Contains Nonbinding Recommendations 
Guidance on Informed Consent for In 
Vitro Diagnostic Device Studies Using 
Leftover Human Specimens that are 
Not Individually Identifiable
 
Guidance for Sponsors, Institutional 
Review Boards, and Food and Drug 
Administration Staff  
 
Document issued on April 25, 2006.  
An agency may not conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB control number. The 
OMB control number for this information collection is 0910-0582 (expires 08/31/2019). 
For questions about this document, contact the Office of In Vitro Diagnostics and Radiological 
Health, Division of Microbiology Devices, 301-796-5461, and Claudia Gaffey, 301-796-6196, 
Claudia.Gaffey@fda.hhs.gov.  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
Office of In Vitro Diagnostics and Radiological Health 
Division of Microbiology Devices 
 
Center for Biologic Evaluation and Research 
Office of Blood Research and Review  Contains Nonbinding Recommendations 
Preface 
Public Comment 
You may submit electronic comments and suggestions at any time for Agency consideration to 
http://www.regulations.gov. Submit written comments to the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 
20852. Identify all comments with the docket number FDA-2006-D-0150. Comments may not be 
acted upon by the Agency until the document is next revised or updated. 
Additional Copies 
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 1588 to identify the guidance you are requesting. 
ii  Contains Nonbinding Recommendations 
Table of Contents 
I.  Introduction.............................................................................................................................1
II.  Scope.......................................................................................................................................3
III.  Background.............................................................................................................................3
IV.  In what circumstances does FDA intend to exercise enforcement discretion as to the 
requirements for informed consent for use of specimens in FDAregulated IVD studies? .............4
V.  What type of records should be kept for these types of studies? ............................................6
VI.  Should sponsors consider anything else in deciding whether or not to conduct a study that 
may fall within the exercise of enforcement discretion contemplated by this guidance? ..............6
VII. What should IRBs do when reviewing the types of IVD studies that are the focus of this 
guidance? ........................................................................................................................................6
VIII. Paperwork Reduction Act of 1995 .........................................................................................7
iii  Contains Nonbinding Recommendations 
Guidance on Informed Consent for In 
Vitro Diagnostic Device Studies Using 
Leftover Human Specimens that are 
Not Individually Identifiable
 
Guidance for Sponsors, Institutional 
Review Boards, and Food and Drug 
Administration Staff 
This guidance represents the current thinking of the Food and Drug Administration (FDA 
or Agency) on this topic.  It does not establish any rights for any person and is not binding 
on FDA or the public.  You can use an alternative approach if it satisfies the requirements 
of the applicable statutes and regulations.  To discuss an alternative approach, contact the 
FDA staff or Office responsible for this guidance as listed on the title page.  
I.  Introduction 
FDA is issuing this guidance to inform sponsors, institutional review boards (IRBs), clinical 
investigators, and agency staff that the FDA intends to exercise enforcement discretion, under 
certain circumstances, with respect to its current regulations governing the requirement for 
informed consent when human specimens are used for FDA-regulated in vitro diagnostic (IVD)1 
device investigations. As described below, FDA does not intend to object to the use, without 
informed consent, of leftover human specimens -- remnants of specimens collected for routine 
clinical care or analysis that would otherwise have been discarded -- in investigations that meet 
the criteria for exemption from the Investigational Device Exemptions (IDE) regulation at 21 
CFR 812.2(c)(3), as long as subject privacy is protected by using only specimens that are not 
individually identifiable. FDA also intends to include in this policy specimens obtained from 
                                                 
1 In vitro diagnostic products are those reagents, instruments, and systems intended for use in the 
diagnosis of disease or other conditions, including a determination of the state of health, in order 
to cure, mitigate, treat, or prevent disease or its sequelae.  Such products are intended for use in 
the collection, preparation, and examination of specimens taken from the human body. 21 CFR 
809.3(a). 
  1  Contains Nonbinding Recommendations 
specimen repositories2 and specimens that are leftover from specimens previously collected for 
other unrelated research, as long as these specimens are not individually identifiable. 
Under FDAs current regulations governing the conduct of IVD device studies, the definition of 
human subject includes individuals on whose specimens an investigational device is used [see 21 
CFR 812.3(p)].  Because these regulations require informed consent for FDA-regulated human 
subject research, except in limited circumstances specified in the regulations,3 informed consent 
is required before specimens can be used in FDA-regulated research [see 21 CFR part 50]. 
This aspect of FDAs human subject protection regulations has created confusion and difficulty 
for persons developing IVDs. Many clinicians, research hospitals, and companies have viewed 
the requirement for informed consent for IVD studies using leftover specimens as unnecessary 
for the protection of human subjects and as overly burdensome and costly. 
FDAs recent Critical Path4 initiative has also focused the agencys concern on unnecessary 
obstacles to medical product development. The agency has received comments from trade 
associations and research institutions that identify the challenge of obtaining informed consent 
for the use of leftover specimens as an unnecessary obstacle and expense for investigational 
efforts.  When leftover specimens are available, it is often difficult, if not impossible, to locate 
the donor and obtain consent.  This difficulty may deter a manufacturers research efforts that 
would bring safe and effective IVDs to market more quickly.  At the same time, many 
researchers maintain that for this particular type of study, the human subject protection values 
that informed consent is intended to ensure either are not implicated, or can be adequately 
safeguarded through less burdensome measures. 
The confusion regarding the application of informed consent requirements to IVD studies and 
concerns about unnecessary obstacles to product development have prompted FDA to issue this 
guidance document.  The agency believes this guidance will facilitate product development in a 
manner consistent with the values of human subject protection. FDA intends that the exercise of 
enforcement discretion expressed in this guidance begin immediately.  In accordance with the 
agencys Good Guidance Practice regulations, 21 CFR 10.115, you may submit comments on 
this guidance at any time.  The agency will consider your comments and determine whether to 
revise the guidance at a later date. 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidance means that something is suggested or 
recommended, but not required. 
                                                 
2 A specimen repository is a common site for storage of collections of human biological 
specimens available for study. 
3 See 21 CFR 50.23(a) and 50.24. 
4"Innovation or Stagnation? -- Challenge and Opportunity on the Critical Path to New Medical 
Products" FDA Report issued on March 16, 2004. This document may be found at: 
http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
  2  Contains Nonbinding Recommendations 
  
II.  Scope 
This document applies only to IVD device investigations regulated by FDA in accordance with 
section 520(g) of Federal Food, Drug, and Cosmetic Act (the Act), 21 USC 360j(g), that are 
exempt from most requirements of the IDE regulation (21 CFR 812) under 21 CFR 812.2(c)(3), 
and that use leftover specimens that are not individually identifiable. A leftover specimen is the 
remnant of a human specimen collected for routine clinical care or analysis that would otherwise 
have been discarded.  A specimen is not individually identifiable when the identity of the subject 
is not known to or may not readily be ascertained by the investigator or any other individuals 
associated with the investigation, including the sponsor. (See Section 4, below.)  This guidance 
also applies to specimens that were previously collected for other unrelated research and that are 
not individually identifiable. 
This guidance will be implemented on the date it is issued. It applies to investigations using 
leftover specimens that are already existing on the date the guidance is issued and investigations 
using specimens that will be collected after the issuance of this guidance, so long as both the 
specimens and the investigations meet the circumstances outlined below (see section 4). 
III.  Background  
FDA's investigational device regulations are intended to encourage the development of new, 
useful devices in a manner that is consistent with public health and safety and with ethical 
standards. (See 21 U.S.C. 360j(g)). Investigators should have freedom to pursue the least 
burdensome means of accomplishing this goal.  However, to ensure that the balance is 
maintained between product development and the protection of public health and safety and 
ethical standards, FDA has established human subject protection regulations addressing 
requirements for informed consent and IRB review that apply to all FDA-regulated clinical 
investigations involving human subjects.  In particular, informed consent requirements further 
both safety and ethical considerations by allowing potential subjects to consider both the 
physical and privacy risks they face if they agree to participate in a trial. 
Under FDA regulations, clinical investigations using human specimens conducted in support of 
premarket submissions to FDA are considered human subject investigations [see 21 CFR 
812.3(p)].  Many IVD studies are exempt from most provisions of 21 CFR part 812, 
Investigational Device Exemptions, under 21 CFR 812.2(c)(3), but FDAs regulations for the 
protection of human subjects (21 CFR parts 50 and 56) apply to all clinical investigations that are 
regulated by FDA [see 21 CFR 50.1; 21 CFR 56.1; 21 U.S.C. 360j(g)(3)(A) & (D)]. 
FDA does have narrow exceptions from the general requirements of informed consent for certain 
emergency and military research,5 but FDA regulations do not contain exceptions from the 
requirements of informed consent on the grounds that the specimens are not identifiable and or 
that they are remnants of human specimens collected for routine clinical care or analysis that 
                                                 
5 21 CFR 50.23 and 50.24. 
  3  Contains Nonbinding Recommendations 
would otherwise have been discarded.  Nor do FDA regulations allow IRBs to decide whether or 
not to waive informed consent for research involving leftover or unidentifiable specimens. 
Leftover specimens are frequently used in feasibility studies and studies to characterize the 
performance of new in vitro diagnostic devices for several reasons. The evaluation of new 
devices often requires the use of specimens with specific laboratory characteristics, e.g., positive 
or negative for a particular disease marker, in order to meet the study inclusion criteria. Routine 
clinical care testing can provide information about the laboratory characteristics of the specimen 
that permit investigators to quickly ascertain whether the specimen will meet the study inclusion 
criteria. The remnants of these specimens thus become valuable to research at a point when they 
are of no value to the patient and are ready to be discarded.  The lower cost of these specimens, 
compared to the cost of specimens collected prospectively for research, makes studies using 
leftover specimens more affordable, permitting manufacturers to conduct studies that otherwise 
may not be done. In addition, banked leftover specimens are a source for unique and possibly 
rare specimens in sufficient quantity to permit the rapid completion of investigations that would 
be difficult if not impossible to conduct in a reasonable timeframe without these specimens. 
FDA believes that it is possible in certain circumstances for IVD device investigations to be 
conducted using leftover specimens obtained without informed consent while protecting the 
human subjects who are the source of such specimens.  When IVD study sponsors use leftover 
specimens for which the subject cannot be identified and where results of the investigational test 
are not communicated to or otherwise associated with the identified subject, concerns associated 
with privacy are minimized.  In addition, these studies do not pose new medical risks to subjects 
from whom the specimens were originally collected: Any risks from specimen collection were 
incurred prior to the involvement of the patient as a subject in an investigation, when the 
specimen was obtained for the patient's own clinical needs, and no risks from erroneous test 
results are presented because the results of the testing are not used for clinical management of the 
subject.  Like leftover specimens that have been collected for routine clinical care, the 
investigational use of leftover specimens previously collected for other research purposes 
involves no additional medical risk, and privacy risks are mitigated by limiting the applicability 
of this guidance to specimens that are not identifiable. 
IV.  In what circumstances does FDA intend to exercise 
enforcement discretion as to the requirements for informed 
consent for use of specimens in FDAregulated IVD studies? 
FDA intends to exercise enforcement discretion as to the informed consent requirements for 
clinical investigators, sponsors, and IRBs if an in vitro diagnostic device investigation is 
performed and all of the following are true: 
a)  The investigation meets the IDE exemption criteria at 21 CFR 812.2(c) (3). 
b)  The study uses leftover specimens, that is, remnants of specimens collected for routine 
clinical care or analysis that would have been discarded. The study may also use 
specimens obtained from specimen repositories or leftover specimens that were 
previously collected for other research purposes. 
  4  Contains Nonbinding Recommendations 
c)  The specimens are not individually identifiable, i.e., the identity of the subject is not 
known to and may not readily be ascertained by the investigator or any other individuals 
associated with the investigation, including the sponsor.  If the specimen is coded,66 it 
will be considered to be not individually identifiable if neither the investigator(s) nor any 
other individuals associated with the investigation or the sponsor can link the specimen to 
the subject from whom the specimen was collected, either directly or indirectly through 
coding systems. 
d)  The specimens may be accompanied by clinical information as long as this information 
does not make the specimen source identifiable to the investigator or any other individual 
associated with the investigation, including the sponsor. 
e)  The individuals caring for the patients are different from and do not share information 
about the patient with those conducting the investigation. 
f)  The specimens are provided to the investigator(s) without identifiers and the supplier of 
the specimens has established policies and procedures to prevent the release of personal 
information. 
g)  The study has been reviewed by an IRB in accordance with 21 CFR Part 56, except as 
described in section 7 of this guidance document. 
Studies that do not fall within the intended enforcement discretion expressed in this 
guidance include (but are not limited to) studies where any of the following is true: 
  The study does not meet the IDE exemption criteria at 21 CFR 812.2(c)(3); 
  the specimens are individually identifiable, i.e., the identity of the subject is known to or 
may be readily ascertained by the investigator or any other individuals associated with 
the investigation, including the sponsor. 
  the specimens were collected specifically for the proposed investigation.  That is, the 
specimens are not leftover from routine clinical care or analysis or leftover from other 
research. 
  the amount of specimen needed for the study is more than would be leftover from what is 
usually collected for routine clinical analysis 
or, 
  the test results will be reported to the subjects health care provider.  For example, in the 
course of comparative studies involving B. anthracis detection devices, it would be 
inappropriate not to report positive results if they occur in the course of an investigation. 
                                                 
6 For the purposes of this document, coded means that: 1) a number, letter, symbol, or 
combination thereof (i.e., the code) has replaced identifying information (such as name or social 
security number) that would enable the investigator or any other individuals associated with the 
investigation, including the sponsor to readily ascertain the identity of the individual to whom 
the specimen pertains; and 2) a key to decipher the code exists, enabling linkage of the 
identifying information to the specimen. 
  5  Contains Nonbinding Recommendations 
V.  What type of records should be kept for these types of 
studies? 
We recommend that sponsors maintain written documentation regarding the factors described in 
section 4 (a)-(g) of this guidance, including the policies and procedures followed by the 
specimen provider to ensure that the subject cannot be identified. FDA may request to inspect 
this documentation.  FDA recommends that IRBs review this documentation before approving an 
investigation paying particular attention to privacy and confidentiality, and the potential for use 
of information from the investigation for clinical patient management. 
VI.  Should sponsors consider anything else in deciding 
whether or not to conduct a study that may fall within the 
exercise of enforcement discretion contemplated by this 
guidance? 
Sponsors should consider whether a study exhibiting the factors relevant to the exercise of 
enforcement discretion described in section 4 will generate sufficient data to support the product 
application they are considering. Although FDA does not intend to reject data from a study 
exhibiting the factors described in section 4 solely because it was conducted without complying 
with the informed consent requirements found in 21 CFR part 50, FDA also does not guarantee 
that the data generated from a study with those characteristics will be sufficient to support a 
premarket clearance or approval.  FDA may determine that additional clinical information is 
important in order to evaluate test results. For some studies, masking of clinical information may 
be problematic and may bias data collection. Sponsors should understand that by choosing to 
conduct an investigation without informed consent, even in a manner consistent with this 
guidance, they accept the risk that they may not be able to provide sufficient information to 
satisfy FDA's premarket review needs. 
VII. What should IRBs do when reviewing the types of IVD 
studies that are the focus of this guidance? 
To facilitate IVD device development, FDA intends to exercise enforcement discretion toward 
IRBs who approve IVD investigations that are consistent with the factors in section 4 of this 
guidance, with respect to the IRB's duties under 21 CFR part 56 regarding informed consent for 
those studies. (Noncompliance with requirements of 21 CFR part 56 not related to informed 
consent is not subject to enforcement discretion under this guidance.) We recommend that the 
IRB review the sponsor's documentation regarding the factors described in Section 4, (a) through 
(f), including the policies and procedures followed by the specimen provider to ensure that the 
subject cannot be identified. IRBs should apply existing FDA regulations, including all informed 
consent requirements, to any other investigational IVD study. We encourage IRBs to contact 
FDA if they have questions about the guidance or a specific study under review (see FDA 
contact information on the title page of this guidance.) 
  6  Contains Nonbinding Recommendations 
VIII.  Paperwork Reduction Act of 1995 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520). 
The time required to complete this information collection is estimated to average 4 hours per 
response, including the time to review instructions, search existing data sources, gather the data 
needed, and complete and review the information collection.  Send comments regarding this 
burden estimate or suggestions for reducing this burden to: 
FDA PRA Staff,  
Office of Operations,  
Food and Drug Administration, 
PRAStaff@fda.hhs.gov 
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number. The OMB control number 
for this information collection is 0910-0582 (expires 08/31/2019). 
  7