quintiles test by ramchandavolu

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									The drug development process. This will help you understand where the investigator and site fit
into the overall process. When a new drug or protein is discovered, the sponsor conducts in-
vitro laboratory studies, computer modeling, and animal studies to assess the biological
activity, safety, pharmacology, and toxicity of the new drug. If the drug looks promising, the
sponsor will file an application with the local regulatory body In theUS, the sponsor files an
Investigational New Drug application (IND). Each country has local regulations regarding the
process involved in the review of the application. Human studies, or clinical trials, are divided
into 4 phases. A Phase I study is the first time a drug or biological agent has been used in a
human and generally involves small numbers of subjects that are healthy volunteers. People
volunteering for Phase I studies must be fully informed that the risks may outweigh the
benefits. With highly toxic treatments such as cancer chemotherapy, healthy volunteers are not
used; patients with the disease are studied. The primary focus of a Phase I study is safety,
including drug metabolism, pharmacology, and toxicities. Phase I studies are also used to
determine drug interactions, dietary interactions, or gender differences. Thus, Phase 1 studies
continue even after Phase II studies have begun. Phase II studies are conducted in patients with
the condition under investigation. The primary outcomes are to collect additional data on the
safety of the drug as well as to test the effectiveness of the drug. Phase I and II studies are both
very well-controlled and closely monitored. Phase III studies are very large, involving hundreds
to thousands of subjects. These studies oftenseek many clinical sites across the world in order
to accrue the required number of subjects. Phase III trials often use a randomized, controlled
design to compare the new drug to a standard treatment. They are often called a pivotal study
since the data gathered is pivotal to the approval process. There may be overlap between study
phases. For example, it is not uncommon to see a Phase II/III study. Each country has local
regulations regarding the drug approval process. The FDA is one example. Afterthe successful
completion of a Phase III study, the sponsor submits a New Drug Application (NDA) to the FDA.
If the review is successful, the FDA approves the application and the drug can be marketed and
sold, for the indication approved. Phase IV studies are designed to determine optimal use of an
already approved drug or to expand the use of the drug to a new population that might benefit.
Phase IV studies

Question 1: True or False: ICH guidelines always override any local regulatory requirements
Rationale: The correct answer is "False"
Your Answer: False
Question 2: What authorities do regulatory agencies have?
Rationale: The correct answer is "All of the above"
Your Answer: All of the above
Question 3: Which of the following is NOT a responsibility of the sponsor?
Rationale: The correct answer is "Communicating regularly with subjects to ensure protocol
Your Answer: Communicating regularly with subjects to ensure protocol compliance

Question 4: What/who is a CRO?
Rationale: The correct answer is "Organization contracted by the sponsor to manage and
coordinate clinical trials"
Your Answer: Organization contracted by the sponsor to manage and coordinate clinical trials
Question 5: The monitors responsibilities include:
Rationale: The correct answer is "Ensuring that the trial is conducted according to protocol,
sponsor SOPs, GCP and applicable ICH guidelines"
Your Answer: Ensuring that the trial is conducted according to protocol, sponsor SOPs, GCP
and applicable ICH guidelines
Question 6: A clinical trial that includes approximately 300 to 1,000 or more subjects and
focuses on the overall risk/benefit of a new drug is considered to be what phase study in the drug
development process?
Rationale: The correct answer is "Phase III"
Your Answer: Phase III
Question 7: ICH guidelines were developed to:
Rationale: The correct answer is "All the above"
Your Answer: All the above
Question 8: True or False: The Institutional Review Board/Independent Ethics Committee is
charged with overseeing the protection of rights human research subjects.
Rationale: The correct answer is "True"
Correct Answer: True
Your Answer: False
Question 9: Per GCP, who is responsible for ensuring that the IRB/IEC used for the study meets
Rationale: The correct answer is "Investigator"
Your Answer: Investigator
Question 10: Who is responsible for the conduct of the trial at the clinical site?
Rationale: The correct answer is "Investigator"
Your Answer: Investigator

Informed Consent process:
based on ICH and local regulatory guidelines: Apply the elements of informed consent in
communication with the subject and documentation of the process, Having a subject with the
potential to enter a clinical trial, prepare appropriate healthcare team members to conduct the
informed consent process, and When a protocol deviation or non-compliance occurs, recognize
and report occurrences appropriately to maintain the ntegrity of the research data. We will
begin with a discussion on subject informed consent. The regulations regarding subject informed
consent are located in ICH GCP 4.8, and in FDA 21 CFR 50 Subpart B for those clinical trials
being conducted under a US IND. Informed consent is defined in ICH GCP Section 1.28 as a
process by which a subject voluntarily confirms his or her willingness to participate in a
particular trial, after having been informed of all aspects of the trial that are relevant to the
subject's decision to participate. FDA 21 CFR 50.27 states that informed consent shall be
documented by the use of a written consent form approved by the IRB and signed and dated by
the subject or subject's legally authorized representative at the time of consent. This is also
consistent with ICH GCP 4.8 and the European Directive (EU). Topics we will review in The

preparation of accurate and complete informed consent documents. Investigators have an ethical
and legal responsibility to ensure that subjects understand what their participation in research
will involve. The process of obtaining appropriate informed consent - which involves more than
just getting a subject to sign a form. It must ensure respect for persons by providing them with
the information they need to decide whether to voluntarily consent. The consideration of
vulnerable populations, such as children or the terminally ill, and local requirements And
attention to the required signatures and dates Each of these topics will be discussed in more
detail. ICH GCP 4.8.10 requires that the written informed consent document include
explanations of the following aspects of the clinical trial: That the trial involves research, The
purpose of the trial, What treatments are involved and the probability for random assignment to
each treatment, Any trial procedures, including invasive procedures, The subject's
responsibilities, Those aspects of the trial that are experimental, The reasonably foreseeable risks
or inconveniences to the subjects, and if applicable to an embryo, fetus, or nursing infant,
Reasonably expected benefits of participation, Alternative procedures or treatments that are
available to the subject, and Any compensation and/or treatment available in the event of a trial-
related injury. Additional required elements to be explained are: Any anticipated payment for
participation, Any anticipated expenses for participating, That the subject's participation is
voluntary and they may refuse to participate or withdraw at any time without penalty, That the
monitors, auditors, the IRB/IEC, and regulatory authorities will be granted direct access to the
subject's medical records for verification of clinical trial procedures and data, without violating
confidentiality, Any records identifying the subject will be kept confidential, That the subject or
their legally acceptable representative will be informed in a timely manner if information
becomes available that may be relevant to the subject's willingness to continue participation,
Whom to contact and the contact information for further information regarding the trial and the
rights of trial subjects, and whom to contact in the event of a trial-related injury, Any foreseeable
reasons that the subject's participation may be terminated, The expected duration of the trial, and
The approximate number of subjects involved in the trial. For those trials conducted under a
US IND, FDA regulations in 21 CFR 50.25 list 8 basic elements which are always required plus
6 additional elements that should be included in informed consent when applicable. These are all
consistent with the ICH elements which we have just reviewed. Other applicable local
regulatory guidelines on informed consent should be reviewed to ensure that all requirements are
met. We have just reviewed 20 required elements that subjects must consider as they try to
comprehend the informed consent they are being asked to read. From the standpoint of "too
much information", that is simply more than the average person can process. Feeling
overwhelmed by all the information, they may just decide not to be in a clinical trial. Their
decision may have more to do with inability to make a decision based on excessive information
than it does with the trial itself. Many potential subjects may be hesitant to tell the investigator
that they are unable to understand all of the information that the regulatory authorities,
IRBs/IECs, and institutions require. Having said this, the role that the investigator plays in the
consenting process cannot be stressed enough. Among the first things the investigator must do
is to prepare accurate/complete informed consent forms as required by regulatory authorities.
The following steps for preparation of the informed consent document will assist in meeting
these requirements for informed consent. In developing the informed consent document, all of
the IRB/IEC requirements must be met in addition to the regulatory requirements. Often the
IRB/IEC has specific requirements for the footer, readability index, signatures, formatting, etc..
For example, some IRBs/IECs require that the informed consent process be witnessed or require

that the subject's initials be entered by the subject on every page of the form. Note that some
regulatory authorities also require a witness to the informed consent process. Most sponsors or
CROs provide informed consent templates for the investigator to review and customize as
necessary. These templates will have all of the appropriate information specific to the clinical
trial. The content in the informed consent document must be consistent with the protocol and
Investigators Brochure. Compare the informed consent document to the protocol to ensure that
procedures are listed accurately, compare it to the investigator's brochure to ensure that known
risks are accurately and completely disclosed. Any changes made to the informed consent form
template will require sponsor or CRO review and approval as well as the IRB/IEC review and
approval. Know your regulatory requirements pertaining to informed consent and seek guidance
from your IRB/IEC and institution. The investigator must look at the subject population for
characteristics such as age, language, and competence. The informed consent must be written in
a language understandable to the subject or legally authorized representative. Some IRBs/IECs
require informed consent forms be written at a reading level that would be understandable to a
10-12 year old child. . Typically the informed consent forms provided by the sponsor or CRO are
written at this level or slightly below. If the form needs to be written at a lower reading level,
consider: Shortening sentences, Selecting words with one or two syllables only, Defining
medical or technical terms, Simplifying the format of the form by including section headings
such as "Visit Procedures by Visit number, and Increasing letter font size. All of these
measures will increase reading comprehension. Although subjects should have a discussion with
the study staff about the study in addition to reading the informed consent, if the person
developing the informed consent form writes it assuming that the subject will not talk to the
investigator or other study staff and that they must obtain all of the information they need to
make their decision from the informed consent form, it is likely that the form will be clear,
complete, without medical/scientific terminology and able to "stand alone". Language also
refers to primary spoken language of the subject population. Some countries have 2 official
languages. Canada, for example, recognizes English and French as official languages. In the US,
many states have a very large population of native Spanish speakers. In these cases, the
informed consent should be translated and submitted to IRB/IEC for review/approval in the
appropriate language for the subjects that are anticipated to be enrolled. Of course, this is only
applicable if the protocol permits enrollment of subjects who do not speak the "language of the
trial". Most sponsors and CROs request that once the informed consent document is customized
for the subject population and local requirements, it is submitted to them for review/feedback
PRIOR to submission to the IRB/IEC. The sponsor or CRO will require or recommend changes
if necessary. The final step in the preparation of the informed consent document is to obtain
approval or a favorable opinion from the IRB/IEC prior to implementing it. All changes to an
informed consent document must be reviewed and approved by the sponsor or CRO and the
IRB/IEC. The informed consent form consists of 2 elements or components: The subject
information sheet, and The signed agreement to participate in the trial However, the process is
more than just the reading and application of signatures on a form. It is a process of information
exchange! The informed consent document is often considered the foundation of the consenting
process but it does not represent the entire process. The document acts as a starting point for the
necessary exchange of information between the investigator and potential research participant.
The process of information exchange includes the elements listed on this slide. Recruitment
procedures may include advertising materials. Advertising is an extension of informed consent -
it may be the first thing that attracts subjects to the trial. Therefore, materials should not be

coercive or designed to unduly influence the subject. Written information materials as well as
verbal information and instructions are provided to assist the subject in understanding the
purpose, procedures, and risks, and benefits of the trial. All recruitment materials and any
written information materials that may be provided to the subject must be reviewed and approved
by the sponsor or CRO as well as the IRB/IEC prior to implementation. There should be time
allotted for the subject to ask questions and receive answers. Finally, there should be some
measure of the subject's understanding. For the most part, investigator judgement is required here
.... by asking the subject open- ended questions to determine the understanding. Remember that
the goal of informed consent is to increase a potential subject's understanding of the trial in
which they are being asked to participate so that they can make a sound decision, one that is right
for them, about enrolling. Informed consent is the "heart" of human subject protection.
Investigators who delegate this responsibility must be sure the designated staff is:
Knowledgeable about the study, and Able to answer questions. Investigators must be
knowledgeable of local regulations regarding who may conduct the consent interview and who
may obtain the consent. For example, in the UK, a qualified staff member such as the nurse is
permitted to discuss the trial with the subject but, the subject must then see the physician to have
an opportunity to ask questions and sign the document. Your sponsor or CRO representative is
able to assist you with understanding local regulations. In addition, even if local regulations
permit qualified site staff to conduct the consent interview and obtain consent, some sponsors or
IRBs/IECs require an investigator to personally perform these responsibilities. If informed
consent is delegated to research staff, they must be appropriately trained in all aspects of the
study as well as in interview techniques. The best practice is to have the designated staff
practice, or role play, the consent process with the investigator. Some monitors may also ask the
site staff to "consent" them in order to evaluate the site's process. There are certain situations in
which special procedures must be implemented. If the subject is unable to read, all written
information should be read and explained to the subject. The entire consent process must be
witnessed by an impartial witness and the informed consent documents will be signed by this
impartial witness as well. If the trial is being conducted under a US IND, the Code of Federal
Regulations requires that: "where some or all of the subjects are likely to be vulnerable to
coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled
persons, ... additional safeguards have been included in the study to protect the rights and welfare
of these subjects". It provides guidance that protection should be proportionate to the risk
involved... and while the assent of vulnerable (cognitively impaired at that time for some reason)
subjects is necessary, it is not sufficient [45 CFR 46.111(b)]. In these situations, the subject must
have someone who can understand the consenting process, and who is legally acceptable to do
so, give consent for him/her. Other country regulatory agencies may have additional regulations
regarding vulnerable subjects. The investigator should become familiar with their country
regulations. Emergency situations may also present conditions where the subject is unconscious
or otherwise unable to provide consent. In an emergency situation where the subject is
unconscious, but requires urgent treatment, and there is no alternative treatment available that
will give the subject a better chance to survive, the following steps should be taken to obtain
informed consent: First, the subject's legal representative should be contacted. If contact cannot
be made in a reasonable period and the IRB/IEC has approved emergency research, proceed and
obtain IC from a legally authorized representative as soon as possible. If, however, the
emergency care staff can reasonably assume that the person would NOT agree to participate in
the trial, even if the inclusion criteria were met, (e.g. some religious groups object to blood

transfusions and any other medical intervention and this might be documented on medical ID
bracelets) then the person should be excluded as a potential subject. (this is based on an FDA
guidance document dated, July 2006, Exception from IC Requirements for Emergency Research)
Local requirements must be followed and procedures documented in the protocol and approved
by IRB/IEC. This information is addressed in ICH 4.8.15 and 21 CFR 50.24. This slide lists
examples of vulnerable subjects. Subjects are considered to be vulnerable if their willingness to
volunteer is unduly influenced by the expectation of benefits associated with participation, or of
a retaliatory response from senior members of hierarchy for refusing to participate. Looking
more closely at the informed consent process for enrolling children into a clinical trial, there are
specific regulations that address this population. ICH 4.8.12 states that when a clinical trial
includes subjects who can be enrolled in the trial only with the consent of the subject's legally
acceptable representative, such as minors, the subject should be informed about the trial to the
extent compatible with the subject's understanding and, if capable, the subject should give assent,
sign and personally date the written informed consent. If the trial is being conducted under a US
IND, 21 CFR 50.55 also provides regulations for eliciting the assent of children. Assent is
useful for making sure children understand the trial and what it means to participate. Children are
likely to feel more in control and more involved in the trial as a result. Investigators must be
aware of any local regulations regarding enrollment of children into a clinical trial. Prior to
participation in a clinical trial, the informed consent must be signed and dated personally by the
subject, or the subject's legally acceptable representative, and by the person who conducted the
informed consent discussion. Remember, consent must be entirely voluntary. Neither the
investigator nor the trial staff should coerce or unduly influence a potential subject to participate
or continue to participate in a trial. Before signing a consent, the subject or the subject's legally
acceptable representative must be provided ample time and opportunity to ask any questions they
may have about the research. (ICH 4.8) Keep in mind that specific country and/or regional laws
or institutional and/or IRB/IEC policies may be more stringent than the ICH. For example: in
Argentina, the law requires that a witness be present for the administration of the informed
consent and the witness must sign the informed consent document as well. It is critical that the
PI and designated staff know the local requirements (such as region, country, IRB/IEC, or
institutional requirements). Next is an exercise on how to address selected questions that may
arise during the informed consent discussion process. There are a total of three multiple choice
questions. Select the best response and click on the "submit' button. At the end of the exercise
you will automatically be placed back into the PowerPoint presentation. The remaining portion
of this module will discuss

regulations related to protocol compliance. These regulations are found in ICH 4.5 and 21 CFR
part 312.60. As outlined in ICH 4.5, the investigator should sign the protocol, or an alternative
contract, to confirm agreement to conduct the trial in compliance with the protocol. Typically,
there is a protocol signature page that has been signed by the sponsor which also requires the
investigator's signature. The investigator should not implement any changes or deviations from
protocol without agreement from the sponsor and prior review and documented approval/
favorable opinion from the IRB/IEC. The investigator or person designated should document
and explain any deviation from the approved protocol. This can be done in the source data or, at
times, sponsors will provide a protocol deviation log where the site staff is asked to record all
protocol changes. By signing FDA Form 1572 the principal investigator agrees to follow the
protocol and conduct the trial in accordance with FDA regulations. Compliance with the protocol
is also addressed in 21 CFR 312.60. Deviations from, or changes to the protocol without prior
approval of the IRB/IEC are permitted only to eliminate an immediate hazard to the subject or if
the change involves a logistical or administrative aspect, such as a change in monitor or
telephone number. In these situations, it is acceptable for the investigator to implement the
change without prior IRB/IEC approval/favorable opinion but these circumstances require
follow-up action. The investigator is required to submit documentation outlining the deviation
the reason for that deviation to the IRB/IEC, to the sponsor and in some countries to the
regulatory authority. The protocol deviation needs to be submitted as soon as possible,
particularly if it was implemented out of a need to eliminate hazard to subjects. A
deviation/violation can be defined as any change to a protocol from what was previously
approved during the period for which approval was given. Although the terms protocol
exception, violation and deviation are used interchangeably, it is important to note that any
deviation or departure from the protocol needs to be brought to the attention of the Sponsor/CRO
and to the IRB/IEC. These terms may be defined more specifically by the sponsor. Remember
that the IRB/IEC provided approval/favorable opinion to conduct the study based on the original
protocol submitted. It is responsible for assessing additional risks or benefits when conducting
review changes and has the authority to terminate research that is not conducted according to it's
requirements. In order for them to fulfill their responsibility of providing ongoing oversight, they
must be informed of changes to the protocol. In some cases, the use of the term "exception"
indicates an approved exception (approved by the sponsor) such as in the enrollment of subjects
that don't meet the strictly defined inclusion/exclusion criteria. In this case, these exceptions
need to be documented in writing and available for monitors and/or auditors to view with the
study records. The documentation may be in the form of a written communication from the
Sponsor granting the exception or in a telephone communication. It is critical to capture the
name, title of sponsor contact approving the exception and the date and time of contact. In most
cases a deviation and a violation are the same. All need to be documented in the source
documents of the subjects and, in some cases, on a protocol deviation form/log if required by

sponsor. Please note that a violation, deviation and/or exception should be a one-time event and
IRB/IEC approval for its implementation does not change the entire protocol. Examples of
protocol non-adherence issues include: Not following inclusion/exclusion criteria. Exceptions
that are approved by the sponsor need to be documented in the investigator's files, Failing to
perform the required tests, or forgetting to have a test done according to the schedule will result
in unobtainable data and possible safety issues for subjects, Not assuring that the subjects adhere
to the required visit schedule. It is helpful to have a system for reminding subjects of upcoming
visits via telephone, visit cards, etc. Not following the randomization scheme when one is
provided, sometimes there is a creative use of the prepared code due to lack of training of site
staff, pharmacy staff, etc., Lack of accurate documentation of dosing, dispensing, return of
medications, Site staff completing subject diaries instead of having the subjects complete their
own diaries, and Not collecting and/or reporting adverse events as required by the protocol.
There will be more detail on adverse event collecting and reporting in module 5. The sponsor
and CRO are to work together to secure compliance with the investigator. If this is not achieved,
then the site may be closed down/terminated from participation in the trial. The sponsor is
obligated to notify the regulatory authority in cases where a study site is terminated prior to
completion of the study. Next is the third and last exercise in this module. In this exercise you
will be given information about a protocol and specific case report form visit entries. In a series
of three multiple choice questions you will be asked to identify protocol deviations and actions
that should be taken, based on the information provided. Select the best response and click on the
"submit' button.
Question 1: True or False: The ICH defines informed consent as a process by which a subject
voluntarily confirms his or her willingness to participate in a trial, after passing all protocol
specific screening procedures.
Rationale: The correct answer is "False"
Your Answer: False
Question 2: Which of the following is NOT an element that is required in the informed consent
Rationale: The correct answer is "Investigator’s responsibilities in conducting the trial"
Your Answer: Investigator’s responsibilities in conducting the trial
Question 3: Which of the following should be considered when preparing an informed consent
Rationale: The correct answer is "All of the above"
Your Answer: All of the above
Question 4: What elements might be included in the exchange of information during informed
Rationale: The correct answer is "Verbal instructions, written materials, and opportunity to ask
Your Answer: Verbal instructions, written materials, and opportunity to ask questions
Question 5: True or False: If the investigator elects to delegate the responsibility for informed
consent to staff they must ensure that the staff is knowledgeable regarding the study and able to
answer questions.
Rationale: The correct answer is "True"
Your Answer: True
Question 6: Which of the following statements is true regarding informed consent in emergency

Rationale: The correct answer is "If the subject is unable to give consent and there is no legal
representative available a life saving study treatment may be given, if there is no other
Your Answer: If the subject is unable to give consent, a protocol may be implemented without
attempting to identify a legal representative
Question 7: What is required in order for the investigator to deviate from the protocol?
Rationale: The correct answer is "Agreement of the sponsor and approval/favorable opinion of
the IRB/IEC"
Your Answer: Approval of the sponsor and agreement by the subject
Question 8: When is a deviation in protocol allowed without prior approval/favorable opinion of
the IRB/IEC?
Rationale: The correct answer is "When there is a need to eliminate an immediate hazard to trial
Your Answer: When there is a need to eliminate an immediate hazard to trial subjects
Question 9: True or False: The investigator is required to document only those deviations from
protocol that were not approved by the sponsor prior implementation.
Rationale: The correct answer is "False"
Your Answer: True
Question 10: Which of the following is NOT an example of protocol non-compliance?
Rationale: The correct answer is "Failure to accrue agreed upon number of subjects"
Your Answer: Failure to accrue agreed upon number of subjects


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