Human Subjects Research: What is Required and Why David Ungar, MD Kathleen Hay, PhD, CIP, Assoc. Director Human Subjects Protection Office (HSPO)

“It is essential that the research community come to value the ethics of research as central to the scientific process.” National Bioethics Advisory Commission

Requirements for Conducting Human Subjects Research at Penn State Hershey

l Ethical Principles for Human Subjects Research l IRB Review of Research l IRB Submission Process l IRB Required Training l Investigator Responsibilities

PHS Study of Untreated Syphilis l ‘Tuskegee Study’, began in1932 l Recruited poor sharecroppers l No informed consent n Deception n Undue influence l Eventual RX of penicillin withheld

National Research Act l Required regulations be put in place: n protect human subjects of research n informed consent n independent review of research l Established a national commission: n National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research n This group wrote the Belmont Report, in 1979, embodying the ethical principles for protection of research subjects

n Respect for Persons u Informed consent u Protection for the vulnerable n Beneficence u Maximize possible benefits u Minimize possible harms n Justice u Fair distribution of research burdens vs. benefits Principles of Human Subject Protection The Belmont Report: Guiding Ethical Principles

Is It Research? l Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge l Case reports are not research (not systematic) l Internal quality improvement activities are not research (not designed to produce generalizable knowledge)

Does It Involve Human Subjects? l Access to private information n Viewing records or using data from a medical chart l Use of data or specimens n If they can be linked to an individual l Interacting/interventions with individuals n Including non-invasive activities, questionnaires/surveys, and procedures

Institution Review Board (IRB) Review of Research

What is the IRB? l Ethics review committee l Advocates for the rights, safety and welfare of subjects l Includes physicians, scientists and non-scientists, and representatives of the community

n Operates under federal regulations, state law and institutional policy n Authority to approve, require modification in, or disapprove research n IRB approval is needed for all human research at Penn State Hershey Penn State Hershey IRB Institutional Review Board

IRB Review Criteria  Informed Consent (Respect for Persons) Will be sought prospectively Includes required elements of information Additional safeguards to protect vulnerable subjects  Risk are Balanced and Minimized (Beneficence) Sound research not to unnecessarily expose subjects to risk Risks are minimized (e.g. - use data or proc. already available) Risk to subjects is reasonable vs. potential benefits Safety provisions & monitoring are adequate Privacy & confidentiality provisions are adequate  Subject Selection is Equitable (Justice) Rationale for inclusion/exclusion criteria Involvement of vulnerable populations justified IRB Review of Research

What The IRB Wants To Know l Do you understand ethical research? n Training requirement l What are you doing? n Procedures/Protocol l Who are you doing it to? n Subject Population n Inclusion/Exclusion Criteria l What are the risks and benefits? l How will you ensure voluntary participation?

Tips for Success in Navigating the Human Subjects Protection System l Start early l Read and follow directions l Understand the process l Ask for help

What Needs IRB Review

What is Human Research? Department of Health & Human Services (DHHS) l Research - a systematic investigation..., designed to develop or contribute to generalizable knowledge. l Human subject - a living individual about whom an investigator conducting research obtains: n data through intervention or interaction with individual, or n identifiable private information – individually identifiable; – reasonably expect not to be observed, recorded or made public (IRB is also the ‘Privacy Board’ at HMC/COM and privacy protection requirements apply to health information of decedents)

FDA Clinical Research l Clinical Investigation - any experiment that involves a test article and one or more human subjects…  Test article - any drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the [Public Health Service Act].  Human subject - an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient. (…includes a human on whose specimen an investigational device is used.) What is Human Research?

How do I determine if my project needs IRB review? l Determining What Needs IRB Review n Decision charts & FAQs on IRB website n Call the Human Subjects Protection Office for a consultation n Request for a formal determination u Use Request for an IRB Determination form

What activities do not require IRB review? l Case report or case series l Quality improvement projects l Quality assessment projects l Medical practice and innovative therapy l Public health practice (disease monitoring or program evaluation)

What activities do require IRB review? l Research involving existing or prospectively collected human specimens or data l Review of medical records l Educational research l Research involving surveys, interviews or focus groups l Clinical trials of investigational drugs and devices

What are the IRB review categories? l Types of review n Exempt from IRB review n Expedited IRB review n Full board (convened) IRB review l Affected by the level of risk and the type of project n Minimal risk

What is minimal risk? Level of risk A study is Minimal Risk when: l both probability and magnitude l of possible harm or discomfort l are not greater than that ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests

IRB Review of Research n Exempt – ‘no risk’ activities ● The IRB must certify the exemption ● Involves only activities from an exemption list: - Research involving normal educa. practices e.g., instructional strategies/curriculum evalu. - Tests, surveys, interviews, or observation (e.g., data de-identified, or no harm if disclosure) - Study of existing records or specimens if not identifiable/linkable, or if from public source

IRB Review of Research  Expedited – no more than ‘minimal risk’ ● IRB Chair or IRB designee may approve ● Involves only activities from an expedited list, such as: - Data / materials collected solely for non-research purposes - Non-invasive recordings in adults (e.g., MRI, EKG) - Survey of indiv./group characteristics (if no manipulation) - Collect samples non-invasively (e.g., saliva, sputum, excreta) - Blood draws (e.g., finger/heel stick, limited venipuncture) ● Not eligible if identification would expose subjects to risk of damage or stigmatization ● Standard informed consent requirements apply

IRB Review of Research  Convened Board Review ● Required for research involving greater than minimal risk ● Pre-review – Insures submission is ready for IRB ● IRB primary reviewer may contact PI for clarifications ● PIs invited to the meeting to answer question (optional) PI may provide phone # to call if IRB has questions PI excused for final deliberation and vote PI receives copy of board minutes outlining IRB requirements

IRB Submission Process

Submit 3 weeks in advance Best to consult with HSPO staff first if unclear Forms & Instructions on web IRB submission should include: l Application Form, and Addenda if applicable l Research protocol l Protocol summary abstract l Informed consent process l Recruitment methods/materials, if applicable l Supporting materials, if applicable

IRB Submission Process

Where to submit  Human Subjects Protection Office and Staff n Phone (717) n Academic Support Bldg. #1140  Electronic Submissions  Use electronic ‘IRB Submission Drop Box’ on server: \\hersheymed.net\files\hspo ‘IRB Submit Instructions’ for e-submissions Also on IRB website under ‘Investigator Resources’

IRB Required Training

IRB Required Training - CITI Collaborative Institutional Training Initiative l CITI Course – Biomedical Research at Penn State, COM & HMC  Required for all investigators/key personnel  Continuing education required every 3 years  Investigators receive automatic CITI reminder  Access instructions on IRB web site:

IRB Required Training - CITI

Medical Student Research Projects

MSR Projects – Example #1 Example #1 – l Med student designs a study l Study will be conducted at HMC and/or off-site l Study involves human subjects

MSR Projects – Example #1 IRB Requirements for Example #1 l Study must be submitted to the Hershey IRB for review using the standard IRB forms l Student must complete the CITI Course training l Hershey IRB reviews and approves study and issues an approval or exemption determination memo n After receiving the IRB approval memo the student may start the research n Student must provide a copy of the IRB approval memo to the Director, Medical Student Research

MSR Projects – Example #2 Example #2 l Medical student plans to work on an IRB-approved study here at Hershey l Study has previously been confirmed exempt or received IRB approval

MSR Projects - Example #2 IRB Requirements for Example #2 l Principal Investigator of the study must submit a Modification Request Form to add the student as a co-investigator l Student must complete the CITI Course l PI receives an IRB approval memo for the addition of the student to the study n After the PI receives this memo the student may commence work on the project n Student must provide a copy of this memo to the Director of Medical Student Research

MSR Project – Example #3 Example #3 l Medical student plans to work as a co-investigator on a study off campus l Study has previously been confirmed exempt or received approval from another IRB

MSR Projects – Example #3 IRB Requirements for Example #3 l Student must submit the following to the Hershey IRB office n MSR proposal n Copy of the approval memo from the other IRB n or letter from the principal investigator at the other institution stating that they agree to supervise the student’s work on the project l Student must complete the CITI Course

MSR Projects – Example #3 IRB Requirements for Example #3 (cont.) l IRB Chair reviews the information to decide if review by the Hershey IRB is required. n If review and approval by the Hershey IRB is required, the study must be submitted to the Hershey IRB using the standard IRB forms as in Example #1. u Student will be notified if Hershey IRB review is required. n If the IRB Chair determines that Hershey IRB review is not required, the student receives a memo stating that review and approval by the Hershey IRB is not necessary. u After this memo is received work may commence on the project. u Student must provide a copy of this memo to the Director of Medical Student Research.

MSR Projects REMEMBER: l IRB approval must be obtained prospectively n Before you start your research. l The IRB does not grant retroactive approval for research that has already taken place.

Key Investigator Responsibilities

Key Responsibilities for Investigators l The principal investigator has the ultimate responsibility for the conduct of the study u The ethical performance of the project u The protection of the rights and welfare of human participants u Strict adherence to the study protocol and any stipulations imposed by the IRB u Complying with applicable federal, state, and local regulations and PSU policies u Ensure key personnel are trained/qualified u Obtaining legally effective informed consent

Key Responsibilities for Investigators l The principal investigator has the ultimate responsibility for the conduct of the study u Ensuring continuing review approval is obtained within the timeframe stipulated u Ensuring no changes in the approved research plan are implemented without prior IRB approval, except where necessary to eliminate apparent immediate hazards to participants u Notifying the IRB of unanticipated problems

Key Responsibilities for Investigators l Obtaining legally effective informed consent from participants or their LAR n Using only the currently approved, date- stamped informed consent documents n Ensuring that only IRB-approved investigators obtain informed consent n Informing subject of any new information

Key Responsibilities for Investigators Continuing Review l Continuing review approval must be obtained within the stipulated timeframe n Approval effective for a maximum of 1 year l Failure to do so results in automatic expiration of IRB approval l PI receives reminder and progress report form to complete

Key Responsibilities for Investigators Modifications to Research l Changes in the research plan must be approved by IRB prior to implementation u IRB must review all changes u Obtain IRB approval before implementing changes, unless necessary to avoid immediate hazard n Types of changes u Protocol amendments - permanent intentional action u Protocol deviations - one-time, unintentional action u Protocol exceptions - one-time, intentional action

Ongoing IRB Review Requirements Unanticipated Problems n Investigators must notify the IRB of any event or report that describes a possible unanticipated problem involving risks to participants or others n Definition: u Unexpected (in nature, severity, or frequency) given the research procedures and participant population u Suggests that the research places participants or others at a greater risk of harm or discomfort related to the research than was previously recognized –Physical, psychological, economic or social harm Submit Problem Report Form & Accumulative Tracking Log

Ongoing IRB Review Requirements Unanticipated Problems n Investigator must report the following promptly to the IRB u Adverse events (unexpected and related or likely related to the research as determined by the PI u Info that indicates a change in the risks or potential benefits u Breaches in confidentiality u Incarceration of subject in study not approved for prisoners u Sponsor imposed suspensions for risk u Unintentional protocol deviations that involved risks u Emergency protocol changes (deviations) u Complaints that indicate risks or can’t be resolved by the research staff

Are there other committees that must review research? l Conflict of Interest Review Committee (CIRC) l Human Use of Radioisotopes Committee l Institutional Biosafety Committee l Anatomic Pathology l Departmental scientific review committees

Resources for Investigators l Human Subjects Protection Office Phone (717) , Academic Support Bldg. #1140 u Individuals Consultations u HSPO Update s IRB/HSPO web site: n Investigator Resources n Instructions and Forms n QA Tools: Templates to help you manage research records l IRB Seminars n IRB New Investigator Series online