1URI

Protection of Human Research Participants

The Research OfficeDivision of

ComplianceFor Information call: 874 -4328

5URI

Infamous Cases: Ethical Violations in Research Involving Humans

Nazi War Crimes of aMedical Nature

The Tuskegee Syphilis Study

The Milgram Study

Death of Jesse Gelsinger ( U Penn- Gene Therapy Research )

The Willowbrook Studies

6URI

INFAMOUS CASES: NAZI WAR CRIMES

In order to ensure the supremacy of the Aryan race, the Nazi Party in Germany desired to find a secret way of sterilizing large populations. Three experiments involving sterilization were in progress when World War II ended in 1945.

• Dried plant juice was put into flour that was fed to the general population. This was supposed to sterilize women predominantly.

• Intra-uterine injections of a silver nitrate solution were given to women, without their consent, during routine physical examinations.

• Men stood at a counter to complete forms while being exposed, without their knowledge, to sterilizing doses of X-radiation.

7URI

NAZI WAR CRIMES

In addition to sterilization experiments, Nazi physician researchers were under great pressure to develop an effective vaccine for typhus fever to administer to German troops.

At Buchenwald concentration camp, experiments were conducted in which prisoners were administered vaccine (or placebo) and then injected with blood from patients with typhus fever.

Between 1942 and 1943, about 729 people were subjected to such experiments and 154 died. In addition, other prisoners served as a “passage group.” In order to keep the virus alive and virulent, the researchers would inject the virus into prisoners. When these people developed the acute illness, their blood was removed and injected into other prisoners.

8URI

NAZI WAR CRIMES

The horrors of the preceding and many other “experiments,” were exposed during and after World War II. The people who conducted these experiments were tried separately from other Nazi war criminals because of their professional status as physicians and the atrocious nature of their crimes.

During the trial at Nuremberg, fundamental ethical principles for the conduct of research involving humans were codified in the Nuremberg Code which sets forth ten conditions that must be met before research involving humans is ethically permissible (e.g., the need for voluntary informed consent of subjects, a scientifically valid research design that could produce fruitful results for the good of society).

9URI

NAZI WAR CRIMES

The Nuremberg Code became the first international standard for the conduct of research. It was followed by the Declaration of Helsinki in 1964 which further defined ethical principles.

To date little use has been made of the data generated from the Nazi experiments. There is ongoing discussion in scientific and ethics communities concerning whether it is ethically permissible to use or publish the data.

10URI

INFAMOUS CASES: THE TUSKEGEE SYPHILIS STUDY

• This study was conducted in the United States and was designed to determine the natural history of untreated latent syphilis.

Over 400 black men with syphilis and about 200 men without syphilis, who served as the controls, were the subjects. The men were recruited without informed consent. In fact, they were misinformed and told that some of the procedures done in the interests of research (e.g., spinal taps) were actually “special free treatments.”

By 1936, it was apparent that many more infected men than controls had developed complications.

Ten years later a report of the study indicated that the death rate among those with syphilis was about twice as high as it was among the controls.

11URI

TUSKEGEE SYPHILIS STUDY

In the 1940’s, when penicillin, known to be effective in the treatment of syphilis, became available, the men were neither informed of this, nor treated with the antibiotic.

The study continued until the first accounts of it appeared in the national press in 1972, at which time an ad hoc advisory panel was formed by the government to give advice on how to assure that such experiments would never again be conducted.

The government continues to pay millions of dollars yearly to surviving subjects and the families of deceased subjects. In 1997 President Clinton apologized to study subjects and their families and called for renewed emphasis on research ethics.

12URI

INFAMOUS CASES: THE MILGRAM STUDY (1963)

Stanley Milgram, Social Psychologist, Yale University

Conducted a study on conflict between obedience to authority and personal conscience.

Research participants were “teachers” asked to deliver electric shock of increasing intensity to “learners” when “learners” gave wrong answers.

“Teachers” were not aware that “learners” were acting.

13URI

The Milgram Study

60% of “teachers” continued to deliver shocks up to 600v while investigators urged them on. All participants continued to at least 300v.

Following this deceptive research, participants were debriefed. Many of the “teachers” explained that they were following orders. (Justification for the Nazi war crimes?)

Ethical Question: Does a researcher have the privilege of exposing a participant to such stress? What is the cost to the research subject?

14URI

INFAMOUS CASES: JESSE GELSINGER-RESEARCH SUBJECT

Jesse was born with a genetic liver disorder– Symptoms were controlled with drugs and a strict

diet before he volunteered. Summer 1999- Jesse volunteered for research

to test the safety of the experimental procedures.

September 1999-Jesse died. Apparently killed by the experimental treatment– Trial was FDA approved– Parents were misled as to the risks

15URI

INFAMOUS CASES: THE WILLOWBROOK STUDY

From 1963 through 1966 studies were carried out at the Willowbrook State School, a New York State institution for “mentally defective persons.”

These studies were designed to gain an understanding of the natural history of infectious hepatitis and subsequently to test the effects of gamma globulin in preventing or ameliorating the disease.

The subjects, all children, were deliberately infected with the hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus preparations.

16URI

THE WILLOWBROOK STUDY

Investigators defended the deliberate injection of these children by pointing out that the vast majority of them acquired the infection anyway while at Willowbrook, and perhaps it would be better for them to be infected under carefully controlled research conditions.

During the course of these studies, Willowbrook closed its doors to new inmates, claiming overcrowded conditions.

17URI

THE WILLOWBROOK STUDY

However, the hepatitis program, because it occupied its own space at the institution, was able to continue to admit new patients. Thus, in some cases, parents found that they were unable to admit their child to Willowbrook unless they agreed to his or her participation in the studies.

This case caused public outcry because of the perception that parents and their children were given little choice about whether to participate in research.

22URI

Institutional ResponsibilitiesMechanisms for the protection of human subjects in research are established by the Code of Federal Regulations 45CFR46 (“The Common Rule”). Please Review the web site of the Department of Health and Human Services, Office of Human Research Protection (OHRP):

http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm

Federal regulations require:

1. Review of research by an Institutional Review Board (IRB)

2. Informed consent of subjects

3. Institutional Assurances of compliance (FWA Policy)

4. Institutional Policy on Scientific Misconduct(See the Research Office web site for a copy of URI Scientific Misconduct Policy).

23URI

Institutional Responsibilities Cont.

Federalwide Assurance (FWA) of Compliance with DHHS Regulations for Protection of Human Research Subjects requires:

That the University of Rhode Island follow federal regulations for all federally sponsored research and all other human subject research regardless of sponsorship.

What is research?When is a human subject involved?

24URI

Research:“...a systematic investigation,

including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge…”

25URI

A Human Subject Is...

“…a living individual about whom an investigator…conducting research obtains:

data through interaction or intervention (e.g., interviews, surveys)

identifiable private information (e.g., medical records, blood or other body tissues)…

26URI

Students as Research Subjects:

University Policy– Investigators may not require students to

participate in research activities as research subjects. Any classroom activity involving research must provide an alternative activity and it must be approved by the URI IRB.

– With appropriate IRB approval an Investigator may ask students to volunteer to participate in a research project.

27URI

Students as Research Subjects, cont.

– Students asked to participate in research projects must be provided with all information necessary to make an informed decision about whether or not to participate.

All elements of the Code of Federal Regulations concerning informed consent must be met.

28URI

Investigator Responsibilities (PI)

• Make initial determination of research with human subjects & need for IRB review

• Submit protocol to IRB for review

• Conduct research after IRB approval

29URI

• Keep IRB informed of protocol changes

• Request protocol continuation or termination

• Store research records (all primary data including informed consent) in a secure place for 3 years following project completion

30URI

“A group of at least five individuals with varying backgrounds to promote complete & adequate review of research studies. An IRB conducts the initial & continuing reviews of a research study”

Source: 45CFR46.107

Institutional Review Boards (IRBs)

31URI

IRB

• Members & chair appointed by the Provost of the University

• for 2-3 year renewable terms

32URI

IRB Composition

Chair At least 5 members to include…

at least one nonscientist

at least one female

one person not affiliated with URI

Vice Provost for Research or designee

minority representation appropriate to study

Representation of major scientific disciplines

35URI

New Protocol Submissions

All research studies, including pilot studies, involving URI investigators and recruiting human subject participants , must be reviewed and approved by the IRB before they begin

To ensure effective review by the IRB, the board must be provided with certain critical information such as: protocol design, consent form(s), recruiting materials, and samples of surveys.

36URI

Protocol Amendments

Changes to an IRB-approved protocol, consent form or other study document must be submitted to the IRB. If changes present no additional risks, review/approval are expedited by the Chair of the IRB.

37URI

Protocol Monitoring

Ongoing research must have IRB review at least annually until human subject enrollment, and intervention is complete. If data contains private identifiable information study will be monitored until data analysis is complete.

Approval is valid for no more than one year from anniversary date of initial IRB review.

39URI

Types of Review

At the University of Rhode Island all research involving human subjects is reviewed by the Office of Compliance and assigned a review category.– Exempt review– Expedited review– Full board review

40URI

Exempt Research

Determined by IRB Chair and the Director of Compliance

Examples of research that is in the exempt category: 1. Research conducted in educational settings on the effectiveness of or

the comparison among instructional techniques, curricula. etc., for program development.

2. Use of educational tests, or surveys when the information is collected in such a way that the human subjects cannot be identified and no risk is placed on same.

41URI

4. Study of existing data/records if publicly available and/or subjects can’t be identified.

5. Research or action projects designed to study or evaluate public benefit or service programs (programs under the Social Security Act).

6. Taste & food quality evaluations.

Source: 45CFR46.101(b)(1-6)

3. Use of educational tests, or surveys not exempt under #2 may be exempt if subjects are elected or appointed officials or if information collected is absolutely confidential by Federal Statute.

44URI

Criteria for IRB Approval of Research

Are the risks to human subjects minimized?

Do potential benefits or knowledge gain warrant the risk to human subjects?

Is selection of human subjects equitable?•Is informed consent sought and documented?

•Are adequate provisions in place to protect privacy & confidentiality?

46URI

Minimal risk:

Social and behavioral research that utilizes survey or interviewing practices could present risks.Sensitive nature of questions being

askedQuestions that illicit disclosure of illegal

behavior

47URI

Equitable Selection

The IRB will review how subjects will be recruited - inclusion & exclusion criteria

48URI

Equitable Selection

The IRB will consider the purpose of the research and the setting in which it will be conducted.

The IRB will consider whether vulnerable populations will be involved. These include children, prisoners, pregnant women, mentally disabled persons, & economically or educationally disadvantaged persons.

49URI

Vulnerable Populations

Pregnant Women, human fetuses and neonates (45CFR46, Subpart B)

Prisoners (45CFR46, Subpart C) Children (45CFR46, Subpart D) Handicapped/mentally disabled Economically/educationally

disadvantaged

Source: 45CFR46.111(b)

52URI

Research Involving Children

“…persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable laws of the jurisdiction (i.e., state law for age of majority for RESEARCH) in which the research will be conducted.”

In RI the age of consent is 18.Source: 45CFR46.402(a)

53URI

Research Involving Children (cont…)

Assent:“…a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.”

Source: 45CFR46.402(b)

54URI

Informed Consent(definition)

…the right of an individual who participates in research to choose what shall or shall not happen to him or her…

55URI

Informed Consent Process

Three conditions required:

1. Full disclosure of research risks and benefits giving subject sufficient opportunity to decide whether or not to participate.2. Informed consent must be in language understandable to the subject and include no exculpatory clauses.

3. Subjects must understand that participation is voluntary.

Source: Belmont Report

60URI

Privacy and Confidentiality

Research is anonymous if there is no link back to the subject by the data he/she has provided. Example: surveys collected without names or other identifiable information, tissues with identifiers removed

If there is a link from data to subject:The researcher is responsible for assuring theprivacy and confidentiality of the subject by protecting the data from inappropriate use.

61URI

Ways for PI’s to assure privacy and confidentiality

• remove identifiers

• separate files for data & identifiers

• Certificates of Confidentiality (Call 874-4328 for more information.)

• locked files, computer passwords, etc.

62URI

Women and Minorities

The IRB must ensure that women & racial & ethnic minorities are appropriately represented in research. If not, justification is needed that inclusion is inappropriate or clearly not feasible.

Also, women of childbearing potential should not be routinely/arbitrarily excluded.

63URI

Research involving Non-English Speakers

Written consent... Must be in understandable language or a

translator must be provided.Investigator must provide credentials of

translatorsOral consent includes … a short written consent summary of oral presentation witnessed (Person fluent in language of participants &

English )

provide copies of consent & protocol in understandable language to subject.

65URI

IRB Actions

Approve Approval Pending (after satisfactory

response to IRB Action Report the IRB empowers the Chair to approve)

Defer (to subcommittee) Table Disapprove

66URI

Report of Adverse Events

Serious events are to be reported immediately to the IRB; other events should be reported in a timely fashion but not later than renewal or termination dates.

Report should include… statement of the event impact on subjects corrective action(s)

68URI

Examples 0f Noncompliance by Investigator

Failure to report adverse events or changes to protocol

Failure to use Informed Consent process Failure to submit timely continuing

review materials Failure to comply with IRB requests Breach of confidentiality

69URI

Suspensions/Terminations

The IRB is authorized to suspend or terminate approved research that is not being conducted in accordance with federal and University policy.