Shannon Simmons BA CIP March 14 2014 Process Improvement Team Vanderbilt Human Research Protections Program Agenda Review Investigator Responsibilities Discuss FDA Warning letters Q amp A ID: 322309
Download Presentation The PPT/PDF document "Investigator Responsibilities for Resear..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Investigator Responsibilities for Research
Shannon Simmons, BA, CIPMarch 14, 2014Process Improvement TeamVanderbilt Human Research Protections ProgramSlide2
Agenda
Review Investigator ResponsibilitiesDiscuss FDA Warning letters Q & ASlide3
PI Responsibilities
In a nutshell, the PI is responsible for:Human Subject Protection Training
Conflict of Interest
IRB Approval
IND/IDE
Study Conduct
Informed Consent Amendments Continuing Review Data Safety Monitoring Adverse Events Complaints Record RetentionIn other words…EVERYTHING!Slide4
FDA Warning Letter
L. Diaz,
MD–
November 4, 2011
Failure
to conduct or adequately supervise the clinical
investigationsDelegated responsibilities, but lacked oversight of the study activities Failure to ensure that the investigation was conducted according to the investigational planIncluded individuals in the study that should have been excluded; not following procedures for classifying AE’s and reporting SAE’s, etc
Failure
to return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the
drug.
Response
from Investigator regarding concerns:
Admission that he had a lack of involvement and oversight in the conduct of the two clinical trials being cited
He found letters from monitors, sponsors, and IRB’s that he had never opened and/or had never seen before (letters that noted the study had been suspended/terminated for failure to submit the continue review reports)
Adverse events were not evaluated/graded per protocol
Admission that he had ignored the clinical trials
Study documentation ended after his SC left in 2007
He had no knowledge of how the studies were monitoredSlide5
FDA Warning Letter
L. Diaz, MD– November 4,
2011(cont)..
FDA
response to investigator
:
It is the PI’s responsibility to ensure the studies were conducted properly and in compliance with FDA regulation in order to protect the rights, safety, and welfare of human subjectsThe PI’s statements indicate systemic failure in the conduct of investigational research and there are significant concerns about the safety of the subjects enrolled in the study and the integrity of the data from the site
Despite the PI’s statement he will not conduct FDA-related clinical trials in the future
the PI is still
required to submit in writing the actions
that has
taken to prevent similar violations in the future (required in 15 working days)
The
FDA letter included the following statement:
“Failure to adequately and promptly explain the violations noted above may result in regulatory action without further notice."Slide6
FDA Warning Letter
A. Ubani, MD,– November 21, 2013
Failed
to
ensure that the investigation was conducted according to the investigational plan.
Protocol requires that subjects are excluded that have a history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last five years.
Two subjects enrolled with history of cancer within the five year exclusion criteria
Protocol requires all subjects that are enrolled to have “high cardiovascular risk” as defined by the inclusion criteria.
Subjects were enrolled who did not fit the definition of being at
“high cardiovascular risk”
as defined by the inclusion criteria in the study protocol.
Response from Investigator regarding concerns:
subjects
will be screened only after all medical records have been received and reviewed against protocol inclusion and exclusion criteria.
FDA response to investigator:
This response is inadequate
because
there are no details
regarding how
the corrective
actions will be implemented.
There are no details
regarding how
it will be ensured
that medical records are received prior to randomization, and how
the PI and the staff will review
those records against protocol inclusion and exclusion criteria.
Without
these details,
it cannot be determined whether the corrective
actions appear sufficient to prevent similar violations from occurring in the future.Slide7
FDA Warning Letter - continued
A. Ubani, MD,– November 21, 2013
Failed
to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the
investigation
required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in
the investigation.Inconsistencies in regards to when lab results were received for visits versus when signature was given by the PI. Date signed off on the lab results were before the date stated that the lab reports were actually received.
Response
from
Invest
igator regarding
concerns:
Laboratory
reports will be promptly revised and documented in a timely
manner
FDA response to investigator:
This response is inadequate response is inadequate because it is unclear what you intend to do with respect to revising laboratory reports.
F
ailure to maintain adequate and accurate case histories with respect to signature dates raises concerns about the validity and integrity of data captured at your site.Slide8
General Responsibilities of Investigators (VI.B.1)
Subject: Procedure for General Responsibilities of InvestigatorsProcedure:
This procedure outlines the general responsibilities of Investigators conducting research involving humans.
I. Investigator Responsibilities.
A. The
Investigator will obtain knowledge
regarding federal, state, and local laws and regulations, institutional policies, IRB policies and procedures, the ethical principles of The Belmont Report, and Good Clinical Practice (GCP) Guidelines, if applicable, prior to conducting research involving humans. B. The
Investigator will assure protection of the participant’s rights and safety
by adequate design and conduct of research, as well as oversight of all research processes and procedures and other research personnel involved in research activities.
C. The
Investigator will apply for IRB review and approval
according to IRB policies and procedures prior to conducting human subjects research.Slide9
General Responsibilities of Investigators
D. The Investigator will complete the required IRB training through the University of Miami Collaborative IRB Training Initiative (CITI). Access to training is available on the VHRPP Website at
http://www. vanderbilt.edu/irb/
on the right hand side of the webpage under “Links”
E. The
Investigator will assure that all key study personnel (KSP) have completed the required Human Subjects training
prior to IRB submission of research applications. In addition, the Investigator will participate and assure that all KSP participate in continuing education at least annually as required by the VHRPP policy.Key study personnel is anyone who will have a significant involvement in the planning, conducting, and analysis of any activity that will involve human research
participants
F
. The
Investigator will respond to all IRB requests
for additional information in regards to verifying knowledge, training, and resources adequate to perform research involving human participants.Slide10
General Responsibilities of Investigators
G. The Investigator will assure that required approvals from other university committees or institutions are granted
prior to beginning research activities.
H. The
Investigator will assure the proper handling, storage, and dispensing of all investigational agents
and when not using the services of the Investigational Drug Service (See VHRPP Procedure XI.B.1 for proper procedure).
I.
The Investigator will disseminate new information
regarding the use of FDA agents in research to participants as he/she becomes aware.Slide11
Training
Investigator Responsibility- To complete initial and annual VU IRB human research protections training.
Initial training
involves the completion of
one of two
“Basic” courses in CITI: “Group
1: Biomedical Research Investigators and Key Study Personnel” Or “Group 2: Social Behavioral Research Investigators and Key Study Personnel” Annual Renewal of IRB Education/Training requires documentation of the completion of at least one of the following:Completion of a CITI Course
Attendance of at least one
IRB
educational
course(e.g., IRB
Essentials,
IRB
News you Can Use, and/or Research Matters); or
Completion of the OHRP “Investigator 101” training module; or
Attendance of a local, regional, and national conference regarding human research protectionsSlide12
Training
Investigator’s Responsibility- To provide training regarding the study (i.e. site initiation visit) and the training for the responsibilities that are delegated.
Investigator’s
Responsibility-
To assure that other Investigators and KSP are adequately trained in human research protections and have met continuing education requirements as well as specific study training.Slide13
Training
The Investigator is also responsible for ensuring that all individuals conducting the research are adequately qualified and licensed to perform the research related procedures.Slide14
FDA Warning Letter
B. Doft, M.D., –June 12, 2013 (Second Time around)
Failure to ensure that the investigation was conducted according to the investigational plan.
Required the subject to have a Best Corrected Visual Acuity (BCVA), using Early Treatment Diabetic Retinopathy Study (EDTRS) charts, of 20/40−20/320.
Two subjects who did not meet this inclusion criterion were included in the study.
Protocol stated that the "Best corrected visual acuity (BCVA) will be measured by trained and certified personnel at the study sites".
BCVA was measured by uncertified personnel in 5 subjects in 14 instances.
VA examiner will be masked to the patients' study eye and will conduct refraction, VA assessments, and low luminance testing . . . No other direct patient care tasks can be performed by the VA examiner".
The VA examiners measured the intraocular pressure (IOP), without being masked to the study eye, in nine subjects
Response from FDA:
Enrollment
of subjects who do not meet eligibility criteria and
failure
to
ensure
that certified and properly masked evaluators measured VA raise concern about the validity and integrity of the data collected at
the site.Slide15
FDA Warning Letter
B. Doft, M.D- Cont (Second Time Around)Failure
to obtain informed consent
Two
subjects underwent study procedures (i.e., BCVA, IOP, ocular imaging, fluorescein angiograms, optical coherence tomography, eye dilation, or the collection of laboratory examples) prior to signing the informed consent form.
A subject underwent screening procedures prior to signing the consent form on the same day. Additionally, the same subject could not read the informed consent form, because the form was provided after the subject’s eyes were dilated.
Response from FDA:
Failure
to obtain informed consent in accordance with 21 CFR Part 50 prior to involving subjects in research raises concerns about
the
protection of study subjects enrolled at
the site
.Slide16
FDA Warning Letter
H. Frazer, Pharm D, Clinical Investigator– June 5, 2013 Failed to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the
investigation
Study
protocol required that patient enter pain assessments into the LogPad, however, five pain assessments were entered by the study coordinator and reflect the study coordinator’s or nursing staff’s assessments, rather than the subject’s assessments.
Response
from Investigator regarding concerns:
Subject was put on a “vent” (ventilator), was sedated, and was unable to participate in the evaluation of pain, via the LogPad or otherwise
Indicated that the study coordinator entered data directly into the LogPads, based on information received either from the nursing staff or from study subjects. Indicated that the study coordinator entered pain scores “based on the staff nurses educated guess as to the pain level when the patient was obviously in pain as evidence of the patient’s tossing and painful expressions on the patient’s face.
Stated that “at times when the patient was either unwilling to complete the pain score or too disoriented to write into the diary or use the LogPad, [the study coordinator] asked the patient what her pain score was and entered that value onto the diary and added the patient’s initials.
Indicated that once made aware of this practice, the site had already enrolled 8 subjects into the study, and all of them had completed the trial. The monitors also challenged the validity of the pain data.
FDA response to
Investigator
:
This response was inadequate it did not provide information that would mitigate the violation’s significant impact on data integrity, reliability, and validity
Failed to provide a corrective action plan.
Slide17
Conflict of Interest
All conflicts of interest (PI and KSP) must be disclosed to the IRB and the Medical Center Conflict of Interest Committee (MCCOIC) or University Conflicts Committee (UCC).Disclosures must be provided with the initial IRB application, at each continuing review and within 10 days of becoming aware of any previously undisclosed financial interest (via a Request for Amendment).
Investigators must
comply
with all recommendations of the MCCOIC and/or the UCC to minimize the conflict.Slide18
Conflict of Interest
New NIH COI reporting requirements compliance date for institutions became effective by August 24, 2012. Changes include:Reducing the minimum payment
researchers will be required to report (from $10,000 to
$5,000
).
Each
Investigator must complete financial conflict of interest training prior to engaging in research related to any PHS-funded grant or contract and at least every four years. Slide19
Types of
IRB
Determinations
Non-Research
Research = systematic investigation designed to develop or contribute to generalizable knowledge.
Case studies
Quality assurance projects
Non-Human Subjects
Human subject = a living individual about whom an Investigator obtains data either through intervention or interaction with the individual or identifiable private information.
De-identified specimens from a repository
BioVUSlide20
Types of
IRB
Determinations
Exempt – 6 categories
Educational tests, surveys, interviews, observations of public behavior
Collection or study of existing data
Expedited – 9 categories; minimal risk
Research on individual or group characteristics
Collection of data from voice, video, or image recordings
Blood draws – 550ml/8wks;
<
2 draws/wk or 50cc (3cc/kg)
Standard – greater than minimal risk
Pharmaceutical/drug studies
Device studies
Intervention studiesSlide21
Investigational Drugs
When the PI holds the IND for the investigational agent, a copy of the FDA acknowledgement letter is required as part of the IRB submission. If the
Sponsor holds the IND
the IRB will accept the IND number pre-printed in the Sponsor’s protocol as verification that the Sponsor has completed filing with the FDA.
When an IND is required the PI will complete the Form
1572 (Investigator Statement, which assures the PI will comply with FDA regulations related to the conduct of an investigation using an investigational drug or biologic) and submit it to the FDA. Slide22
Investigational Devices
When an IDE is required, the Investigator will complete the FDA’s Investigator’s Agreement form for submission to the FDA. A copy of this form must be submitted with the initial IRB application.
The initial IRB submission should also
include all correspondence
from the sponsor and/or FDA
in regards to the determination of
the device as being a non-significant (NSR) or a significant risk device (SR). The research will not start until the IDE letter from the FDA has been submitted to the
IRB.Slide23
Supplemental Form for Devices
The IRB is required to document the basis for risk determination based on the proposed use of a device in the research by
considering the nature of the harm that may result from the use of the device.
The
form (#1134)
requests:
information about the device, if it meets any of the exemption categories, if another IRB has made a determination about the device, as well as if any special training is needed to use the device and
accountability information.Slide24
Study Conduct
Investigators responsibilities during the conduct of an approved research study include:Obtaining and documenting informed consent of subjects or subjects’ legally authorized representative
PRIOR TO
the subjects’ participation in the research unless the IRB has approved a waiver of consent.Slide25
Study Conduct
Obtaining prior approval from the IRB for any modifications of the previously approved research, except those necessary to eliminate apparent immediate hazards to the subject(s).
Ensuring progress reports and request for continuing review
and approval are submitted to the IRB in accordance with VHRPP P&P’s, and the institution’s Federal Wide Assurance. Slide26
Study Conduct
Providing to the IRB prompt reports of any unanticipated problems involving risks to subjects or others.
Providing to the IRB prompt reports of
serious or continuing noncompliance
with the regulations or the requirements or determinations of the IRB.
This requires monitoring and/or internal auditing of your studies.Slide27
FDA Warning Letter
February14, 2012J. Louis G., M.DFailure to conduct the investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by an Institutional Review Board
(IRB)
or
FDA
Implanted
with the control article on the incorrect cervical spine level then performed a second surgery to remove and then reinsert on the correct disc level without that procedure being authorized in the protocol.FDA Response to Investigator: Major
safety concern
because it placed
additional risks
of serious harm due to the
need for
a second surgery only four
days
after the first. These risks include infection, bleeding, risks associated
with
anesthesia, and neurological damage including paralysis and death.
The
subject
was placed
at
increased risk
of developing long-term complications such as worsening pain and disability as
a
result of the critical error
made.Slide28
FDA Warning Letter
February14, 2012J. Louis G., M.D-cont
Failure
to maintain accurate, complete, and current records of each subject’s case
history
Failure
to report adverse events that were a direct result of the implanted device. Note to file states pain in cervical area-event not recorded in Case report FormNote to file pain in shoulder-event not documented in Case report FormPhysician note signed by investigator and the subject’s medical monitor report of persistent hand and forearm numbness noted to be related to device-no documentation to show this event was noted as a SAE in the Case Report Form
FDA response to Investigator:
Inconsistency
and inaccurate records of AEs and SAEs are major subject safety and data quality concerns.
D
iscrepancies
in
reporting
AEs may call into question the integrity and reliability of the data
obtained
during the course of the study
and
increase
the risk of harm
to the participating subjects
. Slide29
FDA Warning Letter
February14, 2012J. Louis G., M.D-cont
Failure
to ensure that an investigation is conducted in accordance with the signed agreement, investigational plan, applicable FDA regulations, and any conditions of approval imposed by an
IRB
or FDA and failure to submit progress reports on the investigation to the sponsor and reviewing
IRB at regular intervalsContinual submission of IRB continuing reviews and progress reports late.
FDA response to Investigator:
Failure
to adhere to these requirements may
increase the risk of harm
to the participating subjects
.Slide30
Adherence to the Protocol
If you agreed to participate in conducting the study you agree to follow the protocol completely.Sites may have different standards of practice however if you agree to participate in the study you MUST follow the protocol.
The only time the investigator may make a modification to research activities without prior
IRB
approval is to
avoid an immediate hazard
to the participant. The PI must report the event to the IRB within 10 working days. Slide31
Informed Consent Process
Continuous process
The Investigator
assures the informed consent process in research is an ongoing exchange of information
between the research team and the study participants throughout the course of a research study. Informed consent is a continuous process of communication and acknowledgement over time, not just a signed document.
Free from
coercion and undue influenceAn Investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that
minimize the possibility of coercion or undue influence
.
Documentation
Provide document for
review
Appropriate for vulnerable population circumstances
Answer questions
Verbalizes
UnderstandingSlide32
Elements of Informed Consent
RequiredResearch (Purpose/Duration/Procedures)Risks/discomfortsBenefits
Alternatives
Confidentiality
Whom to contact
Compensation/
treatment for research related injuryRight to refuse or withdrawhttp://www.ClinicalTrials.gov (FDA regulated studies)AdditionalUnforeseen risks to subject (fetus)
Anticipated reasons for termination from the study by PI
Costs
Consequences of withdrawal by participant
New findings
Number of subjectsSlide33
Informed Consent
FDA Regulated Studies:For all research involving test articles regulated by the U.S. Food and Drug Administration (FDA)
, informed consent documents
should include a statement that a purpose of the study includes an evaluation of the safety of the test article.
Statements
that test articles are safe or statements that the safety has been established in other studies are not appropriate when the purpose of the study includes determination of safety.
In studies that also evaluate the effectiveness of the test article, informed consent documents should include that purpose, but should not contain claims of effectiveness. Slide34
Documentation of Consent:
Should be legible, factual and thorough.
Should include items such as when the person:
was initially provided information about the study;
was given a copy of the consent form;
was contacted to determine interest; and
signed the document.
Include details of special situations.Slide35
Persons Who Cannot Read/Write
The informed consent dialogue is extremely important when the investigator is obtaining informed consent from a research subject who cannot read.
An impartial witness must be present during the initial informed consent conversation.
If the research subject wishes to enroll in the study the subject may consent orally and if able, may sign and date the consent form.
After the subject has consented the witness signs and dates the consent form to attest that:
The subject received the information, the risks/benefits/alternatives were discussed and informed consent was freely given.Slide36
Amendments
Any changes to the IRB approved research must be submitted, reviewed, and approved by the IRB PRIOR to implementation.
The only time the investigator may make a modification to research activities without prior IRB approval is to
avoid an immediate hazard
to the participant. The PI must report the event to the IRB within 10 working days. Slide37
Continuing Review
Continuing Reviews must occur at a frequency no less than 12 months
but
may be
required more often.
Periodic
review of research activity is necessary to determine:If changes in risk/benefit have occurred;
If
there are any unanticipated
findings involving
risks to subjects;
and
If
there is any new information regarding the risks and benefits that should be provided to participants. Slide38
Continuing Review
There is no grace period extending the conduct of research beyond the expiration date of IRB
approval.
Screening and enrollment of new subjects
cannot
occur
after the expiration of IRB approval.If a study expires, the Investigator will
cease all research activities
as instructed in the expiration notice.Slide39
Data Safety Monitoring
The Investigator will provide a detailed description of the data safety monitoring plan (DSMP) in the initial application as well as the study protocol. This is required even in the absence of a DSM or DSMB.
All DSM or DSMB reports are to be
submitted to the IRB within 10 days
of receipt by the Investigator
when the report identifies a new risk or a change in the risk-potential benefit profile
. A “Request for Amendment” will accompany the reports along with the amended documents (e.g., consent document, IRB application). Slide40
IRB Definition (Policy III.L)
Unanticipated Problems Involving Risk to Participants or Others Any serious adverse event that in the Investigator’s
opinion:
Was
unanticipated
(not foreseeable at the time of the occurrence)
or unexpected (not previously seen), ANDInvolved risk to participants or others AND
AND/OR
Any
noncompliance with the
IRB
approved protocol that increased the risk or affected the patients rights, safety or welfare
.
Should be reported to the IRBSlide41
Adverse Events - FDA
Serious Adverse EventFDA defines a serious adverse event as an event that results in any of the following outcomes:
death
;
a
life-threatening
adverse event;inpatient hospitalization or prolongation of existing hospitalization;
a
persistent or significant disability/incapacity
;
a
congenital anomaly/birth defect
; or
requires intervention to prevent permanent impairment
or damage.Slide42
Non-Compliance
Non-Compliance with the ProtocolAn incident involving non-adherence to the protocol, but
One that typically does not have a significant effect on the subjects’ rights, safety or welfare and/or on the integrity of the resultant data.
Non-compliance with the Protocol may result from the actions of the participant, investigator, or study personnel.
The
IRB
should to be notified of any noncompliance with the study protocol that results in an increase in risk or a decrease in potential benefit to participants within 10 business days of the Investigator being notified of the deviation.Slide43
Clinical
investigators are in charge and held accountablePenalties for significant noncompliance
Warning Letters (posted on FDA website
)
Disqualifications/Restrictions/Debarments in conduction FDA regulated research (posted on FDA website)
Criminal prosecutions/prison/finesSlide44
Complaints
It is the responsibility of the Investigator to notify the IRB of any participant or other individual’s complaints regarding the research. The complaint may be reported at continuing review if it involves no risk
to the participants or others or does not change the risk/benefit ratio.Slide45
Complaints
Examples of complaints:Have not received compensationHave been billed for a research procedure
Upset with some aspect of the study
Wants results when the ICD stated they would not be shared
Information regarding study participation has not been sent as promised
ParkingSlide46
Record Retention
Retention of records as required by HHS regulations for at least three years after the completion of the study.
Retention of records as required by FDA when the study was conducted under an
IND is a minimum of two years after the marketing application is approved
for the drug for the indication for which it was being investigated.
All Health Insurance Portability and Accountability Act (HIPAA) related documentation must be maintained for at least six
(6) years from the date of the last use or disclosure of the Protected Health Information (PHI).Slide47
More cartoons from Mayne Cartoon Research Laboratories are at
http://www.researchcartoons.comSlide48
Conclusion
Being the PI of a research study is a huge undertaking that requires attention to detail and a tremendous amount of communication and documentation involving the study team, participants, the IRB, as well as other departments and agencies.
Thank you
for everything you do to ensure the rights, welfare and safety of the research participants we serve are protected. Slide49
QuestionsSlide50
Questions? Comments? Concerns?
For future questions you may contact Shannon Simmons875-4628
s
hannon.d.simmons@vanderbilt.edu