the ethical conduct of research with humans human subjects division box 355752 3935 university way,...

The Ethical Conduct of Research with Humans

Human Subjects DivisionBox 355752

3935 University Way, NESeattle, WA 98105-6613

(206) 543-0098 (T)(206) 685-9502 (F)

http://depts.washington.edu/hsd

Why do human subjects need protections?

Tuskeegee Syphilis Trial harm to individuals: withholding treatment,

deception harm to groups: loss of community trust

Nazi era experiments hypothermia studies: are data collected under

unethical conditions invalid data? starvation disease study: importance of

considering intent and relationship between researcher and researched in evaluating ethics

Why do human subjects need protections?

T-Room Trade Study withholding information from subjects lack of informed consent lack of confidentiality

Hide the Cat study research with minors held to a higher standard

Milgrom’s Obedience to Authority Study inflicted insight unanticipated adverse events

Why do human subjects need protections?

Randomized face lift study research without regulatory oversight

Gene transfer study at U. Penn. use of approved consent procedures importance of reporting adverse events conflict of interest

VCU twin study who’s a study subject?

What protections are in place? Nuremberg Code: non-treatment experiments Helsinki Convention: WMA Health and Human Services: 45 CFR 46 U.S. Food and Drug Administration: 21 CFR 50, 56 Sponsor policies: NIH, etc. State law: medical records, genetic privacy, consent,

tissue from autopsy Institutional policy (UW, VA, etc.) Institutional Review Boards (IRBs) / Human

Subjects Review Committees (HSRCs)

What are my responsibilities as a researcher?

Recognize what activities constitute research with human subjects and obtain appropriate IRB review and approval

Research = A systematic investigation designed to develop or contribute to generalizable knowledge. (45 CFR 46.102 (d)) -- distinct from “practice”

Human Subject = A living individual about whom an investigator… conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information. (45 CFR 46.102(f))

Design research in accord with the ethical principles.

What are the ethical principles on which the regulations and codes are based?

Respect (autonomy of subjects)

Beneficence (benefits outweigh risks)

Justice (selection of subjects is equitable)

The principle of respect Humans should be treated as autonomous agents Those with diminished autonomy are entitled to

protection Implementation of principle is informed consent There is a continuum from prospective explicit

informed consent to complete waiver of consent Issues:

assessing autonomy/competence assessing comprehension protecting vulnerable subjects/populations trust and sharing of authority

Implementing the principle of respect: informed consent

Consent is a continuous process, not a one-time event based on face-to-face conversation requires continuing reiteration

when initial consent obtained under stressduring longitudinal studies

A document evidentiary, but not a legal contract useful information for subjects

names and contact informationreminder about study procedures

Informed Consent Content of consent process based on requirements

stated in the Belmont Report information comprehension voluntariness

“While the importance of informed consent is unquestioned, controversy prevails over the nature and possibility of an informed consent.”

Types of informed consent

• Written consent/assent* forms

• Oral consent/assent

• Proxy consent/assent

• Waiver of consent/assent

*Minors younger than 18 years of age and adults not mentally competent to provide legally effective consent must provide “assent.”

Informed Consent: Basic Rules Short words Short sentences Large type font, wide margins Avoid technical language or jargon Avoid passive tense Do not use first person voice Do not include exculpatory language Use language of subject population

Informed Consent: Basic Rules Use written text or narrative approved by IRB Form must be signed and dated by subject or

legally authorized representative PI or designee administering consent must sign

and date Give copy to subject/ representative Place in medical record if study is relevant to

clinical care

Exceptions to (written) documentation of consent

The consent form is the only record linking subject and research / poses risk, OR

Study risks of harm are no more than minimal

Study involves procedures for which consent is not normally required

Subjects should be provided with documentation if they want to have it

Privacy and Confidentiality

Culture-sensitive; valued highly in U.S. society

Approach issues Use intermediaries Create recruitment method through which

subjects contact researcher Using records to screen prospective subjects

Privacy and Confidentiality Do anonymous research whenever possible Code data with a unique study code (self-

generated?) Destroy identifiers as soon as possible Protect data: removable hard drive; master

list linking code to names stored securely, separately

Protect phone lines, privacy of interview, phone calls, letters that don't refer to study topic, good building security, etc.

Vulnerable Subjects Minors, students Prisoners Pregnant women Fetuses Cognitively impaired Educationally and economically disadvantaged People with acute and chronic diseases or

conditions

What are the ethical principles on which the regulations and codes are based?

Respect (autonomy of subjects)

Beneficence (benefits outweigh risks)

Justice (selection of subjects is equitable)

Beneficence Probability of benefits must outweigh risks of

harm clinical equipoise

Study must maximize benefits and minimize risks of harm good study design, sample size competent researchers

Benefits to society vs. risks of harm to individuals: apples and oranges individual subjects rarely benefit society must place value on research

Beneficence Benefits: neither over- nor under-state Types of benefits:

direct collateral aspirational

Dimensions of benefits: nature magnitude (size and duration) likelihood

Risks of harm Harms are not just physiological

Psycho-social: depression, emotional distress, personal relationships

Socio-economic: stigmatization, loss of insurance, employment, benefit program, housing, economic support

Harms are variable by age, gender, ethnicity, and environment

Harms can result to groups as well as individuals

Researcher Responsibilities

Design research in accord with ethical principles

Respect (autonomy of subjects)

Beneficence (benefits outweigh risks)

Justice (selection of subjects is equitable)

What are the ethical principles on which the regulations and codes are based?

Respect (autonomy of subjects)

Beneficence (benefits outweigh risks)

Justice (selection of subjects is equitable)

Justice/Equitability Assure that results of the study will benefit

the community Avoid exploitation of populations of

convenience Include all affected populations Consider factors like gender, age, ethnicity Consider issues of access:

transportation childcare compensation

Compliance Know the categories of research

“exempt” (no risk)reviewed by Departmentuse “Certificate of Exemption” form

“expeditable” (minimal risk)reviewed by HSRC sub-committeeuse regular HSRC application form

full IRB review (more than minimal risk)reviewed by HSRC at convened meetinguse HSRC application form

Full Review

More than minimal risk Involves investigational drug, device,

surgical intervention Involves experimental psycho-social,

educational, or organizational intervention Involves vulnerable population

No No

Yes

Yes YesNo

Human SubjectsReview Committeereviews, assigns #

Human SubjectsReview Sub-committeereviews;assigns #,reports to full Committee

Department reviews;HSD doesadministrative check;assigns #

ResearchProposal

RiskLevel?

No Risk(“Exempt”)

Certification of Exemption

Minimal Risk(“Expedited”)

HSRC application form

More than minimal risk(“Full Committee”)

HSRC application form

Approves? Approves? Approves?

Approved forno more than

one year

Approved forfive years

Approvaldenied; appeal

possible

HSRC/IRB Review Risk of harm versus potential benefits of study

(includes evaluation of study design only when risk-benefit evaluation is problematic)

Protections of subject privacy and confidentiality (recruitment and data management)

Consent process

Researcher Responsibilities Prepare applications in lay language

(Scientific American) Answer ALL questions -- use “does not

apply” if appropriate In studies of therapeutic or diagnostic

interventions, identify what is experimental and what isn’t

Do not conduct research until final IRB approval

Researcher Responsibilities Assure that non-UW sites obtain IRB

approval Obtain IRB approval for changes before

implementation except to prevent immediate harm to subjects

Apply for continuing review and approval well before current approval period expires

Do not conduct research if approval lapses Report problems promptly

Reporting to IRB, Institution, Sponsor

Unanticipated adverse events or problems Adverse events that are more frequent or

serious than expected Protocol violations Subject complaints, withdrawals for cause Study closure

Researcher ResponsibilitiesDOCUMENT, DOCUMENT, DOCUMENT Research protocols Correspondence IRB application/approvals Continuing reviews Signed consent/assent forms Original data

“If it isn’t written down, we can’t determine if you did it.”

Hot Topics Research with human genetic materials

privacy and confidentiality what to do with test results?

Records-based research with consent without consent: Confidentiality Agreements

Registries, subject pools, and data banks require continuing HSRC approval require informed consent may include “layered” consent

Case studyYou ask a trainee who works in your lab and her husband, whom you ran into in the hall, to donate 10 cc of blood each for one of your established protocols. While enumerating the T cell subsets, you find very low values in the husband. This is worrisome as HIV can cause such low values.

Questions:

Do you tell him?

Do you tell his wife?

What should the consent form have said?

Case study

You have developed a new drug for malaria and wish to test it in humans. Since there are too few cases in the United States, you want to test it in Africa on a population at significant risk for malaria. Unfortunately, the drug is quite expensive to manufacture and you are unlikely to be able to make it available to the population of the country chosen for testing.

Questions:

Is it ethical to use this population when it will not likely be able to benefit from the research?

What will be the considerations regarding informed consent?

Should local standards, which may be lax or nonexistent, be used, or should the

researchers impose outside standards on the research?

Are there obligations of the research team toward the medical community in the country where the testing occurs?

Case StudyA researcher proposes to examine communication processing in aphasic patients. The study would involve three separate sessions, in which patients (or age matched controls recruited from local nursing homes) take a battery of word and sound association tests. The total time involved will be 3-5 hrs. The inclusion criteria for the protocol means that only a few patients (<15) will be available for the study.

Questions:

Will the number of research and control subjects in the study allow the investigators to make meaningful statistical comparisons between the groups?

Is it reasonable to study whatever patients the investigator can recruit, regardless of considerations of statistical validity?

Does this study pose more than minimal risks or harm to the subjects, and, if not, does that make a difference in determining whether or not this study should be conducted?