Chronobiology International, 23(6): 1083–1096, (2006)

Copyright # Informa Healthcare

ISSN 0742-0528 print/1525-6073 online
DOI: 10.1080/07420520601055308

ETHICS, STANDARDS, AND PROCEDURES OF ANIMAL AND

HUMAN CHRONOBIOLOGY RESEARCH

Yvan Touitou,1 Michael H. Smolensky,2 and Francesco Portaluppi3

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1
Faculty of Medicine, Department of Biochemistry and Molecular Biology, Pitié-Salpêtrière,
Paris, France
2
University of Texas-Houston School of Public Health, Houston, Texas, USA
3
Hypertension Center, Department of Clinical and Experimental Medicine, University of
Ferrara, Ferrara, Italy

The majority of research papers published in Chronobiology International report the

findings of investigations conducted on laboratory animals and human beings. The
For personal use only.

editors and the readers of the journal expect the authors of submitted manuscripts
to have made an important contribution to biological rhythm and related research
through the ethical conduct of investigations and unbiased and accurate reporting
of findings. Authors of scientific papers are required to disclose any potential conflict
of interest. The journal accepts only papers that are original work, no part of which has
been submitted for publication elsewhere, except as brief abstracts. The journal and its
editors endorse the compliance of investigators to the principles of the Declaration of
Helsinki of the World Medical Association, which relate to the conduct of ethical
research on human beings, and the Guide for the Care and Use of Laboratory Animals of
the Institute for Laboratory Animal Research of the National Research Council,
which relate to the conduct of ethical research on laboratory and other animals. The
peer review of manuscripts by Chronobiology International thus includes judgment as
to whether or not the investigative methods conform to the standards of good research
practice. This article updates the ethical policies, standards, and procedures for manu-
scripts submitted to Chronobiology International that involve human and animal biologi-
cal rhythm research, both from the perspective of the criteria of quality chronobiology
investigation and from the perspective of humane and ethical research on human
beings and animals.

Keywords Ethics in research, Declaration of Helsinki, Guidelines for animal

and human biological rhythm research, Biological rhythm research methods,
Chronobiology, Chronobiology International

Submitted July 6, 2006, Returned for revision September 30, 2006, Accepted October 6, 2006.
Address correspondence to Yvan Touitou, Department of Biochemistry and Molecular Biology,
Faculty of Medicine, Pierre et Marie Curie, 91 boulevard de l’Hôpital, 75634 Paris Cedex 13, France.
E-mail: touitou@ccr.jussieu.fr

1083
 1084 Y. Touitou et al.

INTRODUCTION
Chronobiology International: The Journal of Basic and Applied Biological
Rhythm Research is the official organ for publication by members of the
International Society of Chronobiology, American Association of
Medical Chronobiology and Chronotherapeutics, Society of Light
Therapy and Biological Rhythms, and Working Time Society, in addition
to numerous other investigators conducting research in chronobiology
and related fields worldwide. The journal publishes articles ranging in
content from the fundamental mechanisms of biological time-keeping
to applied aspects of chronobiology, such as sleep, night and shift
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work, clinical and medical chronobiology, and chronotherapeutics (bio-

logical rhythms and therapeutics). This article updates a previous one
(Touitou et al., 2004) and outlines the standards and procedures
expected by the editors, editorial board, and readers of Chronobiology
International for manuscripts involving human and animal biological
rhythm research from the perspectives of the criteria of quality chrono-
biology investigative and of humane and ethical research methods.
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JOURNAL POLICIES AND PROCEDURES

Authorship
The editors of the journal expect each author to have made an import-
ant scientific contribution to the investigation in which his/her name is
associated and to be thoroughly familiar with the original data. Authors
are also expected to have full access to all the data and to control the
decision of if and where to publish. Each author is expected to take respon-
sibility for the content and completeness of the manuscript and to under-
stand that if any portion of the paper is found to be faulty or fraudulent,
then he/she shares the responsibility for such with the coauthors. An
author’s name can be added or removed from a submitted manuscript
only at his/her request; however, all the coauthors must sign a change of
authorship agreement for any change in authorship to be instituted.

Duplicate Publication
The journal accepts only papers that are original work, no part of
which has been submitted for publication elsewhere, except as brief
abstracts. Material published by the author before submission is
considered prior publication when:

1. an article contains the same data that has been previously published in
another journal;
 Ethics and Standards of Chronobiology Research 1085

2. the original data in the form of figures and/or tables appear in

previously published articles, book chapters, and long abstracts, such
as in the form of the proceedings of meetings;
3. the findings have been widely circulated, copyrighted, or distributed
as archival reports; and
4. the findings have been reported in meeting presentations that are
reproduced and distributed beyond meeting attendees.

Authors with questions as to whether or not their manuscript falls into one of
these categories are invited to consult the journal editors for decision.
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Conflict of Interest
At the time of manuscript submission, authors are required to disclose any
potential conflict of interest (e.g., consultancies, stock ownership, equity inter-
ests, patent-licensing arrangements, etc.). The provided information will be
held in confidence while the paper is under review. If the article is accepted
for publication, information on the potential conflict of interest—including a
lack of control of the decision to publish—will be included on the title page.
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Falsification and Plagiarism

Fabricating a report of research or suppressing or altering data to agree
with one’s desired conclusions is considered falsification. Taking material
from another’s work and submitting it as one’s own is considered plagiarism.

Ethical Procedures
Reviewers have the responsibility to communicate to the editors
concerns of suspected duplicate publication, fraud, plagiarism, as well as
concerns about the possible violation of the ethical standards of animal
or human experimentation. Readers may report that they have seen the
same article elsewhere, or authors may see their own published work
being plagiarized. In all cases, the first action of the journal editor is to
draft a letter to the corresponding author requesting explanation in a non-
judgmental manner. If the author’s explanation is unacceptable, and it
seems that unethical conduct has occurred, the matter will be deliberated
by the editors to determine whether the case is serious enough to warrant a
ban on future submissions from the author(s) and/or if the offending
author’s institution should be informed. The author has the right of
appeal, with the opportunity to present his/her position, to the Publi-
cations Committee. If the infraction is relative minor, the editor may
send the lead author a letter of reprimand, reminding him/her of the
publication policies of the journal. If the manuscript has been published,
 1086 Y. Touitou et al.

the editor has the authority to require the author(s) to publish an apology
in the journal to correct the record. If, through the actions of the author(s),
Chronobiology International has violated the copyright of another journal,
the senior editor of Chronobiology International will inform the editors of
the affected journal of such. Chronobiology International will publish a retrac-
tion notice in the event of a serious case of fraud.

ANIMAL AND HUMAN CHRONOBIOLOGY RESEARCH

The majority of the research papers published in Chronobiology International
represent investigations conducted on laboratory animals and human beings.
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The journal and its editors endorse compliance of investigators with the intent
and principles of the Declaration of Helsinki (2000) of the World Medical Associ-
ation, which stipulates the policy and criteria for ethical research on human
beings, and the Guide for the Care and Use of Laboratory Animals (Institute for
Laboratory Animal Research, National Research Council, 1996), which stipu-
lates the policy and criteria for the conduct of ethical research on laboratory
and other animals. Chronobiology International, like other quality scientific jour-
nals (e.g., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002;283:R281–R283),
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requires that all submitted manuscripts adhere to the mandates of the Declara-
tion of Helsinki and the Guide for the Care and Use of Laboratory Animals. Thus, the
peer review of manuscripts will include judgment of whether or not the
involved research methods are appropriate, ethical, and in conformity with
the standards of good research practice.
The following sections present the basic considerations and
expectations of the journal for human and animal biological rhythm
studies, both from the perspective of the criteria necessary for high-
quality chronobiology research and from the perspective of the humane
and ethical treatment of human beings and laboratory and other animals.

ANIMAL CHRONOBIOLOGY RESEARCH

Ethical Criteria
Good practice principles must be respected. Unlike human beings,
animals cannot provide informed consent; nonetheless, they deserve
humane handling and treatment. Animal experiments are to be under-
taken only for the purpose of advancing knowledge. Consideration
should be given to the appropriateness of the experimental procedures,
selection of species, and number of animals utilized. Only animals that
are lawfully acquired shall be used in laboratory research. The retention
and use of laboratory and other research animals must comply with
local, state, and federal laws. Moreover, the care and use of the studied
animals must confirm to the guidelines established by the Guide for the
 Ethics and Standards of Chronobiology Research 1087

Care and Use of Laboratory Animals (Institute for Laboratory Animal

Research, National Research Council, 1996).
Adherence to the following minimal standards is expected in the
conduct of chronobiologic research on laboratory and other animals.
Animals used in research must receive every consideration for their
comfort; they must be properly housed and fed; and their surroundings
must be kept sanitary. Living conditions must be safe and comfortable
and contribute to the well-being of the animals, taking into account the
particular requirements of the species. For social species, this normally
requires housing in compatible pairs or groups. Animals deserve hygienic
living conditions and appropriate diet and water, cage cleaning, and
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bedding replacement by qualified personnel at appropriate intervals

during weekdays, weekends, and holidays. Soiled bedding should be
removed and replaced with fresh materials. Precautions must be taken
to avoid fluid and food restriction that results in dehydration and weight
loss by keeping and reviewing records of fluid and food intake.
Investigators and staff must be qualified to conduct the animal research,
and animals must be treated humanely in research following all legal statutes
and regulations. Prolonged physical restraint should be avoided. The total
volume of blood withdrawn during experimentation should always be speci-
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fied and must not compromise the health and well-being of the animals.
Surgical and other painful procedures must not be performed on
unanesthetized animals; suffering, discomfort, and pain must be minimized
through the use of appropriate sedation, analgesia/anesthesia, or other
methods that respects the welfare of the animals. If the study protocol
requires the euthanasia of animals, procedures must be conducted in a
painless manner and far away, in a separate room, from other animals.

Chronobiological Criteria
The use of laboratory and other animals for biological rhythm research
requires the investigator’s attention to special considerations. Animals
must be synchronized to light-dark and/or other environmental con-
ditions as mandated by the research protocol, prior to and during experi-
mentation. The Methods section must provide the clock times of
the synchronizer schedule (e.g., artificial or natural environmental light
(L)-dark (D) cycle and/or rest-activity routine) along with the environmental
light intensity and wavelength spectrum. In addition, the ambient
temperature, humidity, noise level, and animal feeding schedule and
diet ought to be described. (Repetitive noise can be stressful and in some
case synchronize animal rhythms; thus, personnel should minimize
unnecessary noise.) Nutritionally adequate food is required. Attention
should be paid to the possible synchronization of the animals through
the periodic maintenance schedule provided by qualified personnel.
 1088 Y. Touitou et al.

For example, under certain situations, the rest-activity and other circadian
rhythms of laboratory animals can be synchronized by feeding time.
Special animal research protocols that entail restricted feeding
schedules, constant environmental conditions, or atypical light-dark
cycles must be described in sufficient detail because they have an impact
on the biological time structure of the animals. Particulars about the age,
gender, strain, and breeding history/genetic manipulation of the study
animals also must be provided. Inbred strains of various species have
been developed for specific research. It is important to monitor inbred
animals periodically for their genetic homozygosity. Transgenic animals
have at least one transferred gene, and care should be taken to preserve
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the unique genetic make-up. Studies involving the biological effects

and response to physical, chemical, and other treatments must include
justification for the selected circadian time(s) of application/exposure.

HUMAN CHRONOBIOLOGY RESEARCH

Ethical Criteria
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The design and conduct of human research protocols must adhere to the
intent and principles of the Declaration of Helsinki proposed by the World
Medical Association in 1964 and its updates thereafter of 1975, 1983, 1989,
1996, and 2000. Research procedures must respect the welfare and rights
of the subjects and as much as possible their cultural, religious, and social
customs. Research must be justifiable in its design to contribute new knowl-
edge, and it must be reviewed and approved by the ethical committee of
the institution(s) where it is to be conducted, as well as the respective insti-
tutions of collaborating scientists. Informed consent must be obtained from
each participant after written and/or oral explanation of the experimental
procedures and their risks, using appropriate and simple language to
ensure a complete understanding. Study of special populations (e.g., chil-
dren, the intellectually impaired, and highly medically dependent or uncon-
scious persons) requires the consent of parents, guardians, or organizations
as specified by local regulations and laws. Each participant is free to decide at
any time to withdraw his/her consent to participate in research without
reprisal or prejudice. The participation in research by college and other
students registered in graded courses must be voluntary and not mandated
as a prerequisite for attaining a passing or superior grade. Students must
give informed consent and be able to withdraw their participation without
prejudice or reprisal of any sort.
Research on human beings must be conducted in safe and appropriate
settings (e.g., clinics, hospitals, academic centers, and research insti-
tutions), that possess facilities and experienced/skilled personnel to
support the investigative protocol and, should it be necessary, to provide
 Ethics and Standards of Chronobiology Research 1089

rapid medical intervention. The risk of discomfort and harm to partici-

pants in research must be minimized. Research protocols entailing blood
samplings must clearly state the total volume that will be withdrawn
during the course of study, which should not exceed the amount com-
monly donated for blood transfusion. Blood sampling during the night
should be performed with procedures apt to minimize discomfort to par-
ticipants; in particular, long catheters and unnecessary sleep disruptions
should be avoided, as should the use of bright light, which might affect
the biological time structure and variables under study. The subject’s
posture has to be specified at the time of blood sampling, and the analytical
variability and precision of the laboratory assays have to be provided.
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The recording, storage, and reporting of human data, both during and
after the conduct of the research, must at all times protect the confidenti-
ality and anonymity of the subjects. Subjects have the right to restrict the
use of their biological samples for any purpose other than that specified
in the research proposal for which consent was provided. Certain types
of human research may entail the use of a placebo, as it is often the most
effective and efficient means of evaluating new medical treatments. Partici-
pants must be informed that they may receive placebo, rather than active,
treatment before asked to give informed consent.
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The reporting of medically relevant findings to patients or other types

of research subjects must be done by certified health professionals of
appropriate training and competence. The field of human genetics is con-
cerned with the study of genes and their alleles. Only physicians with com-
petence in genetic counseling should provide subjects with the results of
genetic tests obtained for research purposes.
Finally, manuscripts must state the source (e.g., industry or foundations) of
the funding for the research. In addition, information regarding the authors’
affiliation with the sponsor(s) and possible conflicts of interest between the
sponsor(s) and investigator(s) must be clearly specified in the letter to the
editor that accompanies the submission of the manuscript to the Journal.

Chronobiological Criteria
The study of human biological rhythms necessitates appropriate
attention to the methods and concepts of chronobiological research.
Although it is impossible to specify the exact expectations of all types of
human chronobiological research, as a minimum, the Methods section of
every manuscript ought to state the temporal features of the sleep-wake or
other involved synchronizers of the biological time structure, along with
the particulars of the age, gender, and health status of the participating sub-
jects. Papers entailing shift-work studies must also clearly define the work
schedule as well as the duties of the workers. Patient studies ought to detail
subject inclusion and exclusion criteria and the clinical tests, questionnaires,
 1090 Y. Touitou et al.

and/or other procedures used to establish diagnoses. Control subjects must

be free of any pathologies and medications. They should have undertaken no
transmeridan flight in the two months preceding the experiment. Specific
information on tobacco use, caffeine intake, and alcoholic beverage con-
sumption before and during the research is required. In addition, patient
studies should state the type (medications, light, etc.), timing (in reference
to the sleep-wake cycle), and dose/intensity of usual treatments. Research
papers pertaining to chronopharmacology—administration time (relative
to the sleep-wake, menstrual, or annual cycle) differences in the kinetics
and effects of medications—are expected to state the rationale for the
choice of the treatment times explored.
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The Methods section should specify the time of the research procedures
(e.g., clock hours, days of the week, months of the year, and, if appropriate,
stages of the menstrual cycle). The Methods section ought to describe the fea-
tures of the study environment (e.g., geographic location, weather, and, when
pertinent, the local time of sunrise and sunset), plus the intensity and wave-
length spectrum of light exposure. Some research may make use of special
experimental designs involving forced-desynchrony, constant-routine, or
time-isolation protocols, and these should be described in sufficient detail.
The statistical analysis of the time series data must be clearly defined and
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consistent with the purpose of the study, the hypotheses to be tested, and the
number of participants or animals involved. Studies must be sufficiently
powered; they must involve sufficient numbers of subjects or animals, and
biological sampling must be done frequently enough to assess the biological
periodicity in question. Ultradian rhythms are ubiquitous phenomena,
ranging from milliseconds to a few hours. Their study requires a unique
investigative protocol involving very frequent biological samplings. Infra-
dian (e.g., weekly, mensual, and seasonal) rhythms are best evaluated on a
circadian basis (i.e., around-the-clock 24 h studies) at intervals of several
days, weeks, and/or months. Indeed, modification of the amplitude or acro-
phase (peak time) of a given infradian rhythm could be related to a modu-
lation of the circadian rhythm of the considered variable. A variety of
complementary statistical methods can be used to analyze the data obtained
from large samples of subjects. The data analysis of small samples is much
more difficult. When data comprise relatively few measurements, especially
from a relative small number of subjects, the aim of data processing is to
decrease interindividual biological variability so as to allow assessment by
conventional methods. Non-parametric tests may be suitable because they
ensure that the absolute values do not influence the results.

THE HELSINKI DECLARATION

The language of the Helsinki Declaration is oriented primarily to the
physician researcher; however, the Declaration pertains to all investigators
 Ethics and Standards of Chronobiology Research 1091

who perform research on human beings. This point is emphasized by the

inclusion of additional wording as shown in parentheses in the clauses that
follow below.

Introduction
1. The World Medical Association has developed the Declaration of Helsinki
as a statement of ethical principles to provide guidance to physicians
(and other health professionals) in medical research involving human
subjects. Medical research involving human subjects includes research
on identifiable human material or identifiable data.
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2. It is the duty of the physician (and other health professionals) to

promote and safeguard the health of the people. The knowledge
and conscience of physicians (and other health professionals) are
dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the
physician with the words, “The health of my patient will be my first
consideration,” and the International Code of Medical Ethics declares
that, “A physician shall act only in the patient’s interest when providing
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medical care which might have the effect of weakening the physical
and mental condition of the patient.”
4. Medical progress is based on research which ultimately must rest, in
part, on experimentation involving human subjects.
5. In medical research on human subjects, considerations related to the
well-being of the human subject should take precedence over the
interests of science and society.
6. The primary purpose of medical research involving human subjects is to
improve prophylactic, diagnostic, and therapeutic procedures and the
understanding of the etiology and pathogenesis of disease. Even the
best-proven prophylactic, diagnostic, and therapeutic methods must
continuously be challenged through research for their effectiveness,
efficiency, accessibility, and quality.
7. In current medical practice and in medical research, most prophylactic,
diagnostic, and therapeutic procedures involve risks and burdens.
8. Medical research is subject to ethical standards that promote respect for
all human beings and protect their health and rights. Some research
populations are vulnerable and need special protection. The particular
needs of the economically and medically disadvantaged must be recog-
nized. Special attention is also required for those who cannot give or
refuse consent for themselves, for those who may be subject to giving
consent under duress, for those who will not benefit personally from
the research, and for those for whom the research is combined with care.
9. Investigators should be aware of the ethical, legal, and regulatory
requirements for research on human subjects in their own countries as
 1092 Y. Touitou et al.

well as applicable international requirements. No national ethical, legal, or

regulatory requirement should be allowed to reduce or eliminate any of
the protections for human subjects set forth in the Declaration of Helsinki.

Basic Principles for All Medical (and Human) Research

10. It is the duty of the physician (and other health professionals) in
medical research to protect the life, health, privacy, and dignity of
the human subject.
11. Medical research involving human subjects must conform to
generally accepted scientific principles, be based on a thorough
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knowledge of the scientific literature and other relevant sources of

information, and be based on adequate laboratory and, where
appropriate, animal experimentation.
12. Appropriate caution must be exercised in the conduct of research
which may affect the environment, and the welfare of animals used
for research must be respected.
13. The design and performance of each experimental procedure
involving human subjects should be clearly formulated in an exper-
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imental protocol. This protocol should be submitted for consideration,

comment, guidance, and approval by a specially appointed ethical
review committee, which must be independent of the investigator,
the sponsor, or any other kind of undue influence. This independent
committee should be in conformity with the laws and regulations of
the country, as well as all other applicable jurisdictions, in which
the research experiment is to be performed. The committee has the
right to monitor ongoing trials. The researcher has the obligation to
provide monitoring information to the committee, especially the
occurrence of any serious adverse events. The researcher should
also submit to the committee, for review, information regarding
funding, sponsors, institutional affiliations, potential conflicts of
interest, and incentives for subjects.
14. The research protocol should always contain a statement of the
ethical considerations involved and should indicate that there is
compliance with the principles enunciated in the Declaration.
15. Medical research involving human subjects should be conducted only
by scientifically qualified persons and under the supervision of one or
more clinically competent medical (or other healthcare) pro-
fessionals. The responsibility for the human subject must always
rest with a medically qualified person and never rest on the subject
of the research, even though the subject has given consent.
16. Every medical research project involving human subjects should be
preceded by the careful assessment of predictable risks and burdens in
comparison with the foreseeable benefits to the subject or to others.
 Ethics and Standards of Chronobiology Research 1093

This does not preclude the participation of healthy volunteers in medical

research. The design of all studies should be publicly available.
17. Physicians (and other health professionals) should abstain from
engaging in research projects involving human subjects unless they
are confident that the risks involved have been adequately assessed
and can be satisfactorily managed. Physicians (and other health pro-
fessionals) should cease any investigation if the risks are found to out-
weigh the potential benefits or if there is conclusive proof of positive
and beneficial results.
18. Medical research involving human subjects should only be conducted
if the importance of the objective outweighs the inherent risks and
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burdens to the subject. This is especially important when the

human subjects are healthy volunteers.
19. Medical research is only justified if there is a reasonable likelihood
that the populations upon whom the research is conducted stand to
benefit from the results of the research.
20. The subjects must be volunteers and informed participants in the
research project.
21. The right of research subjects to safeguard their integrity must always
be respected. Every precaution should be taken to respect the privacy
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of the subject, the confidentiality of the patient and his/her data, and
to minimize the impact of the study on the subject’s physical and
mental integrity as well as personality of the subject.
22. In any research on human beings, each potential subject must be
adequately informed of the aims, methods, sources of funding, any
possible conflicts of interest, institutional affiliations of the researcher,
the anticipated benefits and potential risks of the study, and the dis-
comfort the research may entail. The subject should be informed of
the right to abstain from participation in the study or to withdraw
consent to participate at any time without reprisal. After ensuring
that the subject has understood the information, the physician
(and/or other health professionals) should then obtain the subject’s
freely-given informed consent, preferably in writing. If the consent
cannot be obtained in writing, the non-written consent must be
formally documented and witnessed.
23. When obtaining informed consent for the research project, the
physician (and/or other health professional) should be particularly cau-
tious if the subject is in a dependent relationship with the physician (or
other healthcare investigator) or who may consent under duress. In
that case, the informed consent should be obtained by a well-informed
physician (or other investigator) who is not engaged in the investigation
and who is completely independent of this relationship.
24. For a research subject who is legally incompetent, i.e., is physically or
mentally incapable of giving consent, or who is a legally incompetent
 1094 Y. Touitou et al.

minor, the investigator must obtain informed consent from the

legally authorized representative in accordance with applicable law.
These types of subjects should not be included in research unless
the research is necessary to promote the health of the population
represented and this research cannot instead be performed on
legally competent persons.
25. When a subject deemed legally incompetent, such as a minor child, is
able to give assent to decisions about participation in research, the
investigator must obtain that assent in addition to the consent of
the legally authorized representative.
26. Research on individuals from whom it is not possible to obtain consent,
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including proxy or advance consent, should be done only if the

physical/mental condition that prevents obtaining informed consent
is a necessary characteristic of the research population. The specific
reasons for involving research subjects with a condition that renders
them unable to give informed consent should be stated in the
experimental protocol for consideration and approval by the
governing review committee. The protocol should state that
consent to participate and remain in the research should be
obtained as soon as possible from the individual or legally authorized
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surrogate.
27. Both authors and publishers have ethical obligations. In the publi-
cation of the results of research, the investigators are obliged to pre-
serve the accuracy of the findings. Negative as well as positive results
should be published or otherwise publicly available. Sources of
funding, institutional affiliations, and any possible conflicts of interest
should be declared in the publication. Reports of experimentation
which were not conducted in accordance with the principles laid
down in the Declaration of Helsinki should not be accepted for
publication.

Additional Principles for Medical Research Combined with

Medical Care
28. The physician (or other health professional) may combine medical
research with medical care, only to the extent that the research is
justified by its potential prophylactic, diagnostic, or therapeutic
value. When medical research is combined with medical care,
additional standards apply to protect the patients who are research
subjects.
29. The benefits, risks, burdens, and effectiveness of a new method
should be tested against those of the best current prophylactic, diag-
nostic, and therapeutic methods. This does not exclude the use of
 Ethics and Standards of Chronobiology Research 1095

placebo, or no treatment, in studies where no proven prophylactic,

diagnostic, or therapeutic method exists.

In October 2001, the World Medical Association (WMA) Council issued

the following note of clarification on article 29 to further clarify the
WMA position on the use of placebo-controlled trials:
The WMA is concerned that paragraph 29 of the revised Declaration of
Helsinki (October 2000) has led to diverse interpretations and possible
confusion. It hereby reaffirms its position that extreme care must be
taken in making use of a placebo-controlled trial; in general, this exper-
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imental design should only be used in the absence of existing proven

therapy. However, a placebo-controlled trial may be ethically acceptable,
even if proven therapy is available, under the following circumstances:
Where for compelling and scientifically sound methodological reasons
its use is necessary to determine the efficacy or safety of a prophylactic,
diagnostic, or therapeutic method; or where a prophylactic, diagnostic,
or therapeutic method is being investigated for a minor condition and
the patients who receive placebo will not be subject to any additional
risk of serious or irreversible harm. All other provisions of the Declaration
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of Helsinki must be adhered to, especially the need for appropriate ethical
and scientific review.

30. At the conclusion of the study, every patient (or non-patient subject)
entered into the study should be assured of access to the best proven
prophylactic, diagnostic, and therapeutic methods identified by the
study.
31. The physician (or other health professional) should fully inform
the patient which aspects of his/her care are related to the
research. The refusal of a patient to participate in a study must
never interfere with the patient-physician (or other health
professional) relationship.
32. In the treatment of a patient, where proven prophylactic, diagnostic,
and therapeutic methods do not exist or have been ineffective, the
physician (or other relevant and qualified health professional), with
informed consent from the patient, must be free to use unproven
or new prophylactic, diagnostic, and therapeutic measures, if in the
physician’s (or health professional’s) judgment it offers hope of
saving life, re-establishing health, or alleviating suffering. Where
possible, these measures should be made the object of research,
which is designed to evaluate their safety and efficacy. In all cases,
new information should be recorded and, where appropriate, pub-
lished. The other relevant guidelines of this Declaration of Helsinki
should be followed.
 1096 Y. Touitou et al.

COMMENT
Chronobiology International, its editors, and Publication Committee
expect compliance of investigators and authors to the intent, principles,
and policies of the Declaration of Helsinki (2000) and Guide for the Care and
Use of Laboratory Animals (Institute for Laboratory Animal Research,
National Research Council, 1996). Failure to comply with these important
international standards of ethical research on human beings and animals
will jeopardize and even disqualify the publication of findings in Chronobiol-
ogy International and other reputable journals. The policies and principles
of the referenced guidelines are continually under review and subject to
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change. It is the responsibility of investigators to keep informed of

changes in policy and procedures for human and animal research by con-
sulting the information posted on the websites of the World Medical
Association (http://www.wma.net) and Institute for Laboratory Animal
Research (http://www.nap.edu/readingroom/books/labrats and http://
www.dels.nas.edu/ilar). The journal will also publish information about
future revisions to the guidelines when they become policy.

REFERENCES
For personal use only.

Declaration of Helsinki. (2000) 18th World Medical Association General Assembly, Helsinki,
Finland, June 1964; 29th World Medical Association General Assembly, Tokyo, Japan,
October, 1975; 35th World Medical Association General Assembly, Venice, Italy, October,
1983; 41st World Medical Association General Assembly, Hong Kong, September 1989; 48th
World Medical Association General Assembly, Somerset West, Republic of South Africa,
October, 1996; 52nd World Medical Association General Assembly, Edinburgh, Scotland,
October 2000.
Institute for Laboratory Animal Research, National Research Council. (1996) Guide for the Care and Use
of Laboratory Animals. Washington, D.C.: National Academy Press.
Touitou, Y., Portaluppi, F., Smolensky, M.H., Rensing, L. (2004). Ethical principles and standards for
the conduct of human and animal biological rhythm research. Chronobiol Int. 21:161–170.