Ethics and Medical Research

Richard L. Elliott, MD, PhDProfessor and Director, Medical EthicsMercer University School of Medicine

Ethics and Research

• Who has done research? Published?• When do you think are some ethical

issues in research• Have you encountered ethical issues in

research?

A few questions about ethics in research

• Lack of informed consent – Do patients-subjects know what they are consenting to?

• Mistreatment of subjects – Are subjects being treated fairly, not being abused?

• Falsification of data – Is evidence-based medicine reliable?

• Conflicts of interest – Is unfavorable data suppressed?

• Authorship – Do we really know who is responsible for conducting a study?

Prevalence of scientific misconduct: Fanelli2% scientists admit to serious misconduct – fabrication, falsification, plagiarism34% admit to questionable practices – dropping data points, changing research design to get favorable results

Studying Scientific Misconduct

• International Committee of Medical Journal Editors• Emanuel et al. What makes clinical research ethical?• Data falsification and fabrication• Fall 2012 - The Integrity of Evidence-Based Medicine

– History of ethics in medical research• Tuskegee

– Institutional Review Boards– Medical industry, medical research, and medical

education

ICMJE

• International Committee of Medical Journal Editors– JAMA, NEJM, Lancet, BMJ, many others– http://www.icmje.org/– Authorship, contributorship, and editorship– Peer review– Conflicts of interest– Privacy and confidentiality– Protection of human subjects and animals in research– Obligation to publish negative findings– Overlapping publications

ICMJE - Authorship

• Author means having made substantial intellectual contribution

• Design, data acquisition, and/or analysis• Draft or revision of article, final approval • Each author should be able to take public

responsibility for the work

Ghost authors and “Guest” authors

• Wislar et al. – 896 Corresponding authors published in JAMA, NEJM, Lancet,

PLoS Medicine, Ann Int Med, Nature Medicine• Ghost authorship 11.0% in original research articles• Honorary authorship 25% in original research articles• 21% articles with inappropriate authorship

• Gotzsche et al. PLoS Medicine– http://www.plosmedicine.org/article/info:doi/10.1371/

journal.pmed.0040019 – 75% industry sponsored trial with ghost authors (stats mostly)

• Major textbook of psychiatry ghost authored• Use of Prempro, HRT based on ghost authored paper• Vioxx studies by Merck used honorary and ghost authors

ICMJE – Peer review

• Peer review process not specified by ICMJE• Purpose: to provide fair, disinterested input on

quality of article submitted– Blinded review (identity of author(s) removed)– Random selection of qualified reviewers– Reviewers disclose conflicts of interest– Having a peer read a paper is not peer review– Reviewers paper’s contents

Concerns with peer review

• Not truly blinded• Misuse of information learned during peer

review• Peer review may be biased against

revolutionary ideas

ICMJE – Conflicts of interest

• Freedom from financial or personal interests that create bias– Disclosure vs meaningful disclosure of

financial interests– Other interests: personal relationships,

academic competition, bias about value of work

• Editorial Conflicts of interest– Revenue from advertisers

ICMJE – Privacy and confidentiality

• Protect identity of subjects, patients– Remove identifying information or disguise

• Patient in her 40s vs 46 year old– Informed consent if potentially identifiable

• Author and reviewer confidentiality should be protected

ICMJE – Protection of human subjects

• Paper should state whether study was carried out according to Helsinki Declaration

• IRB approval • Protection of animal subjects

ICMJE – Negative studies

• Publication bias – failure to publish negative trials– Undermines meta-analytic studies of efficacy

• Antidepressants• Many journals require studies to have

been registered with clinicaltrials.gov

ICMJE – Duplicate submissions

• Submit to one journal only• If there are conflicting or competing

publications from the same study, the journal editor should be informed

Emanuel - JAMA

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Scientific validity– Fair subject selection– Favorable risk-benefit ratio– Independent review– Informed consent– Respect for potential and enrolled subjects

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Are the right questions being asked?

• Avoid “trivial pursuits” - LPUs• Resource allocation• Non-maleficence (risks should be justified by possible benefits)

– MCG psychotherapy study

– Scientific validity– Fair subject selection– Favorable risk-benefit ratio– Independent review– Informed consent– Respect for potential and enrolled subjects

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Scientific validity

• Is study carried out properly? Do researchers posses necessary expertise?• Invalid studies – clinical trials against improperly dosed comparison drug• VA study of psychosocial therapies with poorly defined interventions

– What was meant by psychoeducation? Rehabilitation?

– Fair subject selection– Favorable risk-benefit ratio– Independent review– Informed consent– Respect for potential and enrolled subjects

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Scientific validity– Fair subject selection

• Subject recruitment should meet scientific needs• Groups exposed to risks should share in benefits• Not biased by socioeconomic or other factors

– Tuskegee

– Favorable risk-benefit ratio– Independent review– Informed consent– Respect for potential and enrolled subjects

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Scientific validity– Fair subject selection– Favorable risk-benefit ratio

• Potential risks are minimized, potential benefits enhanced• Potential benefits are proportional to or exceed potential risks• Phase I trials?

– Independent review– Informed consent– Respect for potential and enrolled subjects

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Scientific validity– Fair subject selection– Favorable risk-benefit ratio– Independent review

• Review by a party with no stake in outcome of review• Reduce risks of potential conflicts of interest• MCG psychotherapy case – not independent review

– Informed consent– Respect for potential and enrolled subjects

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Scientific validity– Fair subject selection– Favorable risk-benefit ratio– Independent review– Informed consent

• Protection of vulnerable populations – children, incapacitated adults, prisoners, pregnant women, and others

• Must consider possibility of coerced consent via inducements or vulnerability– Willowbrook

• What needs to ne disclosed? Possible financial gain for researchers?– Respect for potential and enrolled subjects

• Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711– Social or scientific value– Scientific validity– Fair subject selection– Favorable risk-benefit ratio– Independent review– Informed consent– Respect for potential and enrolled subjects

• Privacy and confidentiality• Non-identification of subjects

Scientific misconduct (fraud)

• Falsification or fabrication of data• Newton, Mendel, Millikan• Scott S. Reuben faked data in 21 studies on pain medicines• Andrew Wakefield and relationship between vaccines and autism• Woo-Suk Hwang and cloning of human embryonic stem cells• Dipak Das U Conn resveratrol 26 articles retracted• Anil Potti, Duke, individualized treatments for ovarian cancer

– 1/3 of 40 papers retracted, another 1/3 portions retracted• Marc D. Hauser Harvard evolutionary biologist fabricated and falsified data• Eric Poehlman obesity research imprisoned

• Scientific recordkeeping– Importance of lab books in verifying collection of data

Resources

• Medapps.mercer.edu• http://www.wame.org/ethics-resources/we

b-resources-on-publication-and-research-ethics/

• http://www.fic.nih.gov/ResearchTopics/Pages/Bioethics.aspx