meeting prior to starting the trial to discuss 
666  questions about IVD risk, study design, and regulatory requirements. It is often helpful to 
667  have both the IVD and the therapeutic product sponsors at these Q-Submission meetings. In 
668  addition, a sponsor wishing to obtain a written study risk determination of the proposed study 
669  from FDA may submit a study risk determination Q-submission. For further information, see 
670  the guidance entitled Requests for Feedback on Medical Device Submissions: The Pre-
671  Submission Program and Meetings with Food and Drug Administration Staff 
672  (http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocu
673  ments/ucm311176.pdf).    
                                                 
33 Note that certain changes (e.g., a significant change to the design of the device or a change in its indication) 
may require approval of an IDE supplement.  See 21 CFR 812.35; see also guidance entitled Changes or 
Modifications During the Conduct of a Clinical Investigation 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0821
58.pdf). 
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APPENDIX. Important Considerations for Sponsors 
674 
675  This section describes important considerations for sponsors as they prepare an IDE 
676  application.34  When applicable, sponsors should also ensure that laboratories using the 
677  investigational IVD in the investigation are compliant with the Clinical Laboratory 
678  Improvement Amendments and related regulations (42 U.S.C. 263a; 42 CFR Part 493), and 
679  that the investigation is compliant with all applicable statutes, regulations, and conditions of 
680  IRB and/or FDA approval (21 CFR 812.30(b)(1)).  
A.  Contents of an IDE Application 
681 
682    The contents of an IDE application are detailed in 21 CFR 812.20, 812.25, and 
683  812.27. Broadly, these regulations address administrative requirements, description 
684  of the IVD, prior investigations with the IVD, and the proposed investigational plan. 
685    For investigational IVDs that will be part of a therapeutic product trial, sponsors 
686  should also address the following issues, if applicable, in IDE applications: 
687  o  Investigational IVD description. The investigational plan must include a 
688  description of the investigational device (21 CFR 812.25(d)).  The 
689  investigational IVD description should include test principles and technology, 
690  all equipment, reagents and supplies (including calibration or control 
691  materials), and procedures used to conduct the test, as well as a description of 
692  installation requirements and calibration parameters. All analytes detected by 
693  the investigational IVD should be described. As an example, for genetic tests, 
694  a list of all assayed mutations (e.g., SNPs or gene rearrangements) should be 
695  supplied, as well as PCR primers and probe design, if applicable. 
696   
697  As part of the investigational IVD description, all necessary instruments 
698  and/or software should be listed and described. Information pertaining to the 
699  level of software validation that has been performed for the investigational 
700  IVD will be critical in evaluating whether the investigational IVD is being 
701  used appropriately in the context of the study. For investigational IVDs with 
702  highly complex, multivariate algorithmic software, this may be the largest 
703  portion of data submitted to support the IDE.35 
                                                 
34 For general information on IDEs, see Guidance on IDE Policies and Procedures 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080202.htm). 
Additionally, sponsors may consider various resources for information on IVD validation, for example, 
Mansfield et al., Biomarkers for pharmacogenetic and pharmacogenomic studies: Locking down analytical 
performance, (2007a) Drug Discovery Today: Technologies 4:17, and Mansfield et al., Biomarkers for 
pharmacogenetic and pharmacogenomic studies: special issues in analytical performance, (2007b) Drug 
Discovery Today: Technologies 4:21. 
35 For information on the type of documentation FDA will expect for device software, please reference 
Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0895
93.pdf), issued May 11, 2005. 
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704   
705  o  Sample type, acquisition, and processing. Descriptions of the type of 
706  specimen(s) to be tested, specimen collection, processing, storage, sample 
707  identification, and acceptance/rejection criteria should be provided.  
708   
709  o  Intended use. The investigational plan must include the intended use of the 
710  investigational device (21 CFR 812.25(a)).  The intended use for the 
711  investigational IVD should encompass information on the analyte to be 
712  detected and how it relates to the investigational therapeutic product; whether 
713  the IVD produces a quantitative, semi-quantitative, or qualitative result; 
714  specimen type(s); conditions for use; the condition or disease to be screened, 
715  monitored, treated, or diagnosed; the intended use population (i.e., the 
716  population that will be tested using the investigational IVD); frequency of use; 
717  and physiological basis. The intended use population should be adequately 
718  described and justified. From the standpoint of the therapeutic product trial, 
719  testing with the investigational IVD should reflect the appropriate intent-to-
720  treat (or not-to-treat) population. 
721   
722  o  Description of investigational IVD cut-offs. Cut-off values (i.e., clinical 
723  decision points) that distinguish relevant trial populations should be 
724  established for the investigational IVD. The cut-off value should represent a 
725  point where the investigational IVDs analytical performance characteristics 
726  support reliable discrimination of the subject populations. If indeterminate (or 
727  gray) zone values will be produced, the sponsor should discuss how subjects 
728  with test values in the zone will be classified, and the use of indeterminate 
729  zone values in managing subjects in the therapeutic product trial.36 
730   
731  o  Test performance. The investigational IVD has demonstrated analytical 
732  validity, such that it is able to give accurate measurements from subject 
733  specimens. In the context of a therapeutic product trial, where results from the 
734  investigational IVD will be used to guide subject treatment, FDA is 
735  particularly concerned with analytical validity, including precision, 
736  reproducibility, analytic sensitivity, analytic specificity, and accuracy. 
737  Depending on the type of assay, matrix comparison, linearity, and interference 
738  may also be important. 
739   
                                                 
36 An example of use of a cutoff with a gray zone is the 2+ result of the immunohistochemistry HER2 tests. 
Reproducibility studies revealed that readers had a difficult time separating 2+ from 1+ and 3+ results. The 
clinical trial confirmed that fewer persons with 2+ results were having positive drug outcomes than persons with 
clear 3+ results, and, as a result, 2+ results were re-categorized as representing equivocal rather than positive 
results. To address uncertainty of values in this gray zone, clinical practice guidelines recommend retesting 2+ 
results with another type of test.  Wolff et al., Recommendations for Human Epidermal Growth Factor 
Receptor 2 Testing in Breast Cancer, (2014) Arch Pathol Lab Med 138:241. 
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740  Analytical performance around cut-off values is likely to have the largest 
741  impact on subject safety. Failure to select an appropriate cutoff, or failure of 
742  the investigational IVD to perform adequately around the cutoff, may result in 
743  the assignment of subjects to inappropriate treatments. 
744   
745  The amount of information on analytical performance of an investigational 
746  IVD will depend on the nature of the IVD and the therapeutic product trial in 
747  which it is used. For instance, while more limited information on analytical 
748  performance may be sufficient when a IVD is used in an early feasibility 
749  study,37 more comprehensive information on analytical performance will 
750  likely be needed for a registrational or pivotal trial.38 
751   
752  o  Preclinical and/or clinical information. The preclinical and/or clinical 
753  information provided should justify the subjects exposure to the 
754  investigational IVD. 
755   
756  o  Clinical study design. Questions or hypotheses should be clearly stated and 
757  should be addressed by a well-designed and sufficiently powered study. 
7 58 
759  o  Benefit/Risk assessment. The IDE submission must include a risk analysis 
760  that includes a justification for the investigation (21 CFR 812.25(c)).  Further, 
761  in reviewing an IDE application, FDA considers, among other things, whether 
762  the risks to the subjects are not outweighed by the anticipated benefits to the 
763  subjects and the importance of the knowledge to be gained (21 CFR 
764  812.30(b)(4)).  Therefore, the application should contain information on why 
765  the anticipated benefits to the study subjects (or why the importance of the 
766  knowledge to be gained from the trial) outweigh the risks of exposure to the 
767  investigational IVD. The type, magnitude, duration, and probability of the 
768  anticipated benefits should be weighed against the type, severity, duration, 
769  and probability of the risks associated with the use of invasive sampling 
770  techniques, as well as the potential harms that could result from an erroneous 
771  test result by the investigational IVD (such as a false positive or false 
772  negative). The risk of investigational IVD use in therapeutic product trials is 
773  closely related to that posed by the investigational therapeutic product, and 
774  therefore benefit/risk associated with the therapeutic product needs to be 
775  considered in this analysis.  
                                                 
37 For further information about early feasibility device clinical studies, see guidance entitled Investigational 
Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in 
Human (FIH) Studies 
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103.
pdf). 
38 Note that under 21 CFR 812.20(b)(2) and 812.27(a), the IDE application must include a complete and 
comprehensive report of prior investigations of the device (including clinical, animal, and lab testing). 
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B.  FDA Review of IDE Applications 
776 
777  Sponsors should submit their signed IDE application together with accompanying materials 
778  to CDRHs or CBERs Document Control Center (DCC) in accordance with the guidance 
779  entitled eCopy Program for Medical Device Submissions 
780  (http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocu
781  ments/ucm313794.pdf). Upon receipt of an IDE application, sponsors are notified in writing 
782  of the date that FDA received the original application and the IDE number assigned. The 30 
783  day review clock for the IDE application begins on the date stated in the acknowledgement 
784  letter to the sponsor. 
785  Each IDE application received in CDRHs DCC or CBERs DCC is routed to the appropriate 
786  Division, and assigned to a reviewer or review team. The IDE application is first screened for 
787  required content. If the IDE application contains adequate information for review, the review 
788  team then reviews the IDE application within 30 days of receipt. FDA will inform the 
789  sponsor of its decision, or notify the sponsor that the investigation may not begin, within 30 
790  days from the date of receipt of the IDE application.39  
791   
792  If an IDE application is approved or approved with conditions, the sponsor may begin subject 
793  enrollment, up to the number of subjects and investigational sites specified in FDAs decision 
794  letter, once allowed to proceed under IND, if applicable, and upon receipt of IRB approval, 
795  which may occur prior to FDA approval. If FDA does not have outstanding issues that the 
796  sponsor needs to address to support the study of the subject cohort under the proposed 
797  investigational plan, the IDE will be approved without conditions. Alternatively, if FDA has 
798  identified issues that need to be addressed in a timely manner but do not preclude initiation of 
799  subject enrollment in the clinical investigation, the IDE will be approved with conditions. In 
800  the case of approval with conditions, approval is granted and study enrollment may begin 
801  immediately on the condition that, within 45 days from the date of FDAs decision letter, the 
802  sponsor submits information addressing the issues identified in FDAs letter. 
803   
804  In certain instances, resolution of outstanding issues may be necessary before initiation of 
805  subject enrollment. In these instances, the IDE will be disapproved in accordance with 21 
806  CFR 812.30, meaning that the sponsor may not initiate subject enrollment in the 
807  investigation until the sponsor addresses the issues identified in FDAs letter and receives an 
808  approval or approval with conditions letter. In cases of disapproval of the IDE, a sponsor has 
809  the opportunity to respond to the deficiencies by submitting an amendment or, in accordance 
810  with 21 CFR 812.30(c)(1), to request a regulatory hearing under 21 CFR Part 16. 
811   
812  The guidance entitled "FDA Decisions for Investigational Device Exemption Clinical 
813  Investigations" 
814  (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceD
815  ocuments/UCM279107.pdf) provides additional information on this topic. 
                                                 
39 If FDA does not, within 30 days, notify the sponsor that the study may not begin, the IDE application will be 
deemed approved, unless the device is a banned device, in accordance with 21 CFR 812.30(a). 
23