Investigator Responsibilities for
Research
Shannon Simmons, BA, CIP
March 14, 2014
Process Improvement Team
Vanderbilt Human Research Protections Program
Agenda
Review Investigator Responsibilities
 Discuss FDA Warning letters
 Q &A
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PI Responsibilities
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In a nutshell, the PI is responsible for:
◦ Human Subject Protection
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Training
Conflict of Interest
IRB Approval
IND/IDE
Study Conduct
Informed Consent
Amendments
Continuing Review
Data Safety Monitoring
Adverse Events
Complaints
Record Retention
In other words…EVERYTHING!
FDA Warning Letter
L. Diaz, MD– November 4, 2011

Failure to conduct or adequately supervise the clinical investigations
 Delegated responsibilities, but lacked oversight of the study activities

Failure to ensure that the investigation was conducted according to the investigational
plan
 Included 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
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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)
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Adverse events were not evaluated/graded per protocol
•
Admission that he had ignored the clinical trials
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Study documentation ended after his SC left in 2007
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He had no knowledge of how the studies were monitored
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 subjects
• The 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."
FDA Warning Letter
A. Ubani, MD,– November 21, 2013
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Failed to ensure that the investigation was conducted according to the
investigational plan.
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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.
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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.
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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:
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subjects will be screened only after all medical records have been received and reviewed against protocol
inclusion and exclusion criteria.
FDA response to investigator:
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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.
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 Investigator regarding concerns:
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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.
Failure 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.
General Responsibilities of
Investigators (VI.B.1)

Subject: Procedure for General Responsibilities of Investigators
Procedure:
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.
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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.
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C. The Investigator will apply for IRB review and approval according to IRB
policies and procedures prior to conducting human subjects research.
General Responsibilities of
Investigators
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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.
General Responsibilities of
Investigators
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G. The Investigator will assure that required
approvals from other university committees or
institutions are granted prior to beginning research
activities.
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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).
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I. The Investigator will disseminate new
information regarding the use of FDA agents in research
to participants as he/she becomes aware.
Training
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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 protections
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.
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Training
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The Investigator is also responsible for
ensuring that all individuals conducting
the research are adequately qualified and
licensed to perform the research related
procedures.
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
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Response from FDA:
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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.
FDA Warning Letter
B. Doft, M.D- Cont (Second Time Around)
Failure to obtain informed consent
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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.
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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.
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:
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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.
Conflict of Interest
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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.
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.
Types of IRB Determinations

Non-Research
◦ Research = systematic investigation designed to
develop or contribute to generalizable knowledge.
 Case studies
 Quality assurance projects
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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
 BioVU
Types of IRB Determinations
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Exempt – 6 categories
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Expedited – 9 categories; minimal risk
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Standard – greater than minimal risk
◦ Educational tests, surveys, interviews, observations of
public behavior
◦ Collection or study of existing data
◦ 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)
◦ Pharmaceutical/drug studies
◦ Device studies
◦ Intervention studies
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.
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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.
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.
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Supplemental Form for Devices
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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.
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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.
Study Conduct
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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.
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.
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.
FDA Warning Letter
February14, 2012
J. Louis G., M.D
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Failure 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.
FDA Warning Letter
February14, 2012
J. Louis G., M.D-cont
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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 Form
◦ Note to file pain in shoulder-event not documented in Case report Form
◦ Physician 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.
◦ Discrepancies 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.
FDA Warning Letter
February14, 2012
J. 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
intervals
 Continual 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.
Adherence to the Protocol

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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.
Informed Consent Process
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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.
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Free from coercion and undue influence
 An 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.
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Documentation
 Provide document for review
 Appropriate for vulnerable population circumstances
 Answer questions
 Verbalizes Understanding
Elements of Informed Consent
Required
 Research
(Purpose/Duration/Procedures)
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Risks/discomforts
Benefits
Alternatives
Confidentiality
Whom to contact
Compensation/
treatment for research
related injury
Right to refuse or withdraw
http://www.ClinicalTrials.gov
(FDA regulated studies)
Additional
 Unforeseen risks to subject
(fetus)
 Anticipated reasons for
termination from the study by
PI
 Costs
 Consequences of withdrawal
by participant
 New findings
 Number of subjects
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.
Documentation of Consent:
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Should be legible, factual and thorough.
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Should include items such as when the person:
•
•
•
•
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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.
Persons Who Cannot Read/Write
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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.
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.
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.
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.
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).
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), AND
 Involved 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 IRB
Adverse Events - FDA

Serious Adverse Event
FDA defines a serious adverse event as an event
that results in any of the following outcomes:
o death;
o a life-threatening adverse event;
o inpatient hospitalization or prolongation of existing
hospitalization;
o a persistent or significant disability/incapacity;
o a congenital anomaly/birth defect; or
o requires intervention to prevent permanent impairment or
damage.
Non-Compliance

Non-Compliance with the Protocol
◦ An 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.

Clinical investigators are in charge and held
accountable
Penalties for significant noncompliance
 Warning Letters (posted on FDA
website)
 Disqualifications/Restrictions/Debarments
in conduction FDA regulated research
(posted on FDA website)
 Criminal prosecutions/prison/fines

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.

Complaints

Examples of complaints:
Have not received compensation
Have 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
 Parking
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).
More cartoons from Mayne Cartoon Research Laboratories are at
http://www.researchcartoons.com
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.
Questions
Questions? Comments? Concerns?

For future questions you may contact
Shannon Simmons
875-4628
shannon.d.simmons@vanderbilt.edu