Ethics

A. As a Statistician / Statistical Consultant B. Human Subjects Research Protections

Statistical Ethics

• Professional conduct of statistical analyses essential to society

• Use statistics in – Medical diagnoses / biomedical research– Environment / Agriculture– Economy / market research / quality control– Government policy decisions– Scientific and engineering research

Statistical Ethics

• Ethical issues may arise in research from: – deliberate fraudulent behavior

• Collection of data• Recording of data

– use of incorrect procedures– omitting data which do not support a

researcher’s ideas – misuse of statistics in the analysis and

interpretation phase

Statistical Ethics

• American Statistical Association has Ethical Guidelines for Statistical Practice– ASA Committee on Professional Ethics

• Applies to all– Statisticians (and/or those doing the analyses)– Researchers / Funders / Employers– Interested audience

• Not followed in practice due to conflict of interest / poor science / lack of knowledge

Statistical Ethics

• Statistical ethics and statistical validity are highly interdependent

• Poor use of statistics and the increased availability of information creating “hard-nosed” skeptics and “lazy” practitioners

• Guidelines focus on 8 topic areas– Professionalism– Responsibility to funders / employers– Responsibilities in publications and testimony

Professionalism

• Strive for practical significance, not just statistical significance

• Competent understanding of subject matters and software

• Disclose conflicts of interest and resolve them

• Use statistical methodologies suitable to the data

Responsibility to Funders

• Apply statistical sampling and analysis procedures objectively

• Explain potential biases created by altering the sampling /design plan

• Clarify respective roles in studies

• Where appropriate present Funders choices of statistical approaches that vary in cost, precision, scope

Responsibilities to Publications

• Maintain personal responsibility for all work bearing one’s name

• Report statistical and substantive assumptions made in a study

• Report the sources of information and if possible share the data

• Fully report statistical methods used

• Report limits of inference

Statistics and Ethics

• Hypothesis testing and statistical significance– Role of the null and alternative hypotheses– Interpretation of a P-value

• Basic and Applied Social Psychology (BASP) will no longer publish papers containing P values

• http://www.nature.com/news/scientific-method-statistical-errors-1.14700

Statistics and Ethics

• The nature of the conclusion and its scope

• Properties of procedures (long-run behavior) described in terms of a single use

• Not rejecting the null versus a test of bioequvalence

Multiplicity

• What happens when we have many outcomes and do many tests?

• Some technical adjustments are possible, e.g. multiple comparisons procedures

Other issues

• Outliers

• Other rules for excluding data

• “Intent to treat” and LOCF

• Transformations

• Data mining

Some principles

• Transparency– Free from pretense of deceit, readily

understood– Often applied to decision making– It can be applied to the use of statistics

• Issues related to selective reporting– Analyses to understand the data– Analyses to present the findings

Roles of statisticians

Old• I teach formulas and

procedures• I consult• I calculate power• I analyze data• I do tables, not words

New• My students learn to

use concepts• I collaborate• I plan studies• I draw conclusions• I do words and tables

Ethics implications

• In the old scenario, my ethical responsibility is to do good statistics

• In the new scenario, my ethical responsibility is much greater as I’m a leader on the research team

History of Human Subject Research

• First documented trials in 1700’s– Vaccination trials– Researchers and family members as subjects

• Generally, human subject studies carefully scrutinized– Consent of subject key– Generally high regard for medical profession

Nuremberg Code

• After war, 23 Nazi doctors and scientists put on trial – Used concentration camp inmates as subjects– Study commonly led to the death of subject

• As part of sentences, 10 points describing required elements for research with humans

Nuremberg Code

• Informed consent in essential

• Prior animal work is essential

• Risks should be justified by anticipated benefits

• Only qualified scientists conduct research

• Physical/mental suffering be avoided

• Research in which death or severe injury likely should not be performed

Benefits vs Risks

• Benefits: positive value of advantage of being in study– Could be direct effect to individual– Could be more of a societal benefit

• Risks: outcomes that potentially harm the subject– Must assess magnitude and probability– Easy to quantify physical risk– Harder to assess social, legal, financial, psychological

Declaration of Helsinki

• Nuremberg code: Limited effect in US– Medical profession already “knew better”– No real law enacted

• World Medical Association developed code of research ethics (1964)– Focused more on research with therapeutic

intent– Journal editors required this code be followed– Birth of institutional review boards (IRBs)

Beecher Article

• Was an anesthesiologist

• Wrote article in 1966 (NEJM)

• Described 22 examples of studies with controversial ethics

• Heightened awareness of researchers, public, and press to the problem of unethical research ethics

• Possible to happen anywhere

Beecher Article

• Problems– Lack of informed consent / withholding info– Coersion/undue pressure on volunteers– Use/exploitation of vulnerable population– Withholding available treatments– Deception– Risks outweigh benefits

Willowbrook Hepatitis Study

• 1956 study to determine – natural history of viral hepatitis– Inoculation against hepatitis

• Children at institution for mentally retarded deliberately infected with mild form of hepatitis– Lack of full disclosure of risks– Possible coersion – Use of vulnerable population

San Antonio Contraception Study

• 1971 study to determine side effects of an oral contraceptive – Crossover design with half the women getting

oral contraceptive and half getting placebo

• Problems– Informed consent – weren’t told this would

happen– Risks outweigh benefits– Vulnerable group

Tuskegee Syphilis Study

• Public Health Service study (1932-1971)• Study to document natural history of

syphilis in African-American men– Initially enrolled men with and without syphilis– Men were denied antibiotics (1940 penicillin)

• Problems– Lack of informed consent– Deception– Withholding available treatment

Government Involvement

• Syphilis study resulted in Congress getting involved

• Recommended federal regulations be put into place

• 1974 National Commission put into place and asked to identify basic ethical principles of human subject research and develop guidelines

• 1979: Published Belmont Report

Belmont Report

• Required reading for anyone involved in human subject research

• Identified three basic principles– Respect for persons– Beneficence– Justice

• Each should have equal moral force when determining merits of research

Respect for Persons

• Treat individuals as autonomous human beings– Let them choose for themselves

• Provide extra protection for those with limited autonomy– Limited mental capacity– Lack of freedom or influence of others

• Informed Consent / Respect of Privacy

Beneficence

• Minimize harms and maximize benefits– Best possible research design to maximize

benefits / minimize harms– Need favorable risk-benefit ratio– Capable researchers to perform procedures

Justice

• Treat people fairly and design studies so the burdens and benefits are shared equitably– Subject selection– Avoid exploitation of vulnerable populations

More Recent Events

• 1996- Death of Normal Volunteer – Underwent bronchonsopy– Was difficult procedure requiring numerous doses of

lidocaine– Subject “nodded” yes when asked to continue– Later had cardiac arrest due to overdose of lidocaine

• Issues– Doses / limit of lidocaine not in protocol– Subject not observed after procedure– Complete autonomy?

More Recent Events

• 1999: Death in Gene Therapy Trial– 18-year-old James Gelsinger died during a

gene-therapy study to treat enzyme disorders

• Issues– Conflict of interest

• Researcher James Wilson held a 30-percent equity stake in the company that owned the rights to license the drug that Wilson was testing.

– Data safety monitoring incomplete– Informed consent

More Recent Events

• 2001: At Johns Hopkins, Ellen Roche, an otherwise healthy woman, died of respiratory failure after breathing in a chemical that was designed to help scientists study the effects of asthma.

• Later, investigators uncovered evidence that the chemical could be unsafe, evidence the researcher had not found in his literature search. Moreover, the consent forms signed by Roche and other patients made the chemical seem like a benign and federally approved product.

• After a man died during a gene-therapy experiment at the St. Elizabeth Medical Center in Boston in 2001, his family filed a wrongful-death suit, alleging that the man would never have entered the experiment had he been told about the 20 percent financial interest that the researcher and hospital had in the product being tested.

More Recent Events

Fake TV show

• 2010 French psychological experiment staged as game show

• How far will people go in obeying authority– Does TV reinforce this authority

• Participants asked to shock man in booth if question answered incorrectly

• 60% of the participants obeyed orders until the end even with man screaming in pain

Indian Tribe’s Genetic Info

• 2010 - Havasupai Indians issued a “banishment order” to keep Arizona State University employees away

• Had provided DNA samples to ASU for study of diabetes

• Samples had been used to study other illnesses without their knowledge

• Were participants fully informed?

Data Safety and Monitoring Board• DSMB monitors patient safety and evaluates the efficacy

of the intervention • Initial responsibility is to approve the initiation of a clinical

trial• After approval, and at periodic intervals during the course

of the trial, the DSMB responsibilities are to: – review the research protocol, informed consent documents and

plans for data safety and monitoring; – evaluate the progress of the trial, including periodic assessments

of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of the trial site, and other factors that can affect study outcome;

– if appropriate, conduct interim analysis of efficacy in accordance with stopping rules which are clearly defined in advance of data analysis;

– Consider factors external to the study when relevant info becomes available, such as scientific or therapeutic developments that may have an impact on the safety of the participants or the ethics of the trial;

What is an IRB?

• Committee of at least 5 members – Varied professions / expertise– Obtain special competencies from outside

consultants– Sensitive to community attitudes– Sensitive to vulnerable populations

• Trained in institutional regulations, standards of professional conduct

What Does an IRB do?

• Approve, disapprove, or modify current human subjects research

• Conduct continuing reviews

• Observe, monitor, audit

• Suspend or terminate approval

• What constitutes human subjects research?

Definitions

• Human Subject– Living individual about whom and investigator

conducting research obtains• Data through intervention or interaction with an

individual• Identifiable private information

• Research– A systematic investigation designed to

develop or contribute to generalizable knowledge

Criteria for Approval45 CFR 46.111

• Minimizes the risks

• Has reasonable risk/benefit ratio

• Equitable subject selection

• Vulnerable populations addressed

• Informed consent process / documentation

• Confidentiality / privacy maintained

• Data monitored for safety

Level of Review

• 1. Exempt– Low-risk research (as defined by Federal criteria)

• Fits one of 6 categories

– Involves only non-vulnerable population– Does not involve “sensitive” issues– No permanent record of individual

• Does not have to initially be anonymous• Destroy links once data obtained and processed

Six Categories

• Typical education practices • Educational tests, survey procedures, interview

procedures, or observation of public behavior, unless:– human subjects can be identified directly (or linked) and information is sensitive

• Existing data if publicly available or unidentifiable

• Research with public officials or candidates• Evaluation of public or service programs• Taste and food quality evaluations, consumer

acceptance

Level of Review

• 2. Expedited – Meets criteria for minimal risk– Involves activities in one of nine categories– Non-vulnerable populations– Non-sensitive issues

• Minimal risk : No substantive increase beyond risks of ordinary life – IRB needs to be very careful to consider all potential risks

Expedited Review

• Reviewed at same rigor as Full but with a limited number of reviewers– Must go to full review if research to be

disapproved

• Selected categories– Focus groups, collected data not for research

purposes, blood samples, voice or video data, noninvasive collection of biological samples

Level of Review

• Full– Research greater than minimal risk– Research involving vulnerable populations– Sensitive topics (will vary by community)

– All IRB members review protocol

Study #1

• Want to determine prevalence of illicit drug use in pregnant women– Subjects will be from 10 rural and 10 hospitals

in Arizona– Collect urine drug screening , demographics

• Subject identifiers will be stripped

• Waiver of consent is requested

Study #2

• Want to determine prevalence of illicit drug use in a high school– Subjects 16-18 from one urban school– Will screen existing urine samples from previous

protein study– Samples will be stripped of identifiers

– Researchers claim this is exempt research

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

Study #3

• Find risk factors for pancreatic cancer– Registry will be established involving 20 major

health centers– Patients will provide extensive health history

information– Asked to provide health information on family

members (1st and 2nd order relatives)

– Are the family members also research subjects?