irb regulations importance for...
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IRB Regulations Importance for Research
Georgamaly Estronza, MS, CIP IRB Administrator/Research Compliance Officer Human Research Subjects Protection Office Medical Sciences Campus University of Puerto Rico
INTRODUCTION
This course is designed for ANYONE involved in the use of human subjects in research. The course deals with topics ranging from what constitutes a human subject to the details of obtaining IRB approvals.
Human Subjects Research: What is Required and Why
DEFINITIONS
Research is a systematic investigation
designed to develop or contribute to generalizable knowledge.
DEFINITIONS
A human subject is an individual (as well as human embryos, fetuses, and any human tissue or fluids), about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual or (2) identifiable private information.
Thus, the scope of "subject" is interpreted broadly. Even if you are "just interviewing" people or conducting a survey, you are involving human subjects in your research.
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) - IRB Letter is Required for publication
l Internal quality improvement activities are not research (not designed to produce generalizable knowledge)
Does It Involve Human Subjects?
l Access to private information – Viewing records or using data from a medical
chart l Use of data or specimens
– If they can be linked to an individual l Interacting/interventions with
individuals – Including non-invasive activities, questionnaires/
surveys, and procedures
Current Regulations
In 1981, the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) issued regulations based on the Belmont Report:
DHHS issued Code of Federal Regulations (CFR) Title 45
(public welfare), Part 46 (protection of human subjects). FDA issued CFR Title 21 (food and drugs), Parts 50
(protection of human subjects) and 56 (Institutional Review Boards).
Belmont Report
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
Report of the National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research April 18, 1979
– Respect for Persons l Informed consent l Protection for the vulnerable
– Beneficence l Maximize possible benefits l Minimize possible harms
– Justice l Fair distribution of research burdens vs. benefits
Principles of Human Subject Protection The Belmont Report: Guiding Ethical Principles
45 CFR Part 46 - DHHS Policy for Protection of Human Research Subjects- Subpart A Adopted January 13, 1981 Revised June 18, 1991 Also know as “The Common Rule” –Federal Policy for Protection of Human Subjects, June 18, 1991 –adopted by 17 federal agencies
Subpart B-Additional DHHS Protections Pertaining to
Research, Development, and Related Activities Involving Pregnant Women, Fetuses, and Neonates (non-viable and those of uncertain viability)
Subpart C- Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects (adopted in 1981) – Not adopted by the FDA
Subpart D- Additional DHHS Protections for Children Involved as Subjects in Research
Additional Protections Included in 45 CFR 46
Federal-Wide Assurance (FWA00005561)
l The Medical Sciences Campus - UPR, through the FWA, have pledged to protect human subjects and comply with all relevant federal regulations.
l The requirements of the Assurance apply to ALL research, regardless of funding source. Failure by an investigator to adhere to the requirements of the Assurance may cause the institution to have its Assurance suspended or revoked.
Human Research Subjects Protection Office (OPPHI)
l Was created on October 2006 as the administrative support office for the 3 IRBs. – Promote and enhance the ethical conduct of
research – Provide oversight for ongoing human subjects
research – Promote education for investigators, students,
institutional officials and IRB members – Evaluate research conduct that does not comply
with the requirements of the institution
Institutional Review Board
Institutional Review Board (IRB) is an administrative body established to protect the rights and welfare of human research participants recruited to participate in research activities that are conducted under the auspices of the institution with which it is affiliated. IRBs have the authority for all research activities to:
§ Approve or disapprove § Require modifications in § Assess violations § Investigate subject complaints § Conduct continuing reviews
What Is an IRB?
l There is a required minimum of 5 members but these 5 must include: 1 scientist, 1 nonscientist and one person who is not affiliated with the institutions.
l We have physicians, scientists, nurses, health educators, epidemiologists, dentists, pharmacists, social workers and administrators to name but a few.
UPR-Medical Sciences Campus
Type and Volume of Studies at UPR MSC
l Three different IRB panels: – Social Behavioral Research (60% student initiated) – Biomedical Research (Pediatrics, Oncology, HIV-AIDS) – Prisoner Research, Children Research
l Last year submissions 1,261: – Full Board Review Studies 18.9% – Except/Expedited Review 81.8%
l About 30-35 studies reviewed each month (new studies)
UPR Medical Sciences Campus
l UPR/MSC IRB Committees – IRB #1
l Chair: Dra. María del R. González – IRB #2
l Chair: Dra. Vanessa Sepúlveda
– IRB #3 l Chair: Dra. Luz Muñiz
What The IRB Wants To Know
l Do you understand ethical research? – Training requirement
l What are you doing? – Procedures/Protocol
l Who are you doing it to? – Subject Population – Inclusion/Exclusion Criteria
l What are the risks and benefits? l How will you ensure voluntary participation?
Managing Protocol Review
l What requires IRB review? l Which form(s) do you need to complete? l Types of Review
– Initial Review – Continuing Review – Amendments – Adverse Events
l Process of review – Exempt – Expedited – Full
What requires IRB review?
l MSC Policy – All human subjects’ clinical or behavioral
research conducted by UPR MSC investigators, regardless of its source of financial support, must be approved by the IRB unless the IRB determines it to be exempt from their review, and must comply with IRB policies and principles.
Which form(s) do you need to complete?
l For protocol submission: – E-mail account – IRBWISE Account Request Personal Information – Curriculum Vitae (all study personnel directly
involved with the research study) – Training Certificates (all study personnel)
l HIPAA l Human Subjects Protection
Human Subjects Protection and HIPAA Training Requirements
l All investigators and research team members involved in the conduction of research involving human subjects, shall document they have received training in human research subjects protection regulations and the HIPAA law.
– HIPAA
l http://citiprogram.org
– Human Subject Participation Protection l http://citiprogram.org
Types of Reviews
l Level of risk determines route of review Exempt Expedited Full Low Minimal Higher
RISK
What is minimal 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
Exemption from (FULL) IRB Review
l Investigators do not have the authority to determine whether research involving human subjects is exempt from full review. Even if an investigator believes that a project is exempt, an application must be submitted to the IRB Office for a final determination.
Exempt - IRB Review of Research
■ Exempt – ‘no risk’ activities ● 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 Chair or IRB designee may approve (no Cont. Review)
Expedited IRB Review (Minimal Risk)
● Involves only activities from an expedited list, such as: - Data / materials collected solely for non-research purposes (medical records) - 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 l IRB Chair or IRB designee may approve
Full IRB Review
Research that involves greater than minimal risk requires review and approval by a full IRB board including but not limited to research with: Children, prisoners, pregnant women, fetuses and other
vulnerable populations Experimental drugs or devices Most invasive procedures Sensitive questions or is likely to be stressful for the subject
Initial Protocol Submission Process
Online Application: IRBWISE – http://irb.rcm.upr.edu/ (all items must be answered) – Additional Documents (if applies):
l Informed Consents (English/Spanish) – Child Assent
l Proposal l Instruments, questionnaires, surveys l Advertisements l Endorsement Letters l FDA 1572 Form l Investigator’s Brochure or Package Insert l IND Documentation
Background/Significance
l Should contain a cogent summary of previous work and rationale for the study
l Should not be a cut and paste from the grant l References should be included l There should be clear aims and endpoints l What do you hope to gain by doing this
research?
Subject Selection and Enrollment
l How are subjects identified? – Ads, charts, referrals, PI’s own clinic, support
groups, public records. l How, when and by whom are subjects for
contacted about study? – In person? Should be by someone who has
reason to know confidential medical information. – Letters?
Subject Selection and Enrollment
l Inclusion/Exclusion Criteria – Should be a list – Should include appropriate laboratory parameters – Should include appropriate medical exclusions
l Who obtains consent? Who gives consent?
Study Procedures
l Should include sufficient detail to ascertain what subjects will actually experience while in study. – Time commitment. – Setting or site where study procedures occur. – Any “routine” agents to be used – such as
sedation. – Consent form with detail in lay terms.
Biostatistics
l A formal sample size is generally necessary. l Why does the PI need this many subjects? l Are there enough subjects to answer the
study question? l How are the data to be analyzed? l Just because the PI says it is a pilot study
doesn’t mean they don’t need statistics.
Risks and Discomforts
l Should be listed clearly, quantitatively and in order of seriousness.
– Should include risks of withdrawal from current medications. – Non medical risks? Social, legal, financial or psychological
risks? – Is loss of confidentiality a legitimate risk or concern? – What about loss of privacy? – Is there a complete list of adverse events in the drug or
device brochure?
Benefits
l Compensation is not a benefit. l If there are benefits to the individual subjects
these should be discussed first, then any potential benefits to future society.
l A common error we see is the “overstatement” of benefits.
Example of good benefit statement: There will be no direct health benefits to you as a result of your participation in this study.
Safety Monitoring
l How are the data to be monitored and by whom? – Not all studies require a DSMB but if one is necessary who
does it involve? Is it independent? Should it be? – Are there objective criteria for withdrawal of subjects when
safety is in question? – Are there stopping rules? – Is there a plan for reporting to the IRB?
Electronic Signatures
l Students proposing to engage in human subject research must have a faculty member as an advisor. The student cannot be the principal investigator. – Faculty Members
l Department Chair
– Students or medicine residents l Faculty Advisor and Department Director
Procedure for Continuing Review
l Renewal requests through the IRBWISE system at least six weeks before approval expiration date
l Electronic reminders l Include report of AEs l For Projects conducted in one year or less, a
continuing review application to close the file must be submitted.
Procedure for Amendments
l Changes in approved research l Changes in study personnel l Revised Informed Consents (if applies) l Revised Investigator’s Brochures l Protocol Deviations l Protocol Violations
– must be reported within 10 days – Minor violations at continuing review
AEs and SAEs Definitions
l Adverse Event – an unfavorable medical occurrence in a human subject associated with the subject’s participation in the research.
l Serious Adverse Event – an AE that results in any of the following:
– Death – Life threatening – Hospitalization (initial or prolonged) – Incapacity – Congenital abnormality
Relationship between AE and Unanticipated Problems
Example of an Unanticipated Problem that is not AE and Need to be Reported to OHRP 45 CFR Part 46
l An investigator conducting behavioral research collects individually identifiable sensitive information about illicit drug use and other illegal behaviors by surveying college students. The data are stored on a laptop computer without encryption, and the laptop computer is stolen from the investigator’s car on the way home from work.
Other Unanticipated Problems
– Investigator must report the following promptly to the IRB l Adverse events (unexpected and related or likely related to the research as
determined by the PI) l Breaches in confidentiality l Incarceration of subject in study not approved for prisoners l Unintentional protocol deviations that involved risks l Emergency protocol changes (deviations) l Complaints that indicate risks or can’t be resolved by the research staff
Report of AE’s and SAE’s
l Unanticipated problems that are SAEs should be reported within 1 week of becoming aware – Internal SAEs must be reported in 48 hrs.
l Other internal unanticipated problems should be reported within 2 weeks. • Multicenter Protocols – Report offsite SAEs and/
or unexpected AEs to the IRB within 10 working days of notification.
l All SAEs and/unexpected AEs must be summarized in the Continuing Review.
Informed Consent
l Informed Consent Process:
� Information
� Comprehension
� Voluntariness
Informed Consent Basic Elements
l Research – Purpose – Duration – Procedures
l Risks l Benefits l Alternatives
l Confidentiality l Compensation for Injury l Whom to Contact l Right to Refuse or
Withdraw
Consent Process and Forms
l Consent is a process and not just a form. l The form is the document that captures the
signature and records the process of agreement to participate.
l Timing and Place is important – PI should give us details.
l Once consent is signed, person is considered enrolled in study.
Consent Process and Forms
l For long and/or complicated studies, investigators should stress to subjects the importance of keeping their copy of the consent form for reference.
l The original consent form, which is maintained in the investigator’s records, needs to be signed BEFORE ANY RESEARCH TAKES PLACE and dated by the subject.
Consent and Assent
l Adults = those greater than and equal to age 21. l Adults and sophisticated teens can use the “adult”
consent form. l Anyone less than 21 must have a parent or
guardian’s permission (at least one) in order to participate.
l We have an assent form template for kids 7-14. l But assent may be obtained verbally. (IRB Waiver) l We do consider some kids emancipated such as
married teenagers.
What are we looking for?
l OPPHI Primary Reviewer Template – Inconsistencies between documents (Proposal,
IRBWise, Consent Forms) – Purpose (Objectives) – Study Population (gender, #, age, study period) – Summary (IND, # of arms, case-control, vulnerable
population) – Investigator (Staff certificates) – Recruitment (Where, who, how, Ads) – Subject Selection (equitable?) – Incentive (coercive)
What are we looking for? (cont.)
– Risk to participants (relative to research) – Potential Benefit (direct, altruism) – Risk/Benefit Analysis (are risks minimized by study
design and reasonable in view of potential benefits) – Confidentiality (are provisions to protect the privacy
adequate?) – Data oversight (DSMB, stopping rules) – Issues with Research Methodology or Data Analysis
What are we looking for? (cont.)
– Consent Form l Reading Level (6th grade) l MSC Compensation in case of injury paragraph l # pages, Margin 2’’ l E-mail OPPHI l Expected duration of subject’s participation l Approximated number of subjects involved in the study
– Assent (Reading Level) – Proposal (Version and Date, # pages, references) – Instruments (Data Abstraction, CRF, sensitive questions)
IRB Voting Categories
l Approved l Pending – requires minor changes
– Primary reviewer or chairperson may recommend approval
l Deferred – Major concerns – Must undergo another full board meeting
l Disapproved – must re-submit as a new protocol
Remember:
l IRB approval must be obtained
prospectively – Before you start your research.
l The IRB does not grant retroactive approval for research that has already taken place.
Deadlines for Submission
l Yearly calendar of IRB meetings is posted in the IRB website http://irbrcm.rcm.upr.edu/
l IRB Meetings are being held every two weeks
l In order to be considered for a meeting, complete applications must be submitted two weeks prior to the IRB meeting.
Contact us
l For general information and assistance: Human Research Subjects Protection Office UPR Medical Sciences Campus Second Floor Suite A-236 Main Building Phones: (787) 758-2525 Ext. 2510-2515 Website: http://irbrcm.rcm.upr.edu/ Email: [email protected]
Página Web del IRB: http://irbrcm.rcm.upr.edu/
Página IRBWise: http://irb.rcm.upr.edu/
Página: https://www.citiprogram.org/
Resources for Investigators
l OHRP Website • http://www.hhs.gov/ohrp/
l 45 Code of Federal Regulations Part 46 • http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html
l FDA Website • http://www.fda.gov/
l 21 Code of Federal Regulations Part 50 • http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/
CFRSearch.cfm?CFRPart=50
Questions? Please contact:
Georgamaly Estronza, MS, CIP IRB Administrator/Research Compliance Officer [email protected] or 787-758-2525 Ext. 2510-2515