Transcript Ethics Human Subjects Research

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 “hardnosed” 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-methodstatistical-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
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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
New
• I teach formulas and
procedures
• I consult
• I calculate power
• I analyze data
• I do tables, not words
• 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.
More Recent Events
• After a man died during a gene-therapy
experiment at the St. Elizabeth Medical Center
in Boston in 2001, his family filed a wrongfuldeath 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.
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 Approval
45 CFR 46.111
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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
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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?