Federal Register / Vol. 87, No. 69 / Monday, April 11, 2022 / Notices 21127 

TABLE 2—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1 2

Activity; 21 CFR section Number of 

recordkeepers 

Number of 

records per 

recordkeeper 

Total annual 

records 

Average burden per 

recordkeeping Total hours 

Controls for low-acid canned foods; 1.502(b) .......... 2,443 4 9,772 1 ................................ 9,772 

Hazard determinations, controls, and audits; 1.504, 

1.506, 1.511.

56,800 87.74 4,984,036 0.38 (23 minutes) ..... 1,917,174 

Written assurances for food produced under dietary 

supplement current good manufacturing practices; 1.511.

11,701 2.88 33,664 2.25 ........................... 75,744 

Document very small importer/certain small foreign 

supplier status; 1.512(b)(1).

50,450 1 50,450 1 ................................ 50,450 

Written assurances associated with very small importer/certain small foreign supplier; 1.512(b)(3).50,450 2.79 141,084 2.25 ........................... 317,439 

Total ................................................................... ........................ ........................ 5,219,006 ................................... 2,370,579 

1There are no capital costs or operating and maintenance costs associated with the information collection. 

2Figures have been rounded to the nearest one hundredth. 

Upon evaluation of the information 

collection, we are retaining the 

currently approved burden estimates. 

Dated: April 5, 2022. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2022–07617 Filed 4–8–22; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2019–D–3049] 

E8(R1) General Considerations for 

Clinical Studies; International Council 

for Harmonisation; 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 final 

guidance for industry entitled ‘‘E8(R1) 

General Considerations for Clinical 

Studies.’’ The guidance was prepared 

under the auspices of the International 

Council for Harmonisation (ICH), 

formerly the International Conference 

on Harmonisation. The guidance 

describes internationally accepted 

principles and practices for the design 

and conduct of clinical studies of drug 

and biological products. In addition, the 

guidance provides an overview of the 

types of clinical studies that may be 

performed and data sources used during 

the product’s life cycle. The guidance is 

intended to promote the quality of the 

studies submitted to regulatory 

authorities, while allowing for 

flexibility. This guidance revises the 

guidance for industry ‘‘E8 General 

Considerations for Clinical Trials’’ 

issued in December 1997. 

DATES: The announcement of the 

guidance is published in the Federal 

Register on April 11, 2022. 

ADDRESSES: You may submit either 

electronic or written comments on 

Agency guidances 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– 

2019–D–3049 for ‘‘E8(R1) General 

Considerations for Clinical Studies.’’ 

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 


lotter on DSK11XQN23PROD with NOTICES1
21128 Federal Register / Vol. 87, No. 69 / Monday, April 11, 2022 / Notices 

1We support the principles of the ‘‘3Rs,’’ to 

reduce, refine, and replace animal use in testing 

when feasible. We encourage sponsors to consult 

with us if it they wish to use a non-animal testing 

method they believe is suitable, adequate, 

validated, and feasible. We will consider if such an 

alternative method could be assessed for 

equivalency to an animal test method. 

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 this 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 

(CBER), 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. The guidance may also be 

obtained by mail by calling CBER at 

1–800–835–4709 or 240–402–8010. See 

the SUPPLEMENTARY INFORMATION section 

for electronic access to the guidance 

document. 

FOR FURTHER INFORMATION CONTACT: 

Regarding the guidance: Mark 

Levenson, Center for Drug Evaluation 

and Research, Food and Drug 

Administration, Bldg. 21, Rm. 4626, 

Silver Spring, MD 20993–0002, 301– 

796–2097, Mark.Levenson@fda.hhs.gov; 

or Stephen Ripley, Center for Biologics 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 71, Rm. 7301, 

Silver Spring, MD 20993–0002, 240– 

402–7911. 

Regarding the ICH: Jill Adleberg, 

Center for Drug Evaluation and 

Research, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 51, Rm. 6364, Silver Spring, 

MD 20993–0002, 301–796–5259, 

Jill.Adleberg@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

FDA is announcing the availability of 

a final guidance for industry entitled 

‘‘E8(R1) General Considerations for 

Clinical Studies’’. The guidance was 

prepared under the auspices of ICH. ICH 

has the mission of achieving greater 

regulatory harmonization worldwide to 

ensure that safe, effective, high-quality 

medicines are developed, registered, 

and maintained in the most resourceefficient manner. 

By harmonizing the regulatory 

requirements in regions around the 

world, ICH guidelines have 

substantially reduced duplicative 

clinical studies, prevented unnecessary 

animal studies,1 standardized the 

reporting of important safety 

information, standardized marketing 

application submissions, and made 

many other improvements in the quality 

of global drug development and 

manufacturing and the products 

available to patients. 

The six Founding Members of the ICH 

are FDA; the Pharmaceutical Research 

and Manufacturers of America; the 

European Commission; the European 

Federation of Pharmaceutical Industries 

Associations; the Japanese Ministry of 

Health, Labour, and Welfare; and the 

Japanese Pharmaceutical Manufacturers 

Association. The Standing Members of 

the ICH Association include Health 

Canada and Swissmedic. Additionally, 

the Membership of ICH has expanded to 

include other regulatory authorities and 

industry associations from around the 

world (refer to https://www.ich.org/). 

ICH works by involving technical 

experts from both regulators and 

industry parties in detailed technical 

harmonization work and the application 

of a science-based approach to 

harmonization through a consensusdriven process that results in the 

development of ICH guidelines. The 

regulators around the world are 

committed to consistently adopting 

these consensus-based guidelines, 

realizing the benefits for patients and for 

industry. 

As a Founding Regulatory Member of 

ICH, FDA plays a major role in the 

development of each of the ICH 

guidelines, which FDA then adopts and 

issues as guidance for industry. FDA’s 

guidance documents do not establish 

legally enforceable responsibilities. 

Instead, they describe the Agency’s 

current thinking on a topic and should 

be viewed only as recommendations, 

unless specific regulatory or statutory 

requirements are cited. 

In the Federal Register of August 1, 

2019 (84 FR 37649), FDA published a 

notice announcing the availability of a 

draft guidance entitled ‘‘E8(R1) General 

Considerations for Clinical Studies.’’ 

The notice gave interested persons an 

opportunity to submit comments by 

September 30, 2019. After consideration 

of the comments received and revisions 

to the guideline, a final draft of the 

guideline was submitted to the ICH 

Assembly and endorsed by the 

regulatory agencies in October 2021. 

This guidance finalizes the draft 

guidance issued on August 1, 2019. The 

revised final guidance describes 

internationally accepted principles and 

practices in the design and conduct of 

clinical studies of drug and biological 

products. Changes from the 2019 draft 

guidance to the final guidance include 

a reduced emphasis on distinct phases 

of clinical development, the addition of 

examples of novel studies, and 

amendments to appendices. The 

original ICH guidance ‘‘E8 General 

Considerations for Clinical Trials,’’ that 

was issued in 1997 has not undergone 

revision previously. Since the 1997 

guidance was issued, clinical trial 

design and conduct have become more 

complex, impacting the time and 

feasibility of developing drugs. In 

response, the revised guidance directly 

addresses study quality to ensure the 

protection of study participants and the 

generation of reliable and meaningful 

results, while promoting study 

efficiency. The ICH E8(R1) guidance 

focuses on the identification of factors 

that are critical to the study quality and 

the management of risks to those factors. 

Additionally, a wider range of study 

designs and data sources play an 

increasingly important role in drug 

development and are not adequately 

addressed in the original ICH E8 

guidance. Hence, the revised final 

guidance addresses a broad range of 

study designs and data sources. The 

revised final guidance also provides 

updated cross-referencing to other 

relevant ICH guidances that inform the 

design, planning, and conduct of 

clinical research, without reproducing 

the detailed material found in those 

guidances. 

This guidance is being issued 

consistent with FDA’s good guidance 

practices regulation (21 CFR 10.115). 

The guidance represents the current 

thinking of FDA on ‘‘E8(R1) General 

Considerations for Clinical Studies.’’ It 

does not establish any rights for any 

person and is not binding on FDA or the 


lotter on DSK11XQN23PROD with NOTICES1
Federal Register / Vol. 87, No. 69 / Monday, April 11, 2022 / Notices 21129 

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 

collection of information, it does refer to 

previously approved FDA collections of 

information. Therefore, clearance by the 

Office of Management and Budget 

(OMB) under the Paperwork Reduction 

Act of 1995 (PRA) (44 U.S.C. 3501– 

3521) is not required for this guidance. 

The previously approved collections of 

information are subject to review by 

OMB under the PRA. The collections of 

information for investigational new drug 

applications under have been approved 

under OMB control number 0910–0014; 

the collections of information for review 

of new drug applications in have been 

approved under OMB control number 

0910–0001; and the collections of 

information for review of biologic 

licensing applications in have been 

approved under OMB control number 

0910–0338. 

III. Electronic Access 

Persons with access to the internet 

may obtain the guidance at https://

www.regulations.gov, https://

www.fda.gov/drugs/guidancecompliance-regulatory-information/ 

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

regulatory-information/search-fdaguidance-documents, or https://

www.fda.gov/vaccines-blood-biologics/ 

guidance-compliance-regulatoryinformation-biologics/biologicsguidances. 

Dated: April 5, 2022. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2022–07690 Filed 4–8–22; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Office of the Secretary 

Findings of Research Misconduct 

AGENCY: Office of the Secretary, HHS. 

ACTION: Notice. 

SUMMARY: Findings of research 

misconduct have been made against 

Toni M. Brand, Ph.D. (Respondent), 

who was a graduate student in the 

Department of Human Oncology, 

University of Wisconsin-Madison 

(UWM), and subsequently a research 

fellow in the Department of 

Otolaryngology—Head and Neck 

Surgery, University of California San 

Francisco (UCSF). Respondent engaged 

in research misconduct in research 

supported by U.S. Public Health Service 

(PHS) funds, specifically National 

Cancer Institute (NCI), National 

Institutes of Health (NIH), grants P30 

CA014520, K99 CA160639, T32 

CA108462, and U54 CA209891, 

National Center for Research Resources 

(NCRR), NIH, grant UL1 RR025011, 

National Center for Translational 

Sciences (NCATS), NIH, grants U54 

TR000021 and UL1 TR000427, National 

Institute of General Medical Sciences 

(NIGMS), NIH, grant T32 GM081061, 

and National Institute of Dental and 

Craniofacial Research (NIDCR), NIH, 

grant R01 DE023685. The administrative 

actions, including supervision for a 

period of four (4) years, were 

implemented beginning on March 23, 

2022, and are detailed below. 

FOR FURTHER INFORMATION CONTACT: 

Wanda K. Jones, Dr. P.H., Acting 

Director, Office of Research Integrity, 

1101 Wootton Parkway, Suite 240, 

Rockville, MD 20852, (240) 453–8200. 

SUPPLEMENTARY INFORMATION: Notice is 

hereby given that the Office of Research 

Integrity (ORI) has taken final action in 

the following case: 

Toni M. Brand, Ph.D., University of 

Wisconsin-Madison and University of 

California San Francisco: Based on the 

reports of investigations conducted by 

UWM and UCSF and additional analysis 

conducted by ORI in its oversight 

review, ORI found that Dr. Toni M. 

Brand, who was a graduate student in 

the Department of Human Oncology, 

UWM, and subsequently a research 

fellow in the Department of 

Otolaryngology—Head and Neck 

Surgery, UCSF, engaged in research 

misconduct in research supported by 

PHS funds, specifically NCI, NIH, grants 

P30 CA014520, K99 CA160639, T32 

CA108462, and U54 CA209891, NCRR, 

NIH, grant UL1 RR025011, NCATS, 

NIH, grants U54 TR000021 and UL1 

TR000427, NIGMS, NIH, grant T32 

GM081061, and NIDCR, NIH, grant R01 

DE023685. 

ORI found that Respondent engaged 

in research misconduct by knowingly or 

recklessly falsifying or fabricating 

western blot data, by reusing and 

relabeling data to represent expression 

of proteins in control experiments 

measuring the purity of cytoplasmic and 

nuclear cell fractionation, 

measurements of proteins of interest, 

and measurements of the same protein 

under different experimental conditions 

or loading controls, included in twentyfour (24) figures in the following grant 

application submitted to NIDCR, NIH, 

her Ph.D. Thesis Dissertation, and seven 

(7) published papers: 

• K99 DE027699–01, ‘‘Targeting HPVdriven immunosuppressive signaling 

pathways in head and neck cancer,’’ 

submitted to NIDCR, NIH, on June 8, 

2017. 

• Ph.D. Thesis Dissertation, 

‘‘Investigations of Nuclear HER family 

receptors in cancer and resistance to 

cetuximab therapy,’’ Department of 

Human Oncology, UWM, March 21, 

2014 (hereafter referred to as ‘‘Thesis’’). 

• Mapping C-terminal transactivation 

domains of the nuclear HER family 

receptor tyrosine kinase HER3. PLoS 

One 2013 Aug 8;8(8):e71518; doi: 

10.1371/journal.pone.0071518. 

eCollection 2013 (hereafter referred to as 

‘‘PLoS One 2013’’). 

• Nuclear EGFR as a molecular target 

in cancer. Radiother Oncol. 2013 

Sep;108(3):370–7; doi: 10.1016/ 

j.radonc.2013.06.010 (hereafter referred 

to as ‘‘Radiother Oncol. 2013’’). 

Corrected in: Radiother Oncol. 2019 

Jan;130:195; doi: 10.1016/ 

j.radonc.2018.10.011. 

• Nuclear epidermal growth factor 

receptor is a functional molecular target 

in triple-negative breast cancer. Mol 

Cancer Ther. 2014 May;13(5):1356–68; 

doi: 10.1158/1535–7163.MCT–13–1021 

(hereafter referred to as ‘‘Mol Cancer 

Ther. 2014’’). Corrected in: Mol Cancer 

Ther. 2019 Apr;18(4):868; doi: 10.1158/ 

1535–7163.MCT–18–1183. 

• AXL mediates resistance to 

cetuximab therapy. Cancer Res. 2014 

Sep 15;74(18):5152–64; doi: 10.1158/ 

0008–5472.CAN–14–0294 (hereafter 

referred to as ‘‘Cancer Res. 2014’’). 

• The receptor tyrosine kinase AXL 

mediates nuclear translocation of the 

epidermal growth factor receptor. Sci 

Signal. 2017 Jan 3;10(460):eaag1064; 

doi: 10.1126/scisignal.aag1064 

(hereafter referred to as ‘‘Sci Signal. 

2017’’). Retracted in: Sci Signal. 2021 

Nov 9;14(708):eabn0168; doi: 10.1126/ 

scisignal.abn0168. 

• Human Papillomavirus Regulates 

HER3 Expression in Head and Neck 

Cancer: Implications for Targeted HER3 

Therapy in HPV + Patients. Clin Cancer 

Res. 2017 Jun 15;23(12):3072–3083; doi: 

10.1158/1078–0432.CCR–16–2203 

(hereafter referred to as ‘‘Clin Cancer 

Res. 2017’’). Corrected in: Clin Cancer 

Res. 2021 Jul 15;27(14):4129; doi: 

10.1158/1078–0432.CCR–21–2141. 

• Cross-talk Signaling between HER3 

and HPV16 E6 and E7 Mediates 

Resistance to PI3K Inhibitors in Head 

and Neck Cancer. Cancer Res. 2018 May 

1;78(9):2383–95; doi: 10.1158/0008– 

5472.CAN–17–1672 (hereafter referred 

to as ‘‘Cancer Res. 2018’’). 


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