Depending on product type and development stage, investigators initially enroll volunteers or patients into small pilot studies,
and subsequently conduct progressively larger scale comparative
studies. Clinical trials can vary in size and cost, and they can involve
a single research center or multiple centers, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results.
Costs for clinical trials can range into the billions of dollars per approved drug. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory.
Only 10 percent of all drugs started in human clinical trials become an approved drug.
Costs for clinical trials can range into the billions of dollars per approved drug. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory.
Only 10 percent of all drugs started in human clinical trials become an approved drug.
Overview
Trials of drugs
Some clinical trials involve healthy subjects with no pre-existing medical conditions. Other clinical trials pertain to patients with specific health conditions who are willing to try an experimental treatment.
When participants are healthy volunteers who receive financial
incentives, the goals are different than when the participants are sick.
During dosing periods, study subjects typically remain under
supervision for one to 40 nights.
Usually pilot experiments are conducted to gain insights for design of the clinical trial to follow.
There are two goals to testing medical treatments: to learn
whether they work well enough, called "efficacy" or "effectiveness"; and
to learn whether they are safe enough, called "safety". Neither is an
absolute criterion; both safety and efficacy are evaluated relative to
how the treatment is intended to be used, what other treatments are
available, and the severity of the disease or condition. The benefits
must outweigh the risks.
For example, many drugs to treat cancer have severe side effects that
would not be acceptable for an over-the-counter pain medication, yet the
cancer drugs have been approved since they are used under a physician's
care, and are used for a life-threatening condition.
In the US, the elderly constitute 14% of the population, while they consume over one-third of drugs.
People over 55 (or a similar cutoff age) are often excluded from trials
because their greater health issues and drug use complicate data interpretation,
and because they have different physiological capacity than younger
people. Children and people with unrelated medical conditions are also
frequently excluded. Pregnant women are often excluded due to potential risks to the fetus.
The sponsor designs the trial in coordination with a panel of
expert clinical investigators, including what alternative or existing
treatments to compare to the new drug and what type(s) of patients might
benefit. If the sponsor cannot obtain enough test subjects at one
location investigators at other locations are recruited to join the
study.
During the trial, investigators recruit subjects with the
predetermined characteristics, administer the treatment(s) and collect
data on the subjects' health for a defined time period. Data include
measurements such as vital signs,
concentration of the study drug in the blood or tissues, changes to
symptoms, and whether improvement or worsening of the condition targeted
by the study drug occurs. The researchers send the data to the trial
sponsor, who then analyzes the pooled data using statistical tests.
Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device:
- On a specific kind of patient, for example, a patient who has been diagnosed with Alzheimer's disease
- At varying dosages, for example, a 10 milligram dose instead of a 5 milligram dose
- For a new indication
- Evaluation for improved efficacy in treating a patient's condition as compared to the standard therapy for that condition
- Evaluation of the study drug or device relative to two or more already approved/common interventions for that condition, for example, device A versus device B, or therapy A versus therapy B)
While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo.
Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol.
The protocol is the trial's "operating manual" and ensures that all
researchers perform the trial in the same way on similar subjects and
that the data is comparable across all subjects.
As a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method, specifically the experimental step.
The most common clinical trials evaluate new pharmaceutical products, medical devices (such as a new catheter), biologics, psychological therapies, or other interventions. Clinical trials may be required before a national regulatory authority approves marketing of the innovation.
Trials of devices
Similarly to drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket approval.
Device trials may compare a new device to an established therapy, or
may compare similar devices to each other. An example of the former in
the field of vascular surgery is the Open versus Endovascular Repair (OVER trial) for the treatment of abdominal aortic aneurysm, which compared the older open aortic repair technique to the newer endovascular aneurysm repair device. An example of the latter are clinical trials on mechanical devices used in the management of adult female urinary incontinence.
Trials of procedures
Similarly to drugs, medical or surgical procedures may be subjected to clinical trials, such as case-controlled studies for surgical interventions.
History
The concepts behind clinical trials are ancient. The Book of Daniel
chapter 1, verses 12 through 15, for instance, describes a planned
experiment with both baseline and follow-up observations of two groups
who either partook of, or did not partake of, "the King's meat" over a
trial period of ten days. Persian physician Avicenna, in The Canon of Medicine (1025) gave similar advice for determining the efficacy of medical drugs and substances.
Development
Edward Jenner vaccinating James Phipps, a boy of eight, on 14 May 1796. Jenner failed to use a control group.
Although early medical experimentation was often performed, the use of a control group to provide an accurate comparison for the demonstration of the intervention's efficacy, was generally lacking. For instance, Lady Mary Wortley Montagu, who campaigned for the introduction of inoculation (then called variolation) to prevent smallpox,
arranged for seven prisoners who had been sentenced to death to undergo
variolation in exchange for their life. Although they survived and did
not contract smallpox, there was no control group to assess whether this
result was due to the inoculation or some other factor. Similar
experiments performed by Edward Jenner over his smallpox vaccine were equally conceptually flawed.
The first proper clinical trial was conducted by the physician James Lind. The disease scurvy, now known to be caused by a Vitamin C
deficiency, would often have terrible effects on the welfare of the
crew of long distance ocean voyages. In 1740, the catastrophic result of
Anson's circumnavigation attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy. John Woodall, an English military surgeon of the British East India Company, had recommended the consumption of citrus fruit (it has an antiscorbutic effect) from the 17th century, but their use did not become widespread.
Lind conducted the first systematic clinical trial in 1747.
He included a dietary supplement of an acidic quality in the experiment
after two months at sea, when the ship was already afflicted with
scurvy. He divided twelve scorbutic sailors into six groups of two. They
all received the same diet but, in addition, group one was given a
quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water.
The treatment of group five stopped after six days when they ran out of
fruit, but by that time one sailor was fit for duty while the other had
almost recovered. Apart from that, only group one also showed some
effect of its treatment.
After 1750, the discipline began to take its modern shape. John Haygarth demonstrated the importance of a control group for the correct identification of the placebo effect in his celebrated study of the ineffective remedy called Perkin's tractors. Further work in that direction was carried out by the eminent physician Sir William Gull, 1st Baronet in the 1860s.
Frederick Akbar Mahomed (d. 1884), who worked at Guy's Hospital in London, made substantial contributions to the process of clinical trials, where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. He also founded the Collective Investigation Record for the British Medical Association;
this organization collected data from physicians practicing outside the
hospital setting and was the precursor of modern collaborative clinical
trials."
Modern trials
Austin Bradford Hill was a pivotal figure in the modern development of clinical trials.
Sir Ronald A. Fisher, while working for the Rothamsted experimental station in the field of agriculture, developed his Principles of experimental design in the 1920s as an accurate methodology for the proper design of experiments. Among his major ideas, was the importance of randomization – the random assignment of individuals to different groups for the experiment; replication – to reduce uncertainty, measurements should be repeated and experiments replicated to identify sources of variation; blocking
– to arrange experimental units into groups of units that are similar
to each other, and thus reducing irrelevant sources of variation; use of
factorial experiments – efficient at evaluating the effects and possible interactions of several independent factors.
The British Medical Research Council officially recognized the importance of clinical trials from the 1930s. The Council established the Therapeutic Trials Committee
to advise and assist in the arrangement of properly controlled clinical
trials on new products that seem likely on experimental grounds to have
value in the treatment of disease.
The first randomised curative trial was carried out at the MRC
Tuberculosis Research Unit by Sir Geoffrey Marshall (1887–1982). The
trial, carried out between 1946–1947, aimed to test the efficacy of the
chemical streptomycin for curing pulmonary tuberculosis. The trial was both double-blind and placebo-controlled.
The methodology of clinical trials was further developed by Sir Austin Bradford Hill, who had been involved in the streptomycin trials. From the 1920s, Hill applied statistics to medicine, attending the lectures of renowned mathematician Karl Pearson, among others. He became famous for a landmark study carried out in collaboration with Richard Doll on the correlation between smoking and lung cancer. They carried out a case-control study in 1950, which compared lung cancer patients with matched control and also began a sustained long-term prospective study into the broader issue of smoking and health, which involved studying the smoking habits and health of over 30,000 doctors over a period of several years. His certificate for election to the Royal Society
called him "...the leader in the development in medicine of the precise
experimental methods now used nationally and internationally in the
evaluation of new therapeutic and prophylactic agents."
International clinical trials day is celebrated on 20 May.
Types
One way of classifying clinical trials is by the way the researchers behave.
- In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study.
- In an interventional study, the investigators give the research subjects a particular medicine or other intervention to compare the treated subjects with those receiving no treatment or the standard treatment. Then the researchers measure how the subjects' health changes.
Another way of classifying trials is by their purpose. The U.S. National Institutes of Health (NIH) organizes trials into five different types:
- Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, or lifestyle changes.
- Screening trials test the best way to detect certain diseases or health conditions.
- Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
- Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
- Quality of life trials (supportive care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.
- Compassionate use trials or expanded access trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. Usually, this involves a disease for which no effective therapy has been approved, or a patient who has already failed all standard treatments and whose health is too compromised to qualify for participation in randomized clinical trials. Usually, case-by-case approval must be granted by both the United States Food and Drug Administration and the pharmaceutical company for such exceptions.
Another classification is defined by FDA (US Food & Drug
Administration). Different types of clinical research are used depending
on what the researchers are studying. Below are descriptions of some
different kinds of clinical research.
- Treatment Research generally involves an intervention such as medication, psychotherapy, new devices, or new approaches to surgery or radiation therapy.
- Prevention Research looks for better ways to prevent disorders from developing or returning. Different kinds of prevention research may study medicines, vitamins, vaccines, minerals, or lifestyle changes.
- Diagnostic Research refers to the practice of looking for better ways to identify a particular disorder or condition.
- Screening Research aims to find the best ways to detect certain disorders or health conditions.
- Quality of Life Research explores ways to improve comfort and the quality of life for individuals with a chronic illness.
- Genetic studies aim to improve the prediction of disorders by identifying and understanding how genes and illnesses may be related. Research in this area may explore ways in which a person’s genes make him or her more or less likely to develop a disorder. This may lead to development of tailor-made treatments based on a patient’s genetic make-up.
- Epidemiological studies seek to identify the patterns, causes, and control of disorders in groups of people.
An important note: some clinical research is “outpatient,” meaning
that participants do not stay overnight at the hospital. Some is
“inpatient,” meaning that participants will need to stay for at least
one night in the hospital or research center. Be sure to ask the
researchers what their study requires.
A fourth classification is whether the trial design allows changes based on data accumulated during the trial.
- Fixed trials consider existing data only during the trial's design, do not modify the trial after it begins and do not assess the results until the study is complete.
- Adaptive clinical trials use existing data to design the trial, and then use interim results to modify the trial as it proceeds. Modifications include dosage, sample size, drug undergoing trial, patient selection criteria and "cocktail" mix. Adaptive trials often employ a Bayesian experimental design to assess the trial's progress. In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. The aim is to more quickly identify drugs that have a therapeutic effect and to zero in on patient populations for whom the drug is appropriate.
Finally, a common way of distinguishing trials is by phase, which in
simple terms, relates to how close the drug is to being clinically
proven both effective for its stated purpose and accepted by the
regulatory authorities for use for that purpose.
Phases
Clinical trials involving new drugs are commonly classified into five
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 1, 2, and 3, it will usually be
approved by the national regulatory authority for use in the general
population. Before pharmaceutical companies start clinical trials on a
drug, they will also have conducted extensive preclinical studies. Each phase has a different purpose and helps scientists answer a different question.
| Phase | Aim | Notes |
|---|---|---|
| Phase 0 | Pharmacodynamics and pharmacokinetics in humans | Phase 0 trials are optional first-in-human trials. Single subtherapeutic doses of the study drug or treatment are given to a small number of subjects (typically 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). For a test drug, the trial documents the absorption, distribution, metabolization, and removal (excretion) of the drug, and the drug's interactions within the body, to confirm that these appear to be as expected. |
| Phase 1 | Screening for safety | Often the first-in-man trials. Testing within a small group of people (typically 20–80) to evaluate safety, determine safe dosage ranges, and begin to identify side effects. A drug's side effects could be subtle or long term, or may only happen with a few people, so phase 1 trials are not expected to identify all side effects. |
| Phase 2 | Establishing the efficacy of the drug, usually against a placebo | Testing with a larger group of people (typically 100–300) to determine efficacy and to further evaluate its safety. The gradual increase in test group size allows for the evocation of less-common side effects. |
| Phase 3 | Final confirmation of safety and efficacy | Testing with large groups of people (typically 1,000–3,000) to confirm its efficacy, evaluate its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely. |
| Phase 4 | Safety studies during sales | Postmarketing studies delineate additional information, including the treatment's risks, benefits, and optimal use. As such, they are ongoing during the drug's lifetime of active medical use. (Particularly after approval under FDA Accelerated Approval Program) |
Trial design
A fundamental distinction in evidence-based practice 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 retrospectively assess
associations between the treatments given to participants and their
health status, with potential for considerable errors in design and
interpretation.
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 a subject receives. This intent is to prevent researchers from treating the two groups differently. A form of double-blind study called a "double-dummy" design allows additional insurance against bias. In this kind of study, all patients are given both placebo and active doses in alternating periods.
- Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect.
Clinical studies having small numbers of subjects may be "sponsored"
by single researchers or a small group of researchers, and are designed
to test simple questions or feasibility to expand the research for a
more comprehensive randomized controlled trial.
Active control studies
In many cases, giving a placebo to a person suffering from a disease may be unethical.
To address this, it has become a common practice to conduct "active
comparator" (also known as "active control") trials. In trials with an
active control group, subjects are given either the experimental
treatment or a previously approved treatment with known effectiveness.
Master protocol
In
such studies, multiple experimental treatments are tested in a single
trial. Genetic testing enables researchers to group patients according
to their genetic profile, deliver drugs based on that profile to that
group and compare the results. Multiple companies can participate, each
bringing a different drug. The first such approach targets squamous cell cancer,
which includes varying genetic disruptions from patient to patient.
Amgen, AstraZeneca and Pfizer are involved, the first time they have
worked together in a late-stage trial. Patients whose genomic profiles
do not match any of the trial drugs receive a drug designed to stimulate
the immune system to attack cancer.
Clinical trial protocol
A clinical trial protocol
is a document used to define and manage the trial. It is prepared by a
panel of experts. All study investigators are expected to strictly
observe the protocol.
The protocol describes the scientific rationale, objective(s),
design, methodology, statistical considerations and organization of the
planned trial. Details of the trial are provided in documents referenced
in the protocol, such as an investigator's brochure.
The protocol contains a precise study plan to assure safety and
health of the trial subjects and to provide an exact template for trial
conduct by investigators. This allows data to be combined across all
investigators/sites. The protocol also informs the study administrators
(often a contract research organization).
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
issued by the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH). Regulatory authorities in Canada and Australia also follow ICH guidelines. Journals such as Trials, encourage investigators to publish their protocols.
Design features
Informed consent
Example of informed consent document from the PARAMOUNT trial
Clinical trials recruit study subjects to sign a document representing their "informed consent".
The document includes details such as its purpose, duration, required
procedures, risks, potential benefits, key contacts and institutional
requirements.
The participant then decides whether to sign the document. The document
is not a contract, as the participant can withdraw at any time without
penalty.
Informed consent is a legal process in which a recruit is
instructed about key facts before deciding whether to participate.
Researchers explain the details of the study in terms the subject can
understand. The information is presented in the subject's native
language. Generally, children cannot autonomously provide informed
consent, but depending on their age and other factors, may be required
to provide informed assent.
Statistical power
The number of subjects has a large impact on the ability to reliably
detect and measure effects of the intervention. This is described as its
"power". The larger the number of participants, the greater the statistical power and the greater the cost.
The statistical power estimates the ability of a trial to detect a
difference of a particular size (or larger) between the treatment and
control groups. For 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 placebo and trial groups
receiving dosage of 10 mg/dL or more, but only 0.70 to detect a
difference of 6 mg/dL.
Placebo groups
Merely giving a treatment can have nonspecific effects. These are
controlled for by the inclusion of patients who receive only a placebo.
Subjects are assigned randomly
without informing them to which group they belonged. Many trials are
doubled-blinded so that researchers do not know to which group a subject
is assigned.
Assigning a subject 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.
Duration
Timeline of various approval tracks and research phases in the US
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.
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. 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.
For clinical trials involving potential for seasonal influences (such as airborne allergies, seasonal affective disorder, influenza, and skin diseases), the study may be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested.
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.
Marketing
Janet
Yang uses the Interactional Justice Model to test the effects of
willingness to talk with a doctor and clinical trial enrollment.
Results found that potential clinical trial candidates were less likely
to enroll in clinical trials if the patient is more willing to talk
with their doctor. The reasoning behind this discovery may be patients
are happy with their current care. Another reason for the negative
relationship between perceived fairness and clinical trial enrollment is
the lack of independence from the care provider. Results found that
there is a positive relationship between a lack of willingness to talk
with their doctor and clinical trial enrollment. Lack of willingness to
talk about clinical trials with current care providers may be due to
patients' independence from the doctor. Patients who are less likely to
talk about clinical trials are more willing to use other sources of
information to gain a better insight of alternative treatments. Clinical
trial enrollment should be motivated to utilize websites and television
advertising to inform the public about clinical trial enrollment.
Information technology
The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Clinical trial management systems
are often used by research sponsors or CROs to help plan and manage the
operational aspects of a clinical trial, particularly with respect to
investigational sites. Advanced analytics for identifying researchers
and research sites with expertise in a given area utilize public and
private information about ongoing research. Web-based electronic data capture (EDC) and clinical data management systems are used in a majority of clinical trials to collect case report data from sites, manage its quality and prepare it for analysis. Interactive voice response
systems are used by sites to register the enrollment of patients using a
phone and to allocate patients to a particular treatment arm (although
phones are being increasingly replaced with web-based (IWRS) tools which
are sometimes part of the EDC system). While patient-reported outcome were often paper based in the past, measurements are increasingly being collected using web portals or hand-held ePRO (or eDiary) devices, sometimes wireless. Statistical software
is used to analyze the collected data and prepare them for regulatory
submission. Access to many of these applications are increasingly
aggregated in web-based clinical trial portals.
In 2011, the FDA approved a phase 1 trial that used telemonitoring,
also known as remote patient monitoring, to collect biometric data in
patients' homes and transmit it electronically to the trial database.
This technology provides many more data points and is far more
convenient for patients, because they have fewer visits to trial sites.
Ethical aspects
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); in the EU, they are called Ethics committees.
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.
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. In compassionate use
trials the latter becomes a particularly difficult problem. The final
objective is to serve the community of patients or future patients in a
best-possible and most responsible way. See also Expanded access.
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, and then quantified methods may play an important role.
Additional ethical concerns are present when conducting clinical trials on children (pediatrics), and in emergency or epidemic situations.
Conflicts of interest and unfavorable studies
In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research were not published, the Pharmaceutical Research and Manufacturers of America
published new guidelines urging companies to report all findings and
limit the financial involvement in drug companies by researchers. The US Congress signed into law a bill which requires phase II and phase III clinical trials to be registered by the sponsor on the clinicaltrials.gov website compiled by the National Institutes of Health.
Drug researchers not directly employed by pharmaceutical
companies often seek grants from manufacturers, and manufacturers often
look to academic researchers to conduct studies within networks of
universities and their hospitals, e.g., for translational
cancer research. Similarly, competition for tenured academic positions,
government grants and prestige create conflicts of interest among
academic scientists.
According to one study, approximately 75% of articles retracted for
misconduct-related reasons have no declared industry financial support. Seeding trials are particularly controversial.
In the United States, all clinical trials submitted to the FDA as
part of a drug approval process are independently assessed by clinical
experts within the Food and Drug Administration, including inspections of primary data collection at selected clinical trial sites.
In 2001, the editors of 12 major journals issued a joint
editorial, published in each journal, on the control over clinical
trials exerted by sponsors, particularly targeting the use of contracts
which allow sponsors to review the studies prior to publication and
withhold publication. They strengthened editorial restrictions to
counter the effect. The editorial noted that contract research organizations had, by 2000, received 60% of the grants from pharmaceutical companies
in the US. Researchers may be restricted from contributing to the trial
design, accessing the raw data, and interpreting the results.
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, 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
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.
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 state that participating in clinical trials is
voluntary, with the subject having the right not to participate or to
end participation at any time.
Local site investigators
The ethical principle of primum non nocere
("first, do no harm") guides the trial, and if an 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 could 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.
Local investigators 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. Local investigators 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
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
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. A 'covered
clinical study' refers to a trial submitted to the FDA as part of a
marketing application (for example, as part of an NDA or 510(k)), about which the FDA may require disclosure of financial interest of the clinical investigator
in the outcome of the study. For example, the applicant must disclose
whether an investigator owns equity in the sponsor, or owns proprietary
interest in the product under investigation. The FDA defines a covered
study as "...any study of a drug, biological product or device in humans
submitted in a marketing application or reclassification petition that
the applicant or FDA relies on to establish that the product is
effective (including studies that show equivalence to an effective
product) or any study in which a single investigator makes a significant
contribution to the demonstration of safety."
Alternatively, many American pharmaceutical companies have moved
some clinical trials overseas. Benefits of conducting trials abroad
include lower costs (in some countries) and the ability to run larger
trials in shorter timeframes, whereas a potential disadvantage exists in
lower-quality trial management.
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
Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health
organisation tracking clinical trials in developing countries.
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)
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."
Aggregation of safety data during clinical development
Aggregating
safety data across clinical trials during drug development is important
because trials are generally designed to focus on determining how well
the drug works. The safety data collected and aggregated across
multiple trials as the drug is developed allows the sponsor,
investigators and regulatory agencies to monitor the aggregate safety
profile of experimental medicines as they're developed. The value of
assessing aggregate safety data is: a) decisions based on aggregate
safety assessment during development of the medicine can be made
throughout the medicine's development and b) it sets up the sponsor and
regulators well for assessing the medicine's safety after the drug is
approved.
Economics
Clinical
trial costs vary depending on trial phase, type of trial, and disease
studied. A study of clinical trials conducted in the United States from
2004 to 2012 found the average cost of phase I trials to be $1.4 million
and $6.6 million, depending on the type of disease. Phase II trials
ranged from $7 million to $20 million, and phase III trials from $11
million to $53 million.
Sponsor
The
cost of a study depends on many factors, especially the number of sites
conducting the study, the number of patients involved, and whether the
study treatment is already approved for medical use.
The expenses incurred by a pharmaceutical company in administering a phase 3 or 4 clinical trial may include, among others:
- production of the drug(s) or device(s) being evaluated
- staff salaries for the designers and administrators of the trial
- payments to the contract research organization, the site management organization (if used) and any outside consultants
- payments to local researchers and their staff for their time and effort in recruiting test subjects and collecting data for the sponsor
- the cost of study materials and the charges incurred to ship them
- communication with the local researchers, including on-site monitoring by the CRO before and (in some cases) multiple times during the study
- one or more investigator training meetings
- expense incurred by the local researchers, such as pharmacy fees, IRB fees and postage
- any payments to subjects enrolled in the trial
- the expense of treating a test subject who develops a medical condition caused by the study drug
These expenses are incurred over several years.
In the US, sponsors may receive a 50 percent tax credit for clinical trials conducted on drugs being developed for the treatment of orphan diseases. National health agencies, such as the US National Institutes of Health,
offer grants to investigators who design clinical trials that attempt
to answer research questions of interest to the agency. In these cases,
the investigator who writes the grant and administers the study acts as
the sponsor, and coordinates data collection from any other sites. These
other sites may or may not be paid for participating in the study,
depending on the amount of the grant and the amount of effort expected
from them. Using internet resources can, in some cases, reduce the
economic burden.
Investigators
Investigators
are often compensated for their work in clinical trials. These amounts
can be small, just covering a partial salary for research assistants and
the cost of any supplies (usually the case with national health agency
studies), or be substantial and include 'overhead' that allows the
investigator to pay the research staff during times between clinical
trials.
Subjects
Participants
in phase 1 drug trials do not gain any direct health benefit from
taking part. They are generally paid a fee for their time, with payments
regulated and not related to any risk involved. In later phase trials,
subjects may not be paid to ensure their motivation for participating
with potential for a health benefit or contributing to medical
knowledge. Small payments may be made for study-related expenses such as
travel or as compensation for their time in providing follow-up
information about their health after the trial treatment ends.
Participant recruitment and participation
Newspaper advertisements seeking patients and healthy volunteers to participate in clinical trials
Phase 0 and phase 1 drug trials seek healthy volunteers. Most other
clinical trials seek patients who have a specific disease or medical
condition. The diversity observed in society should be reflected in
clinical trials through the appropriate inclusion of ethnic minority populations. Patient recruitment or participant recruitment plays a significant role in the activities and responsibilities of sites conducting clinical trials.
All volunteers being considered for a trial are required to
undertake a medical screening. Requirements differ according to the
trial needs, but typically volunteers would be screened in a medical laboratory for:
- Measurement of the electrical activity of the heart (ECG)
- Measurement of blood pressure, heart rate and body temperature
- Blood sampling
- Urine sampling
- Weight and height measurement
- Drug abuse testing
- Pregnancy testing
It has been observed that participants in clinical trials are
disproportionately white. This may reduce the validity of findings in
respect of non-white patients.
Locating trials
Depending
on the kind of participants required, sponsors of clinical trials, or
contract research organizations working on their behalf, try to find
sites with qualified personnel as well as access to patients who could
participate in the trial. Working with those sites, they may use various
recruitment strategies, including patient databases, newspaper and
radio advertisements, flyers, posters in places the patients might go
(such as doctor's offices), and personal recruitment of patients by
investigators.
Volunteers with specific conditions or diseases have additional
online resources to help them locate clinical trials. For example, the
Fox Trial Finder connects Parkinson's disease trials around the world to volunteers who have a specific set of criteria such as location, age, and symptoms. Other disease-specific services exist for volunteers to find trials related to their condition. Volunteers may search directly on ClinicalTrials.gov to locate trials using a registry run by the U.S. National Institutes of Health and National Library of Medicine.
Research
The
risk information seeking and processing (RISP) model analyzes social
implications that affect attitudes and decision making pertaining to
clinical trials.
People who hold a higher stake or interest in the treatment provided in
a clinical trial showed a greater likelihood of seeking information
about clinical trials. Cancer patients reported more optimistic
attitudes towards clinical trials than the general population. Having a
more optimistic outlook on clinical trials also leads to greater
likelihood of enrolling.
