1. Human Subjects Research Nov. 2009

2. Research Involving Human Subjects and Conducted by Medical Students
Patricia L. Gordon, M.D.
Executive Chair, Institutional Review Board (IRB)
Executive Director, Human Subjects Protection Office (HSPO)
Kathleen Hay, PhD, CIP
Director, HSPO

3. Overview of Presentation
The “why” behind all we do
What needs to be done for a study to be approved?
How do you get it done?
Then what – what do you need to do once a study is approved?

4. Tips for Success in Navigating the Human Subjects Protection System
Human Subjects Research Nov. 2009
Tips for Success in Navigating the Human Subjects Protection System
Start early
Read and follow directions
Understand the process
Ask for help early

5. Research with Human Subjects
Clinical research requires human volunteers
Human participation necessitates public trust
Social contract
Law

6. Public Trust Tested by Historical Abuses
Nuremberg Trials – 1946
Thalidomide – 1961
The Milgram Study – 1963
Tuskegee –
Guatemala –
Human Radiation Experiments
Tuskegee – 400 impoverished sharecroppers; Public Health Service investigators knowingly failed to treat after PCN was readily available
Guatemala – PHS workers infected prison inmates, prostitutes, mentally incapacitated

7. Human Subjects Research Nov. 2009
Principles of Human Subject Protection
The Belmont Report: Guiding Ethical Principles
Respect for Persons
Informed consent
Protection for the vulnerable
Beneficence
Maximize possible benefits
Minimize possible harms
Justice
Fair distribution of research burdens vs. benefits
Respect for Persons
Treat individuals as autonomous agents
Opportunity to choose what shall or shall not happen to them
Provide information needed to make a considered judgment
Protect individuals with diminished autonomy
Extent of protection depends on the risk and likelihood of benefit
Beneficence
Maximize possible benefits; Minimize possible harms
Weigh benefits to the subject and to society
Justice
Research supported by public funds to develop new therapies...
… the subjects should not unduly involve persons from groups unlikely to be among the beneficiaries of the subsequent applications of the research
…should not benefit only those who can afford them
Equitable selection of subjects
Fair distribution of the burdens of research vs. the benefits
Examples of injustice in research
19th and early 20th centuries
Burden: poor ward patients as subjects
Beneficiary of improved care: often went to private patients
Nazi medical experiments - Burden: concentration camp prisoners
Tuskegee syphilis study Burden: disadvantaged rural black men were deprived of effective treatment for the sake of research long after it became 7 7

8. captured in the consent process incorporates two ethical convictions:
Respect for Persons
captured in the consent process
incorporates two ethical convictions:
individuals should be treated as autonomous agents
persons with diminished autonomy are entitled to increased protection

9. Informed Consent
“A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate.”

10. Maximize possible benefits and minimize risks
Beneficence
Do not harm
Maximize possible benefits and minimize risks
Risk: possibility that harm may occur both in the probability of experiencing a harm and the magnitude of the envisioned harm
Benefit: something of positive value related to health or welfare

11. Addressing Beneficence
Good research design
Privacy of confidential medical information
Competent investigators
Favorable risk-benefit ratio
The fewest number of subjects are placed at the least amount of risk to answer a scientifically valid question

12. Fairness in distribution of risks and benefits.
Justice
Fairness in distribution of risks and benefits.
An injustice occurs when:
benefits to which a person is entitled are denied without good reason
or when burdens are imposed unduly

14. Human Subjects Research Nov. 2009
What is the IRB?
Ethics review committee
Advocates for the rights, safety and welfare of subjects
Includes physicians,
scientists and
non-scientists, and
representatives
of the community
The IRB is an ethics review committee to evaluate research
The IRB has the authority to approve, require modification in, or disapprove all research activities
Autonomous from other decision-making authorities
Mission:
Charged with determining if the rights and welfare of research subjects are adequately protected.
To advocate for the rights and welfare of human research participants and
To promote high quality research by fostering an institutional culture embodying the highest ethical standards of human research. 14 14

15. Human Subjects Research Nov. 2009
Penn State Hershey IRB
Institutional
Review
Board
Operates under federal regulations, state law and institutional policy
Authority to approve, require modification in, or disapprove research
IRB approval is needed for all human research at Penn State Hershey 15 15

16. Department of Health & Human Services (DHHS)
What is Human Research?
Department of Health & Human Services (DHHS)
Research - a systematic investigation ..., designed to
develop or contribute to generalizable knowledge.
Human subject - a living individual about whom an
investigator conducting research obtains:
data through intervention or interaction with individual, or
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)

17. What activities require IRB review?
Research involving existing or prospectively collected human specimens or data (e.g. review of medical records)
Educational research
Interaction/interventions with individuals
Research involving surveys, interviews or focus groups
Clinical trials of investigational drugs and devices
Activities driven by an intent to publish or share beyond the institution

18. What activities usually do not require IRB review?*
Human Subjects Research Nov. 2009
What activities usually do not require IRB review?*
Case report or case series
Quality improvement projects
Quality assessment projects
Medical practice and innovative therapy
Public health practice (disease monitoring or program evaluation)
*some exceptions and many journals require IRB review
Case report or case series – report interesting case or cases – educational activity – no statistical methods (subgroup comparisons or tests for prognostic factors) absence of the basic elements of a systematic investigation of a scientific question
Quality improvement projects – goal of improving the performance of institutional practice in relationship to an established standard
If any of the following criteria are met, then the project receives consideration as to whether IRB review is required: generalizability, additional risks or burden, design (randomization or an element that is less than standard of care)
Quality assessment – determine whether aspects of medical practice are being performed in line with established standards 18

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

20. Human Subjects Research Nov. 2009
IRB Review of Research
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 20 20

21. What are the IRB review categories?
Human Subjects Research Nov. 2009
What are the IRB review categories?
Types of review
Exempt from IRB review
Expedited IRB review
Full board (convened) IRB review
Affected by the level of risk and the type of project
The Type of Review is determined by the risk of the study, based on the definition of minimal risk.
Minimal Risk defined as:
the probability and magnitude of harm or discomfort anticipated in the proposed 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.
Dictated by type of project and level of risk
Full board review - greater than minimal risk or vulnerable populations
Expedited review – no more than minimal risk, non-invasive procedures, specific categories identified in regulations
Exempt – not human subjects’ research or specific categories as defined in regulations (e.g. existing data, records or specimens publicly available or anonymized, surveys, observations of public behavior, taste/food quality studies) 21

22. What is minimal risk? Minimal Risk = both probability and magnitude
of possible harm or discomfort
are not greater than that
ordinarily encountered in daily life or during
the performance of routine physical or
psychological examinations or tests

23. Access to Private Medical Information
If no clinical relationship with patient/subject, then no right of access to medical record
This access might be granted by the IRB with a waiver of the informed consent requirement for specific research projects under certain circumstances

24. Confidentiality of Medical Records
MSR Project
Confidentiality of Medical Records
No access to medical records without some clinical access i.e. the patient’s physician (or partner of patient’s physician)
Once you get access you are held to confidentiality. Outside of the research you are not at liberty to reveal anything about the patient/subject to anyone, including the fact that he/she has a medical record here

25. MSR Projects: Exempt vs Expedited
Exempt from IRB review: “no risk”
No identifiers recorded
Surveys - anonymous
Review of publically available information (public disease registry, blogs)
Review of medical records where no identifiers are recorded (no links and no repeat access to medical record)

26. MSR Projects: Exempt vs Expedited
Expedited: always “not more than minimal risk”
Medical record reviews
Surveys or educational tools where identifiers are recorded
Interventional studies with blood samples, urine samples or innocuous tests (ultrasound, MRI, EKG, exercise on healthy people)

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

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

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

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

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

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

33. MSR Projects – Example #3 cont’d
IRB Chair reviews the information to decide if review by the Hershey IRB is required.
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.

34. MSR Projects
REMEMBER:
IRB approval must be obtained prospectively
The IRB does not grant retroactive approval for research that has already taken place.

35. How do I determine if my project needs IRB review?
Decision charts & FAQs on IRB website
Call the Human Subjects Protection Office for a consultation
Request for a formal determination
Submit an ‘IRB Determination’ form
On the IRB website under Frequently Asked Questions
Does the IRB need to look at this project?
We provide links to the Office for Human Research Protections in the DHHS website and links to OHRP’s decision charts
Decision charts are graphic aids to assist IRBs and investigators in determining review requirements for a particular activity
When should a QI/QA project be presented to the IRB
We provide a QI/QA decision tree to assist you with this question

36. CATS IRB Log in at https://irb.psu.edu
Prior to first use – and ask for access to CATS

37. CATS IRB 1 3 2

38. IRB Training – CITI H.S.P. Course
Modules load 1 at a time; short quizzes
Finish course by taking 1 elective
Can ‘Add a Course’ later, if needed
Link here to start a course

39. IRB Submission Process
Submit 8 weeks in advance
Best to consult with HSPO staff first if unclear
Instructions & online process at
IRB Submissions include:
Completing an online submission form
Uploading all supporting documents
Research protocol
Informed consent process and documents
Recruitment methods/materials, if applicable
Supporting materials, if applicable

40. International Research
Student must contact Global Health Center and HSPO 6 months prior to departure date
Student must submit all documents to HSPO by 3 months prior to departure date

41. Other committees that review research
Other reviews needed, when applicable:
Conflict of Interest Review Committee (CIRC)
Human Use of Radioisotopes Committee
Institutional Biosafety Committee
Anatomic Pathology
Departmental scientific review committees
Links and info. on IRB web site

42. After Approval is Received
Do what you said you were going to do.
If you need to change anything, you need IRB approval first.
If something doesn’t go according to plan, the IRB needs to know asap.
The IRB needs to review the study’s progress.
Respond to all communication from the IRB in a timely manner.

43. Key Responsibilities for Investigators
The principal investigator has the ultimate responsibility for the conduct of the study
The ethical performance of the project
The protection of the rights and welfare of human participants
Strict adherence to the study protocol and any stipulations imposed by the IRB
Compliance with applicable federal, state, and local regulations and PSU policies
Assurance that key personnel are trained/qualified
Acquisition of legally effective informed consent
PSU Policy RA14 – The Use of Human Subjects in Research
Principal Investigator’s Assurance Statement – application form
Form FDA 1572 for drug studies
Signed agreement between investigator and sponsor in device trials
FDA Draft Guidance for Industry: Protecting the Rights, Safety, and Welfare of Study Subjects – Supervisory Responsibilities of Investigators

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

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

46. Ongoing IRB Review Requirements
Changes to Research
Changes in the research plan must be approved by IRB prior to implementation
IRB must review all changes
Obtain IRB approval before implementing changes, unless necessary to avoid immediate hazard
Types of changes
Protocol amendments - permanent intentional action
Protocol exceptions - one-time, intentional action

47. Ongoing IRB Review Requirements
Reportable New Information
Investigators must notify the IRB of any new information that falls into one or more of the categories listed on next slide
Within 5 business days
Process:
Researchers report information to the IRB and
IRB determines if the information represents unanticipated problems involving risks to participants or others or non-compliance

48. Ongoing IRB Review Requirements Information that needs to be reported promptly to the IRB
Information that indicates a new or increased risk, or new safety issue:
IB, interim analysis, safety monitoring reports,
Harm experienced by subject or others
1) unexpected
2) probably related as determined
by the HMC PI
Non-compliance w/ federal regs or determinations of IRB
Audit, inspection or inquiry by fed. agency & resulting reports
Reports by RQA and study monitors
Failure to follow the protocol
Breach of confidentiality
Changes to protocol without prior IRB review to eliminate immediate hazard to subject
Incarceration of a subject in a study not approved to involve prisoners
Complaint of a subject that cannot be resolved by the research team
Premature suspensions or termination of a study by the sponsor, investigator or institution
Unanticipated adverse device effect

49. Tips for Success in Navigating the Human Subjects Protection System
Human Subjects Research Nov. 2009
Tips for Success in Navigating the Human Subjects Protection System
Start early
Read and follow directions
Understand the process
Ask for help early

50. Resources for Investigators
Human Subjects Research Nov. 2009
Resources for Investigators
Human Subjects Protection Office
Phone (717) , Academic Support Bldg. #1140
Individual Consultations
IRB/HSPO web site:
Resources/Investigator Resources
Educational requirements – CITI course access
Making an IRB Submission – instructions and templates
IRB Seminars
Dates posted on IRB web site
Select presentations available at