[Federal Register Volume 76, Number 122 (Friday, June 24, 2011)]
[Rules and Regulations]
[Pages 36989-36993]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-15816]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 50

[Docket No. FDA-2003-N-0212; (formerly Docket No. 2003N-0355)]


Medical Devices; Exception From General Requirements for Informed 
Consent

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final 
regulation to confirm, with one change, the interim final rule (IFR) 
entitled ``Medical Devices; Exception From General Requirements for 
Informed Consent.'' This final rule confirms the IFR's establishment of 
a new exception from the general requirements for informed consent to 
permit the use of investigational in vitro diagnostic devices to 
identify chemical, biological, radiological, or nuclear agents without 
informed consent in certain circumstances. FDA has created this 
exception to help ensure that individuals who may have been exposed to 
a chemical, biological, radiological, or nuclear agent are able to 
benefit from the timely use of the most appropriate diagnostic devices, 
including those that are investigational. This final rule adds a 
requirement that the investigator submit the required documentation to 
FDA, in addition to submitting it to the reviewing Institutional Review 
Board (IRB).

DATES: The rule is effective June 24, 2011.

FOR FURTHER INFORMATION CONTACT: Claudia M. Gaffey, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, rm. 5516, Silver Spring, MD 20993-0002, 301-
796-6196.

SUPPLEMENTARY INFORMATION:

I. Background

A. Overview of Final Rule

    In the Federal Register of June 7, 2006 (71 FR 32827), FDA 
published an Interim Final Rule that established an exception from the 
general requirements for informed consent to permit the use of 
investigational in vitro diagnostic devices to identify chemical, 
biological, radiological, or nuclear agents without informed consent in 
specified circumstances. The IFR amended 21 CFR 50.23, to add paragraph 
(e). The rule was issued under the authority set forth in section 
520(g)(3)(D) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) 
(21 U.S.C. 360j(g)(3)(D)). FDA gave interested parties 60 days to 
comment on the IFR. FDA is publishing this final rule that incorporates 
one change in response to comments that the rule did not protect 
against misuse of the exception. This change is described in section II 
of this document.

B. Legal Authority

    This regulation is being issued under the statutory authority 
provided in section 520(g)(3)(D) of the FD&C Act, which outlines the 
criteria under which an exemption from informed consent may be 
permissible. Under section 520(g)(3)(D) of the FD&C Act, informed 
consent is required unless the investigator determines the following in 
writing: (1) There exists a life threatening situation involving the 
human subject of such testing which necessitates the use of such 
device; (2) it is not feasible to obtain informed consent from the 
subject; and (3) there is not sufficient time to obtain such consent 
from the subject's legally authorized representative. Further, a 
licensed physician uninvolved in the testing must agree with this 
three-part determination in advance of using the device unless use of 
the device is required to save the life of the human subject of such 
testing and there is not sufficient time to obtain such concurrence.

II. Highlights of Final Rule

    The preamble to the IFR described the provisions of this rule in 
detail (71 FR 32827). In issuing this final rule, FDA is making one 
change to the IFR, in response to comments that the rule did not 
protect against misuse of this limited exception from informed consent 
requirements. In response to those concerns, FDA is adding a 
requirement that investigators also send the required documentation to 
FDA, not just to the reviewing IRB. This new requirement provides an 
additional level of oversight to help ensure that the limited exception 
criteria are met.

III. Comments on the IFR

    The Agency received comments on the IFR from nine different 
entities. Comments were received from four individual consumers, two 
from consumer groups, and one each from a health professional, a health 
professional group, and a local government. A summary of the comments 
received, grouped by subject matter follows.

A. General Comments

    (Comment 1) Three comments expressed support for the IFR, noting 
that the rule is needed and greatly improves the ability of public 
health laboratories to respond to a public health emergency. In 
contrast, six comments expressed general concern that the rule presents 
too much risk to the consumer. Some comments raised issues that are 
beyond the scope of this rulemaking. For example, one of these comments 
suggested that informed consent documents have a line addressing in 
vitro diagnostic testing; another encouraged the production of 
templates to easily provide the detailed information required to be 
included in the reports.
    (Response) FDA agrees with the comments recognizing that the rule 
will enable better response in public health emergencies. FDA also 
shares the

[[Page 36990]]

general concerns related to ensuring human subject protections. To that 
end, the Agency has ensured that the rule confers several layers of 
human subject protection, including IRB review, review and evaluation 
of the determinations made by the investigator by an independent 
physician, and disclosure of the investigational status of device to 
the subject's health care provider. FDA believes the rule balances the 
need to ensure human subjects are protected with the need to act 
quickly during a public health emergency and avoid potentially 
dangerous delays in using investigational devices to identify chemical, 
biological, radiological, or nuclear agents in human specimens.
    (Comment 2) Two comments noted that the IFR has no provisions to 
prevent abuse.
    (Response) FDA disagrees that the rule has no provisions to prevent 
abuse. The rule requires that the investigator and an independent 
physician each make specific determinations and that an IRB review 
these determinations. The determinations that the investigator and 
independent physician must make require careful consideration related 
to the use of the device and are intended to prevent abuse. However, 
FDA does agree that the IFR could have included an additional measure 
to prevent abuse of the exception; specifically, the IFR could have 
required that an investigator's documentation be submitted to the 
Agency, not just to the reviewing IRB. Although FDA relies on IRBs to 
adequately monitor the procedures set forth by the rule, the Agency 
recognizes that the IFR did not provide a mechanism for FDA to track 
the use of this exception from the general requirements for informed 
consent. Therefore, FDA is adding a requirement that the investigator 
submit to FDA the documentation required in 21 CFR 50.23(e)(1) or 
(e)(2) within 5 working days after the use of the device, in addition 
to submitting this information to the IRB within the same timeframe.
    (Comment 3) One comment expressed concern that the only oversight 
over the determinations made by the investigator and the independent 
physician on behalf of the subject is that of the IRB and it will take 
5 days. The comment claimed that consumers do not have confidence in 
IRB oversight and recommended the development of an open and clear 
process for choosing qualified individuals to be granted the 
extraordinary emergency power to waive informed consent, with 
opportunity for public comment.
    (Response) The Agency agrees that the decision to enter subjects in 
clinical trials without informed consent is not a trivial matter and 
should be made by qualified individuals. The FD&C Act allows for 
carefully considered exceptions to the general requirements for 
informed consent in emergency circumstances. The requirements described 
in this rule follow section 520(g)(3)(D) of the FD&C Act. This rule is 
to be used during emergencies and, among other requirements, only when 
there are no cleared or approved available alternative methods of 
diagnosis to identify the chemical, biological, radiological, or 
nuclear agent that provides an equal or greater likelihood of saving 
the life of the subject.
    In general, the rule assures that the determinations designed to 
safeguard the subject are made by two different and independent 
persons, i.e., the investigator and the independent physician, and that 
the use is then reviewed by the IRB. In the final rule, FDA is adding 
another level of oversight by requiring that investigators submit to 
FDA the same documentation they are required to submit to the IRB. FDA 
notes that this rule is intended for use in situations where public 
health laboratories must employ investigational in vitro diagnostic 
devices to diagnose patients when there are no approved or cleared 
diagnostic devices available that provide an equal or greater 
likelihood of saving patients' lives.
    (Comment 4) Some comments contended that the rule will allow the 
use of experimental tests, which have an unknown rate of inaccurate 
test results.
    (Response) FDA agrees that investigational in vitro diagnostic 
devices do not yet have established performance characteristics and, 
therefore, their accuracy is unknown until data collected during the 
investigation demonstrates the device's performance. FDA believes that 
when an investigational in vitro diagnostic device is needed to 
identify a chemical, biological, radiological, or nuclear agent and no 
cleared or approved alternative method of diagnosis is available that 
provides an equal or greater likelihood of saving the life of the 
subject, the benefits of the investigational in vitro diagnostic device 
outweigh the risks. The rule creates an exception to the general 
requirement for informed consent under these circumstances.
    (Comment 5) One comment stated that if the patient is awake there 
is no justification for not obtaining informed consent.
    (Response) The rule contemplates the scenario when the person 
directing the specimen collection does not know, at the time the 
specimen is collected, that an investigational device may need to be 
used in the future, usually by reference laboratories far from where 
the specimen was collected. Because of the geographic and temporal 
separation between specimen collection and testing for a life-
threatening agent, to obtain informed consent would require a number of 
steps and introduce unacceptable delays, independent of whether the 
patient is physically able to provide informed consent.

B. Notification Obligations

    (Comment 6) One comment stated that the notification obligations of 
the investigator described in the IFR are too complex, stating it 
should be sufficient to have a certification by the laboratory director 
declaring that the investigational test was performed in accordance 
with the rule and to send to the subject a copy of the notice sent to 
the IRB. The comment also noted that the concurrence of an independent 
physician adds no value.
    (Response) The Agency believes that the notification obligations of 
the investigator described in this rule, which are similar to the 
obligations described in other exceptions from the general requirements 
of informed consent under 21 CFR 50.23, are needed because they are 
intended to provide added human subject protections and to prevent 
abuses. Moreover, concurrence of an independent physician is mandated 
by section 520(g)(3)(D) of the FD&C Act.

C. Notification of Public Health Authorities

    (Comment 7) One comment requested the inclusion of explicit 
language in the rule directing the investigator to notify or report 
positive results to public health authorities when appropriate or 
required by State or Federal law.
    (Response) FDA agrees that it is important to report the detection 
of biologic, chemical, nuclear, or radiological agents to public health 
authorities and encourages this practice. FDA expects this reporting to 
occur when appropriate or when required under Federal or State law.

D. Interpretation of the Term ``Investigator''

    (Comment 8) One comment asked whether the term ``investigator'' can 
be interpreted to mean the single entity that deploys the 
investigational device, in which case it would be possible to use a 
centralized IRB and have the deploying entity be responsible for the 
reporting requirements.

[[Page 36991]]

    (Response) For purposes of this regulation, the Agency interprets 
the term ``investigator'' to mean the individual who actually conducts 
a clinical investigation, i.e., under whose immediate direction the 
test article is administered or dispensed or used in the diagnosis or 
treatment of a subject. In the event of an investigation conducted by a 
team of individuals, we use the term ``investigator'' to mean the 
responsible leader of that team. (See 21 CFR 50.3(d)). For purposes of 
this rule, we anticipate that the investigator will generally be the 
director of the clinical laboratory using the investigational device. 
This interpretation does not preclude local IRBs from deferring their 
review to a centralized IRB, provided that the IRB meets the 
requirements of 21 CFR part 56.

E. Written Certification Timing

    (Comment 9) One comment requested that FDA consider extending the 
number of days allowed for submitting the written certification for the 
exception. (Under the rule the investigator has 5 working days after 
the use of the investigational device to submit the investigator's 
determinations and those of the independent physician to the IRB.)
    (Response) FDA disagrees with this comment. The requirement that 
the investigator's determinations and those of the independent 
physician be submitted to the IRB within 5 working days, which is 
similar to the obligations described in other exceptions from the 
general requirements of informed consent under 21 CFR 50.23, are 
intended to assure prompt action by the IRB, as needed.

F. Other Public Health Emergency

    (Comment 10) Two comments contended that the term ``other public 
health emergency'' is vague and should be removed or should be revised 
to specify in exact terms what constitutes a public health emergency 
worthy of this extraordinary exception from informed consent.
    (Response) For purposes of this rule, the term ``other public 
health emergency'' means serious domestic emergencies that have the 
potential to significantly impact public health such as those caused by 
deadly weather disasters or by widespread infectious disease such as 
pandemic influenza.

G. Withdrawal of Previously Collected Data

    (Comment 11) One comment requested that the following preamble 
statement, ``subjects or their legally authorized representatives will 
not be entitled to withdraw previously collected data from the research 
database * * *'' (71 FR 32827 at 32830), be eliminated because it sets 
a dangerous precedent by allowing government research to take priority 
over personal privacy.
    (Response) FDA does not agree to eliminate the referenced 
statement. While a subject may withdraw from a study, FDA reiterates 
that the withdrawal does not extend to the data already obtained during 
the time the subject was enrolled. FDA's longstanding position has been 
that all data collected up to the point of withdrawal is to be 
maintained in the database and included in subsequent analyses, as 
appropriate, in order for the study to be scientifically valid.\1\ If a 
subject withdraws from a study, removal of already collected data would 
undermine the scientific, and therefore the ethical, integrity of the 
research.
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    \1\ See ``Guidance for Sponsors, Clinical Investigators, and 
IRBs--Data Retention When Subjects Withdraw from FDA-Regulated 
Clinical Trials,'' found at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126489.pdf.
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IV. Applicability of 45 CFR Part 46 and Other Legal Requirements

    As described in the IFR, some of the activities described in this 
rule may also constitute non-exempt human subjects research within the 
meaning of 45 CFR part 46, according to the Office for Human Research 
Protection (OHRP) in the Department of Health and Human Services (HHS). 
In particular, the use of the investigational in vitro diagnostic 
device on individually identifiable human specimens as described in 
this rule would not be human subjects research under 45 CFR part 46, 
while the analysis of the individually identifiable data obtained from 
the use of the investigational device to determine the safety and 
effectiveness of the device would be considered human subject research 
under 45 CFR part 46. If the analysis of individually identifiable data 
involves non-exempt human subjects research that is conducted or 
supported by HHS, the institution conducting the analysis must obtain 
an OHRP-approved assurance. In addition, this means that this research 
activity, if not exempt, i.e., the analysis of the individually 
identifiable data, must be reviewed prospectively by an IRB and must be 
conducted with the informed consent of the subjects unless waived. OHRP 
expects that IRBs will often find that informed consent may be waived 
under 45 CFR 46.116(d) for the analysis of the individually 
identifiable data obtained through the use of the investigational 
device. OHRP issued guidance regarding this issue simultaneously with 
the publication of the IFR, on June 7, 2006. This guidance can be found 
at http://www.hhs.gov/ohrp/policy/invitrodev.html. Those interested in 
seeking additional information concerning the application of the 
regulations at 45 CFR part 46 should contact OHRP. We note that 
research conducted or supported by another Department or Agency may be 
subject to other laws and regulations. Sponsors should check to see if 
they are complying with all applicable requirements.

V. Analysis of Economic Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive 
Order 12866 directs Agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The Agency believes that 
this final rule is not a significant regulatory action under the 
Executive order.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this action provides an exception from an 
otherwise applicable requirement for investigators, FDA believes that 
it does not impose a significant burden. The Agency certifies that the 
final rule will not have a significant economic impact on a substantial 
number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $135 million, using the most current (2009) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

VI. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth

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in Executive Order 13132. Section 4(a) of the Executive order requires 
Agencies to ``construe * * * a Federal statute to preempt State law 
only where the statute contains an express preemption provision or 
there is some other clear evidence that the Congress intended 
preemption of State law, or where the exercise of State or authority 
conflicts with the exercise of Federal authority under the Federal 
statute.'' Federal law includes an express preemption provision that 
preempts certain state requirements ``different from or in addition 
to'' certain federal requirements applicable to devices. 21 U.S.C. 
360k; see Medtronic v. Lohr, 518 U.S. 470 (1996); Riegel v. Medtronic, 
128 S. Ct. 999 (2008). This final rule creates requirements for 
specific medical devices under 21 U.S.C. 360k. Papike v. Tambrands, 
Inc., 107 F.3d 737, 740-42 (9th Cir. 1997).

VII. The Paperwork Reduction Act of 1995

    This final rule 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 title, 
description, and respondent description of the information collection 
provisions are shown in the following paragraphs with an estimate of 
the annual reporting and recordkeeping burden. Included in the estimate 
is the time for reviewing instructions, searching existing data 
sources, gathering and maintaining the data needed, and completing and 
reviewing each collection of information.
    Title: Medical Devices; Exception From General Requirements for 
Informed Consent.
    Description: The final rule amends FDA's informed consent 
regulation to provide an exception from the general requirement to 
obtain informed consent from the subject of an investigation involving 
an unapproved or uncleared in vitro diagnostic device intended to 
identify a chemical, biological, radiological, or nuclear agent. For 
the exception to apply, it is necessary for the investigator and an 
independent licensed physician to make the determination and certify in 
writing certain facts concerning the need for use of the 
investigational in vitro diagnostic device without informed consent (21 
CFR 50.23(e)(1)). When reporting the test results to the subject's 
health care provider and, possibly, to the appropriate public health 
authorities, the investigator must disclose the investigational status 
of the in vitro diagnostic device (21 CFR 50.23(e)(4)). If use of the 
device is necessary to preserve the life of the subject and there is 
not sufficient time to obtain the determination of the independent 
licensed physician in advance of using the investigational device, 21 
CFR 50.23(e)(2) provides that the determination must be made within 5 
working days of use of the device. In either case, the certifications 
are submitted to the IRB within 5 working days after the use of the 
device (21 CFR 50.23(e)(3)).
    The information collection requirements in 21 CFR 50.23(e)(1), 
(e)(2), and (e)(4) in the IFR have been approved under OMB control 
number 0910-0586. The information collection requirement in 21 CFR 
50.23(e)(3) (submitting the certifications to the IRB) was considered 
part of the burden for 21 CFR 50.23(e)(1) and (e)(2).
    This final rule makes one change to the regulatory requirements 
established by the IFR. This change requires the investigator to submit 
the documentation required in 21 CFR 50.23(e)(1) and (e)(2) to FDA, in 
addition to the reviewing IRB. The documentation the investigator must 
submit to FDA is identical to the documentation the investigator must 
submit to the IRB.
    Description of Respondents: Clinical laboratory directors, 
physicians who are investigators.
    FDA estimates the burden of the collection of information as 
follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
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                                                                        Number of                      Average  burden                   Total operating
                    21 CFR Part                        Number of      responses per     Total annual    per  response     Total hours     & maintenance
                                                      respondents       respondent       responses        (in hours)                          costs
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50.23(e)(3).......................................             150                3              450            15/60              113             $100
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\1\ There are no capital costs associated with this collection of information.

    From its knowledge of in vitro diagnostic device investigations, 
FDA estimates that there are approximately 150 laboratory directors or 
physicians who could perform this type of testing and, as 
investigators, are required to comply with information collection and 
recordkeeping. FDA estimates that there are approximately 450 naturally 
occurring cases of this type each year. Based on its knowledge of 
similar types of submissions, FDA estimates that it will take about .25 
hour or 15 minutes to prepare each written documentation to be 
submitted to FDA as required by 21 CFR 50.23(e)(3). The estimated 112.5 
total hours was calculated by multiplying the estimated total annual 
response by the hours per response.
    In compliance with the Paperwork Reduction Act of 1995, the 
collection of information in this final rule has been submitted to OMB 
for review. The new information has been submitted as a revision to the 
previously approved collection OMB control number 0910-0586.
    This final rule also refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by OMB under the Paperwork Reduction Act of 1995. 
The collections of information in 21 CFR 56.115 have been approved 
under OMB control number 0910-0130; and the collections of information 
in 21 CFR 50.23(e)(1), (e)(2), and (e)(4) have been approved under OMB 
control number 0910-0586.

VIII. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

List of Subjects in 21 CFR Part 50

    Human research subjects, Prisoners, Reporting and recordkeeping 
requirements, Safety.
    Accordingly, the interim final rule amending 21 CFR part 50 which 
was published at 71 FR 32827 on June 7, 2006, is adopted as a final 
rule with the following change:

[[Page 36993]]

PART 50--PROTECTION OF HUMAN SUBJECTS

0
1. The authority citation for 21 CFR part 50 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 352, 
353, 355, 360, 360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 
241, 262, 263b-263n.


0
2. Revise Sec.  50.23(e)(3) to read as follows:


Sec.  50.23  Exception from general requirements.

* * * * *
    (e) * * *
    (3) The investigator must submit the written certification of the 
determinations made by the investigator and an independent physician 
required in paragraph (e)(1) or (e)(2) of this section to the IRB and 
FDA within 5 working days after the use of the device.
* * * * *

    Dated: June 17, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-15816 Filed 6-23-11; 8:45 am]
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