“responsible research...

University of Balamand, Faculty of Sciences, Biology Department. P.O. Box: 100 Tripoli. Tel: 06-930250, Fax: 06- 930278

UNIVERSITY OF BALAMAND

1st WORKSHOP ON

“RESPONSIBLE RESEARCH CONDUCT”

Implementation of the

2nd

MENA Education Institute

& US National Academy of Sciences

Nov 7, 2014

Organizing Committee

ABDEL-MASSIH Roula

KASSAB Rima

YAMMINE Paolo

University of Balamand

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OUTLINE

1. Welcome Letter------------------------------------------------------------------3

2. Outline Summary----------------------------------------------------------------4

3. Agenda Overview----------------------------------------------------------------6

4. Reading Material---------------------------------------------------------------10

a. “Recommendations for the Conduct, Reporting, editing, and Publication

of Scholarly Work in Medical Journals”, 2013 (ICMJE)

b. “Ethical Guideline to Publication of Chemical Research”, American

Chemical Society (ACS), 2014.

c. “Institutional Review Boards and Independent Ethics

Committees”,Chapter from “Principles of Good Clinical Practice”

McGraw, Michael J; George, Adam N; Shearn, Shawn P; Hall, Rigel L;

Haws, Jr, Thomas F, 2010.

d. “Findings & Consequences of Research Misconduct”

e. “26Guidelines at a Glance on Avoiding Plagiarism”

f. Selections from MENA II Education Institute Booklet on Responsible

Science, 2014.

g. Singapore Statement on Research Integrity, 2010.

5. References


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Dear Participants

Welcome to the first University Of Balamand (UOB) workshop on

“Responsible Research conduct”. The goal of this workshop is to introduce

Science students and professionals to the concept of Responsible Science

and Science Misconduct. The themes of this workshop stem from the US

National Academy of Sciences and the 2nd

MENA Institute on Responsible

Science. These themes focus on the basic values of a scientist as an

individual and as a member of the whole scientific community.

The main topics of this workshop were decided on after meeting

with a group of our postgraduates and discussing the pre- or

misconceptions they have on authorship, plagiarism and scientific

misconduct. Points of tension with their mentors/supervisors were also

discussed and some of these points will be covered in a future workshop.

We thank US-NAS and the Faculty of Sciences at UOB for

funding this workshop. We hope that you will enjoy this meeting and

will transfer the spirit of “Professionalism in Science” all around you!

We look forward to working with you,

Organizing committee


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I-Summary Table:

Session Time Facilitator Objective Activity Approach

Session I – 9:00-11:00

Introduction 10 min

RAM Introduction Team-Aim- Objectives-

Explanation of pre-test

and post-test concept

Pre-test 15 min PY Pre-test To assess the

participants’ pre- or

misconceptions on

research misconduct and

authorship issues

Objective 1 15 min RK Define

Responsible

Research

Conduct

Activity 1:

-List local examples of

science misconduct

Brainstorming

[use overheads/

flipcharts]

Objective 2

- Case Study:

Korean Stem

Cell Case (or

another case)

60 min

10 min

RAM Participants

should be

able to

identify

different

forms of

Research

Misconduct

and suggest

solutions.

Activity 2:

-Each group should

suggest examples of

research misconduct

from the Korean Stem

Cell case

Activity 3:

-Ask groups to suggest

solutions

Divide into

groups-Discuss-

Report back

Divide into

groups-Discuss-

Report back

COFFEE BREAK (30 min) 11:00-11:30

Session II- 11:30-1:00

Objective 3 30 min RK Participants

will

differentiate

between FFP

(falsification,

fabrication,

and

plagiarism)

Activity 4:

- Each group will work

on one form of scientific

misconduct: FFP; then

groups will present their

findings to each other.

- The facilitator will

emphasize the different

forms on scientific

misconduct and how to

avoid them.

Interactive

Lecture +

Jigsaw + group

feedback

Objective 4 60 min PY Participants

will learn

how to give

appropriate

credit for

Activity 5:

-Original scientific texts

and plagiarized passages

or texts without proper

citation will be given to

Group work-

Discuss-Report

back


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intellectual

contribution

groups of participants to

work

-References to read

more about plagiarism

and proper citation will

be distributed.

LUNCH BREAK 60 min (1:00-2:00)

Session III- 2:00-4:00

Objective 4 30 min

60min

RAM,

RK, PY

Participants

will learn

how to give

appropriate

credit for

intellectual

contribution

Activity 6:

Role-play to emphasize

problems with authorship

& acknowledgements

Activity 7:

-Different case studies

concerning authorship will

be distributed to

participants in different

groups so that they can

determine who the authors

should be, order, and who

should be acknowledged.

-Facilitators will collect

results from groups before

and after mini-

lecture/discussion on

ICMJE recommendations

will be done.

-Each group will present

their case either through

role-play or just be

presenting it

- Discussion of results.

Role-Play/

Discussion

Jigsaw-

Interactive

mini-lecture-

Discuss-

Report back-

Role play

BREAK 10 min

Conclusion 20 min Overall Recommendations

Post-test Post-test:

Same as pre-test

Surveys on workshop will be sent with a deadline of 1 week after the workshop by e-mail for feedback.


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II- Agenda and Overview

Responsible Research Conduct

Participants/Audience: This workshop targets science postgraduate (M.Sc.-PhD)

students from the University of Balamand (UOB), lab supervisors, research assistants,

and senior undergraduate students that have applied to graduate school. Maximum

number: 50 participants; they will be divided into groups.

Time-line: 1 day workshop November 7, 2014 [6.5 hrs]

All surveys need to be submitted before November 15, 2014

Facilitators: ABDEL-MASSIH Roula

1 (RAM), KASSAB Rima

1 (RK), YAMMINE Paolo

1 (PY) +

Assistants2

1Associate Professor, University of Balamand (UOB), Lebanon.

2M.Sc. students that have already graduated (or will graduate this summer)

Marie-Anne Boujaoude, Jina Farah, Jean-François Jabbour, Rita El-Khoury, Michel

Kanaan, Dima Moussa, Johny Rashed.

To decide on the main theme of the workshop, we have already met with

some of our postgraduates and discovered that the main point of tension

they have with their supervisors is on paper author issues and

misconceptions they have on plagiarism and scientific misconduct.

A team of 4-5 of these postgraduates will be introduced to active learning

methods that we will use during the workshop in order to allow them to

help us during this activity. These postgraduates will be divided into

different groups during the workshop so that they can ensure the active

involvement of all members. Some of these students are already involved

with us in different activities such as School Health or Science Days.

The assistants will help in the preparation of a small movie or play on

scientific misconduct.

Goal: The goal of the workshop is to expose and sensitize participants to the

concept of Responsible Science

Learning objectives: At the end of this workshop, we expect that

1. Participants will define the main elements of Responsible Conduct of

Research.

2. Participants will identify and recognize the different forms of Scientific

Research Misconduct.


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3. Participants will be able to analyze and differentiate between Falsification,

Fabrication, Plagiarism and other forms of Research Misconduct.

4. Participants will recognize how to give appropriate credit for intellectual

contributions to scientific work/Authorship, Acknowledgement, and proper

citation (to avoid plagiarism).

Assessments:

Pre-test/Post-test

Facilitators will be evaluating the groups and modifications can be made

during the day to make sure that the objectives have been reached.

Group presentations/ Role-play/ feedback

Results of group work before and after lectures and discussions

A survey for feedback will be done to assess the workshop

Approaches:

Introduction: Team- Aim- Objectives- Explanation of pre-test and post-

test concept

Time: 10min Facilitator: Roula Abdel-Massih

Pre-test: to assess the participants’ pre- or misconceptions on research

misconduct and authorship issues.

Time: 15 min Facilitator: Paolo Yammine

Objective 1: Define Responsible Research Conduct

Activity 1: List local examples of science misconduct

(ex: chemists giving patients medication without FDA approval; taking

clinical samples without consent; authorship problems;

falsification/fabrication of data….)

Approach: Brainstorming [use overheads/ flipcharts/ or add

directly to PowerPoint presentation]

Time: 15 min Facilitator: Rima Kassab

Objective 2: Identify different forms of Research Misconduct and

suggest solutions.

Activity 2: Case Study: Korean Stem Cell Case (or another case)

Approach: Divide into groups-Discuss-Report back

Each group should suggest examples of research

misconduct from the case

Time: 60 min Facilitator: Roula Abdel-Massih

Activity 3: Ask groups to suggest solutions


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Approach: Divide into groups-Discuss-Report back (IRB, Ethical & Bio-safety committees, Peer review committees, Turnitin

or other plagiarism software, bioethics courses or seminars, committees to

check compliances…)

Time: 10 min Facilitator: Roula Abdel-Massih

- COFFEE BREAK 30 min

Objective 3: Differentiate between FFP (falsification, fabrication, and

plagiarism)

Activity 4: - Each group will work on one form of scientific

misconduct: FFP; then groups will present their findings to

each other.

- The facilitator will emphasize the different forms on

scientific misconduct and how to avoid them.

Approach: Interactive Lecture + Jigsaw + group feedback

Time: 30 min Facilitator: Rima Kassab

Objective 4: Recognize how to give appropriate credit for intellectual

contribution

Activity 5: -Original scientific texts and plagiarized passages or

texts without proper citation will be given to groups of

participants to work on (with the help of English

Department).

-References to read more about plagiarism and proper

citation will be distributed.

Approach: Group work- Discuss-Report back

Time: 60 min Facilitator: Paolo Yammine

- LUNCH BREAK 60 min

Activity 6: Role-play to emphasize problems with authorship &

acknowledgements

Approach: Role-Play/ Discussion

Time: 30min Facilitator: RAM, RK, PY

Activity 7: -Different case studies concerning authorship will be

distributed to participants in different groups so that they

can determine who the authors should be, order, and who

should be acknowledged.

-Written results (author order, acknowledgement…) will be

taken from different groups without discussion.

-A mini-lecture and discussion on ICMJE recommendations

will be done.


9

-Groups will be asked to review their results and hand in

new results.

-Each group will present their case either through role-play

or just be presenting it

- Discussion of results.

Approach: Jigsaw- Interactive mini-lecture- Discuss-Report back-

Role play

Time: 60 min Facilitator: RAM, RK, PY

- BREAK 10 min

Overall Recommendations

Post-test: Same as pre-test

Time: 20 min

Surveys on workshop will be sent with a deadline of 1 week after the

workshop by e-mail for feedback.


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III- SELECTED READINGS

1- Authorship, Plagiarism, & Intellectual Contribution

a. ICJME Authorship guideline

b. ACS

c. IRB/ETHICS COMMITTEE

d. Research Misconduct

e. Plagiarism Guidelines

2- Selections from MENA II Education Institute Booklet on Responsible Science,

2014.

a. Misconduct

b. Responsible authorship

c. Korean Stem cell case

3- Singapore Statement on Research Integrity


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IV- References

1. Recommendations for the Conduct, Reporting, editing, and Publication of

Scholarly Work in Medical Journals”, 2013 (ICMJE) (www.icmje.org)

http://www.icmje.org/recommendations/

2. “Ethical Guideline to Publication of Chemical Research”, American

Chemical Society (ACS), 2014.

http://pubs.acs.org/page/policy/ethics/index.html

pubs.acs.org/userimages/ContentEditor/1218054468605/ethics.pdf

3. “Institutional Review Boards and Independent Ethics Committees”,

Chapter from “Principles of Good Clinical Practice” McGraw, Michael J;

George, Adam N; Shearn, Shawn P; Hall, Rigel L; Haws, Jr, Thomas F,

2010.

http://www.pharmpress.com/files/docs/principles_clinpract_sample.pdf

4. “Findings & Consequences of Research Misconduct”

http://ori.hhs.gov/education/products/RIandImages/misconduct_cases/find

ings_of_misconduct.pdf

5. “26Guidelines at a Glance on Avoiding Plagiarism”, 2014

http://ori.hhs.gov/plagiarism-0

6. Selections from MENA II Education Institute Booklet on Responsible

Science, 2014.

7. Singapore Statement on Research Integrity, 2010.

www.singaporestatement.org

http://www.icmje.org/

http://www.icmje.org/recommendations/

http://pubs.acs.org/page/policy/ethics/index.html

http://www.pharmpress.com/files/docs/principles_clinpract_sample.pdf

http://ori.hhs.gov/education/products/RIandImages/misconduct_cases/findings_of_misconduct.pdf

http://ori.hhs.gov/education/products/RIandImages/misconduct_cases/findings_of_misconduct.pdf

http://ori.hhs.gov/plagiarism-0

http://www.singaporestatement.org/

SELECTED READINGS

Recommendations for the Conduct, Reporting, Editing, andPublication of Scholarly Work in Medical Journals*Updated December 2013

I. About the RecommendationsA. Purpose of the RecommendationsB. Who Should Use the Recommendations?C. History of the Recommendations

II. Roles and Responsibilities of Authors, Contributors,Reviewers, Editors, Publishers, and OwnersA. Defining the Role of Authors and Contributors

1. Why Authorship Matters2. Who Is an Author?3. Non-Author Contributors

B. Author Responsibilities—Conflicts of Interest1. Participants

a. Authorsb. Peer Reviewersc. Editors and Journal Staff

2. Reporting Conflicts of InterestC. Responsibilities in the Submission and Peer-Review

Process1. Authors2. Journals

a. Confidentialityb. Timelinessc. Peer Reviewd. Integrity

3. Peer ReviewersD. Journal Owners and Editorial Freedom

1. Journal Owners2. Editorial Freedom

E. Protection of Research ParticipantsIII. Publishing and Editorial Issues Related to Publication

in Medical JournalsA. Corrections and Version ControlB. Scientific Misconduct, Expressions of Concern,

and RetractionC. CopyrightD. Overlapping Publications

1. Duplicate Submission2. Duplicate Publication3. Acceptable Secondary Publication4. Manuscripts Based on the Same Database

E. CorrespondenceF. Supplements, Theme Issues, and Special SeriesG. Sponsorship of PartnershipsH. Electronic PublishingI. AdvertisingJ. Journals and the Media

K. Clinical Trial RegistrationIV. Manuscript Preparation and Submission

A. Preparing a Manuscript for Submission to a Med-ical Journal1. General Principles2. Reporting Guidelines3. Manuscript Sections

a. Title Pageb. Abstractc. Introductiond. Methods

i. Selection and Description of Partici-pants

ii. Technical Informationiii. Statistics

e. Resultsf. Discussiong. References

i. General Considerationsii. Style and Format

h. Tablesi. Illustrations (Figures)j. Units of Measurementk. Abbreviations and Symbols

B. Sending the Manuscript to the Journal

I. ABOUT THE RECOMMENDATIONS

A. Purpose of the RecommendationsICMJE developed these recommendations to review

best practice and ethical standards in the conduct and re-porting of research and other material published in medicaljournals, and to help authors, editors, and others involvedin peer review and biomedical publishing create and dis-tribute accurate, clear, unbiased medical journal articles.The recommendations may also provide useful insightsinto the medical editing and publishing process for themedia, patients and their families, and general readers.

B. Who Should Use the Recommendations?These recommendations are intended primarily for use

by authors who might submit their work for publication toICMJE member journals. Many non-ICMJE journals vol-untarily use these recommendations (see www.icmje.org/journals.html). The ICMJE encourages that use but hasno authority to monitor or enforce it. In all cases, authorsshould use these recommendations along with individualjournals’ instructions to authors. Authors should also con-sult guidelines for the reporting of specific study types(e.g., the CONSORT guidelines for the reporting of ran-domized trials); see http://equator-network.org.

* Developed by members of the ICMJE over the period 2011 to 2013.

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rich4/zai-aim/zai-aim/zai22213/-zai0001d13a phillipa S�12 1/31/14 10:52 Art:

Journals that follow these recommendations are en-couraged to incorporate them into their instructions toauthors and to make explicit in those instructions that theyfollow ICMJE recommendations. Journals that wish to beidentified on the ICMJE website as following these recom-mendations should notify the ICMJE secretariat via e-mailat [email protected]. Journals that in the past have re-quested such identification but who no longer followICMJE recommendations should use the same means torequest removal from this list.

The ICMJE encourages wide dissemination of theserecommendations and reproduction of this document in itsentirety for educational, not-for-profit purposes withoutregard for copyright, but all uses of the recommendationsand document should direct readers to www.icmje.org forthe official, most recent version, as the ICMJE updates therecommendations periodically when new issues arise.

C. History of the RecommendationsThe ICMJE has produced multiple editions of this

document, previously known as the Uniform Require-ments for Manuscripts Submitted to Biomedical Journals(URMs). The URM was first published in 1978 as a wayof standardizing manuscript format and preparation acrossjournals. Over the years, issues in publishing that went wellbeyond manuscript preparation arose, resulting in develop-ment of a number of Separate Statements on editorial pol-icy. The entire Uniform Requirements document was re-vised in 1997; sections were updated in May 1999 andMay 2000. In May 2001, the ICMJE revised the sectionsrelated to potential conflicts of interest. In 2003, the com-mittee revised and reorganized the entire document andincorporated the Separate Statements into the text, andrevised it again in 2010. Previous versions of this docu-ment can be found in the “Archives” section of www.icmje.org. This version, now renamed “Recommendations forthe Conduct, Reporting, Editing, and Publication ofScholarly Work in Medical Journals” (ICMJE Recommen-dations), was released in 2013.

II. ROLES AND RESPONSIBILITIES OF AUTHORS,CONTRIBUTORS, REVIEWERS, EDITORS, PUBLISHERS,AND OWNERS

A. Defining the Role of Authors and Contributors1. Why Authorship Matters

Authorship confers credit and has important aca-demic, social, and financial implications. Authorship alsoimplies responsibility and accountability for publishedwork. The following recommendations are intended toensure that contributors who have made substantive intel-lectual contributions to a paper are given credit as authors,but also that contributors credited as authors understandtheir role in taking responsibility and being accountable forwhat is published.

Because authorship does not communicate what con-tributions qualified an individual to be an author, some

journals now request and publish information about thecontributions of each person named as having participatedin a submitted study, at least for original research. Editorsare strongly encouraged to develop and implement a con-tributorship policy, as well as a policy that identifies who isresponsible for the integrity of the work as a whole. Suchpolicies remove much of the ambiguity surrounding con-tributions, but leave unresolved the question of the quan-tity and quality of contribution that qualify an individualfor authorship. The ICMJE has thus developed criteria forauthorship that can be used by all journals, including thosethat distinguish authors from other contributors.

2. Who Is an Author?

The ICMJE recommends that authorship be based onthe following 4 criteria:

1. Substantial contributions to the conception or de-sign of the work; or the acquisition, analysis, or interpre-tation of data for the work; AND

2. Drafting the work or revising it critically for im-portant intellectual content; AND

3. Final approval of the version to be published; AND4. Agreement to be accountable for all aspects of the

work in ensuring that questions related to the accuracy orintegrity of any part of the work are appropriately investi-gated and resolved.

In addition to being accountable for the parts of thework he or she has done, an author should be able toidentify which co-authors are responsible for specific otherparts of the work. In addition, authors should have confi-dence in the integrity of the contributions of their co-authors.

All those designated as authors should meet all fourcriteria for authorship, and all who meet the four criteriashould be identified as authors. Those who do not meet allfour criteria should be acknowledged—see Section II.A.3below. These authorship criteria are intended to reserve thestatus of authorship for those who deserve credit and cantake responsibility for the work. The criteria are not in-tended for use as a means to disqualify colleagues fromauthorship who otherwise meet authorship criteria by de-nying them the opportunity to meet criterion #s 2 or 3.Therefore, all individuals who meet the first criterionshould have the opportunity to participate in the review,drafting, and final approval of the manuscript.

The individuals who conduct the work are responsiblefor identifying who meets these criteria and ideally shoulddo so when planning the work, making modifications asappropriate as the work progresses. It is the collective re-sponsibility of the authors, not the journal to which thework is submitted, to determine that all people named asauthors meet all four criteria; it is not the role of journaleditors to determine who qualifies or does not qualify forauthorship or to arbitrate authorship conflicts. If agree-ment cannot be reached about who qualifies for author-ship, the institution(s) where the work was performed, not

Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals

2 www.icmje.org


the journal editor, should be asked to investigate. If au-thors request removal or addition of an author after man-uscript submission or publication, journal editors shouldseek an explanation and signed statement of agreement forthe requested change from all listed authors and from theauthor to be removed or added.

The corresponding author is the one individual whotakes primary responsibility for communication with thejournal during the manuscript submission, peer review,and publication process, and typically ensures that all thejournal’s administrative requirements, such as providingdetails of authorship, ethics committee approval, clinicaltrial registration documentation, and gathering conflict ofinterest forms and statements, are properly completed, al-though these duties may be delegated to one or more co-authors. The corresponding author should be availablethroughout the submission and peer review process to re-spond to editorial queries in a timely way, and should beavailable after publication to respond to critiques of thework and cooperate with any requests from the journal fordata or additional information should questions about thepaper arise after publication. Although the correspondingauthor has primary responsibility for correspondence withthe journal, the ICMJE recommends that editors send cop-ies of all correspondence to all listed authors.

When a large multi-author group has conducted thework, the group ideally should decide who will be an au-thor before the work is started and confirm who is anauthor before submitting the manuscript for publication.All members of the group named as authors should meetall four criteria for authorship, including approval of thefinal manuscript, and they should be able to take publicresponsibility for the work and should have full confidencein the accuracy and integrity of the work of other groupauthors. They will also be expected as individuals to com-plete conflict-of-interest disclosure forms.

Some large multi-author groups designate authorshipby a group name, with or without the names of individu-als. When submitting a manuscript authored by a group,the corresponding author should specify the group name ifone exists, and clearly identify the group members who cantake credit and responsibility for the work as authors. Thebyline of the article identifies who is directly responsiblefor the manuscript, and MEDLINE lists as authors which-ever names appear on the byline. If the byline includes agroup name, MEDLINE will list the names of individualgroup members who are authors or who are collaborators,sometimes called non-author contributors, if there is a noteassociated with the byline clearly stating that the individualnames are elsewhere in the paper and whether those namesare authors or collaborators.

3. Non-Author Contributors

Contributors who meet fewer than all 4 of the abovecriteria for authorship should not be listed as authors, butthey should be acknowledged. Examples of activities that

alone (without other contributions) do not qualify a con-tributor for authorship are acquisition of funding; generalsupervision of a research group or general administrativesupport; and writing assistance, technical editing, languageediting, and proofreading. Those whose contributions donot justify authorship may be acknowledged individuallyor together as a group under a single heading (e.g. “ClinicalInvestigators” or “Participating Investigators”), and theircontributions should be specified (e.g., “served as scientificadvisors,” “critically reviewed the study proposal,” “col-lected data,” “provided and cared for study patients”, “par-ticipated in writing or technical editing of the manu-script”).

Because acknowledgment may imply endorsement byacknowledged individuals of a study’s data and conclu-sions, editors are advised to require that the correspondingauthor obtain written permission to be acknowledged fromall acknowledged individuals.

B. Author Responsibilities—Conflicts of InterestPublic trust in the scientific process and the credibility

of published articles depend in part on how transparentlyconflicts of interest are handled during the planning, im-plementation, writing, peer review, editing, and publica-tion of scientific work.

A conflict of interest exists when professional judg-ment concerning a primary interest (such as patients’ wel-fare or the validity of research) may be influenced by asecondary interest (such as financial gain). Perceptions ofconflict of interest are as important as actual conflicts ofinterest.

Financial relationships (such as employment, consul-tancies, stock ownership or options, honoraria, patents,and paid expert testimony) are the most easily identifiableconflicts of interest and the most likely to undermine thecredibility of the journal, the authors, and of science itself.However, conflicts can occur for other reasons, such aspersonal relationships or rivalries, academic competition,and intellectual beliefs. Agreements between authors andstudy sponsors that interfere with the authors’ access to allof a study’s data or that interfere with their ability to ana-lyze and interpret the data and to prepare and publishmanuscripts independently may represent conflicts of in-terest, and should be avoided.

1. Participants

All participants in the peer-review and publicationprocess—not only authors but also peer reviewers, editors,and editorial board members of journals—must considertheir conflicts of interest when fulfilling their roles in theprocess of article review and publication and must discloseall relationships that could be viewed as potential conflictsof interest.


www.icmje.org 3


a. Authors

When authors submit a manuscript of any type orformat they are responsible for disclosing all financial andpersonal relationships that might bias or be seen to biastheir work. The ICMJE has developed a Form for Disclo-sure of Conflicts of Interest to facilitate and standardizeauthors’ disclosures. ICMJE member journals require thatauthors use this form, and ICMJE encourages other jour-nals to adopt it.

b. Peer Reviewers

Reviewers should be asked at the time they are askedto critique a manuscript if they have conflicts of interestthat could complicate their review. Reviewers must discloseto editors any conflicts of interest that could bias theiropinions of the manuscript, and should recuse themselvesfrom reviewing specific manuscripts if the potential for biasexists. Reviewers must not use knowledge of the workthey’re reviewing before its publication to further theirown interests.

c. Editors and Journal Staff

Editors who make final decisions about manuscriptsshould recuse themselves from editorial decisions if theyhave conflicts of interest or relationships that pose poten-tial conflicts related to articles under consideration. Othereditorial staff members who participate in editorial deci-sions must provide editors with a current description oftheir financial interests or other conflicts (as they mightrelate to editorial judgments) and recuse themselves fromany decisions in which a conflict of interest exists. Editorialstaff must not use information gained through workingwith manuscripts for private gain. Editors should publishregular disclosure statements about potential conflicts ofinterests related to the commitments of journal staff. Guesteditors should follow these same procedures.

2. Reporting Conflicts of Interest

Articles should be published with statements or sup-porting documents, such as the ICMJE conflict of interestform, declaring:

– Authors’ conflicts of interest; and– Sources of support for the work, including sponsor

names along with explanations of the role of those sourcesif any in study design; collection, analysis, and interpreta-tion of data; writing of the report; the decision to submitthe report for publication; or a statement declaring that thesupporting source had no such involvement; and

– Whether the authors had access to the study data,with an explanation of the nature and extent of access,including whether access is on-going.

To support the above statements, editors may requestthat authors of a study sponsored by a funder with a pro-prietary or financial interest in the outcome sign a state-ment, such as “I had full access to all of the data in this

study and I take complete responsibility for the integrity ofthe data and the accuracy of the data analysis.”

C. Responsibilities in the Submission and Peer-ReviewProcess1. Authors

Authors should abide by all principles of authorshipand declaration of conflicts of interest detailed in sectionIIA and B of this document.

2. Journals

a. Confidentiality

Manuscripts submitted to journals are privileged com-munications that are authors’ private, confidential prop-erty, and authors may be harmed by premature disclosureof any or all of a manuscript’s details.

Editors therefore must not share information aboutmanuscripts, including whether they have been receivedand are under review, their content and status in the reviewprocess, criticism by reviewers, and their ultimate fate, toanyone other than the authors and reviewers. Requestsfrom third parties to use manuscripts and reviews for legalproceedings should be politely refused, and editors shoulddo their best not to provide such confidential materialshould it be subpoenaed.

Editors must also make clear that reviewers shouldkeep manuscripts, associated material, and the informationthey contain strictly confidential. Reviewers and editorialstaff members must not publicly discuss the authors’ work,and reviewers must not appropriate authors’ ideas beforethe manuscript is published. Reviewers must not retain themanuscript for their personal use and should destroy papercopies of manuscripts and delete electronic copies aftersubmitting their reviews.

When a manuscript is rejected, it is best practice forjournals to delete copies of it from their editorial systemsunless retention is required by local regulations. Journalsthat retain copies of rejected manuscripts should disclosethis practice in their Information for Authors.

When a manuscript is published, journals should keepcopies of the original submission, reviews, revisions, andcorrespondence for at least three years and possibly in per-petuity, depending on local regulations, to help answerfuture questions about the work should they arise.

Editors should not publish or publicize peer reviewers’comments without permission of the reviewer and author.If journal policy is to blind authors to reviewer identity andcomments are not signed, that identity must not be re-vealed to the author or anyone else without the reviewers’expressed written permission.

Confidentiality may have to be breached if dishonestyor fraud is alleged, but editors should notify authors orreviewers if they intend to do so and confidentiality mustotherwise be honored.


4 www.icmje.org


b. Timeliness

Editors should do all they can to ensure timely pro-cessing of manuscripts with the resources available to them.If editors intend to publish a manuscript, they should at-tempt to do so in a timely manner and any planned delaysshould be negotiated with the authors. If a journal has nointention of proceeding with a manuscript, editors shouldendeavor to reject the manuscript as soon as possible toallow authors to submit to a different journal.

c. Peer Review

Peer review is the critical assessment of manuscriptssubmitted to journals by experts who are usually not partof the editorial staff. Because unbiased, independent, crit-ical assessment is an intrinsic part of all scholarly work,including scientific research, peer review is an importantextension of the scientific process.

The actual value of peer review is widely debated, butthe process facilitates a fair hearing for a manuscript amongmembers of the scientific community. More practically, ithelps editors decide which manuscripts are suitable fortheir journals. Peer review often helps authors and editorsimprove the quality of reporting.

It is the responsibility of the journal to ensure thatsystems are in place for selection of appropriate reviewers.It is the responsibility of the editor to ensure that reviewershave access to all materials that may be relevant to theevaluation of the manuscript, including supplementarymaterial for e-only publication, and to ensure that reviewercomments are properly assessed and interpreted in the con-text of their declared conflicts of interest.

A peer-reviewed journal is under no obligation to sendsubmitted manuscripts for review, and under no obligationto follow reviewer recommendations, favorable or negative.The editor of a journal is ultimately responsible for theselection of all its content, and editorial decisions may beinformed by issues unrelated to the quality of a manu-script, such as suitability for the journal. An editor canreject any article at any time before publication, includingafter acceptance if concerns arise about the integrity of thework.

Journals may differ in the number and kinds of man-uscripts they send for review, the number and types ofreviewers they seek for each manuscript, whether the re-view process is open or blinded, and other aspects of thereview process. For this reason and as a service to authors,journals should publish a description of their peer-reviewprocess.

Journals should notify reviewers of the ultimate deci-sion to accept or reject a paper, and should acknowledgethe contribution of peer reviewers to their journal. Editorsare encouraged to share reviewers’ comments with co-reviewers of the same paper, so reviewers can learn fromeach other in the review process.

As part of peer review, editors are encouraged to re-view research protocols, plans for statistical analysis if sep-

arate from the protocol, and/or contracts associated withproject-specific studies. Editors should encourage authorsto make such documents publicly available at the time ofor after publication, before accepting such studies for pub-lication. Some journals may require public posting of thesedocuments as a condition of acceptance for publication.

Journal requirements for independent data analysisand for public data availability are in flux at the time of thisrevision, reflecting evolving views of the importance of dataavailability for pre- and post-publication peer review. Somejournal editors currently request a statistical analysis of trialdata by an independent biostatistician before acceptingstudies for publication. Others ask authors to say whetherthe study data are available to third parties to view and/oruse/reanalyze, while still others encourage or require au-thors to share their data with others for review or reanaly-sis. Each journal should establish and publish their specificrequirements for data analysis and posting in a place whichpotential authors can easily access.

Some people believe that true scientific peer reviewbegins only on the date a paper is published. In that spirit,medical journals should have a mechanism for readers tosubmit comments, questions, or criticisms about publishedarticles, and authors have a responsibility to respond ap-propriately and cooperate with any requests from the jour-nal for data or additional information should questionsabout the paper arise after publication (see Section III).

ICMJE believes investigators have a duty to maintainthe primary data and analytic procedures underpinning thepublished results for at least 10 years. The ICMJE encour-ages the preservation of these data in a data repository toensure their longer-term availability.

d. Integrity

Editorial decisions should be based on the relevance ofa manuscript to the journal and on the manuscript’s orig-inality, quality, and contribution to evidence about impor-tant questions. Those decisions should not be influencedby commercial interests, personal relationships or agendas,or findings that are negative or that credibly challenge ac-cepted wisdom. In addition, authors should submit forpublication or otherwise make publicly available, and edi-tors should not exclude from consideration for publication,studies with findings that are not statistically significant orthat have inconclusive findings. Such studies may provideevidence that combined with that from other studiesthrough meta-analysis might still help answer importantquestions, and a public record of such negative or incon-clusive findings may prevent unwarranted replication ofeffort or otherwise be valuable for other researchers consid-ering similar work.

Journals should clearly state their appeals process andshould have a system for responding to appeals and com-plaints.


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3. Peer Reviewers

Manuscripts submitted to journals are privileged com-munications that are authors’ private, confidential prop-erty, and authors may be harmed by premature disclosureof any or all of a manuscript’s details.

Reviewers therefore should keep manuscripts and theinformation they contain strictly confidential. Reviewersmust not publicly discuss authors’ work and must not ap-propriate authors’ ideas before the manuscript is published.Reviewers must not retain the manuscript for their per-sonal use and should destroy copies of manuscripts aftersubmitting their reviews.

Reviewers are expected to respond promptly to re-quests to review and to submit reviews within the timeagreed. Reviewers’ comments should be constructive, hon-est, and polite.

Reviewers should declare their conflicts of interest andrecuse themselves from the peer-review process if a conflictexists.

D. Journal Owners and Editorial Freedom1. Journal Owners

Owners and editors of medical journals share a com-mon purpose, but they have different responsibilities, andsometimes those differences lead to conflicts.

It is the responsibility of medical journal owners toappoint and dismiss editors. Owners should provide edi-tors at the time of their appointment with a contract thatclearly states their rights and duties, authority, the generalterms of their appointment, and mechanisms for resolvingconflict. The editor’s performance may be assessed usingmutually agreed-upon measures, including but not neces-sarily limited to readership, manuscript submissions andhandling times, and various journal metrics.

Owners should only dismiss editors for substantial rea-sons, such as scientific misconduct, disagreement with thelong-term editorial direction of the journal, inadequateperformance by agreed-upon performance metrics, or in-appropriate behavior that is incompatible with a positionof trust.

Appointments and dismissals should be based on eval-uations by a panel of independent experts, rather than by asmall number of executives of the owning organization.This is especially necessary in the case of dismissals becauseof the high value society places on freedom of speechwithin science and because it is often the responsibility ofeditors to challenge the status quo in ways that may con-flict with the interests of the journal’s owners.

A medical journal should explicitly state its governanceand relationship to a journal owner (eg, a sponsoring soci-ety).

2. Editorial Freedom

The ICMJE adopts the World Association of MedicalEditors’ definition of editorial freedom, which holds thateditors-in-chief have full authority over the entire editorial

content of their journal and the timing of publication ofthat content. Journal owners should not interfere in theevaluation, selection, scheduling, or editing of individualarticles either directly or by creating an environment thatstrongly influences decisions. Editors should base editorialdecisions on the validity of the work and its importance tothe journal’s readers, not on the commercial implicationsfor the journal, and editors should be free to express criticalbut responsible views about all aspects of medicine withoutfear of retribution, even if these views conflict with thecommercial goals of the publisher.

Editors-in-chief should also have the final say in deci-sions about which advertisements or sponsored content,including supplements, the journal will and will not carry,and they should have final say in use of the journal brandand in overall policy regarding commercial use of journalcontent.

Journals are encouraged to establish an independenteditorial advisory board to help the editor establish andmaintain editorial policy. Editors should seek input asneeded from a broad array of advisers, such as reviewers,editorial staff, an editorial board, and readers, to supporteditorial decisions and potentially controversial expressionsof opinion, and owners should ensure that appropriate in-surance is obtained in the event of legal action against theeditors, and should ensure that legal advice is availablewhen necessary. If legal problems arise, the editor shouldinform their legal adviser and their owner and/or publisheras soon as possible. Editors should defend the confidenti-ality of authors and peer-reviewers (names and reviewercomments) in accordance with ICMJE policy (see SectionII C.2.a). Editors should take all reasonable steps to checkthe facts in journal commentary, including that in newssections and social media postings, and should ensure thatstaff working for the journal adhere to best journalisticpractices including contemporaneous note-taking andseeking a response from all parties when possible beforepublication. Such practices in support of truth and publicinterest may be particularly relevant in defense against legalallegations of libel.

To secure editorial freedom in practice, the editorshould have direct access to the highest level of ownership,not to a delegated manager or administrative officer.

Editors and editors’ organizations are obliged to sup-port the concept of editorial freedom and to draw majortransgressions of such freedom to the attention of the in-ternational medical, academic, and lay communities.

E. Protection of Research ParticipantsWhen reporting experiments on people, authors

should indicate whether the procedures followed were inaccordance with the ethical standards of the responsiblecommittee on human experimentation (institutional andnational), or if no formal ethics committee is available,with the Helsinki Declaration as revised in 2008 (link towww.wma.net/en/30publications/10policies/b3/index.html).


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If doubt exists whether the research was conducted inaccordance with the Helsinki Declaration, the authorsmust explain the rationale for their approach and demon-strate that the institutional review body explicitly approvedthe doubtful aspects of the study.

Patients have a right to privacy that should not beviolated without informed consent. Identifying informa-tion, including names, initials, or hospital numbers, shouldnot be published in written descriptions, photographs, orpedigrees unless the information is essential for scientificpurposes and the patient (or parent or guardian) gives writ-ten informed consent for publication. Informed consentfor this purpose requires that an identifiable patient beshown the manuscript to be published. Authors shoulddisclose to these patients whether any potential identifiablematerial might be available via the Internet as well as inprint after publication. Patient consent should be writtenand archived with the journal, the authors, or both, asdictated by local regulations or laws. Applicable laws varyfrom locale to locale, and journals should establish theirown policies with legal guidance. Since a journal that ar-chives the consent will be aware of patient identity, somejournals may decide that patient confidentiality is betterguarded by having the author archive the consent and in-stead providing the journal with a written statement thatattests that they have received and archived written patientconsent.

Nonessential identifying details should be omitted. In-formed consent should be obtained if there is any doubtthat anonymity can be maintained. For example, maskingthe eye region in photographs of patients is inadequateprotection of anonymity. If identifying characteristics arede-identified, authors should provide assurance, and edi-tors should so note, that such changes do not distort sci-entific meaning.

The requirement for informed consent should be in-cluded in the journal’s instructions for authors. When in-formed consent has been obtained, it should be indicatedin the published article.

When reporting experiments on animals, authors shouldindicate whether institutional and national standards forthe care and use of laboratory animals were followed. Fur-ther guidance on animal research ethics is available fromthe International Association of Veterinary Editors’ Con-sensus Author Guidelines on Animal Ethics and Welfare(http://veteditors.org/ethicsconsensusguidelines.html).

III. PUBLISHING AND EDITORIAL ISSUES RELATED TO

PUBLICATION IN MEDICAL JOURNALS

A. Corrections and Version ControlHonest errors are a part of science and publishing and

require publication of a correction when they are detected.Corrections are needed for errors of fact. Matters of debateare best handled as letters to the editor, as print or elec-tronic correspondence, or as posts in a journal-sponsored

online forum. Updates of previous publications (e.g., anupdated systematic review or clinical guideline) are consid-ered a new publication rather than a version of a previouslypublished article.

If a correction is needed, journals should follow theseminimum standards:

• The journal should publish a correction as soon aspossible detailing changes from and citing the original pub-lication; the correction should be on an electronic or num-bered printpage that is included in an electronic or a printTable of Contents to ensure proper indexing

• The journal should post the new article version withdetails of the changes from the original version and thedate(s) on which the changes were made.

• The journal should archive all prior versions of thearticle. This archive can be either directly accessible toreaders or can be made available to the reader on request

• Previous electronic versions should prominentlynote that there are more recent versions of the article.

• The citation should be to the most recent version.Errors serious enough to invalidate a paper’s findings

may require retraction.

B. Scientific Misconduct, Expressions of Concern, andRetraction

Scientific misconduct includes but is not necessarilylimited to data fabrication; data falsification including de-ceptive manipulation of images; and plagiarism. Some peo-ple consider failure to publish the results of clinical trialsand other human studies a form of scientific misconduct.While each of these practices is problematic, they are notequivalent. Each situation requires individual assessmentby relevant stakeholders. When scientific misconduct is al-leged, or concerns are otherwise raised about the conduct orintegrity of work described in submitted or published papers,the editor should initiate appropriate procedures detailedby such committees such as the Committee on PublicationEthics (COPE) (publicationethics.org/resources/flowcharts)and may choose to publish an expression of concern pend-ing the outcomes of those procedures. If the proceduresinvolve an investigation at the authors’ institution, the ed-itor should seek to discover the outcome of that investiga-tion, notify readers of the outcome if appropriate, and ifthe investigation proves scientific misconduct, publish aretraction of the article. There may be circumstances inwhich no misconduct is proven, but an exchange of lettersto the editor could be published to highlight matters ofdebate to readers.

Expressions of concern and retractions should not sim-ply be a letter to the editor. Rather, they should be prom-inently labelled, appear on an electronic or numbered printpage that is included in an electronic or a print Table ofContents to ensure proper indexing, and include in theirheading the title of the original article. Online, the retrac-tion and original article should be linked in both directionsand the retracted article should be clearly labelled as re-


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tracted in all its forms (Abstract, full text, PDF). Ideally,the authors of the retraction should be the same as thoseof the article, but if they are unwilling or unable the editormay under certain circumstances accept retractions byother responsible persons, or the editor may be the soleauthor of the retraction or expression of concern. The textof the retraction should explain why the article is beingretracted and include a complete citation reference to thatarticle. Retracted articles should remain in the public do-main and be clearly labelled as retracted.

The validity of previous work by the author of a fraud-ulent paper cannot be assumed. Editors may ask the au-thor’s institution to assure them of the validity of earlierwork published in their journals, or they may retract it. Ifthis is not done, editors may choose to publish an an-nouncement expressing concern that the validity of previ-ously published work is uncertain.

The integrity of research may also be compromised byinappropriate methodology that could lead to retraction.

See COPE flowcharts for further guidance on retrac-tions and expressions of concern. See Section IV.g.i. forguidance about avoiding referencing retracted articles.

C. CopyrightJournals should make clear the type of copyright under

which work will be published, and if the journal retainscopyright, should detail the journal’s position on the trans-fer of copyright for all types of content, including audio,video, protocols, and data sets. Medical journals may askauthors to transfer copyright to the journal. Some journalsrequire transfer of a publication license. Some journals donot require transfer of copyright and rely on such vehiclesas Creative Commons licenses. The copyright status of ar-ticles in a given journal can vary: Some content cannot becopyrighted (for example, articles written by employees ofsome governments in the course of their work). Editorsmay waive copyright on other content, and some contentmay be protected under other agreements.

D. Overlapping Publications1. Duplicate Submission

Authors should not submit the same manuscript, inthe same or different languages, simultaneously to morethan one journal. The rationale for this standard is thepotential for disagreement when two (or more) journalsclaim the right to publish a manuscript that has been sub-mitted simultaneously to more than one journal, and thepossibility that two or more journals will unknowingly andunnecessarily undertake the work of peer review, edit thesame manuscript, and publish the same article.

2. Duplicate Publication

Duplicate publication is publication of a paper thatoverlaps substantially with one already published, withoutclear, visible reference to the previous publication.

Readers of medical journals deserve to be able to trustthat what they are reading is original unless there is a clear

statement that the author and editor are intentionally re-publishing an article (which might be considered for his-toric or landmark papers, for example). The bases of thisposition are international copyright laws, ethical conduct,and cost-effective use of resources. Duplicate publication oforiginal research is particularly problematic because it canresult in inadvertent double-counting of data or inappro-priate weighting of the results of a single study, whichdistorts the available evidence.

When authors submit a manuscript reporting workthat has already been reported in large part in a publishedarticle or is contained in or closely related to another paperthat has been submitted or accepted for publication else-where, the letter of submission should clearly say so andthe authors should provide copies of the related material tohelp the editor decide how to handle the submission. Seealso Section IV.B.

This recommendation does not prevent a journal fromconsidering a complete report that follows publication of apreliminary report, such as a letter to the editor or anabstract or poster displayed at a scientific meeting. It alsodoes not prevent journals from considering a paper that hasbeen presented at a scientific meeting but was not pub-lished in full, or that is being considered for publication inproceedings or similar format. Press reports of scheduledmeetings are not usually regarded as breaches of this rule,but they may be if additional data tables or figures enrichsuch reports. Authors should also consider how dissemina-tion of their findings outside of scientific presentations atmeetings may diminish the priority journal editors assignto their work. An exception to this principle may occurwhen information that has immediate implications forpublic health needs to be disseminated, but when possible,early distribution of findings before publication should bediscussed with and agreed upon by the editor in advance.

Sharing with public media, government agencies, ormanufacturers the scientific information described in a pa-per or a letter to the editor that has been accepted but notyet published violates the policies of many journals. Suchreporting may be warranted when the paper or letter de-scribes major therapeutic advances; reportable diseases; orpublic health hazards, such as serious adverse effects ofdrugs, vaccines, other biological products, medical devices.This reporting, whether in print or online, should notjeopardize publication, but should be discussed with andagreed upon by the editor in advance when possible.

The ICMJE does not consider results posted in clinicaltrial registries as previous publication if the results are pre-sented in the same, ICMJE-accepted registry in which ini-tial registration of trial methods occurred and if the resultsare posted in the form of brief structured abstracts or ta-bles. The ICMJE encourages authors to include a state-ment with the registration that indicates that the resultshave not yet been published in a peer-reviewed journal,and to update the results registry with the full journal ci-tation when the results are published.


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Editors of different journals may together decide tosimultaneously or jointly publish an article if they believethat doing so would be in the best interest of public health.However, the National Library of Medicine (NLM) in-dexes all such simultaneously published joint publicationsseparately, so editors should include a statement makingthe simultaneous publication clear to readers.

Authors who attempt duplicate publication withoutsuch notification should expect at least prompt rejection ofthe submitted manuscript. If the editor was not aware ofthe violations and the article has already been published,then the article might warrant retraction with or withoutthe author’s explanation or approval.

See COPE flowcharts for further guidance on han-dling duplicate publication.

3. Acceptable Secondary Publication

Secondary publication of material published in otherjournals or online may be justifiable and beneficial, espe-cially when intended to disseminate important informationto the widest possible audience (e.g., guidelines producedby government agencies and professional organizations inthe same or a different language). Secondary publicationfor various other reasons may also be justifiable providedthe following conditions are met:

1. The authors have received approval from the edi-tors of both journals (the editor concerned with secondarypublication must have access to the primary version).

2. The priority of the primary publication is respectedby a publication interval negotiated by both editors withthe authors.

3. The paper for secondary publication is intended fora different group of readers; an abbreviated version couldbe sufficient.

4. The secondary version faithfully reflects the dataand interpretations of the primary version.

5. The secondary version informs readers, peers, anddocumenting agencies that the paper has been published inwhole or in part elsewhere—for example, with a note thatmight read, “This article is based on a study first reportedin the [journal title, with full reference]”—and the second-ary version cites the primary reference.

6. The title of the secondary publication should indi-cate that it is a secondary publication (complete orabridged republication or translation) of a primary publi-cation. Of note, the NLM does not consider translations tobe “republications” and does not cite or index them whenthe original article was published in a journal that is in-dexed in MEDLINE.

When the same journal simultaneously publishes anarticle in multiple languages, the MEDLINE citation willnote the multiple languages (for example, Angelo M. Jour-nal networking in nursing: a challenge to be shared.Rev Esc Enferm USP. 2011 Dec 45[6]:1281-2,1279-

80,1283-4. Article in English, Portuguese, and Spanish.No abstract available. PMID 22241182).

4. Manuscripts Based on the Same Database

If editors receive manuscripts from separate researchgroups or from the same group analyzing the same data set(for example, from a public database, or systematic reviewsor meta-analyses of the same evidence), the manuscriptsshould be considered independently because they may dif-fer in their analytic methods, conclusions, or both. If thedata interpretation and conclusions are similar, it may bereasonable although not mandatory for editors to give pref-erence to the manuscript submitted first. Editors mightconsider publishing more than one manuscript that overlapin this way because different analytical approaches may becomplementary and equally valid, but manuscripts basedupon the same dataset should add substantially to eachother to warrant consideration for publication as separatepapers, with appropriate citation of previous publicationsfrom the same dataset to allow for transparency.

Secondary analyses of clinical trial data should cite anyprimary publication, clearly state that it contains secondaryanalyses/results, and use the same identifying trial registra-tion number as the primary trial.

Sometimes for large trials it is planned from the be-ginning to produce numerous separate publications regard-ing separate research questions but using the same originalpatient sample. In this case authors may use the originalsingle trial registration number, if all the outcome param-eters were defined in the original registration. If the authorsregistered several substudies as separate entries in, for ex-ample, clinicaltrials.gov, then the unique trial identifiershould be given for the study in question, The main issueis transparency, so no matter what model is used it shouldbe obvious for the reader.

E. CorrespondenceMedical journals should provide readers with a mech-

anism for submitting comments, questions, or criticismsabout published articles, usually but not necessarily alwaysthrough a correspondence section or online forum. Theauthors of articles discussed in correspondence or an onlineforum have a responsibility to respond to substantial criti-cisms of their work using those same mechanisms andshould be asked by editors to respond. Authors of corre-spondence should be asked to declare any competing orconflicting interests.

Correspondence may be edited for length, grammati-cal correctness, and journal style. Alternatively, editors maychoose to make available to readers unedited correspon-dence, for example, via an online commenting system.Such commenting is not indexed in Medline unless it issubsequently published on a numbered electronic or printpage. However the journal handles correspondence, itshould make known its practice. In all instances, editors


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must make an effort to screen discourteous, inaccurate, orlibellous comments.

Editors have the prerogative to reject correspondencethat is irrelevant, uninteresting, or lacking cogency, butthey also have a responsibility to allow a range of opinionsto be expressed and to promote debate.

In the interests of fairness and to keep correspondencewithin manageable proportions, journals may want to settime limits for responding to published material and fordebate on a given topic.

F. Supplements, Theme Issues, and Special SeriesSupplements are collections of papers that deal with

related issues or topics, are published as a separate issue ofthe journal or as part of a regular issue, and may be fundedby sources other than the journal’s publisher. Becausefunding sources can bias the content of supplementsthrough the choice of topics and viewpoints, journalsshould adopt the following principles, which also apply totheme issues or special series that have external fundingand/or guest editors:

1. The journal editor must be given and must takefull responsibility for the policies, practices, and content ofsupplements, including complete control of the decision toselect authors, peer reviewers, and content for the supple-ment. Editing by the funding organization should not bepermitted.

2. The journal editor has the right to appoint one ormore external editors of the supplement and must takeresponsibility for the work of those editors.

3. The journal editor must retain the authority tosend supplement manuscripts for external peer review andto reject manuscripts submitted for the supplement with orwithout external review. These conditions should be madeknown to authors and any external editors of the supple-ment before beginning editorial work on it.

4. The source of the idea for the supplement, sourcesof funding for the supplement’s research and publication,and products of the funding source related to content con-sidered in the supplement should be clearly stated in theintroductory material.

5. Advertising in supplements should follow the samepolicies as those of the primary journal.

6. Journal editors must enable readers to distinguishreadily between ordinary editorial pages and supplementpages.

7. Journal and supplement editors must not acceptpersonal favors or direct remuneration from sponsors ofsupplements.

8. Secondary publication in supplements (republica-tion of papers published elsewhere) should be clearly iden-tified by the citation of the original paper and by the title.

9. The same principles of authorship and disclosure ofpotential conflicts of interest discussed elsewhere in thisdocument should be applied to supplements.

G. Sponsorship or PartnershipVarious entities may seek interactions with journals or

editors in the form of sponsorships, partnerships, meetings,or other types of activities. To preserve editorial indepen-dence, these interactions should be governed by the sameprinciples outlined above for Supplements, Theme Issuesand Special Series (Section III.F).

H. Electronic PublishingMost medical journals are now published in electronic

as well as print versions, and some are published only inelectronic form. Principles of print and electronic publish-ing are identical, and the recommendations of this docu-ment apply equally to both. However, electronic publish-ing provides opportunities for versioning and raises issuesabout link stability and content preservation that are ad-dressed here.

Recommendations for corrections and versioning aredetailed in Section III.A.

Electronic publishing allows linking to sites and re-sources beyond journals over which journal editors have noeditorial control. For this reason, and because links to ex-ternal sites could be perceived as implying endorsement ofthose sites, journals should be cautious about external link-ing. When a journal does link to an external site, it shouldstate that it does not endorse or take responsibility or lia-bility for any content, advertising, products, or other ma-terials on the linked sites, and does not take responsibilityfor the sites’ availability.

Permanent preservation of journal articles on a jour-nal’s website, or in an independent archive or a crediblerepository is essential for the historical record. Removingan article from a journal’s website in its entirety is almostnever justified as copies of the article may have been down-loaded even if its online posting was brief. Such archivesshould be freely accessible or accessible to archive mem-bers. Deposition in multiple archives is encouraged. How-ever, if necessary for legal reasons (e.g., libel action), theURL for the removed article must contain a detailed reasonfor the removal, and the article must be retained in thejournal’s internal archive.

Permanent preservation of a journal’s total content isthe responsibility of the journal publisher, who in the eventof journal termination should be certain the journal filesare transferred to a responsible third party who can makethe content available.

Journal websites should post the date that nonarticleweb pages, such as those listing journal staff, editorialboard members, and instructions for authors, were last up-dated.

I. AdvertisingMost medical journals carry advertising, which gener-

ates income for their publishers, but journals should not bedominated by advertisements, and advertising must not beallowed to influence editorial decisions.

Journals should have formal, explicit, written policies


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for advertising in both print and electronic versions. Bestpractice prohibits selling advertisements intended to bejuxtaposed with editorial content on the same product.Advertisements should be clearly identifiable as advertise-ments. Editors should have full and final authority for ap-proving print and online advertisements and for enforcingadvertising policy.

Journals should not carry advertisements for productsproven to be seriously harmful to health. Editors shouldensure that existing regulatory or industry standards foradvertisements specific to their country are enforced, ordevelop their own standards. The interests of organizationsor agencies should not control classified and other nondis-play advertising, except where required by law. Editorsshould consider all criticisms of advertisements for publi-cation.

J. Journals and the MediaJournals’ interactions with media should balance com-

peting priorities. The general public has a legitimate inter-est in all journal content and is entitled to important in-formation within a reasonable amount of time, and editorshave a responsibility to facilitate that. However media re-ports of scientific research before it has been peer-reviewedand fully vetted may lead to dissemination of inaccurate orpremature conclusions, and doctors in practice need tohave research reports available in full detail before they canadvise patients about the reports’ conclusions.

An embargo system has been established in somecountries and by some journals to assist this balance, andto prevent publication of stories in the general media be-fore publication of the original research in the journal. Forthe media, the embargo creates a “level playing field,”which most reporters and writers appreciate since it mini-mizes the pressure on them to publish stories before com-petitors when they have not had time to prepare carefully.Consistency in the timing of public release of biomedicalinformation is also important in minimizing economicchaos, since some articles contain information that haspotential to influence financial markets. The ICMJE ac-knowledges criticisms of embargo systems as being self-serving of journals’ interests and an impediment to rapiddissemination of scientific information, but believe thebenefits of the systems outweigh their harms.

The following principles apply equally to print andelectronic publishing and may be useful to editors as theyseek to establish policies on interactions with the media:

• Editors can foster the orderly transmission of med-ical information from researchers, through peer-reviewedjournals, to the public. This can be accomplished by anagreement with authors that they will not publicize theirwork while their manuscript is under consideration orawaiting publication and an agreement with the media thatthey will not release stories before publication of the orig-inal research in the journal, in return for which the journal

will cooperate with them in preparing accurate stories byissuing, for example, a press release.

• Editors need to keep in mind that an embargo sys-tem works on the honor system—no formal enforcementor policing mechanism exists. The decision of a significantnumber of media outlets or biomedical journals not torespect the embargo system would lead to its rapid disso-lution.

• Notwithstanding authors’ belief in their work, verylittle medical research has such clear and urgently impor-tant clinical implications for the public’s health that thenews must be released before full publication in a journal.When such exceptional circumstances occur, the appropri-ate authorities responsible for public health should decidewhether to disseminate information to physicians and themedia in advance and should be responsible for this deci-sion. If the author and the appropriate authorities wish tohave a manuscript considered by a particular journal, theeditor should be consulted before any public release. Ifeditors acknowledge the need for immediate release, theyshould waive their policies limiting prepublication public-ity.

• Policies designed to limit prepublication publicityshould not apply to accounts in the media of presentationsat scientific meetings or to the abstracts from these meet-ings (see Duplicate Publication). Researchers who presenttheir work at a scientific meeting should feel free to discusstheir presentations with reporters but should be discour-aged from offering more detail about their study than waspresented in the talk, or should consider how giving suchdetail might diminish the priority journal editors assign totheir work (see Duplicate Publication).

• When an article is close to being published, editorsor journal staff should help the media prepare accuratereports by providing news releases, answering questions,supplying advance copies of the article, or referring report-ers to appropriate experts. This assistance should be con-tingent on the media’s cooperation in timing the release ofa story to coincide with publication of the article.

K. Clinical Trial RegistrationThe ICMJE’s clinical trial registration policy is de-

tailed in a series of editorials (see Updates and Editorials[www.icmje.org/update.html] and FAQs [www.icmje.org/faq_clinical.html]).

Briefly, the ICMJE requires, and recommends that allmedical journal editors require, registration of clinical trialsin a public trials registry at or before the time of firstpatient enrollment as a condition of consideration for pub-lication. Editors requesting inclusion of their journal onthe ICMJE website list of publications that follow ICMJEguidance [icmje.org/journals.html] should recognize thatthe listing implies enforcement by the journal of ICMJE’strial registration policy.

The ICMJE defines a clinical trial as any research proj-ect that prospectively assigns people or a group of people to


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an intervention, with or without concurrent comparison orcontrol groups, to study the cause-and-effect relationshipbetween a health-related intervention and a health out-come. Health-related interventions are those used to mod-ify a biomedical or health-related outcome; examples in-clude drugs, surgical procedures, devices, behaviouraltreatments, dietary interventions, quality improvement in-terventions, and process-of-care changes. Health outcomesare any biomedical or health-related measures obtained inpatients or participants, including pharmacokinetic mea-sures and adverse events. The ICMJE does not define thetiming of first patient enrollment, but best practice dictatesregistration by the time of first patient consent.

The ICMJE accepts registration in any registry thatis a primary register of the WHO International ClinicalTrials Registry Platform (ICTRP) (www.who.int/ictrp/network/primary/en/index.html) or in ClinicalTrials.gov,which is a data provider to the WHO ICTRP. The ICMJEendorses these registries because they meet several criteria.They are accessible to the public at no charge, open to allprospective registrants, managed by a not-for-profit orga-nization, have a mechanism to ensure the validity of theregistration data, and are electronically searchable. An ac-ceptable registry must include the minimum 20-item trialregistration dataset (http://prsinfo.clinicaltrials.gov/trainTrainer/WHO-ICMJE-ClinTrialsgov-Cross-Ref.pdf or www.who.int/ictrp/network/trds/en/index.html) at the time ofregistration and before enrollment of the first participant.The ICMJE considers inadequate trial registrations missingany of the 20 data fields or those that have fields thatcontain uninformative information. Although not a re-quired item, the ICMJE encourages authors to include astatement that indicates that the results have not yet beenpublished in a peer-reviewed journal, and to update theregistration with the full journal citation when the resultsare published.

The purpose of clinical trial registration is to preventselective publication and selective reporting of researchoutcomes, to prevent unnecessary duplication of researcheffort, to help patients and the public know what trials areplanned or ongoing into which they might want to enroll,and to help give ethics review boards considering approvalof new studies a view of similar work and data relevant tothe research they are considering. Retrospective registra-tion, for example at the time of manuscript submission,meets none of these purposes. Those purposes apply also toresearch with alternative designs, for example observationalstudies. For that reason, the ICMJE encourages registrationof research with non-trial designs, but because the exposureor intervention in non-trial research is not dictated by theresearchers, the ICMJE does not require it.

Secondary data analyses of primary (parent) clinicaltrials should not be registered as separate clinical trials, butinstead should reference the trial registration number ofthe primary trial.

The ICMJE encourages posting of clinical trial results

in clinical trial registries but does not require it. As notedabove in Section III.2, the ICMJE will not consider trialresult registration to be previous publication if the resultsare posted in the same primary clinical trial registry as theinitial registration and if the results are presented in theform of a brief (�500 word) structured abstract or table,but may consider as prior publication more detailed regis-try descriptions of trial results, and results published inregistries other than the primary trial registry.

The ICMJE recommends that journals publish thetrial registration number at the end of the abstract. TheICMJE also recommends that, whenever a registrationnumber is available, authors list this number the first timethey use a trial acronym to refer either to the trial they arereporting or to other trials that they mention in the man-uscript.

Editors may consider whether the circumstances in-volved in a failure to appropriately register a clinical trialwere likely to have been intended to or resulted in biasedreporting. If an exception to prospective registration ismade, trials must be registered and the authors should in-dicate in the publication when registration was completedand why it was delayed. Editors should publish a statementindicating why an exception was allowed. The ICMJE em-phasizes that such exceptions should be rare, and that au-thors failing to prospectively register a trial risk its inad-missibililty to our journals.

IV. MANUSCRIPT PREPARATION AND SUBMISSION

A. Preparing a Manuscript for Submission to a MedicalJournal1. General Principles

The text of articles reporting original research is usu-ally divided into Introduction, Methods, Results, and Dis-cussion sections. This so-called “IMRAD” structure is notan arbitrary publication format but a reflection of the pro-cess of scientific discovery. Articles often need subheadingswithin these sections to further organize their content.Other types of articles, such as meta-analyses, may requiredifferent formats, while case reports, narrative reviews, andeditorials may have less structured or unstructured formats.

Electronic formats have created opportunities for add-ing details or sections, layering information, cross-linking,or extracting portions of articles in electronic versions.Supplementary electronic-only material should be submit-ted and sent for peer review simultaneously with the pri-mary manuscript.

2. Reporting Guidelines

Reporting guidelines have been developed for differentstudy designs; examples include CONSORT (www.consort-statement.org) for randomized trials, STROBE for obser-vational studies (http://strobe-statement.org/), PRISMAfor systematic reviews and meta-analyses (http://prisma-statement.org/), and STARD for studies of diagnostic


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accuracy (www.stard-statement.org/). Journals are encour-aged to ask authors to follow these guidelines because theyhelp authors describe the study in enough detail for it tobe evaluated by editors, reviewers, readers, and other re-searchers evaluating the medical literature. Authors of re-view manuscripts are encouraged to describe the methodsused for locating, selecting, extracting, and synthesizingdata; this is mandatory for systematic reviews. Goodsources for reporting guidelines are the EQUATOR Net-work (www.equator-network.org/home/) and the NLM’sResearch Reporting Guidelines and Initiatives (www.nlm.nih.gov/services/research_report_guide.html).

3. Manuscript Sections

The following are general requirements for reportingwithin sections of all study designs and manuscript for-mats.

a. Title Page

General information about an article and its authorsis presented on a manuscript title page and usually in-cludes the article title, author information, any disclaimers,sources of support, word count, and sometimes the num-ber of tables and figures.

Article title. The title provides a distilled description ofthe complete article and should include information that,along with the Abstract, will make electronic retrieval ofthe article sensitive and specific. Reporting guidelines rec-ommend and some journals require that information aboutthe study design be a part of the title (particularly impor-tant for randomized trials and systematic reviews and meta-analyses). Some journals require a short title, usually nomore than 40 characters (including letters and spaces) onthe title page or as a separate entry in an electronic sub-mission system. Electronic submission systems may restrictthe number of characters in the title.

Author information. Each author’s highest academicdegrees should be listed, although some journals do notpublish these. The name of the department(s) and institu-tion(s) or organizations where the work should be attrib-uted should be specified. Most electronic submission sys-tems require that authors provide full contact information,including land mail and e-mail addresses, but the title pageshould list the corresponding authors’ telephone and faxnumbers and e-mail address.

Disclaimers. An example of a disclaimer is an author’sstatement that the views expressed in the submitted articleare his or her own and not an official position of the insti-tution or funder.

Source(s) of support. These include grants, equipment,drugs, and/or other support that facilitated conduct of thework described in the article or the writing of the articleitself.

Word count. A word count for the paper’s text, exclud-ing its abstract, acknowledgments, tables, figure legends,

and references, allows editors and reviewers to assesswhether the information contained in the paper warrantsthe paper’s length, and whether the submitted manuscriptfits within the journal’s formats and word limits. A separateword count for the Abstract is useful for the same reason.

Number of figures and tables. Some submission systemsrequire specification of the number of Figures and Tablesbefore uploading the relevant files. These numbers alloweditorial staff and reviewers to confirm that all figures andtables were actually included with the manuscript and,because Tables and Figures occupy space, to assess if theinformation provided by the figures and tables warrants thepaper’s length and if the manuscript fits within the jour-nal’s space limits.

Conflict of Interest declaration. Conflict of interest in-formation for each author needs to be part of the manu-script; each journal should develop standards with regardto the form the information should take and where it willbe posted. The ICMJE has developed a uniform conflict ofinterest disclosure form for use by ICMJE member jour-nals (www.icmje.org/coi_disclosure.pdf ) and the ICMJEencourages other journals to adopt it. Despite availabilityof the form, editors may require conflict of interest decla-rations on the manuscript title page to save the work ofcollecting forms from each author prior to making an ed-itorial decision or to save reviewers and readers the work ofreading each author’s form.

b. Abstract

Original research, systematic reviews, and meta-analyses require structured abstracts. The abstract shouldprovide the context or background for the study and shouldstate the study’s purpose, basic procedures (selection ofstudy participants, settings, measurements, analyticalmethods), main findings (giving specific effect sizes andtheir statistical and clinical significance, if possible), andprincipal conclusions. It should emphasize new and impor-tant aspects of the study or observations, note importantlimitations, and not overinterpret findings. Clinical trialabstracts should include items that the CONSORT grouphas identified as essential (www.consort-statement.org/resources/downloads/extensions/consort-extension-for-abstracts-2008pdf/). Funding sources should be listed sep-arately after the Abstract to facilitate proper display andindexing for search retrieval by MEDLINE.

Because abstracts are the only substantive portion ofthe article indexed in many electronic databases, and theonly portion many readers read, authors need to ensurethat they accurately reflect the content of the article. Un-fortunately, information in abstracts often differs from thatin the text. Authors and editors should work in the processof revision and review to ensure that information is consis-tent in both places. The format required for structuredabstracts differs from journal to journal, and some journalsuse more than one format; authors need to prepare their


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abstracts in the format specified by the journal they havechosen.

The ICMJE recommends that journals publish theclinical trial registration number at the end of the abstract.The ICMJE also recommends that, when a registrationnumber is available, authors list that number the first timethey use a trial acronym to refer to the trial they are re-porting or to other trials that they mention in the manu-script.

c. Introduction

Provide a context or background for the study (that is,the nature of the problem and its significance). State thespecific purpose or research objective of, or hypothesistested by, the study or observation. Cite only directly per-tinent references, and do not include data or conclusionsfrom the work being reported.

d. Methods

The guiding principle of the Methods section shouldbe clarity about how and why a study was done in a par-ticular way. The section should include only informationthat was available at the time the plan or protocol for thestudy was being written; all information obtained duringthe study belongs in the Results section.

i. Selection and Description of Participants

Clearly describe the selection of observational or ex-perimental participants (healthy individuals or patients, in-cluding controls), including eligibility and exclusion crite-ria and a description of the source population. Because therelevance of such variables as age, sex, or ethnicity is notalways known at the time of study design, researchersshould aim for inclusion of representative populations intoall study types and at a minimum provide descriptive datafor these and other relevant demographic variables. If thestudy was done involving an exclusive population, for ex-ample in only one sex, authors should justify why, exceptin obvious cases (e.g., prostate cancer).” Authors shoulddefine how they measured race or ethnicity and justify theirrelevance.

ii. Technical Information

Specify the study’s main and secondary objectives—usually identified as primary and secondary outcomes.Identify methods, equipment (give the manufacturer’sname and address in parentheses), and procedures in suffi-cient detail to allow others to reproduce the results. Givereferences to established methods, including statisticalmethods (see below); provide references and brief descrip-tions for methods that have been published but are notwell-known; describe new or substantially modified meth-ods, give the reasons for using them, and evaluate theirlimitations. Identify precisely all drugs and chemicals used,including generic name(s), dose(s), and route(s) of admin-

istration. Identify appropriate scientific names and genenames.

iii. Statistics

Describe statistical methods with enough detail to en-able a knowledgeable reader with access to the original datato judge its appropriateness for the study and to verify thereported results. When possible, quantify findings andpresent them with appropriate indicators of measurementerror or uncertainty (such as confidence intervals). Avoidrelying solely on statistical hypothesis testing, such as Pvalues, which fail to convey important information abouteffect size and precision of estimates. References for thedesign of the study and statistical methods should be tostandard works when possible (with pages stated). Definestatistical terms, abbreviations, and most symbols. Specifythe statistical software package(s) and versions used. Dis-tinguish prespecified from exploratory analyses, includingsubgroup analyses.

e. Results

Present your results in logical sequence in the text,tables, and figures, giving the main or most importantfindings first. Do not repeat all the data in the tables orfigures in the text; emphasize or summarize only the mostimportant observations. Provide data on all primary andsecondary outcomes identified in the Methods Section. Ex-tra or supplementary materials and technical details can beplaced in an appendix where they will be accessible but willnot interrupt the flow of the text, or they can be publishedsolely in the electronic version of the journal.

Give numeric results not only as derivatives (for exam-ple, percentages) but also as the absolute numbers fromwhich the derivatives were calculated, and specify the sta-tistical significance attached to them, if any. Restrict tablesand figures to those needed to explain the argument of thepaper and to assess supporting data. Use graphs as an al-ternative to tables with many entries; do not duplicate datain graphs and tables. Avoid nontechnical uses of technicalterms in statistics, such as “random” (which implies a ran-domizing device), “normal,” “significant,” “correlations,”and “sample.”

Separate reporting of data by demographic variables,such as age and sex, facilitate pooling of data for subgroupsacross studies and should be routine, unless there are com-pelling reasons not to stratify reporting, which should beexplained.

f. Discussion

Emphasize the new and important aspects of the studyand the conclusions that follow from them in the contextof the totality of the best available evidence. Do not repeatin detail data or other information given in other parts ofthe manuscript, such as in the Introduction or the Resultssection. For experimental studies, it is useful to begin the


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discussion by briefly summarizing the main findings, thenexplore possible mechanisms or explanations for these find-ings, compare and contrast the results with other relevantstudies, state the limitations of the study, and explore theimplications of the findings for future research and forclinical practice.

Link the conclusions with the goals of the study butavoid unqualified statements and conclusions not ade-quately supported by the data. In particular, distinguishbetween clinical and statistical significance, and avoid mak-ing statements on economic benefits and costs unless themanuscript includes the appropriate economic data andanalyses. Avoid claiming priority or alluding to work thathas not been completed. State new hypotheses when war-ranted, but label them clearly.

g. References

i. General Considerations

Authors should provide direct references to originalresearch sources whenever possible. Although references toreview articles can be an efficient way to guide readers to abody of literature, review articles do not always reflect orig-inal work accurately. On the other hand, extensive lists ofreferences to original work on a topic can use excessivespace. Fewer references to key original papers often serve aswell as more exhaustive lists, particularly since referencescan now be added to the electronic version of publishedpapers, and since electronic literature searching allowsreaders to retrieve published literature efficiently.

Do not use conference abstracts as references: they canbe cited in the text, in parentheses, but not as page foot-notes. References to papers accepted but not yet publishedshould be designated as “in press” or “forthcoming.” Infor-mation from manuscripts submitted but not acceptedshould be cited in the text as “unpublished observations”with written permission from the source.

Avoid citing a “personal communication” unless itprovides essential information not available from a publicsource, in which case the name of the person and date ofcommunication should be cited in parentheses in the text.For scientific articles, obtain written permission and con-firmation of accuracy from the source of a personal com-munication.

Some but not all journals check the accuracy of allreference citations; thus, citation errors sometimes appearin the published version of articles. To minimize such er-rors, references should be verified using either an electronicbibliographic source, such as PubMed, or print copies fromoriginal sources. Authors are responsible for checking thatnone of the references cite retracted articles except in thecontext of referring to the retraction. For articles publishedin journals indexed in MEDLINE, the ICMJE considersPubMed the authoritative source for information aboutretractions. Authors can identify retracted articles in MED-LINE by searching PubMed for “Retracted publication

[pt]”, where the term “pt” in square brackets stands forpublication type, or by going directly to the PubMed’s listof retracted publications (www.ncbi.nlm.nih.gov/pubmed?term�retracted�publication�[pt]).

References should be numbered consecutively in theorder in which they are first mentioned in the text. Identifyreferences in text, tables, and legends by Arabic numeralsin parentheses.

References cited only in tables or figure legends shouldbe numbered in accordance with the sequence establishedby the first identification in the text of the particular tableor figure. The titles of journals should be abbreviated ac-cording to the style used for MEDLINE (www.ncbi.nlm.nih.gov/nlmcatalog/journals). Journals vary on whetherthey ask authors to cite electronic references within paren-theses in the text or in numbered references following thetext. Authors should consult with the journal to which theyplan to submit their work.

ii. Style and Format

References should follow the standards summarized inthe NLM’s International Committee of Medical JournalEditors (ICMJE) Recommendations for the Conduct, Re-porting, Editing and Publication of Scholarly Work inMedical Journals: Sample References (www.nlm.nih.gov/bsd/uniform_requirements.html) webpage and detailed inthe NLM’s Citing Medicine, 2nd edition (www.ncbi.nlm.nih.gov/books/NBK7256/). These resources are regularlyupdated as new media develop, and currently include guid-ance for print documents; unpublished material; audio andvisual media; material on CD-ROM, DVD, or disk; andmaterial on the Internet.

h. Tables

Tables capture information concisely and display itefficiently; they also provide information at any desiredlevel of detail and precision. Including data in tables ratherthan text frequently makes it possible to reduce the lengthof the text.

Prepare tables according to the specific journal’s re-quirements; to avoid errors it is best if tables can be directlyimported into the journal’s publication software. Numbertables consecutively in the order of their first citation in thetext and supply a title for each. Titles in tables should beshort but self-explanatory, containing information that al-lows readers to understand the table’s content without hav-ing to go back to the text. Be sure that each table is cited inthe text.

Give each column a short or an abbreviated heading.Authors should place explanatory matter in footnotes, notin the heading. Explain all nonstandard abbreviations infootnotes, and use symbols to explain information ifneeded. Symbols may vary from journal to journal (alpha-bet letter or such symbols as *, †, ‡, §), so check eachjournal’s instructions for authors for required practice.


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Identify statistical measures of variations, such as standarddeviation and standard error of the mean.

If you use data from another published or unpublishedsource, obtain permission and acknowledge that sourcefully.

Additional tables containing backup data too extensiveto publish in print may be appropriate for publication inthe electronic version of the journal, deposited with anarchival service, or made available to readers directly by theauthors. An appropriate statement should be added to thetext to inform readers that this additional information isavailable and where it is located. Submit such tables forconsideration with the paper so that they will be availableto the peer reviewers.

i. Illustrations (Figures)

Digital images of manuscript illustrations should besubmitted in a suitable format for print publication. Mostsubmission systems have detailed instructions on the qual-ity of images and check them after manuscript upload. Forprint submissions, figures should be either professionallydrawn and photographed, or submitted as photographic-quality digital prints.

For X-ray films, scans, and other diagnostic images, aswell as pictures of pathology specimens or photomicro-graphs, send high-resolution photographic image files.Since blots are used as primary evidence in many scientificarticles, editors may require deposition of the original pho-tographs of blots on the journal’s website.

Although some journals redraw figures, many do not.Letters, numbers, and symbols on figures should thereforebe clear and consistent throughout, and large enough toremain legible when the figure is reduced for publication.Figures should be made as self-explanatory as possible,since many will be used directly in slide presentations.Titles and detailed explanations belong in the legends—not on the illustrations themselves.

Photomicrographs should have internal scale markers.Symbols, arrows, or letters used in photomicrographs shouldcontrast with the background. Explain the internal scaleand identify the method of staining in photomicrographs.

Figures should be numbered consecutively accordingto the order in which they have been cited in the text. If afigure has been published previously, acknowledge theoriginal source and submit written permission from thecopyright holder to reproduce it. Permission is requiredirrespective of authorship or publisher except for docu-ments in the public domain.

In the manuscript, legends for illustrations should beon a separate page, with Arabic numerals corresponding tothe illustrations. When symbols, arrows, numbers, or let-ters are used to identify parts of the illustrations, identifyand explain each one clearly in the legend.

j. Units of Measurement

Measurements of length, height, weight, and volumeshould be reported in metric units (meter, kilogram, orliter) or their decimal multiples.

Temperatures should be in degrees Celsius. Bloodpressures should be in millimeters of mercury, unless otherunits are specifically required by the journal.

Journals vary in the units they use for reporting hema-tologic, clinical chemistry, and other measurements. Au-thors must consult the Information for Authors of the par-ticular journal and should report laboratory information inboth local and International System of Units (SI).

Editors may request that authors add alternative ornon-SI units, since SI units are not universally used. Drugconcentrations may be reported in either SI or mass units,but the alternative should be provided in parentheseswhere appropriate.

k. Abbreviations and Symbols

Use only standard abbreviations; use of nonstandardabbreviations can be confusing to readers. Avoid abbrevia-tions in the title of the manuscript. The spelled-out abbre-viation followed by the abbreviation in parenthesis shouldbe used on first mention unless the abbreviation is a stan-dard unit of measurement.

B. Sending the Manuscript to the JournalManuscripts should be accompanied by a cover letter

or a completed journal submission form, which should in-clude the following information:

A full statement to the editor about all submissions andprevious reports that might be regarded as redundant publica-tion of the same or very similar work. Any such work shouldbe referred to specifically and referenced in the new paper.Copies of such material should be included with the sub-mitted paper to help the editor address the situation. Seealso Section III.D.2.

A statement of financial or other relationships that mightlead to a conflict of interest, if that information is not includedin the manuscript itself or in an authors’ form. See also Sec-tion II.B.

A statement on authorship. Journals that do not usecontribution declarations for all authors may require thatthe submission letter includes a statement that the manu-script has been read and approved by all the authors, thatthe requirements for authorship as stated earlier in thisdocument have been met, and that each author believesthat the manuscript represents honest work if that infor-mation is not provided in another form See also SectionII.A.

Contact information for the author responsible forcommunicating with other authors about revisions and fi-nal approval of the proofs, if that information is not in-cluded in the manuscript itself.

The letter or form should give any additional informa-tion that may be helpful to the editor, such as the type or


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format of article in the particular journal that the manu-script represents. If the manuscript has been submitted pre-viously to another journal, it is helpful to include the pre-vious editor’s and reviewers’ comments with the submittedmanuscript, along with the authors’ responses to thosecomments. Editors encourage authors to submit these pre-vious communications. Doing so may expedite the reviewprocess and encourages transparency and sharing of exper-tise.

Many journals provide a presubmission checklist tohelp the author ensure that all the components of the sub-

mission have been included. Some journals also requirethat authors complete checklists for reports of certain studytypes (for example, the CONSORT checklist for reports ofrandomized controlled trials). Authors should look to seeif the journal uses such checklists, and send them with themanuscript if they are requested.

The manuscript must be accompanied by permissionto reproduce previously published material, use previouslypublished illustrations, report information about identifi-able persons, or to acknowledge people for their contribu-tions.


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Copyright © 2014 American Chemical Society 1

Ethical Guidelines to Publication of Chemical Research

The guidelines embodied in this document were revised by the Editors of the Publications Division of the American Chemical Society in May 2014.

Preface

The American Chemical Society serves the chemistry profession and society at large in many ways, among them by publishing journals which present the results of scientific and engineering research. Every editor of a Society journal has the responsibility to establish and maintain guidelines for selecting and accepting papers submitted to that journal. In the main, these guidelines derive from the Society’s definition of the scope of the journal and from the editor’s perception of standards of quality for scientific work and its presentation.

An essential feature of a profession is the acceptance by its members of a code that outlines desirable behavior and specifies obligations of members to each other and to the public. Such a code derives from a desire to maximize perceived benefits to society and to the profession as a whole and to limit actions that might serve the narrow self-interests of individuals. The advancement of science requires the sharing of knowledge between individuals, even though doing so may sometimes entail forgoing some immediate personal advantage.

With these thoughts in mind, the editors of journals published by the American Chemical Society now present a set of ethical guidelines for persons engaged in the publication of chemical research, specifically, for editors, authors, and manuscript reviewers. These guidelines are offered not in the sense that there is any immediate crisis in ethical behavior, but rather from a conviction that the observance of high ethical standards is so vital to the whole scientific enterprise that a definition of those standards should be brought to the attention of all concerned.

We believe that most of the guidelines now offered are already understood and subscribed to by the majority of experienced research chemists. They may, however, be of substantial help to those who are relatively new to research. Even well-established scientists may appreciate an opportunity to review matters so significant to the practice of science.

Guidelines

A. Ethical Obligations of Editors of Scientific Journals

1. An editor should give unbiased consideration to all manuscripts offered for publication, judging each on its merits without regard to race, religion, nationality, sex, seniority, or institutional affiliation of the author(s). An editor may, however, take into account relationships of a manuscript immediately under consideration to others previously or concurrently offered by the same author(s).

2. An editor should consider manuscripts submitted for publication with all reasonable speed.

3. The sole responsibility for acceptance or rejection of a manuscript rests with the editor. Responsible and prudent exercise of this duty normally requires that the editor seek advice from reviewers, chosen for their expertise and good judgment, as to the quality and reliability of manuscripts submitted for publication. However, manuscripts may be rejected without external review if considered by the editors to be inappropriate for the journal. Such rejections may be based on the failure of the manuscript to fit the scope of the journal, to be of current or sufficiently broad interest, to provide adequate depth of content, to be written in acceptable English, or other reasons.

4. The editor and members of the editor’s staff should not disclose any information about a manuscript under consideration to anyone other than those from whom professional advice is sought. (However, an editor who solicits, or otherwise arranges beforehand, the submission of manuscripts may need to disclose to a prospective author the fact that a relevant manuscript by another author has been received or is in preparation.) After a decision has been made about a manuscript, the editor and members of the editor’s staff may disclose or publish manuscript titles and authors’ names of papers that have been accepted for


publication, but no more than that unless the author’s permission has been obtained. If a decision has been made to reject a manuscript for ethical violations, the editor and members of the editor’s staff may disclose the manuscript title and authors' names to other ACS journal editors.

5. An editor should respect the intellectual independence of authors.

6. Editorial responsibility and authority for any manuscript authored by an editor and submitted to the editor’s journal should be delegated to some other qualified person, such as another editor of that journal or a member of its Editorial Advisory Board. Editorial consideration of the manuscript in any way or form by the author-editor would constitute a conflict of interest, and is therefore improper.

7. Unpublished information, arguments, or interpretations disclosed in a submitted manuscript should not be used in an editor’s own research except with the consent of the author. However, if such information indicates that some of the editor’s own research is unlikely to be profitable, the editor could ethically discontinue the work. When a manuscript is so closely related to the current or past research of an editor as to create a conflict of interest, the editor should arrange for some other qualified person to take editorial responsibility for that manuscript. In some cases, it may be appropriate to tell an author about the editor’s research and plans in that area.

8. If an editor is presented with convincing evidence that the main substance or conclusions of a report published in an editor’s journal are erroneous, the editor should facilitate publication of an appropriate report pointing out the error and, if possible, correcting it. The report may be written by the person who discovered the error or by an original author.

9. An author may request that the editor not use certain reviewers in consideration of a manuscript. However, the editor may decide to use one or more of these reviewers, if the editor feels their opinions are important in the fair consideration of a manuscript. This might be the case, for example, when a manuscript seriously disagrees with the previous work of a potential reviewer.

B. Ethical Obligations of Authors

Authors are expected to adhere to the following ethical guidelines; infractions may result in the application of sanctions by the editor(s), including but not limited to the suspension or revocation of publishing privileges.

1. An author’s central obligation is to present an accurate and complete account of the research performed, absolutely avoiding deception, including the data collected or used, as well as an objective discussion of the significance of the research. Data are defined as information collected or used in generating research conclusions. The research report and the data collected should contain sufficient detail and reference to public sources of information to permit a trained professional to reproduce the experimental observations.

2. An author should recognize that journal space is a precious resource created at considerable cost. An author therefore has an obligation to use it wisely and economically.

3. When requested, the authors should make every reasonable effort to provide data, methods, and samples of unusual materials unavailable elsewhere, such as clones, microorganism strains, antibodies, etc., to other researchers, with appropriate material transfer agreements to restrict the field of use of the materials so as to protect the legitimate interests of the authors. Authors are encouraged to submit their data to a public database, where available.

4. An author should cite those publications that have been influential in determining the nature of the reported work and that will guide the reader quickly to the earlier work that is essential for understanding the present investigation. Except in a review, citation of work that will not be referred to in the reported research should be minimized. An author is obligated to perform a literature search to find, and then cite, the original publications that describe closely related work. For critical materials used in the work, proper citation to sources should also be made when these were supplied by a nonauthor.

5. Any unusual hazards inherent in the chemicals, equipment, or procedures used in an investigation should


be clearly identified in a manuscript reporting the work. Authors should inform the editor if a manuscript could be considered to report research that, based on current understanding, can be reasonably expected to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agricultural crops and other plants, animals, the environment, or materiel.

6. Fragmentation of research reports should be avoided. A scientist who has done extensive work on a system or group of related systems should organize publication so that each report gives a well-rounded account of a particular aspect of the general study. Fragmentation consumes journal space excessively and unduly complicates literature searches. The convenience of readers is served if reports on related studies are published in the same journal, or in a small number of journals.

7. In submitting a manuscript for publication, an author should inform the editor of related manuscripts that the author has under editorial consideration or in press. Copies of those manuscripts should be supplied to the editor, and the relationships of such manuscripts to the one submitted should be indicated.

8. It is improper for an author to submit manuscripts describing essentially the same research to more than one journal of primary publication, unless it is a resubmission of a manuscript rejected for or withdrawn from publication. It is generally permissible to submit a manuscript for a full paper expanding on a previously published brief preliminary account (a “communication” or “letter”) of the same work. However, at the time of submission, the editor should be made aware of the earlier communication, and the preliminary communication should be cited in the manuscript.

9. An author should identify the source of all information quoted or offered, except that which is common knowledge. Information obtained privately, as in conversation, correspondence, or discussion with third parties, should not be used or reported in the author’s work without explicit permission from the investigator with whom the information originated. Information obtained in the course of confidential services, such as refereeing manuscripts or grant applications, should be treated similarly.

10. An experimental or theoretical study may sometimes justify criticism, even severe criticism, of the work of another scientist. When appropriate, such criticism may be offered in published papers. However, in no case is personal criticism considered to be appropriate.

11. The co-authors of a paper should be all those persons who have made significant scientific contributions to the work reported and who share responsibility and accountability for the results. Authors should appropriately recognize the contributions of technical staff and data professionals. Other contributions should be indicated in a footnote or an “Acknowledgments” section. An administrative relationship to the investigation does not of itself qualify a person for co-authorship (but occasionally it may be appropriate to acknowledge major administrative assistance). Deceased persons who meet the criterion for inclusion as co-authors should be so included, with a footnote reporting date of death. No fictitious name should be listed as an author or coauthor. The author who submits a manuscript for publication accepts the responsibility of having included as co-authors all persons appropriate and none inappropriate. The submitting author should have sent each living co-author a draft copy of the manuscript and have obtained the co-author’s assent to co-authorship of it.

12. The corresponding author must reveal to the editor and to the readers of the journal any potential and/or relevant competing financial or other interest (of all authors) that might be affected by publication of the results contained in the authors’ manuscript. Conflicts of interest and sources of funding of the research reported must be clearly stated at the time of manuscript submission and will be included in the published article. In addition, all authors must declare (1) the existence of any significant financial interest (>$5,000 or >5% equity interest) in corporate or commercial entities dealing with the subject of the manuscript; (2) any employment or other relationship (within the past three years) with entities that have a financial or other interest in the results of the manuscript (to include paid consulting, expert testimony, honoraria, and membership of advisory boards or committees of the entity). The corresponding author must advise the editor at the time of submission either that there is no conflict of interest to declare, or should disclose potential conflicts of interest that will be acknowledged in the published article.


13. Plagiarism is not acceptable in ACS journals. ACS journals adhere to the U.S. National Science Foundation definition of plagiarism as “the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit” (45 Code of Federal Regulations, Section 689.1). Authors should not engage in plagiarism - verbatim or near-verbatim copying, or very close paraphrasing, of text or results from another’s work. Authors should not engage in self-plagiarism (also known as duplicate publication) - unacceptably close replication of the author’s own previously published text or results without acknowledgement of the source. ACS applies a “reasonable person” standard when deciding whether a submission constitutes self-plagiarism/duplicate publication. If one or two identical sentences previously published by an author appear in a subsequent work by the same author, this is unlikely to be regarded as duplicate publication. Material quoted verbatim from the author’s previously published work must be placed in quotation marks. In contrast, it is unacceptable for an author to include significant verbatim or near-verbatim portions of his/her own work, or to depict his/her previously published results or methodology as new, without acknowledging the source. (Modeled with permission from Society for Industrial and Applied Mathematics: Authorial Integrity in Scientific Publication http://www.siam.org/books/plagiarism.php.)

14. The American Chemical Society Publications rules and ethical guidelines provide mandatory standards of practice in experimental studies performed using biological samples obtained from animals or human subjects. Studies submitted for publication approval must present evidence that the described experimental activities have undergone local institutional review assessing safety and humane usage of study subject animals. In the case of human subjects authors must also provide a statement that study samples were obtained through the informed consent of the donors, or in lieu of that evidence, by the authority of the institutional board that licensed the use of such material. Authors are requested to declare the identification or case number of institution approval as well as the name of the licensing committee in a statement placed in the section describing the studies’ Material and Methods.

15. Images should be free from misleading manipulation. When images are included in an account of research performed or in the data collection as part of the research, an accurate description of how the images were generated and produced should be provided.

C. Ethical Obligations of Reviewers of Manuscripts

1. Inasmuch as the reviewing of manuscripts is an essential step in the publication process, and therefore in the operation of the scientific method, every scientist has an obligation to do a fair share of reviewing.

2. A chosen reviewer who feels inadequately qualified to judge the research reported in a manuscript should return it promptly to the editor.

3. A reviewer (or referee) of a manuscript should judge objectively the quality of the complete manuscript and the Supporting Information, including the experimental and theoretical data, the interpretations and exposition, with due regard to the maintenance of high scientific and literary standards. A reviewer should respect the intellectual independence of the authors.

4. A reviewer should be sensitive to the appearance of a conflict of interest when the manuscript under review is closely related to the reviewer’s work in progress or published. If in doubt, the reviewer should return the manuscript promptly without review, advising the editor of the conflict of interest or bias. Alternatively, the reviewer may wish to furnish a signed review stating the reviewer’s interest in the work, with the understanding that it may, at the editor’s discretion, be transmitted to the author.

5. A reviewer should not evaluate a manuscript authored or co-authored by a person with whom the reviewer has a personal or professional connection if the relationship would bias judgment of the manuscript.

http://www.siam.org/books/plagiarism.php


6. A reviewer should treat a manuscript sent for review as a confidential document. It should neither be shown to nor discussed with others except, in special cases, to persons from whom specific advice may be sought; in that event, the identities of those consulted should be disclosed to the editor.

7. Reviewers should explain and support their judgments adequately so that editors and authors may understand the basis of their comments. Any statement that an observation, derivation, or argument had been previously reported should be accompanied by the relevant citation. Unsupported assertions by reviewers (or by authors in rebuttal) are of little value and should be avoided.

8. A reviewer should be alert to failure of authors to cite relevant work by other scientists, bearing in mind that complaints that the reviewer’s own research was insufficiently cited may seem self-serving. A reviewer should call to the editor’s attention any substantial similarity between the manuscript under consideration and any published paper or any manuscript submitted concurrently to another journal.

9. A reviewer should act promptly, submitting a report in a timely manner. Should a reviewer receive a manuscript at a time when circumstances preclude prompt attention to it, the unreviewed manuscript should be returned immediately to the editor. Alternatively, the reviewer might notify the editor of probable delays and propose a revised review date.

10. Reviewers should not use or disclose unpublished information, arguments, or interpretations contained in a manuscript under consideration, except with the consent of the author. If this information indicates that some of the reviewer’s work is unlikely to be profitable, the reviewer, however, could ethically discontinue the work. In some cases, it may be appropriate for the reviewer to write the author, with copy to the editor, about the reviewer’s research and plans in that area.

11. The review of a submitted manuscript may sometimes justify criticism, even severe criticism, from a reviewer. When appropriate, such criticism may be offered in published papers. However, in no case is personal criticism of the author considered to be appropriate.

12. Reviewers should notify editors of concerns with respect to manuscripts that report research that, based on current understanding, can be reasonably expected to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agricultural crops and other plants, animals, the environment, or materiel.

D. Ethical Obligations of Scientists Publishing outside the Scientific Literature

1. A scientist publishing in the popular literature has the same basic obligation to be accurate in reporting observations and unbiased in interpreting them as when publishing in a scientific journal.

2. Inasmuch as laymen may not understand scientific terminology, the scientist may find it necessary to use common words of lesser precision to increase public comprehension. In view of the importance of scientists’ communicating with the general public, some loss of accuracy in that sense can be condoned. The scientist should, however, strive to keep public writing, remarks, and interviews as accurate as possible consistent with effective communication.

3. A scientist should not proclaim a discovery to the public unless the experimental, statistical, or theoretical support for it is of strength sufficient to warrant publication in the scientific literature. An account of the experimental work and results that support a public pronouncement should be submitted as quickly as possible for publication in a scientific journal. Scientists should, however, be aware that disclosure of research results in the public press or in an electronic database or bulletin board might be considered by a journal editor as equivalent to a preliminary communication in the scientific literature.

8Institutional Review Boardsand Independent EthicsCommittees

Michael R. Jacobs

Institutional Review Boards (IRBs) and Independent Ethics Committees

(IECs) are charged with protecting the rights and safety of clinical trial parti-

cipants. The regulations that guide the review, approval, and conduct of

human research refer to these independent boards as IRBs or IECs. In 2001

the Association for the Accreditation of Human Research Protection

Programs (AAHRPP) was formed. Since that time many institutions have

reorganized the various support and review services connected with human

subject research including the IRB as one component of their Human

Research Protection Program (HRPP). Similarly to the IRB, these programs

have as their primary mission the protection of human research subjects.

Some IRB responsibilities such as clinical trial monitoring, investigator and

research participant education, and auditing of research records may be

shifted to specialized units within the HRPP. These programs may also facil-

itate investigator–sponsor relationships to promote safe, ethical research

practices. In many institutions in the USA the committee also serves as the

Health Insurance Portability and Accountability Act of 1996 (HIPAA)

privacy board for research-related activities.

There are at least three systems used by institutions to fulfill human

research ethics review requirements.1 It is important to determine the IRB

that will be responsible for reviewing and approving the research. Some

institutions require their own IRB to review all research, while others rely

solely on the use of a central IRB, or permit central IRB review for certain

types of studies. Central IRBs are particularly useful for multicenter studies

because only one IRB is responsible for approval of the protocol and informed

consent form. This can make meeting this regulatory requirement more effi-

cient. The possible advantages and disadvantages of central versus local IRB

Sample chapter from Principles of Good Clinical Practice

review have been well described by Fitzgerald and Phillips.1 A potential

concern when using a central IRB surrounds the ability of that committee

to understand relevant local issues. Local issues typically relate to the capa-

bilities of the Principal Investigator (PI) to carry out the research, the ade-

quacy of institutional resources to safely perform the research, and any

considerations that should be given to potential study participants such as

cultural or economic factors. In the European Community where a national

health agency can attest to the capabilities of the clinician and institutional

resources, some argue that there are no local issues related to whether the

research is ethical or not.2 The premise is, in theory, true; yet it is founded on

the assumption that all good clinicians will be good researchers. Considering

the current regulatory mandates, it is unlikely that the requirement for review

and approval of research by local IRBs will be abandoned in the near future.

Given this, sponsors and investigators should make certain which IRB review

process applies to their study.

Composition, procedures, and function

Composition

The IRB must consist of at least five members reflecting diversity of scien-

tific and non-scientific backgrounds and professional specialties and also

cultural interests, include both sexes, and have at least one member who is

not affiliated with the institution directly or through a family member

(usually referred to as the community member). While the minimum num-

ber of members is set at five, most IRBs will consist of slightly more to

accommodate additional expertise and to assure that a quorum can be

convened to conduct the meeting. A factor that drives committee compo-

sition is the nature of research that is reviewed. Through regulations, the

International Conference on Harmonisation (ICH), the Department of

Health and Human Services (DHHS), and the Food and Drug

Administration (FDA) require that IRBs consist of members who collec-

tively have sufficient expertise to evaluate the quality of the science, medical

aspects of the proposed research, and the ethics of conducting a study. The

net effect of this regulation is to require that at least one member of

the committee be a physician, since there is no other way to obtain the

expertise required to evaluate the study’s medical aspects. IRBs are permit-

ted to use an alternate member system, where the alternate member may

attend if the primary member is not available. Also, the IRB may invite

outside consultants if necessary to provide insight into scientific or ethical

issues that are beyond the expertise of the convened committee. While

consultants can assist in the review of a protocol, they cannot participate

in the voting for approval of the research.


122 | Principles of Good Clinical Practice

IRBmembership is also influenced by the population eligible to participate

in the protocol. Vulnerable populations specifically addressed in the DHHS,

FDA, or ICH regulations include children, prisoners, pregnant women,

fetuses, and the handicapped and mentally impaired. In order to review

research that includes these participant groups, the regulations require that

individuals with expertise about those populations and who understand how

theymight be vulnerable be included on the committee. However, these are by

no means the only potentially vulnerable groups of study participants.

Students can be vulnerable if participating in research being conducted by a

faculty member. Similarly, employees and staff members might be considered

vulnerable if asked to participate in research directed by the department head.

The IRB needs to be cognizant that there are a number of social, economic,

and cultural reasons that might make an individual vulnerable. Furthermore,

the underlying disease state and clinical prognosis can affect how the patient

perceives the planned intervention and may create vulnerability.

Unlike the ICH and DHHS, the FDA requires committee membership that

can assess the proposed research according to ‘acceptability . . . in terms of

institutional commitments.’ The effect of this section of the regulations is to

allow an institution to restrict research that falls outside of its standards or

places an undue burden on institutional resources. While an institution might

prohibit IRB-approved research from being conducted, the institution cannot

permit the conduct of research that has not received IRB approval.

Procedures and functions

The requirements for IRB operations and procedures are described in 21 CFR

Part 56, Subpart C, and ICH E6 Sections 3.2 and 3.3. These sections identify

whatmust be accomplished to be in compliancewith the regulations, and does

not recommend specific methods that must be implemented. Thus, each

institution establishes its own policies and procedures to achieve the goal of

protecting the rights and safety of human research participants. Because of

this, it is in the best interest of the sponsor to work with investigators expe-

rienced with the IRB submission requirements of the institution. FDA and

ICH regulations both require that IRBs follow written procedures for initial

and continuing reviews, the frequency of continuing reviews, prompt report-

ing of changes to the research, prompt reporting of unexpected events,

adverse reactions, and deviations from or non-compliance with the protocol.

Under FDA and ICH regulations, IRBs can approve a research protocol,

require modifications to the protocol in order to gain approval, disapprove

the research, or suspend or terminate research that has already received

approval. The IRB’s determination must be communicated in writing within

a ‘reasonable time’ and should provide specific recommendations for changes

needed to secure approval, or if approved, the conditions of approval.


Institutional Review Boards and Independent Ethics Committees | 123

The ICH E6Guideline for Good Clinical Practice is written primarily for

research that requires full board review at a convened meeting. Expedited

review (i.e., review conducted by the IRB chairperson or designee) is men-

tioned only as it relates to ‘minor changes’ to a protocol that has already

received full board approval. In contrast, FDA regulations identify categories

of research that can be exempted or follow an expedited review process and

do not go to full committee. Of the four categories of research that qualify for

a review exemption, the one most pertinent to IRBs that review biomedical

research concerns the emergency use of an investigational drug or device. The

first use of an investigational drug or device in an emergency situation is

exempt from IRB review; however, such use must be reported to the IRB

within 5 working days. Any subsequent use of the drug or device at that

institution requires the approval of the protocol at a convened meeting of the

full IRB. Research that qualifies for expedited review and approval is no

more than minimal risk or for minor modifications of research that has

already receive full board approval. Examples of research that is exempt

from review or may be expedited under DHSS regulations are found

Table 8.1 Categories of exempt research

1 Research conducted in established or commonly accepted educational settings, involving normal

educational practices, such as (i) research on regular and special education instructional strategies, or (ii)

research on the effectiveness of or the comparison among instructional techniques, curricula, or class-

room management methods.

2 Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey

procedures, interview procedures, or observation of public behavior, unless: (i) information obtained is

recorded in such a manner that human subjects can be identified, directly or through identifiers linked to

the subjects; and (ii) any disclosure of the human subjects' responses outside the research could

reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial

standing, employability, or reputation.

3 Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey

procedures, interview procedures, or observation of public behavior that is not exempt under paragraph

(b)(2) of this section, if: (i) the human subjects are elected or appointed public officials or candidates for

public office; or (ii) federal statute(s) require(s) without exception that the confidentiality of the personally

identifiable information will be maintained throughout the research and thereafter.

4 Research, involving the collection or study of existing data, documents, records, pathological specimens,

or diagnostic specimens, if these sources are publicly available or if the information is recorded by the

investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to

the subjects.

5 Research and demonstration projects which are conducted by or subject to the approval of department

or agency heads, and which are designed to study, evaluate, or otherwise examine: (i) public benefit or

service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible

changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels

of payment for benefits or services under those programs.

6 Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without

additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level

and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the

level found to be safe, by the Food andDrug Administration or approved by the Environmental Protection

Agency or the Food Safety and Inspection Service of the US Department of Agriculture.



in Table 8.1 and Table 8.2. Most research that involves a drug or device will

exceed the criteria for minimal risk and will require full board review.

Protection of human subjects

The process for the protection of human research subjects is multifaceted. The

underlying principles for the protection of research subjects are found in the

Nuremberg Code, the Declaration of Helsinki, and the Belmont Report,

Table 8.2 Categories of research that may be reviewed by expedited procedures

Research activities that present no more than minimal risk and fall into one of the following categories are

eligible for review expedited by the IRB through the expedited review procedure.

1 Clinical studies of drugs and medical devices only when condition (a) or (b) is met.

a Research on drugs for which an investigational new drug application (21 CFR Part 312) is not

required. (Note: Research on marketed drugs that significantly increases the risks or decreases the

acceptability of the risks associated with the use of the product is not eligible for expedited review.)

b Research on medical devices for which (i) an investigational device exemption application (21 CFR

Part 812) is not required; or (ii) themedical device is cleared/approved formarketing and themedical

device is being used in accordance with its cleared/approved labeling.

2 Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows:

a from healthy, non-pregnant adults who weigh at least 110 pounds. For these subjects, the amounts

drawn may not exceed 550 mL in an 8week period and collection may not occur more frequently

than 2 times per week;

b or from other adults and children, considering the age, weight, and health of the subjects, the

collection procedure, the amount of blood to be collected, and the frequency with which it will be

collected. For these subjects, the amount drawnmay not exceed the lesser of 50mL or 3mL per kg in

an 8week period and collection may not occur more frequently than 2 times per week.

3 Prospective collection of biological specimens for research purposes by non-invasive means.

4 Collection of data through non-invasive procedures (not involving general anesthesia or sedation)

routinely employed in clinical practice, excluding procedures involving X-rays or microwaves. Where

medical devices are employed, they must be cleared/approved for marketing. (Studies intended to

evaluate the safety and effectiveness of the medical device are not generally eligible for expedited

review, including studies of cleared medical devices for new indications.)

5 Research involvingmaterials (data, documents, records, or specimens) that have been collected, or will be

collected solely for non-research purposes (such as medical treatment or diagnosis).

6 Collection of data from voice, video, digital, or image recordings made for research purposes.

7 Research on individual or group characteristics or behavior (including, but not limited to, research on

perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and

social behavior) or research employing survey, interview, oral history, focus group, program evaluation,

human factors evaluation, or quality assurance methodologies.

8 Continuing review of research previously approved by the convened IRB as follows:

a where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have

completed all research-related interventions; and (iii) the research remains active only for long-term

follow-up of subjects; or

b where no subjects have been enrolled and no additional risks have been identified; or

c where the remaining research activities are limited to data analysis.

Continuing review of research, not conducted under an investigational new drug application or

investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has

determined and documented at a convened meeting that the research involves no greater than minimal risk

and no additional risks have been identified.



which were discussed in Chapter 1. The charge to IRBs is to apply these

principles in the evaluation of every aspect of the proposed research activity

to protect the rights, safety, and well-being of study participants. Concurrent

with this, the IRB staff assists investigators in maintaining adherence to

regulatory mandates and institutional policies. It is not surprising, therefore,

that when a research protocol is submitted to multiple IRBs the final deter-

minations of the committees, their questions, and requests for additional

information can vary greatly.3,4

Stress has been placed on the IRB by ‘mission creep’: the real or perceived

need to consider all potential risks, not just to study participants but potential

risks to researchers and the institution itself.5 As part of the research approval

process, IRBswill also consider issues thatmight not appear directly related to

research risks such as investigator and/or institutional conflicts of interest, the

scientific validity of a study, as well as the secure storage of and appropriate

access to research records. Increasingly many sponsored trials request (or

require) the collection and storage of biological specimens for future research,

which presents another series of challenges for IRBs. This may be particularly

problematic when studies using DNA are reviewed because of the potential to

stigmatize certain ethnic or cultural groups.6 It has been suggested that IRBs

consider the risks to third parties (individuals not directly involved in the

research) depending on the degree of risk to them.7,8

For many situations encountered by the IRB, there is little in the way of

regulatory guidance. As a result, IRBs may establish substantially different

submission requirements and review processes to fulfill regulatory mandates.

The ultimate impact of these added responsibilities and diversity of review

approaches is the potential for delays in starting the research. The effort

required to ensure the adherence with regulatory and institutional policies

also diverts IRB efforts from its primary mission of protecting the rights and

welfare of human research participants.5

The materials that the IRB should obtain and review to make an approval

determination are listed in Table 8.3. It should be noted that FDA regulations

do not explicitly require that the committee obtain the Investigator’s Brochure

(IB). The need to review the IB is inferred fromCFR 21.56.111, where the IRB

is required to assess risks and determine that the risks are reasonable in

relation to the anticipated benefits. Sponsors and investigators do a remark-

able job in making these materials available to investigative teams and the

IRB. The process may be particularly onerous in some institutions where

‘hard copies’ (as opposed to electronic copies) must be submitted. Despite

providing all of this information, sponsors and investigators still encounter

difficulties in obtaining IRB approval. This suggests that the major problem is

not a lack of information, but failure to provide the information in the format

and detail the IRB needs to conduct its review. Alternatively, sponsors and

investigators may not understand the IRB review process or the IRB may not



Table 8.3 Documents the IRB/IEC should obtain

Materials submitted IRB considerations Potential problems

Trial protocol(s) and

amendment(s)

The protocol is current and all

amendments have been

incorporated or appended.

All protocol elements are not adequately

detailed. This frequently occurs when

biosamples are being collected.

See Table 6.3.

Investigator's

brochure

Currently approved IB IB lacks required information. Studies

referred to in the protocol not detailed in

the brochure. Is the brochure submitted

the most current?

Written informed

consent form(s) and

consent form updates

Reading level. Adherence to local IRB

requirements for the format and any

standard language.

Failure to follow local IRB consent form

template. Use of consent form language

that differs substantially from

institutional standards. Incorporating

HIPAA language into the consent when

the institution uses a standalone HIPAA

authorization.

Subject recruitment

materials

Provides sufficient detail to inform

the potential participant of study

requirements, duration, and

compensation.

The recruitment process does not protect

the patient's confidentiality, and/or

privacy. Will patients receive unsolicited

phone calls or letters?

Written information

to be provided to

subjects

Reading level. Not coercive. Indicate

that the materials are related to a

research activity.

Reading level is appropriate, but

problems exist with type size and ease of

use.

Available safety

information

All of the available information

regarding preclinical studies and

sufficient safety data to support the

use of the test article for the

expected duration of participant

enrollment.

Although usually provided in the IB,

additional preclinical and clinical data, or

safety reports may exist that have not

been incorporated into the IB.

Information about

payments and

compensation to

subjects

Compensation should not create an

unfair inducement for study

participation. Timing and method of

payment should be clear. Pro-rating

for partial study completion should

be explained.

The process should be clear to the IRB

and the study participant. Some

institutions require that a W-9 be

completed before processing a check.

This should be reflected in protocol and

consent form.

Investigator's current

curriculum vitae and/

or other evidence of

qualifications

Licensure and training necessary to

safely perform all study-related

activities. Inclusion of other study

team members where special

expertise is required.

There are many laboratory tests and

clinical procedures that are used for

screening and monitoring. It should be

clear that qualified individuals are being

used to interpret this information.

Any other documents

required by the

IRB/IEC

Completion of an IRB-approved

course in human subjects' research.

Not all investigative team members have

completed IRB training. This will delay

study start.



have done a sufficient job of communicating its needs to those seeking to

conduct the study. Further complicating matters is the lack of research and

guidance on how IRBs should approach the review and approval of research.9

The sections that follow are not intended to provide the details of the various

documents reviewed by the IRB. Instead, they highlight the kind of informa-

tion generally expected to be available to IRB members when protocols are

discussed.

Review of the protocol, Investigator's Brochure, andinformed consent

The IRB bases its decisions largely on the review of the documents provided by

the sponsor and the PI. While the sponsor provides the bulk of materials that

need to be submitted to the IRB, it is up to the investigator to ensure that the

application is made in accordance with local IRB policies and procedures.

Failure to ‘follow the submission guidelines’ occurs frequently and may result

in delays in starting the study.10 Some IRBs may invite the PI to the IRB

meeting to present the research protocol and to clarify study-related issues,

but even with this additional input, written documentation will be needed to

support the basis of IRB’s decision.

For industry-sponsored trials the protocol and IB are developed by experts

in their field of research. As a result the need for the study, the design, and

procedures required by the protocol most often have a sound scientific basis.

Roadblocks may be encountered when these documents are submitted to the

IRB for ‘local review.’ Regulatory authorities require local review to ensure

that research subjects’ rights are protected, taking into account the unique

characteristics of the population served by the institution (e.g., religious,

cultural, or economic) as well as the ability of the investigators and the

institution to provide the care and services required by the protocol in light

of existing commitments and resources. The problems encountered as a result

of the local review of research are well documented.2,11–13 Yet, for the

foreseeable future it is not likely that the requirement for local review will

change. Given this, there are steps that can be taken by study sponsors and

investigators to minimize these difficulties as discussed below.

Protocol review

The research protocol is the principal document the IRB uses to determine

whether the research should be approved at all. Depending on institutional

requirements, one or more copies of the sponsor’s full protocol will need to

be submitted. The protocol should be the most current version and should have

already incorporated any preexisting amendments. Many IRBs use a primary

reviewer system whereby one member receives a copy of all original study



documents. When this process is used, the IRB usually requires the submission

of a protocol summary, which highlights the key aspects of the trial and is

distributed to all committee members. The protocol summary is not as detailed

as the full protocol but provides sufficient information for the committee to

understand the key components of the research. These components include a

brief overview of the condition being treated, inadequacies of current therapeu-

tic interventions, the rationale of the study, the purpose of the study, identifi-

cation of the primary outcome parameter, eligibility requirements, the

treatment plan, the risks and how these have been minimized, the benefits,

alternative treatments, sample size estimation, the primary and secondary out-

come parameters, and plans for statistical analysis.14 Because IRBs consist of

members with scientific and non-scientific backgrounds, as well as community

representatives, protocol summaries need to be written in uncomplicated lan-

guage and avoid technical jargon. Sponsors and investigators should not assume

that what is clear to them will automatically be clear to all IRB members.

Background

A short section providing the background of the condition being treated

should be included.Most committees will not need extensive education about

commonly encountered disease states such as hypertension, heart failure, or

diabetes. But even in these conditions the proposed intervention might be

directed at one component of the disease such as peripheral neuropathy,

management of edema, or preserving renal function. In these circumstances,

the backgroundmaterial should provide a basis for the committee to conclude

that the intervention has the potential to improve or favorably alter the course

of the disease. The FDA or the EuropeanMedicines Agency (EMA) may have

published a guidance document that impacts on the design of the study. The

guidance might suggest the need for a placebo arm, or recommend specific

efficacy or safety criteria. IRB members, and sometimes the local investiga-

tors, are not always aware that the protocol was designed to conform to a

specific guidance. A simple statement in the background that informs the

committee of the guidance will facilitate their review.

Lack of details within the protocol can generate questions from the IRB

and slow the process. While the purpose of the study might be clear (compare

new drug A with established drug B), the rationale for conducting the study

may not be readily apparent. Is the rationale that not all patients respond to

the established drug so a new drug is needed? Or does the new drug have a

better side-effects profile or offer the prospect of a more convenient dosage

form or less frequent dosing? This information helps IRB members to under-

stand why the study is important and should be conducted. It also introduces

the prospects for potential benefit for study subjects and others with the

underlying condition. The committee will want to see the rationale presented

to study subjects in the consent document.



Primary outcome parameter

Identification of the primary outcome is essential to the conduct of the

research, and should be clearly defined. The protocol should provide the basis

for selecting the primary outcome variable and how it will be accurately

measured. Some studies may use a primary outcome parameter that is a

surrogate for the benefit the intervention is expected to achieve. For example,

a study of an antihypertensive agent might use blood pressure lowering as an

outcome although the real goal is to reduce cardiovascular morbidity and

mortality. The sponsor should provide the rationale as to how the outcome is

associated with the disease process being investigated. For comparative stud-

ies, the protocol should not only address the differences in outcome measures

that can be shown to be statistically significantly different, but should also

explain whether those differences have any clinical significance.

Eligibility criteria

IRBs look carefully at the eligibility criteria for the study. Inclusion and

exclusion criteria are the first step the sponsor and investigator make in

protecting study subjects. Again, adequate details should be provided to

define the study population. The eligibility criteria should not be expressed

in generalities (normal renal function) when specific criteria can easily be

defined. Some protocols might define normal renal function as a serum cre-

atinine <1.5mg/dL; others as a creatinine clearance >80mL/min. If the later

definition is applied, how is this determined?Was it a 24-hour urine collection

or an estimated creatinine clearance? If estimated, which formula is being

used? The protocol should clearly state when eligibility assessments will be

performed in relation to obtaining informed consent from the subject. The

committee will look to determine whether eligibility is based on clinical and

demographic information that already exists as part of the usual care the

individual receives or whether eligibility will be determined on the basis of

information collected and procedures performed solely for the purpose of the

research. These and other issues will impact on inconveniences to the subject

and may result in having to withdraw a subject who is no longer eligible to

participate.

Study intervention and procedures

While the background, purpose, and eligibility criteria of the research gener-

ally raise few questions from the IRB, the procedures and interventions iden-

tified in the study methodology represent potential sources of risk, and thus

receive very careful IRB attention. The IRB should consider all possible

sources of risk. Some of these, such as the use of an investigational device

or drug and research-related procedures, are easily recognized. Others such as

inconveniences due to travel, emotional harm, and loss of confidentiality may

be difficult to ascertain or may result from local conditions and therefore not



be fully addressed in the sponsor’s protocol. It is particularly helpful to the

committee if the protocol identifies the interventions that are standard of care

and those that are done solely for the purpose of the study. Input from the PI at

each site is essential in making this determination since what represents

standard of care at one institution may not at another. IRB members look

for specific information in the protocol as it relates to the source of risk. In

biomedical research, IRBs frequently consider the risks of drugs, devices, and

study-related procedures. When the drugs and devices are investigational, the

sponsor must assume the primary role for informing the committee.

Individual investigators generally are not familiar enough with the drug or

device to answer specific questions even if they have attended an investigators’

meeting. Some of the information that IRBs will want to review may exist in

the IB, but as mentioned above, not all members may receive a copy of the IB

prior to the meeting. Furthermore, some elements of the methodology result

from decisions made internally by the sponsor during protocol development

or may be required by regulatory guidances and it may not be easily discern-

ible why they were included.

Drug-related risks

In the case of a drug not yet approved formarketing, the extent of information

available can vary considerably. Findings may be limited to the results of

animal testing (for first-in-human studies) or may be much more substantial,

reflecting the drug’s tolerability and efficacy based on the exposure of thou-

sands of study participants. To facilitate protocol review, the sponsor should

incorporate the main findings of the pre-clinical and clinical studies reported

in the IB into the protocol. The committee will be looking for justification of

the dose and duration of treatment. For example, how did the pre-clinical

studies influence the selection of the dosage that will be tested in humans?

How does tolerability shown in a two-week human safety study support the

transition to a six-month efficacy study?Most IRBswill not have the expertise

to make an extrapolation of the results of animal testing to first-in-human

studies and conclude that the dose being tested is safe. In order to facilitate the

review process, it is worthwhile for the sponsor to address these issues in the

protocol to educate the IRB about the regulatory guidances and scientific

basis for the dose and duration of drug exposure. Issues surrounding dose

selection for early clinical trials will become more complex if sponsors more

actively pursue microdose studies or other FDA drug development

initiatives.15

While not an infallible method for predicting Adverse Events (AEs),

identifying similarities in structure or pharmacological activity of the inves-

tigational drug to those of marketed products with established side-effect

profiles provides valuable information to the committee. The question

raised by Cohen, ‘Should we tolerate tolerability as an objective in early drug



development?’ relates directly to the drug safety concerns of the IRB.16 Early-

phase trials provide the opportunity to characterize a drug’s kinetics and

dynamics, which can then be used to inform the next series of human trials.

Most committees review early-phase clinical trials with the understanding

that rare, but serious, AEs are not likely to be identified even after substantial

numbers of subjects have been studied.17 While it is unlikely that an abso-

lutely safe drug will ever be marketed, IRB members are very aware that a

number of medications have been approved and marketed only to be with-

drawn shortly thereafter because of rare, but serious side-effects. If the med-

ication is not withdrawn from the market, regulatory authorities might

require the addition of warning statements or restrict the types of patients

who should receive the drug. Lacking any information to the contrary, these

warnings might be extended to the whole class of drugs. This can impact on

the IRB’s assessment of risks for investigational drugs that are pharmacolog-

ically or structurally similar to the drug that was withdrawn. For this type of

drug, the sponsor should not only include but highlight the portions of the

protocol that identify and minimize the potential for this AE.

Device-related risks

Regulatory approval prior to the initiation of a device trial is required in the

USA and Japan as opposed to the European Union, which has been suggested

to impact development costs and the rapidity of bringing new devices to

market.18 Most countries have established criteria for classifying medical

devices based primarily on the potential for risk. Some of the factors that

are considered in making this determination include the characteristics of the

device (invasive vs. non-invasive), duration of use (short-term vs. long-term),

and the need for specialized training for safe and effective use of the device.

The FDA identifies devices as ‘significant risk or non-significant risk.’

However, this determination applies only to the device and not to the manner

in which the device will be used in the study. It is possible, therefore, that a

non-significant-risk device could be determined by the IRB to be a significant-

risk device on the basis of its intended use, the patient population being

studied, or the consequences of device failure. In the USA, IRBs are also

responsible for the approval of humanitarian use devices (HDEs) within their

institutions. These are devices intended for use in conditions likely to affect

fewer than 4000 patients yearly, making the conduct of a clinical trial nearly

impossible. Many IRBs will have little or no experience with this type of

device, so the sponsor should be prepared to educate the committee members

by providing regulatory guidance information and identifying the sponsor’s

responsibilities.

Procedure-related risks

Study-related procedures contribute to the overall risks associated with the

protocol, even if they are not experimental in and of themselves. It is of great



value to the committee if the sponsor and PI clearly delineate those procedures

that are considered standard of care from those performed solely for the

purposes of the study. Making this determination is not always easy and can

vary among research sites depending on local practices and the expertise avail-

able.19 For example, the standard of care for certain conditions might be to

obtain a chest radiograph at yearly intervals. The protocol might require that

the study participant have had a chest radiograph performed within the previ-

ous six months. If a patient’s last radiograph was obtained nine months ago, a

radiograph will be required to qualify for the study. This is not part of the

standard of care, so the radiation burden, though minimal, is still attributable

to the research. Depending on the institution, the PI may be required to submit

the protocol to a committee separate from the IRB for an assessment of radi-

ation risks. The number and frequency of study visits might also be in excess of

what would be considered standard of care; thus contributing to the incon-

veniences experienced within the study. It is imperative that the sponsor work

closely with the site’s PI to identify local issues related to study procedures.

Another kind of procedural risk relates to the need to withdraw other

therapies in order to qualify a patient for the study. Today, most diseases

have at least one drug, and sometimes dozens of drugs, indicated for the

treatment of that condition. It is not unusual, therefore, to have potential

participants discontinue medications in order to meet eligibility criteria.

While it might be possible to restrict eligibility to newly diagnosed patients,

this approach severely hampers study enrollment. Most IRBs are experienced

with studies that require withdrawal of what might be very effective therapy

for a patient in order to participate in a clinical trial.When effective therapy is

withdrawn, the underlying condition would be expected to deteriorate, which

might lead to the return of minor annoying symptoms or a disease flare of

substantial clinical significance. For those studies in which withdrawal of

other therapies is required, the protocol should explain in detail how partici-

pants will be monitored to detect worsening of the underlying condition and

minimize the duration of poor disease control. In addition, some method of

rescue therapy or rescue medication may be included in the protocol as an

additional safety measure for patients.

The use of a placebo control group will receive careful attention from the

IRB. A complete discussion of the ethical use of placebos in clinical research

goes far beyond the purpose of this chapter; however, it is important to recog-

nize that including a placebo control arm in a clinical trial can result in a clash

of scientific, ethical, and regulatory principles.20 Asmentioned above, multiple

therapeutic options exist for mostmedical conditions. Given this, why should a

placebo control group ever be used? Amdur and Biddle have proposed an

algorithm for the ethical use of placebos.21 They suggest a number of factors

that IRBs should consider in evaluating the ethical use of a placebo control in

clinical research. Among these are the effectiveness and tolerability of current



treatments, the long-term and short-term harms that might result from placebo

use, and the potential value for the treatment of future patients with that

condition. Consideration of the ethical use of placebos is not restricted to

clinical drug trials. A similar concern exists for studies that might require a

sham surgical procedure22 or the insertion of a device that is not activated.23

Once again, communication between the sponsor and the site investigator is

critical, as is providing the rationale for using a placebo in the trial.

Methodology

Separate from study-related procedures is the study methodology. In addition

to the general design of the trial (superiority, equivalence, non-inferiority),

other aspects of the trial that are important to the IRB include the manner of

randomization, stratification based on one or more patient characteristics,

blinding procedures, choice of comparator, use of placebo, sample size esti-

mation, and planned data analysis. It might appear that many aspects of the

studymethods fall outside of the purview of the IRB because they do not relate

directly to individual participants’ risks. However, they frequently do relate to

the collective risks of study participants. For example, the lower boundary for

non-inferiority trials must be established in order to estimate sample size.24

The rationale for selecting this boundary should be explained. It might be

acceptable to the committee if the inferiority boundary is set at 30% less

effective if the comparator is associated with significant toxicities and the

consequences of treatment failure are not life-threatening. On the other hand,

this margin would likely not be acceptable if the comparator was highly

effective and caused minimal toxicity. In either case, the sponsor should

provide the rationale for why this lower limit was selected. Individual clinical

investigators generally cannot provide a satisfactory answer to the committee,

resulting in delays in starting the study.

Sample size estimations are important to the committee. Most often sam-

ple size calculations are based on an efficacy end point because it can be

clearly defined and the variability in participant response to the intervention

can be estimated from responses observed in similar studies of the same

disease state. Though possible, it is impractical to base the sample size esti-

mation on safety outcomes due to their unpredictability and low rates of

occurrence, which would necessitate a large study population. Despite the

relative ease with which a sample size can be determined for most studies,

many investigator-initiated trials, and even those supported by NIH funding,

may be underpowered to detect a significant treatment effect.25,26 Studies

conducted by the pharmaceutical industry rarely suffer from this problem

but may appear to enroll an excessive number of participants. Studies like this

might be ‘overpowered’ for the primary end point; that is, the clinical question

could be answered with fewer participants enrolled. Overpowered studies

can create problems during the review process because each of the study



participants will still need to complete all of the study-related procedures

(which might include blood sampling and radiation exposure) or be random-

ized to a less-effective treatment even though the study outcome could be

determined based on a smaller number of subjects. Nonetheless, a case can be

made for enrolling more than the number of participants required to ensure

efficacy in order to better detect rare AEs and improve safety.

The regulatory landscape is changing with regard to the design of clinical

trials, driven by the high costs of conducting human research and difficulties

in recruiting and retaining study participants. Alternative strategies such as

microdosing are being advocated by regulatory agencies.15 In addition, adap-

tive trial designs are being suggested that will permit changes in the method of

randomization, the doses being evaluated, and even modification of the pri-

mary outcome parameter.27–30 Many IRBs do not have access to statisticians

or others who arewell versed in these types of clinical trial methodologies. It is

in the best interest of the sponsor to assist committee members by providing

the basics behind the design of these trials.

Special concerns related to biobanks

Any experienced clinician is aware that patients differ in their response to a

drug. A clinically effective dose in one patient may result in serious toxicity in

another. With the development of sensitive analytical techniques, demo-

graphic and clinical characteristics such as age, weight, and renal and hepatic

function were identified that influence the pharmacokinetic profile of a vari-

ety of drugs. Although the kinetics of a drug are still of major importance in

understanding the factors that contribute to the efficacy and safety of a drug,

differences remain among individuals that cannot be explained by kinetics

alone. Increasingly, industry-sponsored protocols are asking study partici-

pants to provide a blood or tissue sample to identify genetic polymorphisms

that result in a different response among drug recipients. Other uses of banked

materials include proteomic and biomarker studies that might be useful in the

identification of new therapeutic targets. Despite the extensive detail provided

in the sponsor’s protocol regarding eligibility criteria, randomization proce-

dures, safety monitoring, and possible adverse effects, the procedures for

collection and use of biological samples sometimes receive less than a para-

graph within the protocol. This lack of informationmay result in delays in the

approval of this portion of the research. Because the procedures and risks of

genetic research are different from other research-related risks, some IRBs

require a separate consent form for genetic research. Questions frequently

posed by the IRB related to research on stored blood or tissues that should be

addressed in the protocol are listed in Table 8.4. Sponsors are responsible for

providing this information to the committee as the local investigator will

generally not be well versed in how the biobank will be operated and the

steps taken to protect the confidentiality of the donor.



Table 8.4 Protocol elements and tissue banks

1.1 Title

* Should state that it is a tissue bank

1.2 Objectives

* Purpose of the bank, why is it important?* Who is it for?* What kind of testing will be performed?

1.3 Background

1.4 Eligibility criteria

* How are participants identified?* Will normals be used?* Samples from outside sources?

1.5 Treatment plan

* How will samples be collected? Departures from standard of care?* Consider how clinical and demographic information will be handled.* What types of testing will be performed?

– Only for the disease the patient has or unrelated? Alzheimer's?– Genetic testing?– Other disease states? Hep. B, Hep. C, HIV?

* What happens to future test results?* Procedures for releasing samples to other investigators.* Plans to compensate for new product development.

1.6 Risks

* Major concern – confidentiality.* Inaccurate pathological diagnosis.* Due to alterations in procedures to accommodate specimen collection.

1.7 Benefits

* Generally none for the participant.* It is fair to include potential to benefit patients with similar conditions; societal benefits.

1.8 Alternative treatments

* Don't participate.

1.9 Data collection and statistics

* Generally not an issue.

1.10 Other issues that should be addressed

* Coded samples – possibility to identity participant.* Certificate of confidentiality.



Investigator's Brochure

The ICHE6Guideline forGoodClinical Practice describes the recommended

content of the IB. Although the protocol describes what will be done during

the study and how itwill be done, it is the IB that provides the insight as towhy

certain procedures and monitoring parameters have been incorporated into

the protocol. The IB serves as a resource for the IRB and the investigator to

determine everything that is known (andwhat is not known) about the drug or

device being studied. For drugs and devices in early development, there may

be little or no published literature regarding the product’s efficacy or safety.

Consequently, in making its judgment for approving a protocol the IRB will

rely heavily on the information provided in this document. As with the pro-

tocol, questions will be raised based on information that is referred to but not

provided or that is not clear. For example, it is not unusual for participant

accrual to proceed at a slower than expected rate, which may open the study

to sites well after the original start date. Or the IB version submitted by the

investigatormay be dated two years prior to the date the protocol is scheduled

for IRB review. How can the committee know that this the current version?

The IB might also state that extended dosing studies in humans have been

started and that long-term toxicity studies in rats are pending. Has this work

been completed? Even IBs that are up to date may not include important

information. For the IB to state that the chemical structure of the drug is well

characterized, while no structure is provided, is a disservice to the committee.

Most IRB committees will not have the expertise of a medicinal chemist

available to them, but the ability of a clinician to compare the structure with

that of a marketed agent with a known side-effect profile can provide a

context for expected efficacy and toxicity. Sponsors can help themselves by

keeping the IB current and by providing local investigators with information

to be shared with the IRB related to studies that are in progress but not yet

appearing in the IB.

Informed consent

While considerable attention is given to the consent document, the IRB is

equally concerned about the process and timing for obtaining consent.

Informed consent is discussed in Chapter 3. The material conveyed here

relates primarily to potential barriers that may be encountered by sponsors

and investigators to getting the consent form approved.

Some problems are easily predicted and thus avoidable. One of the

frequently encountered problems is the inclusion of HIPAA language within

the consent document. Some institutions require that HIPAA authorizations

be obtained on a separate, study-specific document. The research consent

informs participants of the study rationale, procedures, risks, and alternatives,



and their rights and responsibilities. The HIPAA authorization informs parti-

cipants that as a consequence of their involvement in the study, private health

information will be shared with the sponsor, the IRB, and regulatory author-

ities. Another theoretical reason for separating the HIPAA authorization from

the research consent is to minimize institutional liability if either of these

documents is found to be deficient in some manner. The local investigator

should be able to provide some guidance to the sponsor as to which approach

the institution uses.

Another common problem with consent forms lies within the injury state-

ment. This is no doubt the result of the increase in litigation surrounding

clinical research, which exposes sponsors, researchers, institutions, and even

members of the IRB.31 The IRB should make sure that the injury statement

conforms to the language in the contract with the site. The contract will likely

contain specific methods for allocating liability to the sponsor or the institu-

tion at which the research is being conducted. This process, although essential

to describe before the trial is initiated, is of little concern to the research

participant and should not be included in the consent form. Trials sponsored

by the pharmaceutical industry are more likely to offer coverage for medical

expenses resulting from a research-related injury than those supported inter-

nally or through government funding.32 Injury statements tend to be written

at a higher level than other portions of the consent and few meet the Institute

of Medicine guidelines for compensation for research-related injuries.32

Injury statements may contain wording that waives or appears to restrict

the rights of the participant to receive treatment for research-related injuries.

Language is sometimes included that places a certain level of responsibility on

the research participant, such as, ‘if you followed your doctor’s instructions’

or ‘if you followed all study-related procedures.’ In some cases even the PI and

the institution are included through further modifications such as ‘procedures

that were properly performed . . . .’ Since study participants do not give

up their rights to pursue a legal remedy in the event of an injury, it is unclear

why these apparent restrictions appear in the consent form, except to inhibit

participants from reporting problems. The language is so vague that study

participants might feel that they have no recourse for treatment as a result of

a missed appointment or failure to complete a study procedure. While all

involved in the research enterprise are concerned about potential liability, the

risks assumed by research participants are real and are usually accepted with

no guarantee of benefit.

Qualifications of the investigator and investigative team

Patients expect that the clinical care they receive will be provided by physi-

cians, nurses, and other health professionals who are qualified to deliver

these services. Clinical researchers must meet this standard and fulfill other



obligations to the sponsor, regulatory authorities, and IRBs. The significance

of the additional obligations relates to the protection of study participants and

the credible use of new drugs or devices in future patients. Stated another way,

the research team must be committed to patient care and scientific integrity.

Ultimately one individual at the site is responsible for meeting these commit-

ments – the PI.

The process by which the IRB determines that an investigator is qualified

to conduct a clinical study relates to their ability to meet criteria established

by the IRB, the institution hosting the research, the sponsor, and reg-

ulatory authorities. Investigator responsibilities are outlined in the ICH E6

Guideline for Good Clinical Practice and in an FDA Guidance for Industry.

The IRB needs evidence that the PI (usually a physician, podiatrist, or dentist)

is capable of providing the medical care required by the study and can facilitate

access to specialists in the event of a Serious Adverse Event (SAE). Evidence for

this typically comes from the investigator’s curriculum vitae. If the investigator

is expected to perform a procedure as part of the research, the IRB may seek

evidence that the investigator is authorized by the institution to carry out the

procedure. Most IRBs will require the investigator to submit an FDA 1572

form or clinical trial agreement to demonstrate that the investigator intends to

fulfill commitments made to the sponsor, and agrees to permit the sponsor and

regulatory authorities access to records assuring adherence to the study pro-

tocol and to verify data collected during the study. Investigators will need to

establish that they have received training in the conduct of human research and

that it is in date. The IRB will usually ask the investigator to identify the total

number of trials in which they are participating, the number of participants

enrolled, and personnel who will be committed to the trial. Additional discus-

sion of investigator qualifications can be found in Chapter 4.

Risk–benefit analysis

One of the first decisions made by the IRB chairperson, or designee, is

determining the level of risk associated with the proposed research.

Occasionally, industry sponsors are interested in de-identified data extracted

from medical records, which could qualify for an exemption from IRB

review. Examples of these kinds of studies include retrospective evaluations

of prescribing patterns for certain conditions, or a meta-analysis of existing

data. The FDA regulations are silent with regard to exempt research related

to drug or device studies, except for the special casewhere emergency use of a

drug or device is required. In the USA, adherence to HIPAA regulations is

required and can influence the manner in which data is collected.

Prospective studies that are found to be of minimal risk may qualify for

expedited review and approval. Minimal risk is defined in these terms: ‘the

probability and magnitude of harm or discomfort anticipated in the research



are not greater in and of themselves than those encountered in daily life or

during the performance of routine physical or psychological examinations or

tests.’ Differences in interpretation of ‘minimal risk’ can result in vastly

diverse determinations among IRBs. This is particularly true in the applica-

tion of the FDA standards for research involving children.33 Some kinds of

survey research might lead to the identification of issues that clearly are not

minimal risk.34 The difficulties encountered in applying the minimal risk

standard have resulted in some IRBs abandoning this category in favor of a

full board review for all prospective studies.

Most drug or device research exceeds minimal risk and requires full board

review. The criteria for IRB approval of FDA-regulated research are found

in Table 8.5.While the criteria are clear and succinct, problems with approval

can occur because each ethics committee, consciously or unconsciously,

develops a working definition for words such as ‘minimized,’ ‘benefits,’

‘risks,’ ‘equitable,’ ‘reasonable,’ ‘appropriate,’ and ‘adequate.’

Furthermore, even within the committee definitions can and do change

from protocol to protocol depending on the drug or device being evaluated,

the research team, the research location, the condition under study, and the

population being studied. Better consistency within and among IRBs could

be achieved if the words mentioned above could be assigned a relative

value. Being able to quantify benefits and risks offers the possibility of

manipulating these ‘values’ to establish whether benefits outweigh risks.35

The viability of this approach related to the benefit–risk assessment for a

population has been described.36 While useful in the context of societal

benefit–risk, it is not clear how this can be consistently applied to measure

benefit–risk for individual research subjects. Being unable to quantify ben-

efits and risks does not necessarily mean that sponsors and investigators are

helpless and subject to the whims of the individual IRBs. Methods are

available, although they are not always employed, that can help the IRB

better understand exactly what benefits might come to participants and that

the risks are appropriate and have been minimized to the extent possible.

The following paragraphs, based on the FDA criteria for approval of

Table 8.5 Requirements for approval of research

* Risks to subjects are minimized* Risks to subjects are reasonable in relation to anticipated benefits* Selection of subjects is equitable* Informed consent will be sought* Informed consent will be documented* Where appropriate, adequate provisions for data monitoring to ensure subject safety* Where appropriate, adequate provisions to protect subject privacy and confidentiality* Adequate safeguards to protect the rights and welfare of vulnerable subjects



research, describe what sponsors and investigators can do to educate IRB

members and facilitate the review process.

Risks to subjects are minimized

The first step the sponsor and investigator can take is to identify all the risks

and inconveniences associated with participating in the protocol. Most often

the identification of risks is restricted to those related to the drug or device

under investigation. While the IRB, the sponsor, and investigator might con-

sider the investigational intervention the most important risk, as discussed

above it is only one of the risks and inconveniences associated with the

protocol. Once all of the risks are identified, the sponsor and investigator

can facilitate the IRB review process by making a candid assessment of risks

that the participant would experience as part of routine care, and those that

are solely related to the research. Some risks undoubtedly result from

research, such as use of placebo, surveys, and additional blood sampling;

others might be less clear. If two radiographs are standard of care, are three?

Some studies do not permit the use of medications that are considered as

standard of care and investigators will implement a washout period in order

to qualify patients for the study. Have the risks of withdrawing effective

treatments been addressed? Similar considerations need to be given to every

aspect of the protocol, including the amount of blood being drawn over the

course of a study and the number of office visits.

Once all the risks have been identified, the sponsor and investigator can

begin to address how these risks have been minimized. The specifics of how

risks have been minimized will vary according to the research, but fall into

three broad areas: selection and qualification of study participants, study-

related methods and procedures, and monitoring and follow-up. Ultimately

the sponsor can facilitate the review process by demonstrating how the pro-

tocol selects participants appropriately, and avoids enrolling individuals who

are at higher risk of experiencing an AE; how study visits and procedures are

scheduled to coincide as much as possible with usual clinical care activities;

and for those risks that cannot be entirely eliminated, that appropriate mon-

itoring methods have been included to reduce AEs. As local investigators

usually will not have the insight to answer questions about how the protocol

was developed, the sponsor should provide this information.

Risks to subjects are reasonable in relation to anticipated benefits

This is the only requirement for approval that mentions potential benefits to

research participants. Most drug and device protocols are quite explicit

regarding potential risks; however, potential benefits often are not discussed.

The ICH E6 Guideline for Good Clinical Practice states that the IB should

present information ‘that enables a clinician, or potential investigator, to

understand it and make his/her own unbiased risk–benefit assessment of the

appropriateness of the proposed trial.’ Often the background provided in the



study protocol does not convey any of the benefits that might be expected to

the individual or society through the development of the drug or device. The

sponsor has the best insight as to the potential benefits and should include

their thinking on these. Regulations require that the available information

allow an ‘unbiased risk–benefit assessment.’ While omission of any assess-

ment by the sponsor of benefits versus risks will permit an unbiased assess-

ment, it may also result in an assessment that is not fully informed. The IRB

makes the final determination on what risks are reasonable in relation to

possible benefits, and is free to ignore the assessment of the sponsor.

Selection of subjects is equitable

The purpose of equitable subject selection is to ensure that the risks of

research are spread out over the groups of individuals who are expected to

benefit from the findings – the principle of justice described in the Belmont

Report. Both the sponsor and local investigator need to be involved inmeeting

this goal. The local IRB will scrutinize eligibility criteria and recruitment

methods as part of fulfilling this requirement, but can only influence recruit-

ment at the institutional level. Sponsors can help by providing information

about other sites involved in multicenter trials to show their efforts in distrib-

uting risks.

Informed consent will be sought

Merely providing an informed consent template is insufficient. As recently

published articles point out, informed consent is a process; there is an over-

reliance on the consent form itself; and methods for assessing participants’

understanding of the risks, benefits, and their responsibilities are largely

inadequate.37,38 Despite all the details given in the sponsor’s protocol for

study-related procedures, little is routinely provided to the research team

concerning the sponsor’s expectations for the timing and process of obtaining

informed consent. Ultimately, the local IRB is responsible for ensuring that

appropriate methods are used to obtain consent. Even so, sponsors can assist

in meeting this important obligation to research participants.

Informed consent will be documented

Again, over-reliance on the consent document is frequently observed.

Investigators need to document not only that consent was obtained, as

evidenced by the signed consent form, but also that the process, timing, and

circumstances surrounding consent are documented in the medical record.

The record should reflect any questions asked by the participant, how they

were answered, and the methods used by the investigator to determine the

participants’ comprehension of each of the informed consent elements.

Sponsors can take an active role in achieving this goal through investigator

training and by providing forms or checklists to assist investigators in

documenting the consent process.



Where appropriate, adequate provisions for data

monitoring to ensure subject safety

As with other sections of a sponsored research protocol, great detail is pro-

vided related to AEs and how they should be reported to the sponsor. Care is

taken to clearly discriminate between what will be considered a side-effect of

the drug from those events that will be attributed to the underlying disease.

Reporting requirements for the local investigator are outlined, and study

monitors make frequent site visits to assure that reports are accurate and

submitted in a timely fashion. What is often missing, but is of major impor-

tance to the IRB, is a discussion of how these reports will be handled once they

are received by the sponsor. This is especially true formulticenter trials, where

AEsmay find their way to the site investigator and eventually to the IRBweeks

or months after they have occurred. IRB members understand that instant

access to AEs or unanticipated problems is unrealistic; but they would like

some assurances that a process is being followed that will assist them in

protecting research participant enrolled at their institution. This process is

usually omitted from the clinical trial protocol. Lacking any information, the

IRB is likely to assume that there is no plan to look at adverse and unantici-

pated events in a timely manner. This raises questions that the sponsor must

answer, resulting in delays in starting the study. The process for handling

these occurrences should be described in some detail. It is useful for the

sponsor to include rules that site investigators can employ to determine

whether a study participant should be removed from the trial. Similarly, a

schedule for assessing all reported events and disseminating this information

to investigators and IRBs will allay some concerns.

As discussed by Silverman, not every trial will require a Data Safety

Monitoring Board (DSMB).39 At the same time, a protocol mentioning that

a DSMB will be constituted is of little value to the IRB. It is more important

for the sponsor to provide a timeframe for the constitution of the DSMB and

to share the plan developed by the board for interim analyses, stopping rules,

and other patient safety issues. Timely submissions of DSMB reports to the

IRB provide evidence that the sponsor and DSMB members are taking par-

ticipant safety seriously. Unfortunately, some reports come to the IRB merely

stating that the DSMB hasmet and decided that the trial should continue. This

information is useless to the IRB. DSMBs should provide some assessment of

the total number of study participants enrolled, the rate of study enrollment,

the frequency of study violations and deviations, and an acknowledgement

that AEs were reviewed, in addition to the decision to continue the study.

Where appropriate, adequate provisions to protect

subject privacy and confidentiality

One of the underlying premises of medical research is the hope that the

results will be generalizable, and offer society improved methods for the



identification, understanding, treatment, and prevention of disease. To

achieve this goal, health information from hundreds or thousands of indivi-

duals is combined, and distilled to provide innovative therapies. Researchers

and sponsors have a responsibility to protect the health information of an

individual. Inadvertent disclosures of health information potentially can

affect the individual’s ability to obtain a job or health insurance, or could

otherwise stigmatize the individual in the community. In the USA, HIPAA

regulations require that individuals be told how their health information will

be used, for how long it will be made available, and whowill have access to it.

Since its implementation, investigators have identified HIPAA disclosure as

another barrier to research recruitment for all kinds of research.40,41

Furthermore, sponsors and investigators may need to make changes to the

research plan in order to remain compliant with the rule.42

Two other issues that IRBs deal with regularly relate to HIV testing and

screening for drugs of abuse. Laws related to HIV testing vary according to

jurisdiction. Some states require pre- and post-test counseling andmay require

the use of a separate consent form. Sponsors have an understandable interest

inmaking sure that participants enrolled in a trial are not using drugs of abuse.

Not only might illegal drug use confuse the results of the study, but these

participants may, at least in theory, expose the sponsor to additional study

costs and liability. Since recreational drug use is illegal in most countries,

collecting and documenting this illegal activity may expose the individual to

prosecution and legal sanctions. In order to protect study participants, IRBs

may require that the sponsor obtain a certificate of confidentiality.

Adequate safeguards to protect the rights and welfare of vulnerable subjects

Children, prisoners, pregnant women, the handicapped, and mentally

impaired individuals are widely considered as vulnerable to exploitation in

research. Special protections are given to these populations through 45 CFR

Part 46 Subparts B, C, and D and to children in FDA-regulated research

through 21 CFR Part 50 Subpart C. The ICH E6 Guideline for Good

Clinical Practice expands the definition of vulnerable groups by including

thosewho have a subordinate role in a hierarchical structure, such as students,

employees, or members of the armed forces. Many of the potential problems

involving vulnerable subjects can be dealt with through modifications of the

eligibility criteria. When this cannot be done, the process of informed consent

will fall under closer scrutiny. Consent procedures for vulnerable populations

are fully addressed in Chapter 3.

Continuing review

DHHS, FDA, and ICH guidelines each require that the IRB ‘should conduct

continuing review of each ongoing trial at intervals appropriate to the degree



of risk to human subjects, but at least once per year.’ At the time of first

approval, the IRB should determine how frequently the research should be

reviewed for reapproval. The one-year interval is commonly applied to most

research; however, early-phase drug or device studies may need to be resub-

mitted at three- or six-month intervals. Some investigator-initiated research

or research using innovative therapies where risks are unknown may need to

be reported to the IRB on a case-by-case basis. Continuing reviews address a

wide range of issues including the number of participants enrolled and their

demographics, AE reporting, the need for changes to the informed consent

document, and a literature review to show that the research question being

addressed is still important.43 IRBs are at some disadvantage when multicen-

ter trials are subjected to continuing review in that the committee usually does

not have access to the totality of information available to the sponsor.

Generally, their review will be based on the participants recruited at their

site, which may or may not reflect the experience in the entire trial. Some

sponsors facilitate the review process by providing local investigators with

regular updates regarding enrollment and summaries of AEs. Despite the

importance of the continuing review process, IRBs are frequently cited for

failing to provide adequate continuing review of research.44

Final thoughts

Investigators and sponsors often experience frustration in dealing with local

IRBs. Although some IRBs appear to have the mission of blocking clinical

research, this is rarely the case. Sponsors, investigators, and IRB members

each work to meet regulatory mandates and ‘follow the rules.’ Unfortunately,

the rules are not always very specific and sometimes seem to come from

different games. The sponsors’ chances for success are improved by selecting

investigators who have established relationships with their local IRB and

understand the information that is needed to assure a timely and thorough

review.

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of the IRB review process at six institutions. Acad Med 2007; 82(7): 654–660.5. Gunsalus CK et al. The Illinois White Paper: improving the system for protecting human

subjects: counteracting IRB ‘mission creep’. Qual Inq 2007; 13(5): 617–649.

6. Meslin EM,QuaidKA. Ethical issues in the collection, storage, and research use of human

biological materials. J Lab Clin Med 2004; 144(5): 229–234.



7. Jonathan K.Missing the forest: further thoughts on the ethics of bystander risk in medical

research. Camb Q Healthc Ethics 2007; 16(4): 483–490.8. ResnickDB, Sharp RR. Protecting third parties in human subjects research. [Cover story].

IRB: Ethics & Human Research 2006; 28(4): 1–7.

9. Candilis PJ et al. The need to understand IRB deliberations. IRB: Ethics & HumanResearch 2006; 28(1): 1–5.

10. Stair TO et al.Variation in institutional review board responses to a standard protocol fora multicenter clinical trial. Acad Emerg Med 2001; 8(6): 636–641.

11. Burman W et al. The effects of local review on informed consent documents from a

multicenter clinical trials consortium. Control Clin Trials 2003; 24(3): 245–255.12. Dilts DM, Sandler AB. Invisible barriers to clinical trials: the impact of structural, infra-

structural, and procedural barriers to opening oncology clinical trials. J Clin Oncol 2006;24(28): 4545–4552.

13. Nowak KS et al. Reforming the oversight of multi-site clinical research: a review of two

possible solutions.Accountability in Research: Policies&QualityAssurance 2006; 13(1):11–24.

14. Colt HG, Mulnard RA. Writing an application for a human subjects institutional review

board. Chest 2006; 130(5): 1605–1607.15. Kimmelman J. Ethics at Phase 0: clarifying the issues. J Law Med Ethics 2007; 35(4):

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16. Cohen A. Should we tolerate tolerability as an objective in early drug development? Br JClin Pharmacol 2007; 64(3): 249–252.

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23. Connolly SJMD et al. Pacemaker therapy for prevention of syncope in patients with

recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a

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26. Rosoff PM.Can underpowered clinical trials be justified? IRB: Ethics&HumanResearch2004; 26(3): 16–19.

27. Koch A. Biostatistical methods for demonstrating efficacy in the regulatory setting.Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2005; 48(5):

572–579.

28. Freidlin B, Simon R. Adaptive signature design: an adaptive clinical trial design for

generating and prospectively testing a gene expression signature for sensitive patients.Clin Cancer Res 2005; 11(21): 7872–7878.

29. Kelly PJ et al.An adaptive group sequential design for phase II/III clinical trials that select asingle treatment from several. J Biopharm Stat 2005; 15(4): 641–658.

30. Zhang L, Rosenberger WF. Response-adaptive randomization for clinical trials withcontinuous outcomes. Biometrics 2006; 62(2): 562–569.

31. Mello MM et al. The rise of litigation in human subjects research. Ann Intern Med 2003;

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32. Paasche-Ortow MK, Brancati FL. Assessment of medical school institutional review

board policies regarding compensation of subjects for research-related injury. Am JMed 2005; 118(2): 175–180.

33. Shah S et al.Health law and ethics. How do institutional review boards apply the federal

risk and benefit standards for pediatric research? JAMA 2004; 291(4): 476–482.

34. Sharp HM, Orr RD. When ‘minimal risk’ research yields clinically-significant data,

maybe the risks aren’t so minimal. Am J Bioethics 2004; 4(2): W32–W6.35. Chuang-Stein CER, Pritchett Y.Measures for conducting comparative benefit:risk assess-

ment. Drug Inf J 2008; 42(3): 223–233.36. Garrison LP Jr et al. Assessing a structured, quantitative health outcomes approach to

drug risk–benefit analysis. Health Aff (Millwood) 2007; 26(3): 684–695.37. May T et al. Viewpoint: IRBs, hospital ethics committees, and the need for ‘translational

informed consent’. Acad Med 2007; 82(7): 670–674.

38. Sabik L et al. Informed consent: practices and views of investigators in a multinational

clinical trial. IRB: Ethics & Human Research 2005; 27(5): 13–18.39. Silverman H. Ethical issues during the conduct of clinical trials. Proc Am Thorac Soc

2007; 4(2): 180–184; discussion 4.

40. Ness RB. Influence of the HIPAA Privacy Rule on health research. JAMA 2007; 298(18):2164–2170.

41. Dunlop AL et al. The impact of HIPAA authorization on willingness to participate in

clinical research. Ann Epidemiol 2007; 17(11): 899–905.42. De Wolf VA et al. Part II: HIPAA and disclosure risk issues. IRB: Ethics & Human

Research 2006; 28(1): 6–11.

43. Gordon B, Prentice E. Continuing review of research involving human subjects: approach

to the problem and remaining areas of concern. IRB 1997; 19(2): 8–11.

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316–323.



Findings and Consequences of Research Misconduct

DEFINING RESEARCH MISCONDUCT Any institution that applies for or receives Public Health Services (PHS) support for biomedical or behavioral research, research training or activities related to that research or research training are subject to ORI’s guidelines defining and enforcing research misconduct. Activities applicable to ORI guidelines include:

• “Grant applications or proposals; • Research training or activities related to that research or research training and

training programs; • Activities related to research or research training, such as the operation of tissue

and data banks or the dissemination of research information; • Plagiarism of research records produced in the course of PHS supported research,

research training or activities related to that research or research training.” (DHHS 2005)

ORI defines “research misconduct” as: “…fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results.

• Fabrication is making up data or results and recording or reporting them. • Falsification is manipulating research materials, equipment, or processes, or

changing or omitting data or results such that the research is not accurately represented in the research record.

• Plagiarism is the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit.

• Research misconduct does not include differences of opinion.” “To be considered research misconduct, actions must:

• represent a “significant departure from accepted practices”; • have been “committed intentionally, or knowingly, or recklessly”; and • be ‘proven by a preponderance of evidence.’”

CONSEQUENCES OF MISCONDUCT Findings of research misconduct may result in debarment or a voluntary exclusion agreement. In 2005 ORI received 265 allegations of research misconduct; only eight resulted in either a Voluntary Exclusion Agreement or debarment (Weiss). Individuals and institutions may be disbarred or excluded. Debarred individuals or institutions may not participate in any research and supervisory roles involving Federal procurement or non-procurement transactions; debarments are government wide. Debarments are the result of an ORI investigation where ORI determines that there is reasonable evidence to

conclude that research misconduct has occurred. Voluntary Exclusion Agreements are often the result of an agreement between ORI and the alleged individual or institution in lieu of a full investigation; they are, metaphorically speaking, a plea of “No Contest”. Excluded individuals or institutions may also be prohibited from participating in research involving Federal procurement and non-procurement transactions; however, sometimes individuals or institutions may only be prohibited from participating in advisory roles. Individuals and institutions who are debarred or enter into voluntary exclusion agreements are placed on ORI’s public list PHS Administrative Action Bulletin Board for a period of three years. The FDA maintains a separate list of debarment or other administrative actions. In two complete years of data available on the ORI website for Public Health Services (2006 – 2007),1 ORI during its oversight review for the U.S. Public Health Services found reasonable evidence to warrant administrative action regarding research misconduct in twenty-four cases. Twenty-one of the twenty-four closed investigations involved data falsification and/or fabrication. One of those twenty-one cases involved the use of images as data. In that case, the investigator, a doctoral student, darkened with a marking device multiple sections of the image including the original autoradiographical film. One of the twenty-four cases involved data destruction and falsification of records to hide the data destruction. One other case involved mail fraud, criminally negligent homicide, and making false statements. In years 2006 and 2007, fifteen of the twenty-four closed investigations involved some kind of student—doctoral students, graduate students, postdoctoral students, medical residents, and even one undergraduate student. Nine of the twenty-four closed investigations involved researchers in other categories. Consequences for research misconduct depend upon the severity of the misconduct. In the aforementioned years, fifteen closed investigations resulted in a Voluntary Exclusion Agreement and eight in debarment. One individual was excluded for two years, three individuals were excluded for five years, and two individuals were excluded permanently/lifetime; the remaining nine were excluded for three years. Eight individuals were debarred ranging from three to five years. The most severe of those, the criminally negligent homicide, entailed a seventy-one month imprisonment, payment of restitution of over $690,000, and a lifetime government-wide debarment from “participating in any and all Federal agency transactions to protect the public interest overall”. At minimum four—three students and one professor—of the twenty-four closed investigations required the retraction of a published manuscript even if it involved multiple co-authors; one required that data be corrected in the published manuscript. Individuals who are excluded may sometimes continue to participate in federally funded research. In those cases the individual may not be a PI and the PI or other supervisory authority must submit to ORI a Supervisory Plan designed to ensure the scientific integrity of research conducted by the excluded individual before that individual can participate in the research. 1 Detailed data for 2005 is no longer available as of January 2008.

http://ori.dhhs.gov/misconduct/documents/Alert_04-08.pdf

CAUSES OF MISCONDUCT Science, as a field, rests on the foundation that the methods described in the research are accurate. One may disagree with the conclusions, the methodology, the assumptions within the research, etc. but everyone must be able to assume that the data and the procedures are presented accurately. Science is self-correcting in the sense that falsifications will eventually be corrected via ongoing research (Goodstein 2002). Goodstein identifies three motives, or risk factors, commonly present in research misconduct:

“…the perpetrators (1) were under career pressure, (2) knew, or thought they knew, what the result would be if they went to all the trouble of doing the work properly, and (3) were in a field in which individual experiments are not expected to be precisely reproducible.”

Publication keyed to positive outcomes creates an environment prone to career pressure driven misconduct. Research misconduct resulting from the second risk factor is a transgression against the scientific method in addition to the body of knowledge. “Perpetrators think they know how an experiment would come out if they did it properly, and they decide against going to all the trouble of doing it right” (Goodstein 2002). The third risk factor is rarely a motivation in and of itself; rather it is a risk factor for why egregious research misconduct—fabrication, falsification, and deliberate data misrepresentation—occurs more prevalently in the biomedical and related sciences where replication and repetition is pronouncedly more difficult. Discovering research misconduct in these areas usually comes about by a colleague’s reporting it, a later admission of guilt, or secondary experiments reliant upon that research does not perform as expected (Goodstein 2002).

EXAMPLE CASES:

UAB: The BCX-34 and BioCryst Case UAB has been teaching research integrity courses since the mid 90’s; we are working to develop methods to more accurately evaluate the efficacy of these programs. A case of misconduct at UAB occurred in the late 90’s involving UAB President J. Claude Bennett and the pharmaceutical manufacturer BioCryst. UAB was contracted to conduct a Phase III double-blind, randomized, placebo controlled trial of the topical formulation of BCX-34, which was being billed as a potential treatment for psoriasis associated with cutaneous T-cell lymphoma. Dr. W. Mitchell Sams Jr., chairman of the dermatology department at UAB and an expert on T-cell lymphoma, was to conduct the double blind study of BCX-34’s efficacy. Renee Peugeot, a nurse, was later hired to assist with the study. Peugot is the wife of Harry Snyder Jr., the scientist overseeing the study for the company.

The UAB BioCryst BCX-34 case involved image manipulation in addition to multiple other instances of research misconduct. Peugeot in early study trials traced lesions very loosely making them appear larger than the very tight tracings she performed in later trials, a clear instance of image processing which, in the continuum between best practices and misconduct, falls on the side of misconduct. When numerical data related to lesion size was found to be missing from a patient’s chart, and Peugeot was asked about the data, she wrote in a number claiming to have remembered it from an examination performed over a week earlier. This was judged to be an instance of data fabrication. Furthermore, Peugeot and Sams often disagreed, in front of patients, over the size and redness of lesions. It was Peugeot’s assessments that were recorded on patient charts and not Sams’s assessments, a biochemist and M.D. and the study leader. Dr. William Cook, hired by UAB to be Snyder’s boss, requested examination of the randomization schedule (the “code key” identifying control and experimental patients) after BioCryst made public announcements regarding BCX-34’s positive efficacy in the early trials for FDA approval. Cook wanted to begin writing the scientific paper. He found that the data results did not match the information supplied to the FDA and NASDAQ. Cook then asked a study coordinator, a subordinate of Snyder, for the printed copy locked in a cabinet. Again the data results neither matched the public data nor the data results from the randomization charts supplied by Snyder. Snyder created a false randomization chart, a clear instance of data falsification as defined by ORI. The FDA barred Sams for life from testing drugs due to his failure to properly supervise the studies. Peugeot and Snyder were found guilty in criminal court of conspiracy, mail fraud, and making false statements to the FDA. Subsequent studies not performed by Sams, Peugeot, Snyder, or Bennett revealed that BCX-34 performed at least equally as well as the placebo in 30% of cases and the placebo outperformed BCX-34 in reducing lesions in 70% of cases. Where did the reasoning go wrong? The UAB BCX-34 case involves clear examples of data fabrication, falsification, and misrepresentation. Peugeot fabricated data by writing data onto patient charts not based upon clinical examinations. Snyder falsified data by creating alternate randomization schedules. Peugeot misrepresented data, if not falsified and fabricated data, by subjectively drawing lesions to give the impression of positive treatment outcomes. We may ask two different questions: Why are these actions scientifically wrong? Why are these actions morally wrong? Here we are concerned with the latter question. T-cell lymphoma has no known cure. The BioCryst executives were claiming, based upon falsified data, that BCX-34 provided a potential cure for T-cell lymphoma, a deadly form of cancer. If the falsified data had not been discovered by Cook, BCX-34 may have been on the path towards FDA approval. The health of patients utilizing BCX-34 would have been highly compromised; patients may have forgone other treatments with positive

effects for BCX-34 with no positive effects. As medical professionals Peugeot, Snyder, and others violated their Hippocratic Oath of “do no harm”—their data falsification, fabrication, and misrepresentation entailed a potential for malfeasance. In presumed marketing of BCX-34, if awarded FDA approval, BioCryst would have violated the principle of truthfulness. Once exposed, the misrepresentation of BCX-34’s efficacy would have undermined public confidence in medical testing, health professionals, researchers (some of whom, like Sams, perform dual functions as educators), and the broader scientific community whom the public views as impartial seekers of the truth. Medical professionals and researchers are stewards of public health. Korea: Hwang Woo-suk’s Cloning and Stem Cell Research One of the best known cases of research misconduct occurred in 2005; Hwang Woo-suk’s fabricated and falsified data involving the cloning of eleven stem cell lines from 11 patients:

• Digital photographs of two stem cells had been manipulated to make it seem as though they were 11 stem cells from 11 patients cloned.2

• DNA comparison tests were misrepresented as comparing DNA from the donor and a cloned stem cell when they really compared DNA from the donor and an embryo from the donor.

• There were also problems with the human subjects practices: not describing the consent process consent forms of collaborators in the US were approved by the IRB but

not signed participants suffered side effects not listed in the consent form graduate students enrolled as participants describing methods other than those used colleagues were coerced to donate oocytes and without IRB or equivalent

approval According to Donald Kennedy, editor-in-chief of Science as a consequence of this case journals now more closely scrutinize “high risk” papers—research that is of significant public interest, has unexpected or counterintuitive results. Where did the reasoning go wrong? In interviews, Dr. Woo-suk stated he firmly believed in the validity of the methods described in the research papers that were not methods actually employed and that one day the fabricated research would be validated by others in the field. His blind faith in the

2 Refer to Wade article in the New York Times to see the images and the process used.

falsified procedures became more important than performing responsible research and the search for knowledge. It stands to reason that the methods described in the research papers would be replicated by others in the search for patient specified cloned embryonic stem cell medical treatments. His reasoning was short-sighted as others would eventually come forth claiming that the methods described failed to produce cloned embryonic stem cells. Dr. Woo-suk’s reasoning amounted to “the ends will justify the means” based upon a hope, not evidence and data. His reporting falsified and fabricated data undermined public confidence in the scientific community, undermined the profession, and tainted the public’s acuity of the ethics of researchers in a field that is itself ethically controversial in the public arena. In coercing female colleagues to provide oocytes, Dr. Woo-suk violated their autonomy as subjects—i.e., they could not dissent from participating; they were not provided informed consent with the possibility dissenting prior to undergoing medical procedures. Furthermore, as colleagues and subordinates of Dr. Woo-suk, they couple be considered subjects with diminished capacity for autonomy and voluntariness. The procedures for acquiring oocytes entail the potential for long-term harm. The female colleagues reproductive capacity could have been negatively affected by a procedure not the result of their voluntary choice. The line between researcher and subject was blurred. The IRB regulations differentiate between the two groups as the interests of one, the researcher, are sometimes mutually exclusive from the interests of the other, the subjects. Dr. Woo-suk placed a higher value on the research than the well-being of his female colleagues who simultaneously became subjects. In blurring the line between researcher and subject, the colleagues may have then felt a vested interest in the positive outcome of the research project thereby participating in research misconduct or at minimum not desiring to report the misconduct of another. References Birch, D.M. and Cohen, G. 2001. “How a cancer trial ended in betrayal.” Baltimore Sun;

June 24: http://www.bio-cryst.com/thefraud.pdf . Last viewed May 28, 2008. Department of Health and Human Services, Office of Research Integrity. 2005. “Public

Health Service Policies on Research Misconduct; Final Rule.” Federal Register; 70(94): 28369-28400. http://ori.dhhs.gov/documents/FR_Doc_05-9643.shtml. Last viewed May 30, 2008.

Goodstein, D. 2002. “Scientific Misconduct.” Academe Online; 88(1):

http://www.aaup.org/AAUP/pubsres/academe/2002/JF/Feat/good.htm. Last viewed May 28, 2008.

http://www.bio-cryst.com/thefraud.pdf

http://ori.dhhs.gov/documents/FR_Doc_05-9643.shtml

http://www.aaup.org/AAUP/pubsres/academe/2002/JF/Feat/good.htm

Office of Research Integrity, Handling Misconduct - Case Summaries:

http://ori.dhhs.gov/misconduct/cases/. Last viewed January 31, 2008. Office of Science and Technology Policy. 2000. “Federal Policy on Research

Misconduct: Preamble for Research Misconduct Policy” Federal Register; 65(235): 76260-76264. http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2000_register&docid=fr06de00-72. Last viewed May 28, 2008.

Turner, E. H., et. al. 2008. “Selective Publication of Antidepressant Trials and Its

Influence on Apparent Efficacy”. New England Journal of Medicine; 358(3): 252 – 260

Wade, N. 2005. “Clone Scientist Relied on Peers and Korean Pride.” New York Times;

Dec. 25. http://www.nytimes.com/2005/12/25/science/25clone.html. Last viewed May 28, 2008.

Weis, R. 2006. “Deception by Researchers Relatively Rare: But the Few Scientists Who

Falsify Data Are Difficult to Police, Experts Say.” Washington Post; Jan. 15: A19. http://www.washingtonpost.com/wp-dyn/content/article/2006/01/14/AR2006011400935.html. Last viewed May 28, 2008.

http://ori.dhhs.gov/misconduct/cases/

http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2000_register&docid=fr06de00-72

http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2000_register&docid=fr06de00-72

http://www.washingtonpost.com/wp-dyn/content/article/2006/01/14/AR2006011400935.html.%20Last%20viewed%20May%2028

http://www.washingtonpost.com/wp-dyn/content/article/2006/01/14/AR2006011400935.html.%20Last%20viewed%20May%2028

26 Guidelines at a Glance on Avoiding Plagiarism

Avoiding plagiarism, self-plagiarism, and other questionable writing practices: A guide to ethical

writing

The following guidelines are taken from "Avoiding plagiarism, self-plagiarism, and other questionable

writing practices: A guide to ethical writing" by Miguel Roig.

Guideline 1: An ethical writer ALWAYS acknowledges the contributions of others and the source of

his/her ideas.

Guideline 2: Any verbatim text taken from another author must be enclosed in quotation marks.

Guideline 3: We must always acknowledge every source that we use in our writing; whether we

paraphrase it, summarize it, or enclose it quotations.

Guideline 4: When we summarize, we condense, in our own words, a substantial amount of material into

a short paragraph or perhaps even into a sentence.

Guideline 5: Whether we are paraphrasing or summarizing we must always identify the source of the

information.

Guideline 6: When paraphrasing and/or summarizing others’ work we must reproduce the exact meaning

of the other author’s ideas or facts using our words and sentence structure.

Guideline 7: In order to make substantial modifications to the original text that result in a proper

paraphrase, the author must have a thorough understanding of the ideas and terminology being used.

Guideline 8: A responsible writer has an ethical responsibility to readers, and to the author/s from whom

s/he is borrowing, to respect others’ ideas and words, to credit those from whom we borrow, and

whenever possible, to use one’s own words when paraphrasing.

Guideline 9: When in doubt as to whether a concept or fact is common knowledge, provide a citation.

Guideline 10: Authors who submit a manuscript for publication containing data, reviews, conclusions,

etc., that have already been disseminated in some significant manner (e.g., published as an article in

another journal, presented at a conference, posted on the internet) must clearly indicate to the editors and

readers the nature of the previous dissemination.

http://ori.hhs.gov/avoiding-plagiarism-self-plagiarism-and-other-questionable-writing-practices-guide-ethical-writing

http://ori.hhs.gov/avoiding-plagiarism-self-plagiarism-and-other-questionable-writing-practices-guide-ethical-writing

https://ori.hhs.gov/plagiarism-5










Guideline 11: Authors of complex studies should heed the advice previously put forth by Angell &

Relman (1989). If the results of a single complex study are best presented as a ‘cohesive’ single whole,

they should not be partitioned into individual papers. Furthermore, if there is any doubt as to whether a

paper submitted for publication represents fragmented data, authors should enclose other papers

(published or unpublished) that might be part of the paper under consideration (Kassirer & Angell, 1995).

Similarly, old data that have been merely augmented with additional data points and that are

subsequently presented as a new study can be an equally serious ethical breach.

Guideline 12: Because some instances of plagiarism, self-plagiarism, and even some writing practices

that might otherwise be acceptable (e.g., extensive paraphrasing or quoting of key elements of a book)

can constitute copyright infringement, authors are strongly encouraged to become familiar with basic

elements of copyright law.

Guideline 13: While there are some situations where text recycling is an acceptable practice, it may not

be so in other situations. Authors are urged to adhere to the spirit of ethical writing and avoid reusing their

own previously published text, unless it is done in a manner consistent with standard scholarly

conventions (e.g., by using of quotations and proper paraphrasing).

Guideline 14: Authors are strongly urged to double-check their citations. Specifically, authors should

always ensure that each reference notation appearing in the body of the manuscript corresponds to the

correct citation listed in the reference section and vice versa and that each source listed in the reference

section has been cited at some point in the manuscript. In addition, authors should also ensure that all

elements of a citation (e.g., spelling of authors’ names, volume number of journal, pagination) are derived

directly from the original paper, rather than from a citation that appears on a secondary source. Finally,

authors should ensure that credit is given to those authors who first reported the phenomenon being

studied.

Guideline 15: The references used in a paper should only be those that are directly related to its

contents. The intentional inclusion of references of questionable relevance for purposes of manipulating a

journal’s or a paper’s impact factor or a paper’s chances of acceptance is an unacceptable practice.

Guideline 16: Authors should follow a simple rule: Strive to obtain the actual published paper. When the

published paper cannot be obtained, cite the specific version of the material being used, whether it is

conference presentation, abstract, or an unpublished manuscript.







Guideline 17: Generally, when describing others’ work, do not rely on a secondary summary of that work.

It is a deceptive practice, reflects poor scholarly standards, and can lead to a flawed description of the

work described. Always consult the primary literature.

Guideline 18: If an author must rely on a secondary source (e.g., textbook) to describe the contents of a

primary source (e.g., an empirical journal article), s/he should consult writing manuals used in her

discipline to follow the proper convention to do so. Above all, always indicate the actual source of the

information being reported.

Guideline 19: When borrowing heavily from a source, authors should always craft their writing in a way

that makes clear to readers, which ideas are their own and which are derived from the source being

consulted.

Guideline 20: When appropriate, authors have an ethical responsibility to report evidence that runs

contrary to their point of view. In addition, evidence that we use in support of our position must be

methodologically sound. When citing supporting studies that suffer from methodological, statistical, or

other types of shortcomings, such flaws must be pointed out to the reader.

Guideline 21: Authors have an ethical obligation to report all aspects of the study that may impact the

independent replicability of their research.

Guideline 22: Researchers have an ethical responsibility to report the results of their studies according to

their a priori plans. Any post hoc manipulations that may alter the results initially obtained, such as the

elimination of outliers or the use of alternative statistical techniques, must be clearly described along with

an acceptable rationale for using such techniques.

Guideline 23: Authorship determination should be discussed prior to commencing a research

collaboration and should be based on established guidelines, such as those of the International

Committee of Medical Journal Editors.

Guideline 24: Only those individuals who have made substantitve contributions to a project merit

authorship in a paper.

Guideline 25: Faculty-student collaborations should follow the same criteria to establish authorship.

Mentors must exercise great care to neither award authorship to students whose contributions do not

merit it, nor to deny authorship and due credit to the work of students.

Guideline 26: Academic or professional ghost authorship in the sciences is ethically unacceptable.










For details of the whole document check ORI (Office of Research Integrity) WEBSITE:

http://ori.hhs.gov/sites/default/files/plagiarism.pdf

Singapore Statement on Research Integrity

Preamble. The value and benefits of research are vitally dependent on the integrity of research. While there can be and are national and disciplinary differences in the way research is organized and conducted, there are also principles and professional responsibilities that are fundamental to the integrity of research wherever it is undertaken.

1. Integrity: Researchers should take responsibility for the trustworthiness of their research.

2. Adherence to Regulations: Researchers should be aware of and adhere to regulations and policies related to research.

3. Research Methods: Researchers should employ appropriate research methods, base conclusions on critical analysis of the evidence and report findings and interpretations fully and objectively.

4. Research Records: Researchers should keep clear, accurate records of all research in ways that will allow verification and replication of their work by others.

5. Research Findings: Researchers should share data and findings openly and promptly, as soon as they have had an opportunity to establish priority and ownership claims.

6. Authorship: Researchers should take responsibility for their contributions to all publications, funding applications, reports and other representations of their research. Lists of authors should include all those and only those who meet applicable authorship criteria.

7. Publication Acknowledgement: Researchers should acknowledge in publications the names and roles of those who made significant contributions to the research, including writers, funders, sponsors, and others, but do not meet authorship criteria.

8. Peer Review: Researchers should provide fair, prompt and rigorous evaluations and respect confidentiality when reviewing others' work.

9. Conflict of Interest: Researchers should disclose financial and other conflicts of interest that could compromise the trustworthiness of their work in research proposals, publications and public communications as well as in all review activities.

10. Public Communication: Researchers should limit professional comments to their recognized expertise when engaged in public discussions about the application and importance of research findings and clearly distinguish professional comments from opinions based on personal views.

11. Reporting Irresponsible Research Practices: Researchers should report to the appropriate authorities any suspected research misconduct, including fabrication, falsification or plagiarism, and other irresponsible research practices that undermine the trustworthiness of research, such as carelessness, improperly listing authors, failing to report conflicting data, or the use of misleading analytical methods.

12. Responding to Irresponsible Research Practices: Research institutions, as well as journals, professional organizations and agencies that have commitments to research, should have procedures for responding to allegations of misconduct and other irresponsible research practices and for protecting those who report such behavior in good faith. When misconduct or other irresponsible research practice is confirmed, appropriate actions should be taken promptly, including correcting the research record.

13. Research Environments: Research institutions should create and sustain environments that encourage integrity through education, clear policies, and reasonable standards for advancement, while fostering work environments that support research integrity.

14. Societal Considerations: Researchers and research institutions should recognize that they have an ethical obligation to weigh societal benefits against risks inherent in their work.

RESPONSIBILITIES

PRINCIPLES

Honesty in all aspects of research

Accountability in the conduct of research

Professional courtesy and fairness in working with others

Good stewardship of research on behalf of others

The Singapore Statement on Research Integrity was developed as part of the 2nd World Conference on Research Integrity, 21-24 July 2010, in Singapore, as a global guide to the responsible conduct of research. It is not a regulatory document and does not represent the official policies of the countries and organizations that funded and/or participated in the Conference. For

official policies, guidance, and regulations relating to research integrity, appropriate national bodies and organizations should be consulted. Available at: www.singaporestatement.org