WelcomeThe University of Texas at Arlington

Office of Research Integrity and Compliance Human Research Protections Program (HRPP)

Tier II TrainingResponsible Conduct in Human Subject Research

The Principal Investigator and the Key Personnel

are required to complete compliance education . . .

• Members of the Institutional Review Board;

• The listed Principal Investigator;

• Sub- or Co-Investigators named on an Application for Research;

• All listed investigators on FDA Form 1572 for FDA-regulated investigations;

• A member of the group of key personnel on a Grant Application (e.g. NIH);

• A subcontractor or consultant associated with a federally-sponsored study;

So who are the Key Personnel ?

More key personnel . . .

• A Clinical Research Coordinator, Graduate Research (GRA) or Teaching Assistant (GTA) involved in any direct interactions with research subjects, including involvement in the process whereby Informed Consent is acquired from potential research subjects;

• Departmental Administrative and/or support staff directly involved with the completion of required forms or the support of thesis and doctoral students.

If it isn’t documented, it did

not happen

The Tuskegee Tragedy

• In 1932 the American Government promised 399 men – all had Syphilis, all residents of Macon County, Alabama, all poor, all African American – free treatment for Bad Blood. It lasted until 1972. [Syphilis Study Ad Hoc Panel (1973)]

• Although the study was initially planned for 6 mos., it was allowed to continue for 4o years. The men were never told they were being enrolled as research subjects; they were promised free medical care (treatment for bad blood) and $100 burial money.

• Treatment was withheld even after Penicillin became available.• The researchers referred to these lives as, expendable!

IRBs…doing their best to insure history does not repeat itself!

The Nuremberg Code (1947)

• In the name of research, numerous atrocities were conducted on civilian prisoners held in WWII camps.

• As part of the verdict in the Nuremberg War Crimes Trials of 23 German doctors, the Court enumerated some rules for “permissible Medical Experiments”, now known as the Nuremberg Code. These rules include:

• Voluntary consent• Benefits outweigh risks• Ability of the subject to terminate participation

• The Nuremberg Code was never legislatively enacted. Although it is not a law, researchers around the world follow its standards for ethical reasons.

Click here to learn more:http://www.ushmm.org/research/doctors/

Jesse GelsingerSeptember 17, 1999

University of Pennsylvania Institute for Human Gene Therapy

Jesse died at the age of 18, on September 17, 1999.

Read Jesse’s Intent, written by Paul – his father. http://www.guineapigzero.com/jesse.html

The Belmont Report

• (Foundation document) Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The three main sections will be reviewed on an upcoming slide.

• Authors: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The report was released on April 18, 1979.

“IRB” History• Nuremberg code (1947)• Public Health Service (PHS) Policy and the National Institutes of Health (NIH)

Clinical Center (1966) began Independent Ethics Committees (early IRB-type reviewing committees)

• Syphilis Study (revealed) – AD Hoc Panel assigned to review the case (1973) • National Research Act, July 12, 1974 (PL94-348)• 45 CFR 46 (Codes of Federal Regulation [CFR] federal laws) under section

491 PHS Act (1974)• National Commission for the Protection of Human Subjects of Biomedical and

Behavioral Research (1974-1978)• 1979 – National Commission’s Belmont Report• 1981 – Major revisions to federal regulations (e.g., 21 CFR 56)• 56 FR 28803, June 18, 1991• The Common Rule (Federal Policy), Subpart A, 45CFR 46 (latest revision June

18, 1991)

This institution is an approved research institution by a DHHS Federalwide Assurance

(FWA). What is an Assurance?

• A type of contract between us and the federal government.• A promise to conduct ethical research in compliance with

the Department of Health and Human Services (DHHS) regulations for the protection of human subjects of research as found in 45 CFR 46.

• Establishes a partnership to protect the rights and welfare of the human subjects of research.

• Identifies a signatory official.– Ronald L. Elsenbaumer, PhD

Vice President for Research

What Constitutes Ethical Human Research?

• A valid and important question

• Valid methodology

• Balance between risks/benefits

• Independent ethical review

• Informed consent

According to 45 CFR 46

Fundamental Ethical Constructs A Guide for Human Research: The Belmont

Report

• Beneficence “an obligation” (do no harm, and maximize benefits/minimize harms)

• Justice (who ought to receive the benefits of the research and bear its burdens)

• Respect for persons (individuals should be treated as autonomous agents and those with diminished autonomy are entitled to protection)

#1

#2

#3

The Buck Stops here!

• Principal Investigator (PI)– Faculty, student or staff

• Conduct of study• Personnel supervision• Protecting the rights,

safety and welfare of

research subjects . . .

Any number of research team members may be delegated certain research related duties BUT the PI is

ultimately responsible (federally and ethically) for the conduct of the research.

What Regulations Apply?• Common Rule 56 FR 28003 (Subpart A, 45 CFR 46)• 45 CFR 46• 45 CFR 160, 164• 38 CFR 16 (Veteran Affairs)• DHHS Office for Human Research Protections (OHRP)

regulations are applied for the sake of consistency in many non-FWA institutions

• Institutional policies• Statutes• Ethical codes• State and local law• Any many more! It depends on the research focus.

Scientific Misconduct

• Public Health Service (PHS) regulations

• Official Definition: Misconduct in science means fabrication, falsification, plagiarism or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducing and reporting research. It does not include honest error or honest differences in interpretations or judgments of data.

• Retaliation against a “whistle-blower” who made an allegation of misconduct in good faith, may itself, be construed as an act of misconduct.

Compliance MonitoringConducted by any of the following and more!

• The Office of Research Integrity and ComplianceQuality Improvement Program for Human Subject Research (QIP)

• FDA• OHRP • NCQA or AAHRPP• Sponsor/Cooperative Group Monitoring• Internal Auditing Mechanisms

These visits are not always announced. The research conduct of the individual investigator represents and

affects all of us. . .

Investigator RecordsMost common findings during monitoring of site records

• Missing original signed ICDs• Documentation lacking of initial date of subject pre-screening (for

those who do not meet inclusion criteria) or patient enrollment• Documentation of the initial procedure or treatment date for each

subject or patient• Refer to the Quality Improvement for Human Subject Research (QIP)

program guidelines located on the IRB Website for program description and the specific documentation required for compliance and to achieve successful program audits

Visit OHRP to learn some surprising facts!http://www.hhs.gov/ohrp/references/findings.pdf

What Counts as Research?

• Quest for generalizable knowledge– (The research data will be shared in public venues: publication, thesis, dissertation,

invited presentation, etc.

• Organized data gathering• Non-standard therapeutic or diagnostic approach• Decisions made by computer or protocol, rather

than by patient or caregiver• Presence of risk (even “soft” risk) beyond that of

standard care

OHRP Definition of Researchin Regs 45 CFR 46.102(e)

• 45CFR46.102(d) “Research” means a systematic investigation designed to develop or contribute to generalizable knowledge.

• Activities which meet this definition constitute “research” for purposes of these regulations, whether or not they are supported or funded under a program which is considered research for other purposes.

OHRP Definition of Human Subjectin Regs 45 CFR 46.102(f)

“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.

Risk/Benefit

• Risk - A probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study.

• Minimal Risk – where the probability and magnitude of harm or discomfort in the study is not greater than those ordinarily encountered in daily life, in performance of routine physical or psychological testing.

Vulnerable Subjects• Additional protections are required

(45CFR46, Subparts B,C,D)• Children (e.g., <18 yrs, unemancipated minors)

• Cognitive disorders• Prisoners• Pregnant women• Minorities

This is not an all inclusive list. Consider, for example, that under certain circumstances, a specific socio/economic population could represent a vulnerable population.

Are “Soft Risks” Important?• Risks re: confidentiality, stigmatization,

embarrassment, social/legal risk are explicitly mentioned in FDA and OHRP documents as potential exclusions from categorization as “minimal risk”

• Once in awhile, the consequences can be severe

Do not assume “no physical risk” means no risk.

Deception• Deception interferes with the subject’s ability to give

informed consent• Ethical concerns are increased whenever the protection of

informed consent is compromised• Use of deception must be scientifically AND ethically

justified AND approved by the IRB• It is not permissible to use deception to obtain enrollments

What is an IRB?

• An Institutional Review Board (IRB) is a board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct continuing review of biomedical and behavioral research involving the participation of human subjects in accordance with the regulations of the DHHS, FDA and OHRP.

IRB ResponsibilitiesCriteria for IRB approval of research

• Risks to subjects are minimized;• Risks are reasonable in relation to

anticipated benefit;• Selection of subjects is equitable;• Informed consent is sought from each

subject;• Informed consent is appropriately

documented.

The responsibilities of the IRB are mandated by

45 CFR 46.111

Levels of IRB Review

• Exempt– Little to no risk involved

• Expedited (Short Review)– Research that does not exceed minimal risk

– (See 45 CFR 46.102(i) for the definition of minimal risk)

• Full Review (Convened Meeting)– Research that exceeds minimal risk

Exempt Review

Does not mean do NOTHING!

When the PI determines that the research involves little to no risk, someone other than the PI must agree (in writing) with the determination. That someone is the IRB Chair (or the designee of the IRB Chair).

Exempt Review

Risks to subjects are minimized; Review is performed by IRB chairperson or designated experienced reviewer.

Example: anonymous survey of a healthy adult population.

No signed consent document is required!

When *IRB Review Not Needed?45 CFR 46.101 (EXEMPT)

• Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (i) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.

• Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless: (i) information is recorded in such a a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) and disclosure of the human subjects’ responses outside the research could reasonable place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation.

• *The IRB mentioned here refers to the convened Board.

When IRB Review Not Needed?45 CFR 46.101(EXEMPT)

• Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement) survey or interview procedures, (if no identifiers and no confidentiality risk) or observation of public behavior that is not exempt under paragraph (2 above), if (i) the human subjects are elected or appointed public officials or candidates for public office; or (ii) Federal statutes(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.

• 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.

When IRB Review Not Needed?45 CFR 46.101(EXEMPT)

• Research and demonstration projects which are conducted by or subject to the approval of Department of Agency heads, and which are designed to study, evaluate, or other examine: (i) public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs.

• Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the FDA or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Dept of Agriculture.

Expedited (Short Review)

Minimal risk to human subjects and involves only procedure in the categories:1. Research on drugs for which an newinvestigational new drug application is not required.2. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture from

(a) healthy, non-pregnant adults weighing at least 110 pounds, not exceeding 550

ml in an 8 week period, and no morethan 2 times per week.

Expedited (Short Review)(b) Other adults and children, considering the age, weight, and

health of subjects. Amount drawn may not exceed the lesser of 50 ml or 3ml per kg in an 8 week period, with collection no more than 2 times

per week.3. Biological specimens by noninvasive means: Hair and nail clippings, excreta, saliva, placenta after delivery, amniotic fluid obtained at time of rupture, subgingival plaque, mucosal and skin cells

by scraping, swabbing, sputum.

Expedited (Short Review)

4. Collection of data through noninvasive procedures, excluding x-rays or microwaves. Examples: physical sensors on the body surface; moderate exercise; testing of sensory acuity.

5. The study of existing data, documents, records, pathological specimens.

Expedited (Short Review)6. Collection of data from voice, video, digital, or

image recordings made for research purposes.

7. Research on individual or group characteristics or behavior.

8. Continuing review of research previously approved by the convened IRB where (a) project is closed to accrual (b) the research remains active only for long-term follow-up. (c) remaining research activities are limited to data analysis.

Expedited (Short Review)

9. Continuing review of research that is not greater than minimal risk,

but had to undergo initial review by a convened IRB because it did not meet the criteria of categories 2 through 7.

Special Note: Related grant protocol packet must be included in the original submission.

Full Review (Convened Meeting)

• If a study does not fit in the short review scenario, it exceeds minimal risk and must, by default, undergo full review.

• Requires the attention of an official meeting of the IRB with an operating quorum.

• Investigator(s) must attend the meeting to present the project parameters, explaining the subjects’ involvement.

Types of Review

• Initial Review• Continuing Review of ongoing research

– (required for periods not to exceed 12 months)• Study Closure

– notification of closure is required from the PI• Amendment Review (Minor Modifications)

– Includes any deviation from the original approval: amendments, revisions & modifications and requires IRB approval prior to implementation

• Adverse Event / Unanticipated Problems Review

Adverse Events

• Unanticipated Problems• Information that impact on the risk/benefit ratio should be

promptly reported to, and reviewed by the IRB to ensure adequate protection of the welfare of the subjects. (FDA (1998) Information Sheets)

• All investigators are required to report to the IRB any injury (harm caused by involvement in research), deaths and unexpected serious adverse experiences.

• When reporting, the Investigator must determine the relationship between the event and the study (definite, possible, probable, doubtful, unknown, not related)

Informed Consent• Informed consent is not a document, it is a

process. The informed consent document (ICD) provides documentation of the process.

• Telephone Consenting requires careful documentation

• Confidentiality• Consider Data/Safety Monitoring• Use 2nd person (you), rather than 1st person (I).

– Use of “I understand…” on the research ICD is prohibited.

• Use well defined headings for each section.

The Process of Informed Consent

• An exchange of information between the subject and the investigator (or qualified designee) before, during and sometimes even after participation.

Formatting the Consent Document • Instructions available on the ICD templates located athttp://www.uta.edu/ra/RC/Forms/InternalForms/ICD_Sample_-_Full_Review.doc

Document must be written non-technical terms, understandable by a 7th grade reading level.• Format: includes header with project title and investigator name, version date mm/dd/yyyy• Footer must include page number in # of total and an area for initial of subject for each page.• No less than 12 pt. font• Written to the potential subject• Use of standard format is required unless a waiver has been granted.

When Can Consent be Waived?45 CFR 46.116 (d)(1)-(4)

If the research poses . . .

• No more than minimal risk

• Research not practicable with consent

• Subjects’ rights not adversely affected, AND

• Information available later, if practicable

or

See also 45 CFR 46.116(c)(1)(2)

When Can the Requirement to Obtain Signed Consent be Waived?

45 CFR 46.117(c)(1)(2)

• The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern; or

• That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

• In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research.

Final determination must be made by the IRB . . .

When is Consent Needed?45 CFR 46.116

• Except as provided elsewhere in this or other subparts, no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative.

Required Elements of the Consent Form

• Introductory paragraph stating:

1. Invitation to participate in research

2. Admonishment to read the document and ask questions.

3. Make it clear that it is his decision to become involved.

Elements of Consent Form

• Purpose

Specific purpose of the project, how it is related to other knowledge.

• DurationSubject’s time commitment to the project.

Elements of Consent Form

• Procedures – Describe what the subject will do, see, where he will go, what equipment will be used and how. If specimens are collected, explain when, where, and how much will be needed for the project.

Hold all technical language to a minimum and when used, explain in lay-language the difficult terms.

Elements of Consent Form

• Possible Risk/Discomforts

State in lay-terms any known risk, side effect or inconvenience that this project may cause. Also state there may be unanticipated risk or discomforts that are unknown.

Elements of Consent Form

• Possible Benefits Describe potential benefits that may occur due to their participation. If there is no expected benefit, clearly state this fact.

• Compensation in the form of payments If there is compensation for the subject,

state clearly the amount for the amount of participation; e.g. prorating

Elements of Consent Form

• Financial CostsList any financial responsibility that the subject

might incur during the project duration.

Explain what parts of the study will be at no charge.

Elements of Consent Form

• Alternative Procedures/Treatments

Provide information about other choices that be available to the subject. If there are no alternatives, state explicitly.

Elements of Consent Form

• Contact for QuestionsTwo individuals with appropriate phone numbers

must be included. The subject may questions concerning the research or research-related injuries.

A statement as to questions about rights as a participant, with IRB phone number (Refer to online template).

Elements of Consent Form

• ConfidentialityVerbatim paragraph, tailored to fit the realm of specific

project• Compensation for Medical Treatment

– If applicable to the research Verbatim paragraph, tailored to fit the realm of specific

project. Remember that research related injury might be physical, psychological, social, financial or other!

• Additional Elements (if applicable) per 45CFR46.116(8)(b)(1)-(6)

Elements of Consent Form

• Voluntary Participation This does not have to be a verbatim

paragraph, but all elements must be present.(No penalty or loss of benefits by not participating or withdrawing from the study)

• Signature AreaVolunteerParent (guardian), if applicableInvestigator or presenter of consentWitness (if applicable)

Child Assent

• A short, easy to understand Assent (agreement) document may be adapted to allow the minor to sign. This does not negate the required formal ICD to be signed by the parent(s) or legal guardian.

• An Assent is required when enrolling children.– Based on the child’s ability to agree

• A child agrees to participate; a parent or legal guardian grants permission for the child to participate.

• The Assent is attached to the ICD and has its own signature line for the child.

Narrative Description Guidelines• Name of the Principal

Investigator• Project Title• Placed to be conducted• Objective• Summary• Methods of Recruitment• Research Data• Specific Role of Human

Subjects• Specific Risk to Subjects

• Benefits to Subjects• Inducements• Subjects confidentiality• Informed Consent• Adverse Reaction Reporting• Pertinent literature

(bibliographic listing)• Location of Records

– Be specific

Charts and technical information may be inserted into the Narrative. This document is written to the IRB; the ICD is written to the prospectively enrolled subject.

Conflict of Interest (COI)

• All Principal Investigators (PI) must have a completed Conflict of Interest form on file in the Office of Research Integrity and Compliance.

– The Principal Investigator must disclose any potential or actual conflict of interests to the UTA IRB and to the department chair at the time of submission of their protocol. The attestation of actual or potential conflict of interest will be reviewed for approval and continuing management in accordance with UTA’s procedures.

Visit the official site!http://www.uta.edu/ra/RC/HumanSubjects.php

The UTA Office of Research Integrity and Compliance site provides a Reference Library, Forms (.pdf and .doc), research news, policies, SOPs, a HIPAA KIT, and more!

• UTA Office of Research Integrity and Compliance– Box 19188, 202 E. Border St., Suite 201

Arlington, TX 76019-0188(817) 272-3723

• The office is accountable for regulatory reporting and ensuring institutional considerations for overall compliance in human subject and animal research, biosafety, conflict of interest, export control, time and effort reporting, scientific misconduct, and research integrity.

IRB Meetings . . .• Schedule: The UTA IRB meets each 3rd Tuesday. Check the human

subjects website for specific dates for meetings and submission deadlines.

• Packet dissemination – Incomplete packets will not be reviewed

• Presentation of full review and non-minor modifications– IRB meetings are closed meetings; letters of invitation are

forwarded from the Office of Research Integrity and Compliance to presenting investigators or other approved guests

• Committee deliberations and votes– Conflict of Interest: The PI and any IRB member who may have

some level of involvement with the research must be excused from the room during IRB deliberation and voting. IRB decisions are forwarded in writing to the attention of the PI.

IRB Members are prohibited from sharing the content of Board discussions following the meeting. As required by 45 CFR 46, information intended for release is forwarded to the appropriate investigator (institutional official or department) in writing, over the signature of the Chair.

Funding

A grant account (number) will not be provided until IRB approval for the project has been achieved.

Contact the UTA Office of Grants and Contract Services for funding assistance. Go to http://www.uta.edu/ra/GCS/gcs.html

If the grant proposal indicates human subjects, the packet will additionally be forwarded to the IRB for review.

Submission Guidelines• Full Review

– Submit a Form #1, Narrative, Informed Consent Document (ICD), Investigator Curriculum Vitae or other statement of qualifications.

– Applicable attachments

• Expedited Review Submit a Form #1

• Exempt Submit a Form#1A

• All forms must have original signatures. Fax copies can not be accepted.

• Compliance Education components (Tier II or Responsible Conduct in Human Subject Research [certification course]) MUST be completed PRIOR to submission.

The Original includes the Form #1 or 1A, Narrative, ICD and any applicable attachments

File Maintenance & Security• Database management

– A variety of study file data are maintained by the IRB Manager on your behalf in the ProIRB database in the ORIC.

• IRB Number designation– All protocols are given and IRB Number. It is important that the

PI keep up with the IRB number and associated information• Archival records

– Titles 21, 38 & 45 require that the IRB maintain research records for three years after the completion of the research; all investigators are required to keep research records for 3 years after the completion of the research or if the study is funded the sponsors wishes shall prevail.

All research records held by the ORIC are auditable by various federal offices for periods up to five years after the research has been completed.

If it isn’t documented, it did

not happen

Final reminder . . .

Burning Questions ?

Contact the Office of Research Integrity and

Compliance (ORIC)by calling (817) 272-3723 or . . .

Email to:kvalsin @uta.edu orpwmyrick@uta.edu

Thank you for participating!

The UTA Office of Research Integrity and Compliance appreciates your commitment to the protection of human

research subjects.

Test Your Knowledge . . .

• The following link below will take you to a MSWord query to test your knowledge and understanding of the information presented.

• http://www.uta.edu/ra/RC/Forms/HumanSubject/TierII_Online_questions.doc

• Once you have completed the questions, print the post-test and sign/date where indicated. Mail or deliver to the Office of Research Integrity and Compliance. Answer all questions correctly to receive credit for the training.

Acknowledgements

• Dale E. Hammerschmidt,MD, Associate Professor of Medicine, University of Minnesota, Editor of Journal of Laboratory Medicine, Dir. Of Education in Research Ethics and Compliance

• Dunn, C., Chadwick, G. (1999) Protecting Study Volunteers in Research,CenterWatch, Inc., Boston, MA

• Department of Health and Human Services (DHHS)• Office for Human Research Protections (OHRP)• National Institutes of Health (NIH)• Food and Drug Administration (FDA)• Veteran Health Affairs (VHA)