26856 Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices

FEDERAL RESERVE SYSTEM

Formations of, Acquisitions by, and

Mergers of Bank Holding Companies

The companies listed in this notice

have applied to the Board for approval,

pursuant to the Bank Holding Company

Act of 1956 (12 U.S.C. 1841 et seq.)

(BHC Act), Regulation Y (12 CFR Part

225), and all other applicable statutes

and regulations to become a bank

holding company and/or to acquire the

assets or the ownership of, control of, or

the power to vote shares of a bank or

bank holding company and all of the

banks and nonbanking companies

owned by the bank holding company,

including the companies listed below.

The applications listed below, as well

as other related filings required by the

Board, are available for immediate

inspection at the Federal Reserve Bank

indicated. The application also will be

available for inspection at the offices of

the Board of Governors. Interested

persons may express their views in

writing on the standards enumerated in

the BHC Act (12 U.S.C. 1842(c)). If the

proposal also involves the acquisition of

a nonbanking company, the review also

includes whether the acquisition of the

nonbanking company complies with the

standards in section 4 of the BHC Act

(12 U.S.C. 1843). Unless otherwise

noted, nonbanking activities will be

conducted throughout the United States.

Additional information on all bank

holding companies may be obtained

from the National Information Center

website at www.ffiec.gov/nic/.

Unless otherwise noted, comments

regarding each of these applications

must be received at the Reserve Bank

indicated or the offices of the Board of

Governors not later than June 8, 2001.

A. Federal Reserve Bank of

Philadelphia (Michael E. Collins, Senior

Vice President) 100 North 6th Street,

Philadelphia, Pennsylvania 19105–

1521:

1. Chester Valley Bancorp, Inc.,

Downingtown, Pennsylvania; to become

a bank holding company by acquiring

100 percent of the voting shares of First

Financial Savings Assocoation,

Downingtown, Pennsylvania.

2. Franklin Financial Services

Corporation, Chambersburg,

Pennsylvania; to acquire 15.8 percent of

the voting shares of American Home

Bank, National Association, Lancaster,

Pennsylvania.

B. Federal Reserve Bank of Atlanta

(Cynthia C. Goodwin, Vice President)

104 Marietta Street, NW., Atlanta,

Georgia 30303–2713:

1. Hancock Holding Company,

Gulfport, Mississippi; to merge with

Lamar Capital Corporation, Purvis,

Mississippi, and thereby indirectly

acquire voting shares of Lamar Bank,

Purvis, Mississippi.

Board of Governors of the Federal Reserve

System, May 9, 2001.

Jennifer J. Johnson

Secretary of the Board.

[FR Doc. 01–12167 Filed 5–14–01; 8:45 am]

BILLING CODE 6210–01–S

FEDERAL RESERVE SYSTEM

Sunshine Act Meeting

AGENCY HOLDING THE MEETING: Board of

Governors of the Federal Reserve

System.

TIME AND DATE: 11 a.m., Monday, May

21, 2001.

PLACE: Marriner S. Eccles Federal

Reserve Board Building, 20th and C

Streets, NW., Washington, DC 20551.

STATUS: Closed.

MATTERS TO BE CONSIDERED:

1. Personnel actions (appointments,

promotions, assignments,

reassignments, and salary actions)

involving individual Federal Reserve

System employees.

2. Any items carried forward from a

previously announced meeting.

CONTACT PERSON FOR MORE INFORMATION:

Michelle A. Smith, Assistant to the

Board; 202–452–3204.

SUPPLEMENTARY INFORMATION: You may

call 202–452–3206 beginning at

approximately 5 p.m. two business days

before the meeting for a recorded

announcement of bank and bank

holding company applications

scheduled for the meeting; or you may

contact the Board’s Web site at http://

www.federalreserve.gov for an

electronic announcement that not only

lists applications, but also indicates

procedural and other information about

the meeting.

Dated: May 11, 2001.

Robert deV. Frierson,

Associate Secretary of the Board.

[FR Doc. 01–12316 Filed 5–11–01; 12:27 pm]

BILLING CODE 6210–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Committee on Vital and Health

Statistics: Meeting

Pursuant to the Federal Advisory

Committee Act, the Department of

Health and Human Services announces

the following advisory committee

meeting.

Name: National Committee on Vital and

Health Statistics (NCVHS), Subcommittee on

Standards and Security.

Time and Date: 9 a.m. to 5 p.m., May 31,

2001; 9 a.m. to 2 p.m., June 1, 2001.

Place: Room 705A, Hubert H. Humphrey

Building, 200 Independence Avenue, SW.,

Washington, DC 20201.

Status: Open.

Purpose: At this hearing, the subcommittee

will hear testimony regarding the process and

outcomes for assessing requests for changes

to the transaction standards designated under

HIPAA, as well as assess industry progress in

identifying a consensus standard for

electronic signatures.

Notice: In the interest of security, the

Department has instituted stringent

procedures for entrance to the Hubert H.

Humphrey building by non-government

employees. Thus, persons without a

government identification card will need to

have the guard call for an escort to the

meeting.

Contact Person for More Information:

Substantive program information as well as

summaries of meetings and a roster of

committee members may be obtained from J.

Michael Fitzmaurice, Ph.D., Senior Science

Advisor for Information Technology, Agency

for Health Care Research and Quality, 2101

East Jefferson Street, #600, Rockville, MD

20852, phone: (301) 594–3938; or Marjorie S.

Greenberg, Executive Secretary, NCVHS,

National Center for Health Statistics, Centers

for Disease Control and Prevention, Room

1100, Presidential Building, 6525 Belcrest

Road, Hyattsville, Maryland 20782,

telephone (301) 458–4245. Information also

is available on the NCVHS home page of the

HHS website: http://www.ncvhs.hhs.gov/

where an agenda for the meeting will be

posted when available.

Dated: May 7, 2001.

James Scanlon,

Director, Division of Data Policy, Office of

the Assistant Secretary for Planning and

Evaluation.

[FR Doc. 01–12211 Filed 5–14–01; 8:45 am]

BILLING CODE 4151–05–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Reports and Guidance Documents;

Availability, etc.: Ethical and Policy

Issues in International Research;

Clinical Trials in Developing Countries

SUMMARY: Notice of Publication of the

Executive Summary of the report,

‘‘Ethical and Policy Issues in

International Research: Clinical Trials in

Developing Countries’’, by the National

Bioethics Advisory Commission (NBAC)

SUPPLEMENTARY INFORMATION: The

President established the National

Bioethics Advisory Commission (NBAC)

on October 3, 1995 by Executive Order

12975 as amended. The functions of

NBAC are as follows:

Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices 26857

(a) Provide advice and make

recommendations to the National

Science and Technology Council and to

other appropriate government entities

regarding the following matters:

(1) The appropriateness of

departmental, agency or other

governmental programs, policies,

assignments, missions, guidelines, and

regulations as they relate to bioethical

issues arising from research on human

biology and behavior; and

(2) applications, including the clinical

applications, of that research.

(b) Identify broad principles to govern

the ethical conduct of research, citing

specific projects only as illustrations for

such principles.

(c) Shall not be responsible for the

review and approval of specific projects.

(d) In addition to responding to

requests for advice and

recommendations from the National

Science and Technology Council, NBAC

also may accept suggestions of issues for

consideration from both the Congress

and the public. NBAC may also identify

other bioethical issues for the purpose

of providing advice and

recommendations, subject to the

approval of the National Science and

Technology Council. The members of

NBAC are as follows:

Harold T. Shapiro, Ph.D., Chair

Patricia Backlar

Arturo Brito, M.D.

Alexander Morgan Capron, LL.B.

Eric J. Cassell, M.D., M.A.C.P.

R. Alta Charo, J.D.

James F. Childress, Ph.D.

David R. Cox, M.D., Ph.D.

Rhetaugh G. Dumas, Ph.D., R.N.

Laurie M. Flynn

Carol W. Greider, Ph.D.

Steven H. Holtzman

Bernard Lo, M.D.

Lawrence H. Miike, M.D., J.D.

Thomas H. Murray, Ph.D.

William C. Oldaker, LL.B.

Diane Scott-Jones, Ph.D.

Ethical and Policy Issues in

International Research: Clinical Trials

in Developing Countries; Executive

Summary

Introduction

In recent years, the increasingly global

nature of health research, and in

particular the conduct of clinical trials

involving human participants (1), has

highlighted a number of ethical issues,

especially in those situations in which

researchers or research sponsors from

one country wish to conduct research in

another country. The studies in question

might simply be one way of helping the

host country address a public health

problem, or they might reflect a research

sponsor’s assessment that the foreign

location is a more convenient, efficient,

or less troublesome site for conducting

a particular clinical trial. They might

also represent a joint effort to address an

important health concern faced by both

parties.

As the pace and scope of international

collaborative biomedical research have

increased during the past decade, longstanding questions about the ethics of

designing, conducting, and following up

on international clinical trials have

reemerged. Some of these issues have

begun to take center stage because of the

concern that research conducted by

scientists from more prosperous

countries in poorer nations that are

more heavily burdened by disease may,

at times, be seen as imposing ethically

inappropriate burdens on the host

country and on those who participate in

the research trials. The potential for

such exploitation is cause for a

concerted effort to ensure that

protections are in place for all persons

who participate in international clinical

trials.

As with other National Bioethics

Advisory Commission (NBAC) reports,

several issues and activities prompted

the Commission’s decision to address

this topic. First, several members of the

public suggested that NBAC’s mandate

to examine the protection of the rights

and welfare of human participants in

research extends to international

research conducted or sponsored by

U.S. interests. In this respect, one

particular dimension of research

conducted internationally has attracted

a great deal of attention, namely

whether the existing rules and

regulations that normally govern the

conduct of U.S. investigators or others

subject to U.S. regulations remain

appropriate in the context of

international research, or whether they

unnecessarily complicate or frustrate

otherwise worthy and ethically sound

research projects.

A second circumstance—the changing

landscape of international research—

also is relevant. Increasingly, scientists

from developing countries are becoming

more involved as collaborators in

research, as many of the countries from

which these investigators come have

developed their capacity for technical

contributions to research projects and

for appropriate ethical review of

research protocols. Although the source

of funding for such collaborative

research is likely to continue to be the

wealthier, developed countries,

collaborators from developing countries

are seeking—justifiably—to become

fuller and more equal partners in the

research enterprise. Finally, the current

landscape of international research also

reflects the growing importance of

clinical trials conducted by

pharmaceutical, biotechnology, and

medical device companies. Some

observers believe that market forces

have pressured private companies to

become more efficient in the conduct of

research, which may—absent

vigilance—compromise the protection

of research participants. Although the

extent, relevance, and force of these

pressures are widely debated, it is clear

that such pressures can exist regardless

of the funding source.

Scope of This Report

This report discusses the ethical

issues that arise when research that is

subject to U.S. regulation is sponsored

or conducted in developing countries,

where local technical skills and other

key resources are in relatively scarce

supply. Within this context, the

Commission’s attention was focused on

the conduct of clinical trials involving

competent adults, in particular those

trials—such as Phase III drug studies—

that can lead to the development of

effective new treatments. Complex and

important ethical concerns are likely to

be more pressing in clinical trials than

in many other types of research

investigations; thus, the focus of this

report has been limited accordingly.

Although much of the discussion in this

report is relevant to other types of

research, the particular characteristics of

research endeavors other than clinical

trials probably merit their own ethical

assessment.

This report centers on the principal

ethical requirements surrounding the

conduct of clinical trials conducted by

U.S. interests abroad, and in particular

the need for such trials to be directly

relevant to the health needs of the host

country. Other major topics addressed

include ethical issues surrounding the

choice of research designs, especially in

situations where a placebo control is

proposed when an established effective

treatment is known to exist; issues

arising in the informed consent process

in cultures whose norms of behavior

differ from those in the United States;

what benefits should be provided to

research participants and by whom after

their participation in a trial has ended;

and what benefits, if any, should be

made available to others in the host

community or country. Finally, it makes

recommendations about the need for

developed countries to assist developing

countries in building the capacity to

become fuller partners in international

research. Until this goal can be met,

however, recommendations are made

regarding how the United States should

26858 Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices

proceed in settings in which systems for

protecting human participants

equivalent to those of the United States

have not yet been established.

Essential Requirements for the Ethical

Conduct of Clinical Trials

Many of the ethical concerns

regarding the treatment of human

participants in international research

are similar to those raised in

conjunction with research conducted in

the United States (2). They include,

among others, choosing the appropriate

research question and design; ensuring

prior scientific and ethical review of the

proposed protocol; selecting

participants equitably; obtaining

voluntary informed consent; and

providing appropriate treatment to

participants during and after the trial.

These concerns are consistent with

principles endorsed in many

international research ethics documents.

NBAC believes that two types of

ethical requirements—substantive and

procedural—must be carefully

considered and distinguished when

human research is conducted, regardless

of the location. The principles

embodied in the ‘‘Belmont Report:

Ethical Principles and Guidelines for

the Protection of Human Subjects of

Research’’ serve as a foundation for the

substantive ethical requirements

incorporated into the system of

protection of human participants in the

United States. The ‘‘Belmont Report’’

sets forth three basic ethical principles,

which provide an analytical framework

for understanding many of the ethical

issues arising from research involving

human participants: respect for persons,

beneficence, and justice. NBAC believes

that in order to be ethically sound,

research conducted with human beings

must, at a minimum, be consistent with

the ethical principles underlying the

‘‘Belmont Report’’. In addition, ethically

sound research must satisfy a number of

important procedural requirements,

including prior ethical review by a body

that is competent to assess compliance

with these substantive ethical

principles. U.S. research regulations

also set forth more specific rules to

guide ethics review committees (3) (and

researchers) in their work. NBAC

believes that when conducting clinical

trials abroad, U.S. researchers and

sponsors should comply with these

substantive ethical requirements for the

protection of human research

participants.

Recommendation 1.1 lists protections

that should be provided for individuals

participating in U.S. governmentsponsored clinical trials, whether

conducted domestically or abroad (4).

Although existing U.S. law and

regulations impose limits on the extent

to which non-federally funded research

is subject to oversight, the Commission

believes that these requirements should

extend to all clinical trials, regardless of

who sponsors or conducts them.

Recommendation 1.1

The U.S. government should not

sponsor or conduct clinical trials that do

not, at a minimum, provide the

following ethical protections:

(a) prior review of research by an

ethics review committee(s);

(b) minimization of risk to research

participants;

(c) risks of harm that are reasonable in

relation to potential benefits;

(d) adequate care of and

compensation to participants for

injuries directly sustained during

research;

(e) individual informed consent from

all competent adult participants in

research;

(f) equal regard for all participants;

and

(g) equitable distribution of the

burdens and benefits of research.

Recommendation 1.2

The Food and Drug Administration

should not accept data obtained from

clinical trials that do not provide the

substantive ethical protections outlined

in Recommendation 1.1.

Responsiveness of the Research to the

Health Needs of the Population

Sponsoring or conducting research in

developing countries often poses special

challenges arising from the combined

effects of distinctive histories, cultures,

politics, judicial systems, and economic

situations. In addition, in countries in

which extreme poverty afflicts so many,

primary health care services generally

are inadequate, and a majority of the

population is unable to gain access to

the most basic and essential health

products and services. As a result of

these difficult conditions, the people in

these countries are often more

vulnerable in situations (such as clinical

trials) in which the promise of better

health seems to be within reach.

Whether the research sponsor is the

U.S. government or a private sector

organization, some justification is

needed for conducting research abroad

other than a less stringent or

troublesome set of regulatory or ethical

requirements. Moreover, when the

United States (or any developed

country) proposes to sponsor or conduct

research in another country when the

same research could not be conducted

ethically in the sponsoring country, the

ethical concerns are more profound, and

the research accordingly requires a more

rigorous justification.

To meet the ethical principle of

beneficence, the risks involved in any

research with human beings must be

reasonable in relation to the potential

benefits. Plainly, the central focus of

any assessment of risk is the potential

harm to research participants

themselves (in terms of probability and

magnitude), although risks to others also

are relevant. The potential benefits that

are weighed against such risks may

include those that will flow to the fund

of human knowledge as well as to those

now and in the future whose lives may

be improved because of the research. In

addition, some of the benefits must also

accrue to the group from which the

research participants are selected.

NBAC understands the principle of

justice to require that a population,

especially a vulnerable one, should not

be the focus of research unless some of

the potential benefits of the research

will accrue to that group after the trial.

Thus, in the context of international

research—and particularly when the

population of a developing country has

been sought as a source of research

participants—U.S. and international

research ethics require not merely that

research risks are reasonable in relation

to potential benefits, but also that they

respond to the health needs of the

population being studied. This is

because, according to the principles of

beneficence and justice, only research

that is responsive to these needs can

offer relevant benefits to the population.

Recommendation 1.3

Clinical trials conducted in

developing countries should be limited

to those studies that are responsive to

the health needs of the host country.

Choosing a Research Design and the

Relevance of Routine Care

Making a determination about the

appropriate design for a clinical trial

depends on various contextual

considerations, so that what might be an

ethically acceptable design in one

situation could be problematic in

another. For example, it might be

unethical to conduct a clinical trial for

a health condition in a country in which

that condition is unlikely to be found.

In comparison, the same trial might be

quite appropriately conducted where

the trial results could be important to

the local population. A more

challenging question is whether a

research design that could not be

ethically implemented in the sponsoring

country can be ethically justified in a

host country when the health problem

Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices 26859

being addressed is common to both

nations.

In this report, NBAC is especially

interested in exploring the following

question: Can a research design that

could not be ethically implemented in

the sponsoring, developed country be

ethically justified in the country in

which the research is conducted? In all

cases, there is an ethical requirement to

choose a design that minimizes the risk

of harm to human participants in

clinical trials and that does not exploit

them. Because the choice of a study

design for any particular trial will

depend on these and other factors, it

would be inappropriate—indeed

wrong—to prescribe any particular

study design as ethical for all research

situations. Nevertheless, under certain,

specified conditions, one or another

design can be held to be ethically

preferable.

Recommendation 2.1

Researchers should provide ethics

review committees with a thorough

justification of the research design to be

used, including the procedures to be

used to minimize risks to participants.

Providing Established Effective

Treatment as the Control

From the perspective of the protection

of human participants in research, one

of the most critical issues in clinical

trial design concerns the use and

treatment of control groups, which often

are an essential component in

methodologies used to guard against

bias. Although placebos are a frequently

used control for clinical trials, it is

increasingly commonplace to compare

an experimental intervention to an

existing established effective treatment.

These types of studies are called activecontrol (or positive control) studies,

which are often extremely useful in

cases in which it would not be ethical

to give participants a placebo because

doing so would pose undue risk to their

health or well-being.

Within the context of active treatment

concurrent controls, it is useful to

consider whether, and if so under what

circumstances, researchers and sponsors

have an obligation to provide an

established effective treatment to the

control group even if it is not available

in the host country. This report adopts

the phrase an established effective

treatment to refer to a treatment that is

established (it has achieved widespread

acceptance by the global medical

profession) and effective (it is as

successful as any in treating the disease

or condition). It does not mean that the

treatment is currently available in that

country.

Investigators must carefully explain

and ethics review committees must

cautiously scrutinize the justification for

the selection of the research design,

including the level of care provided to

the control group. If in a proposed

clinical trial the control group will

receive less care than would be

available under ideal circumstances, the

burden on the investigator to justify the

design should be heavier. Furthermore,

representatives of the host country,

including scientists, public officials,

and persons with the condition under

study, should have a strong voice in

determining whether a proposed trial is

appropriate.

Recommendation 2.2

Researchers and sponsors should

design clinical trials that provide

members of any control group with an

established effective treatment, whether

or not such treatment is available in the

host country. Any study that would not

provide the control group with an

established effective treatment should

include a justification for using an

alternative design. Ethics review

committees must assess the justification

provided, including the risks to

participants, and the overall ethical

acceptability of the research design.

Community Involvement in Research

Design and Implementation

Over the past three decades,

researchers increasingly have

deliberately involved communities in

the design of research. In addition,

research participants, health advocates,

and other members of the communities

from which participants are recruited

have requested, and in some cases

demanded, involvement in the design of

clinical trials. By consulting with the

community, researchers often gain

insight about whether the research

question is relevant and responsive to

health needs of the community

involved.

In addition, community consultation

can improve the informed consent

process and resolve problems that arise

in this process because of the use of

difficult or unfamiliar concepts. Such

discussions can provide insight into

whether the balance of benefits and

harms in the study is considered

acceptable and whether the

interventions and follow-up procedures

are satisfactory. Community

consultation is particularly important

when the researcher does not share the

culture or customs of the population

from which research participants will be

recruited.

Recommendation 2.3

Researchers and sponsors should

involve representatives of the

community of potential participants

throughout the design and

implementation of research projects.

Researchers should describe in their

proposed protocol how this will be

done, and ethics review committees

should review the appropriateness of

this process. When community

representatives will not be involved, the

protocol presented to the ethics

committee should justify why such

involvement was not possible or

relevant.

Fair and Respectful Treatment of

Participants

The requirement to obtain voluntary

informed consent from human

participants before they are enrolled in

research is a fundamental tenet of

research ethics. It was the first

requirement proclaimed in the

Nuremberg Code in 1947, and it has

appeared in all subsequent published

national and international codes,

regulations, and guidelines pertaining to

research ethics, including those in many

developing countries.

Nevertheless, discussion is ongoing

about the value and importance of

particular procedural approaches to

informed consent in other countries.

Problems involving the interpretation

and application of the requirement to

obtain voluntary informed consent—and

its underlying ethical principles—arise

for researchers, ethics review

committees, and others. In some

countries, the methods used in U.S.-

based studies for identifying appropriate

groups for study, enrolling individuals

from those groups in a protocol, and

obtaining informed voluntary consent

might not succeed because of different

cultural or social norms. Meeting the

challenge of developing alternative

methodologies requires careful attention

to the ethical issues involved in

recruiting research participants and

obtaining their consent, which is

necessary in order to ensure justice in

the conduct of research and to avoid the

risk of exploitation.

Recommendation 3.1

Research should not deviate from the

substantive ethical standard of

voluntary informed consent.

Researchers should not propose,

sponsors should not support, and ethics

review committees should not approve

research that deviates from this

substantive ethical standard.

26860 Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices

Disclosure Requirements

The basic disclosure requirements for

satisfying the informed consent

provisions in U.S. research regulations

focus on the information needed by a

potential participant in order to decide

whether or not to participate in a study.

Requirements for disclosure of

information in the research setting

usually exceed those for disclosure in

clinical contexts. Indeed, the extent of

disclosure of medical information to

patients in clinical settings differs

among cultures and can influence

judgments about the amount and kind of

information that should be disclosed in

research settings. In the United States,

the requirements for disclosure of

information to potential participants in

research are specific and detailed (45

CFR 46.116). The Commission has

found some evidence that disclosures

relating to diagnosis and risk, research

design, and possible post-trial benefits

are not always clearly presented in

clinical trials conducted in developing

countries, even though the current U.S.

regulations include such requirements.

For example, one disclosure

requirement in the U.S. regulations

focuses on potential benefits: ‘‘a

description of any benefits to the subject

or to others which may reasonably be

expected from the research’’ (45 CFR

46.116(a)(1)). Traditionally, such a

disclosure has been required to ensure

that potential participants understand

whether there is any possibility that the

intervention itself might benefit them

while they are enrolled in the study.

There is, however, no specific mention

of any possible post-trial benefits in

current U.S. regulations. The

Commission believes that, because this

information is relevant to participants’

decisions to participate in the trial,

prospective participants should be

informed of the potential benefits, if

any, that they might receive after the

trial is over.

Recommendation 3.2

Researchers should develop culturally

appropriate ways to disclose

information that is necessary for

adherence to the substantive ethical

standard of informed consent, with

particular attention to disclosures

relating to diagnosis and risk, research

design, and possible post-trial benefits.

Researchers should describe in their

protocols and justify to the ethics

review committee(s) the procedures

they plan to use for disclosing such

information to participants.

Recommendation 3.3

Ethics review committees should

require that researchers include in the

informed consent process and consent

documents information about what

benefits, if any, will be available to

research participants when their

participation in the study in question

has ended.

Ensuring Comprehension

In some cultures, the belief system of

potential research participants does not

explain health and disease using the

concepts and terms of modern medical

science and technology. However,

despite this potential barrier to adequate

understanding, if they are willing to

devote the time and effort to do so,

researchers often are often able to devise

creative measures to overcome this

barrier. Despite the acknowledged

difficulties of administering tests of

understanding, NBAC supports the idea

of incorporating these tests into research

protocols.

Recommendation 3.4

Researchers should develop

procedures to ensure that potential

participants do, in fact, understand the

information provided in the consent

process and should describe those

procedures in their research protocols.

Recommendation 3.5

Researchers should consult with

community representatives to develop

innovative and effective means to

communicate all necessary information

in a manner that is understandable to

potential participants. When

community representatives will not be

involved, the protocol presented to the

ethics review committee should justify

why such involvement is not possible or

relevant.

Recognizing the Role of Others in the

Consent Process

In some cultures, investigators must

obtain permission from a community

leader or village council before

approaching potential research

participants. Yet, it is important to

distinguish between obtaining

permission to enter a community for the

purpose of conducting research and for

obtaining individual informed consent.

In their reports, NBAC consultants all

noted that the role of community

leaders or elders is an integral part of

the process of recruiting research

participants. Although these reports

typically use the terminology of consent

to refer to the community’s permission

or a leader’s authorization for the

researchers to approach individuals,

NBAC will use this term to refer to the

permission or authorization given by the

individual being recruited as a research

participant.

The need to obtain permission from a

community leader before approaching

individuals does not need to

compromise the ethical standard

requiring the individual’s voluntary

informed consent to participate in

research. Gaining permission from a

community leader is no different, in

many circumstances, from the common

requirement in this country of obtaining

permission from a school principal

before involving pupils in research or

from a nursing home director before

approaching individual residents. An

ethical problem arises only when the

community leader exerts pressure on

the community in a way that

compromises the voluntariness of

individual consent. In NBAC’s view, if

the political system in a country or the

local situation makes it impossible for

individuals’ consent to be voluntary and

that fact is known in advance, then,

because U.S. researchers cannot adhere

to the substantive ethical standard of

informed consent, it would be

inappropriate for them to choose such

settings.

Recommendation 3.6

Where culture or custom requires that

permission of a community

representative be granted before

researchers may approach potential

research participants, researchers

should be sensitive to such local

requirements. However, in no case may

permission from a community

representative or council replace the

requirement of a competent individual’s

voluntary informed consent.

Recommendation 3.7

Researchers should strive to ensure

that individuals agree to participate in

research without coercion or undue

inducements from community leaders

or representatives.

Family Members

It is customary although not required

in some societies for other members of

a potential research participant’s family

to be involved in the informed consent

process. For example, in cultures in

which men are expected to speak for

their unmarried adult daughters and

husbands are expected to speak for their

wives, a woman may not be permitted

to consent on her own behalf to

participate in research. In most

instances, the need to involve the family

is not intended as a substitute for

individual consent, but rather as an

additional step in the process. In many

cases, family members may be

Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices 26861

approached before an individual is

asked directly to participate in a

research project. However, seeking

permission from family members

without engaging the potential research

participants at all clearly departs from

the ethical standard of informed

consent. On the other hand, potential

participants might also choose to

involve others, such as family members,

in the consent process. Indeed,

involving family or community

members in the informed consent

process need not diminish, and might

even enhance, the individual’s ability to

make his or her own choices and to give

informed consent (or refusal).

It is often possible to obtain

individual informed consent, which

may require and indeed benefit from the

involvement of family or community

members, while at the same time

preserving cultural norms. Such

involvement ranges from providing

written information sheets for potential

participants to take home and discuss

with family members to holding

community meetings during which

information is presented about the

research and community consensus is

obtained. When the potential

participant wishes to involve family

members in the consent discussion, the

researcher should take appropriate steps

to accommodate this desire.

Recommendation 3.8

When a potential research participant

wishes to involve family members in the

consent process, the researcher should

take appropriate steps to accommodate

this wish. In no case, however, may a

family member’s permission replace the

requirement of a competent individual’s

voluntary informed consent.

Consent by Women

A strict requirement that a husband

must first grant permission before

researchers may enroll his wife in

research treats the woman as

subordinate to her husband and as less

than fully autonomous. In reality, it may

be impossible to conduct some research

on common, serious health problems

that affect only women without

involving the husband in the consent

procedures. In such cases, a likely

consequence would be a lack of

knowledge on which to base health care

decisions for women in that country.

The prospect of denying such a

substantial benefit to all women in a

particular culture or country calls for a

narrow exception to the requirement

that researchers use the same

procedures in the consent process for

women as for men, one that would

allow for obtaining the permission of a

man in addition to the woman’s own

consent.

Recommendation 3.9

Researchers should use the same

procedures in the informed consent

process for women and men. However,

ethics review committees may accept a

consent process in which a woman’s

individual consent to participate in

research is supplemented by permission

from a man if all of the following

conditions are met:

(a) it would be impossible to conduct

the research without obtaining such

supplemental permission; and

(b) failure to conduct this research

could deny its potential benefits to

women in the host country; and

(c) measures to respect the woman’s

autonomy to consent to research are

undertaken to the greatest extent

possible.

In no case may a competent adult

woman be enrolled in research solely

upon the consent of another person; her

individual consent is always required.

Minimizing the Therapeutic

Misconception

One barrier to understanding the

relevant, important aspects of any

proposed research is what has been

called the therapeutic misconception.

This term refers to the belief that the

purpose of a clinical trial is to benefit

the individual patient rather than to

gather data for the purpose of

contributing to scientific knowledge.

The therapeutic misconception has been

documented in a wide range of

developing and developed countries.

It is important to distinguish the

confusion that arises from the

therapeutic misconception from a

related consideration. In the research

setting, participants often receive

beneficial clinical care. In some

developing countries, the type and level

of clinical care provided to research

participants may not be available to

those individuals outside the research

context. It is not a misconception to

believe that participants probably will

receive good clinical care during

research. But it is a misconception to

believe that the purpose of clinical trials

is to administer treatment rather than to

conduct research. Researchers should

make clear to research participants, in

the initial consent process and

throughout the study, which activities

are elements of research and which are

elements of clinical care.

Recommendation 3.10

Researchers working in developing

countries should indicate in their

research protocols how they would

minimize the likelihood that potential

participants will believe mistakenly that

the purpose of the research is solely to

administer treatment rather than to

contribute to scientific knowledge (see

also Recommendation 3.2).

Addressing Procedural Requirements in

the Consent Process

A number of issues may arise during

the process of obtaining informed

consent that require careful scrutiny

before determining whether voluntary

informed consent can be obtained.

These include, for example, determining

when it is necessary to obtain written

consent and when oral consent should

be permitted; when, if ever, it is

appropriate to withhold important and

relevant information from potential

participants; the need in some cultures

to obtain a community leader’s or a

family member’s permission before

seeking an individual’s consent; and

standards of disclosure for research

participants in cultures in which people

lack basic information about modern

science or reject scientific explanations

of disease in favor of traditional

nonscientific beliefs.

In light of the cultural variation that

might arise in international clinical

trials, the Commission was especially

interested in problems that may arise

from expecting researchers in

developing countries to adhere strictly

to the substantive and procedural

imperatives of the U.S. requirements for

informed consent. NBAC was

particularly interested in exploring

ways of dealing with the situation that

arises when cultural differences

between the United States and other

countries make it difficult or impossible

to adhere strictly to the U.S. regulations

that stipulate particular procedures for

obtaining informed consent from

individual participants. In general, it is

important to distinguish procedural

difficulties from those that reflect

substantive differences in ethical

standards. Clearly, more research is

needed in this area.

Recommendation 3.11

U.S. research regulations should be

amended to permit ethics review

committees to waive the requirements

for written and signed consent

documents in accordance with local

cultural norms. Ethics review

committees should grant such waivers

only if the research protocol specifies

how the researchers and others could

verify that research participants have

given their voluntary informed consent.

26862 Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices

Recommendation 3.12

The National Institutes of Health, the

Centers for Disease Control and

Prevention, and other U.S. departments

and agencies should support research

that addresses specifically the informed

consent process in various cultural

settings. In addition, those U.S.

departments and agencies that conduct

international research should sponsor

workshops and conferences during

which international researchers can

share their knowledge of the informed

consent process.

Access to Post-Trial Benefits

Discussions of the ethics of research

with human beings usually center on

issues regarding research design and

approval and how individuals’ rights

and welfare are protected when they are

enrolled in research protocols. The same

has been true of the U.S. regulations,

which only tangentially address what

happens after a research project has

ended by requiring that research

participants must be informed in

advance about what compensation, if

any, will be provided if they are injured

during the course of the research. Other

questions about what should happen

after a trial is completed are left

unaddressed by U.S. guidelines.

Thus, central questions in the context

of international research include the

following: What benefits (in the form of

a proven, effective medical intervention)

should be provided to research

participants, and by whom, after their

participation in a trial has ended, and

what, if anything, should be made

available to others in the host

community or country? Although these

questions are relevant in terms of the

ethical assessment of research—

regardless of where the research is

conducted—they are being posed with

special force, especially regarding

serious diseases that affect large

numbers of people in developing

countries. Therefore, the question of

what benefits, if any, research sponsors

should make available to participants or

others in the host country at the

conclusion of a clinical trial is

particularly significant for those who

live in developing countries in which

neither the government nor the vast

majority of the citizenry can afford the

intervention resulting from the research.

Of course, this is especially germane

when a drug is proven to be effective in

a clinical trial.

An ethically relevant feature that

distinguishes most developing from

developed countries is the lack of access

to adequate health care by a large

majority of the population. Many

developed countries have long provided

universal access to primary health care

through a national health service or

government-based insurance system.

However, in the developing world,

especially in the poorest countries in

Africa and Asia, substantially fewer

health care services are available (if

any), and where they are available,

access is severely limited. Access to

health care is an important issue in

research ethics, because an ethically

appropriate clinical trial design requires

an assessment of the level and nature of

care or treatment available outside the

research context, as well as any possible

future health benefits that might arise

from the research.

Recognizing that it is sometimes

difficult to distinguish research from

treatment when routine health care is

inadequate or nonexistent, it cannot be

denied that it may be difficult for

participants, whose health status may be

altered by their participation in a

clinical trial, to distinguish between

participating in research and receiving

clinical care. Consequently, if all

interventions by the research team cease

at the end of a trial, participants may

experience a loss and feel that the

researchers in their clinical role have

abandoned them. This sense of loss can

take several forms, the starkest of which

arises when participants are left worse

off at the conclusion of the trial than

they were before the clinical trial began.

Being worse off does not mean that they

were harmed by the research. It can

simply mean that their medical

condition has deteriorated because they

were in what turned out to be the less

advantageous arm of the protocol. Such

an outcome—particularly when

participants are worse off than they

would have been had they received

standard treatment or if they had been

in the other arm of the trial—underlines

the extent to which any research project

can depart from the Hippocratic goal of

‘‘first, do no harm,’’ despite the best

intentions and efforts of all concerned.

When such a result occurs, efforts to

restore participants at least to their

pretrial status could be regarded as

attempts to reverse a result that would

otherwise be at odds with the ethical

principles of nonmaleficence and

beneficence.

Ironically, people who have benefited

from an experimental intervention may

also experience a loss if the intervention

is discontinued when the project ends.

It might be said that this is a risk the

participant accepted by enrolling in the

trial. But participants who are ill when

they enter the research protocol may not

be able to appreciate fully how they will

feel when they face a deterioration in

their medical condition (once the trial is

completed) after having first

experienced an improvement, even if

the net result is a return to the status

quo ante. One of the ways to mediate or

reduce the burden of such an existential

loss (the experience of loss as perceived

by the research participant) and to

sustain an appropriate level of trust

between potential participants and the

research enterprise is to continue to

provide to research participants an

intervention that has been shown to be

efficacious in the clinical trial if they

still need it once the trial is over.

Recommendation 4.1

Researchers and sponsors in clinical

trials should make reasonable, good

faith efforts before the initiation of a

trial to secure, at its conclusion,

continued access for all participants to

needed experimental interventions that

have been proven effective for the

participants. Although the details of the

arrangements will depend on a number

of factors (including but not limited to

the results of a trial), research protocols

should typically describe the duration,

extent, and financing of such continued

access. When no arrangements have

been negotiated, the researcher should

justify to the ethics review committee

why this is the case.

Providing Benefits to Others

Once it is recognized that research

projects should sometimes arrange to

provide post-trial benefits to

participants, a question arises about the

justice of differentiating between former

trial participants and others in the host

community who need similar medical

treatments. Is the distinction between

former research participants and those

who were not merely arbitrary?

Applying a competing concept of

justice, typically referred to as the

principle of fairness—treat like cases

alike, and treat different cases

differently—to this situation requires a

consideration of whether family

members (or others) who suffer from the

same illness as the participants should

be treated as ‘‘like cases’’ with respect

to receiving an effective treatment.

Similarly, are the claims to treatment of

people who were eligible for and willing

to participate in a clinical trial but who

for any number of reasons were not

selected comparable to the claims of

those who were selected? Or are such

cases not sufficiently similar because

participants undertook the risks and

experienced the inconveniences of the

research?

In NBAC’s view, the relevant

distinction between research

participants and these other groups of

Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices 26863

individuals is that research participants

are exposed to the risks and

inconveniences of the study. Moreover,

a special relationship exists between

participants and researchers that does

not exist for others. These are the ethical

considerations that support the

argument to provide effective

interventions to research participants

after a trial is completed.

On what basis then can one justify an

ethical obligation to make otherwise

unaffordable (or undeliverable) effective

interventions available to members of

the broader community or host country?

Given that global inequities in wealth

and resources are so vast, expecting

governmental or industrial research

sponsors to seek to redress this

particular global inequity is unfair and

unrealistic, especially when no such

requirement exists in other spheres of

international relationships. Typically, it

is not the primary purpose of clinical

trials to seek to redress these inequities.

Recommendation 4.2

Research proposals submitted to

ethics review committees should

include an explanation of how new

interventions that are proven to be

effective from the research will become

available to some or all of the host

country population beyond the research

participants themselves. Where

applicable, the investigator should

describe any pre-research negotiations

among sponsors, host country officials,

and other appropriate parties aimed at

making such interventions available. In

cases in which investigators do not

believe that successful interventions

will become available to the host

country population, they should explain

to the relevant ethics review

committee(s) why the research is

nonetheless responsive to the health

needs of the country and presents a

reasonable risk/benefit ratio.

These concerns prompt the question

of whether research sponsors should

consider implementing arrangements,

such as prior agreements (arrangements

made before a clinical trial begins that

address the post-trial availability of

effective interventions to the host

community and/or country after the

study has been completed), that would

allow some of the fruits of research to

be available in the host country when

the research is over. Such arrangements

would be responsive to the health needs

of the host country. The parties to these

agreements usually include some

combination of producers, sponsors,

and potential users of research products.

Although only a limited number of prior

agreements, either formal (legally

binding) or informal, are in place in

international collaborative research

today, it is useful to consider what role

such agreements should play in the

future.

Recommendation 4.3

Wherever possible, preceding the start

of research, agreements should be

negotiated by the relevant parties to

make the effective intervention or other

research benefits available to the host

country after the study is completed.

Mechanisms to Ensure the Protection of

Research Participants in International

Clinical Trials

The two principal approaches used to

ensure the protection of human

participants in international clinical

trials are (1) relying on assurance

processes and reviews by U.S.

Institutional Review Boards (IRBs) to

supplement and enhance local measures

or determining that a host country or

host country institution has a system of

protections in place that is at least

equivalent to that of the United States

and (2) helping host countries build the

capacity to independently conduct

clinical trials and to conduct their own

scientific and ethical review. In

addition, a regulatory provision permits

the substitution of foreign procedures

that afford protections to research

participants that are ‘‘at least

equivalent’’ to those provided in the

Common Rule. Clarification of the scope

and limits of these mechanisms and

their use would increase public

confidence that a valid system of

protections is in place for participants

in clinical trials conducted abroad.

Negotiating Assurances of Compliance

U.S. researchers or sponsors and their

collaborators often encounter

difficulties with some of the procedural

and administrative aspects of the U.S.

research regulations or their

implementation and at times perceive

U.S. regulations as unnecessarily rigid.

Among the many concerns NBAC heard

were those relating to the process of

negotiating assurances. An assurance is

a document that commits an institution

to conduct research ethically and in

accordance with U.S. federal

regulations. An approved assurance is a

prerequisite to federally conducted or

sponsored research.

In December 2000, the U.S. Office of

Human Research Protections (OHRP)

launched a new Federalwide Assurance

(FWA) and IRB registration process. The

process for filing institutional

assurances with OHRP for protecting

human research participants has been

simplified by replacing Single, Multiple,

and Cooperative Project Assurances

with the FWA, one for domestic

research and one for international

research. Each legally separate

institution must obtain its own FWA,

and assurances approved under this

process would cover all of the

institution’s federally supported human

research. The proposed system

eliminates the assurance documents

now in place and replaces them with

either a Federalwide Domestic

Assurance or a Federalwide

International Assurance, covering all

federally supported human research.

NBAC was encouraged that OHRP is

taking these steps to revise and simplify

the current assurance process. It is not

clear at this writing, however, whether

the new FWA process will eliminate the

problems and inconsistencies that exist

among agencies such as the Department

of Health and Human Services (DHHS),

the Agency for International

Development, and the Food and Drug

Administration (FDA), or the difficulties

expressed by researchers who are

familiar with the previous assurance

system. Moreover, it should be noted

that the assurance process itself does

not provide a failsafe system of

protections. Because weaknesses in this

system have been noted in failures at

U.S. research institutions, care should

be taken not to rely too heavily on this

single mechanism to achieve protections

abroad, especially when it is not clear

that OHRP will provide a visible

presence in the host country (through,

for example, site visits). However, it will

be important to evaluate the success of

these new initiatives.

Recommendation 5.1

After a suitable period of time, an

independent body should

comprehensively evaluate the new

assurance process being implemented

by the Office for Human Research

Protections.

Ethics Review

It is now widely accepted that

research involving human participants

should be conducted only after an

appropriate ethics review has occurred.

When research is sponsored or

conducted in accordance with U.S.

research regulations (and within the

boundaries of these regulations), an

appropriately constituted and

designated IRB is empowered to make

these assessments. However,

spokespersons from developing

countries have maintained that those

who live in the countries in which the

research is to be conducted are in the

best position to decide what is

appropriate, rather than those who may

be unfamiliar with local health needs

26864 Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices

and culture. It is argued that committees

that are familiar with the researchers,

institutions, potential participants, and

other factors associated with a study are

likely to provide a more careful and

fully informed review than a committee

or other group that is geographically

displaced or distant and that only local

committees can exercise the kind of

balanced and reasoned judgment

required to review research protocols.

The concept of local review has been a

cornerstone of the U.S. system for

protecting human participants. Whether

this standard can or should be applied

to research sponsored or conducted

abroad was a focus of Commission

deliberations.

NBAC found that the requirement for

local review is occasionally tested and

sometimes weakened when research is

conducted in developing countries. In

some cases, review by a local committee

raises the potential for conflict of

interest—or at least a heightened

interest in approving research—when it

means that valuable research funds

would flow to a local institution.

Although several developing countries

have instituted national research ethics

guidelines, and in some countries,

ethics review is becoming more

established, many difficulties and

challenges to local review remain,

including lack of experience with and

expertise in ethics review principles

and processes; conflict of interest among

committee members; lack of resources

for maintaining the committees; the

length of time it can take to obtain

approvals; and problems involved with

interpreting and complying with U.S.

regulations.

In NBAC’s view, efforts to enhance

collaboration in research must take into

account the capacity of ethics review

committees in developing countries to

review research and the need for U.S.

researchers and sponsors to ensure that

their research projects, at the very least,

are conducted according to the same

ethical standards and requirements

applied to research conducted in the

United States. This has led NBAC to

conclude that when clinical trials

involve U.S. and foreign interests, these

protocols must still be reviewed and

approved by a U.S. IRB and by an ethics

review committee in the host country,

unless the host country or host country

institution has in place a system of

equivalent substantive ethical

protections.

Ideally, equivalent (although not

necessarily identical) systems for

providing protections to research

participants in developing countries

would exist at both the national and

institutional levels. In countries in

which a system equivalent to the U.S.

system exists at the national level, some

institutions may be incapable of

conducting research in accordance with

that system. However, it is difficult to

conceive of institutional systems being

declared equivalent in the absence of an

equivalent national system, although it

may be possible in a few extremely rare

cases. When multiple sponsors are

participating in research, possibly all

from developed countries, determining

which ethics review committees (and

how many) are required poses

additional complexities. Because there

may be legitimate reasons to question

the capacity of host countries to support

and conduct prior ethics review, NBAC

believes that with respect to research

sponsored and conducted by the United

States, it will be necessary for an ethics

review committee from the host country

and a U.S. IRB to conduct a review. The

FDA’s regulatory provisions for

accepting foreign studies not conducted

under an investigational new drug

application or an investigational device

exemption do not address whether the

foreign nation’s system must meet U.S.

ethical standards.

Recommendation 5.2

The U.S. government should not

sponsor or conduct clinical trials in

developing countries unless such trials

have received prior approval by an

ethics review committee in the host

country and by a U.S. Institutional

Review Board.

However, if the human participants

protection system of the host country or

a particular host country institution has

been determined by the U.S.

government to achieve all the

substantive ethical protections outlined

in Recommendation 1.1, then review by

a host country ethics review committee

alone is sufficient.

Recommendation 5.3

The Food and Drug Administration

should not accept data from clinical

trials conducted in developing countries

unless those trials have been approved

by a host country ethics review

committee and a U.S. Institutional

Review Board. However, if the human

participants protection system of the

host country or a particular host country

institution has been determined by the

U.S. government to achieve all the

substantive ethical protections outlined

in Recommendation 1.1, then review by

a host country ethics review committee

alone is sufficient.

Lack of Resources as a Barrier to Ethics

Review

Ethics review committees in

developing countries may have

difficulty complying with U.S.

regulations because they lack the funds

necessary to carry out their

responsibilities. In previous reports,

NBAC has recognized that there are

costs to providing protection to human

participants in research, and researchers

and institutions should not be put in the

position of having to choose between

conducting research and protecting

participants. Therefore, an additional

means of enhancing international

collaborative research is to make the

necessary resources available for

conducting ethics reviews.

Recommendation 5.4

Federal agencies and others that

sponsor international research in

developing countries should provide

financial support for the administrative

and operational costs of host country

compliance with requirements for

oversight of research involving human

participants.

Equivalent Protections

Although many countries have

promulgated extensive regulations or

have officially adopted international

ethical guidelines invoking high

standards for research involving human

participants, the former Office for

Protection from Research Risks (OPRR)

never determined that any guidelines or

rules from other countries—even

countries such as Australia and Canada,

where research ethics requirements

closely parallel (and to some extent

exceed) those of the United States’afford

protections equal to those provided by

U.S. regulations. If these variations

cannot be mediated by joint efforts,

difficulties may arise in international

research that will prevent important and

ethically sound research from going

forward.

In June 2000, OHRP became the

agency responsible for making

determinations of equivalent protections

for DHHS. However, to date, OHRP has

not provided criteria for determining

what constitutes equivalent protections

or made any such determinations about

other countries’ guidelines. In lieu of

having developed a process for making

equivalent protections determinations,

in the past OPRR relied on its usual

process for negotiating assurances with

foreign institutions to ensure the

adequate protection of human

participants.

Because the number of U.S.-

sponsored studies undertaken in

Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices 26865

collaboration with other countries is

increasing (including many studies that

have different procedural requirements),

there is a need to enhance the efficiency

of those efforts through increased

harmonization and understanding,

without compromising the protection of

research participants. A way must be

found to adhere to widely accepted

substantive ethical principles while at

the same time avoiding the undue

imposition of regulatory procedures that

are peculiar to the United States.

Recommendation 5.5

The U.S. government should identify

procedural criteria and a process for

determining whether the human

participants protection system of a host

country or a particular host country

institution has achieved all the

substantive ethical protections outlined

in Recommendation 1.1.

Building Host Country Capacity To

Review and Conduct Clinical Trials

A unique feature of international

collaborative research is the degree to

which economically more prosperous

countries can enhance and encourage

further collaboration by leaving the host

community or country better off as a

result. The kinds of benefits that could

be realized as a result of the

collaboration would depend on local

health conditions, the state of economic

development, and the scientific

capabilities of the particular host

country. The provision of post-trial

benefits to participants or others in the

form of effective interventions is one

option. The appropriateness of

providing a benefit other than the

intervention will depend on the nature

of the benefit and on the economic and

technological state of development of

the host country. In most cases, offering

assistance to help build local research

capacity is another viable option. These

two options are not, of course, mutually

exclusive. But no matter what form the

benefit takes, the ultimate goal of

providing it is to improve the welfare of

those in the host country.

Approaches to capacity building are

related to, but not fully dependent on,

the clarification and improvement of

current U.S. procedures for ensuring the

protection of research participants in

international clinical trials. Progress can

and should occur simultaneously in

both realms. Capacity building to

conduct research could include

activities undertaken by investigators or

sponsors during a clinical trial to

enhance the ability of host country

researchers to conduct research (e.g.,

training and education) or to provide

research infrastructure (e.g., equipment)

so that future studies might proceed.

Building capacity to conduct scientific

and ethics review of studies, on the

other hand, is primarily a matter of

providing training and helping to

establish systems designed to review

proposed protocols and sustain

mutually beneficial partnerships with

other more experienced review bodies,

including U.S. IRBs.

To enhance research collaborations

between developing and developed

nations, it is important to increase the

capacity of resource-poor countries to

become even more meaningful partners

in international collaborative research.

Making the necessary resources

available for improving the technical

capacity to conduct and sponsor

research, as well as the ability to carry

out prior ethics review, is one way to

move forward in this effort.

Recommendation 5.6

Where applicable, U.S. sponsors and

researchers should develop and

implement strategies that assist in

building local capacity for designing,

reviewing, and conducting clinical trials

in developing countries. Projects should

specify plans for including or

identifying funds or other resources

necessary for building such capacity.

Recommendation 5.7

Where applicable, U.S. sponsors and

researchers should assist in building the

capacity of ethics review committees in

developing countries to conduct

scientific and ethical review of

international collaborative research.

Conclusions

The ethical standards that NBAC is

recommending for conducting research

in other countries are minimum

standards. Host countries might find it

worthwhile to adopt human research

participant protections that go beyond

the protections that are currently

provided under the U.S. system if these

higher standards further promote the

rights, dignity, and safety of research

participants as well as the credibility of

research results.

Ethical behaviors and commitments

are not barriers to the research

enterprise. Indeed, ethical behavior is

not only an essential ingredient in

sustaining public support for research, it

is an integral part of the process of

planning, designing, implementing, and

monitoring research involving human

beings. Just as good science requires

appropriate research design,

consideration of statistical factors, and a

plan for data analysis, it must also be

based on sound ethical principles. Only

then can research succeed in being

efficient and cost-effective, while at the

same time embodying appropriate

protections for the rights and welfare of

human participants. Researchers and

sponsors should strive to conduct

research in the United States and abroad

in a way that furthers these aspirations,

even though, regrettably, financial,

logistical, and public policy obstacles

often stand in the way of immediately

achieving this goal.

Although the recommendations in

this report focus principally on clinical

trials conducted by U.S. researchers or

sponsors in developing countries, it will

be important to consider their

application to other areas of research.

However, even though many ethical

issues that arise in clinical trials also

arise in other types of research, the

relevance, scope, and implications of

NBAC’s recommendations in other

types of studies may be very different.

Similarly, many of the issues and

recommendations discussed in this

report may equally apply to research

conducted in the United States.

The relationships and, ultimately, the

level of trust established among

individuals, institutions, communities,

and countries are determined by

complex and often contradictory social,

cultural, political, economic, and

historical factors. It is essential,

therefore, that sponsors, the countries

from which they come, and researchers

work together to enhance these

collaborations by creating an

atmosphere that is based on trust and

respect. Finally, because attention will

continue to focus on the ethical and

policy issues that arise in international

research in general and regarding

clinical trials in particular, this report

provides another opportunity for

ongoing public dialogue about how to

provide appropriate protection to all

research participants.

Notes

1. In past reports, the Commission has used

the term human subject to describe an

individual enrolled in research. This term is

widely used and is found in the Federal

Policy for the Protection of Human Subjects

(45 CFR 46). For many, however, the term

subject carries a negative image, implying a

diminished position of those enrolled in

research in relation to the researcher. NBAC

recognizes that merely changing terminology

cannot achieve the desired goal of true

participation by individuals who volunteer

for research, and NBAC does not imply that

a truly participatory role is always the case.

Nevertheless, for purposes of simplicity and

from a desire to encourage a more equal role

for research volunteers, in this report the

term participants is adopted to describe those

who are enrolled in research.

2. An upcoming NBAC report on the

oversight of research conducted with human

26866 Federal Register / Vol. 66, No. 94 / Tuesday, May 15, 2001 / Notices

participants in the United States will address

the implications of the findings and

conclusions of this report in the context of

domestic research.

3. In the United States, committees that

review the ethics of human research

protocols are referred to in regulation and

practice as Institutional Review Boards

(IRBs). In other countries, different names

might be used, such as research ethics

committees or ethics review committees. In

this report, references and recommendations

that are specific to the United States will

refer to these committees as IRBs. References

and recommendations that refer to such

committees generally regardless of their

geographic location will call them ethics

review committees.

4. Although these protections are generally

meant to apply to all research involving more

than minimal risk, there are exceptions in

certain guidelines for informed consent to be

waived in research involving minimal risk.

FOR FURTHER INFORMATION ABOUT THE

REPORT CONTACT: Eric M. Meslin, Ph.D.,

Executive Director, National Bioethics

Advisory Commission, or to obtain

copies of the report contact the NBAC

office at 6705 Rockledge Drive, Suite

700, Bethesda, Maryland 20892–7979,

telephone number (301) 402–4242, fax

number (301) 480–6900. Copies may

also be obtained through the NBAC

website: www.bioethics.gov.

Dated: May 9, 2001.

Eric M. Meslin,

Executive Director, National Bioethics

Advisory Commission.

[FR Doc. 01–12142 Filed 5–14–01; 8:45 am]

BILLING CODE 4167–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 00E–1413]

Determination of Regulatory Review

Period for Purposes of Patent

Extension; Xenical

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) has determined

the regulatory review period for Xenical

and is publishing this notice of that

determination as required by law. FDA

has made the determination because of

the submission of an application to the

Commissioner of Patents and

Trademarks, Department of Commerce,

for the extension of a patent that claims

that human drug product.

ADDRESSES: Submit written comments

and petitions to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Claudia V. Grillo, Regulatory Policy

Staff (HFD–007), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–594–5645.

SUPPLEMENTARY INFORMATION: The Drug

Price Competition and Patent Term

Restoration Act of 1984 (Public Law 98–

417) and the Generic Animal Drug and

Patent Term Restoration Act (Public

Law 100–670) generally provide that a

patent may be extended for a period of

up to 5 years so long as the patented

item (human drug product, animal drug

product, medical device, food additive,

or color additive) was subject to

regulatory review by FDA before the

item was marketed. Under these acts, a

product’s regulatory review period

forms the basis for determining the

amount of extension an applicant may

receive.

A regulatory review period consists of

two periods of time: A testing phase and

an approval phase. For human drug

products, the testing phase begins when

the exemption to permit the clinical

investigations of the drug becomes

effective and runs until the approval

phase begins. The approval phase starts

with the initial submission of an

application to market the human drug

product and continues until FDA grants

permission to market the drug product.

Although only a portion of a regulatory

review period may count toward the

actual amount of extension that the

Commissioner of Patents and

Trademarks may award (for example,

half the testing phase must be

subtracted, as well as any time that may

have occurred before the patent was

issued), FDA’s determination of the

length of a regulatory review period for

a human drug product will include all

of the testing phase and approval phase

as specified in 35 U.S.C. 156(g)(1)(B).

FDA recently approved for marketing

the human drug product Xenical

(orlistat). Xenical is a lipase inhibitor

indicated for obesity management that

acts by inhibiting the absorption of

dietary fats. Subsequent to this

approval, the Patent and Trademark

Office received a patent term restoration

application for Xenical (U.S. Patent No.

4,598,089) from HLR Technology

Corporation, and the Patent and

Trademark Office requested FDA’s

assistance in determining this patent’s

eligibility for patent term restoration. In

a letter dated August 7, 2000, FDA

advised the Patent and Trademark

Office that this human drug product had

undergone a regulatory review period

and that the approval of Xenical

represented the first permitted

commercial marketing or use of the

product. Shortly thereafter, the Patent

and Trademark Office requested that

FDA determine the product’s regulatory

review period.

FDA has determined that the

applicable regulatory review period for

Xenical is 3,969 days. Of this time,

3,091 days occurred during the testing

phase of the regulatory review period,

while 878 days occurred during the

approval phase. These periods of time

were derived from the following dates:

1. The date an exemption under

section 505 of the Federal Food, Drug,

and Cosmetic Act (the act) (21 U.S.C.

355) became effective: June 12, 1988.

The applicant claims June 24, 1988, as

the date the investigational new drug

application (IND) became effective.

However, FDA records indicate that the

IND effective date was June 12, 1988,

which was 30 days after FDA receipt of

the IND.

2. The date the application was

initially submitted with respect to the

human drug product under section 505

of the act: November 27, 1996. The

applicant claims November 26, 1996, as

the date the new drug application

(NDA) for Xenical (NDA 20–766) was

initially submitted. However, FDA

records indicate that NDA 20–766 was

submitted on November 27, 1996.

3. The date the application was

approved: April 23, 1999. FDA has

verified the applicant’s claim that NDA

20–766 was approved on April 23, 1999.

This determination of the regulatory

review period establishes the maximum

potential length of a patent extension.

However, the U.S. Patent and

Trademark Office applies several

statutory limitations in its calculations

of the actual period for patent extension.

In its application for patent extension,

this applicant seeks 1,824 days of patent

term extension.

Anyone with knowledge that any of

the dates as published are incorrect may

submit to the Dockets Management

Branch (address above) written

comments and ask for a redetermination

by July 16, 2001. Furthermore, any

interested person may petition FDA for

a determination regarding whether the

applicant for extension acted with due

diligence during the regulatory review

period by November 15, 2001. To meet

its burden, the petition must contain

sufficient facts to merit an FDA

investigation. (See H. Rept. 857, part 1,

98th Cong., 2d sess., pp. 41–42, 1984.)

Petitions should be in the format

specified in 21 CFR 10.30.

Comments and petitions should be

submitted to the Dockets Management

Branch. Three copies of any information