Compliance with the FDA Guidances on Investigator Responsibilities and the Form 1572

Compliance with the FDA
Guidances on Investigator
Responsibilities and
the Form 1572

Presented by
Paul Below, CCRA, CCRT
P. Below Consulting, Inc.

About the Speaker

• Clinical research consultant and GCP trainer based in
Minneapolis, MN since 2003
• Involved in project management, monitoring, auditing and
training for pharmaceutical and medical device client.
• Started career as a study coordinator in 1996
• ACRP CCRA since 2001 and ACRP Credentialed Trainer
since 2008
• Adjunct faculty for St. Cloud State University’s Masters
Degree Program in Applied Clinical Research
• Past President of the Minnesota Chapter ACRP

Learning Objectives

• Describe the general purpose and history of development
of the FDA’s Investigator Responsibilities Guidance for
Industry
• Define what the FDA considers to be adequate supervision
of study staff and other third parties
• Explain what the FDA considers to be the appropriate
delegation and adequate training of study-related tasks
• Examine investigator responsibilities outlined in the
guidance for protecting study subjects
• Discuss the FDA’s expectations for how to complete the
Form FDA 1572
Copyright © 2011 - P. Below Consulting, Inc. 3

Investigator Responsibilities Guidance

• Final version issued in
October 2009
• Initial draft issued May
2007
• Applicable to clinical trials
of drugs, biologics, and
medical devices


Guidance Purpose

To clarify for investigators and sponsors the FDA’s
expectations concerning investigator responsibilities:
 To supervise a clinical study in which some study
tasks are delegated to employees or colleagues of
the investigator or other third parties
 To protect the rights, safety, and welfare of study
subjects


About Guidance Documents

• Represents FDA's “current thinking” on ways to comply
with the regulations
• Not legally binding
• Can use an alternative approach if it satisfies the
regulations
• The use of the word “should” means something is
suggested or recommended but not required
• Non-compliance should not be cited in a FDA Form 483
(“Notice of Inspectional Observations” or written list of
discrepancies noted during an FDA inspection)


http://www.fda.gov/RegulatoryInformation/Guidances/ucm122046.htm7

Investigator
Responsibilities
Guidance History

Copyright © 2011 - P. Below Consulting, Inc.

Guidance History

FDA Guidance – Guideline for the Monitoring of Clinical
Investigations (January 1988):
“The monitor should visit the investigator at the site of
the investigation frequently enough to assure that … the
investigator is carrying out the agreed-upon
activities and has not delegated them to other
previously unspecified staff.”


Guidance History

FDA Guidance – A Guide to Informed Consent –
Information Sheet (January 1998):
“The clinical investigator is responsible for ensuring that
informed consent is obtained from each research
subject before that subject participates in the research
study. FDA does not require the investigator to
personally conduct the consent interview. The
investigator remains ultimately responsible, even when
delegating the task of obtaining informed consent to
another individual knowledgeable about the research.”


Guidance History

FDA Guidance – ICH Guidelines for Good Clinical Practice
(May 1997):
“The investigator should maintain a list of appropriately
qualified persons to who the investigator has delegated
significant trial-related duties” (Section 4.1.5)
“The investigator should ensure that all persons assisting
with the trial are adequately informed of the protocol, the
investigational product(s), and their trial-related duties and
functions” (Section 4.2.4)


Guidance History

Specific tasks indicated in ICH GCP that can be delegated:
 Making trial-related medical decisions
 Documenting and explaining protocol deviations
 Performing investigational product accountability
 Explaining correct use of investigational product and
check that subject is following instructions properly
 Obtaining informed consent
 Making CRF corrections


Recent Warning Letter

“According to the trial staff list for Protocol X, your clinical research
coordinators … were delegated responsibilities, including but not
limited to, affirmation of inclusion and exclusion criteria and
assessment of adverse events, serious adverse events, and study
endpoints. You had informed the FDA investigator that as you were
inexperienced in conducting clinical trials, you mainly relied on your
clinical research coordinators to conduct the study and complete the
study’s paperwork. In FDA’s review of the resumes of Mr. X and
Ms. X, … these individuals did not appear to be
qualified, certified, or significantly medically trained and licensed to
be independently making judgments related to determination of
eligibility of subjects for enrollment into the study and/or making the
determination as to whether or not adverse events were related to
the use of the investigational drug.”



“The protocol specified that the person obtaining informed
consent must be sufficiently trained on medical issues, so that
questions could be adequately addressed. The protocol
specifically required that this person have an M.D., Ph.D., or RN
degree. .. For all subjects enrolled into this study (Subjects 1001-
1008 and 1010-1013), the informed consent document and the
assent form for children 10-17 years of age were not obtained by
an MD, PhD, or RN, as required by the protocol.”
“For Subjects 1001-1007, X was not administered by the
principal investigator or a sub-investigator, as required by the
protocol. Instead, the X was administered by a study coordinator,
contrary to the criteria specified in the protocol.”



“We note that Ms. X served as the primary study coordinator … and
was terminated from your site as of December 4, 2006. We wish to
emphasize, however, that as the clinical investigator, it was your
ultimate responsibility to ensure that the studies were conducted
properly and in compliance with FDA regulations to protect the
rights, safety, and welfare of study subjects. We note that the
monitors from two different studies notified you on multiple
occasions that Ms. X was failing to follow the protocols and/or
incorrectly completing certain study-related tasks. Among the tasks
identified by the monitors were those for which she had not been
delegated authority. The fact that you permitted her to continue as
study coordinator despite these repeated notices indicates your
failure to conduct the study in accordance with the investigational
plans and the lack of adequate supervision on your part.”



“In a written affidavit signed by you during the FDA
inspection, you noted that you thought the training provided by
the monitors to you and your study coordinators was
sufficient, and that if there were problems, the monitors would
let you know. You further asserted that you did not know that
you had to supervise the study and ensure that the study
coordinators were correctly doing such things as completing
source records and case report forms, filling out adverse event
and hospitalization forms, and notifying the IRB and sponsor on
time.”


Supervision of the Study



• Drugs/Biologics
(21 CFR Part 312):
Investigators commit
themselves to personally
conduct or supervise the
investigation
• Medical Devices
(21 CFR Part 812):
Investigators commit
themselves to supervise all
testing involving human
subjects



• Common practice for investigators to delegate certain
study-related tasks to employees, colleagues or other third
parties (entities not under direct supervision of the
investigator)
• When tasks are delegated, the investigator is responsible
for providing adequate supervision of those to whom tasks
are delegated
• The investigator is accountable for regulatory violations
resulting from failure to adequately supervise the conduct
of the clinical study


Adequacy of Supervision

FDA focuses on four major areas to assess “adequacy”:
 Are individuals who are delegated tasks qualified to
perform such tasks?
 Did the study staff receive adequate training on how
to conduct the delegated tasks and were provided
with an adequate understanding of the study?
 Is there adequate supervision and involvement by the
investigator in the ongoing conduct of the study?
 Is there adequate supervision or oversight of any
third parties involved in the conduct of the study?


Appropriate Delegation

Individuals delegated tasks should be qualified by
education, training, and experience (and state licensure
where relevant) to perform the delegated tasks



Appropriate delegation is especially important for tasks
considered clinical or medical in nature such as:
 Evaluating study subjects to assess clinical response
to an investigational therapy (i.e., global assessment
scales)
 Providing medical care
to subjects during the
course of the study



• Most clinical/medical tasks require formal medical
training and may also have licensing or certification
requirements (may vary by jurisdiction such as states or
countries)
• Licensing requirements should be taken into account
when delegating specific tasks
• In all cases, qualified physician (or dentist, when
appropriate) should be responsible for all trial-related
medical decisions and care (ICH GCP section 4.3.1)


Texas Statutes Scope of Practice

• Physicians: Texas Occupations Code (151-167).
Special section on delegation of certain medical tasks
(Chapter 157). Available at:
http://www.statutes.legis.state.tx.us/Docs/OC/htm/OC.157.htm
• Physician Assistants: Texas Occupations Code
(204.202) – Scope Of Practice. Available at:
http://law.onecle.com/texas/occupations/204.202.00.html


Texas Statutes Scope of Practice

• Advanced Practice Nurses: Guidelines for Determining
APN Scope of Practice. Available at:
http://www.bon.texas.gov/practice/apn-scopeofpractice.html
• Registered Nurses: Texas Administrative Code (Rule
217.11) – Standards of Nursing Practice
• General nursing practice information available at:
http://www.bon.texas.gov/practice/gen_practice.html



During inspections of sites, FDA has identified the following
tasks that have been inappropriately delegated:
 Screening evaluations including obtaining medical
histories and assessment of inclusion/exclusion
criteria
 Physical examinations
 Evaluation of adverse events
 Assessment of primary study endpoints
 Obtaining informed consent



• The protocol may specify
the qualifications of
individuals to perform
certain protocol-required
tasks
• The protocol must be
followed even if state law
permits individuals with
different qualifications to
perform the task



If the state allows nurse
practitioners or physician
assistants to perform physical
examinations under supervision
of a physician, but the protocol
specifies that physical
examinations must by done by
a physician, then a physician
must perform such exams.



• Investigators should maintain a list of appropriately
qualified persons to who significant trial-related duties
have been delegated (ICH GCP section 4.1.5)
• The list should also include:
 Description of the delegated tasks
 Identification of dates on involvement in the study
 Identification of the training that individuals have received
that qualifies them to perform the delegated tasks (can
refer to an individual’s CV on file)
• Separate lists should be maintained for each study
conducted


Appropriate Training

Investigator should ensure there is adequate training for
all staff participating in the study including new staff hired
after the study has begun to meet unanticipated workload
or replace staff



Staff should be:
 Familiar with purpose of the study and protocol
 Have adequate understanding of the specific details
of the protocol and investigational product needed to
perform assigned task
 Aware of regulatory requirements and acceptable
standards for conduct of clinical trials and human
subjects protection
 Competent to perform or trained to perform
delegated tasks
 Informed of pertinent changes during conduct of trial


If the sponsor provides
training, the investigator
should ensure that their
staff receive the
sponsor’s training or
receive the training
materials from that
training that is pertinent
to the staff’s role in the
study


Supervision of Study Conduct

• Each study site should
have a distinct
individual identified as
the investigator who
has supervisory
responsibilities
• Investigators should
have sufficient time to
conduct and supervise
the study (ICH GCP
section 4.2.2)



• Sub-investigators should
report directly to the
investigator
• The Investigator should
have authority to terminate
the sub-investigator’s
involvement in the study
• Sub-investigators should
not be delegated the
primary supervisory
responsibility for the site



The following factors may affect the ability of the
investigator to adequately supervise the study:
 Inexperienced staff
 Demanding workload for staff
 Complex trials
 Large number of subjects enrolled at the site
 Seriously ill subject population
 Conducting multiple concurrent studies
 Conducting study from a remote location or at
multiple sites


Supervision Plan

The investigator should develop a plan for supervision that
might include the following elements:
 Routine meetings with staff to review trial
progress, adverse events, and protocol amendments
 Routine meetings with sponsor’s monitors
 Procedure for the timely correction and documentation
of problems identified
 Procedure for documenting or reviewing performance
of delegated tasks in a satisfactory and timely manner
(e.g., observation of the performance of selected
assessments or independent verification by repeating
selected assessments)

Supervision Plan

Investigator plan (continued):
 Procedure for ensuring that the consent process is
conducted per 21 CFR part 50
 Procedure for ensuring that information in source
documentation is accurately captured on CRFs
 Procedure for dealing with data queries and
discrepancies identified by the sponsor monitor
 Procedure for ensuring study staff comply with the
protocol, adverse event assessment and reporting
requirements
 Procedure for addressing medical and ethical issues that
arise during the course of the study in a timely manner

Supervision of Third Parties

• Investigators should take steps to ensure that staff not
under their direct employ (e.g., site management
organization [SMO] employees) are qualified and have
received adequate training
• Investigators should be “particularly cautious” when
SMOs complete source
documents, CRFs, investigational product accountability
records and IRB correspondence)
• A sponsor who retains an SMO shares responsibility for
the quality of work performed by the SMO



If outside staff performance of
study-related tasks is not
adequate and cannot be made
satisfactory, the investigator
should document the
deficiencies in writing to the
staff member’s supervisor and
inform the sponsor



• Many critical study functions are performed by parties not
involved in direct patient care or under direct control of
the investigator such as lab testing, radiologic
assessments, and ECGs
• When these services are retained by the sponsor, the
sponsor is responsible for ensuring that these parties are
competent and are fulfilling their study responsibilities



When an investigator retains outside services for testing
with special equipment or expertise not available at the
site, the investigator should take steps to ensure that the
facility is adequate (e.g., has required certifications or
licenses)



• The investigator may also institute procedures to ensure
that records coming from outside facilities are authentic
and accurate particularly if the assessments are crucial
to the evaluation of efficacy, safety of an invention, or
decision to include or exclude subjects
• Investigators should carefully review external reports for
results that are inconsistent with clinical presentation
• If investigators detect possible errors or that results from
a central laboratory or testing facility may be
questionable, they should contact the sponsor
immediately


Medical Device Considerations

Field clinical engineers
(device sponsor employees)
should be supervised by the
investigator because they
have the potential to bias the
outcome of the study, affect
the quality of research data,
and/or compromise the rights
and welfare of the human
subjects


Medical Device Considerations

• The field clinical engineer’s activities should be
described in the protocol
• If the field clinical engineer has face-to-face contact with
subjects or conducts activities directly affecting the
subject, those activities should be described in the
informed consent


Protecting Study Subjects


Primary Physician Notification

• The investigator should
inform the subject’s primary
physician about the subject’s
participation in the trial (if
they have a primary physician
and agree to the disclosure)
• ICH GCP section 4.3.3
previously only
“recommended” the above


Study Related Medical Care

• During the subject’s participation, the investigator or
designated sub-investigator should ensure that
reasonable medical care is provided to the subject for
any adverse event, including clinically significant
laboratory values, related to trial participation (ICH GCP
section 4.3.2)
• Subjects should receive appropriate medical evaluation
and treatment until resolution of any emergent condition
related to the study intervention even if the follow-up
period extends beyond the end of the study


Non-Study Related Medical Care

• The investigator should inform
the subject when medical care
is needed for conditions or
illnesses unrelated to the
study intervention or the
disease under study (ICH
GCP section 4.3.2)

• The subject should also be advised to seek appropriate
care from the physician who was treating the illness
prior to the study or assist the subject in obtaining
needed medical care

Investigator Availability

• Investigators should be available to subjects during the
study for medical care related to study participation
• “Particularly important” when the study drug has a
significant toxicity or abuse potential
• For study drugs with potentially
fatal toxicity, the investigator
should be readily available by
phone or other electronic
communication 24 hours a day
and in reasonably close proximity
to subjects (not in another state or on prolonged travel)


Investigator Availability

• Subjects should be clearly educated on the possible
need for investigator contact and provided all contact
information (phone numbers, email addresses) in writing
• Prior to undertaking a study, prospective investigators
should consider their availability to the extent needed
given the nature of the trial
• During any period of unavailability, the investigator
should delegate responsibility for medical care to a
specific qualified physician who will be readily available
to subjects during that time


Protocol Violations and Subject Risk

• Failure to comply with the protocol sometimes exposes
subjects to unreasonable risks
• For example, enrolling subjects who
violate certain study inclusion &
exclusion criteria or failing to perform
safety assessment intended to detect
drug toxicity are considered failures to
protect the rights, safety and welfare of
human subjects
• Investigators should minimize these
risks by closely adhering to the study
protocol

Form FDA 1572


Form FDA 1572 Guidance

• Final version issued in
May 2010
• Applicable to clinical trials
of drugs and biologics
(but NOT medical
devices)


What is the Form FDA 1572?

An agreement signed by
the investigator to provide
certain information to the
sponsor and assure that
he/she will comply with
FDA regulations related to
the conduct of a clinical
investigation of an
investigational drug or
biologic


When should the 1572 be
signed by the investigator?

• Whenever a sponsor selects a new investigator to
participate in a clinical trial being conducted under an
IND, the sponsor must obtain a completed and signed
1572 before permitting the investigator to begin
participation in the trial (21 CFR 312.53(c))
• The investigator should sign the form only after being
given “enough information” to be informed about the
study and to understand their commitments
• Having “enough information” typically means that the
investigator has read and understands the protocol and
investigator’s brochure and is familiar with the human
subjects protection and GCP regulations

Must the investigator
be a physician?

• NO - The regulations do not require that the investigator
be a physician
• Sponsors are required to select only investigators
qualified by training and experience as appropriate
experts to investigate the drug (21 CFR 312.53(a))
• In the event the clinical investigator is a non-physician, a
qualified physician (or dentist, when appropriate) should
be listed as a subinvestigator for the trial and should be
responsible for all trial-related medical (or dental)
decisions


What are the minimum
qualifications of an investigator?

• The regulations do not specify the minimum requirements
nor do the regulations specify what qualifications an
investigator must have in order to be considered qualified
by training and experience to conduct a clinical
investigation
• Sponsors have discretion in determining what
qualifications, training, and experience will be needed
• Qualifications should include familiarity with human
subject protection regulations (i.e., 21 CFR Parts 50 and
56) and GCP regulations (i.e., 21 CFR Part 312) and
standards (e.g., ICH E6) for the conduct of clinical studies


Does the 1572
need to be submitted to FDA?

• NO - Although the sponsor is required to collect the 1572
from the investigator, FDA does not require the form to
be submitted to the agency
• Many sponsors submit the 1572 to
FDA, however, because it collects, in one
place, information that must be submitted to FDA under
21 CFR 312.23(a)(6)(iii)(b)


When must a 1572 be updated?

• If there are changes to information contained on a
signed 1572 (e.g., an IRB address change, the addition
of new sub-investigators, the addition of a clinical
research lab), the investigator should document the
changes in the clinical study records and inform the
sponsor of these changes, so that they can
appropriately update the IND
• The 1572 itself does not need to be revised nor a new
form completed and signed by the investigator. The
sponsor can accumulate certain changes and submit
this information to the FDA in an information
amendment or a protocol amendment


Must investigators outside
of the United States sign a 1572?

• If a foreign clinical study is conducted under an IND, then
all FDA IND regulations, including the requirement to
obtain a signed 1572, must be met
• In addition, investigators are responsible for complying
with the applicable laws and regulations of the country in
which the study is being conducted, regardless of
whether the study is being conducted under an IND.
• FDA recommend that sponsors obtain signed, written
statements from investigators acknowledging their
commitment to comply with local laws and requirements


Must a new 1572 be signed when the
OMB expiration is reached?

NO - There is no need to
prepare and sign a new
1572 when the OMB
expiration date has been
reached


Does FDA expect a
double-sided 1572?

• NO - Either a double-sided or two-page document is
acceptable
• However, FDA recommends that if a two-page document
is used that it be stapled so that there is no question
about what form the investigator signed


Does the 1572 need to be typed?

• NO - It is acceptable to print the blank form from FDA’s
website and hand-write or type the information onto the
form
• Typed forms are preferable because they are usually
more legible
• The completed form must be signed and dated by the
investigator (either by hand or using an acceptable
electronic method)


How should an investigator’s name
appear on the 1572?

• Section #1 should contain
the investigator’s full legal
name (e.g., name on the
investigator’s birth
certificate or marriage
certificate)
• Titles, degrees, and/or
professional qualifications
may follow the
investigator’s legal name,
if desired


What address should be
entered into Section #1?

• The address where the
investigator can be
reached by mail or in
person should be entered
in Section #1 of the 1572
• Usually, this corresponds
to the investigator’s work
or business address

Can co-investigators be
listed in Section #1?

• The term “co-investigator”
is not defined in FDA
regulations
• Under 21 CFR 312.3(b),
each co-investigator is an
investigator and must sign
a separate 1572
• It is acceptable to have
more than one
investigator at a single site
(each of whom has signed
a 1572)

Does the CV need to be
updated during a clinical study?

NO - FDA regulations do
not require a CV or other
statement of qualifications
to be updated during a
clinical study


Are CVs required to be
signed and dated?

• NO - FDA regulations do
not require a CV to be
signed and dated
• The investigator's dated
signature on the 1572 is
sufficient to attest to the
accuracy of the CV or
other statement of
qualifications submitted
with the 1572


What qualifies as a research
facility for Section #3?

• Section #3 is intended to
identify facilities where study
activities will be conducted
and data will be generated
• This includes facilities where
subjects will be seen and
study procedures performed
• Other sites may also be listed
(e.g., research lab where IP is
prepared, storage facility
where IP is kept, or a location
where tissue specimens are
collected)

If subjects are seen at more than one
site, should all sites be listed?

• YES - The names and
addresses of each of the
study sites should be
identified in Section #3
• However, if the protocol
specifies that the
investigative product can
be administered at a
subject’s home, the
subjects' home addresses
do not have to be listed on
the 1572


What qualifies as a clinical laboratory
for Section #4?

Section #4 is intended to
identify clinical laboratories
or testing facilities directly
contributing to or
supporting the clinical study


Should satellite labs doing additional
testing be listed?

• If a laboratory is sending
samples to a satellite or
other contract labs for
additional testing, it is not
necessary to list these
facilities
• It is only necessary to list
the primary laboratory,
provided that laboratory
can trace the samples to
each of the satellite and/or
contract labs where the
tests were performed

Who should be listed as a
sub-investigator in Section #6?

• The purpose of Section #6
is to capture information
about individuals who will
assist the investigator and
make a direct and
significant contribution to
the data
• The decision to list an
individual depends on
whether he/she is
performing significant
clinical trial-related duties


Who should be listed as a
sub-investigator in Section #6?

• In general, if an individual is directly involved in the
performance of procedures and the collection of data
required by the protocol, that person should be listed

• If the protocol notes that
each subject needs to
visit a specified internist
who will perform a full
physical to qualify
subjects for the clinical
investigation, that
internist should be listed
in Section #6

Should research nurses or residents
be listed in Section #6?

• Hospital staff, including nurses, residents, or fellows and
office staff who provide ancillary or intermittent care but
who do not make a direct and significant contribution to
the clinical data, do not need to be listed individually
• It is not necessary to include
in this section a person with
only an occasional role in the
conduct of the research, (e.g.,
an on-call physician who
temporarily dealt with a possible
adverse effect or a temporary
substitute for any research staff)

Should residents on rotation

• For staff residents on rotation, it may be difficult to
prospectively identify those individuals who might
perform specified protocol procedures or collect clinical
data. Specific names of the rotational staff do not have
to be listed in Section #6
• Instead, the names of
rotational individuals
and the procedures
they are expected to
perform should be
included in the clinical
study records

Should a pharmacist

• The decision about whether to list a pharmacist is a
matter of judgment, dependent upon the contribution that
the individual makes to the study.
• For example, a research pharmacist may prepare test
articles and maintain drug accountability for many clinical
studies that are ongoing concurrently at an institution.
• Because the pharmacist would not be making a direct
and significant contribution to the data for a particular
study, it would not be necessary to list the pharmacist as
a sub-investigator in Section #6, but he/she should be
listed in the investigator’s study records.


Should a study coordinator

• Generally, a coordinator has
a greater role in performing
critical study functions
(I.e., recruits
subjects, collects and
evaluates study data, and
maintains study records)
and making direct and
significant contributions to
the data
• Therefore, the research coordinator should usually be
listed in Section #6 of the 1572


Are CVs necessary for
sub-investigators in Section #6?

• NO - The regulations at 21 CFR 312.53(c)(1)(viii) require
only that sub-investigators’ names be listed in Section #6
of the 1572
• The investigator must ensure that all associates,
colleagues, and employees assisting with the conduct of
the clinical investigation are aware of their obligations
including complying with the IND regulations


Questions


Compliance with the FDA Guidances on Investigator Responsibilities and the Form 1572

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