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,
Clinical Investigators
and FDA Staff
Guidance on Informed Consent
for In Vitro Diagnostic Device
Studies Using Leftover Human
Specimens that are Not
Individually Identifiable
Document issued on April 25, 2006

For questions regarding this document contact Sally Hojvat, Ph.D., at 240-276-0496 or by
email at sally.hojvat@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 Diagnostic Device Evaluation and Safety
Center for Biologic Evaluation and Research
Office of Blood Research and Review

OMB Control No. 0910-0582
Expiration Date: 04/30/2016
See additional PRA statement in Section 8 of this guidance

Contains Nonbinding Recommendations

Preface
Public Comment
Written comments and suggestions may be submitted at any time for Agency
consideration to Division of Dockets Management, Food and Drug Administration, 5630
Fishers Lane, Room 1061, (HFA-305), Rockville, MD, 20852. Alternatively, electronic
comments may be submitted to http://www.fda.gov/dockets/ecomments. Please identify
your comments with the docket number 2006D-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 at:
http://www.fda.gov/cdrh/oivd/guidance/1588.pdf, or to receive this document by your fax
machine, call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111
from a touch-tone telephone. Press 1 to enter the system. At the second voice prompt,
press 1 to order a document. Enter the document number (1588) followed by the pound
sign (#). Follow the remaining voice prompts to complete your request.
For questions regarding the use or interpretation of this guidance contact: Sally Hojvat,
PhD at 240-276-0496, or by email at sally.hojvat@fda.hhs.gov.

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Contains Nonbinding Recommendations

Table of Contents
1.

INTRODUCTION............................................................................................................. 4

2.

SCOPE ............................................................................................................................... 5

3.

BACKGROUND ............................................................................................................... 6

4.

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?....................................................................................... 7

5.

WHAT TYPE OF RECORDS SHOULD BE KEPT FOR THESE TYPES OF
STUDIES? ......................................................................................................................... 9

6.

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? ................................................................ 9

7.

WHAT SHOULD IRBS DO WHEN REVIEWING THE TYPES OF IVD
STUDIES THAT ARE THE FOCUS OF THIS GUIDANCE?.................................... 9

8.

PAPERWORK REDUCTION ACT OF 1995.............................................................. 10

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Contains Nonbinding Recommendations

Guidance for Sponsors, Institutional Review
Boards, Clinical Investigators and FDA Staff
Guidance on Informed Consent for In
Vitro Diagnostic Device Studies Using
Leftover Human Specimens that are Not
Individually Identifiable
This guidance represents the Food and Drug Administration's (FDA's) current
thinking on this topic. It does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and regulations. If you
want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.

1.

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 FDAregulated 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 specimen repositories2 and specimens that are leftover from specimens previously
collected for other unrelated research, as long as these specimens are not individually
identifiable.
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).
2
A specimen repository is a common site for storage of collections of human biological specimens
available for study.

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Under FDA’s 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 FDA’s 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.
FDA’s recent “Critical Path4” initiative has also focused the agency’s 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 manufacturer’s 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 agency’s 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.

2.

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
3

See 21 CFR 50.23(a) and 50.24.
"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

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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).

3.

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 FDA’s
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 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.

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21 CFR 50.23 and 50.24.

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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.

4.

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).

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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.
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,6 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:
•
•
•
•
or,

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

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.

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•

5.

the test results will be reported to the subject’s 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.

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.

6.

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.

7.

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

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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.)

8.

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:
Department of Health and Human Services
Food and Drug Administration
Office of Chief Information Officer
Paperwork Reduction Act (PRA) Staff
1350 Piccard Drive, Room 400
Rockville, MD 20850

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 04/30/2016.

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