INTRODUCTION
TO CLINICAL RESEARCH
Clinical trials have
revolutionised the way disease is prevented, detected or treated and early
death avoided. They continue to be an expanding area of research. They are
central to the work of pharmaceutical companies, which cannot make a claim
about a new drug or medical device until there is sufficient evidence on its
efficacy. Trials originating from the academic or public sector are more common
because they also evaluate existing therapies in different ways or
interventions that do not involve a commercial product. Many health care
professionals are expected to conduct their own trials or to participate in
trials by recruiting subjects. They should have a sufficient understanding of
the scientific and administrative aspects, including an awareness of the
regulations and guidelines associated with clinical trials, which are now more
stringent in many countries, making it more difficult to set up and run trials.
Early
construction of a Clinical Trial:
James Lind, a Scottish
naval physician, has conducted the first clinical trial. During a sea voyage in
1747, he chose 12 sailors with similarly severe cases of scurvy and examined
six treatments, each given to two sailors. They were cider, diluted sulphuric
acid, vinegar, seawater, a mixture of several foods including nutmeg and
garlic, and oranges and lemons. They were made to live in the same part of the
ship and with the same basic diet. Lind felt it was important to standardise
their living conditions to ensure that any change in their disease is unlikely to
be due to other factors. After about a week, both sailors given fruit had
almost completely recovered, compared to little or no improvement in the other
sailors. This dramatic effect led Lind to conclude that eating fruit was
essential to cure scurvy, without knowing that it was specifically due to
vitamin C. The results of his trial were supported by observations made by
other seamen and physicians.
Lind had little doubt
about the value of fruit. Two important features of his trial were: a
comparison between two or more interventions and an attempt to ensure that the
subjects had similar characteristics.
The requirement for these two features has not changed and it is an
indication that how important they are in conducting good trials that aim to
provide reliable answers.
Fundamental
concepts:
There are two distinct
study designs used in health research: observational and experimental.
Observational studies do not intentionally involve intervening in the way
individuals live their lives or how they are treated. However, clinical trials
are specifically designed to intervene and then evaluate some health-related
outcome with one or more of the following:
·
to diagnose or detect disease
·
to treat an existing disorder
·
to prevent disease or early death
·
to change behavior, habits or other lifestyle
factors
Some trials evaluate
new drugs or medical devices that will later require a licence (or marketing
authorisation) for human use from a regulatory authority, if a benefit is
shown. This allows the treatment to be marketed and routinely available to the
public.
Other trials are based
on therapies that are already licensed, but will be used in different ways,
such as a different disease group or in combination with other treatments. An
intervention could be a single treatment or therapy namely an administered
substance that is injected, swallowed, inhaled or absorbed through the skin, an
exposure such as radiotherapy, a surgical technique or a medical dental device.
A combination of interventions can be referred to as a regimen, such as,
chemotherapy plus surgery in treating cancer. Other interventions could be
educational or behavioural programmes or dietary changes.
Any administered drug
or micronutrient that is examined in a clinical trial with the specific purpose
of treating, preventing or diagnosing disease is usually referred to as an
Investigational Medicinal Product (IMP) or Investigational New Drug (IND). An
IMP could be a newly developed drug or one that is already licensed for human
use. Most clinical trial regulations that are part of law in several countries
cover studies using an IMP and sometimes medical devices.
What
Is a Clinical Study?
A clinical study
involves research using human volunteers (also called participants) that is
intended to add to medical knowledge. There are two main types of clinical
studies: clinical trials and observational studies. Clinical Trials includes
both interventional and observational studies.
Clinical
Trials
In a clinical trial
(also called an interventional study), participants receive specific
interventions according to the research plan or protocol created by the
investigators. These interventions may be medical products, such as drugs or
devices; procedures; or changes to participants' behavior, for example, diet.
Clinical trials may compare a new medical approach to a standard one that is
already available or to a placebo that contains no active ingredients or to no
intervention. Some clinical trials compare interventions that are already
available to each other. When a new product or approach is being studied, it is
not usually known whether it will be helpful, harmful, or no different than
available alternatives (including no intervention). The investigators try to
determine the safety and efficacy of the intervention by measuring certain
outcomes in the participants. For example, investigators may give a drug or
treatment to participants who have high blood pressure to see whether their
blood pressure decreases.
Clinical trials used in
drug development are sometimes described by phase. These phases are defined by
the Food and Drug Administration (FDA).
Note: Some people who
are not eligible to participate in a clinical trial may be able to get
experimental drugs or devices outside of a clinical trial through an Expanded
Access Program. See more information on expanded access from the National
Library of Medicine.
Observational
Studies
In an observational
study, investigators assess health outcomes in groups of participants according
to a protocol or research plan. Participants may receive interventions, which
can include medical products, such as drugs or devices, or procedures as part of
their routine medical care, but participants are not assigned to specific
interventions by the investigator (as in a clinical trial). For example,
investigators may observe a group of older adults to learn more about the
effects of different lifestyles on cardiac health.
Who
Conducts Clinical Studies?
Every clinical study is
led by a principal investigator, who is often a medical doctor. Clinical
studies also have a research team that may include doctors, nurses, social
workers, and other health care professionals. Clinical studies can be
sponsored, or funded, by pharmaceutical companies, academic medical centers,
voluntary groups, and other organizations, in addition to Federal agencies such
as the National Institutes of Health, U.S. Department of Defense, and U.S.
Department of Veterans Affairs. Physicians, health care providers, and other
individuals can also sponsor clinical research.
Where
Are Clinical Studies Conducted?
Clinical studies can
take place in many locations, including hospitals, universities, doctors'
offices, and community clinics. The location depends on who is conducting the
study.
How
Long Do Clinical Studies Last?
The length of a
clinical study varies, depending on what is being studied. Participants are
told how long the study will last before enrolling.
Reasons
for Conducting Clinical Studies
In general, clinical
studies are designed to add to medical knowledge related to the treatment,
diagnosis, and prevention of diseases or conditions. Some common reasons for
conducting clinical studies include:
•
Evaluating one or more interventions
(for example, drugs, medical devices, approaches to surgery or radiation
therapy) for treating a disease, syndrome, or condition
•
Finding ways to prevent the initial
development or recurrence of a disease or condition. These can include
medicines, vaccines, or lifestyle changes, among other approaches.
•
Evaluating one or more interventions
aimed at identifying or diagnosing a particular disease or condition
•
Examining methods for identifying a condition
or risk factors for that condition
•
Exploring and measuring ways to improve
the comfort and quality of life of people with a chronic illness through
supportive care
Participating
in Clinical Studies
A clinical study is
conducted according to a research plan known as the protocol. The protocol is
designed to answer specific research questions as well as safeguard the health
of participants. It contains the following information:
• The reason for conducting the study
• Who may participate in the study (the
eligibility criteria?)
• The number of participants needed
• The schedule of tests, procedures, or
drugs and their dosages
• The length of the study
• What information will be gathered
about the participants?
Who
Can Participate in a Clinical Study?
Clinical studies have
standards outlining who can participate, called eligibility criteria, which are
listed in the protocol. Some research studies seek participants who have the
illnesses or conditions that will be studied. Other studies are looking for
healthy participants. And some studies are limited to a predetermined group of
people who are asked by researchers to enroll.
Eligibility. The
factors that allow someone to participate in a clinical study are called
inclusion criteria, and the factors that disqualify someone from participating
are called exclusion criteria. These are based on things such as age, gender,
the type and stage of a disease, previous treatment history, and other medical
conditions.
How
Are Participants Protected?
Informed consent is a
process in which researchers provide potential and enrolled participants with
information about a clinical study. This information helps people decide
whether they want to enroll, or continue to participate, in the study. The
informed consent process is intended to protect participants and should provide
enough information for a person to understand the risks of, potential benefits
of, and alternatives to the study. In addition to the informed consent
document, the process may involve recruitment materials, verbal instructions,
question-and- answer sessions, and activities to measure participant
understanding. In general, a person must sign an informed consent document
before entering a study to show that he or she was given information on risks,
potential benefits, and alternatives and understands it. Signing the document
and providing consent is not a contract. Participants may withdraw from a study
at any time, even if the study is not over. See Questions to Ask a health care
provider or researcher about participating in a clinical study.
Institutional review
boards. Each federally supported or conducted clinical study and each study of
a drug, biological product, or medical device regulated by FDA must be
reviewed, approved, and monitored by an institutional review board (IRB). An
IRB is made up of physicians, researchers, and members of the community. Its
role is to make sure that the study is ethical and the rights and welfare of
participants are protected. This includes making sure that research risks are
minimized and are reasonable in relation to any potential benefits, among other
things. The IRB also reviews the informed consent document.
In addition to being
monitored by an IRB, some clinical studies are also monitored by data
monitoring committees (also called data safety and monitoring boards).
Various Federal
agencies, including the Office of Human Subjects Research Protection (OHRP) and
FDA, have the authority to determine whether sponsors of certain clinical
studies are adequately protecting research participants.
Relationship
to Usual Health Care
Typically participants
continue to see their usual health care providers while enrolled in a clinical
study. While most clinical studies provide participants with medical products
or interventions related to the illness or condition being studied, they do not
provide extended or complete health care. By having the participant's usual
health care provider work with the research team, the participant can make sure
that the study protocol will not conflict with other medications or treatments
being received.
Considerations
for Participation
Participating in a
clinical study contributes to medical knowledge. The results of these studies
can make a difference in the care of future patients by providing information
about the benefits and risks of therapeutic, preventative, or diagnostic
products or interventions.
Clinical trials provide
the basis for the development and marketing of new drugs, biological products,
and medical devices. Sometimes, the safety and the effectiveness of the experimental
approach or use may not be fully known at the time of the trial. Some trials
may provide participants with the prospect of receiving direct medical
benefits, while others do not. Most trials involve some risk of harm or injury
to the participant, although it may not be more than the risks related to
routine medical care or disease progression. (For trials approved by IRBs, the
IRB has decided that the risks of participation have been minimized and are
reasonable in relation to anticipated benefits.) Many trials require
participants to undergo additional procedures, tests, and assessments based on
the study protocol. These will be described in the informed consent document
for a particular trial. A potential participant should also discuss these issues
with members of the research team and with his or her usual health care
provider.
Questions
to Ask
Anyone interested in
participating in a clinical study should know as much as possible about the
study and feel comfortable asking the research team questions about the study,
the related procedures, and any expenses. The following questions might be
helpful during such a discussion. Answers to some of these questions are
provided in the informed consent document. Many of these questions are specific
to clinical trials, but some also apply to observational studies.
•
What is being studied?
•
Why do researchers believe the
intervention being tested might be effective? Why might it not be effective?
Has it been tested before?
•
What are the possible interventions that
I might receive during the trial?
•
How will it be determined which
interventions I receive (for example, by chance)?
•
Who will know which intervention I
receive during the trial? Will I know? Will members of the research team know?
•
How do the possible risks, side effects,
and benefits of this trial compare with those of my current treatment?
•
What will I have to do?
•
What tests and procedures are involved?
•
How often will I have to visit the
hospital or clinic?
•
Will hospitalization be required?
•
How long will the study last?
•
Who will pay for my participation?
•
Will I be reimbursed for other expenses?
•
What type of long-term follow-up care is
part of this trial?
•
If I benefit from the intervention, will
I be allowed to continue receiving it after the trial ends?
•
Will results of the study be provided to
me?
•
Who will oversee my medical care while I
am in the trial?
•
What are my options if I am injured
during the study?
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