Federal Register, Volume 83 Issue 221 (Thursday, November 15, 2018)

[Federal Register Volume 83, Number 221 (Thursday, November 15, 2018)]
[Proposed Rules]
[Pages 57378-57386]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-24822]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 50, 312, and 812

[Docket No. FDA-2018-N-2727]
RIN 0910-AH52

Institutional Review Board Waiver or Alteration of Informed
Consent for Minimal Risk Clinical Investigations

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is proposing
to amend its regulations to implement a provision of the 21st Century
Cures Act (Cures Act). This proposed rule, if finalized, would allow an
exception from the requirement to obtain informed consent when a
clinical investigation poses no more than minimal risk to the human
subject and includes appropriate safeguards to protect the rights,
safety, and welfare of human subjects. The proposed rule, if finalized,
would permit an Institutional Review Board (IRB) to waive or alter
certain informed consent elements or to waive the requirement to obtain
informed consent, under limited conditions, for certain FDA-regulated
minimal risk clinical investigations.

DATES: Submit either electronic or written comments on this proposed
rule by January 14, 2019.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before January 14, 2019. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of January 14, 2019. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your

[[Page 57379]]

comment does not include any confidential information that you or a
third party may not wish to be posted, such as medical information,
your or anyone else's Social Security number, or confidential business
information, such as a manufacturing process. Please note that if you
include your name, contact information, or other information that
identifies you in the body of your comments, that information will be
posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions.'')

Written/Paper Submissions

Submit written/paper submissions in the following ways:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2018-N-2727 for ``Institutional Review Board Waiver or Alteration
of Informed Consent for Minimal Risk Clinical Investigations.''
Received comments, those filed in a timely manner (see ADDRESSES), will
be placed in the docket and, except for those submitted as
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: With regard to the proposed rule:
Janet Norden, Office of Good Clinical Practice, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002,
301-796-1127, or Carol Drew, Office of Good Clinical Practice, Food and
Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-
0002, 301-796-3505.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Background and Description of the Proposed Regulation
A. Background
B. Description of the Proposed Regulation
III. Proposed Effective Date
IV. Legal Authority
V. Economic Analysis of Impacts
A. Benefits of the Proposed Rule
B. Cost Savings of the Proposed Rule
C. Costs of the Proposed Rule
D. Executive Order 13771
VI. Analysis of Environmental Impact
VII. Paperwork Reduction Act of 1995
VIII. Consultation and Coordination With Indian Tribal Governments
IX. Federalism
X. References

I. Executive Summary

A. Purpose of the Proposed Rule

The purpose of this proposed rule is to implement the statutory
changes made to the Federal Food, Drug, and Cosmetic Act (FD&C Act) by
section 3024 of the Cures Act (Pub. L. 114-255) to allow for a waiver
or alteration of informed consent when a clinical investigation poses
no more than minimal risk to the human subject and includes appropriate
safeguards to protect the rights, safety, and welfare of human
subjects. The proposed rule, if finalized, would permit an IRB to waive
or alter certain informed consent elements or to waive the requirement
to obtain informed consent, under limited conditions, for certain
minimal risk clinical investigations.

B. Summary of the Major Provisions of the Proposed Rule

The major provisions of the proposed rule would add Sec. 50.22 to
part 50 (21 CFR part 50) to allow IRBs responsible for the review,
approval, and continuing review of clinical investigations to approve
an informed consent procedure that waives or alters certain informed
consent elements or that waives the requirement to obtain informed
consent for certain minimal risk clinical investigations. In order for
an IRB to approve a waiver or alteration of informed consent
requirements for minimal risk clinical investigations, the proposed
rule would require an IRB to find and document four criteria that are
consistent with the ``Federal Policy for the Protection of Human
Subjects'' (the Common Rule) (56 FR 28001, June 18, 1991). FDA believes
proposed Sec. 50.22 would provide appropriate safeguards to protect
the rights, safety, and welfare of the human subjects participating in
such clinical investigations. We are also proposing conforming
amendments to FDA's regulations, including Sec. 50.20, 21 CFR 312.60,
and 21 CFR 812.2.

C. Legal Authority

Sections 505(i)(4) and 520(g)(3) of the FD&C Act (21 U.S.C.
355(i)(4) and 360j(g)(3)), as amended by section 3024 of the Cures Act,
in conjunction with FDA's general rulemaking authority in section
701(a) of the FD&C Act (21 U.S.C. 371(a)), serve as FDA's principal
legal authority for this proposed rule.

D. Costs and Benefits

We do not anticipate additional costs associated with this
rulemaking. This proposed rule would help enable the conduct of certain
minimal risk clinical investigations for which the requirement to
obtain informed consent is waived or for which certain elements of
informed consent are waived or altered. We expect benefits in the form
of healthcare advances from such minimal risk clinical investigations
and from harmonization of FDA's informed consent regulations with the
Common

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Rule's provision for waiver of informed consent for certain minimal
risk research. We cannot quantify all of these benefits because of the
lack of relevant data available to FDA. The benefits that we are able
to quantify are the cost savings to IRBs because the time burdens of
reviewing certain minimal risk clinical investigations under differing
requirements would be reduced. The estimated cost savings of the
proposed rule are approximately $237.6 thousand, with a lower bound of
$59.4 thousand and an upper bound of $950.5 thousand. The estimated
annualized costs savings of the proposed rule are approximately $27
thousand, with a lower bound of approximately $6,762 and an upper bound
of approximately $108.2 thousand, discounted at 3 percent over 10
years. The estimated annualized costs savings of the proposed rule are
approximately $26 thousand, with a lower bound of approximately $6,509
and an upper bound of $104.1 thousand, discounted at 7 percent over 10
years.

II. Background and Description of the Proposed Regulation

A. Background

On December 13, 2016, the Cures Act was signed into law, amending
certain provisions of the FD&C Act. FDA is proposing to update its
regulations to reflect some of those changes that are now in effect.
Specifically, section 3024 of the Cures Act amended sections 520(g)(3)
and 505(i)(4) of the FD&C Act to provide FDA with the authority to
permit an exception from informed consent requirements when the
proposed clinical testing poses no more than minimal risk to the human
subject and includes appropriate safeguards to protect the rights,
safety, and welfare of the human subject. This proposed rule, if
finalized, would implement this statutory change.
Sections 505(i) and 520(g) of the FD&C Act require FDA to publish
regulations governing the use in human subjects of drugs and devices in
clinical investigations. In 1962, amendments to section 505(i) of the
FD&C Act provided that FDA regulations must ensure that informed
consent for investigational use of drugs (including biological
products) in human beings is obtained except where it is not feasible
or it is contrary to the best interests of such human beings. The
Medical Device Amendments of 1976 subsequently added section 520(g) to
the FD&C Act. Among other requirements, section 520(g)(3)(D) of the
FD&C Act directed that FDA regulations governing investigational use of
devices require that informed consent be obtained except where the
investigator determines in writing that there exists a life-threatening
situation involving the human subject of such testing that necessitates
the use of such device and it is not feasible to get the consent of the
subject and there is not sufficient time to obtain such consent from
the subject's representative. Section 520(g)(3)(D) of the FD&C Act
further provided that a licensed physician not involved in the research
must also concur in this determination, unless immediate use is
necessary to save the subject's life and there is not time to get
concurrence.
In 1979, FDA proposed revisions to its regulations governing
informed consent (44 FR 47713, August 14, 1979). The Agency recognized
in the preamble to its proposed rule that the statutory language
regarding exceptions from informed consent for investigational drugs
differed from that regarding investigational devices. However, the
Agency explained that its prior regulations implementing the statutory
exception from informed consent for investigational drugs ``carefully
limited'' the exception to certain situations that assume ``the patient
subject is seriously ill'' and did not differ greatly from the new
statutory exceptions from informed consent for devices (see 44 FR 47713
at 47718). When FDA issued final revisions to its informed consent
regulations in 1981, it adopted a single set of requirements for
informed consent for all FDA-regulated clinical investigations, which
reflected the device standard in section 520(g)(3)(D) of the FD&C Act
(see 46 FR 8942, January 27, 1981). FDA explained its intent to adopt a
single standard that reflected the most current congressional thinking
on informed consent (see 44 FR 47713 at 44718; 46 FR 8942 to 8944).
Currently, FDA's regulations governing the protection of human
subjects (21 CFR parts 50 and 56) allow exception from the general
requirements of informed consent only in life-threatening situations
when certain conditions are met (Sec. 50.23) or when the requirements
for emergency research are met (Sec. 50.24). In all other cases, FDA
regulations require that a human subject provide informed consent
before participating in a clinical investigation. At this time, FDA's
regulations do not allow an exception from the general requirements of
informed consent for minimal risk clinical investigations.
In contrast, the Common Rule has included waiver of informed
consent provisions for minimal risk research since it was originally
issued in 1991 (56 FR 28001). The Common Rule sets forth requirements
for the protection of human subjects involved in research that is
conducted or supported by the Department of Health and Human Services
(HHS) (see 45 CFR 46, Subpart A) and 15 other Federal departments and
agencies. The purpose of the Common Rule is to promote uniformity,
understanding, and compliance with human subject protections as well as
to create a uniform body of regulations across the Federal departments
and agencies.\1\ The Common Rule standard has permitted an IRB to waive
the requirements to obtain informed consent, or to allow changes to, or
omission of, some or all elements of informed consent if the IRB finds
and documents that: (1) The research involves no more than minimal risk
to the subjects; (2) the waiver or alteration will not adversely affect
the rights and welfare of the subjects; (3) the research could not
practicably be carried out without the waiver or alteration; and (4)
whenever appropriate, the subjects will be provided with additional
pertinent information after participation (45 CFR 46.116(d); 56 FR
28001 at 28017).\2\
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\1\ 80 FR 53931 at 53935, September 8, 2015.
\2\ References to the Common Rule in this document are to the
1991 version of the Common Rule, unless otherwise noted. A final
rule that revised the 1991 version of the Common Rule adopted an
effective and general compliance date of January 19, 2018 (82 FR
7149, January 19, 2017). On January 22, 2018, an interim final rule
was published that delayed the effective and general compliance date
of the revisions until July 19, 2018 (83 FR 2885). On June 19, 2018,
a final rule was published that further delays the general
compliance date until January 21, 2019, while allowing the use of
three burden-reducing provisions for certain research during the
delay period (83 FR 28497). The revised version of the Common Rule,
including amendments made by the January 22, 2018 interim final rule
and the June 19, 2018 final rule, is referred to in this document as
the ``revised Common Rule.''
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FDA amended its regulations in parts 50 and 56 to conform them to
the Common Rule in 1991 (56 FR 28001 at 28025) but diverged from the
Common Rule's provision for waiver or alteration of informed consent
for minimal risk research at 45 CFR 46.116(d). In explaining the reason
for this departure, FDA cited sections 505(i) and 520(g)(3)(D) of the
FD&C Act \3\ and stated that the FD&C Act ``requires informed consent
to be obtained from all subjects except in very limited circumstances''
and that the Agency did ``not have the authority under the act to

[[Page 57381]]

waive this requirement'' (53 FR 45671 at 45679, November 10, 1988).
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\3\ FDA's proposed rule also cited section 507 of the FD&C Act,
which established requirements for the conduct of clinical
investigations of antibiotic drugs and provided the same exceptions
from the informed consent requirements as those provided under
section 505(i). Section 125 of the Food and Drug Administration
Modernization Act of 1997 repealed section 507 of the FD&C Act.
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The Common Rule provision recognizes that there may be proposed
research that cannot practicably be conducted without a waiver or
alteration of informed consent, but the research would contribute
valuable medical or scientific knowledge and would present no more than
minimal risk to subjects. FDA believes this is also true for some
minimal risk FDA-regulated clinical investigations. On March 13, 2014,
the Secretary's Advisory Committee on Human Research Protections
(SACHRP) considered whether the Common Rule standard for waiver of
informed consent for minimal risk research would be appropriate and
helpful for FDA-regulated clinical investigations. SACHRP recommended
to the Secretary of HHS that FDA adopt the provisions for waiver of
informed consent that existed under the Common Rule at that time at 45
CFR 46.116(d). On October 26, 2016, SACHRP reiterated that
recommendation to the Secretary.\4\
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\4\ SACHRP's recommendations are available at https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2014-july-3-letter-attachment-c/index.html and https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-b-november-2-2016-letter/index.html.
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FDA believes that the Common Rule provision has provided
appropriate safeguards to protect the rights, safety, and welfare of
human subjects participating in certain minimal risk research for over
25 years. Consistent with SACHRP's recommendations, FDA also believes
that this standard is appropriate for FDA-regulated clinical
investigations posing no more than minimal risk to human subjects. The
Cures Act statutory revision authorizes FDA to permit an exception from
informed consent requirements when the proposed clinical testing poses
no more than minimal risk to the human subject and includes appropriate
safeguards to protect the rights, safety, and welfare of the human
subject. This enables FDA to harmonize with the Common Rule's well-
established waiver provision for certain minimal risk research, thereby
facilitating investigators' ability to conduct minimal risk clinical
investigations that could contribute substantially to the development
of products to diagnose or treat diseases or other conditions, without
compromising subjects' rights, safety, or welfare. Because some
clinical research is subject to both FDA and HHS requirements,
harmonization of this waiver provision should also reduce burden on the
research community.
The Common Rule was recently revised (82 FR 7149, January 19,
2017), introducing new terminology and regulatory provisions. Although
it retains the same criteria for IRB waiver or alteration of informed
consent as were included in the 1991 version of the Common Rule, it
adds a fifth criterion, i.e., ``if the research involves using
identifiable private information or identifiable biospecimens, the
research could not practicably be carried out without using such
information or biospecimens in an identifiable format'' (new
requirement at 45 CFR 46.116(f)(3)(iii)). We are proposing to adopt the
four criteria from the 1991 version of the Common Rule. At this time,
we are not proposing to adopt the new fifth criterion in the revised
Common Rule, which has a general compliance date of January 21, 2019;
however, we invite comments on this issue. Section 3023 of the Cures
Act requires the Secretary of HHS, to the extent practicable and
consistent with other statutory provisions, to harmonize the
differences between the HHS human subject regulations and FDA's human
subject regulations. FDA will be working with others in HHS to carry
out this statutory directive with respect to new terminology and
regulatory provisions in the revised Common Rule, such as this new
fifth criterion.
Subsequent to the Cures Act amendment to the FD&C Act, FDA issued a
guidance document for immediate implementation, entitled
``Institutional Review Board Waiver or Alteration of Informed Consent
for Clinical Investigations Involving No More Than Minimal Risk to
Human Subjects'' (82 FR 34535, July 25, 2017). This guidance informed
sponsors, investigators, and IRBs that FDA does not intend to object to
an IRB waiving or altering informed consent requirements, as described
in the guidance, for certain minimal risk clinical investigations. In
addition, the guidance informed sponsors, investigators, and IRBs that
FDA does not intend to object to a sponsor initiating, or an
investigator conducting, a minimal risk clinical investigation for
which an IRB waives or alters the informed consent requirements as
described in the guidance. FDA intends to withdraw the guidance after
regulations to implement section 3024 of the Cures Act become
effective.
Obtaining informed consent from those who volunteer to participate
in research is a fundamentally important principle of human subject
protection. FDA is issuing this proposed rule to permit IRB waiver or
alteration of informed consent in limited circumstances, consistent
with the Cures Act. Given the variety and complexity of clinical
investigations being conducted in today's research environment, FDA is
soliciting additional stakeholder input on the types of FDA-regulated
minimal risk clinical investigations for which sponsors would
anticipate requesting a waiver or alteration of informed consent from
the IRB.

B. Description of the Proposed Regulation

FDA proposes to add Sec. 50.22, ``Exception from informed consent
requirements for minimal risk clinical investigations'' to part 50. The
proposed exception would allow the IRB responsible for the review,
approval, and continuing review of the clinical investigation to
approve an informed consent procedure that does not include or that
alters some or all of the elements of informed consent in Sec.
50.25(a) and (b) of FDA's current regulations, or that waives the
requirement to obtain informed consent, provided that the IRB finds and
documents that:
The clinical investigation involves no more than minimal
risk to the subjects;
the waiver or alteration of informed consent will not
adversely affect the rights and welfare of the subjects;
the clinical investigation could not practicably be
carried out without the waiver or alteration of informed consent; and
whenever appropriate, the subjects will be provided with
additional pertinent information after participation.
Consistent with the amendments made by section 3024 of the Cures
Act, Sec. 50.22(a) would limit the application of a waiver or
alteration of informed consent under proposed Sec. 50.22 to clinical
investigations that involve no more than minimal risk. FDA regulations
and the Common Rule have shared the same definition of ``minimal risk''
since 1991 (see 56 FR 28025, June 18, 1991; Sec. 50.3(k); 45 CFR
46.102(i)).\5\
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\5\ In the revised Common Rule, the definition of ``minimal
risk'' is found at 45 CFR 46.102(j).
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Proposed Sec. 50.22 also provides for appropriate safeguards to
protect the rights, safety, and welfare of human subjects. Proposed
Sec. 50.22(b) requires the reviewing IRB to find that the waiver or
alteration will not adversely affect the rights and welfare of the
subjects. To make this finding, IRBs may consider, for example, whether
the waiver or alteration has the potential to negatively affect the
subjects' well-being or whether the subject population in

[[Page 57382]]

general would likely object to a waiver or alteration being granted for
the research in question. It would not be necessary for an IRB to find
that obtaining informed consent would be harmful or contrary to the
best interests of subjects in order to satisfy this criterion.
Proposed Sec. 50.22(c) requires the reviewing IRB to find that the
clinical investigation could not practicably be carried out without the
waiver or alteration. If scientifically sound research can be
practicably carried out using only consenting subjects, FDA believes it
should be carried out without involving nonconsenting subjects. By
practicable, FDA means, for example: (1) That recruitment of consenting
subjects does not bias the science and the science is no less rigorous
as a result of restricting it to consenting subjects or (2) that the
research is not unduly delayed by restricting it to consenting
subjects. The emphasis is on situations where it is impracticable to
carry out the clinical investigation, as designed, without the waiver
or alteration, rather than on situations where it is not feasible to
obtain informed consent from human subjects.
Finally, proposed Sec. 50.22(d) requires the reviewing IRB to find
that, whenever appropriate, the subjects will be provided with
additional pertinent information after participation. For example, an
IRB may determine that information that had been previously withheld
about the clinical investigation to prevent bias must be provided to
subjects following their participation.
If an IRB finds and documents the criteria set forth in proposed
Sec. 50.22(a) to (d), the proposed rule would provide for the IRB to
approve an informed consent procedure that does not include or that
alters some or all of the elements of informed consent in Sec.
50.25(a) and (b), or that waives the requirement to obtain informed
consent. This means that an IRB may waive entirely, under proposed
Sec. 50.22, the requirement to obtain informed consent, which would
constitute a waiver of all elements under Sec. 50.25(a), (b), and (c).
However, regarding an alteration to the informed consent document, the
proposed rule would not permit an IRB to approve an informed consent
document with an omission or alteration of the specific informed
consent element set forth in Sec. 50.25(c), which requires that a
statement regarding the inclusion of clinical trial information at
https://www.ClinicalTrials.gov be provided in informed consent
documents and processes for applicable clinical trials, as defined in
section 402(j)(1)(A) of the Public Health Service Act, 42 U.S.C.
282(j)(1)(A).
FDA revised its informed consent regulations to add Sec. 50.25(c)
in response to section 801 of the Food and Drug Administration
Amendments Act of 2007 (FDAAA) (Pub. L. 110-85, September 27, 2007).
Section 801 of FDAAA amended section 505(i)(4) of the FD&C Act to
direct the Secretary of HHS ``to require inclusion in the informed
consent documents and process a statement that clinical trial
information for such clinical investigation has been or will be
submitted for inclusion in the registry data bank pursuant to
subsection (j) of section 402 of the Public Health Service Act.'' Under
proposed new Sec. 50.22, if an IRB approved the use of a consent
procedure that omitted or altered certain elements in Sec. 50.25(a)
and (b), the informed consent document and/or oral presentation
provided to subjects would still need to include the statement at Sec.
50.25(c) without alteration. As FDA has previously explained, requiring
a uniform statement that cannot be altered helps to ensure that
potential clinical trial participants receive a consistent and accurate
message that is consistent with the intent of the statutory requirement
and are directed to the specific website that contains the clinical
trial databank (see 76 FR 256 at 261, January 4, 2011).
Proposed Sec. 50.22 should not be confused with the provision of
the current regulations that allows for a waiver of documentation of
informed consent by an IRB in certain situations; the waiver for
documentation of informed consent referenced in Sec. 50.27 and found
in Sec. 56.109(c), remains unchanged.
We are also proposing three conforming amendments to Sec. Sec.
50.20, 312.60, and 812.2 of our current regulations to reflect the
proposed exception from informed consent for minimal risk clinical
investigations. FDA is proposing to revise the introductory clause of
Sec. 50.20, General requirements of informed consent, to include
reference to proposed Sec. 50.22 as one of the limited exceptions to
the general requirements for informed consent. Thus, the introductory
clause to Sec. 50.20 is proposed to read, ``Except as provided in
Sec. Sec. 50.22, 50.23, and 50.24. . . .''
In addition, we are proposing a conforming amendment to the second
sentence in Sec. 312.60, General responsibilities of investigators, of
our current regulations on investigational new drug applications to
reference part 50 generally rather than list each specific exception to
the informed consent requirements in part 50. This would simplify the
regulatory text and make it clear that the investigator is responsible
for obtaining the informed consent of each human subject to whom the
drug is administered in accordance with part 50, which includes
proposed Sec. 50.22.
The remaining conforming amendment we are proposing in part 812,
Investigational Device Exemptions (IDEs), Sec. 812.2(b)(1)(iii), would
make it clear that the investigator must obtain informed consent in
accordance with part 50, which includes proposed Sec. 50.22. To
simplify the current regulatory text, we are proposing to remove the
reference to documentation being waived under Sec. 56.109(c), as the
relevant section of the regulations in part 50 (i.e., Sec. 50.27)
refers investigators to Sec. 56.109(c) and need not be repeated. Thus,
the provision of the abbreviated requirements for IDEs in Sec.
812.2(b)(1)(iii) would be simplified to read, ``(iii) Ensures that each
investigator participating in an investigation of the device obtains
from each subject under the investigator's care, informed consent in
accordance with part 50 of this chapter.''

III. Proposed Effective Date

FDA proposes that any final rule that may issue based on this
proposal become effective 30 days after its date of publication in the
Federal Register.

IV. Legal Authority

Title III, section 3024 of the Cures Act amended sections 520(g)(3)
and 505(i)(4) of the FD&C Act to provide FDA with the authority to
permit an exception from informed consent requirements when the
proposed clinical testing poses no more than minimal risk to the human
subject and includes appropriate safeguards to protect the rights,
safety, and welfare of the human subject. This statutory amendment was
signed into law and became effective on December 13, 2016. We are
proposing these regulations to reflect these statutory changes to the
FD&C Act, including appropriate human subject protection safeguards.
Thus, sections 520(g)(3) and 505(i)(4) of the FD&C Act, as amended by
section 3024 of the Cures Act, in conjunction with FDA's general
rulemaking authority in section 701(a) of the FD&C Act, serve as our
principal legal authority for this proposed rule.

V. Economic Analysis of Impacts

We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory

[[Page 57383]]

Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform
Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 13563 direct us
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). We believe that this proposed rule is not a significant
regulatory action as defined by Executive Order 12866. Executive Order
13771 requires that the costs associated with significant new
regulations ``shall, to the extent permitted by law, be offset by the
elimination of existing costs associated with at least two prior
regulations.'' We believe that the proposed rule, if finalized, is an
Executive Order 13771 deregulatory action and does not require us to
identify cost offsets.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because this proposed rule would not impose new requirements
on any entity and therefore has no associated compliance costs, we
propose to certify that the proposed rule will not have a significant
economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to 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 $150 million, using the most current (2017) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.

A. Benefits of the Proposed Rule

The proposed rule would amend FDA's current informed consent
regulations to harmonize with the 1991 version of the Common Rule's
provision for waiver of the requirement to obtain informed consent for
certain minimal risk research. We expect benefits in the form of
healthcare advances stemming from additional minimal risk clinical
investigations that would proceed using a waiver or alteration of
informed consent, and from harmonization with the Common Rule's
provision for waiver of the requirement to obtain informed consent for
certain minimal risk research. The Common Rule provision is currently
used by numerous other Federal departments and agencies. Some clinical
research is subject to both FDA's regulations and the Common Rule, so
harmonization of this specific waiver provision would benefit those
entities that conduct, sponsor, or review certain minimal risk clinical
investigations by reducing confusion and burden created by the need to
comply with differing requirements.

B. Cost Savings of the Proposed Rule

The proposed rule would harmonize FDA's informed consent
regulations with the 1991 version of the Common Rule's provision for
waiver of the requirement to obtain informed consent for certain
minimal risk clinical investigations. As in a previous economic
analysis of the 2017 revisions to the Common Rule (Ref. 1), we attempt
to quantify the effects of the proposed rule where possible. We
conducted a search for active IRBs regulated by both FDA and the Office
for Human Research Protections (OHRP) in HHS in the ``Office for Human
Research Protections (OHRP) Database for Registered IORGs & IRBs,
Approved FWAs, and Documents Received in the Last 60 Days'' (Ref. 2).
Using this data, we are able to determine whether an IRB is active or
inactive, and whether it is regulated by FDA, OHRP, or both. We
multiply the number of active IRBs by the percentage of IRBs regulated
by both FDA and OHRP to yield an estimate of 2,442 active IRBs that are
regulated by both FDA and OHRP (= 3,507 x 0.696). We expect that some
of these IRBs would be affected by the proposed rule, and would
experience a reduction in the time burden of determining whether to
approve a waiver of the requirement to obtain informed consent for a
minimal risk clinical investigation by reviewing it under a harmonized
standard.\6\ We estimate that 50 percent of affected IRBs would incur
time savings from the proposed rule, with a lower bound of 25 percent
of affected IRBs and an upper bound of 100 percent of affected IRBs. We
estimate that for affected IRBs, cost savings would be incurred in the
form of time savings to IRB administrators, IRB chairs, IRB voting
members, and IRB administrative staff from evaluating a minimal risk
clinical investigation under FDA's and the Common Rule's harmonized
regulations for waiving the requirement to obtain informed consent.
Based on discussion with FDA subject matter experts (Ref. 3), we
estimate that the reduced time burden of the proposed rule is 30
minutes (0.5 hours), with a lower bound of 15 minutes (0.25 hours) and
an upper bound of 60 minutes (1 hour).
---------------------------------------------------------------------------

\6\ As previously discussed, the revised Common Rule adds a
fifth criterion to the waiver or alteration of informed consent
requirements (see section II.A). Although FDA is not proposing to
adopt the fifth criterion in this rulemaking, for clinical
investigations subject to both the Common Rule and FDA regulations,
if an IRB finds and documents that research satisfies the criteria
for waiver of the requirement to obtain informed consent for minimal
risk research under the revised Common Rule, then that research
would also meet the standards for waiver of the requirement to
obtain informed consent in FDA-regulated clinical investigations
described in this proposed rule.
---------------------------------------------------------------------------

We draw from Bureau of Labor Statistics data to estimate hourly
wage rates for IRB chairs, IRB voting members, and IRB administrative
staff in 2016 dollars. Based on an economic analysis of impacts of
revisions to the Common Rule (Ref. 1), we use wages for postsecondary
education administrators to proxy for IRB administrator wages (Ref. 4),
wages for office and administrative support workers to proxy for IRB
administrative staff wages (Ref. 5), and wages for postsecondary health
teachers to proxy for the wages of IRB chairs and IRB voting members
(Ref. 6). We double each hourly wage to account for benefits and
overhead, yielding wage rates of $134.50 for IRB administrators (=
$67.25 x 2), $35.94 for IRB administrative staff (= $17.97 x 2),
$109.40 for IRB chairs (= $54.70 x 2), and $109.40 for IRB voting
members (= $54.70 x 2). We estimate that each of these forms of labor
would experience time savings as a result of the proposed rule ranging
from 15 to 60 minutes, with a central estimate of 30 minutes. We also
estimate that time savings would be incurred by one IRB administrator,
one IRB administrative staff, one IRB chair, and one IRB voting member.
We multiply the number of active IRBs regulated by the percentage of
IRBs affected by the proposed rule, the estimated reduced time burden
of the proposed rule, and the sum of each IRB wage rate to yield a
total estimated cost savings of approximately $237,631 (= 2,442 x 0.50
x 0.50 x [$134.50 + $109.40 + $109.40 + $35.94]), with lower bound
estimated cost savings of approximately $59,408 (= 2,442 x 0.25 x 0.25
x [$134.50 + $109.40 + $109.40 + $35.94]) and upper bound estimated
cost savings of approximately $950,524 (= 2,442 x 1 x 1 x [$134.50 +
$109.40 + $109.40 + $35.94]). The net present value of the cost savings
of the proposed rule is approximately $230.7 thousand, discounted at 3
percent, with a lower bound of approximately $57.7 thousand and an
upper bound of approximately

[[Page 57384]]

$922.8 thousand. The net present value of the cost savings of the
proposed rule are approximately $222.1 thousand, discounted at 7
percent, with a lower bound of approximately $55.5 thousand and an
upper bound of approximately $888.3 thousand. The annualized cost
savings of the proposed rule are approximately $27 thousand, discounted
at 3 percent over 10 years, with a lower bound of approximately $6,762
and an upper bound of approximately $108.2 thousand. The annualized
cost savings of the proposed rule are approximately $26 thousand
discounted at 7 percent over 10 years, with a lower bound of
approximately $6,509 and an upper bound of approximately $104.1
thousand. The estimated cost savings of the proposed rule to IRBs are
summarized in table 1.

Table 1--Cost Savings of the Proposed Rule to IRBs
----------------------------------------------------------------------------------------------------------------
Low Middle High
----------------------------------------------------------------------------------------------------------------
No. of active IRBs.............................................. 3,507 3,507 3,507
Percentage of IRBs regulated by FDA and OHRP.................... 69.6% 69.6% 69.6%
No. of active IRBs regulated by FDA and OHRP.................... 2,442 2,442 2,442
Percentage of FDA/OHRP regulated IRBs affected by the proposed 25% 50% 100%
rule...........................................................
Reduced time burden of the proposed rule (hours)................ 0.25 0.5 1
Hourly wage, IRB administrator.................................. $134.50 $134.50 $134.50
Hourly wage, IRB chair.......................................... $109.40 $109.40 $109.40
Hourly wage, IRB voting member.................................. $109.40 $109.40 $109.40
Hourly wage, IRB administrative staff........................... $35.94 $35.94 $35.94
Total cost savings of the proposed rule......................... $59,408 $237,631 $950,524
Net present value of the proposed rule (3%)..................... $57,677 $230,710 $922,839
Net present value of the proposed rule (7%)..................... $55,521 $222,085 $888,340
Annualized cost savings of the proposed rule (3%, 10 years)..... $6,762 $27,046 $108,185
Annualized cost savings of the proposed rule (7%, 10 years)..... $6,509 $26,035 $104,141
----------------------------------------------------------------------------------------------------------------

C. Costs of the Proposed Rule

D. Executive Order 13771

Executive Order 13771 requires that the costs associated with
significant new regulations ``shall, to the extent permitted by law, be
offset by the elimination of existing costs associated with at least
two prior regulations.'' We believe that the proposed rule, if
finalized, is deregulatory under Executive Order 13771 and does not
require us to identify cost offsets.
The net present value of the cost savings of the proposed rule are
approximately $222.1 thousand, discounted at 7 percent, with a lower
bound of approximately $55.5 thousand and an upper bound of
approximately $888.3 thousand. The annualized cost savings of the
proposed rule are approximately $15,546, discounted at 7 percent on an
infinite time horizon, with a lower bound of approximately $3,886 and
an upper bound of approximately $62,184. Discounted at 3 percent, the
net present value of the cost savings of the proposed rule are
approximately $230.7 thousand, with a lower bound of approximately
$57.7 thousand and an upper bound of approximately $922.8 thousand. The
annualized cost savings of the proposed rule are approximately $6,921,
discounted at 3 percent on an infinite time horizon, with a lower bound
of approximately $1,730 and an upper bound of approximately $27,685.
The estimated net cost savings under Executive Order 13771 are
summarized in table 2.

Table 2--Summary of Executive Order 13771 Net Cost Savings
--------------------------------------------------------------------------------------------------------------------------------------------------------
Lower bound Upper bound Lower bound Upper bound
Primary (7%) (7%) (7%) Primary (3%) (3%) (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs.................................. .............. .............. .............. .............. .............. ..............
Present Value of Cost Savings........................... $222,085 $55,521 $888,340 $230,710 $57,677 $922,839
Present Value of Net Cost Savings....................... 222,085 55,521 888,340 230,710 57,677 922,839
Annualized Costs........................................ .............. .............. .............. .............. .............. ..............
Annualized Cost Savings................................. 15,546 3,886 62,184 6,921 1,730 27,685
Annualized Net Cost Savings............................. 15,546 3,886 62,184 6,921 1,730 27,685
--------------------------------------------------------------------------------------------------------------------------------------------------------

VI. Analysis of Environmental Impact

We have 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.

VII. Paperwork Reduction Act of 1995

This proposed rule refers to previously approved collections of
information found in FDA regulations. These collections of information
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). IRB
actions related to the waiver or alteration of informed consent
requirements are currently approved under OMB control numbers 0910-
0014, 0910-0078, 0910-0130, and 0910-0755. Therefore, FDA tentatively
concludes the requirements in this document are not subject to
additional review by OMB.

VIII. Consultation and Coordination With Indian Tribal Governments

We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We

[[Page 57385]]

have tentatively determined that the rule does not contain policies
that would have a substantial direct effect on one or more Indian
Tribes, on the relationship between the Federal Government and Indian
Tribes, or on the distribution of power and responsibilities between
the Federal Government and Indian Tribes. The Agency solicits comments
from tribal officials on any potential impact on Indian Tribes from
this proposed action.

IX. Federalism

We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the Executive Order and,
consequently, a federalism summary impact statement is not required.

X. References

The following references are on display in the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.

1. Government Publishing Office, ``Federal Policy for the Protection
of Human Subjects'', 82 FR 7149 (January 19, 2017), available at:
https://www.gpo.gov/fdsys/pkg/FR-2017-01-19/pdf/2017-01058.pdf,
accessed on September 20, 2017.
2. Memorandum to File, FDA summary of data analysis; HHS, ``Office
for Human Research Protections (OHRP) Database for Registered IORGs
& IRBs, Approved FWAs, and Documents Received in Last 60 Days'',
prepared by Christian Brown, FDA, September 20, 2017.
3. Memorandum to File, FDA staff meeting on the Institutional Review
Board Waiver or Alteration of Informed Consent for Minimal Risk
Clinical Investigations rulemaking, prepared by Christian Brown,
FDA, September 20, 2017, addendum August 20, 2018.
4. Bureau of Labor and Statistics, ``Occupational Employment and
Wages, May 2016, 11-9033 Education Administrators, Postsecondary'',
available at: https://www.bls.gov/oes/2016/may/oes119033.htm,
accessed on September 20, 2017.
5. Bureau of Labor and Statistics, ``Occupational Employment and
Wages, May 2016, 43-0000 Office and Administrative Support
Occupations (Major Group)'', available at: https://www.bls.gov/oes/2016/may/oes430000.htm, accessed on September 20, 2017.
6. Bureau of Labor and Statistics, ``May 2016 National Occupational
Employment and Wage Estimates, United States'', available at:
https://www.bls.gov/oes/2016/may/oes_nat.htm, accessed on September
20, 2017.

List of Subjects

21 CFR Part 50

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

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 812

Health records, Medical devices, Medical research, Reporting and
recordkeeping requirements.

Therefore under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 50,
312, and 812 be amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

0
1. The authority citation for 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. In Sec. 50.20 revise the first sentence to read as follows:

Sec. 50.20 General requirements for informed consent.

Except as provided in Sec. Sec. 50.22, 50.23, and 50.24, no
investigator may involve a human being as a subject in research covered
by these regulations unless the investigator has obtained the legally
effective informed consent of the subject or the subject's legally
authorized representative. * * *
0
3. Add Sec. 50.22 to subpart B to read as follows:

Sec. 50.22 Exception from informed consent requirements for minimal
risk clinical investigations.

The IRB responsible for the review, approval, and continuing review
of the clinical investigation described in this section may approve an
informed consent procedure that does not include or that alters some or
all of the elements of informed consent set forth in Sec. 50.25(a) and
(b), or that waives the requirement to obtain informed consent,
provided the IRB finds and documents the following:
(a) The clinical investigation involves no more than minimal risk
to the subjects;
(b) The waiver or alteration will not adversely affect the rights
and welfare of the subjects;
(c) The clinical investigation could not practicably be carried out
without the waiver or alteration; and
(d) Whenever appropriate, the subjects will be provided with
additional pertinent information after participation.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

0
4. The authority citation for part 312 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371;
42 U.S.C. 262.

0
5. Revise Sec. 312.60 to read as follows:

Sec. 312.60 General responsibilities of investigators.

An investigator is responsible for ensuring that an investigation
is conducted according to the signed investigator statement, the
investigational plan, and applicable regulations; for protecting the
rights, safety, and welfare of subjects under the investigator's care;
and for the control of drugs under investigation. An investigator shall
obtain the informed consent of each human subject to whom the drug is
administered, in accordance with part 50 of this chapter. Additional
specific responsibilities of clinical investigators are set forth in
this part and in parts 50 and 56 of this chapter.

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

0
6. The authority citation for part 812 continues to read as follows:

Authority: 21 U.S.C. 331, 351, 352, 353, 355, 360, 360c-360f,
360h-360j, 360bbb-8b, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C.
216, 241, 262, 263b-263n.

0
7. Revise Sec. 812.2 (b)(1)(iii) to read as follows:

Sec. 812.2 Applicability.

* * * * *
(b) * * *
(1) * * *
(iii) Ensures that each investigator participating in an
investigation of the

[[Page 57386]]

device obtains from each subject under the investigator's care,
informed consent in accordance with part 50 of this chapter.
* * * * *

Dated: November 7, 2018.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2018-24822 Filed 11-13-18; 8:45 am]
BILLING CODE 4164-01-P