[Federal Register Volume 88, Number 160 (Monday, August 21, 2023)]
[Notices]
[Page 56894]
[FR Doc No: 2023-17996]

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SECURITIES AND EXCHANGE COMMISSION

Sunshine Act Meeting

TIME AND DATE: Notice is hereby given, pursuant to the provisions of
the Government in the Sunshine Act, Public Law 94-409, that the
Securities and Exchange Commission will hold an Open Meeting on
Wednesday, August 23, 2023 at 10:00 a.m.

PLACE: The meeting will be webcast on the Commission's website at
www.sec.gov.

STATUS: This meeting will begin at 10:00 a.m. (ET) and will be open to
the public via webcast on the Commission's website at www.sec.gov.

MATTERS TO BE CONSIDERED:
    1. The Commission will consider whether to adopt rule amendments to
narrow an exemption from the requirement under the Securities Exchange
Act of 1934 that any Commission-registered broker-dealer become a
member of a national securities association if it effects securities
transactions elsewhere than an exchange where it is a member.
    2. The Commission will consider whether to adopt rules and
amendments under the Investment Advisers Act of 1940 (``Advisers Act'')
for private fund advisers and whether to adopt amendments to the
compliance rule under the Advisers Act.

CONTACT PERSON FOR MORE INFORMATION: For further information and to
ascertain what, if any, matters have been added, deleted or postponed,
please contact Vanessa A. Countryman from the Office of the Secretary
at<PHONE_NUMBER>.
    Authority: 5 U.S.C. 552b.

    Dated: August 16, 2023.
Sherry R. Haywood,
Assistant Secretary.
[FR Doc. 2023-17996 Filed 8-17-23; 11:15 am]
BILLING CODE 8011-01-P


[Federal Register Volume 81, Number 236 (Thursday, December 8, 2016)]
[Notices]
[Page 88695]
[FR Doc No: 2016-29376]

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DEPARTMENT OF HOMELAND SECURITY

Federal Emergency Management Agency

[Internal Agency Docket No. FEMA-4285-DR; Docket ID FEMA-2016-0001]

North Carolina; Amendment No. 15 to Notice of a Major Disaster
Declaration

AGENCY: Federal Emergency Management Agency, DHS.

ACTION: Notice.

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SUMMARY: This notice amends the notice of a major disaster declaration
for the State of North Carolina (FEMA-4285-DR), dated October 10, 2016,
and related determinations.

DATES: Effective Date: November 21, 2016.

FOR FURTHER INFORMATION CONTACT: Dean Webster, Office of Response and
Recovery, Federal Emergency Management Agency, 500 C Street SW.,
Washington, DC 20472,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION: The notice of a major disaster declaration
for the State of North Carolina is hereby amended to include the
following areas among those areas determined to have been adversely
affected by the event declared a major disaster by the President in his
declaration of October 10, 2016.

    Montgomery County for Public Assistance, including direct
federal assistance.
    Beaufort, Bertie, Brunswick, Camden, Carteret, Chowan, Columbus,
Craven, Currituck, Dare, Duplin, Edgecombe, Gates, Greene, Harnett,
Hertford, Hyde, Jones, Lenoir, Martin, Moore, Northampton, Onslow,
Pasquotank, Pender, Perquimans, Pitt, Robeson, Sampson, Tyrrell,
Washington, Wayne, and Wilson Counties for Public assistance
[Categories C-G] (already designated for Individual Assistance and
assistance for debris removal and emergency protective measures
[Categories A and B], including direct federal assistance, under the
Public Assistance program).
    New Hanover and Pamlico Counties for Public Assistance
[Categories C-G] (already designated for assistance for debris
removal and emergency protective measures [Categories A and B],
including direct federal assistance, under the Public Assistance
program).

The following Catalog of Federal Domestic Assistance Numbers (CFDA)
are to be used for reporting and drawing funds: 97.030, Community
Disaster Loans; 97.031, Cora Brown Fund; 97.032, Crisis Counseling;
97.033, Disaster Legal Services; 97.034, Disaster Unemployment
Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048,
Disaster Housing Assistance to Individuals and Households In
Presidentially Declared Disaster Areas; 97.049, Presidentially
Declared Disaster Assistance--Disaster Housing Operations for
Individuals and Households; 97.050 Presidentially Declared Disaster
Assistance to Individuals and Households--Other Needs; 97.036,
Disaster Grants--Public Assistance (Presidentially Declared
Disasters); 97.039, Hazard Mitigation Grant.

W. Craig Fugate,
Administrator, Federal Emergency Management Agency.
[FR Doc. 2016-29376 Filed 12-7-16; 8:45 am]
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Page 1 of 8 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 APR 14, 2006 MEMORANDUM: OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES SUBJECT: Initial Ethical Review of Carbofuran Human Dermal Study FROM: John M. Carley TO: John Liccione, HED REF: Arnold, J. D. ( 1978) Comparison of Cholinesterase Inhibition and Effects of Furadan 4F and FMC 35001 4EC. Unpublished study prepared by Quincy Research Center. 92 p. ( MRID 92829)

I have performed an initial review of available information concerning the referenced document. This review characterizes the ethical conduct of the research in terms of both current ethical standards and ethical standards prevailing when the study was performed. The review applies the " Summary Framework for Ethical Assessment Using Seven Criteria of Emanuel et al." developed by the EPA Science Policy Committee's Human Studies Work Group. The completed " framework" is attached. This framework was derived from the work of Emanuel, et al. ( 2000), which summarizes seven general principles for ethical treatment of human subjects in scientific research. The Emanuel article was primarily directed at those who consider proposals for new medical research and decide which are worthy of funding or approval. These are very different decisions from those we in EPA must make when we determine whether we can ethically consider already completed human studies.

The Emanuel article reflects current standards for ethical research prevailing in the U. S. This study was conducted in the U. S. in 1978, but cites no standard of ethical research conduct. I have applied FIFRA § 12( a)( 2)( P) and assumed the Declaration of Helsinki ( 1975) to have prevailed when the research was conducted.

A. Summary Assessment of Ethical Conduct of the Research Page 2 of 8 Here is a summary of my observations about the study under the seven headings used in the Emanuel framework. Supporting details are in the attachment.

1. Value of the Research to Society: This research has never been published, suggesting its purpose was not mainly to obtain generalizable knowledge. Its stated purpose was " to compare the effects of single cutaneous applications of Furadan 4F and FMC 35001 4EC in men exposed to high temperature and humidity." The study may provide some information on the toxicity of carbofuran to humans that could help to inform EPA's assessment of human health risks.

2. Scientific Validity of the Research: I defer to others for a full review of the scientific validity of this study. If it were determined not to have scientific validity, it would also not be ethically acceptable.

3. Subject Selection: Subjects were 20 healthy adult men, median age 36. Restriction to men was consistent with the stated intent to explore occupational exposure patterns. The pool from which subjects were drawn consisted mainly of unemployed semi skilled workers.

4. Risk Benefit Ratio: Potential symptoms were accurately listed in the information for volunteers, but risks were not minimized by the study design, which committed to dose escalation until toxic signs were observed. Volunteers were also told plainly that they would not benefit from participating. How the potential societal benefit of improved safety for production workers was weighed against the risks to subjects  either by the investigator or by the review committee  was not reported.

5. Independent Ethical Review: The protocol and related materials, including both the procedures and the information associated with informed consent, were reported to have been approved by the Community Review Committee, Inc., of Kansas City, MO. It is unusual in research from this period to have as much information as is provided here about the purpose and membership and freedom from conflicts of interest of the reviewing oversight committee.

6. Informed Consent: Both the information for subjects and the consent form itself were remarkable clear and complete for research conducted in this period. Subjects were given no indication, however, that the design of the research required dose escalation until frank toxic signs were elicited. Documentation is of poor readability, but it appears that no mention was made of the results of the previous human toxicity studies with carbofuran.

7. Respect for Potential and Enrolled Subjects: Subjects' privacy was not compromised. They were free to withdraw at any time.

B. Compliance with Ethical Standards Prevailing when the Research Was Conducted Page 3 of 8 No standard of ethical research conduct is cited, either by the reviewing ethics committee or by the authors. The research was conducted in the U. S. after 1972, so FIFRA § 12( a)( 2)( P) applies. In addition, as clinical research this falls within the scope of the Declaration of Helsinki. I have applied both standards in assessing the conduct of this study.

  FIFRA Sec. 12( a)( 2)( P) states: " In general, [ i] t shall be unlawful for any person . . . to use any pesticide in tests on human beings unless such human beings ( i) are fully informed of the nature and purposes of the test and of any physical and mental health consequences which are reasonably foreseeable therefrom, and ( ii) freely volunteer to participate in the test."

Although the information provided to subjects was extraordinarily complete for research from this period, subjects were not told that the design of the study required dose escalation until frank toxic effects were elicited. Instead they were told that " The purpose of the testing . . . is to find out the maximum safe dosage when applied to the skin . . . . The nature of the test compound . . . is such that we do not expect serious complications from its use." This falls short of the requirement that they be " fully informed of . . . any physical . . . consequences which are reasonably foreseeable."

  Basic Principle # 2 of the Declaration of Helsinki ( 1975) reads " The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to a specially appointed independent committee for consideration, comment and guidance."

The study asserts that the protocol was approved by the ethics committee, but the protocol itself is not available.

  Basic Principle # 5 of the Declaration of Helsinki ( 1975) reads " Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison to foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interest of science and society."

Societal benefits are not explicitly weighed against the risks to subjects. Comparable benefit could probably have been achieved through better methods of measuring ChE inhibition, without proceeding to elicitation of frank toxicity requiring administration of an antidote.

C. Standards for Judging Ethical Acceptability Page 4 of 8 On February 6, 2006, EPA published a final rule, " Protections for Subjects in Human Research," effective on April 7, 2006. Section 26.1704 of that regulation provides in pertinent part:

EPA shall not rely on data from any research initiated before [ effective date of the final rule] if there is clear and convincing evidence that the conduct of the research was fundamentally unethical ( e. g., the research was intended to seriously harm participants or failed to obtain informed consent), or was significantly deficient relative to the ethical standards prevailing at the time the research was conducted.

In addition, section 26.1703 of the final rule provides in pertinent part:

EPA shall not rely on data from any research involving intentional exposure of any human subject who is a pregnant woman ( and therefore her fetus) or child.

I have applied the standards in sections 26.1704 and 26.1703 in arriving at the conclusions below.

D. Conclusion All subjects were adult males. Section 26.1703 therefore does not prohibit reliance on this study.

Although there are some gaps in the documentation of the ethical conduct of this study, it is extraordinarily well documented for research from this period. There is no clear evidence that the research was intended to harm participants, or that it was fundamentally unethical in other ways. Deficient documentation does not itself constitute evidence that the ethical conduct of this study was deficient relative to standards prevailing when it was conducted.

From the documentation available, I have identified several deficiencies relative to the standards of FIFRA § 12( a)( 2)( P) and the 1975 Declaration of Helsinki. These deficiencies do not, in my judgment, amount to " clear and convincing evidence" that this study was " fundamentally unethical." This review, however, does not take a position on either the persuasiveness of the evidence or the overall significance of the identified deficiencies relative to prevailing ethical standards. This decision is deferred pending review of the research by the Human Studies Review Board as required by EPA regulation before EPA takes an action relying on this study.

Attachment Cited reference:

Emanuel, E.; Wender, D.; Grady, C. ( 2000) What Makes Clinical Research Ethical? JAMA 283: 2701 2711. Page 5 of 8 Framework for Ethical Assessment Using Seven Criteria of Emanuel et al. 1 April 14, 2006 Arnold, JD ( 1978) Comparison of Cholinesterase Inhibition and Effects of Furadan 4F and FMC 35001 4EC. Unpublished study prepared by Quincy Research Center. 92 p. MRID 92829.

1. Value: This research has never been published, suggesting its purpose was not mainly to advance generalizable knowledge. The study may, however, provide some information on the toxicity of carbofuran to humans that could help to inform EPA's assessment of human health risks.

a. What was the stated purpose of the research? "[ T] o compare the effects of single cutaneous applications of Furadan 4F and FMC 35001 4EC in men exposed to high temperature and humidity." [ p. 7]

b. Does it evaluate a diagnostic or therapeutic intervention that could lead to improvements in health or well being? No c. Does it test a hypothesis that can generate important knowledge about structure or function of human biological systems? No d. Will society benefit from the knowledge gained from this research? Will its results be disseminated?

It has never been published. Subjects were told " We do not expect you to derive any benefit from taking the test compound; however it is essential to determine the levels of this test compound when applied to the skin surface that are safe for the people manufacturing the compound as well as the people exposed to it during its use." [ p. 62]

e. What government, organization, company and/ or institution( s) funded the research? FMC ( registrant)

2. Scientific Validity: I defer to others for a full review of the scientific validity of this study. If it were determined not to have scientific validity, it would also not be ethically acceptable.

a. Did the research have a clear scientific objective? " Specific goals were: ( 1) To determine the effects of treatment on plasma and erythrocyte cholinesterase activity; ( 2) To determine the minimum dose level of each treatment which induces symptoms of cholinesterase inhibition; ( 3) to determine the effects of the two treatments on neurovegetative signs, pupil size and eye accommodation, and laboratory values." [ p. 7]

b. Was the research designed using accepted principles, methods, and reliable practices? I defer to the science reviewer Page 6 of 8 c. In what way were human subjects intentionally dosed in this research, and what endpoints were identified or measured? Subjects entered the clinic the evening before dosing. After eating a standard breakfast they entered a controlled environment with high temperature and humidity. They were pre tested for ChE and neurovegetative signs immediately before administration of the dose and repeatedly from 15 minutes to 6 h. post dose. For four hours post dose subjects alternated 5 minutes on an exercise machine with 15 minutes of rest, all the time in the chamber with elevated temperature and humidity. The initial dose of each compound was 0.5 mg/ kg; after evaluation of symptoms and data, doses escalated by doubling. Escalation was discontinued for 4F at 4.0 mg/ kg because of frank toxic signs in both subjects, and continued for 4EC up to 16.0 mg/ kg. Subjects remained in the clinic for 24 hours postdose Measures included RBC and plasma ChEI, pulse, blood pressure, pupil size, eye accommodation, and ECG.

d. Did the research design have sufficient power to definitively test the objective? I defer to the science reviewer e. To what purpose is the study used, or proposed for use, in the Agency? To inform the WOE in carbofuran reassessment 3. Fair Subject Selection: Subjects were 20 healthy adult men, median age 36. Restriction to men was consistent with the stated intent to explore occupational exposure patterns. The pool from which subjects were drawn consisted mainly of semi skilled workers without steady jobs.

a. Were the groups and individuals recruited and enrolled determined solely on the basis of the scientific goals of the study? Twenty healthy adult men participated in the research. Limitation to adult men was consistent with the stated intent to explore occupational exposure patterns.

b. Were any susceptible groups used in the study, such as children, prisoners, infirm, or impoverished? Did the burden of participation fall disproportionately on a particular group? The pool from which volunteers were drawn was described in these terms: "[ V] olunteers were 19 to 58 year old men with 60% between 20 and 40 and a median age of 34. Seventeen percent were black, 80% were white, and 3% were from other ethnic groups. Fifty two percent had completed the twelfth grade, and 16 percent had attended college. Sixty percent were semi skilled workers and 8% were steadily employed." [ p. 85]

4. Favorable Risk Benefit Ratio: Potential symptoms were accurately listed in the information for volunteers, but risks were not minimized by the study design, which committed to dose escalation until toxic signs were observed. Volunteers were also told plainly that they would not benefit from participating. How the potential societal benefit of improved safety for production workers was weighed against the risks to subjects  either by the investigator or by the review committee  was not reported.

a. How were the risks to individual subjects minimized? Research was conducted in a clinic under medical supervision. Subjects were told what kinds of symptoms they might experience, and encouraged to report any complaints. Atropine was available in the clinic, and was administered intravenously to the two subjects who received the 4 mg/ kg dose of Furadan 4F. A study design with a more robust baseline and better methods for analyzing ChE inhibition could probably have generated comparable knowledge without exposing the subjects to doses producing frank toxic signs requiring administration of an antidote.

b. If the research presents no health related benefits to individual subjects, what are the societal benefits in terms of knowledge from the study, and do these justify the excess risk to individual subjects? The results of this research may have been used to improve safety of Furadan production workers. Page 7 of 8 c. What compensation was paid to the participants in the study? Not reported.

5. Independent Review: The protocol and related materials, including both the procedures and the information associated with informed consent, were reported to have been approved by the Community Review Committee, Inc., of Kansas City, MO. It is unusual in research from this period to have as much information as is provided here about the purpose and membership and freedom from conflicts of interest of the reviewing oversight committee.

a. Was the research asserted to have been overseen by an ethics review body? Yes, the protocol and informed consent materials were reportedly reviewed and approved by the Community Review Committee, Inc., of Kansas City, MO. [ p. 83]

b. Was the research subject to independent review by individuals unaffiliated with the clinical research? " No member of the committee has any financial or professional relationship with the Quincy Research Center or its officers." [ p. 83]

c. Was the research conducted in compliance with the Common Rule? The research predates the Common Rule d. Does/ did the research institution ( or any institution participating in the research) hold a Federal Wide Assurance or Multi Project Assurance during the period of the study? n/ a e. Was the research conducted in compliance with another standard? What standard? No ethical standard was cited. FIFRA § 12( a)( 2)( P) applies, as does the Declaration of Helsinki ( 1975).

6. Informed Consent: Both the information for subjects and the consent form itself were remarkably clear and complete for research conducted in this period. Subjects were given no indication, however, that the design of the research required dose escalation until frank toxic signs were elicited. Documentation is of poor legibility, but it appears that no mention was made of the results of the previous human toxicity studies with carbofuran.

a. Does the research assert that informed consent was obtained from participants? Yes b. How and under what circumstances was informed consent obtained? " The purposes, procedures, and risks of the study were explained to the volunteers. This information was included in the consent form ( Appendix C), which was signed by every man before admission. Both the information process and the consent form had been approved by the Community Review Committee, Inc. ( Appendix A)" [ p. 12]

" The purpose of the testing . . . is to find out the maximum safe dosage when applied to the skin . . . . The nature of the test compound . . . is such that we do not expect serious complications from its use." [ p. 62] These statements in the volunteer information do not suggest the commitment in the design of the research to continue dose escalation until frank signs of toxicity were elicited.

7. Respect for Potential and Enrolled Subjects: Subjects' privacy was not compromised. They were free to withdraw at any time.

a. Was information about individual subjects managed so as to ensure their privacy? " The collection and submission of the medical information from this study will be accomplished with strict adherence to professional standards of confidentiality." [ p. 64] Page 8 of 8 b. Were subjects free to withdraw from the research without penalty? " As a volunteer, I understand that I am free to withdraw and discontinue my participation at any time upon my request. Both participation in the study as well as possible withdrawal are at my own free will without coercion, duress, or intimidation of any sort." [ p. 64]

1 Emanuel, E; Wender, D; Grady, C ( 2000) What Makes Clinical Research Ethical? JAMA 283: 2701 2711.