Clinical Research Overview Download

Informational Program for Site Staff Less Experienced in Conducting Clinical Research
Topic: Clinical Research Overview
Contents
Topic: Clinical Research Overview ........................................................................................ 1
Legal Disclaimer ................................................................................................................... 2
Introduction ........................................................................................................................... 3
Why is this Topic important? ................................................................................................. 3
Topic Details ......................................................................................................................... 3
Intro: Investigational Product Development Process ............................................................. 4
Investigational Product Development Process ...................................................................... 4
Types of Clinical Study Design.............................................................................................. 6
Study Design Variations ........................................................................................................ 7
Study Protocol....................................................................................................................... 8
Contents of the Study Protocol.............................................................................................. 8
Key Stakeholders in Clinical Research .................................................................................. 9
Introduction to ICH GCP ....................................................................................................... 9
Responsibilities of a Clinical Investigator............................................................................... 9
Introduction to IRB/IEC ....................................................................................................... 10
Investigator/Sponsor Responsibilities towards IRB/IEC....................................................... 10
Tips for conducting a Successful Clinical Study .................................................................. 11
Review Questions ............................................................................................................... 11
Topic Summary ................................................................................................................... 13
Remember .......................................................................................................................... 13
Informational Program for Site Staff Less Experienced in Conducting Clinical Research Page 1 of 13
Legal Disclaimer
These materials were prepared by or for TransCelerate BioPharma (“TransCelerate”). They
are intended merely to provide background information and awareness to clinical trial
Investigators and clinical trial site personnel. By using these materials, you signify your
assent to the below terms of use. If you do not agree to the terms, please do not use these
materials.
These materials are not tailored to any particular factual situation and are provided 'AS IS'
WITHOUT WARRANTY OF ANY KIND, EITHER EXPRESSED OR IMPLIED, INCLUDING,
BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY, FITNESS
FOR A PARTICULAR PURPOSE, OR NON-INFRINGEMENT. TransCelerate and its
members do not accept any responsibility for any loss of any kind including loss of revenue,
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consequential loss whatsoever to any person using these materials or acting or refraining
from action as a result of the information contained in these materials. Any party using these
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modified or not, are suitable for the particular use and are accurate, current, commercially
reasonable under the circumstances, and comply with all applicable laws and regulations.
TransCelerate does not certify, qualify, endorse, represent, or warrant that any clinical trial
Investigator or clinical trial site personnel that may review these materials are competent to
work on any particular clinical trial or clinical trials generally.
Nothing in these materials should be construed as legal advice. As always, all users are
responsible for ensuring their compliance with all applicable laws and regulations for the
relevant jurisdiction. The person presenting these materials is a paid actor hired for this
purpose, not a medical professional.
Introduction
Welcome to the Topic: Clinical Research Overview.
This topic will provide an introduction to clinical research, Investigational Product

development, and clinical study design processes. You will need approximately 40 minutes
to review the topic.
Why is this Topic important?

Short Version (Page text) Long Version (Audio text)
· Clinical research is a complex process Hi there, my name is Dr. Paul Wang. Though I
that demonstrates the safety and started my career as a research scientist, I’ve
efficacy of new or modified drugs. been working as an Investigator for the last
· Research helps test, compare, rule thirteen years.
out, and finally select one or more
treatments. As healthcare professionals, it is our job to
· Each phase of clinical research is maximize benefit and minimize risks to our
necessary for creating a viable patients and subjects. One way to ensure this is
therapeutic product. to release drugs and other therapeutic products
· Clinical studies help determine safety to the market only after their safety is assured.
and efficacy of drugs, or medical Clinical research is a complex process that
devices. demonstrates the safety and efficacy of new or
· Pharmaceutical companies are not modified drugs. Research helps test, compare,
permitted to market new drugs until rule out, and finally select one or more
their safety and efficacy are proven to treatments and each phase of clinical research
local Regulatory Authorities. is necessary for creating a viable therapeutic
product. Clinical studies help determine safety
and efficacy of drugs, or medical devices. In
fact, pharmaceutical companies are not
permitted to market new drugs until their safety
and efficacy are proven to relevant authorities
via clinical research and clinical studies.
Topic Details
This topic will provide information on:
· Clinical Research
· Investigational Product Development Process
· Clinical Study Design
· Responsibilities of the Investigator during a Clinical Study
· Tips for Successful Clinical Studies
Intro: Investigational Product Development Process

The Investigational Product development process refers to the different phases of clinical
research. This process is comprised of multiple phases.
In some cases, an additional phase after Phase IV is also considered.
Investigational Product Development Process
Discovery Phase: In the Discovery phase, researchers investigate new experimental

products. New chemical entities or NCEs, new molecular entities or NMEs: a drug that
contains active moiety, or active molecule, or new biologics, emerge from the process of
drug discovery. The Discovery phase is conducted in the laboratory and can take from
between 2 to 10 years. Human subjects are not used.
Pre-clinical Phase: The Pre-clinical phase is conducted in the lab and can last from
between 1 to 3 years. In vitro experiments (that is, using test tube or cell culture) and in vivo
experiments (that is, testing in animals) are used to investigate wide-ranging doses of the
NCE, or new chemical entities. This helps obtain preliminary efficacy, toxicity, and
pharmacokinetic information. The Pre-clinical phase helps pharmaceutical companies decide
whether an NCE has scientific merit for further development as an investigational new drug.
The Investigational Product is not yet tested on human subjects.
Phase I: In Phase I, researchers test a new Investigational Product or treatment in a small

group of subjects for the first time to evaluate safety, determine a safe dosage range, and to
identify adverse events. The focus is on pharmacokinetics, that is, the time needed for
absorption, distribution, metabolism, and excretion of the drug. The subjects may have pre-
existing targeted diseases like cancer, or they may be healthy volunteers. Since this stage
requires constant and critical monitoring of subjects, Phase I studies are generally
conducted in an inpatient setting and monitored by specialized Phase I monitoring units. A
Phase I study can last up to a year.
Phase II: In Phase II, the Investigational Product or treatment is given to a large group of
subjects, approximately 200 to 300, who already have the condition. The aim is to test the
efficacy and safety of the product or treatment. Phase II studies are sometimes divided into
Phase IIA and Phase IIB. Phase IIA is designed to assess the dose, that is, how much of the
drug should be given to each subject. Phase IIB is designed to study efficacy, that is, how
well the drug works at the prescribed doses. A Phase II study can last for up to 2 years.
Phase III: In Phase III, the Investigational Product or treatment is given to thousands of
people to compare efficacy, monitor side effects, and compare it to existing conventional
therapy treatments for the same therapeutic area. Information collected during Phase III is
analyzed to determine if the Investigational Product or treatment can be used safely. Other
reasons for conducting a Phase III study include:
· label expansion, i.e., to show that the drug works for additional types of patients or
diseases beyond the original use for which the drug was approved for marketing
· to obtain additional safety data
· to support marketing claims for the drug
· to address additional indications suggested by phases I to III
Phase III can last anywhere between 1 to 4 years. Following successful completion of, and
favorable results from, Phase III, drug applications are submitted by the Sponsor to the local
regulatory authority. Additional documents and samples of finished products or related
substances may need to be submitted along with the proposal. In order to provide approval,
Regulatory Authorities may audit the Sponsor, one or more investigative sites, and
investigative data, and hold public or closed discussions with advisory panels. Regulatory
Authorities may accept or reject advisory recommendations.
Phase IV: Phase IV studies are conducted after the Investigational Product or treatment has
been marketed. Phase IV is used to gather information on the Investigational Product’s
effect in various populations and any adverse events that may occur with long-term use.
Phase IV is sometimes referred to as a post-marketing surveillance study or post-
authorization study.
Some studies might also use an additional phase to observe:
• Effect on different age, gender, or ethnic groups
• Effect on population groups excluded as subjects during the study, for e.g: pregnant
women
• Interaction of the drug with other drugs
• To continue observations for ‘fast track’ Investigational Products
• For competitive reasons, for e.g: to discover new markets
• To provide information to the medical community
Always remember: Safety is a primary concern in all phases of drug study.
Types of Clinical Study Design

Clinical study design is the formulation of studies and experiments, as well as observational
studies in medical, clinical, and other types of research. It determines the treatment plan for
specific groups of subjects participating in each study. The design to be followed for each
study is documented in the study protocol.
Masked Study: Masking is a means of minimizing potential bias in a clinical study. In a

masked study, involved parties do not know whether the subject is receiving the
Investigational Product, a placebo, or a comparator product. Sometimes, entire studies, or
individual subjects, can be unmasked for emergency reasons.
· Single Mask: Subject does not know which treatment they are receiving. Some site
staff know which treatment the subject(s) are receiving; others do not.
· Double Mask: Neither the subjects nor the researchers know which group each
subject belongs to: control or the test. The key that identifies the subjects and which
group they belong to is held by a third party and not revealed to the researchers until
the study is over.
· Did you know? A masked study is also known as a blinded study.
Unmasked Study: In an Unmasked Study, all parties concerned know the treatment. This is
also known as an open-label study or an unblinded study. Sometimes, an originally masked
study can be unmasked for emergency reasons, e.g: if subject experiences an event that
meets the expediting criteria (serious, unexpected, possible relation to the study drug).
Uncontrolled Study: In an Uncontrolled Study, no control groups are established. All

subjects receive the same treatment.
· Control Group: Researchers of certain clinical studies prefer to divide subjects into
2 groups. One is called the experimental group and the other, the control group.
During the course of the clinical study, the subjects in the experimental group are
administered with the study drug or treatment procedure, whereas the control group
is not provided with the study drug. By comparing the data obtained from the
experimental group with that of the control group, researchers can nullify the external
factors (factors other than the study drug) that may be affecting the overall condition
of the participants.
Placebo Controlled Study: In a Placebo Controlled Study, the effect of a drug is compared
with the effect of a placebo (an inactive substance designed to resemble the drug). Subjects
receive either the drug being studied or a placebo. A placebo controlled study can also be
either masked or unmasked.
· Did you know? A placebo is used only when it will not expose study subjects to
excessive risks of harm by treating with a placebo. For some studies, use of a
placebo is even considered unethical (cancer, diabetes, etc.)
Active Control Study: In an Active Control study, a product that is currently marketed is
used to treat the control group of subjects, while the active Investigational Product is used to
treat another group. A currently marketed product is typically one considered to be the
Standard of Care for a given indication.
Study Design Variations

Part of the study design is to determine whether to combine or vary treatment patterns for
specific subjects in order to observe the efficacy of combined treatment options.
Parallel Study: In a Parallel Study, two groups of treatment, A and B, are given so that one
subject group receives only A while another group receives only B. The two treatments can
either consist of two completely different Investigational Products, or different doses of the
same product (as shown in the image here). One of the arms can even use a placebo
(placebo arm).
· Randomization: Participants in a clinical study are allocated to different treatment

groups by a process called randomization. Randomization prevents bias by ensuring
that any differences between the groups at study entry are due to chance alone.
· Did you know? BID is an abbreviation for "bis in die" which in Latin means twice a
day.
A Parallel Study Set-up:
Crossover Study: A Crossover Study is conducted with a minimum of 2 treatment groups.

Subjects receive one treatment for a specified duration. Then, they are switched (“crossed
over”) to a different treatment for the remainder of the study. This allows for evaluation of all
treatment arms in a single subject.
· Washout: A period during which subjects receive no treatment for the indication
under study, so that the effects of a previous treatment can be eliminated.
A Crossover Study Set-up:
Study Protocol
The Study Protocol indicates how the clinical study must be conducted to ensure subject
safety and data integrity. It is created by the Sponsor and must be accurately executed by
Investigators.
Did you know? Protocol noncompliance accounts for the highest number of Investigator
errors during the conduct of a study. According to metrics published by the FDA Office of
Scientific Inspections in 2014, 73% of all Investigator related deficiencies came from protocol
noncompliance in 2013.
Contents of the Study Protocol

The Study Protocol typically includes the following sections:
· Objectives of the study

· Disease/ Condition being studied
· Selection & withdrawal of subjects
· Treatment of subjects
· Dosage and administration of Investigational Product(s)
· Handling of Investigational Product (dosage, storage, preparation, compliance
evaluation)
· Study design description (number of visits, procedures to be performed, treatment
assignment and statistical design)
· Assessment of safety
· Process for submitting safety data to Sponsor
· Data collection, assessment, and analysis methods
· Permissible and prohibited medication and treatments at screening and during
course of study
· Direct access to Source Documents
Key Stakeholders in Clinical Research

Stakeholders refer to persons or groups that have a vested interest in a clinical decision and
the evidence that supports that decision. This includes Sponsors, Researchers, Study
Investigators & Professional societies, Regulatory authorities and Investigational
Committees, businesses, policymakers, etc.
1. Sponsor: As per ICH-GCP 1.53 (ICH: International Conference on Harmonization;

GCP: Good Clinical Practices), a Sponsor is an individual, company, institution, or
organization which takes responsibility for the initiation, management, and/or
financing of a clinical study.
2. Investigator Site: Clinical studies can take place in hospitals, universities, doctors'
offices, and community clinics. The Investigator Site is the location(s) where study-
related activities are conducted. The type of site is selected by the Sponsor and is
based on a number of factors: resources (facilities/ personnel), required
characteristics of the subject pool (treatment, disease state), experience level of the
study Investigator and staff, etc.
3. Regulatory Authority: Per ICH 1.49, Regulatory Authorities include authorities that
review submitted clinical data and conduct inspections. These bodies are sometimes
referred to as competent authorities. Examples of regulatory authority include
government agencies like the EMA, FDA, MHRA, and PDMA. Check the Glossary to
see what these acronyms stand for.
Introduction to ICH GCP

ICH: The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings
together regulatory authorities and pharmaceutical industry to discuss scientific and
technical aspects of drug registration.
GCP: Good Clinical Practice (GCP) is an international ethical and scientific quality standard
for designing, conducting, recording, and reporting trials that involve the participation of
human subjects. Compliance with this standard provides public assurance that the rights,
safety, and well-being of trial subjects are protected, and that the clinical trial data is
credible. GCP is one of the guidelines established in the ICH project.
Responsibilities of a Clinical Investigator

As an Investigator, I have a number of responsibilities towards subjects, site staff, Sponsors,
Regulatory Authorities, review boards and committees.
Compliance: The Investigator (as per ICH 1.34) is responsible for compliance activities
such as:
· Protecting the rights, safety, and welfare of the study subjects

· Conducting the study according to the protocol and applicable local regulations
· Compliance with IRB/IEC requirements
· Ensuring that procedures are in place for obtaining informed consent
· Reporting adverse events
· Assuring that only qualified personnel perform study activities
Delegation: In order to successfully manage their tasks, Investigators can, and should,
delegate tasks based on education, training, experience, licensure, and workload of their site
staff. They should also:
· Track delegation of all study tasks by site personnel on delegation log.

· Ensure study team members are trained in applicable study information provided by
Sponsor when available.
· Complete training and delegation PRIOR to study staff performing any study-related
task.
· Document all training programs so that the details are available for review during
inspection, Sponsor visits, audits, or inspections.
Did you know? The Investigator is responsible for all ethical and protocol noncompliance in
a study. This includes any violations in delegated tasks performed by study staff.
Introduction to IRB/IEC
Per ICH GCP sections 1.31 and 1.27 respectively, an Institutional Review Board (IRB) or
Independent Ethics Committee (IEC) is an independent body constituted of medical
professionals and non-medical members. The IRB/IEC review and approve/ provide
favorable opinion on the study protocol, the suitability of the Investigator(s), facilities, and the
methods and material to be used in obtaining and documenting informed consent of the
study subjects.
Investigator/Sponsor Responsibilities towards IRB/IEC

Investigators and Sponsors have responsibilities to the IRB/IEC. The following activities may
be performed either by the Investigator or the Sponsor depending on the region of the world.
Please check your local requirements to confirm the completion of these responsibilities.
1. Before the Study

a. Investigator to:
i. Receive written approval to start study
ii. Receive written approval for informed consent and each item of
information given to subjects
iii. Remember: In some countries this responsibility is delegated to
Sponsor.
2. During the Study
a. Investigator to:
i. Understand reporting requirements for protocol deviations/
noncompliance
ii. Ensure safety reporting
iii. Ensure periodic study reporting
iv. Remember: In some countries this responsibility is delegated to
Sponsor.
3. After the Study
a. Investigator to:
i. Send study close-out documents as specified
ii. Comply with safety reporting requirements
iii. Remember: In some countries this responsibility is delegated to

Sponsor.
Tips for conducting a Successful Clinical Study

1. Practice Good Organization and Documentation Skills
a. Follow ICH and GCP guidelines.
b. Follow the protocol rigorously.
c. File all essential documents and keep them current.
d. Ensure Investigational Product logs are updated and current.
e. Document decisions & critical conversations: sign, date, file.
f. Ensure written documents are clear, factual, concise, and complete.
g. Allow time for review of subject charts, tests, etc, and document the review in
clinical study documentation.
2. Communicate Frequently with the Sponsor & Study Team
a. Ensure awareness and training of study staff with Sponsor provided
information.
b. Keep site staff updated with any new information made available by the
Sponsor.
c. Review Sponsor updates to the protocol and IB, along with safety reports
received and any other communication from the Sponsor.
d. Confer regularly with the Sponsor regarding study progress.
3. Base Decisions on Observations and Worse Case Assumptions
a. Ensure accuracy by documenting all issues and facts surrounding study
assessments in a timely manner.
b. Assume that clinical study documentation will live forever, so ensure that all
documentation is neutral and factual, and that it eliminates ambiguity.
Review Questions
Review Question 1 of 6: Which phase comes first: Discovery or Pre-clinical?
There is ONE correct answer.
· Discovery
· Pre-clinical
Review Question 2 of 6: What is the key feature of each of these Phases?
The correct matches are shown below.
Discovery Pre-clinical Phase I Phase II Phase III Phase IV
Search for an Conduct Test on Test in Test in Post-market

experimental tests in the healthy subjects subjects testing for
Investigation lab and on volunteers (effective (long term long-term
al Product animals for safety dose, adverse safety and
adverse events and efficacy
events) efficacy)
Review Question 3 of 6: What is Randomization?
· Process by which treatment is stopped for a period of time and then switched
· Process by which a study is unmasked due to safety concerns
· Process by which the study protocol builds in safety measures to assess for AEs
· Process by which study subjects are allocated to different treatment groups
Review Question 4 of 6: During which clinical research phase is the safety of the
Investigational Product determined?
· In Phase I
· In Phase II
· In Phase III
· In all the above phases
Review Question 5 of 6: Who is responsible for conducting the clinical study at the
site?
· Sponsor
· Investigator
· Institutional Review Board
· Independent Ethics Committee
Review Question 6 of 6: During his 2nd visit, one of your subjects, Mr. Pinto, mentions
that he is feeling better than ever. When it is time for the pharmacokinetic blood draw,
he is surprised as no blood was collected during his 1st visit. You realize this has
been a mistake on part of the study staff. The protocol clearly states that a blood
sample must be collected at EVERY visit. As the Investigator, what should you do?
Based on the scenario above, ALL the answers below are correct.
· Review the study visit requirements, including dosing and pharmacokinetic

blood draws, with Mr. Pinto.
· Review the study visit requirements, including dosing and pharmacokinetic
blood draws, with the Study Coordinator who conducted the first visit. Ensure
he/she understands the protocol.
· Document any discussion and training of study coordinator and research staff
of study requirements.
· Investigate the underlying reason why the blood draw was missed and not
discovered earlier, and consider a plan moving forward to prevent another
occurrence.
· Alert Sponsor and IRB/IEC about the missed blood draw, the reason of this
deviation, and prevention action.
Topic Summary
· Clinical research is a complex process that demonstrates the safety and efficacy of
new or modified drugs.
· Research helps test, compare, rule out, and finally select one or more treatments.
· Each phase of clinical research is necessary for creating a viable therapeutic
product.
· Pharmaceutical companies are not permitted to market new drugs until their safety
and efficacy are proven to local Regulatory Authorities.
· Clinical studies help determine safety and efficacy of drugs, and also medical
devices.
Remember
Please consult ICH/GCP guidelines and maintain a close partnership with the Sponsor and/
or study designee during the course of the clinical study- as a team working together you
can be successful and have a positive experience.

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Informational Program for Site Staff Less Experienced in Conducting Clinical Research

Topic: Clinical Research Overview

This topic will provide an introduction to clinical research, Investigational Product

Why is this Topic important?

Intro: Investigational Product Development Process

In some cases, an additional phase after Phase IV is also considered.

Investigational Product Development Process

Discovery Phase: In the Discovery phase, researchers investigate new experimental

Phase I: In Phase I, researchers test a new Investigational Product or treatment in a small

· to obtain additional safety data

· to support marketing claims for the drug

· to address additional indications suggested by phases I to III

Some studies might also use an additional phase to observe:

• Effect on different age, gender, or ethnic groups

• Interaction of the drug with other drugs

• To continue observations for ‘fast track’ Investigational Products

• For competitive reasons, for e.g: to discover new markets

• To provide information to the medical community

Always remember: Safety is a primary concern in all phases of drug study.

Types of Clinical Study Design

Masked Study: Masking is a means of minimizing potential bias in a clinical study. In a

Uncontrolled Study: In an Uncontrolled Study, no control groups are established. All

Study Design Variations

· Randomization: Participants in a clinical study are allocated to different treatment

A Parallel Study Set-up:

Crossover Study: A Crossover Study is conducted with a minimum of 2 treatment groups.

A Crossover Study Set-up:

Contents of the Study Protocol

· Objectives of the study

Key Stakeholders in Clinical Research

1. Sponsor: As per ICH-GCP 1.53 (ICH: International Conference on Harmonization;

Introduction to ICH GCP

Responsibilities of a Clinical Investigator

· Protecting the rights, safety, and welfare of the study subjects

· Track delegation of all study tasks by site personnel on delegation log.

Investigator/Sponsor Responsibilities towards IRB/IEC

1. Before the Study

iii. Remember: In some countries this responsibility is delegated to

Tips for conducting a Successful Clinical Study

There is ONE correct answer.

Review Question 2 of 6: What is the key feature of each of these Phases?

The correct matches are shown below.

Discovery Pre-clinical Phase I Phase II Phase III Phase IV

Search for an Conduct Test on Test in Test in Post-market

Review Question 3 of 6: What is Randomization?

There is ONE correct answer.

There is ONE correct answer.

There is ONE correct answer.

· Review the study visit requirements, including dosing and pharmacokinetic

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