Definition:
Clinical research is a Branch of healthcare science & research study that involves human
volunteers designed to determine the safety and effectiveness of a drug, biologic (such as a
vaccine), device (such as vagus nerve stimulator) or other treatment or behavioural
intervention.
Carefully conducted clinical trials are the fastest and safest way to find treatments that
improve health in people.
The Food and Drug Administration (FDA) requires that all new treatments be tested in
clinical trials before they are reviewed for approval. Observational trials address health issues
in large groups of people in natural settings.
Clinical research includes:
∙Medical and behavioral research involving volunteer participants
∙Investigations that are carefully developed and conducted with clinical outcomes recorded
Identification of better ways to prevent, diagnose, treat, and understand human disease
∙Trials that test new treatments, clinical management, and clinical outcomes, and
long–term studies
∙Strict scientific guidelines
∙Ethical principles to protect participants.
Because clinical trials are required for any new therapy before FDA approval, significant
improvements in healthcare would be impossible without volunteer participants. Participants
in clinical trials can play a more active role in their own health care, gain access to new
research treatments before they are widely available, and help others by contributing to
medical research.
Research is vital because:
∙Clinical trials test how well new approaches and interventions work in people
∙These approaches can be medical, behavioural, or management
∙Each study answers scientific questions
∙Each study helps scientists prevent, screen for, diagnose, manage, and treat a disease
∙People who participate in clinical trials contribute to the knowledge of how a disease
progresses.
Some benefits of taking part in a clinical trial are:
∙Participants have access to promising new approaches often not available outside the
clinical trial setting
∙The drug, vaccine or other intervention being studied may be more effective and
productive than the standard approach (although there is no guarantee that participants
will receive the experimental drug, vaccine, or other intervention)
∙Participants receive careful medical attention from a research team of doctors and other
health professionals
∙Participants may be the first to benefit from the study
∙Results from the study may help others in the future.
All clinical trials have guidelines about who can participate. The factors that allow someone
to participate in a clinical trial will vary from study to study. These criteria are based on the
goals of the study and include such factors as age, the type and stage of a disease, previous
treatment history, and other medical conditions. Some research studies seek participants with
illnesses or conditions to be studied in the clinical trial, while others need healthy
participants. The criteria are used to identify appropriate participants needed to answer the
scientific questions being asked while keeping them safe.
The main goal of using volunteers in a clinical trial is to prove, by scientific means, the
experimental treatment's effects and limitations on a wide variety of people. Research
procedures with volunteers are designed to develop new knowledge, not to benefit study
participants directly. Before joining a clinical trial, a person must qualify for the study:
∙Some research studies seek participants with illnesses or conditions to be studied in the
clinical trial.
∙Some research studies need volunteers who do not have the disease being studied. A
person with the condition being studied is called a “patient volunteer” and has a known
health problem.
∙Participates in research to better understand, diagnose, treat, or cure that disease or
condition.
∙Supports research procedures to help develop new knowledge (these procedures may or
may not benefit the participant).
∙A person may also volunteer who is at risk for the condition being studied. A volunteer
who does not have the condition being studied is called a “control” and:
∙Participates in clinical research to test a new vaccine, microbicide, or other strategy or
intervention needed when developing a new technique, such as a blood test or imaging
device.
∙Helps define the limits of "normal."
∙Serves as a control for participant groups and is often matched to participants on
characteristics such as age, gender, or family relationship.
∙Receives the same test, procedure, vaccine, or microbicide the participant group receives.
Some volunteers serve as controls by not taking the test vaccines, microbicides, or other
strategies. Or these volunteers may receive doses large enough only to show that it is
present but not at a level that can treat the condition. Investigators learn about a disease
process by comparing how each volunteer reacts to the trial. Some studies require a major
commitment of time and effort. Some studies may involve some discomfort. The research
procedure may also carry some risks. The consent process for volunteers includes a
detailed discussion of the study's procedures and tests.
Intended to increase knowledge about how well a diagnostic test or treatment works in a
particular patient population.
∙To test hypothesis formulated from observations and or intuition.
∙Ultimately, to understand better one’s world and make “Sense of it.”
All clinical trials have guidelines about who can participate—these are specified in the
inclusion/exclusion criteria:
∙Factors that allow someone to participate in a clinical trial are "inclusion criteria."
∙Factors that exclude or do not allow participation in a clinical trial are "exclusion criteria
“
These factors may include:
oAge
oGender
oThe type and stage of a disease
oPrevious treatment history
oSpecific lab values
Other medical conditions Inclusion and exclusion criteria are not used to reject people
personally. The criteria are used to:
oIdentify appropriate participants
oKeep them safe
oHelp ensure that researchers can answer the questions they want answered
The clinical trial study team, which includes doctors, nurses, and other health care
professionals, checks the health of the participant at the beginning of the trial, gives specific
instructions for participating in the trial, monitors the participant carefully during the trial,
and stays in touch after the trial is completed. Some clinical trials involve more tests and
doctor visits than the participant would usually have for an illness or condition. Clinical trial
participation is most successful when the study protocol is carefully followed, including
frequent contact with the clinical trial team.
Usually, clinical trials compare a new product, vaccine, management strategy, or therapy with
another already existing. This comparison helps determine if the new one is as successful as
or better than the existing one. In some studies, participants may be assigned to receive a
placebo (an inactive product that resembles the test product but without its treatment value).
Comparing a new product with a placebo can be the fastest and most reliable way to
demonstrate the new product’s therapeutic effectiveness and efficacy. Placebos are not used if
a participant will be put at risk (standard of care)—particularly in the study of treatments for
serious illnesses—by not having effective therapy. Potential participants are told if placebos
will be used in the study before they enter a trial. For studies using placebos:
∙Clinical trial investigators must be able to show that withholding active therapy from
participants for a short time is unlikely to result in physical harm.
∙Participants must give voluntary, informed consent.
∙Investigators must closely monitor participants in these studies. Most studies compare
new products or regimens with an approved therapy (for example, standard of care) for
therapeutic trials.
Randomization is when two or more alternative treatments are assigned to volunteers by
chance instead of choice. The assigned treatment is administered with the highest level of
professional care. The results of each treatment are compared at specific points during a trial,
which may last for years. When one treatment is found superior, the trial is stopped so that
the fewest participants possible receive the less beneficial treatment. In single- or double-
blind studies (also called single- or double-masked studies), participants do not know which
medicine is being used, so they can describe what happens without bias. Masked studies are
designed to prevent research team members or study participants from influencing the results.
Therefore, scientifically accurate conclusions are more likely. Members of the research team
are not told which participants receive which medication, so their observations will not be
biased. If medically necessary, it must always be possible to find out what participants have
taken:
∙In single-blind studies, only the participant is not told what is being administered
∙In a double-blind study, the pharmacist is the only person who knows what is being
administered.
Clinical trials take place all over the world:
∙Health care providers’ offices
∙Medical centers
∙Community and university hospitals and clinics
∙Veterans’ and military hospitals Clinical trials may include participants at one or two
highly specialized centres. Or they may involve hundreds of locations at the same time.
Good Clinical Practice (GCP) is an international quality standard that governments can
transpose into regulations for clinical trials involving human subjects. GCP guidelines
include the protection of human rights as a subject in clinical trials and assurance of the
safety and efficacy of the newly developed compounds. GCP guidelines also include
standards on how clinical trials should be conducted and a definition of the roles and
responsibilities of clinical trial sponsors, clinical research investigators, and monitors. Good
clinical laboratory practice (GCLP) guidelines focus on good laboratory practice and good
clinical practice guidelines/standards for medical testing laboratories conducting clinical
trials in developing countries.
Some risks of taking part in a clinical trial are:
∙New vaccines, microbicides, and other strategies under study are not always better than
the standard care to which they are being compared.
∙New treatments may have unexpected side effects or risks worse than standard care.
∙Health insurance and managed care providers may or may not cover all participant care
costs in a study.
∙Participants may be required to make more visits to the doctor than they would if not in
the clinical trial.
∙Participants in randomized trials cannot choose the kind of intervention they will Receive.
The clinical research process includes:
∙Pre-clinical testing
∙Investigational New Drug Application (IND)
∙Phase I (assess safety)
∙Phase II (test for effectiveness)
∙Phase III (large-scale testing)
∙Licensing (approval to use)
∙Approval (available for prescription)
∙Post-marketing studies (special studies and long-term effectiveness/use).
The elements and principles of clinical research are:
oProtocol
oProtocol review
oSponsor
oEligibility criteria
oInformed consent
oTypes of clinical trials
oPhases of clinical trials
oActivities during clinical trials
oClinical trial participants.
Ethics means:
∙Respect for persons
∙Beneficence, which means to do good—in clinical research, beneficence means even
more— to do no harm or maximize possible benefits and minimize possible harm
∙Justice or fairness Scientific research has produced many social benefits but has posed
some troubling ethical questions.
Public attention was drawn to these questions by reported abuses of human subjects in
biomedical experiments:
• During the Nuremberg War Crime Trials after World War II, the Nuremberg Code was
drafted as a set of standards for judging physicians and scientists who had conducted
biomedical experiments on prisoners. This code became the prototype of many later codes
intended to assure that research involving human subjects would be carried out ethically.
• The Tuskegee Study of Untreated Syphilis in the Negro Male (also known as the Tuskegee
Syphilis Study, Public Health Service Syphilis Study, or the Tuskegee Experiment) was a
clinical study conducted between 1932 and 1972 in Tuskegee, Alabama, by the U.S. Public
Health Service. 399 poor, mostly illiterate African Americans with syphilis were recruited for
research related to the natural progression of the disease if left untreated. The trial
participants were not offered treatment for syphilis when it became available.
3 ethical principles guide clinical research
The Belmont Report17 was developed by The National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research on April 18, 1979, to:
∙Summarize the basic ethical principles identified by the Commission during its
deliberations
∙State basic ethical principles and guidelines that should assist in resolving the ethical
problems surrounding conducting research with human subjects. Ethical principles must
guide all research activities, including:
∙All phases of research, including formation of research questions, design of the study,
conduct of research, analysis of data, and interpretation of findings
∙Dissemination of new knowledge in the form of presentations and publications.
Clinical research is conducted according to a plan (a protocol) or action plan. The protocol
acts like a “recipe” for conducting the trial. The plan describes what will be done in the study,
how it will be conducted, and why each part of it is necessary. The protocol or plan is
carefully designed to safeguard the participants’ health and answer specific research
questions. The same protocol is used by every doctor or research centre participating in the
trial. A protocol describes:
∙Who is eligible to participate in the trial
∙Details about tests, procedures, medications, and dosages
∙The length of the study and what information will be gathered A protocol is led by a
principal investigator. The principal investigator is often a doctor. Research team
members regularly monitor the participants’ health to determine the study’s safety,
effectiveness and efficacy.
A protocol is a study plan on which each clinical trial is based. The plan is carefully
designed to safeguard the health of the participants as well as answer specific research
questions. A protocol describes what types of people may participate in the trial, the schedule
of tests, procedures, medications, and dosages, and the length of the study.
An Institutional Review Board (IRB) must approve and monitor clinical trials in the United
States. The IRB ensures that the risks are minimal and are worth any potential benefits. An
IRB is an independent committee. Physicians, statisticians, and members of the community
belong to an IRB. The committee ensures that clinical trials are ethical and that the rights of
all participants are protected. U.S. regulations require all research institutions in the United
States that conduct or support biomedical research involving people to meet specific
requirements. An IRB must initially approve and periodically review the research. Some
research institutions have more than one IRB. During protocol reviews, networks review and
assess what other networks are doing to see what information applies to what they are doing.
∙Sponsor
∙Investigator
∙Clinical Research Associate
∙Clinical Research Coordinator
∙Data Manager
∙Statistician
∙Patients
∙IRB
∙Regulatory Body
Clinical trials are sponsored or funded by various organizations or individuals, including:
Physicians
∙Foundations
∙Medical institutions
∙Voluntary groups
∙Pharmaceutical companies
∙Federal agencies such as the National Institutes of Health, the Department of Defense,
Centers for Disease Control and Prevention (CDC), and the Department of Veterans
Affairs Trials can occur at sites as varied as hospitals, universities, doctor’s offices, or
community clinics.
A person is responsible for the conduct of the clinical trial at a trial site. If a trial is conducted
by a team of individuals at a trial site, the investigator is the responsible leader of the team
and may be called the principal investigator.
Responsibilities: Investigator
Investigators Qualifications
Adequacy of Resources
Medical Care of Study Participants
Communication with the IRB / IEC
Compliance with the Protocol
Investigational Product care
Records and Reports
Progress Reports
Safety Reporting
Stopping or suspending a study
Final report by investigator
Randomization & unbinding
The Informed Consent
A person who handles most of the administrative responsibilities of a clinical trial, acts
as a liaison between the investigative site and sponsor and reviews all data and records
before a monitor’s visit.
∙Functions as an extension of Investigator.
∙Involved in operational duties – recruiting, scheduling, completing CRFs, and
administering tests.
A person appointed by the Sponsor or Contract Research Organisation (CRO) for
monitoring and reporting the trial progress and for data verification.
∙The monitor ensures that the trial is conducted, recorded and reported in accordance with
the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and
the applicable regulatory requirements.
Responsibilities: Monitor
Main line of communication between sponsor and site
Site feasibility Training and support to site staff & selection
Protocol & GCP Compliance
Document completeness & maintenance
Source Data Verification
Trial material accounting
Monitoring reports & other office documentations
Prepare and assist in IRB, Regulatory and internal audit, or inspection
Assist in IRB and Regulatory Submission
Assist in IRB and Regulatory Submission
Ensure timely AE & SAE reporting
Informed consent is the process of providing potential participants with essential facts about a
clinical trial before they decide to participate. The process of informed consent, which means
“providing additional information,” continues throughout the study. Members of the research
team explain the details of the study.
This explanation helps people make a decision that is right for them. Informed consent is not
a contract or a piece of paper but a process.
Informed consent must be provided:
• In the participants’ native language
• At an appropriate educational level, Translation or interpretive assistance can be provided
for participants with limited language skills.
The research team provides an informed consent document that includes details about the
study:
• Its purpose
• Duration
• Required procedures
• Who to contact for more information
• An explanation of risks and potential benefits. The participant then decides whether to sign
the document. In many communities, illiteracy and mistrust exist toward anyone who asks for a signature as a commitment. Sometimes, people fear their signatures may lead to unexpected
obligations because they attach great importance to legal formalities. Volunteers are free to
withdraw from a study entirely or to refuse particular treatments or tests at any time
(sometimes, however, this will make them ineligible to continue the study).
Protocol feasibility: To assess from the region(s)/country(ies) where the clinical study is
to be conducted, agreement on critical study criteria like inclusion-exclusion criteria,
comparator drug, and study procedures outlined in the Protocol Synopsis, to prevent the
need for protocol amendments later in the planning process.
∙A secondary objective is to provide information to support the finalization of the
country/region allocation.
∙Site feasibility: involves assessing site potential based on multivariate factors like
Principal Investigators' experience & interest in Clinical Research, patient inflow,
accessibility to the site, availability of patients that meet the study criteria, and other
related factors that affect the accrual rates and proper conduct of study related activities.
This is done to ensure that appropriate sites/Principal Investigators are identified.
It can be defined as a systematic, planned process to evaluate and select an investigator and
site for the conduct of the clinical trial.
Factors involved in selection
–Reputation in the field
–Facilities desirable for trial conduct
–Access to the patient population
–Accessible geographic location
–Anticipated time for initiation and completion of trial
–EC–the ability to process protocols fairly and expeditiously.
Purpose
–Achieve uniformity in approach by all investigators
–Review and discuss the protocol
–Answer questions
–Generate enthusiasm
–Get everyone to know each other and develop a sense of teamwork and trust
–Review potential difficulties, issues, and problems
–Review administrative ground rules.
–Review administrative ground rules.
Study initiation is done to review protocol, processes, and procedures to ensure that all
site personnel understand the requirements of the trial.
∙Sites are initiated after all regulatory & ethical documentation is complete, after IP and
other supplies are shipped and before any patients are enrolled.
Purpose
•To verify
– protection of rights and well-being of subjects
–reported trial data is accurate, complete, and verifiable
–the trial complies with the following:
–Protocol and amendments
–Regulatory requirements
–Enrolment
–Drug supply.
After ensuring the study is complete
CRF received
All study material is accounted for
All investigational product is accounted for, and the balance is returned to the sponsor.
Ensure payment completion.
Start-Up
∙Delegate responsibilities
∙Educate research team
∙Enrollment plan
∙Study documents
Conduct
∙Protocol compliance
Documentation
∙Record retention
∙Trial drug accountability
∙Safety reporting
Close Out
∙Final drug accountability
∙Preparation of records for archiving
∙Storage or destruction of lab samples
∙Data query resolution
∙Notification to governing regulatory body
Investigator’s Boucher
∙Protocol
∙Informed Consent Form
∙Case Report Form
∙Financial Disclosure Form
∙EC Approval Letter
∙Clinical Trial Agreements and Budget
∙Lab Normal Ranges
∙Sample Labels
∙Pre-trial Monitoring Report
∙Signed Agreements between 2 parties.
A structured & planned approach to managing various research activities/functions at a site to
ensure execution through compliance and strict adherence to safety standards -through
periodic monitoring per a pre-determined/planned monitoring plan.
