Document ID: FDA-2018-N-2727-0001
Agency: fda
Document Type: Proposed Rule
Title: Institutional Review Board Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations
Posted Date: 2018-11-15T05:00Z

[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

[[Page 57380]]

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

    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.

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