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Investigator obligations&qualifications&IRB/IEC

The investigator, the individual with the primary responsibility for the conduct of the study at the local
site. This is not meant to diminish the activities that are handled by the investigator's staff; however, it is
important to understand that the investigator has the ultimate responsibility. The investigator may
delegate authority to perform tasks to appropriately qualified team members but will always remain
responsible for the conductof the study. The function and requirements of Institutional Review Boards
(IRBs) in the US and Independent Ethics Committees (IECs) internationally will also be reviewed. The
learning objectives for Module 2 are that: As an investigator or member of the research team, you will
be able to do the following, based on ICH and local regulatory guidelines: Explain the roles and
associated responsibilities of the investigator in theconduct of clinical trials, Understand the initiation of
a clinical trial at the investigator site, and know how to accurately complete FDA Form 1572, if an IND
study, as a statement of the investigator, Be aware of the resources needed for successful completion of
the trial at the investigator site, and Explain the composition and function of the IRB/IEC in the conduct
of clinical trials Please note that FDA Form 1572 is the statement of theinvestigator document that is
required for clinical trials conducted in the United States and with clinical trials conducted outside the
US under a US IND. Per International Conference of Harmonization (ICH) and local regulatory
authorities, the responsibilities of investigators who agree to participate in the conduct of clinical trials
include all of the items noted on this slide. These responsibilities are outlined in ICH Section 4 (.1-.13).
They are also referenced in multiple parts of the FDA Title 21 Code of Regulations (CFR) and guidance
documents, or in applicable local regulatory documents. This is clearly not a one person job. Covering all
of these responsibilities would be too demanding, even for an investigator dedicated solely to clinical
trials research. Successful clinical trials require a team that works well together. In addition
toinvestigator responsibilities, we will also talk about what resources are needed to participate in clinical
trials. ICH 4.1 states that the investigator should be qualified by education, training and experience to
assume responsibility for the proper conduct of the trial. The investigator should meet all qualifications
specified by the applicable regulatory requirements, and should provide evidence of such qualifications
via an up-to-date CVor other relevant documentation. In some countries, only physicians and dentists
can serve as principal investigators. In the US, if acceptable to the sponsor, the principal investigator (PI)
can be a physician, dentist or other qualified individual, such as a Ph.D., pharmacist, nurse practitioner,
etc. However, as stated in ICH 4.3, should the protocol require investigational product (IP) to be
dispensed to subjects or medicalprocedures/assessments, there must be a physician on the research
team to perform or oversee these functions. The European Directive (EU) is more explicit and defines an
investigator as a "doctor or a person following a profession agreed in a Member State for investigations
because of the scientific background and the experience in patient care it requires" Legislation in each
EU member state is expected to define the acceptableprofessional qualifications of an investigator. The
investigator should be thoroughly familiar with the appropriate use of the IP as described in the
protocol, and current Investigator's Brochure (IB) or product information label. Some sponsors or
protocols call for an investigator with expertise in a therapeutic area or type of research. Sponsors may
have other requirements of investigators as well, such as... A requirement toprovide their medical
license or license number, or Due diligence as an employer: meaning that they should check to ensure
that no employee assisting in the clinical trial is disqualified from clinical research by competent
authorities. This information is public knowledge. Sponsors may also require that personnel receive
training to ensure inter-rater reliability, such as for CNS trials, or training on an electronic data capture
system tobe used in the clinical trial, or to provide evidence of GCP training. Clinical investigator
Investigator obligations&qualifications&IRB/IEC

agreements can include: An agreement from the PI to adhere to the protocol. Typically sponsors require
that a protocol signature page or protocol amendment page be signed and dated by the PI as
documentation of agreement to comply with the protocol. The PI should not implement any deviations
from or changes to the protocol without prioragreement by the sponsor, except where needed to
prevent immediate hazards to trial subjects. Agreements might also include: An agreement to the legal
terms and the investigator budget and payment schedule as negotiated in the clinical trial agreement.
This is also referred to as the investigator contract. If the research is being done at a hospital or hospital-
based outpatient area, a responsible administrator for the hospitalmay also need to sign the contract or
clinical trial agreement. In some countries, only an approved party from within the hospital
administration department is required to sign the contract. The sponsor or sponsor representative will
inform the investigator of which signatures are acceptable for the project. And last, If applicable per
regulations, a "Statement of Investigator" is signed by the PI indicating understanding and
commitmentto comply with GCP. These "statements of investigators" vary across regulatory authorities.
The FDA, requires the completion of Form FDA 1572 for clinical trials conducted under an IND. Not all
trials are conducted under a US IND. Therefore, the discussion on this slide through slide number 18 is
applicable only for those studies conducted under a US IND. The completed Form FDA 1572 serves as
thesigned investigator statement for IND studies. Sponsors are required to obtain a completed and
signed Form FDA 1572 for each principal investigator participating in a clinical trial to be submitted to
the FDA. The sponsor or CRO will provide investigators with this form, along with instructions for
completion, when the sponsor plans to submit the clinical trial data to the FDA for a marketing
application (NDA). The Form FDA1572, as such, is not applicable to medical device trials; however, an
Investigator's Agreement provided by the sponsor and signed by the PI is still required, as outlined in
21CFR812.20 b.4. First, always look in the upper right-hand corner of the form and check the expiration
date. Make sure an expired form is not being used. The current version of form 1572 is available on the
FDA website, In Box 1: Fill in thefull name, credentials and address of the PI. Degrees such
as MD, PhD, or DO that indicate appropriate credentials for conducting the study should be listed. The
address of the PI could be their office address, which may be different from where subjects are treated.
The information in this box needs to be an address where the PI can be reached by mail; therefore, a
P.O. Box is acceptable. In Box 2: Mark the appropriate box with an"X". A resume or curriculum vitae is
typically what sponsors request or accept from investigators. Form 1572 and the CV of the PI is what the
sponsor submits to the FDA under an IND. Should the PI or other information on this form change
throughout the course of a trial, a new 1572 must be completed and submitted to the sponsor for
submission to the FDA as an IND amendment. In Box 3: Document the complete address. This should
include the physical location of the facility where subjects are treated on the protocol, including where
study drug is administered, or where study tests or procedures are performed, as well as, where
Investigational Product (IP) will be stored. This address needs to be listed even if it is the same as the
address in Box 1. There may be more than one facility if this is acceptable to the sponsor. Also, it asks for
name/address of the site, so record the name of the facility even if it is the name of the physician
followed by Inc or LLC. For example: "Marcus Welby MD, Inc". Each site listed on form 1572 should have
at least one qualified investigator affiliated with it. This can be either the PI or a sub-investigator.
Continuing with FDA Form 1572... In Box 4: Document the complete name and street address of all
laboratories analyzing specimens collected per protocol requirements. The sponsor and/or the protocol
will indicate whether a central and/or local lab will be used. If a local lab is used, the sponsor may
Investigator obligations&qualifications&IRB/IEC

request that you provide a complete printout of all the normal laboratory ranges as well as laboratory
certifications and licenses from that lab. In Box 5: Write the name and address of the IRB or IEC that is
providing the final approval and oversight of the clinical trial being conducted at all of the sites listed in
box #3. In Box 6: List all the subinvestigators involved in the trial. The FDA's intent is that all physicians
as well as others, such as nurses, technicians, etc. who are performing evaluations and assisting in the
conduct of the study should be noted in this box. Subinvestigators may change frequently. It is more
important to add new sub-investigators than it is to delete currently listed sub-investigators who are no
longer assisting in the conduct of the trial. Remember that the agreement is between the FDA and the
investigator; therefore, the investigator can choose whom to list as sub-investigators. In Box 7:
Document the protocol and protocol number. Most sponsors request that protocol title and number
match the protocol cover page verbatim; therefore do not use abbreviations unless they are used on the
protocol cover page. Box 8: This is the most commonly overlooked section of the form. Phase I-III trials
are conducted under an IND; therefore, these studies must adhere to 21 CFR Sections 11, 50, 54, 56, and
312. Phase IV trials usually involve marketed products which are not regulated in the same way since
they already approved. (There are regulations that apply to marketed products but we will not cover
them in this presentation). Some sponsors, primarily because it has become an industry standard when
conducting research involving humans, conduct Phase IV trials in compliance with part 50 (informed
consent) and 56 (IRB approval) and for that reason may request that a Form FDA 1572 be completed,
although this is not required by the FDA. In a Phase IV trial, neither box in section 8 would be checked.
Box 9: This section lists the commitments that the PI is agreeing to when signing and dating form 1572.
For example, some things the PI is agreeing to include: Conducting the study in accordance with the
protocol, Ensuring that the requirements of informed consent are met based on 21 CFR Part 50,
Obtaining IRB review and approval based on 21 CFR Part 56, Reporting adverse events in accordance
with 21 CFR 312.64, and Ensuring that associates, colleagues and employees are aware of their legal
obligations in the conduct of the clinical trial. PIs therefore must train or ensure training for any
untrained staff in GCP and protocol required procedures. Boxes 10 and 11: Require the handwritten
signature of the principal investigator listed in box 1 and the handwritten date of signature. The
investigator is responsible for: Obtaining IRB/IEC favorable opinion (In some countries the investigator is
only responsible for obtaining favorable opinion from the local IRB/IEC and the sponsor or sponsor
representative will correspond with the central IRB/IEC on behalf of the investigator), Enrolling the
required number of appropriate subjects, Maintaining accountability for all IP and clinical supplies,
Administering IP to qualified subjects according to protocol, and Observing, measuring, and recording
drug effects and other data as required in the protocol Keep in mind, that the investigator can delegate
these responsibilities to other qualified members of his/her team. The investigator has overall
accountability and therefore, should be aware of the training and skills of the team and delegate
appropriately. For example, the investigator may have a study nurse coordinator who prepares
materials for the IRB/IEC, a pharmacist may be responsible for drug accountability, and a data manager
may be responsible for the collection of data. In addition, the investigator is responsible for: Evaluating,
managing, and reporting adverse experiences to the sponsor and IRB/IEC. Submitting protocol changes
(deviations and amendments) and annual reviews/reports to the IRB/IEC. Be aware that some IRB/IECs
may request more frequent reports. Notifying the IRB/IEC of any problems that pose a threat to the
welfare of subjects, and Retaining study records and making them available for audits as necessary. ICH
4.9.7 states "Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
Investigator obligations&qualifications&IRB/IEC

investigator/institution should make available for direct access all requested trial-related records". More
specific information regarding these responsibilities will be provided in modules 3, 4, and 5 of this
program. The next section of this module will discuss the regulations concerning the provision of
adequate resources to conduct the trial and the medical care of the trial subjects. ICH 4.2 states that the
investigator should have an adequate number of qualified staff and adequate facilities available
throughout the entire trial period in order to conduct the trial properly and safely. This slide lists
examples of esearch staff. Therefore, in order to comply with this regulation, there must be a sufficient
number of coordinators and physicians to adhere to protocol and monitor compliance to protocol and
GCP. The investigator should ensure that all persons assisting with the trial are adequately informed of
the protocol, investigational product and their trial-related duties and functions as delegated by the
investigator. The investigator should maintain a list of appropriately qualified persons to whom the
investigator has delegated significant trial-related duties. Examples of "significant trial related duties"
might include: Administration of informed consent process, and Conducting procedures required by
protocol such as physical exam, venipuncture, administering IP and IP accountability, communication
with IRB/IEC, etc. The sponsor may provide a form for the investigator to use where the name of each
staff member is listed, what responsibilities the investigator has delegated, and the staff member's
signature and initials. This form may be called something like a "Site Responsibility and Signature Form
or "Delegation of Responsibility and Signature Form". Per ICH 8.3.24 a signature sheet should exist in the
essential documents. The qualifications and eligibility to conduct a trial and/or provide medical
supervision should be documented via a CV or other relevant document, as noted in ICH 8.2.10. Any
changes in delegation of responsibility and/or changes in staff need to be documented as they occur on
the sponsor provided form. Should the sponsor not provide a form, the investigator should design their
own form and maintain current information. Adequate numbers of trained and experienced staff is not
all that is required. The research staff should have sufficient time and motivation to complete their
responsibilities. The investigator should have sufficient time to properly conduct, supervise, and
complete the trial within the agreed upon period. This means that the investigator should not have
100% of his/her time committed to clinical practice or academic work. The investigator needs dedicated
time to meet with research staff, review protocols and amendments, present (should be pronounced
"present" with a long "e" like present information, not "present" as in being there or a gift) at IRB/IEC
meetings, answer questions from both staff and subjects, and oversee the research operations.
Participation in multiple clinical trials also can deplete resources. Many places that do research regularly
will conduct internal audits to be sure all members of the team are in compliance with regulatory
requirements and that the research data is accurate and of good quality. Successfully completing a
study takes commitment and motivation. The sponsor invests significant resources in each clinical site
and expects consistent performance throughout the research. Some clinical trials can be several
months, but many trials run for years. An example of this would be evaluating cancer treatments that
follow subjects for the rest of their lives. This requires the investigator and the study team to keep their
time commitment and momentum going indefinitely. Examples of equipment often required by
protocols include laboratory equipment, fax machine, ECG machine and blood pressure monitor. Some
sponsors may require temperature logs to document adequatefunctioning of the refrigerator or other
monitoring data to ensure that equipment failure does not affect the conduct of the study. An example
might be a backup generator at your facility, to protect drug storage quality in case of a power outage. If
you do not have the necessary equipment required by the protocol, notify the sponsor/CRO as they may
Investigator obligations&qualifications&IRB/IEC

be willing to provide some equipment. Some examples of other resources required by a specific protocol
might include: Overnight mailing of medical specimens, A freezer with the temperature maintained at a
specific level for preservation of specimens, Access to medical services such as a CT scan/MRI scanner,
or Adequate space to store necessary documents and report forms. It is important to understand what
the project requires before opening the study. Most sponsors will require a site selection visit prior to
including the site in the trial in order to verify that the site has the resources necessary to run the trial
including sufficient equipment and study personnel. In addition to equipment and study personnel, the
study may require clinical procedures. For example, a study may request that a blood pressure be taken
every 5 minutes after administration of the investigational product. There would need to be enough
qualified staff available to carry out the study requirements. The site can negotiate with the sponsor. In
the above example, the site may request a blood pressure monitor. However, the blood pressure
monitor still needs a team member to review the blood pressure readings. Additional equipment may
help, but the study may still require additional staff resources. The number one reason clinical trials are
delayed is due to inadequate subject recruitment. The investigator needs to consider how they will gain
access to subjects who are potentially eligible for the research study. A variety of methods might be
considered, including accessing various databases, or a retrospective analysis of investigator's patients.
Most countries have rules to protect the privacy of health information. The investigator needs to be
familiar with the rules of the country in which they are conducting the trial. A variety of methods of
recruitment of subjects might be used. Some countries prohibit the use of advertising. The investigator
must be familiar with country specific regulations and guidelines regarding subject recruitment.
Remember that recruitment procedures are subject to IRB/IEC review and approval. These are
considered an extension of informed consent. Telephone contact may involve pre-screens over the
telephone and many IRB/IECs require review of pre-screen scripts and questionnaires. Remember to
keep in mind any country specific privacy rules. The strategy for recruitment should be planned based
on the nature of the study and eligible subjects, as well as, the enrolment target set by the sponsor. It is
recommended that a screening log be used to record all subjects who have contacted you about the
trial, the source of recruitment (i.e. where did they learn of the trial) and the outcome of screen. Should
you have problems recruiting subjects, this document will assist you in identifying what is and is not
working or what alternative recruitment method you might consider. Not all country regulations require
a screening log be maintained, but it is standard industry practice to require a screening log. ICH 4.3
states that all trial related medical decisions need to be made by a qualified physician or dentist and not
by non-medical research staff. During and following a subject's participation in a trial, the investigator
and/or institution should ensure that adequate medical care is provided to monitor and treat for
adverse events and clinically significant lab values related to the trial. Subjects should be informed when
medical care is needed for intercurrent illnesses of which the investigator becomes aware. If the subject
agrees, it is recommended that the investigator inform the subject's primary care physician about their
participation in a clinical trial. While respecting the subject's rights, the investigator should make every
reasonable effort to determine their reason for withdrawing prematurely from a trial. Subject
compliance may be increased if investigators make a point to meet with the subject at every visit. The
last section of this module discusses communication with the Institutional Review Board and the
Independent Ethics Committee, as well as essential documents required when conducting a clinical trial.
Regulations regarding Institutional Review Boards or Independent Ethics Committees are found in
Section 3 of the ICH Good Clinical Practice Guidelines and if the study is under a US IND, in the FDA
Investigator obligations&qualifications&IRB/IEC

Federal Code of Regulations 21 CFR part 56. Other local regulatory agencies may have additional
guidelines regarding review boards. The purpose of these independent bodies is to ensure the
protection of the rights, safety and well-being of human subjects involved in a trial by reviewing,
approving and providing continuing review of trials, protocols and amendments, and methods and
material to be used in obtaining and documenting informed consent of trial subjects and recruiting trial
subjects. Section 3 of ICH GCP outlines responsibilities, procedures and record keeping for IRB/IECs, and
gives guidance on composition, function and operation. The major guiding principle should be respect
for the dignity and safety of subjects. It should be taken into account that the aims of clinical research
as such should never rank higher than the protection of the individual's rights and health. Special
attention should be paid to trials that may include vulnerable subjects, which is a term summarising all
those people whose social status might need special support or care. Vulnerable subjects may include
incapacitated adults, children, prisoners, etc. The world of Ethics Committees and IRBs is not the same
when comparing countries worldwide. There is quite a variety of established country systems. For
example, in France one has to submit to only one Ethics Committee, whereas in Germany there are
quite a number of Ethics Committees. Note that IECs provide "favorable opinions" while IRBs provide
approvals for protocols, amendments, informed consent materials, and advertisements. IRBs are more
common to the US. In the US, there are regulations that govern IRBs. IRBs can be inspected by the FDA.
In the US, typically hospitals and academic centers are affiliated with their own IRB. There also exist
independent IRBs that clinical investigators, who are not affiliated with an institution which has an IRB,
can contract with, for example, private practice physicians. The legal status, composition, functions,
operations and regulatory requirements may differ among countries but should allow the IRB/IECs to act
in agreement with Good Clinical Practice as described in ICH. The IRB/IEC should consist of a reasonable
number of members, who collectively have the qualifications and experience to review and evaluate the
science, medical aspects and ethics of the proposed trial. Per ICH 3.2 the composition of the IRB/IEC
should be as follows: At least 5 members, At least 1 member whose primary area of interest is in a
nonscientific area, At least 1 member who is independent of the institution/trial site, and Only those
members who are independent of the investigator and the sponsor should vote or provide opinion on
trial related matters. The investigator may provide information on any aspect of the trial, but should not
participate in the deliberations of the IRB/IEC or in the vote/opinion. The members collectively should
have the qualifications and experience to review and evaluate the science, and medical aspects of the
proposed trial. FDA 21 CFR 56.107 states that the composition of the IRB/IEC: Have a minimum of 5
members, Every nondiscriminatory effort is to be made to assure that no committee consists entirely of
men or entirely of women (note that the ICH does not address gender), There should be at least one
scientist and one non scientist, At least one non-affiliate, meaning not affiliated with the institution, and
Assure that there is no conflict of interest, for example, an investigator may not vote on his/her own
clinical trial IRB/IECs are to provide independent, competent and timely review of the ethics of a
proposed trial. This review needs to be done before the commencement of the trial. The requirements
for process and the suitability and feasibility of the trial. Furthermore applicable laws and regulations
must be taken into account. Also the statistical methodology will be reviewed, items like inclusion and
exclusion criteria and endpoints - basically the whole trial design will be reviewed and guided by the
question of whether the risk-benefit ratio remains justifiable. When a trial is to be carried out with the
consent of the subject's legally acceptable representative, the IRB/IEC should determine that the
proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets
Investigator obligations&qualifications&IRB/IEC

applicable regulatory requirements for such trials. Where the protocol indicates that prior consent of
the trial subject or the subject's legally acceptable representative is not possible, the IRB/IEC should
determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical
concerns and meets applicable regulatory requirements for such trials (i.e. in emergency situations).
The IRB/IEC should perform its functions according to written standard operating procedures (or SOPs),
which should be publicly available. Such SOPs should state the authority under which the committee is
established, outline functions and duties, membership requirements, internal procedures and quorum
requirements. A list of IRB/IEC members and their qualifications should be maintained. The IRB/IEC
should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to
human subjects, but at least once per year - therefore a regular evaluation of the ethics should be
guaranteed. A procedure for following up on the progress of a trial should be established, encompassing
the time between approval and termination of the trial. In the SOPs it should be specified that no
subject should be admitted to a trial before the IRB/IEC issues its written approval or favourable opinion
of the trial. Also specifying that no deviations from, or changes to, the protocol should be initiated
without prior written IRB/IEC approval or favourable opinion of an appropriate amendment, except
when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only
logistical or administrative aspects of the trial (for example, a change of medical monitor(s) and
telephone number(s)). This is a list of documents that minimally must be included in a new study packet
that is submitted to the IRB/IEC for review. Some IRB/IECs require additional documents as well. A full
copy of the protocol, The informed consent form, The investigator's brochure, Any advertisements to be
used for recruitment, Any materials or supplies that are to be given to subjects, Information regarding
any subject payment, and in addition, The IRB/IEC may request to see any questionnaires included in the
protocol. Other documents may be requested according to country or local requirements. Multiple
steps may be involved in preparing a new study packet for an IRB/IEC submission and review. The
sponsor usually provides a template containing all the required elements of an Informed Consent Form.
The local site merges this template with their local requirements. An example would be adding the local
investigators name and phone number where appropriate in the consent. The local investigator then
sends the modified consent back to the sponsor for their review and approval. Once approved by the
sponsor, the site sends it with all the attached documents to the local IRB/IEC or if the site is using a
central IRB/IEC, the sponsor (if country regulations permit) may submit this on behalf of the investigator.
When the IRB/IEC has approved or given a favorable opinion of the appropriate documents, the IRB/IEC
sends a letter stating that the study was approved/given favorable opinion. This letter should include
the date of approval/favorable opinion, the protocol version or date, the informed consent version or
date and if any advertisements are approved, the version/date of the advertisement. Some IRB/IECs will
stamp and date the actual consent form to demonstrate which consent has been reviewed and
approved. Copies of the approval letter and the stamped consent are sent back to the sponsor for their
records. The regulations require that the IRB/IEC conduct an ongoing review at minimum on an annual
basis. The IRB/IEC may choose to conduct this review more frequently. This information should be
included in the approval letter. The investigator is required to provide the IRB/IEC with progress reports.
These reports may include: the number of subjects accrued, a summary of subject experiences (such as
benefits and adverse reactions), the number of withdrawals and the reasons for withdrawals, research
results to date (if available), any changes to the risk/benefit assessment in the original protocol and any
new information since the last review. Any amendments or changes to the protocol must be reviewed
Investigator obligations&qualifications&IRB/IEC

and approved by the IRB/IEC prior to implementing the change unless the change is for immediate
safety reasons. The IRB/IEC must also be notified when a site is closing a study. Currently, all serious
safety reports are sent to all investigators participating in a clinical trial with this compound. For a multi-
site international study, the investigator may receive a large volume of reports from all over the world.
They must all be submitted to the IRB/IEC for review. If the site is using a central or national IRB/IEC,
these reports may be submitted by the sponsor on behalf of the site (if country regulations permit).
However, if the investigator is using a local IRB/IEC, the site is typically responsible for submission to
their own IRB/IEC. Good record keeping is essential. The research monitor will be checking to be sure all
safety reports have been submitted to the IRB/IEC. In some countries a study can be submitted to an
IRB/IEC for expedited review which means the full committee does not need to be convened. Expedited
reviews can be done for research that poses only minimal risk and for minor changes to already
approved research. For example, if the phone number of the sponsor changes, or if a typographical error
is found in the protocol and is corrected. When the sponsor or CRO sends changes to the investigator,
the cover letter usually specifies whether the changes will require a full IRB/IEC review or not. Again, this
is very country specific and the investigator needs to be familiar with the rules of the country. An
example of a study with minimal risk might be an anonymous questionnaire that is left in a waiting room
for subjects to complete. All research should be reviewed by an IRB/IEC. The IRB/IEC may waive the
need for informed consent as the risks are very small and the information being collected is in the public
domain. For example, a study of how long it takes people to order from a menu. If the researcher is
sitting in a restaurant and is only recording the time it takes to place an order, there is probably no need
for consent. The IRB/IEC may also waive written consent and only require verbal consent. An example
might be a study where passers-by are asked to complete a short questionnaire. By answering the
questions they are giving implicit consent. They are free to walk away if they are not interested in
participating. The IRB/IEC might only require that the researcher tell potential subjects what the topic of
the research is and how long it will take to answer the questions. An exemption from IRB/IEC
requirements is a very rare circumstance. In these cases the research needs to be treating a life-
threatening event where standard treatment is not available or helpful. The exceptions for informed
consent are that the patient is unable to give consent due to the medical condition. The nature of the
medical condition is such that the investigator can't wait until the patient's legal representative is
available, the research must hold the possibility of helping the patient, there is no other reasonable
alternative available, or there is no way to get consent in advance of the event. The take away point is
that it is a very rare circumstance that would allow use of an investigational product that has not been
approved by the IRB/IEC or the administration of an investigational product to a patient without the
patient's consent. Essential documents are those documents which individually and collectively permit
evaluation of the conduct of a trial and the quality of the data produced. These documents serve to
demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good
Clinical Practice and with all applicable regulatory requirements. Most of the essential documents are
generated before the beginning of the clinical phase of a trial. They are trial specific meaning that they
are directly related to the trial. Most of these documents will be used by all the countries involved in
the trial, for example the Investigator's Brochure, the protocol, and the case report form. According to
ICH-GCP guidelines, there are three "categories" of essential documents. The documents generated:
Before the clinical phase of a trial commences, those generated During the clinical conduct of the trial,
and those generated After completion or termination of the trial Each document needs to be kept on
Investigator obligations&qualifications&IRB/IEC

file at the local site, with the sponsor or, in both locations. We will briefly review the major documents
in the next several slides. A full listing can be found in ICH section 8. The primary documents required
before initiating a study include the: Investigator's Brochure, A full copy of the protocol and
amendments, The informed consent form, A signed agreement, Documentation of IRB/IEC approval, and
Monitor reports for pre-trial suitability and trial initiation There may be additional documents required
by the sponsor. The Investigator's Brochure is a complete compendium of what is known about the
investigational drug. If the Investigator's Brochure has not been recently revised, there may also be a list
of SAE (or serious adverse events) attached. The sponsor will require a copy of the blank IRB/IEC
approved informed consent. Only the site will maintain the originals of the informed consents signed by
the subjects. The signed agreement is usually a contract between the sponsor and the local investigator.
The monitor reports are what the monitor has documented during site visits. There is usually a site visit
looking at suitability of the site (such as, is there appropriate staff and resources) and a site visit for trial
initiation that reviews the trial and the sponsor's expectations of the local site. The pre-trial suitability
report will be kept by the sponsor and is typically not found in the investigator files. A letter of this visit
is typically kept at the site. The trial initiation report or its equivalent will be located in both the sponsor
files and the investigator files. If a sponsor permits, these two visits may be combined. The documents
listed on the slide are the most common documents required to be filed at the site during the course of
the study. This includes any updates or changes to the Investigator's Brochure, protocol, informed
consent form, etc. The investigator must ensure the IRB/IEC has been notified of any changes since the
original submission. Documentation of strict accountability of investigational agents, monitor reports,
which may be in the form of a letter from the monitor, and signed consent forms are required. The
original signed consent form is typically filed with the patient's medical records. Many sites find it is best
practice to also keep a copy in the research office or in another designated location. Other documents
needed during the course of a study may include: the completed Case Report Forms (or CRF), any
corrections to the CRF including who made the correction and why, documentation of any serious
adverse events or adverse events and the reporting of these events, and a subject screening log. This log
is a list of all the individuals who were screened for the study, and usually includes an indication of
whether or not the person enrolled into the study and if not, why? Examples would include, the
individual was not eligible and why, or possibly after review of the study commitment, the individual
decided not to participate. In addition to the documents required and maintained prior to starting the
trial and during the conduct of the trial, there are documents that are required at the completion of a
study and must be kept filed at the site.. Some of the documents required at the completion of the trial
may include the up-to-date drug/device accountability record, a final letter or report from the monitor,
and updated reports to the IRB/IEC to inform the committee of any final details such as how many
subjects enrolled, how many completed, how many dropped out and of course any safety information
that has not been previously reported. Most IRB/IECs have a specific format for this report. The
investigator should become familiar with the requirements of the IRB/IEC. In summary, in this module,
we have reviewed: Investigator qualifications, investigator responsibilities, resources needed to conduct
a trial, a brief review of IRB/IEC functions, and documents needed prior, during, & after a trial.

Question 1: True or False: Most investigators can manage a clinical trial without involving other staff.
Rationale: The correct answer is "False"
Your Answer: False
Investigator obligations&qualifications&IRB/IEC

Question 2: Which of the following items is NOT an investigator qualification?
Rationale: The correct answer is "A PhD in statistics"
Your Answer: A PhD in statistics
Question 3: True or False: A 1572 Form must be completed for a trial being conducted under a US IND.
Rationale: The correct answer is "True"
Your Answer: True
Question 4: Some of the documents required prior to study enrollment include:
Rationale: The correct answer is "All of the above"
Your Answer: All of the above
Question 5: Which of the following is an investigator responsibility?
Rationale: The correct answer is "Making sure subjects have made an informed consent"
Your Answer: Making sure subjects have made an informed consent
Question 6: Which of the following best describes the resources needed for a clinical trial?
Rationale: The correct answer is "Qualified staff, sufficient time, motivation"
Your Answer: Qualified staff, sufficient time, motivation
Question 7: True or False: A clinical trial may require specific resources such as a freezer with a
temperature of -20 Celsius.
Rationale: The correct answer is "True"
Your Answer: True
Question 8: True or False: An investigator does not need to be knowledgeable in the specialty area of the
clinical trial.
Rationale: The correct answer is "False"
Your Answer: False
Question 9: At the end of a clinical trial, an investigator finds that the pharmacist did not keep accurate
drug accountability records. Who is responsible?
Rationale: The correct answer is "The investigator because he/she is in charge of the protocol"
Your Answer: The investigator because he/she is in charge of the protocol
Question 10: True or False: If a subject on a clinical trial suffers an unexpected side effect, the
investigator has a responsibility to be sure the subject gets any needed medical care.
Rationale: The correct answer is "True"
Your Answer: True
Question 11: Was the activity effective in meeting the identified needs?
This program is designed to educate physicians and research staff on the ICH guidelines for Good
Clinical Practice in the conduct of clinical trials.
Your Answer: Yes
Question 12: Explain at least 4 roles/responsibilities of the investigator
Your Answer: 5
Question 13: Accurately complete Form FDA 1572
Your Answer: 5
Question 14: Determine resources needed for successful completion of a clinical trial
Your Answer: 5
Question 15: Explain the composition and function of the IRB/IEC in the conduct of a clinical trial
Your Answer: 5

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