integrating research and publication ethics: a new culture margaret rees chair uk association for...
TRANSCRIPT
Integrating research and publication ethics: a new culture
Margaret ReesChair UK Association for Research Ethics (AfRE)
@AfREnews
Reader Emeritus in Reproductive Medicine, University of OxfordVisiting Professor, University of Glasgow, Karolinska Institute and
University of Turku Adjunct Associate ProfessorRobert Wood Johnson Medical School,
at Rutgers University.
Editor in Chief MaturitasExecutive Director European Menopause and Andropause Society
(EMAS)
Background: who am I Researcher and supervisor: basic science Researcher: clinical trials and PI Chair National Health Service Research Ethics Committee (NRES)2006-
2013 Member Open University Human Research Ethics Committee Council member University of Oxford Research Ethics Committee
(CUREC)2009-2014 President European Menopause and Andropause Society (EMAS)2012-
2015 Chair UK Association for Research Ethics (AfRE) Secretary of the Committee on Publication Ethics (COPE) Member Elsevier ethics committee Editor in Chief J Br Menopause Soc/ Menopause International 1998-2008 Editor in Chief Maturitas, Elsevier 2008- present Executive Director EMAS 2015
Ethics in research and publication from start to finish
Funding Ethical approval for
research Recruit participants/
collect data Publication Journal ethical
assessment
Why: Nuremberg trial Medical experiments were undertaken upon concentration camp inmates and
other living human subjects, without their consent, in the course of which experiments the defendants committed the murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts
23 physicians and scientists
Crimes against humanity
A) High-Altitude Experiments B) Freezing Experiments C) Malaria Experiments D) Lost (Mustard) Gas Experiments E) Sulfanilamide Experiments F) Bone, Muscle, and Nerve Regeneration and Bone Transplantation Experiments G) Sea-Water Experiments H) Epidemic Jaundice Experiments I) Sterilization Experiments J) Spotted Fever (Fleckfieber) Experiments K) Experiments with Poison L) Incendiary Bomb Experiments
World Medical Association
Formed in 1945 Represents physicians world wide Non political Non governmental Addresses non clinical medical issues such
as ethics and education
Declaration of Helsinki
First written in 1964 it is: ‘ a statement of ethical principles to provide
guidance to physicians and other participants in medical research involving human subjects’
Both clinical trials and non-therapeutic research
Most recently updated version 2013
Declaration of Helsinki: key elements
Protection of patient rights Informed consent Independent approval Scientific/medical basis Appropriate risk benefit Subject well being takes precedence over
other considerations
Lack of ethical approval and editors and publishers A red flag How was the study conducted Fabrication and falsification The China Bazaar Systematic reviews Clinical guidelines Journal actions: request for further
details from authors/ retraction of papers/ request for institution to investigate
Fujii and Boldt Anaesthesiologist Yoshitaka Fujii, formerly of Toho University in Tokyo 200
retractions: bogus studies, 126 involved randomized controlled trials Joachim Boldt 89 retractions: leading advocate of colloids Boldt ‘None of the studies examined had received an ethical opinion from
the Rhineland-Palatinate Medical Association (Landesärztekammer Rheinland-Pfalz). In the majority of these cases, the principal investigator had failed to register planned research projects with the Rhineland-Palatinate Medical Association, and the relevant office at Ludwigshafen Hospital. Many cases revealed no record of formal consent by study participants or indeed evidence that study participants had been provided with sufficient information prior to enrolment.’
http://blogs.bmj.com/bmj/2012/07/24/steve-yentis-infamous-names-in-anaesthesia-part-one/
Geographical Origin Published Articles 2012-2014
10
Asia11%
Europe55%
N.Amer.
18%
S.Amer.4%
Austral.10%
Africa1%
Mid.East1%
Maturitas is an international publication: almost 50% of published papers are from outside Europe.
Ethics and guide for authors Human and animal rights (Elsevier)
If the work involves the use of animal or human subjects, the author should ensure that the work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans
Authors should include a statement in the manuscript that informed consent was obtained for experimentation with human subjects. The privacy rights of human subjects must always be observed.
COPE discussion document with HRA (2014) Background There are a number of legitimate and valuable tools for gaining information
and evidence for scientific advance and improving health care. These include research, evaluation, audit, and others. There is a real danger that UK “researchers” using tools other than “research”, duly following guidance in UK research regulation stating a lack of need for ethical review, find that journal editors will not consider their manuscript for publication because editors dispute the definition of what needs or does not need ethical review.
Summary of COPE forum discussion The editor's position, when presented with a research paper, is to make sure that by
the best standards that are available, or best relevant standards, that the work has been proven to be ethical. It is hard to define when formal ethics approval is required for some types of research, and defining what is research is tricky.
The key is demonstrating to the editor that due process has been followed, and there should be transparency, including reference to the guidance and standards that the authors have followed, and proof, where required, that those standards or processes have been followed.
We need to empower and support those research communities that do not have an ethical review infrastructure in a sensitive manner, and in accordance with their cultures. There should be transparency around the constitution of ethics committees.
The minimum standards that could be applied should be institutional regulations as well as local legislation, and due process needs to be demonstrated and proved to the editor by the researcher so that the editor can be satisfied that the relevant standards have been applied.
China Bazaar
Companies prepare original papers from scratch with data provided by their clients or fabricate data, arrange to add scientists’ names to already accepted papers, and sell finished manuscripts.
Among the most popular options for finished manuscripts are meta-analyses, perhaps because they require no original data. One legitimate analysis published in PLOS ONE in June 2013 found that from 2003 to 2011, meta-analysis papers from China rose more than 16 times faster than did such papers from the United States.
Copycat papers with similar phrases.......
http://news.sciencemag.org/asiapacific/2014/10/copycat-papers-flag-continuing-headache-china
Guidelines•These guidelines were first published in 2008.•They were then revised in 2011, when the authors learnt that Professor Joachim Boldt is under investigation following allegations of research fraud. Whilst remaining open minded as to whether these allegations would prove to be true or false, they felt that since the guidelines used six of his references there was a need to review them to see if any changes were needed after removing these six references.•The text and recommendations remained exactly as before and one review reference was added to replace the Boldt references removed.
COPE guidance: submitted manuscript
Contact the author and await explanation Stop processing of paper until satisfactory
explanation provided with evidence of ethical approval/ informed consent
If explanation unsatisfactory ask institution to investigate
http://publicationethics.org/files/u2/All_flowcharts.pdf
Example of a letter to authorThank you for submitting your paper for consideration for publication in Maturitas. This paper is not suitable for consideration for publication in Maturitas at the present time as:
We have noticed that this manuscript does not provide sufficient information for us to judge whether the study you describe in this manuscript was conducted according to accepted ethical guidelines for the treatment of humans.
There is lack of evidence of informed consent and ethical approval as specified in our guide for authors.
I would be grateful if you could clarify how this research was carried out, specifically did you have ethical approval and was consent obtained.
If you have received ethical approval could you please send me copy of the letter.
While we are aware that legislation varies throughout the world and not all research requires ethical approval, we would like you to provide supporting evidence such as a letter from the chair of your IRB stating that ethical approval was not required for this study.
Until we have heard from you we cannot proceed further with the review/publication of your paper.
Expression of concern: The Journal of Bone and Joint Surgery
The Journal of Bone and Joint Surgery received a letter from the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, stating that the trial on which this study was based was performed without authorization from the MHRA and without a favorable ethical opinion from a recognized research ethics committee, both of which are required by the Medicines for Human Use (Clinical Trials) Regulations (2004).
Additionally, the MHRA stated that permission was not obtained from the organization where the research was undertaken, as required by the Department of Health Policy. It has been reported to me that the research patients were treated at a private practice facility. There are differing reports as to whether or not the lead author, Dr. David Connell, retained records of his research findings.
It has been reported to me that there is an ongoing investigation in the United Kingdom by the General Medical Council (GMC) into possible unethical behavior. We will inform our readers of the outcome of this investigation when it is complete.
How: applying for ethical approval
Preparation of the application: IRAS, or university REC, protocol, CV, PIS, consent form, peer review
Does it need ethical review Proportionate review Participant information sheet Consent Advertising Trial registration
Ethical approval for studies in humans
Research requires ethical approval and informed consent either through NHS or University RECs
BUT DOES NOT REQUIRE NHS REC REVIEW IN UK for
Service evaluation Audit Surveillance Usual practice (in public health)
Types of research requiring ethical approval through the NHS
Clinical trials of medicinal products or devices Studies administering questionnaires/
interviews Studies human or other biological samples or
data Research tissue bank Research database
Proportionate review http://www.nres.nhs.uk/applications/proportionate-review/
The aim of proportionate review is for studies which present minimal risk or burden for participants to be reviewed by a proportionate review sub-committee within 14 days of receipt of a valid application.
I Research using data or tissue that is anonymous TO THE RESEARCHER II Research using existing tissue samples already taken with consent for
research III Research using “extra tissue” (e.g. further blood taken at time of routine
sampling or tissue taken at “clinically directed” operation) IV Questionnaire research that does NOT include highly sensitive areas or
where accidental disclosure would NOT have serious consequence V Research interview / focus group that does NOT include highly sensitive
areas or where accidental disclosure would NOT have serious consequences VI Research surveying the safety or efficacy of established non drug
treatments, involving limited intervention and NO change to the patients’ treatment
The following types of application always require review at a full REC meeting:
Clinical trials of investigational medicinal products (CTIMP’s) Clinical investigations of medical devices prior to CE marking Research involving adults lacking capacity and subject to the Mental
Capacity Act 2005 Invasive basic science studies involving healthy volunteers Research involving exposure to ionising radiation which could be
additional to that received in routine clinical care for any participant Research tissue banks Research databases Prison research Studies funded by the US department for Health and Human
Sciences
Application logistics
One application will provide a decision for the whole of the UK for HRA
IRAS form filter questions/ university filters All elements of the application need to be consistent eg
number of participants, timing and types of intervention PIS and consent forms need to be clear and follow the
recommended guidance Peer/ statistical review: supervisor, R and D, the grant
giving body The research must be justified
Participant information sheets
Standard formats of information sheets Language must be easily comprehensible and
avoid use technical language Why approached Must not be coercive Clinical trials should not be presented too
enthusiastically Side effects of interventions clearly stated Patient support groups
Participant information sheets
What interventions are study specific Travel expenses Confidentiality Use of samples and data Publication : images and quotations and
anonymity Publication plan: hot topic at present for clinical
trials Who to complain to
REC/IRB/ethics committee
A REC is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects.
HRA REC members are expected to undergo regular training and RECs are appraised annually
AfRE university framework
What is a REC?
A REC should contain a mixture of people who reflect the currency of public opinion (‘lay’ members), as well as people who have relevant formal qualifications or
professional experience that can help the REC understand particular aspects of research proposals (‘expert’ members).
i.e. societal representation
Would you approve this study?
This questionnaire study for an educational project will examine what people attending GPs surgery think about routine screening for sexually transmitted infections (STIs).
Questionnaires, PIS and consent forms will be given to people in the waiting area by the student.
Consent will be obtained by the student in the GP waiting area by the student.
Participants will then be expected to complete the questionnaires again in the waiting area and return this to the student before leaving the surgery.
Questionnaires will ask about previous STIs and their treatment as well as names of all sexual partners and details about types of sexual activity and sexual orientation.
There is no assurance that the GPs support the study and that the student has been trained in taking consent.
What concerns would you have about this study?
A head of department wants to collect 10ml urine samples from 50 staff members in their department to validate an assay for a biomarker under investigation for a potentially fatal degenerative disease. The assay will be undertaken in the department by technical staff using individual unnamed samples.
The study invitation will be disseminated by email to all staff members and the information and consent state that lack of participation will not affect career prospects.
Once written consent has been obtained the head of department will give participants unlabelled bottles to be placed in a designated laboratory fridge once filled with urine.
How: publication (what editors look out for)
Detail ethical approval and informed consent (name, date, reference number, approval letter....)
Authorship Competing interests Plagiarism Duplicate/ salami slice submission Fake data Fake peer reviewers Sting papers
An unethical ethics committee (COPE case) A paper was submitted, detailing a double blind placebo controlled food challenge to
a group of children. The reviewer considered the study unethical because he was concerned consent could not have been properly informed. He believed there was a very small risk of anaphylaxis—even death—and had this been explained to the parents, they would not have consented.
After investigation it transpired that the chairman of the ethics committee tagreed the proposal was part of normal clinical practice rather than a clinical trial so did not require ethics committee approval overruling the committee. The study went ahead.
There was concern that the chairman had overruled his/her own committee. The editor contacted the chief executives of the hospital trusts, detailing the
allegations and requested an investigation.
No ethics approval or informed consent (COPE case) A thesis published by a student was submitted for publication. One of the journal
editors found the research unethical and asked for confirmation of ethics committee approval.
It was found that not only was the approval obtained post research but also that the subjects were not aware that they had been randomised into two groups for surgery. The only consent forms available were those for surgery and consent that their data could be used for research. There are long term implications of the research. The author wanted to prove that omission of an expensive drug in a third world scenario could lead to no change in results. There were over a dozen articles indicating the contrary. The author seemed to base his hypothesis on one article in the literature. Following the investigation, the article was withdrawn by the author.
COPE agreed that the editorial team had a moral responsibility to take further action as there was a possibility that patients may be put at risk ie write to the ethics committee/ medical board requesting investigation.
Contributor/author An “author” is generally considered to be someone who has made substantive
intellectual contributions to a published study, and biomedical authorship continues to have important academic, social, and financial implications. An author must take responsibility for at least one component of the work, should be able to identify who is responsible for each other component, and should ideally be confident in their co-authors’ ability and integrity
Authorship credit should be based on 1) substantial contributions to conception and design, acquisition of data, or analysis
and interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the version to be published. Authors should meet conditions 1, 2, and 3. Acquisition of funding, collection of data, or general supervision of the research group
alone does not constitute authorship. http://www.icmje.org/ethical_1author.html
Contributor/ Authorship
Gift eg head of department automatically put on even though no contribution
Ghost eg medical writer Dropped Added Dead
Competing interest Cite by company name or other description, all commercial and/or financial
relationships within the past 3 years that may be relevant to the topic of the manuscript and might be perceived as a real or potential conflict of interest.
"Relevant" means that the relationship involves the same or similar subject matter; the same, similar or competing drug or device, product or service, intellectual property or asset, or has the potential to result in financial, professional or other personal gain or loss for you or an immediate family member (spouse or child).
Employment (other than primary affiliation; e.g., consulting) Commercial Research Grant Other Commercial Research Support Honoraria from Speakers Bureau Ownership Interest (including patents) Consultant/Advisory Board Other (e.g., expert testimony) NOT TO STATE MEANS THAT AUTHORS COULD BE DECEIVED
Submissions are checked for overlap with iThenticate but this will not pick up simultaneous submissions and here editors rely on
peer reviewers.
Duplicate salami slice submission Unlike duplicate publication , which involves reporting the exact same data in two or more
publications, salami slicing it involves breaking up or segmenting a large study into two or more publications. These segments are referred to as "slices"
of a study As a general rule, as long as the "slices" of a broken up study share the same hypotheses,
population, and methods, this is not acceptable practice. The same "slice" should never be published more than once.
The reason: according to the U.S. Office of Research Integrity, salami slicing can result in a distortion of the literature by leading unsuspecting readers to believe that data presented in each salami slice (i.e., journal article) is derived from a different subject sample. This not only skews the "scientific database" but it creates repetition that wastes readers' time as well as the time of editors and reviewers, who must handle each paper separately. Further, it unfairly inflates the author's citation record.
There are instances where data from large clinical trials and epidemiological studies cannot be published simultaneously, or are such that they address different and distinct questions with multiple and unrelated endpoints. In these cases, it is legitimate to describe important outcomes of the studies separately. However each paper should clearly define its hypothesis and be presented as one section of a much larger study.
Most journals request that authors who either know or suspect a manuscript submitted for publication represents fragmented data should disclose this information, as well as enclose any other papers (published or unpublished) that might be part of the paper under consideration.
Fake data
Following an investigation into research misconduct, the Journal of Clinical Investigation has retracted a cancer genetics paper from a laboratory at the National Institutes of Health due to “data falsification and fabrication” of four figures and a table in the paper.
The paper, “FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer,” describes an overexpressed gene in mouse prostate cancers that appears to suppress immune system cells.
The journal retracted the paper following an investigation into author Stephanie K. Watkins, then a postdoctoral fellow at the National Cancer Institute
Fake dataEditorial retractionScience, with the concurrence of author Donald P. Green, is retracting the 12 December 2014 Report “When contact changes minds: An experiment on transmission of support for gay equality” by LaCour and Green.The reasons for retracting the paper are as follows: (i) Survey incentives were misrepresented. To encourage participation in the survey, respondents were claimed to have been given cash payments to enroll, to refer family and friends, and to complete multiple surveys. In correspondence received from Michael J. LaCour’s attorney, he confirmed that no such payments were made. (ii) The statement on sponsorship was false. In the Report, LaCour acknowledged funding from the Williams Institute, the Ford Foundation, and the Evelyn and Walter Haas Jr. Fund. Per correspondence from LaCour’s attorney, this statement was not true. In addition to these known problems, independent researchers have noted certain statistical irregularities in the responses. LaCour has not produced the original survey data from which someone else could independently confirm the validity of the reported findings. Michael J. LaCour does not agree to this Retraction.Published online 28 May 201510.1126/science.aac6638
Effects of fabricated data: MMR vaccine and Wakefield
The Lancet paper was a case series of 12 child patients; it reported a proposed “new syndrome” of enterocolitis and regressive autism and associated this with MMR as an “apparent precipitating event.” But in fact:
Three of nine children reported with regressive autism did not have autism diagnosed at all. Only one child clearly had regressive autism
Despite the paper claiming that all 12 children were “previously normal,” five had documented pre-existing developmental concerns..........................
Cite this as: BMJ 2011; 342:c5347
MMR scare and consequences Wakefield AJ, Murch SH, Anthony
A, Linnell, Casson DM, Malik M, et al. Ileal lymphoid nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637-41 [retracted].2010
Reduced use of vaccines in children
In addition to measles outbreaks UK and US, other infections are resurgent eg whooping cough
Fake peer reviewers BioMed Central uncovered about fifty manuscripts in their editorial system that involved fake
peer reviewers. Most of the cases were not published because they were discovered by a manuscript editor on a
final pre-publication check. The five or so that have been published will go through some sort of re-review, which may result in expressions of concern or retraction.
The narrative seems similar to that in the growing number of cases of peer review manipulation we’ve seen recently. What tipped off the editor was minor spelling mistakes in the reviewers’ names, and odd non-institutional email addresses that were often changed once reviews had been submitted, in an apparent attempt to cover the fakers’ tracks. Those “reviewers” had turned in reports across several journals, spanning several subjects.
It would seem that a third party, perhaps marketing services helping authors have papers accepted, was involved.
http://retractionwatch.com/2014/11/25/publisher-discovers-50-papers-accepted-based-on-fake-peer-reviews/
http://publicationethics.org/news/cope-statement-inappropriate-manipulation-peer-review-processes
Conclusion Ethical approval and informed
consent must be obtained in accordance with local legislation.
Journals scrutinise papers Journals will examine whether
ethical approval and informed consent were obtained
Journals may ask ethics committees and institutions to investigate their decisions
Journals are concerned about the long term effects of poorly conducted/ unethical studies
Would you approve this study?
This questionnaire study for an educational project will examine what people attending GPs surgery think about routine screening for sexually transmitted infections (STIs).
Questionnaires, PIS and consent forms will be given to people in the waiting area by the student.
Consent will be obtained by the student in the GP waiting area by the student.
Participants will then be expected to complete the questionnaires again in the waiting area and return this to the student before leaving the surgery.
Questionnaires will ask about previous STIs and their treatment as well as names of all sexual partners and details about types of sexual activity and sexual orientation.
There is no assurance that the GPs support the study and that the student has been trained in taking consent.
What concerns would you have about this study?
A head of department wants to collect 10ml urine samples from 50 staff members in their department to validate an assay for a biomarker under investigation for a potentially fatal degenerative disease. The assay will be undertaken in the department by technical staff using individual unnamed samples.
The study invitation will be disseminated by email to all staff members and the information and consent state that lack of participation will not affect career prospects.
Once written consent has been obtained the head of department will give participants unlabelled bottles to be placed in a designated laboratory fridge once filled with urine.
What should the editor do?
A journal editor receives a paper with research on health status based on a postal questionnaire sent to two groups of people. The first group of people had undergone a potentially life saving procedure 10 years previously. The control group consisted of healthy people who had not had surgery and who were not known to have the condition. Potential participants were selected from a healthcare provider database. Participants were provided with a stamped addressed envelope to return the completed questionnaire to the researcher. The methods section does not state if ethical approval or informed consent were obtained. The results presented in the paper are based on 1,000 responses. What should the editor do?
What concerns should an editor have?
A journal editor receives a paper from an unknown institution claiming that wearing tight underwear increases the risk of breast and testicular cancer. It is a cohort study undertaken by a group of epidemiologists and the department of engineering who measured the elastic modulus of the underwear. How should the editor proceed?