[Federal Register: June 7, 2006 (Volume 71, Number 109)]
[Rules and Regulations]               
[Page 32827-32834]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr07jn06-12]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 50

RIN 0910-AC25
[Docket No. 2003N-0355]

 
Medical Devices; Exception From General Requirements for Informed 
Consent

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing this interim 
final rule to amend its regulations to establish 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. The agency is taking this action because it is 
concerned that, during a potential terrorism event or other potential 
public health emergency, delaying the testing of specimens to obtain 
informed consent may threaten the life of the subject. In many 
instances, there may also be others who have been exposed to, or who 
may be at risk of exposure to, a dangerous chemical, biological, 
radiological, or nuclear agent, thus necessitating identification of 
the agent as soon as possible. FDA is creating 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.

DATES: This rule is effective June 7, 2006. Submit written or 
electronic comments by August 7, 2006.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments
.


FOR FURTHER INFORMATION CONTACT: Claudia M. Gaffey, Center for Devices 
and Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 240-276-0496, ext. 109.

SUPPLEMENTARY INFORMATION:

[[Page 32828]]

I. Background

    U.S. Federal, State, and local authorities have developed and are 
refining a comprehensive public health plan to prepare for, and respond 
to, the threat of terrorism and other potential public health 
emergencies. A critical element in responding to such emergencies is 
the ability to correctly and quickly identify the chemical, biological, 
radiological, or nuclear agents that may have caused, or may cause, 
human disease or injury. The devices included within the scope of this 
rule are those for the detection of agents that have the potential to 
be used in acts of chemical, biological, radiological, or nuclear 
terrorism, or that can lead to other potential public health 
emergencies. Examples of these agents include Bacillus anthracis 
(anthrax); Yersinia pestis(plague); ricin (a lethal chemical agent); 
and cobalt-60, a radiological material that could be used to build a 
dirty bomb. Although it is not possible to provide an all inclusive 
list of etiological agents that would be identified under conditions 
that meet the criteria described in this rule, critical biologic agents 
such as Category A Diseases/Agents (available at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.bt.cdc.gov/agent/agentlist-category.asp) or specific chemical agents (http://

http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.bt.cdc.gov/chemical/) that are used by the federal government for 

regulatory and emergency planning purposes, may serve as examples of 
the types of agents within the scope of this rule. Select agents as 
defined in 42 CFR 73.1, that would suggest a terrorism event or other 
public health emergency, may be considered as other examples. Most in 
vitro diagnostic devices used to identify such agents have been 
developed (and more are under development) by the Centers for Disease 
Control and Prevention (CDC), and the Department of Defense (DOD). Some 
nongovernment entities are also developing such in vitro diagnostic 
devices. In most instances, these are the only devices available to 
provide timely diagnostic information on the identity of these agents, 
although they may not yet have been approved or cleared by FDA.
    Many of these devices have not yet been approved or cleared by FDA 
because clinical studies involving devices used for the identification 
of such agents frequently cannot be conducted. Studies may not be 
possible because natural exposure to these agents is rare or never 
occurs, and there may not be enough exposed subjects to enroll in a 
study. Studies also may not be possible because it is not ethical to 
expose healthy human volunteers to a life-threatening toxic substance 
or organism to determine the ability of the unapproved diagnostic 
device to correctly identify the agent. While these unapproved devices 
may not have been evaluated on specimens collected from human subjects, 
testing (procedural) validation and other analytical studies generally 
have been conducted (or are being conducted) by the sponsors.
    Some of these devices may be under clinical investigation, while 
others may not have reached that stage of development. For purposes of 
this rule we are considering the term ``investigational device'' to 
include those devices being evaluated in a clinical investigation as 
well as those that are undergoing preclinical and/or analytical 
evaluation.
    Given all of these facts, the agency believes that the use of these 
investigational diagnostic devices in limited circumstances is 
justified when the devices are needed to identify the causative agent 
in a potential public health emergency and thereby enable authorities 
to promptly provide appropriate care to those exposed, and to provide 
preventive therapies (if available) to others in the affected 
geographic region(s).
    Under FDA's regulations informed consent must be obtained before an 
investigational in vitro diagnostic device may be used unless an 
exception under part 50 (21 CFR part 50) applies. Institutional review 
board (IRB) review and approval is also required, unless an exception 
under part 56 (21 CFR part 56) applies. Under the IRB regulations 
investigations may be reviewed by an IRB through a joint review 
process, reliance upon the review of another qualified IRB (e.g., at 
the research site, a central IRB, an independent or commercial IRB), or 
similar arrangements. (See 21 CFR 56.114.) Therefore, absent an 
applicable exception, investigational in vitro diagnostic devices used 
to identify chemical, biological, radiological, or nuclear agents in 
human specimens may only be used after obtaining informed consent from 
each subject whose specimen is tested, and with IRB review and 
approval.
    If a terrorism event (such as dissemination of B. anthracis spores 
in the mail system in 2001) or other potential public health emergency 
occurs (such as the multistate outbreak of monkeypox in persons exposed 
to pet prairie dogs in 2003), the timely identification of the 
etiological agent may be critical to the lives of the affected subjects 
as well as to the general population who may also have been exposed. 
The risk to subjects and others exposed could be life-threatening, and 
difficult to assess and address without the use of these 
investigational devices. Identification of the agent could be delayed 
significantly or precluded while the investigator seeks to obtain 
informed consent. Also, in some cases, storing the specimen while 
awaiting consent could have an adverse effect on the specimen and 
compromise the test results. The consequences of delay could be 
catastrophic for subjects and for public health in general.
    Consider the following possible scenario in which a terrorist event 
is not suspected until a public health laboratory cultures an unusual 
or rare organism. When a patient presents to a health care facility 
with symptoms suggesting a systemic microbial infection, blood and 
other specimens are typically collected to determine the identity of 
the causative organism. The clinical laboratory would determine that 
the specimens contain an unusual organism that cannot be identified by 
the tests available in that laboratory. Because many clinical 
laboratories do not have the capability or resources to identify 
unusual organisms or those to which humans are rarely exposed 
naturally, the organism (culture isolate) or collected specimen would 
be referred to a public health laboratory. The public health laboratory 
would use in vitro diagnostic devices, including those that are 
investigational, to try to identify the cultured organism or detect its 
presence directly in the specimen.
    In this scenario, the referring laboratory would not have obtained 
informed consent when the specimen was collected because the person 
directing that the specimen be collected would not have known at the 
time that the infecting organism could be reliably identified only by 
using an investigational device. To obtain informed consent would 
require a number of steps and introduce unacceptable delays. The public 
health laboratory would have to contact the referring laboratory that 
collected the specimen or the physician who ordered the cultures in 
order to locate the subject (or the subject's legally authorized 
representative). Once located, the subject or the subject's legally 
authorized representative would need to be contacted, provided the 
informed consent information, and given the opportunity to ask 
questions and sign the informed consent document. The referring 
laboratory or health care facility would then have to notify the public 
health laboratory that informed consent had been obtained.

[[Page 32829]]

Only at that point could testing be performed.
    The scenario described in the previous paragraph is one example and 
is not the only set of circumstances in which this exception to 
informed consent might apply. The new exception would also apply if the 
event were not terrorism-related but was another type of potential 
public health emergency, such as sporadic outbreaks resulting from the 
spread of an emerging infectious agent that has the potential to cause 
a life-threatening situation, as in the case of Severe Acute 
Respiratory Syndrome (SARS) or the potential for a pandemic influenza 
virus strain. This rule would not apply in a situation which is not 
life-threatening or where there is a cleared or approved available 
alternative method of diagnosis that provides an equal or greater 
likelihood of saving the life of the subject, such as the in vitro 
diagnostic devices for identifying agents causing certain known 
sexually transmitted diseases such as Chlamydia trachomatis, Neisseria 
gonorrhoeae, human papillomavirus, human immunodeficiency virus, etc. 
The emergency nature of the event may or may not be suspected at the 
time the specimen is collected, and the laboratory involved may or may 
not be a public health laboratory. Finally, even if the nature of the 
event is suspected, the person collecting the specimen may not know the 
investigational status of the in vitro diagnostic device and thus would 
not know that informed consent should be obtained from the patient. 
These variables are examples and are not meant to be the exclusive 
circumstances in which this rule might apply. The exception has been 
constructed in somewhat general terms because we can not anticipate the 
circumstances of every emergency involving a chemical, biological, 
radiological, or nuclear agent that may occur.
    The process for obtaining informed consent in the scenarios 
described previously would introduce dangerous delays or could 
compromise the effectiveness of the testing. This process would delay 
not only the diagnosis and possibly lifesaving treatment of the 
subject, but would also delay recognition of a terrorism event or other 
public health emergency, with serious public health consequences.
    To avoid potentially dangerous delays in using investigational in 
vitro diagnostic devices to identify these agents, FDA is creating a 
new limited exception, within the restrictions of section 520(g)(3)(D) 
of the act (21 U.S.C. 360j(g)(3)(D)), from the requirement of informed 
consent. The exception applies to investigational in vitro diagnostic 
tests used to identify agents, when a specimen is collected without the 
recognition that an investigational test will have to be used.

II. Current Exceptions From the General Requirements for Informed 
Consent

    Two exceptions from the general requirements for informed consent 
are described in Sec.  50.23. Section 50.23(a) provides that informed 
consent shall be deemed feasible unless, before use of the test 
article, both the investigator and a physician who is not otherwise 
participating in the clinical investigation certify in writing all of 
the following: The human subject is confronted by a life-threatening 
situation necessitating the use of the test article; informed consent 
cannot be obtained from the subject because of an inability to 
communicate with, or obtain legally effective consent from, the 
subject; time is not sufficient to obtain consent from the subject's 
legally authorized representative; and there is available no 
alternative method of approved or generally recognized therapy that 
provides an equal or greater likelihood of saving the life of the 
subject. An inability to communicate in the context of Sec.  50.23(a) 
means that the subject is in a coma or unconscious. (See 46 FR 8942 at 
8946, January 27, 1981). Section 50.23(d) states that, under 10 U.S.C. 
1107(f), the President may waive the prior informed consent requirement 
for the administration of an investigational new drug to armed forces 
personnel in connection with the personnel's participation in a 
particular military operation. The waiver is based on a finding by the 
President that obtaining consent is not feasible, is contrary to the 
best interests of the military personnel, or is not in the interests of 
national security (64 FR 54180, October 5, 1999). Currently FDA is re-
examining this regulation in light of the recent amendment of 10 U.S.C. 
1107 by the Ronald W. Reagan National Defense Authorization Act for 
Fiscal Year 2005 which changed the criteria that may be used by the 
President for waiving informed consent.
    In addition, Sec.  50.24 provides an exception from the informed 
consent requirements for emergency research. Section 50.24 is intended 
to permit the study of potential improvements in the treatment of life-
threatening conditions where current treatment is unproven or 
unsatisfactory, in order to improve interventions and patient outcomes. 
The exception applies to limited research activities involving human 
subjects who are in need of emergency medical intervention, but cannot 
give informed consent because of their medical condition. (See 61 FR 
51498 at 51499, October 2, 1996.) Section 50.24 is intended to be used 
in circumstances that are different than those described in this rule, 
i.e., planned clinical research of a specific investigational article 
that will be studied in a specific class of patients.
    The situation described in this document does not meet the 
requirements of the current exceptions from the general requirements 
for informed consent in Sec.  50.23. It does not satisfy the 
requirements of Sec.  50.23(a) because the subject may be physically 
able to provide informed consent. It does not satisfy the requirements 
of Sec.  50.23(d) because that exception applies only to administration 
of investigational drugs to military personnel by DOD. In addition, 
Section 50.24 is generally not applicable because, in the situations 
addressed in that section, subjects are not able to consent because of 
their medical condition. In contrast, in the situations addressed in 
this document, it is not the condition of the subject that prevents the 
subject from giving informed consent, but rather the fact that, by the 
time it is known that the laboratory needs to use an investigational 
device to identify the etiological agent, the subject is physically 
separated from the specimen, and there is not enough time to locate the 
subject or the subject's legally authorized representative and obtain 
informed consent.

III. Revisions

    FDA is creating a new exception from the general requirements for 
informed consent to address situations associated with preparing for, 
and responding to, chemical, biological, radiological, or nuclear 
terrorism or other potential public health emergencies. The exception 
applies when investigational in vitro diagnostic devices are used and 
the investigator is unable to obtain timely informed consent from 
subjects (or their legally authorized representatives) whose specimens 
are being tested. The new limited exception is applicable only when it 
is not feasible to obtain informed consent because, at the time the 
specimen is collected, it may not be known that an investigational 
device would need to be used on that specimen, and delay in diagnosis 
could be life-threatening to the subject.
    This exception is contingent on several determinations that must be 
made before using the investigational device, and later certified in 
writing, by

[[Page 32830]]

both the investigator and, if time permits, by a physician who is not 
otherwise participating in the clinical investigation. These 
determinations are:
     The human subject is confronted with a life-threatening 
situation necessitating the use of the investigational in vitro 
diagnostic device;
     Informed consent cannot be obtained from the subject 
because:
    1. There was no reasonable way for the person directing that the 
specimen be collected to know at the time the specimen was collected, 
that there would be a need to use the investigational device on that 
specimen and;
    2. Time is not sufficient to obtain consent from the subject 
without risking the life of the subject;
     Time is not sufficient to obtain consent from the 
subject's legally authorized representative; and
     There is no available alternative approved or cleared 
method 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.
    Under this interim final rule, the investigator has 5 working days 
after using the investigational device to submit to the IRB these 
determinations as well as the review and evaluation of an independent 
licensed physician. However, if, in the opinion of the investigator, 
there is not sufficient time to obtain the determination of an 
independent licensed physician in advance of using the investigational 
device, the independent physician is required to review and evaluate 
the determinations of the investigator and the investigator is required 
to submit this documentation to the IRB within 5 working days after 
using the device.
    Until the investigational in vitro diagnostic device is used, it 
will not be known whether there has been actual exposure to a chemical, 
biological, radiological, or nuclear agent and whether that agent is 
life-threatening. Nonetheless, FDA believes the possibility of such 
exposure itself represents a life-threatening situation for the subject 
because, until the investigational in vitro diagnostic device is used, 
it is unknown to what agent, if any, the subject has been exposed or 
how the subject should be treated.
    FDA expects that in accordance with routine clinical practice, the 
investigator will provide the test results obtained using the 
investigational in vitro diagnostic device to the subject's health care 
provider and that the results will be used in the clinical management 
of the human subject. It is possible that, in certain circumstances, 
the test results will also be reported to the appropriate public health 
authorities. This reporting will occur when appropriate and/or required 
by State or Federal law. Under the regulation, at the time the result 
of the test is reported (whether to the subject's health care provider 
and/or to the appropriate public health officials), the investigator is 
required to disclose the investigational status of the device used to 
perform the diagnostic test.
    The investigator is also responsible for providing the IRB with the 
information required in Sec.  50.25, the elements of informed consent, 
and the procedures that will be used to provide this information to 
each subject or to the subject's legally authorized representative. 
Section 50.25(a) requires that the following information be provided to 
each subject:
     A statement that the study involves research and an 
explanation of its purposes and the expected duration of the subject's 
participation;
     A description of the procedures to be followed, and 
identification of any procedures which are experimental;
     A description of any reasonably foreseeable risks or 
discomforts to the subject;
     A description of any benefits to the subject or others 
which may be reasonably expected from the research;
     A disclosure of appropriate alternative procedures or 
courses of treatment, if any, that might be advantageous to the 
subject;
     A statement of the extent, if any, to which 
confidentiality of records identifying the subject will be maintained 
and that notes the possibility that FDA may inspect the records;
     For more than minimal risk research, an explanation as to 
whether any compensation and an explanation as to whether any medical 
treatments are available if injury occurs and, if so, what they consist 
of, or where further information may be obtained; and
     An explanation of whom to contact for answers to pertinent 
questions about the research and research subjects' rights, and whom to 
contact in the event of a research-related injury to the subject.
    Section 50.25(b) requires this additional information when it is 
appropriate:
     A statement that the particular treatment or procedure may 
involve risks to the subject (or to the embryo or fetus, if the subject 
is or may become pregnant) which are currently unforeseeable;
     Anticipated circumstances under which the subject's 
participation may be terminated by the investigator without regard to 
the subject's consent;
     Any additional costs to the subject that may result from 
participation in the research;
     The consequences of a subject's decision to withdraw from 
the research and procedures for orderly termination of participation by 
the subject;
     A statement that significant new findings developed during 
the course of the research which may relate to the subject's 
willingness to continue participation; and
     The approximate number of subjects involved in the study. 
This information will be provided at the time the test results are sent 
to the subject's health care provider and to public health authorities, 
if public health reporting is required by Federal, State, or local law.
    In this rule, we are requiring investigators to provide all 
information described in Sec.  50.25 except the information in Sec.  
50.25(a)(8) concerning voluntary participation. Normally under the 
regulations subjects voluntarily agree to participate in research 
before the research begins. In the circumstances covered by this rule, 
an individual provides a specimen for diagnostic testing without the 
knowledge of either the patient or the physician that an 
investigational in vitro diagnostic (IVD) will be necessary. When the 
investigational IVD is used at a setting remote from the patient and 
treating physician in this case, it is not practicable (because of the 
time and distance involved to contact the patient or the patient's 
legally authorized representative) to obtain consent for the use of the 
device. Under this rule, by the time the patient is informed that an 
investigational device has been used to test his/her specimen, the 
investigation is already underway, and the time at which a subject 
would normally consent to voluntary participation has past. Therefore, 
the investigator is not responsible for providing the information 
described in Sec.  50.25(a)(8) concerning voluntary participation. In 
addition, subjects or their legally authorized representatives will not 
be entitled to withdraw previously collected data from the research 
database, because it is critical that FDA obtain and have available for 
review all data on the investigational in vitro diagnostic device's use 
in order to determine whether it is safe and effective. As a result, it 
is the responsibility of the IRB to ensure the adequacy of the 
information required in Sec.  50.25 (except for the requirements

[[Page 32831]]

under Sec.  50.25(a)(8)) concerning voluntary participation) and to 
ensure that procedures for providing this information to the subject or 
the subject's legally authorized representative are in place. The IRB 
is responsible for this even if an exception under Sec.  56.104(c) 
exists under which the emergency use of the test article would be 
reported to the IRB within 5 working days. We recognize that, in this 
situation, the IRB may be delayed in assuring that these procedures are 
in place.

IV. Applicability of 45 CFR Part 46 and Other Legal Requirements

    According to the Office for Human Research Protection (OHRP) in the 
Department of Health and Human Services (HHS), some of the activities 
described in this rule may also constitute non-exempt human subjects 
research within the meaning of 45 CFR part 46. 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 is issuing 
guidance regarding this issue simultaneously with the publication of 
this interim final rule which can be found at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.hhs.gov/ohrp/policy/index.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. Legal Authority

    FDA believes the statutory authority provided in section 
520(g)(3)(D) of the act permits this limited exception to obtaining 
informed consent for the use of investigational in vitro diagnostic 
devices to identify chemical, biological, radiological, or nuclear 
agents in potential terrorism events or other potential public health 
emergencies. Section 520(g)(3)(D) of the act specifically states when 
an exception from informed consent is permissible. Under section 
520(g)(3)(D) of the 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.
    As noted earlier, FDA believes that, if the presence of an agent is 
suspected, there exists a life-threatening situation for the subjects 
whose specimens have been sent to laboratories. Until the laboratory 
identifies the agent to which the subject has been exposed or by which 
the subject has been infected, specific treatment cannot be provided. 
However, this limited exception applies only if it is also not feasible 
to obtain informed consent because there is an inability to 
communicate, in a timely manner, with the subject or the subject's 
legally authorized representative, and there was no reasonable way to 
know, at the time the specimen was collected, that there would be a 
need to use the investigational device on that specimen. In such a 
situation, the act would permit a limited exception to obtaining 
informed consent.
    In accordance with section 521 of the act (21 U.S.C. 360k), state 
or local requirements that are different from, or in addition to, the 
requirements in this rule are expressly preempted. This rule 
establishes 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. Consequently, 
State and local laws that require that informed consent be obtained in 
those situations are preempted.

VI. Issuance of an Interim Final Rule and Effective Date

    FDA is proceeding without notice and comment rulemaking because the 
Nation needs to have this regulation in place immediately to be 
prepared to deal effectively with a terrorism event or other potential 
public health emergency. Under the provisions of the Administrative 
Procedure Act at 5 U.S.C. 553(b)(B), FDA finds for good cause that 
prior notice and comment on this rule are impracticable and contrary to 
the public interest. The absence of this exception was an impediment to 
the most efficient and effective public health response to the SARS 
outbreak. We do not want the absence of such an exception to be an 
impediment to our response to an outbreak of Avian flu or some other 
public health emergency. It is critical that FDA act quickly now to 
ensure that, in the future, individuals who may have been exposed to a 
chemical, biological, radiological, or nuclear agent have the benefit 
of the timely use of the most appropriate diagnostic devices, including 
those that are investigational. For the same reasons, the agency is 
making this interim final rule effective as of the date of publication.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this interim 
final rule 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.

VIII. Analysis of Impacts

    FDA has examined the impacts of this interim 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 rule is consistent with the regulatory philosophy and principles 
identified in the Executive order. In addition, the rule is not an 
economically significant regulatory action as defined by the Executive 
order.

[[Page 32832]]

    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this interim final rule provides an 
exception from an otherwise applicable requirement for investigators, 
FDA believes that it does not impose a significant burden. The agency 
therefore certifies that this 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 issuing ``any rule that 
includes any Federal mandate that may result in an expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100 million or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $115 million, using the most current (2003) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
interim final rule to result in any 1-year expenditure that would meet 
or exceed this amount.

IX. Paperwork Reduction Act of 1995

    This interim 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 (the PRA) (44 U.S.C. 3501-
3520). The information collection requirements for this interim final 
rule have been approved under the emergency processing provisions of 
the PRA. The assigned OMB approval number for this collection of 
information is 0910-0586. This approval expires on November 30, 2006.
    A description of these provisions is given in the following 
paragraphs with an estimate of the annual reporting 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.
    FDA invites comments on the following topics: (1) Whether the 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility: (2) the accuracy of FDA's estimate of the burden of the 
collection of information, including the validity of the methodology 
and assumptions used; (3) ways to enhance the quality, utility, and 
clarity of the information to be collected; and (4) ways to minimize 
the burden of the collection of information on respondents, including 
through the use of automated collection techniques, when appropriate, 
and other forms of information technology.

Medical Devices: Informed Consent: Investigational In Vitro Diagnostic 
Device To Identify a Chemical, Biological, Radiological, or Nuclear 
Threat Agent

    Description: This interim 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 not cleared 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. 
The investigator submits this written certification to the IRB. 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. The investigator must also provide the IRB with the 
information required in Sec.  50.25 and the procedures that will be 
used to provide this information to each subject or the subject's 
legally authorized representative at the time the test results are 
provided to the subject's health care provider and possibly to the 
public health authorities.
    Description of Respondents: Clinical laboratories, physicians.
    FDA estimates the burden of the collection of information as 
follows:

                                                 Table 1.--Estimated Average Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              No. of         Annual Frequency       Total Annual        Hours per
                    21 CFR Section                         Respondents         per Response          Responses           Response         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
50.23(e)(1) and (e)(2)                                                150                     3                450                  2                900
--------------------------------------------------------------------------------------------------------------------------------------------------------
50.23(e)(4)                                                           150                     3                450                  1                450
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total Hours                                                                                                                                        1,350
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

    FDA is adding Sec.  50.23(e)(1) to provide an exception to the 
general rule that informed consent is required for the use of an 
investigational in vitro diagnostic device for the purpose of preparing 
for and responding to a chemical, biological, radiological, or nuclear 
terrorism event or other public health emergency, if the investigator 
and an independent licensed physician make the determination and later 
certify in writing that: (1) There is a life-threatening situation 
necessitating the use of the investigational device; (2) obtaining 
informed consent from the subject is not feasible because there was no 
way to predict the need to use the investigational device when the 
specimen was collected, and there is not sufficient time to obtain 
consent from the subject or the subject's legally authorized 
representative; and (3) no satisfactory alternative device is 
available. Under this interim final rule these determinations are made 
before the device is used, and the written certifications are made 
within 5 working days after the use of the device. 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, Sec.  
50.23(e)(2) provides that the certifications 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 of the use of the 
device. From its knowledge of the industry, FDA estimates that there 
are approximately 150 laboratories that

[[Page 32833]]

could perform this type of testing. FDA estimates that in the United 
States each year there are approximately 450 naturally occurring cases 
of diseases or conditions that are identified in CDC's list of category 
`A' biological threat agents. The number of cases that would result 
from a terrorist event or other public health emergency is uncertain. 
Based on its knowledge of similar types of submissions, FDA estimates 
that it will take about 2 hours to prepare each certification.
    Section 50.23(e)(4) provides that an investigator must disclose the 
investigational status of the device and what is known about the 
performance characteristics of the device at the time test results are 
reported to the subject's health care provider and public health 
authorities. Under this interim final rule, the investigator provides 
the IRB with the information required by Sec.  50.25 and the procedures 
that will be used to provide this information to each subject or the 
subject's legally authorized representative. Based on its knowledge of 
similar types of submissions, FDA estimates that it will take about 1 
hour to prepare this information and submit it to the health care 
provider and, where appropriate, to public health authorities.

X. Federalism

    FDA has analyzed this interim final rule in accordance with the 
principles set forth in Executive Order 13132 on Federalism (64 FR 
43255, August 10, 1999). FDA has concluded that the rule raises 
federalism implications because, in accordance with section 521 of the 
act, this rule preempts State and local laws that require that informed 
consent be obtained before an investigational in vitro diagnostic 
device may be used to identify a chemical, biological, radiological, or 
nuclear agent in suspected terrorism events and other potential public 
health emergencies that are different from, or in addition to, the 
requirements of this regulation.
    In accordance with the Executive order, preemption of State law is 
restricted to the minimum level necessary to achieve the objective of 
the statute to protect the public health by ensuring that individuals 
who may have been exposed to such an agent are able to benefit from the 
timely use of the most appropriate diagnostic devices, including those 
that are investigational. Also in accordance with the Executive order, 
officials at FDA consulted with the States on the effect of this rule 
on State law.
    The new exception from informed consent is available in a very 
narrowly defined set of circumstances. Under these circumstances, a 
specimen already would have been taken from the individual. The 
individual would not be subjected to any further specimen collection or 
other procedure in order for the investigational device to be used on 
the specimen. In addition, in the circumstances in which the exception 
would apply, it is not only the health of the individual from whom the 
specimen was taken that would be at risk. It is possible that other 
people, perhaps many other people, would have been exposed to the 
chemical, biological, radiological, or nuclear agent as well.
    In conclusion, the agency believes that it has complied with all of 
the applicable requirements under Executive Order 13132 and has 
determined that this final rule is consistent with the Executive order.

XI. Civil Justice Reform

    This rule has been reviewed under Executive Order 12988, Civil 
Justice Reform. This regulation meets the applicable standards set 
forth in sections 3(a) and 3(b)(2) of Executive Order 12988.

XII. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this interim 
final rule. Submit a single copy of electronic comments or two paper 
copies of any mailed comments, except that individuals may submit one 
paper copy. Comments are to be identified with the docket number found 
in brackets in the heading of this document. Received comments may be 
seen in the Division of Dockets Management between 9 a.m. and 4 p.m., 
Monday through Friday.

List of Subjects in 21 CFR Part 50

    Human research subjects, Prisoners, Reporting and recordkeeping 
requirements, Safety.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
50 is amended as follows:

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. Section 50.23 is amended by adding paragraph (e) to read as follows:


Sec.  50.23  Exception from general requirements.

    (e)(1) Obtaining informed consent for investigational in vitro 
diagnostic devices used to identify chemical, biological, radiological, 
or nuclear agents will be deemed feasible unless, before use of the 
test article, both the investigator (e.g., clinical laboratory director 
or other responsible individual) and a physician who is not otherwise 
participating in the clinical investigation make the determinations and 
later certify in writing all of the following:
    (i) The human subject is confronted by a life-threatening situation 
necessitating the use of the investigational in vitro diagnostic device 
to identify a chemical, biological, radiological, or nuclear agent that 
would suggest a terrorism event or other public health emergency.
    (ii) Informed consent cannot be obtained from the subject because:
    (A) There was no reasonable way for the person directing that the 
specimen be collected to know, at the time the specimen was collected, 
that there would be a need to use the investigational in vitro 
diagnostic device on that subject's specimen; and
    (B) Time is not sufficient to obtain consent from the subject 
without risking the life of the subject.
    (iii) Time is not sufficient to obtain consent from the subject's 
legally authorized representative.
    (iv) There is no cleared or approved available alternative method 
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.
    (2) If use of the investigational device is, in the opinion of the 
investigator (e.g., clinical laboratory director or other responsible 
person), required to preserve the life of the subject, and time is not 
sufficient to obtain the independent determination required in 
paragraph (e)(1) of this section in advance of using the 
investigational device, the determinations of the investigator shall be 
made and, within 5 working days after the use of the device, be 
reviewed and evaluated in writing by a physician who is not 
participating in the clinical investigation.
    (3) The investigator must submit the documentation required in 
paragraph (e)(1) or (e)(2) of this section to the IRB within 5 working 
days after the use of the device.
    (4) An investigator must disclose the investigational status of the 
in vitro diagnostic device and what is known

[[Page 32834]]

about the performance characteristics of the device in the report to 
the subject's health care provider and in any report to public health 
authorities. The investigator must provide the IRB with the information 
required in Sec.  50.25 (except for the information described in Sec.  
50.25(a)(8)) and the procedures that will be used to provide this 
information to each subject or the subject's legally authorized 
representative at the time the test results are provided to the 
subject's health care provider and public health authorities.
    (5) The IRB is responsible for ensuring the adequacy of the 
information required in section 50.25 (except for the information 
described in Sec.  50.25(a)(8)) and for ensuring that procedures are in 
place to provide this information to each subject or the subject's 
legally authorized representative.
    (6) No State or political subdivision of a State may establish or 
continue in effect any law, rule, regulation or other requirement that 
informed consent be obtained before an investigational in vitro 
diagnostic device may be used to identify chemical, biological, 
radiological, or nuclear agent in suspected terrorism events and other 
potential public health emergencies that is different from, or in 
addition to, the requirements of this regulation.

    Dated: May 31, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-8790 Filed 6-6-06; 8:45 am]

BILLING CODE 4160-01-S