Federal Register / Vol. 88, No. 180 / Tuesday, September 19, 2023 / Notices 64445 

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Evidence; Draft Guidance for Industry; 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. 

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the 2019 draft guidance for industry 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Effectiveness draft guidance) and the 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written comments on the draft guidance 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draft guidance before it begins work on 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 WellControlled 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 


ddrumheller on DSK120RN23PROD with NOTICES1
64446 Federal Register / Vol. 88, No. 180 / Tuesday, September 19, 2023 / Notices 

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 wellcontrolled 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/guidancecompliance-regulatory-information/ 

guidances-drugs, https://www.fda.gov/ 

vaccines-blood-biologics/guidancecompliance-regulatory-informationbiologics, https://www.fda.gov/ 

regulatory-information/search-fdaguidance-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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

National Institute on Aging; Notice of 

Closed Meeting 

Pursuant to section 1009 of the 

Federal Advisory Committee Act, as 

amended, notice is hereby given of the 

following meeting. 

The meeting will be closed to the 

public in accordance with the 

provisions set forth in sections 

552b(c)(4) and 552b(c)(6), title 5 U.S.C., 

as amended. The grant applications and 

the discussions could disclose 

confidential trade secrets or commercial 

property such as patentable material, 

and personal information concerning 

individuals associated with the grant 

applications, the disclosure of which 

would constitute a clearly unwarranted 

invasion of personal privacy. 

Name of Committee: National Institute on 

Aging Special Emphasis Panel; Interorgan 

signal. 

Date: October 19–20, 2023. 

Time: 10:00 a.m. to 6:00 p.m. 

Agenda: To review and evaluate grant 

applications. 

Place: National Institute on Aging, 

Gateway Building, 7201 Wisconsin Avenue, 

Bethesda, MD 20892 (Virtual Meeting). 

Contact Person: Nijaguna Prasad, Ph.D., 

Scientific Review Officer, Scientific Review 

Branch, National Institutes of Health, 

National Institute on Aging, 7201 Wisconsin 

Avenue, Gateway Building, Suite 2W200, 

Bethesda, MD 20892, (301) 496–9667, 

prasadnb@nia.nih.gov. 

(Catalogue of Federal Domestic Assistance 

Program Nos. 93.866, Aging Research, 

National Institutes of Health, HHS) 

Dated: September 14, 2023. 

Miguelina Perez, 

Program Analyst, Office of Federal Advisory 

Committee Policy. 

[FR Doc. 2023–20239 Filed 9–18–23; 8:45 am] 

BILLING CODE 4140–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

National Institute of Diabetes and 

Digestive and Kidney Diseases; 

Amended Notice of Meeting 

Notice is hereby given of a change in 

the meeting of the Digestive Diseases 


ddrumheller on DSK120RN23PROD with NOTICES1