Major Modifications and Additions to HMC IRB Manual 2/01/2010 Page # Modification/Addition Justification 14 IRB member with a COI is not counted toward quorum FDA and OHRP guidance 15 Policy and Procedure manual fully reviewed every 2 years Reflects current practice. Interim changes reviewed and approved by IRB. 18 Administrative fee increased (from $1500 to $2000) Reflects current practice 25, 28 FDA contacts for reporting Facilitate reporting 33 Faculty member who is investigator must accompany resident/student when the resident/student is presenting to IRB Reflects current practice. 34 Telephone conference for IRB meeting Allowed in extraordinary circumstances. OHRP guidance 3/28/2000 44-47 Continuing Review Chapter updated Per OHRP guidance 10/20/09 53-55 Adverse Event and Unanticipated Problems Chapter updated Per OHRP (12/17/09) and FDA (4/2007) guidance 56-58 Protocol Deviation Chapter added Reflects current practice. 59-60 Quality Improvement Audit Chapter added Reflects current practice. 64 Consent Document Handling Clarified Reflects current practice. 68 Definition of Children updated Pennsylvania Law – 35 P.S. 10101 (2004) 86-88 IND/IDE guidance added Facilitate assistance to investigator 89-93 HUD Procedure added Reflects current practice.
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Major Modifications and Additions to HMC IRB Manual 2/01/2010
Page # Modification/Addition Justification
14 IRB member with a COI is not counted toward quorum FDA and OHRP
guidance
15 Policy and Procedure manual fully reviewed every 2
years
Reflects current
practice. Interim
changes reviewed and
approved by IRB.
18 Administrative fee increased (from $1500 to $2000) Reflects current
practice
25, 28 FDA contacts for reporting
Facilitate reporting
33 Faculty member who is investigator must accompany
resident/student when the resident/student is presenting
to IRB
Reflects current
practice.
34 Telephone conference for IRB meeting Allowed in
extraordinary
circumstances. OHRP
guidance 3/28/2000
44-47 Continuing Review Chapter updated Per OHRP guidance
10/20/09
53-55 Adverse Event and Unanticipated Problems Chapter
updated
Per OHRP (12/17/09)
and FDA (4/2007)
guidance
56-58 Protocol Deviation Chapter added Reflects current
practice.
59-60 Quality Improvement Audit Chapter added Reflects current
practice.
64
Consent Document Handling Clarified Reflects current
practice.
68 Definition of Children updated
Pennsylvania Law –
35 P.S. 10101 (2004)
86-88 IND/IDE guidance added Facilitate assistance to
investigator
89-93 HUD Procedure added Reflects current
practice.
HAMOT MEDICAL CENTER
INSTITUTIONAL REVIEW BOARD
POLICY AND PROCEDURE MANUAL FOR THE
PROTECTION OF HUMAN RESEARCH
SUBJECTS
2010
These policies and procedures have been developed in conjunction with
FDA and HHS Guidelines and Regulations for Institutional Review Boards
If the research fails to meet one of the two criteria, human subjects are not involved
and the research can be found exempt from IRB review on that basis.
If the research meets the criteria for involving human subjects, it must fulfill one or
more of the following criteria to be considered exempt:
1. Research conducted in established or commonly accepted educational settings,
involving normal educational practices, such as:
a. research on regular and special education instructional categories, or
b. research on the effectiveness of, or the comparison among instructional
techniques, curricula or classroom management methods.
42
2. Research involving only the use of educational tests (cognitive, diagnostic,
aptitude, achievement) if:
a. the data are recorded so that subjects cannot be identified in any way,
b. none of the investigator's own current students are subjects. (If
someone other than the investigator has contact with subjects, the study
can be exempt.)
3. Research involving only observation of public behavior. When subjects can be
identified in any way and any of the following conditions apply, the study must
undergo expedited or quorum review if:
a. the subject's responses or conduct (if they became public) may place the
subject at risk of criminal or civil liability or be damaging to the
subject's financial standing or employability,
b. the subject's responses deal with sensitive aspects of personal behavior
for example; illegal conduct, drug use, sexual behavior, use of alcohol,
c. the investigator participates in the activities being observed.
4. Research involving only surveys or interviews. If subjects can be identified in
any way or if subjects are children the study must undergo expedited or
quorum review.
5. Research involving only surveys or interviews of elected or appointed public
officials or candidates for public office is eligible for exemption. (Public
officials are defined as those individuals elected or appointed to local, state or
federal office.)
6. Research involving the collection or study of existing data (retrospective
study) including documents, records, pathological specimens, or diagnostic
specimens that are publicly available, or if the information is recorded by the
investigator in such a manner that human subjects cannot be identified in any
way. To qualify for exemption, the existing data must be de-identified as part
of health care operations by medical staff who are employed by the institution,
residents, medical interns, employees, or individuals who have signed a
Business Associate Agreement with the institution.
7. If the subjects are filmed or videotaped, the research can not qualify as exempt
and must undergo expedited or quorum review. However, some benign studies
(as determined by the chairperson) in which subjects are audiotaped may
qualify for exemption.
43
8. Taste and food quality evaluations and consumer acceptance studies, if
wholesome foods without additives are consumed or 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. Department of Agriculture.
Procedures:
1. The investigator must follow the research approval process (Appendix C),
complete a protocol development form (Appendix D), when applicable, and
consent (Appendix D), as appropriate, and then submit the protocol (Appendix
D) for approval and/or modification.
2. The approved protocol is then submitted to the IRB Administrator for review by
the Administrator and/or Chairperson to determine if the protocol meets the
criteria for exemption from Committee review.
3. The investigator is notified in writing, regarding the disposition of the project
(Appendix E).
(For students, written approval must be obtained from the investigator's school or
college IRB and the HMC IRB Administrator before beginning any research
activities involving human subjects.)
Note: The following schools and colleges located in Erie and the surrounding area
have their own IRBs: Penn State Erie - The Behrend College; Edinboro University
of Pennsylvania; Gannon University
4. When the project does not qualify for exemption, the Administrator or designee
will assist the investigator to prepare the protocol and consent for expedited or
quorum review.
5. When external funding is involved or institutional assurances are required, the
IRB Chairperson and/or Administrator will determine whether the research is
eligible for exemption, even if the investigator has obtained an exemption from
his/her college or university.
Note: Emergency (one-time) use of a test article can be exempt from IRB review,
provided such emergency is reported to the IRB within five working days (Ch. XI
Emergency (One-Time) Use of a Test Article).
44
CHAPTER V
MONITORING STUDIES
CONTINUING AND FINAL REVIEWS
All Quorum and Expedited Reviews will be subject to continuing and final reviews.
A. Continuing Review:
1. The IRB shall continue to review the approved project until it is concluded or
discontinued and no subjects/patients are being followed.
2. The IRB shall have authority to observe or have a third party observe the
consent process and the research (45 CFR 46.109 (e)).
3. Continuing review shall occur to assure that the investigation is being
conducted in compliance with the requirements, understandings, and
recommendations of the IRB, the FDA, and the HHS.
4. The frequency of continuing review will be determined at the time of initial
review and will occur at least once per year, will be recorded in the IRB
minutes, and the investigator will be notified in writing of the continuing
review date. When setting the interval for continuing review, the IRB will
consider:
The nature of any risks posed by the research project;
The degree of uncertainty regarding the risks involved;
The vulnerability of the subject population;
The experience of the investigators in conducting research;
The IRB’s previous history with the investigators;
The projected rate of enrollment;
Whether the research project involves novel interventions;
45
The associated animal studies when they indicate a significant risk for
humans;
The anticipated rate of severe adverse reactions.
5. The frequency of continuing review may be modified at any time as declared
necessary by the IRB.
6. The IRB may determine that certain projects need verification, from sources
other that the investigator, that no material changes have occurred since the
previous IRB review. When making this determination, the IRB will consider
whether:
a. the investigator has previously failed to comply with HHS regulations
or IRB Policy;
b. a concern exists that material changes may have occured without IRB
approval;
c. significant discrepancies were detected in information submitted to the
IRB.
The Chairperson will notify the investigator that verification of data is necessary.
Possible actions include, but are not limited to: 1) direct communication between a
representative of the IRB and the sponsor or their designee; 2) review of progress
reports from monitoring visits; 3) review of the Investigator Binder and at least five
consecutive signed consent forms (or all consent forms when less than five subjects
are enrolled); 4) review of individual case report forms and the corresponding medical
charts.
B. Final Review
A final review is accomplished to formally close a study by the IRB. An
investigation or research project may be closed for several reasons including:
1. has met the completion date of the original protocol,
2. is closed by the commercial sponsor, or
3. all follow-up is complete.
46
C. Procedure for Continuing and Final Reviews
A Study Summary Chart identifying the status of all active projects is maintained
with the IRB files and updated bi-monthly to ensure timely review of ongoing
research protocols (Appendix H).
1. The Administrator reviews the Study Summary Chart for projects requiring
continuing or final review and forwards a letter and a Continuing/Final Review
Form to the investigator (copy to the coordinator) approximately six weeks
before the scheduled review (Appendix D, E).
2. The investigator must complete the Continuing/Final Review Form and
submit, with a copy of the currently used consent form, to the Administrator
three weeks in advance of the scheduled review. The Administrator checks
each form for completeness, resolves any questions, and places the study on
the meeting agenda.
3. When the Continuing Review Form has not been received by the Administrator
three weeks before the meeting, one phone call will be made to the
investigator/coordinator and one certified letter will be sent to the investigator
as a reminder to complete and submit the Continuing Review Form. If no
response is submitted before the scheduled IRB meeting, approval will be
terminated (See Chapter II for termination process – Please note: OHRP does
not require that a report be sent to them when a project is terminated for this
reason.)
4. A summary of all projects is forwarded to the committee for review on week
before the scheduled meeting. (The completed forms are available at the
meeting, as well as the study folder.) For continuing reviews the summary
includes:
The number of subjects accrued;
A summary of: 1) serious adverse events related/possibly related to the
study , 2) unanticipated problems that increase risk to subjects or others, 3)
withdrawal of subjects from the research, 3) complaints about the research
since the last IRB review;
A summary of any relevant recent literature, interim findings, and
amendments or modifications to the research since the last review;
47
Any other relevant information, especially information about risks
associated with the research; and
A copy of the current informed consent document and any newly proposed
consent document. The Administrator will review the document to verify
that the most accurate, up-to-date version is provided to the subject. If the
site is not using the appropriate version, the Administrator will report this
to the Committee and the Investigator. As part of the consent document
review, the IRB will consider whether any significant new information has
been adequately disclosed and whether risks and discomforts have been
appropriately described.
5. As with initial review, the following requirements must be satisfied:
a. risks to subjects are minimized and reasonable,
b. selection of subjects is equitable,
c. informed consent will be obtained,
d. informed consent will be appropriately documented,
e. where appropriate, the research plan makes adequate provision
for monitoring the data collected to ensure the safety of subjects,
f. where appropriate, there are adequate provisions to protect the
privacy of subjects and to maintain the confidentiality of data,
g. additional safeguards have been included in the study to protect
the rights and welfare of vulnerable subjects.
6. The IRB may:
a. approve the continuing review information as submitted.
b. require modifications, conditions or amendments to the protocol,
consent document, or research process to allow the study to
continue (changes should be submitted to the IRB within ten
working days),
c. request additional information (should be submitted to the IRB
within ten working days),
d. convert the continuing review to a final review and provide the
investigator with the rationale for doing so. The investigator can
appeal this decision. (see Chapter III - Appeal Procedures.)
6. A letter is forwarded to the investigator and copied to other pertinent parties
indicating continuing review approval or termination of the project (Appendix
E). The study summary chart is updated regarding continuing or final review.
For continuing studies, the next review date is listed.
48
CHAPTER VI
STUDY PERSONNEL
Investigator
Investigators must have the appropriate scientific and medical background, as well as
expertise in the area in which the research will be conducted.
Investigators are responsible to:
1. submit to the IRB Administrator
a. a Request for Approval form (Appendix D), b. a Documentation of Research Approval form c. the protocol, d. the investigator's brochure, e. reports of any previous animal and/or human studies, f. materials to be used in obtaining the consent of human subjects, g. any advertisements for recruiting subjects, h. a curriculum vitae (CV), except when the investigator is on staff at Hamot
Medical Center, Regional Cancer Center, or Shriners’ Hospitals for Children. A CV will also be required if requested by one of the members of the IRB.
i. following approval; a periodic written progress report (continuing review), and
j. a final report.
Note: Failure to respond to IRB requests (eg, continuing or final reports) will
result in withdrawal of IRB approval.
2. successfully complete the IRB Basic Education Program
3. attend the IRB meeting to initially present the protocol or additional
information (When a resident or student presents to the IRB, he/she must be
accompanied by a faculty member who is an investigator for the study.),
4. await written IRB approval before involving human subjects in the study,
5. receive an "Exemption" letter before involving human subjects in any exempt
research project,
49
6. submit any changes to a protocol or consent form to the IRB within ten
calendar days of receipt (if applicable). Changes may include:
a. adding investigators, b. changing methods for conducting the trial, c. modifying consent forms, etc.
7. Receive written expedited or full approval before implementing changes,
8. comply promptly with accurate and adequate information to all IRB requests
concerning a protocol,
9. conduct the clinical investigation according to the protocol:
a. Protocol
1) Each clinical investigation shall have a written plan.
2) All changes or revisions to a protocol, and reasons therefore, shall be
documented by the investigator, dated, and maintained with the
protocol.
b. Amendments/changes
1) An investigator shall not implement a change in the protocol, if the
change or deviation may increase the risk to subjects or may adversely
affect the validity of the investigation or the rights of the human
subjects without the prior review and written approval of the sponsor
of the investigation and the IRB.
2) If changes to a protocol become necessary, investigators must obtain
IRB approval before instituting such changes.
3) The entire amended protocol and consent form must be submitted for
review and approval by the IRB.
a) Major changes are those that directly affect the level of risk to the
subjects. Major changes must undergo quorum review. Examples
include, but are not limited to:
the addition of new, vulnerable populations as subjects,
changes in strategies or interventions,
alterations in drug dosage or period of administration, or
changes in enrollment age that negatively affect risk or result in
recruitment of a vulnerable population.
b) Minor changes are those that do not affect the level of risk to
subjects. (See Chapter IV, B. Expedited Review)
50
When a change is made to eliminate or reduce the risk to human subjects, it may be
implemented before review or approval by the sponsor and the IRB. The investigator
shall notify the sponsor and the IRB in writing within ten (10) working days after
implementation.
In drug and biologic studies, the investigator must notify the sponsor of proposed
changes in a protocol. For significant risk devices, except when the deviations are
necessary to protect the life or physical well-being of a subject in an emergency, FDA
must approve all changes or deviations from the investigational plan that may affect
the plan's scientific soundness or subject rights, safety, or welfare. Deviations that are
necessary to prevent harm should be reported to the IRB and to the sponsor, who
should report the deviations to FDA.
The procedure for submitting protocol changes to the IRB includes:
a. A detailed letter describing the nature of the requested changes, the
reasons for making each change, and any possible effect the changes may
have on subjects.
b. For changes involving a different principal investigator or a new co-
investigator, attach the new investigator's name, signature, and title.
Investigator qualifications (curriculum vitae) may be requested.
c. For changes to the consent form, submit a new consent form with
notations indicating any language on the new form that differs from that
previously approved by the Committee.
d. For modifications to any other attachment(s), submit the changes with
notations indicating any language that differs from that originally
approved.
10. notify the IRB promptly of:
a. serious adverse reactions (See Chapter VII)
b. unanticipated problems that result in increased risk
c. protocol deviations that result in increased risk
d. termination of human subject involvement, and
e. completion of the study (See Chapter V).
11. maintain records of all submissions to and all actions by the IRB regarding the
clinical investigation,
51
12. retain all study records (case report forms, office files, appointment books,
regulatory documents, correspondence, etc.,) for:
a. drug and biologic studies
1) at least two years following the date on which the study drug is
approved by the FDA for marketing for the purposes that were the
subject of the investigation, or
2) at least five years following the date on which the results of the clinical
investigation for a research or marketing permit is requested for the
purposes that were the subject of the investigation,
b. device studies
1) for two years after the later of the following dates: the date on which
the investigation is terminated or completed or, the date that the
records are no longer required to support a premarket approval
application or a notice of completion of a product development
protocol.
Note: For device studies, the investigator must maintain a record of the
exposure of each subject to the investigational device, including the
date and time of each use, and any other therapy.
13. report significant new findings to subjects, particularly if it could affect their
willingness to participate,
14. transfer records to another person or group who will accept responsibility for
the records, e.g., the manufacturer, or another investigator in the event the
investigator retires, relocates, or for any other reason withdraws from the
responsibility of maintaining records for the period of time required. (Written
notice of such transfer must be submitted to the IRB and the sponsor.)
To comply with FDA record retention requirements, clinical investigators
should arrange to be kept informed by study sponsors of the status of the
application for their respective studies.
52
Note: The investigator may maintain all study records or, in those cases in which the subject
is a patient in a hospital or other facility, the records may be maintained as part of the patient
hospital or clinical record. If a hospital or clinic keeps the records, the investigator must
ensure that the records are retained at least for the length of time set forth by the regulations.
An investigator may retain records either in their original form or by means of microfilm,
microfiche, photocopies, or other accurate reproductions of the original records. If copies are
used, however, they must be legible and the investigator is required to assure that such
reproductions are true and accurate copies of the original. When reproduction techniques
(e.g., microfilming) are used, a reader and photocopying equipment should be readily
available. If written notes, erasure marks, or other changes are not apparent on the
reproduction, a notation of this fact should be clear on the reproduction of the record and the
original records should be retained for the time required.
Raw data, entered directly into a computer system, are considered to be the original or true
copy of the data whether it is printed out as a hard copy or stored as computer files. An
acceptable computerized data collection system would be one that: (1) allows data entry only
by authorized individuals; (2) controls the ability to delete or alter previously entered data
and provides an audit trail for such data changes (e.g., modification file); (3) protects the data
base from tampering; and (4) ensures data preservation. If records are retained in a computer
data system, suitable equipment should be readily available to produce a hard copy of the
data. Data should be retrievable in such a fashion that all information regarding each
individual in a study is attributable to that individual, i.e., case report equivalents must be
available.
FDA may audit any and all records that might support microfilm, microfiche, or other stored
data. These records must be maintained just as paper case report forms must be maintained.
Coordinator
Research Coordinators must meet the employment requirements of Hamot Medical Center
and successfully complete the IRB Basic Education program. In addition, the Research
Coordinator must complete one of the following:
the Comprehensive Clinical Research Coordinator Education Program from Barnett
International (FDA-regulated research). A comparable program may fulfill this
requirement pending IRB Chairperson review and approval;
Foundations of Clinical Research Self Study Program, The Center for Clinical
Research Practice, available through the IRB Administrator (FDA-regulated research);
Hamot Research Coordinator Education Program available through the IRB
Administrator (non-IND/IDE research).
53
CHAPTER VII
ADVERSE EVENTS AND UNANTICIPATED PROBLEMS
INVOLVING RISKS TO SUBJECT/PATIENT OR OTHERS
A. Definitions
1. Adverse Event (AE)
Any unfavorable and unintended diagnosis, symptom, sign, syndrome, or
disease that occurs during the subject’s enrollment in a study if absent or less
severe at baseline.
2. Serious Adverse Event (SAE)
Any adverse experience that is considered related or possibly related to the
study and results in any of the following outcomes:
a. death
b. a life-threatening adverse experience (Any adverse drug experience that
places the subject, in the opinion of the investigator, at immediate risk
of death from the reaction as it occurred, i.e., it does not include a
reaction that, had it occurred in a more severe form, might have caused
death).
c. inpatient hospitalization or prolongation of existing hospitalization
d. a persistent disability/incapacity (A substantial disruption of a person’s
ability to conduct normal life functions.)
e congenital anomaly/birth defect
Additionally, important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse
experience when, based upon appropriate medical judgment, they may
jeopardize the patient or subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.
54
Examples of such medical events include allergic bronchospasm requiring
intensive treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in hospitalization, or the development of
drug dependency or drug abuse.
3. Unanticipated Problem (UP)
Any incident, experience, event, or outcome that meets ALL of the
following criteria:
a. Unexpected (in terms of nature, severity, or frequency) given (a)
the research procedures that are described in the protocol-related
documents and (b) the characteristics of the population being
studied.
b. Related or possibly related to participation in the project
c. Suggests that the project places subjects/patients at greater risk
of harm.
B. Relatedness – defined as the best estimate of the PI at the time that the SAE or UP is
reported of the causal relationship between an intervention and the serious adverse
event/unanticipated problem.
1. Unrelated – event is clearly due to extraneous causes (e.g.,
underlying disease, the environment, etc.)
2. Possibly related - Must include at least 2 of the following:
a. A reasonable temporal relationship to the intervention;
b. Could not readily have been produced by the subject’s
clinical state;
c. Could not readily have been due to environmental or other
interventions;
d. Follows a known pattern of response to the intervention.
3. Related – Must include all 4 of the following:
a. A reasonable temporal relationship to the intervention;
b. Could not readily have been produced by the subject’s
clinical state or have been due to environmental or other
interventions;
c. Follows a known pattern of response to the intervention;
d. Disappears or decreases with reduction in dose or cessation
of intervention and recurs with re-exposure.
55
C. Reporting
1. Investigators are responsible to:
a. record and report all AEs, SAEs, and UPs to the Sponsor/Manufacturer
per Sponsor/Manufacturer requirements (typically defined in research
protocol.)
b. record and report all SAEs, and UPs to the IRB as follows:
1) By telephone within 24 hours (or within 24 hours of knowledge of
the event) followed by a written report within five days after the
event using the appropriate IRB form (Serious Adverse Event or
Unanticipated Problem form [Appendix I]).
2) At continuing review
D. Actions taken by IRB
The IRB will evaluate all reports of Serious Adverse Events and Unanticipated
Problems at a convened meeting. Some of these reports will be on-site events and
others will be off-site events (ie., multicenter trial). The committee will consider
whether corrective actions or substantive changes need to be instituted in response to
these reports. Possible actions include:
Modification of inclusion/exclusion criteria;*
Implementation of additional procedures for monitoring subjects/patients;*
Suspension of enrollment of new subjects/patients;*
Suspension of research procedures in currently enrolled subjects;*
Modification of informed consent documents to include description of newly
recognized risks;*
Provision of new information regarding risks to previously enrolled
subjects/patients.*
* For clinical trials, this will often be addressed in a study amendment.
56
CHAPTER VIII
PROTOCOL DEVIATIONS
Federal regulations require that IRBs develop written procedures that will ensure prompt
reporting by the study team of any changes in research activity. Protocol deviations represent
one such change in the IRB-approved research. Protocol deviations must be reported to the
IRB by the investigator or his/her designee. These reports are reviewed by the IRB to
determine whether the previously approved protocol, informed consent document,
risk/benefit ratio, and study procedures remain acceptable. The IRB also uses reports of
protocol deviations as a way of tracking adherence to the protocol and Good Clinical
Practice. If the investigator is not implementing the protocol as approved, the IRB may
choose to suspend or terminate that approval.
A. DEFINITIONS
1. Protocol Deviation – A failure to follow procedures specified in the approved
research submission.
2. Pre-approved Protocol Deviation – A prospective decision by the investigator,
sponsor, and IRB to allow a deviation from the approved research submission.
3. Minor Protocol Deviation – A deviation that has little or no impact on subject
Safety, the risk/benefit ratio, value of data collected, research design, or scientific
conclusions.
4. Major Protocol Deviation – A deviation that has harmed or posed a significant
risk to a subject, or has compromised the scientific integrity of the study.
B. PROCEDURES
1. Pre-approved Protocol Deviations
a) When the investigator wants to deviate from the approved research
submission (e.g., wishes to enroll a subject who does not meet the
approved inclusion/exclusion criteria; wants to schedule a follow-up
visit outside the study window because the patient is out of town; etc.)
57
he/she must submit a written request to the IRB Administrator.
Included with this request should be written approval for the deviation
from the Sponsor. Depending on the nature of the deviation, approval
may be given through expedited review by the Chairperson,
Administrator or designee, as appropriate. Whenever a potential
concern exists regarding subject safety, the deviation will be presented
to the full IRB for review.
b) If the deviation is approved as submitted, the investigator will be
notified in writing.
c) If the requested deviation results in significant safety/study design
concerns, the investigator may be asked to provide additional
information to the committee or be asked to attend the next IRB
meeting to explain his/her request. The IRB decision regarding the
requested deviation will be conveyed to the investigator in writing.
d) If the requested deviation is considered a revision of research activity,
the IRB may require that the change be submitted as an amendment to
the protocol.
2. Minor Protocol Deviations
When minor protocol deviations occur, they may be reported at the time of continuing
review. These deviations do not affect the scientific soundness of the research plan or
the rights, safety, or welfare of the human subjects. Examples of minor deviations
include: 1) drawing blood samples close to, but not precisely, at the specified time
points; 2) a subject who cancels their follow-up visit and is unable to reschedule until
after the study window has closed; 3) inadvertently skipping questions on a quality of
life questionnaire in an investigational drug study.
3. Major Protocol Deviations
a) The principal investigator is responsible for reporting all Major
Protocol Deviations to the IRB as soon as possible, but no later than 5
working days after the investigator becomes aware of the event.
b) These deviations should be reported using the Protocol Deviation Form
(Appendix J).
58
c) If the deviation resulted in a Serious Adverse Event, the Serious
Adverse Event Form must be completed, as well.
d) If IRB members ask for additional information regarding the deviation,
this will be communicated to the investigator by the Administrator and
a written response requested. At the Chairperson’s discretion, the PI
may be asked to attend the next IRB meeting to explain the reason for
the protocol deviation, how the subject was impacted, and how the
deviation will be prevented in the future.
e) The Protocol Deviation Form, Serious Adverse Event Form (if
applicable) and additional information (if requested) will be distributed
to the IRB members at the next regularly scheduled meeting.
f) The committee will consider the information submitted by the PI and
determine whether the response was adequate or whether additional
actions or follow-up is needed. Further actions may include, but are not
limited to:
1) revisions to the protocol, consent document, or corrective action
plan;
2) audit of the study by the IRB;
3) increased frequency of continuing review;
4) suspension or termination of the study.
g) The PI will be notified, in writing, of the IRB decision after the
protocol deviation is reviewed.
59
CHAPTER IX
QUALITY IMPROVEMENT AUDIT
The Office of Human Research Protection has recommended that the IRB move toward a
system of interacting with investigators that is proactive and emphasizes prevention of harm.
To accomplish this, the Administrator will perform a Quality Improvement Audit of
Investigational Drug, Investigational Device, and Humanitarian Use Device Projects. This QI
audit is intended to evaluate and improve both institutional systems and individual research
projects with emphasis placed on the responsible conduct of research.
Because research involving investigational drugs/devices typically present the greatest risk of
harm to subjects, and humanitarian use device (HUD) projects can be particularly difficult to
implement, these projects are the main focus of the QI Audit. The audit will allow the IRB to
provide timely feedback/education to the investigators regarding implementation of
subject/patient protections. It will not only help investigators/staff identify areas that are or
could become non-compliant with regulatory standards, but will also provide methods to
meet best practices. The audit will allow the IRB to verify that Research/HUD projects are
being conducted in an appropriate fashion.
As new Research/HUD projects are instituted, the Principal Investigator (PI) and Study
Coordinator will be asked to notify the IRB Administrator when the first subject/patient is
enrolled in the project. Every effort will be made to schedule the Quality Improvement Audit
within one month of enrollment. The Administrator will review the Investigator (Regulatory)
Binder, Medical Chart, and Case Report Form (when possible) utilizing the Quality
Improvement Audit Form (Appendix K). The review may also include interview of study
personnel and observation of Research/HUD practices. The presence of the Principal
Investigator/Study Coordinator during the review is optional. If desired, a brief meeting can
be scheduled to discuss the results after the audit is complete. A written report of the Quality
Improvement Audit will be forwarded to the PI with copies to the Study Coordinator and IRB
Chairperson. The PI can provide a written response to the report, if desired, within 30 days of
report receipt. The response should include: 1) identification of any inaccuracies; 2) an
explanation of circumstances (extenuating or otherwise) that could account for certain
findings, and 3) acknowledgement of findings requiring correction. The PI’s comments will
be forwarded to the IRB Chairperson for review, attached to the QI Audit report, and placed
in the IRB file. The report may be forwarded to the IRB for review at the IRB Chairperson’s
discretion. This will typically occur if a significant deviation from standard practice has been
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identified, the deviation threatened the safety of participants, or the process that lead to the
deviation has been inadequately addressed. The IRB will take action, as appropriate.
If during the audit, the Administrator identifies noncompliance that may be serious or
continuing, the Administrator will:
immediately notify the PI or the PI designee
promptly notify the IRB Chairperson.
If the compliance is found to be serious/continuing, the Chairperson will follow pertinent
IRB procedure (Chapter II, Suspension and Termination of a Clinical Investigation).
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CHAPTER X
INFORMED CONSENT
When a clinical investigation places any human subject at risk, the investigator must first
obtain and document informed consent of the subject or the subject's legally authorized
representative. Pennsylvania law, P.S. 1301.811A, requires the physician investigator to
obtain informed consent when administering an experimental medication, using an
experimental device or using an approved medication or device in an experimental manner.
All investigators obtaining consent for subject enrollment must be approved by the IRB.
Under the Department of Health and Human Services (HHS) regulations, information
provided for the purposes of oral or written informed consent may not include any
exculpatory language through which the subject is made to waive, or appear to waive, any of
his/her legal rights, including release of the investigator, the sponsor, or the institution or its
agents from liability for negligence.
The consent document itself is a written summary of the information that should be provided
to the subject including any human subject who is a control (Appendix D). (Many clinical
investigators use the consent document as a guide for the verbal explanation of the study.
Reading grade level of the document should be a maximum of 8th grade.) The subject's
signature provides documentation of consent to participate, but this is only one part of the
consent process.
The entire informed consent process should:
1. give a subject adequate information concerning the study,
2. provide adequate opportunity for the subject to consider all options,
3. provide adequate opportunity for the investigator or designee to respond to the
subject's questions,
4. ensure to the best of the investigator's ability, that the subject has
comprehended this information,
5. obtain the subject's voluntary agreement and signature to participate, and
6. continue to provide information as the subject or situation requires.
To be effective, the process should provide ample opportunity for the investigator and the
subject to exchange information.
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The IRB should ensure that technical and scientific terms are adequately explained or that
common terms are substituted. The IRB should ensure that the informed consent document
properly translates complex scientific concepts into simple words that the typical subject can
read and comprehend. The IRB Administrator will perform a preliminary review of each
consent document to ensure federal requirements are met.
A. Elements
(Note: The first eight basic elements of informed consent are designated in 21
CFR 50.25. The remaining elements (9-12) are required by Hamot IRB.)
1. A statement that the study involves research, an explanation of the purpose of
the research, the expected duration of the subject's participation, the
approximate number of subjects who will participate in the study, a description
of the procedures to be followed, and identification of any procedures that are
experimental.
2. A description of any reasonably foreseeable risks or discomforts to the subject.
3. A description of any benefits to the subject or to others that may reasonably be
expected from the research.
4. A disclosure of appropriate alternative procedures or courses of treatment, if
any, that might be advantageous to the subject.
5. A statement describing the extent, if any, to which confidentiality of records
identifying the subject will be maintained, and the possibility that the Food and
Drug Administration (FDA) may inspect the records.
Note: State that research records may become part of a participant's hospital or
medical records. Explain that for all drug and device studies records will be
kept confidential to the extent permissible by law.
6. For research involving more than minimal risk, an explanation as to whether
any compensation will be paid to subjects, whether any medical treatment will
be available if injury occurs, and, if so, what the treatment consists of, or
where further information may be obtained.
7. An explanation of who to contact for answers to pertinent questions about the
research, the research subject's rights, and who to contact in the event of a
research-related injury to the subject. (Phone numbers should be included.)
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8. A statement that participation is voluntary, that the subject may refuse to
participate or discontinue participation at any time, and that the refusal or
discontinuation will involve no penalty or loss of benefits to which the subject
is otherwise entitled.
9. A statement that significant new findings that may develop during the course
of the research and may relate to the subject's willingness to continue
participation will be provided to the subject.
10. A statement that the subject's questions about the research have been
answered.
11. A statement that the subject will receive a copy of the consent form.
12. Lines for the following signatures and dates for each:
a. the subject or the subject's authorized representative,
b. the investigator, and
c. an impartial witness.
B. Additional Elements
When appropriate, one or more of the following elements of information shall also be
included in the consent form:
1. A statement that the particular treatment or procedure may involve risks to the
subject (or to the embryo or fetus, if the subject is or may become pregnant)
that are currently unforeseeable.
2. Anticipated circumstances under which the subject's participation may be
terminated by the investigator without regard to the subject's consent.
3. Financial Considerations:
a. Describe any monetary rewards or payments to the subject for
participating; include the payment schedule and an explanation of the
extent to which payment will be made if the subject withdraws or is
removed from the study prior to its completion.
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b. Explain any costs associated with participation. For studies involving
clinical treatment, this includes expenses associated with the study that
would not ordinarily be incurred with standard treatment for the
subject's condition.
c. For studies involving more than minimal risk, state whether or not costs for
medical treatment will be provided if injury occurs as a consequence of the
research.
d. For studies involving more than minimal risk, state whether or not any
money will be paid voluntarily as compensation for injury (eg, for lost
wages or for pain and suffering) that occurs as a consequence of the
research.
e. For all sponsored studies, state who is sponsoring the study, who will
receive study funds, and how these funds will be used. For studies in
which the IRB has identified a significant conflict of interest (COI),
inform the subject regarding the COI and how it will be managed.
4. The consequences of a subject's decision to withdraw from the research, and
procedures for orderly termination of participation by the subject.
5. A statement that informs participants if the research is being performed to
fulfill requirements for a doctoral dissertation, master's thesis, or classroom
assignment.
6. The approximate number of subjects involved in the study.
C. Documentation
A copy of the signed consent document must be placed on the patient's chart/medical
record after consent is obtained. A copy should be immediately given to the patient.
The original should be placed with the study records. The actual procedure for
obtaining legally effective, adequate, and appropriate informed consent will be fully
documented by using one of the following forms:
1. A written document including the "basic elements" of informed consent, as
well as the "additional elements" as appropriate, may be read to the subject
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or the subject’s legally authorized representative; however, both must be
given adequate opportunity to read and sign the written consent. A copy of
the consent document must be given to the subject at the time the consent
form is signed.
2. In rare instances, such as in studies of subjects in emergency situations, or with
impaired sight (e.g., blind or dyslexic), or illiterate subjects who are fully
capable of consenting, but are not capable of reading or signing a consent
form, the IRB may approve the use of a short form document with an oral
narrative.
The short-form consent document with the oral narrative must include:
a. a narrative that contains all the information and elements of the standard
consent form.
b. the signature of the impartial witness on the narrative and the short-form
consent document to verify that the oral and written information are the
same. A witness must be present when the narrative is read to the subject.
c. the signature of the authorized representative on the short-form consent
document stating the subject willingly agrees to participate in the research
described in the narrative.
d. the signature of the investigator on both the narrative and the short-form
consent document.
The investigator then gives the subject copies of both the narrative and the
short-form consent document. The investigator must submit a letter to the
sponsor and the IRB (addressed to the IRB) requesting this procedure and
explaining why it is appropriate, with a copy of the narrative that will be
read to the subjects and the short-form consent document.
3. Non-English Speaking Study Subjects
a. When the study subject population includes non-English speaking people,
or the clinical investigator or the IRB anticipates that the consent
interviews will be conducted in a language other than English, the IRB
should require that an accurately translated consent document be prepared.
The translated document and the original approved consent form should be
given to the subject.
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b. If a non-English speaking subject is unexpectedly encountered,
investigators will not have a written translation of the consent document
and must rely on oral translation. Investigators should carefully consider
the ethical/legal ramifications of enrolling subjects when a language
barrier exists. If the subject does not clearly understand the information
presented, the subject's consent will not truly be informed and may not be
legally effective. (If investigators enroll subjects without an IRB-approved
written translation, a "short form" written consent document in a language
the subject understands should be used to document that the elements of
informed consent were presented orally.)
4. A person who speaks and understands English, but does not read and write,
can be enrolled in a study by "making their mark" on the consent document.
Development of a short form or a narrative statement is not required, but an
impartial witness should be present to attest to the adequacy of the consent
process and to the subject's voluntary agreement. The signatures required by 21
CFR 50.27(b)(2) are necessary. These include:
a. the subject or the representative,
b. the impartial witness, and
c. the investigator or the person obtaining the informed consent.
C. Waiver
1. Informed consent may be waived in an emergency situation
(Emergency Use of a Test Article, A.4.).
2. The IRB may approve a consent procedure which does not include, or
which alters, some or all of the elements of informed consent, or waive
the requirements to obtain informed consent provided the IRB finds and
documents that:
a. the research involves no more than minimal risk to the subjects;
b. the waiver or alteration will not adversely affect the rights and
welfare of the subjects;
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c. the research could not practicably be carried out without the
waiver or alteration; and
d. whenever appropriate, the subjects will be provided with additional
pertinent information after participation.
Note: Written informed consent may be required at the discretion of
the IRB chairperson, even if the study poses "no" or "minimal" risk.
3. The reason for waiving consent (as appropriate) must be documented on
the approval letter and in the minutes of the IRB meeting in which the
waiver is reviewed or approved. Protocol-specific information