What Are Clinical Trials?

Clinical trials are experiments done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison. Clinical trials generate data on safety and efficacy.

They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial – their approval does not mean that the therapy is ‘safe’ or effective, only that the trial may be conducted.

Depending on product type and development stage, investigators initially enroll volunteers and/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.

Trials can be quite costly, depending on a number of factors. 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.

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 only 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. Women, children and people with unrelated medical conditions are also frequently excluded. For women, a major reason for exclusion is the possibility of pregnancy and the unknown risks to the fetus.

The sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative/existing treatments to compare to the new drug and what type(s) of patients might benefit. If the sponsor cannot obtain enough subjects at one location, investigators at other locations are recruited to join the study.

During the trial, investigators recruit patients with the predetermined characteristics, administer the treatment(s) and collect data on the patients’ health for a defined time period.

Subjects are volunteers who are not paid for participating. However, the investigators are paid.

Data include measurements such as vital signs, concentration of the study drug in the blood and/or tissues, changes to symptoms and whether health outcomes. 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 (e.g., patients who have been diagnosed with Alzheimer’s disease)
  • At a different dose (e.g., 10-mg dose instead of 5-mg dose)
  • For a new indication
  • Is more effective for the patient’s condition than the standard therapy
  • Relative to two or more already approved/common interventions for that disease (e.g., device A vs. device B, therapy A vs. therapy B)

While most clinical trials test one alternative to the novel intervention, some expand to three or four.

Except for small, single-location trials, the design and objectives are speciied 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 patients and that the data is comparable across all patients.

Because 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 drugs, 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, medical devices are sometimes subjected to clinical trials. Device trials may compare a new device to an established therapy to a new device, 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 is the LEOPARD trial, which compares EVAR devices.

Clinical Trial 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. 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 0

Pharmacodynamics and pharmacokinetics in humans: Phase 0 trials are the first-in-human trials. Single subtherapeutic doses of the study drug or treatment 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). 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: Testing within a small group of people (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 of 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 (100–300) to see if it is effective and to further evaluate its safety. The gradual increase in test group size allows less-common side effects to be progressively sought.

Phase 3

Final confirmation of safety and efficacy: Testing with 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.

Phase 4

Sentry 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.

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 only observe associations (correlations) between the treatments experienced by participants and their health status. However, under certain conditions, causal effects can be inferred from observational studies.

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 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 researchers or a small group of researchers, and are designed to test simple questions. In the field of rare diseases, sometimes the number of patients is the limiting factor for the size of a clinical trial.

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).

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

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 and key contacts. 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.

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.


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 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.

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).

Top Photo: National Center for Complementary and Integrative Health, National Institutes of Health