J A N U A R Y 1 3 , 2 0 1 5

Research Ethics (Why do we do research?)

David D. Lo, MD, PhDDistinguished Professor, Biomedical Sciences

Senior Associate Dean, ResearchUCR School of Medicine

Disclosures

None of the faculty, planners, speakers, providers nor CME committee have any relevant financial

relationships with commercial interestThere is no commercial support for this CME activity

Today’s Discussion

• Human curiosity, the motivations to do research, and ways to guide proper conduct of research

• Case studies on science (?)• Regulatory aspects of research

Research – Why?

• Modern medicine is considered to be• Science-based (for development of new drugs and

devices), and • Evidence-based (for application of thoroughly evaluated

and tested practice)• Application of modern medical practices is also tied to

research to clarify disease classes (pathophysiology) as well as mechanism-based therapeutic approaches

• All this comes from application of modern Scientific Method as we discussed in the first seminar

• So we don’t just practice medicine using the wisdom our forefathers passed down (though Doctoring is still a tradition)

Research Conduct:Professionalism

• Are we Superheroes

• or Drones?

As with professionalism in clinical practice, there is professionalism in the conduct of research

What is “Professional” Behavior?

• Motivation: Shared goals for higher scientific achievements rather than position and power

• Professional detachment and respect –separating work priorities from personal issues

• Continuing education – ongoing learning and acquisition of new skills

• Advocacy – taking responsibility for advancing the cause in the community (e.g., promoting science education)

Responsible Scientific Conduct

• We expect science to be an honest search for basic truths in Nature

• We expect Scientists to demonstrate these truths according to established rules

• Rules for formulating hypotheses • Rules for designing experiments and acquiring data• Rules for analyzing and reporting the results

• Another level of expectations come with modern academic research

• Rules for academic scholarship• Rules for scientific rigor• Rules for documentation

“I have had my results for a long time:but I do not yet know how I am to arrive at them.”

~Karl Friedrich Gauss

Responsible Scientific Conduct

• Given our cultural expectations and conventional rules of behavior, responsible conduct is viewed to be violated when:

• False hypotheses are posed• Experimental conventions are ignored• Ad hoc methods of analysis are applied• Poor scholarship overlooks prior work• Data is not faithfully documented

• Some of these violations may be the result of laziness or poor training; the level of the offense rises when violations are intentional

Case Studies

• Plagiarism in China: Who’s going to check anyway?

• Dr. Oz: Why present “medicine” without evidence?

• Diedrich Stapel: It sounds almost right?

• The Baltimore Case: Misconduct or missed responsibility?

Plagiarism: Perverse Incentives

• Recently, a collection of scientific journals published by Zhejiang University in Hangzhou ignited a firestorm by publicizing results from a 20-month experiment with software that detects plagiarism. The software, called CrossCheck, rejected nearly a third of all submissions on suspicion that the content was pirated from previously published research.

• In some cases, more than 80 percent of a paper’s content was deemed unoriginal

• What’s going on?

Plagiarism: Perverse Incentives

• What’s going on?

• Academic positions in China are not that easy to get, and salaries are not terribly high. As an incentive to academics, salaries get a considerable boost from the number of publications as well as the journal’s impact factor (not necessarily the citations of their papers)• There are numerous Chinese language science journals not

reviewed by western scientists• Not only is there evidence for a high incidence of

plagiarism, there are also instances of review fraud – authors reviewing their own papers using false email identities

• Incentives are poorly suited to objective scientific research

Are raspberry ketones a 'miracle' fat burner? Dr. Oz weighs in

• Sales of Raspberry Ketones took off after an episode of the Dr. Oz show where he described them as "the No. 1 miracle in a bottle to burn your fat.”• A handful of studies from Asia suggested that these ketones

could burn fat – but these were studies on rodents or cells• The Dr. Oz show presented before and after images of

women who used raspberry ketones, but these women also dieted and worked out.

• Good medical science? Honest reporting of research?

Are raspberry ketones a 'miracle' fat burner? Dr. Oz weighs in

• Dr. Mehmet Oz has credibility (!?!?)• Professor and Vice-Chair of Surgery at Columbia University• MD from University of Pennsylvania • He’s handsome, and has a TV show

• But then again…• Recent tallies (Slate; BMJ) shows claims mostly NOT backed

up by evidence in the medical literature. For example:• Daily zinc for weight loss: reduces hunger by increasing

leptin. Randomized trials showed no effect• Omega-3 fatty acid DHA for cardiovascular health. No

consistent evidence, but some adverse effects• Vitamin D to prevent cancer, fight off colds, slow down

aging. Multiple reviews found inconclusive evidence.• Bottom line: Good TV is not the same as good science

Diedrich Stapel: Sounds Correct

• Dr. Diedrich Stapel was considered a rising star in Social Psychology studies on behavior and attitudes

• Example of one study:• He used a subway station and analyzed people waiting in

that station about attitudes toward race• Claimed that if the station had more litter, white people

tended to sit further away from a black person sitting in the station – claimed as evidence for greater bias against racial minorities in the presence of environmental untidiness

• Interesting, and maybe makes sense……except that the study was never actually done

Diedrich Stapel: Sounds Correct

• Dr. Diedrich Stapel had graduated several PhD students and published with collaborators from many other institutions• It turns out that he kept the data sets himself and performed

his own statistical analyses• But the data was entirely fabricated and was discovered

because the statistics didn’t match claimed sample sizes

• What went wrong with our peer review? The papers were initially accepted readily without close analysis because the conclusions were not too far out of line and seemed to make sense. Yet still interesting enough to show up in CNN, etc.

• In one study by a psychologist who interviewed scientists found guilty of misconduct, he found that one attitude was that they were so smart that they knew the correct answer and didn’t want to waste time doing the actual experiment!

The Baltimore Case

• In 1986, a Cell paper was published from a collaboration between the labs of David Baltimore (Nobel laureate, discoverer of reverse transcriptase) and Thereza Imanishi-Kari• Paper claimed that expression of a transgenic antibody

could alter the remaining antibody repertoire• In other words, the presence of one fixed antibody could

influence the response of other B cells, supporting the idea that a network regulates immune responses

• While a fairly dramatic claim, it did seem to support the Network Theory of Niels Jerne (who got a Nobel for that)

The Baltimore Case

• Things started to fall apart when a postdoc in Imanishi-Kari’s lab claimed that the key results in the paper were fabricated

• Colleagues didn’t support this accusation, so the postdoc ended up going to two NIH scientists (not immunologists) and the affair ended up in congressional testimony, retraction/non-retraction, investigations, and so on.

• Ultimately, the question came down to interpretation of one type of assay that can be open to interpretation, as well as poor record-keeping, but having a high profile Nobel laureate raised the stakes

• So did peer review fail? Was there creative interpretation of data? Or just poor record-keeping?• If one or more, does this count as scientific misconduct?

A Matter of Intent

• Of course, it’s bad when the misconduct is intentional, as in the case of this internal memo from the tobacco industry:

So What Exactly is Scientific Misconduct?

• “Fabrication, falsification, or plagiarism in proposing, performing, or reviewing research or in reporting research results” (FFP)

• All research institutions that receive federal funds must have policies and procedures to investigate and report misconduct

• Scientists who violate standard other than FFP are said to engage in “questionable research practices”(QRP)

Regulation and Scientific Misconduct

• What purpose does regulation have in research?

• Protection from harm• Protections against dangerous substances• Protections for animal and human subjects

• Protection from misconduct• Protections against conflict of interest• Protections against research misconduct

Environmental Health and Safety (EHS)

• Oversight of chemicals, radiation, ergonomics, and biohazards

Office of Research Integrity (ORI)

• Oversight of animal care, human subjects, conflict of interest, research misconduct, and biohazards (select agents, recombinant DNA)

Biological Use Authorization:Protection From Stuff We Should Be Scared Of

• Infectious organisms (bacteria, viruses, mold, fungi, yeast, parasites, prions, etc.) that may cause disease in healthy humans, or cause significant environmental or agricultural impact

• Work with human, sheep and primate tissues, fluids, cells

• Recombinant DNA

• Transgenic plants, insects or animals

• Human gene therapy

• Select agents

• Intentional release of recombinant DNA to the environment

• Work with animals known to be potential reservoirs of zoonotic diseases

• All work at Biosafety Level 2 (BSL2) and higher

New Issues: Novel Lethal Pathogens

• In 2005, the Spanish Flu (1918) was reconstructed and shown to have severe pathogenesis in mice

• Work with H5N1 (“Bird Flu” – a ~65% case fatality rate in humans!) made mutated forms that are more transmissable in mammals• Should such studies be allowed?

• Concept of “Dual Use” research

Animal Welfare

• Definitions of “animals” and “research”• Under the Animal Welfare Act of 1966, USDA policy

covers animals used for research, exhibition, transport, and dealers, but not those used in agriculture production, or pets (the cute animals!)

• All warm-blooded animals used for research are covered except those in the genus Rattus (Rats!), Mus(Mice), and any birds• Fish, reptiles, amphibians, insects, etc. are not

covered • Policy affects research facilities, housing enclosures

and exercise facilities, availability of veterinary care, destruction (‘euthanasia’)

Institutional Animal Care and Use Committee (IACUC)

• Any research using animals (including rodents and birds) requires a process for review and approval of experimental protocols• The IACUC consists of research scientists, a veterinarian,

and a community representative• Protocols must be approved in advance of any research,

so that inappropriate methods (animal welfare, statistical analysis, etc.) are avoided or improvements may be suggested

• Protocols are guided by the principles of • Replacement – methods to avoid using animals if possible• Refinement – enhance animal well-being and minimize

pain and distress• Reduction – obtaining sufficient information with minimal

numbers of animals

Human Subjects

• The Belmont Report (1979) – providing principles and guidelines for rules for the protection of human subjects -• 1. Respect for persons: protecting the autonomy of all

people and treating them with courtesy and respect and allowing for informed consent. Researchers must be truthful and conduct no deception.

• 2. Beneficence: The philosophy of "Do no harm" while maximizing benefits for the research project and minimizing risks to the research subjects.

• 3. Justice: ensuring reasonable, non-exploitative, and well-considered procedures are administered fairly —the fair distribution of costs and benefits to potentialresearch participants — and equally.

Conflicts of Interest

• Based on the notion that objective research may be undermined in situations where the researcher also has a financial interest in the outcome of the research• Guideline: ~$10,000 in income or equity interest valued

at $10,000 or more• Management position (e.g., in a company), ownership

of intellectual property• Includes similar guidelines for spouse or dependent

children

• Such financial interests are not banned; rather, they must be disclosed, on the principle that full disclosure and transparency is sufficient protection against bias

The University/Institution and Responsible Scientific Conduct

• Faculty in the University are expected to perform Research and Creative Work as part of “The Call”; similar expectations are true in clinical appointments

• The University provides a place where scientific research can be performed

• Granting agencies award the funds to the University not the Principal Investigator

So• The University is responsible for insuring the responsible

conduct of science, including identifying conflicts of interest and investigating allegations of misconduct

Anybody with a UCR SOM appointment is covered by this

Investigating Scientific Misconduct

• Investigations are initiated when allegations are made to an appropriate office• Allegations of misconduct can include plagiarism,

fraud, misuse of funds, etc.• Allegations can come to the University Office of

Research Integrity or the funding agency (NIH Office of Research Integrity, NSF, etc.)

• On campus, the Vice Chancellor for Research is responsible for investigating allegations• A panel is enlisted, including expert consultants• Data notebooks and computers may be impounded

as evidence for the investigation• Testimony is taken from the Investigator and other

witnesses• The outcome of investigations is reported to the

University and relevant funding agency

Investigating Scientific Misconduct

• Protections?• In principle, “whistleblowers” are anonymous and also

protected from retaliation• Frivolous allegations can be dismissed

• However, • Investigators under investigation are not explicitly given

right to counsel• No guarantee of timely handling (due process)• Expert consultants and review panels are chosen without

input from the accused• No right to confront the accuser• Malicious unfounded allegations are not punished

• Findings of misconduct can result in disqualification from receiving research funds

Responsible Scientific Conduct (reprise)

• Given our cultural expectations and conventional rules of behavior, responsible conduct is viewed to be violated when:

• False hypotheses are posed• Experimental conventions are ignored• Ad hoc methods of analysis are applied• Poor scholarship overlooks prior work• Data is not faithfully documented

• Some of these violations may be the result of laziness or poor training; the level of the offense rises when violations are intentional

Can “Misconduct” Be Accidental?

• Not a philosophical question; • Sloppiness may be poor science even if not

intentional misconduct, and it can still lead to allegations of fraud

• Poor practice (methods, analysis, interpretation, reporting) is certainly poor science, but is the researcher’s obligation sufficient to consider this misconduct?

Conclusions

• Research is done in part because of natural human curiosity but also because of a desire to improve our conditions, such as in clinical practice (“The Standard of Practice”)

• Professional attitudes are just as important in research as it is in clinical practice

• Research misconduct can be the product of misguided or perverse incentives

• Regulatory systems are in place to protect the researchers as well as research subjects