
[Federal Register Volume 88, Number 180 (Tuesday, September 19, 2023)]
[Notices]
[Pages 64445-64446]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-20228]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-D-2318]


Demonstrating Substantial Evidence of Effectiveness Based on One 
Adequate and Well-Controlled Clinical Investigation and Confirmatory 
Evidence; Draft Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a draft guidance for industry entitled 
``Demonstrating Substantial Evidence of Effectiveness Based on One 
Adequate and Well-Controlled Clinical Investigation and Confirmatory 
Evidence.'' This guidance complements the 2019 draft guidance for 
industry entitled ``Demonstrating Substantial Evidence of Effectiveness 
for Human Drug and Biological Products'' (the 2019 Effectiveness draft 
guidance) and the 1998 guidance for industry entitled ``Providing 
Clinical Evidence of Effectiveness for Human Drug and Biological 
Products'' (the 1998 Effectiveness guidance). Although FDA's 
evidentiary standard has not changed since 1998, there is a need for 
more Agency guidance to describe how one adequate and well-controlled 
clinical investigation and confirmatory evidence can be used to meet 
the substantial evidence requirement.

DATES: Submit either electronic or written comments on the draft 
guidance by December 18, 2023 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

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 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 as follows:
     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-2023-D-2318 for ``Demonstrating Substantial Evidence of 
Effectiveness Based on One Adequate and Well-Controlled Clinical 
Investigation and Confirmatory Evidence.'' Received comments 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, 240-402-7500.
     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.govinfo.gov/content/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, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the draft guidance to 
the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10001 New Hampshire Ave., 
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002; or the 
Office of Communication, Outreach, and Development, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. 
Send one self-addressed adhesive label to assist that office in 
processing your requests. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Eithu Lwin, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 22, Rm. 6236, Silver Spring, MD 20993-0002, 301-796-0728; or Anne 
Taylor, Center for Biologics Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7242, Silver 
Spring, MD 20993-0002, 240-402-8113.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Demonstrating Substantial Evidence of Effectiveness Based on 
One Adequate and Well-Controlled Clinical Investigation and 
Confirmatory Evidence.'' This guidance complements the 2019 draft 
guidance entitled ``Demonstrating Substantial Evidence of Effectiveness 
for Human Drug and

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Biological Products'' issued on December 20, 2019 (84 FR 70196) and the 
1998 guidance entitled ``Providing Clinical Evidence of Effectiveness 
for Human Drug and Biological Products'' issued on May 15, 1998 (63 FR 
27093).
    In 1962, Congress required for the first time that new drugs be 
shown to be effective as well as safe. A new drug's effectiveness must 
be established by substantial evidence. FDA has interpreted this 
substantial evidence requirement as generally requiring two adequate 
and well-controlled clinical investigations, each convincing on its 
own, to establish effectiveness.
    In 1997, Congress amended section 505(d) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) (21 U.S.C. 355(d)) to make clear that FDA 
may consider data from one adequate and well-controlled investigation 
and confirmatory evidence to constitute substantial evidence if FDA 
determines that such data are sufficient to establish effectiveness. 
FDA issued the 1998 Effectiveness guidance in response to this 
legislative change. In 2019, the Agency concluded that more guidance 
was needed on the flexibility in the amount and type of evidence needed 
to meet the substantial evidence standard and issued the 2019 
Effectiveness draft guidance, which discussed a number of approaches 
that can yield evidence that meets the statutory standard for 
substantial evidence.
    Although both the 1998 Effectiveness guidance and the 2019 
Effectiveness draft guidance provide examples of how a single adequate 
and well-controlled clinical investigation and confirmatory evidence 
can be used to support a marketing application, these guidances are not 
intended to provide a comprehensive discussion of meeting the 
substantial evidence standard based on one adequate and well-controlled 
clinical investigation and confirmatory evidence. Thus, there is a need 
for more Agency guidance to describe how one adequate and well-
controlled clinical investigation and confirmatory evidence can be used 
to meet the substantial evidence requirement.
    When one adequate and well-controlled clinical investigation and 
confirmatory evidence are considered together to assess effectiveness, 
the quality and quantity of the confirmatory evidence are also 
important considerations. Confirmatory evidence should be evidence 
generated from quality data derived from an appropriate source. The 
quantity of confirmatory evidence needed in a development program will 
be impacted by the features of, and results from, the single adequate 
and well-controlled clinical investigation that the confirmatory 
evidence is intended to substantiate.
    This draft guidance describes these considerations in greater 
detail. It also provides examples of the types of evidence that could 
be considered confirmatory evidence that can be used with one adequate 
and well-controlled clinical investigation to demonstrate substantial 
evidence of effectiveness. Finally, the draft guidance includes 
recommendations for early engagement with the Agency for sponsors who 
intend to establish substantial evidence of effectiveness with one 
adequate and well-controlled clinical investigation and confirmatory 
evidence.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on 
``Demonstrating Substantial Evidence of Effectiveness Based on One 
Adequate and Well-Controlled Clinical Investigation and Confirmatory 
Evidence.'' It does not establish any rights for any person and is not 
binding on FDA or the public. You can use an alternative approach if it 
satisfies the requirements of the applicable statutes and regulations.

II. Paperwork Reduction Act of 1995

    While this guidance contains no new collection of information, it 
does refer to previously approved FDA collections of information. The 
previously approved collections of information are subject to review by 
the Office of Management and Budget (OMB) under the Paperwork Reduction 
Act of 1995 (PRA) (44 U.S.C. 3501-3521). The collections of information 
in 21 CFR parts 58, 312, 314, and 601 have been approved under OMB 
control numbers 0910-0119, 0910-0014, 0910-0001, and 0910-0338, 
respectively. In addition, the collections of information pertaining to 
FDA's guidance entitled ``Formal Meetings Between the FDA and Sponsors 
or Applicants of PDUFA Products'' have been approved under OMB control 
number 0910-0001.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or 
https://www.regulations.gov.

    Dated: September 14, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-20228 Filed 9-18-23; 8:45 am]
BILLING CODE 4164-01-P


