USE OF HUMAN SUBJECTS IN RESEARCH Ruth A. Mulnard, RN, DNSc, FAAN Associate Professor, Nursing Science Vice Chair, Institutional Review Boards.

USE OF HUMAN SUBJECTS IN RESEARCH

Ruth A. Mulnard, RN, DNSc, FAANAssociate Professor, Nursing Science

Vice Chair, Institutional Review Boards

Definition of Research

Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge (45CFR 46.102).

Definition of Human Subject

Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains: (1) Data through intervention or

interaction with the individual, or(2) Identifiable private information.

Definition of INTERVENTION / INTERACTION Intervention includes both physical

procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.

Interaction includes communication or interpersonal contact between investigator and subject. What about web-based research?

Definition of PRIVATE INFORMATION Private information includes information about

behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.

How Are We Regulated?InternationalInternational– ICH GuidelinesICH GuidelinesFederalFederal– OHRP (Office for Human Research Protections) OHRP (Office for Human Research Protections)

has jurisdiction over Department of Health and has jurisdiction over Department of Health and Human Services (DHHS) via Human Services (DHHS) via 45CFR4645CFR46

– FDA (Food and Drug Administration) has FDA (Food and Drug Administration) has jurisdiction over all research involving food, jurisdiction over all research involving food, biologics, drugs and devices via biologics, drugs and devices via 21 CFR21 CFR

State of CaliforniaState of California– Department of Health Services (DHS)Department of Health Services (DHS)LocalLocal guidance and policy guidance and policy– UC Office of the President (UCOP)UC Office of the President (UCOP)– Institutional Review Board (IRB)Institutional Review Board (IRB)

Department of Health and Human Services (DHHS)

45CFR Part 46 “Common Rule” 45CFR Part 46 “Common Rule” (enforced by OHRP): (enforced by OHRP):

““The Common RuleThe Common Rule”: Federal Policy ”: Federal Policy for the Protection of Human for the Protection of Human Subjects Subjects – Subpart A: Basic HHS Policy (basic Subpart A: Basic HHS Policy (basic

human subjects, IRB regulations)human subjects, IRB regulations)– Subpart B: Pregnant women, Fetuses Subpart B: Pregnant women, Fetuses

and Neonatesand Neonates– Subpart C: PrisonersSubpart C: Prisoners– Subpart D: MinorsSubpart D: Minors

Food and Drug Administration (FDA)

21CFR Parts 50 and 56 (enforced by 21CFR Parts 50 and 56 (enforced by FDA)FDA)– IDE (Part 312) - Investigational New IDE (Part 312) - Investigational New

Device ExemptionDevice Exemption

– IND (Part 812) - Investigational New IND (Part 812) - Investigational New Drugs/ BiologicsDrugs/ Biologics

State of California - CA Health and Safety Code: Section 24170-24179.5

Protection of Human Subjects in Protection of Human Subjects in Medical Experimentation ActMedical Experimentation Act

Requires "experimental subject's bill Requires "experimental subject's bill of rights" of rights"

Last page of the ICFLast page of the ICF

Defines Legally Authorized Defines Legally Authorized Representative (use of surrogate)Representative (use of surrogate)

Specifies that children 7 years of age Specifies that children 7 years of age or older must or older must alsoalso consent to consent to research, not just their parent (LAR)research, not just their parent (LAR)

Key Events that Influenced Policy Development Nazi doctors trial 1946 The Tuskegee syphilis study 1932-

1972 Radiation exposure studies 1944-1974 Thalidomide tragedy (Kefauver

Amendment 1962) The Milgram obedience experiments

1972 U. Pennsylvania gene therapy 1999

The Tuskegee Study U.S. Public Health Service project 600 low-income African-American males, 400

of whom had syphilis infections, monitored for 40 years.

Free medical examinations were given but participants were not told about their disease.

When penicillin became available in the 1950s, the study continued and participants were denied treatment. In some cases, researchers intervened to prevent treatment by other physicians.

Many participants died of syphilis. The study was stopped in 1973 by the U.S. DHEW only after its existence was publicized.

The Development of Human Subjects Protection Policy

The Hippocratic Oath The Nuremburg Code of 1947 Declaration of Helsinki 1964 National Research Act of

1974 The Belmont Report of 1979

The Nuremburg Code

Informed consent without coercion Human experiments should be based on

animal experimentation Anticipated results should justify the

experiment Only qualified scientists should conduct

medical research Physical and mental suffering should be

avoided No expectation of death or disabling injury

Basic Ethical Principles

Respect for Persons Individuals should be treated as autonomous agents Individuals with diminished autonomy are entitled to

protections Beneficence

Do not harm Maximum possible benefits, and minimize potential

harms Justice

Fair distribution of burdens and benefits of research

Respect for Persons

Treat individuals as autonomous persons; allow individuals to choose for themselves

Persons with limited autonomy need additional protection, even to the point of excluding them from activities that may harm them. The extent of protection should depend upon the risk of harm, and the likelihood of benefit.

The judgment that any individual lacks autonomy should be periodically re-evaluated, and will vary across situations.

Respect for Persons: Autonomy

Subject must be capable of acting on personal goals

Investigator must respect the considered opinions of the subjects

Participation MUST be freely given. Cannot deny medical care for decision not to participate in research.

Respect for Persons: Protections Those not fully capable of self

determination must be protected, including: The very young, the cognitively

impaired, some physically incapacitated

Those who are subject to coercion staff and students of investigator prisoners

Respect for Persons: Available Protections

Exclusion from study Surrogate consent Assent of minors age 7 or older Prohibition on excessive

inducements for participation

Application of Respect for Persons

Informed Consent Process Information - Does the consent form provide all the

information necessary for the individual to make a reasoned decision?

Comprehension - Is the consent form crafted in language understandable to the potential participant?

Voluntariness - Does the consent form clearly indicate that participation in the research is voluntary?

What additional protections can be in place to protect those with limited autonomy?

How to determine whether one lacks the autonomy to make a reasoned decision? (per study assessment, not a blanket decision)

Beneficence

“First, do no harm.” Maximize possible benefits and

minimize possible harms. Risk-benefit analysis

Unavoidable risks Benefits may not accrue to research

subject

Beneficence

The IRB should determine whether the risks to subjects are reasonable in relation to anticipated benefits

Obligations of beneficence affect both the researcher and society – investigators are required to give forethought

on maximization of benefits and reduction of risk that may be involved in the research

society should recognize the longer term benefits and risk that may result from the improvement of knowledge, and from the development of novel medical, psychological, and social processes and procedures

Applications of Beneficence

Assessment of Risks and Benefits Risk refers to the probability of harm; when considering

risk, one should consider both the probability and the severity of the envisioned harm; while the term, benefit refers to something that promotes health, well-being, or welfare.

What are the risks of harm to the participants (consider physical, psychological, social, and economic harms)? Are the risks justified? Can they be minimized?

Can the research design be improved to minimize risk and maximize benefit?

What are the benefits (to the participant; to society)?

Justice

Treat people fairly

Do not exploit those who are readily available or malleable

Fair distribution of the risks and the benefits of research based upon the problem/issue under investigation

Applications of Justice

Selection of Subjects Is the potential subject pool appropriate for the

research?

Is it appropriate to involve vulnerable populations (e.g., economically disadvantaged; limited cognitive capacity) in the research or are they being enrolled because it is convenient or because they are easily manipulated as a result of their situation?

Are the recruitment procedures fair and impartial?

Are the inclusion and exclusion criteria fair and appropriate?

Implementation: Informed Consent Informed consent is a process, not a

piece of paper. Consent for all full committee

protocols must be written and for clinical studies must be witnessed.

Verbal consent (a waiver of documentation) may be possible for other kinds of research [using a study information sheet]

Consent form must be understandable to the subject and not excessively technical.

Informed Consent (con’t)

Consent must identify risks, benefits, and possible outcomes.

Consent must be obtained by an appropriate member of the investigative team.

The subject must have an opportunity to ask questions and raise concerns.

Financial interests must be disclosed.

Applications of the General Principles

Consideration of the three general principles in the conduct of research lead to the consideration of:

Informed Consent process

Risk/Benefits assessment

Selection of research participants

Implementation: The IRB (Institutional Review Board)

Delegated to institution Federal-Wide Assurance (FWA) in place with

OHRP Reports to VC for Research

UCI – 2 medical, 1 social-behavioral, 1 compliance, plus a separate biomedical team for all expedited studies

Medical committee composed of physicians, scientists, other medical personnel, pharmacists, community representatives.

Community member (non-scientific) must be present for IRB to proceed.

IRB Responsibilities

Safeguard rights, safety and well-being of all trial subjects (with special attention to vulnerable subjects)

Obtain the following documents: Trial protocol and all amendments Informed consent and any updates Subject recruitment procedures,

anything written to subjects Investigator’s Brochure and applicable

safety data Investigator’s qualifications

IRB Responsibilities

Review of the proposed research Approval / favorable opinion Minor changes required to make it

approvable Disapproval / negative opinion Termination / suspension of prior

approval Consider the qualifications of the

investigator to conduct the research

IRB Responsibilities

May request additional information not supplied by investigator and/or sponsor

Must conduct continuing review of protocol at least once a year (time interval should be appropriate to risk)

Review the amount and method of payment No coercion, pro-rated for partial completion

IRB Responsibilities Require that information given to subjects as

part of informed consent is in accordance with the regulations;

Require documentation of informed consent or may waive documentation in accordance with the regulations;

Notify investigators and the institution in writing of its decision to approve or disapprove proposed research or of modifications required to secure IRB approval of the research activity;

Authority of the IRB

Approve or disapprove research Suspend or terminate approval that is not

being done in accordance with IRB requirements, or that has resulted in unexpected harm to subjects

May observe or have a third party observe the consent process and the research

May apply sanctions to investigators No one can overturn IRB decision – not even

university administration

Boundaries between Practice and Research

The distinction between practice and research is blurred; often because they occur together.

The IRB must ensure that the researcher (and the participant) distinguishes practice from research in both social science and biomedical research

Minimize the potential for therapeutic misconception – when one believes the purpose of clinical research is to treat rather then to gain knowledge

Investigator Responsibilities

Obtain all required approvals prior to commencing the research (CRFA, DSMB, IRB, CTPRMC, ICTS)

Obtain informed consent of all human subjects or their legally authorized representatives (unless waived) and use only the currently approved, stamped consent form

Make no changes without prior review and approval by the IRB

Obtain re-review at least every 365 days

Full Committee Review

Full Committee Research Most common level of review Requires full committee vote (majority

decides) 2 reviewers plus staff are assigned to

review Scientific review - IRB reviews the

science as it relates to risk/benefit ratio

Other Levels of Review

Expedited No greater than minimal risk (e.g. blood

samples from healthy donors, hair or saliva specimens)

Reviewed by one committee member or Chair unless problems identified

No greater than minimal risk – Means that the probability and magnitude of

harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests

Other Levels of Review

Exempt registrationExempt from federal regulationsVirtually no risk (e.g. retrospective data

analysis, discarded pathology materials – de-identified)

Investigator cannot decide if their research is exempt – IRB must decide

3 year registration required at UCI De Novo Review

Expedited and full committee research that extends beyond 7 years must be submitted as a new protocol

Case study #1

Investigator X wants to do a study where cadavers will be run through an x-ray machine to scan for healed fractures. No information about the cadavers or their living relatives is required.

Is this research?

Is this human subjects research?

Research or Not??

Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge (45CFR 46.102).

Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains: (1) Data through intervention or interaction

with the individual, or(2) Identifiable private information.

Case study #2

An Instructor wants to have all students in a class interview each other to practice interviewing skills. The results will not be written up or distributed outside the classroom in any way.

Is this research?

Is this human subjects research?

Case study #3

A physician wants to compare Tylenol with Advil for controlling headache. He plans to prescribe Tylenol on odd days and Advil on even days. Then compare the results. Both drugs already are approved by the FDA to treat headache and are available over the counter.

Is this research?

Is this human subjects research?

Does the physician automatically have access to his patients’ medical records for research purposes because of being the treating physician?

Case study #4

A Professor in a social science course includes 10% of the course grade for participation in various research projects within the school.

Is this educational practice allowable? Does this violate anyone’s rights?

How could this requirement be structured so it doesn’t violate any rights?

Advancement of IRB Processes All IRB processes are now electronic:

Reporting of adverse events, unanticipated problems, protocol violations, protocol deviations

Modification requests (e-Mod) Continuing protocol applications (e-CPA) Initial IRB Application (e-APP) Non Human Subjects Determination form

Case Study #5

A patient with a rare form of incurable cancer is offered a clinical trial opportunity at the Comprehensive Cancer Center by his treating physician. The clinical trial is testing whether two medications that are FDA-approved for other forms of cancer, are effective in this rare form of cancer.

Is this research?What would be the level of review at the IRB?Is it coercive to offer this trial to somewhat so desperate?

Take Home LessonsHuman Subject Protection Rules

The rules are there to protect the subjects from excessive risk or exploitation.

The welfare and reputation of the institution and the investigators are also at stake.

The investigator is responsible for knowing the relevant regulations.

When in doubt, ask the IRB staff.

UCI IRB Accomplishments

UCI achieved re-accreditation from AAHRPP in Fall of 2011 - five-year accreditation

UCI is part of systemwide MOU for all UC campuses – intent to rely on one IRB

UCI has MOU with CHOC for research UCI has MOU with Miller’s Childrens,

Memorial Med Ctr, and CHOC UCI has reliance agreements with

commercial IRBs http://www.rgs.uci.edu/ora/rp/hrpp/index.htm