A fundamental distinction in
evidence-based medicine is between
observational studies and
randomized controlled trials. Types of
observational studies in
epidemiology, such as the
cohort study and the
case-control study, provide less compelling evidence than the randomized controlled trial. In
observational studies,
the investigators only observe associations (correlations) between the
treatments experienced by participants and their health status or
diseases. However, under certain conditions, causal effects can be
inferred from these studies.
Under the right conditions, a randomized controlled trial can provide
compelling evidence that the study treatment causes an effect on human
health.
Currently, some Phase 2 and most Phase 3 drug trials are designed as randomized,
double-blind, and
placebo-controlled.
- Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo.
- Blind: The subjects involved in the study do not know which
study treatment they receive. If the study is double-blind, the
researchers also do not know which treatment is being given to any given
subject. This 'blinding' is to prevent biases, since if a physician
knew which patient was getting the study treatment and which patient was
getting the placebo, he/she might be tempted to give the (presumably
helpful) study drug to a patient who could more easily benefit from it.
In addition, a physician might give extra care to only the patients who
receive the placebos to compensate for their ineffectiveness. A form of
double-blind study called a "double-dummy" design allows additional
insurance against bias or placebo effect. In this kind of study, all
patients are given both placebo and active doses in alternating periods
of time during the study.
- Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect.
Although the term "clinical trials" is most commonly associated with
the large, randomized studies typical of Phase 3, many clinical trials
are small. They may be "sponsored" by single physicians or a small group
of physicians, and are designed to test simple questions. In the field
of rare diseases, sometimes the number of patients might be the limiting
factor for a clinical trial. Other clinical trials require large
numbers of participants (who may be followed over long periods of time),
and the trial sponsor is a private company, a government health agency,
or an academic research body such as a university.
Active comparator studies
Of note, during the last 10 years or so, it has become a common
practice to conduct "active comparator" studies (also known as "active
control" trials). In other words, when a treatment is clearly better
than doing nothing for the subject (
i.e. giving them the
placebo), the alternate treatment would be a standard-of-care therapy.
The study would compare the 'test' treatment to standard-of-care
therapy.
A growing trend in the pharmacology field involves the use of
third-party contractors to obtain the required comparator compounds.
Such third parties provide expertise in the logistics of obtaining,
storing, and shipping the comparators. As an advantage to the
manufacturer of the comparator compounds, a well-established comparator
sourcing agency can alleviate the problem of
parallel importing (importing a patented compound for sale in a country outside the patenting agency's sphere of influence).
[citation needed]
Clinical trial protocol
A
clinical trial protocol
is a document used to gain confirmation of the trial design by a panel
of experts and adherence by all study investigators, even if conducted
in various countries.
The protocol describes the scientific rationale, objective(s),
design, methodology, statistical considerations, and organization of the
planned trial. Details of the trial are also provided in other
documents referenced in the protocol, such as an
investigator's brochure.
The protocol contains a precise study plan for executing the clinical
trial, not only to assure safety and health of the trial subjects, but
also to provide an exact template for trial conduct by investigators at
multiple locations (in a "multicenter" trial) to perform the study in
exactly the same way. This harmonization allows data to be combined
collectively as though all investigators (referred to as "sites") were
working closely together. The protocol also gives the study
administrators (often a
contract research organization),
as well as the site team of physicians, nurses and clinic
administrators, a common reference document for site responsibilities
during the trial.
The format and content of clinical trial protocols sponsored by
pharmaceutical, biotechnology or medical device companies in the United
States, European Union, or Japan have been standardized to follow Good
Clinical Practice guidance
[15]
issued by the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH).
[16] Regulatory authorities in Canada and Australia also follow ICH guidelines. Some journals, e.g.
Trials, encourage trialists to publish their protocols in the journal.
Design features
Informed consent
An essential component of initiating a clinical trial is to recruit
study subjects following procedures using a signed document called "
informed consent".
[17]
Generally, children participating in clinical trial cannot autonomously
provide informed consent, but depending on their age and other factors,
may be required to provide
informed assent.
Informed consent is a legally defined process of a person being told
about key facts involved in a clinical trial before deciding whether or
not to participate. To fully describe participation to a candidate
subject, the doctors and nurses involved in the trial explain the
details of the study using terms the person will understand. Foreign
language translation is provided if the participant's native language is
not the same as the study protocol.
The research team provides an informed consent document that includes
trial details, such as its purpose, duration, required procedures,
risks, potential benefits and key contacts. The participant then decides
whether or not to sign the document in agreement. Informed consent is
not an immutable contract, as the participant can withdraw at any time
without penalty.
Statistical power
The number of patients enrolled in a study has a large bearing on the
ability of the study to reliably detect the size of the effect of the
study intervention. This is described as the "
power" of the trial. The larger the sample size or number of participants in the trial, the greater the statistical power.
However, in designing a clinical trial, this consideration must be
balanced with the fact that more patients make for a more expensive
trial. The power of a trial is not a single, unique value; it estimates
the ability of a trial to detect a difference of a particular size (or
larger) between the treated (tested drug/device) and control (placebo or
standard treatment) groups. By example, a trial of a
lipid-lowering
drug versus placebo with 100 patients in each group might have a power
of 0.90 to detect a difference between patients receiving study drug and
patients receiving placebo of 10 mg/dL or more, but only have a power
of 0.70 to detect a difference of 5 mg/dL.
Placebo groups
Merely giving a treatment can have nonspecific effects, and these are
controlled for by the inclusion of a placebo group. Subjects in the
treatment and placebo groups are assigned
randomly
and blinded as to which group they belong. Since researchers can behave
differently to subjects given treatments or placebos, trials are also
doubled-blinded so the researchers do not know to which group a subject
is assigned.
Assigning a person to a placebo group can pose an ethical problem if
it violates his or her right to receive the best available treatment.
The
Declaration of Helsinki provides guidelines on this issue.
Phases
Clinical trials involving new drugs are commonly classified into four
phases. Each phase of the drug approval process is treated as a
separate clinical trial. The drug-development process will normally
proceed through all four phases over many years. If the drug
successfully passes through Phases 0, 1, 2, and 3, it will usually be
approved by the national regulatory authority for use in the general
population.
- Phase 0: Pharmacodynamics and Pharmacokinetics
- Phase 1: Screening for safety
- Phase 2: Establishing the efficacy of the drug, usually against a placebo
- Phase 3: Final confirmation of safety and efficacy
- Phase 4: Sentry studies during sales
Each phase has a different purpose and helps scientists answer a different question:
In Phase 0 trials are the first-in-human trials. Single
subtherapeutic doses of the study drug are given to a small number of
subjects (10 to 15) to gather preliminary data on the agent's
pharmacodynamics (what the drug does to the body) and pharmacokinetics
(what the body does to the drugs).
[18]
In Phase 1 trials, researchers test an experimental drug or treatment
in a small group of people (20-80) for the first time to evaluate its
safety, determine a safe dosage range, and identify side effects.
In Phase 2 trials, the experimental treatment is given to a larger
group of people (100-300) to see if it is effective and to further
evaluate its safety.
In Phase 3 trials, the treatment is given to large groups of people
(1,000-3,000) to confirm its effectiveness, monitor side effects,
compare it to commonly used treatments, and collect information that
will allow it to be used safely.
In Phase 4 trials, postmarketing studies delineate additional
information, including the treatment's risks, benefits, and optimal use.
Before pharmaceutical companies start clinical trials on a drug, they conduct extensive
preclinical studies.
Length
Clinical trials are only a small part of the research that goes into
developing a new treatment. Potential drugs, for example, first have to
be discovered, purified, characterized, and tested in labs (in cell and
animal studies) before ever undergoing clinical trials. In all, about
1,000 potential drugs are tested before just one reaches the point of
being tested in a clinical trial.
[citation needed]
For example, a new cancer drug has, on average, six years of research
behind it before it even makes it to clinical trials. But the major
holdup in making new cancer drugs available is the time it takes to
complete clinical trials themselves. On average, about eight years pass
from the time a cancer drug enters clinical trials until it receives
approval from regulatory agencies for sale to the public.
[19] Drugs for other diseases have similar timelines.
Some reasons a clinical trial might last several years:
- For chronic conditions such as cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient.
- For drugs that are not expected to have a strong effect (meaning a
large number of patients must be recruited to observe 'any' effect),
recruiting enough patients to test the drug's effectiveness (i.e.,
getting statistical power) can take several years.
- Only certain people who have the target disease condition are
eligible to take part in each clinical trial. Researchers who treat
these particular patients must participate in the trial. Then they must
identify the desirable patients and obtain consent from them or their
families to take part in the trial.
The biggest barrier to completing studies is the shortage of people
who take part. All drug and many device trials target a subset of the
population, meaning not everyone can participate. Some drug trials
require patients to have unusual combinations of disease
characteristics. It is a challenge to find the appropriate patients and
obtain their consent, especially when they may receive no direct benefit
(because they are not paid, the study drug is not yet proven to work,
or the patient may receive a placebo). In the case of cancer patients,
fewer than 5% of adults with cancer will participate in drug trials.
According to the Pharmaceutical Research and Manufacturers of America
(PhRMA), about 400 cancer medicines were being tested in clinical trials
in 2005. Not all of these will prove to be useful, but those that are
may be delayed in getting approved because the number of participants is
so low.
[20]
For clinical trials involving a seasonal indication (such as
airborne allergies,
seasonal affective disorder,
influenza,
and others), the study can only be done during a limited part of the
year (such as spring for pollen allergies), when the drug can be tested.
This can be an additional complication on the length of the study, yet
proper planning and the use of trial sites in the Southern, as well as
the Northern Hemisphere allows for year-round trials, which can reduce
the length of the studies.
[21][22]
Clinical trials that do not involve a new drug usually have a much
shorter duration. (Exceptions are epidemiological studies, such as the
Nurses' Health Study.
Administration
Clinical trials designed by a local investigator, and (in the US)
federally funded clinical trials, are almost always administered by the
researcher who designed the study and applied for the grant. Small-scale
device studies may be administered by the sponsoring company. Clinical
trials of new drugs are usually administered by a
contract research organization
(CRO) hired by the sponsoring company. The sponsor provides the drug
and medical oversight. A CRO is contracted to perform all the
administrative work on a clinical trial. For Phases 2, 3 and 4, the CRO
recruits participating researchers, trains them, provides them with
supplies, coordinates study administration and data collection, sets up
meetings, monitors the sites for compliance with the clinical protocol,
and ensures the sponsor receives data from every site. Specialist
site management organizations
can also be hired to coordinate with the CRO to ensure rapid IRB/IEC
approval and faster site initiation and patient recruitment. Phase 1
clinical trials of new medicines are often conducted in a specialist
clinical trial clinic, with dedicated pharmacologists, where the
subjects can be observed by full-time staff. These clinics are often run
by a CRO which specialises in these studies.
At a participating site, one or more research assistants (often
nurses) do most of the work in conducting the clinical trial. The
research assistant's job can include some or all of the following:
providing the local
institutional review board
(IRB) with the documentation necessary to obtain its permission to
conduct the study, assisting with study start-up, identifying eligible
patients, obtaining consent from them or their families, administering
study treatment(s), collecting and statistically analyzing data,
maintaining and updating data files during followup, and communicating
with the IRB, as well as the sponsor and CRO.
Ethical conduct
Clinical trials are closely supervised by appropriate regulatory
authorities. All studies involving a medical or therapeutic intervention
on patients must be approved by a supervising
ethics committee
before permission is granted to run the trial. The local ethics
committee has discretion on how it will supervise noninterventional
studies (observational studies or those using already collected data).
In the US, this body is called the
Institutional Review Board
(IRB). Most IRBs are located at the local investigator's hospital or
institution, but some sponsors allow the use of a central
(independent/for profit) IRB for investigators who work at smaller
institutions.
To be ethical, researchers must obtain the full and
informed consent
of participating human subjects. (One of the IRB's main functions is to
ensure potential patients are adequately informed about the clinical
trial.) If the patient is unable to consent for him/herself, researchers
can seek consent from the patient's legally authorized representative.
In
California, the state has prioritized the individuals who can serve as the legally authorized representative.
[23]
In some US locations, the local IRB must certify researchers and
their staff before they can conduct clinical trials. They must
understand the federal patient privacy (
HIPAA)
law and good clinical practice. The International Conference of
Harmonisation Guidelines for Good Clinical Practice is a set of
standards used internationally for the conduct of clinical trials. The
guidelines aim to ensure the "rights, safety and well being of trial
subjects are protected".
The notion of informed consent of participating human subjects exists
in many countries all over the world, but its precise definition may
still vary.
Informed consent is clearly a 'necessary' condition for ethical
conduct but does not 'ensure' ethical conduct. The final objective is to
serve the community of patients or future patients in a best-possible
and most responsible way. However, it may be hard to turn this objective
into a well-defined, quantified, objective function. In some cases this
can be done, however, for instance, for questions of when to stop
sequential treatments (see
Odds algorithm), and then quantified methods may play an important role.
Additional ethical concerns are present when conducting
clinical trials on children (
pediatrics).
Commercial ties and unfavorable studies
Due to repeated accusations and findings that some clinical trials conducted or funded by
pharmaceutical companies
may report only positive results for the preferred medication, the
industry has been looked at much more closely by independent groups and
government agencies.
[24]
In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research was not published, the
Pharmaceutical Research and Manufacturers of America
have published new guidelines urging companies to report all findings
and limit the financial involvement in drug companies of researchers.
[25] US congress signed into law a bill which requires phase II and phase III clinical trials to be registered by the sponsor on
the clinical trials website run by the NIH.
[26]
Drug researchers not directly employed by pharmaceutical companies
often look to companies for grants, and companies often look to
researchers for studies that will make their products look favorable.
Sponsored researchers are rewarded by drug companies, for example with
support for their conference/symposium costs. Lecture scripts and even
journal articles presented by academic researchers may actually be
'ghost-written' by pharmaceutical companies.
[27]
Some researchers who have tried to reveal ethical issues with clinical
trials or who tried to publish papers that show harmful effects of new
drugs or cheaper alternatives have been threatened by drug companies
with lawsuits.
[28][29]
Safety
Responsibility for the safety of the subjects in a clinical trial is
shared between the sponsor, the local site investigators (if different
from the sponsor), the various IRBs that supervise the study, and (in
some cases, if the study involves a marketable drug or device), the
regulatory agency for the country where the drug or device will be sold.
For safety reasons, many clinical trials of drugs are designed to
exclude women of childbearing age, pregnant women, and/or women who
become pregnant during the study. In some cases, the male partners of
these women are also excluded or required to take birth control
measures.
Sponsor
Throughout the clinical trial, the sponsor is responsible for
accurately informing the local site investigators of the true historical
safety record of the drug, device or other medical treatments to be
tested, and of any potential interactions of the study treatment(s) with
already approved medical treatments. This allows the local
investigators to make an informed judgment on whether to participate in
the study or not. The sponsor is also responsible for monitoring the
results of the study as they come in from the various sites, as the
trial proceeds. In larger clinical trials, a sponsor will use the
services of a
data monitoring committee
(DMC, known in the US as a data safety monitoring board). This
independent group of clinicians and statisticians meets periodically to
review the
unblinded
data the sponsor has received so far. The DMC has the power to
recommend termination of the study based on their review, for example if
the study treatment is causing more deaths than the standard treatment,
or seems to be causing unexpected and study-related serious
adverse events.The sponsor is responsible for collecting
adverse event
reports from all site investigators in the study, and for informing all
the investigators of the sponsor's judgment as to whether these adverse
events were related or not related to the study treatment. This is an
area where sponsors can slant their judgment to favor the study
treatment.
The sponsor and the local site investigators are jointly responsible for writing a site-specific
informed consent
that accurately informs the potential subjects of the true risks and
potential benefits of participating in the study, while at the same time
presenting the material as briefly as possible and in ordinary
language. FDA regulations and ICH guidelines both require "the
information that is given to the subject or the representative shall be
in language understandable to the subject or the representative." If the
participant's native language is not English, the sponsor must
translate the informed consent into the language of the participant.
[30]
Local site investigators
A physician's
first duty
is to his/her patients, and if a physician investigator believes the
study treatment may be harming subjects in the study, the investigator
can stop participating at any time. On the other hand, investigators
often have a financial interest in recruiting subjects, and can act
unethically to obtain and maintain their participation.
The local investigators are responsible for conducting the study
according to the study protocol, and supervising the study staff
throughout the duration of the study. The local investigator or his/her
study staff are also responsible for ensuring the potential subjects in
the study understand the risks and potential benefits of participating
in the study; in other words, they (or their legally authorized
representatives) must give truly informed consent. They are responsible
for reviewing all adverse event reports sent by the sponsor. (These
adverse event reports contain the opinion of both the investigator at
the site where the adverse event occurred, and the sponsor, regarding
the relationship of the adverse event to the study treatments). They
also are responsible for making an independent judgment of these
reports, and promptly informing the local IRB of all serious and study
treatment-related adverse events.
When a local investigator is the sponsor, there may not be formal
adverse event reports, but study staff at all locations are responsible
for informing the coordinating investigator of anything unexpected. The
local investigator is responsible for being truthful to the local IRB in
all communications relating to the study.
Institutional review boards (IRBs)
Approval by an
Institutional Review Board
(IRB), or ethics board, is necessary before all but the most informal
medical research can begin. In commercial clinical trials, the study
protocol is not approved by an IRB before the sponsor recruits sites to
conduct the trial. However, the study protocol and procedures have been
tailored to fit generic IRB submission requirements. In this case, and
where there is no independent sponsor, each local site investigator
submits the study protocol, the consent(s), the data collection forms,
and supporting documentation to the local IRB. Universities and most
hospitals have in-house IRBs. Other researchers (such as in walk-in
clinics) use independent IRBs.
The IRB scrutinizes the study for both medical safety and protection
of the patients involved in the study, before it allows the researcher
to begin the study. It may require changes in study procedures or in the
explanations given to the patient. A required yearly "continuing
review" report from the investigator updates the IRB on the progress of
the study and any new safety information related to the study.
Regulatory agencies
If a clinical trial concerns a new regulated drug or medical device
(or an existing drug for a new purpose), the appropriate regulatory
agency for each country where the sponsor wishes to sell the drug or
device is supposed to review all study data before allowing the
drug/device to proceed to the next phase, or to be marketed. However, if
the sponsor withholds negative data, or misrepresents data it has
acquired from clinical trials, the regulatory agency may make the wrong
decision. However, if leaders of the regulatory agency are friendly to
industry, they may pressure staff scientists to make decisions favorable
to industry, disregard their findings, or make it otherwise difficult
for them to do their job.
[31]
In the US, the FDA can
audit
the files of local site investigators after they have finished
participating in a study, to see if they were correctly following study
procedures. This audit may be random, or for cause (because the
investigator is suspected of fraudulent data). Avoiding an audit is an
incentive for investigators to follow study procedures.
Alternatively, many American pharmaceutical companies have moved
their clinical trials overseas. By doing this they are able to avoid
many of the FDA’s regulations, since the FDA rarely investigates
clinical trials outside the United States. This increases the ability of
pharmaceutical companies to skew results obtained overseas in order to
make a profit.
[32]
Different countries have different regulatory requirements and
enforcement abilities. An estimated 40% of all clinical trials now take
place in Asia, Eastern Europe, and Central and South America. "There is
no compulsory registration system for clinical trials in these countries
and many do not follow European directives in their operations", says
Dr. Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health
organisation tracking clinical trials in developing countries.
[33]
Beginning in the 1980s, harmonization of clinical trial protocols was
shown as feasible across countries of the European Union. At the same
time, coordination between Europe, Japan and the United States led to a
joint regulatory-industry initiative on international harmonization
named after 1990 as the
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
[34]
Currently, most clinical trial programs follow ICH guidelines, aimed at
"ensuring that good quality, safe and effective medicines are developed
and registered in the most efficient and cost-effective manner. These
activities are pursued in the interest of the consumer and public
health, to prevent unnecessary duplication of clinical trials in humans
and to minimize the use of animal testing without compromising the
regulatory obligations of safety and effectiveness."
[35]
