shutterstock 493763653For many of us, it is not uncommon to take a medication and think nothing of the work that went into putting it into our bodies. In our moment of need, we are interested in results, not the process that makes our wellness possible. However, there are extensive steps a treatment goes through before it is available for public use. New treatments must pass the clinical research process, where they are rigorously researched, tested, and clinically trialed. The Institutional Review Board (IRB) and the Food and Drug Administration (FDA) must also approve them before they end up in the hands of providers and the public.

 Preclinical Research

Before development of a new treatment, it must first be proven that a new procedure or treatment will be better than what is currently available. This is achieved through extensive preclinical research, in what is commonly known as the preclinical stage. This stage may include testing on non-human subjects, with a goal of gathering toxicity, efficacy, and pharmacokinetic (drug and tissue interaction) information.

What is a Clinical Trial?

When preclinical research suggests that the new treatment has the potential to improve care of patients, development moves into clinical trials. Clinical trials test whether the new treatment is safe for and works in humans.

Clinical trials are used to test many things:

  • New treatment or procedure (not yet approved by the FDA)
  • New uses of existing drugs (already approved by the FDA)
  • New medical equipment
  • New combination of treatments
  • New tests to find/track disease
  • Uses of alternative medicines

Clinical Trial Participants

With informed consent, subjects may join a clinical trial if they adequately meet the conditions of the study. The subjects may join in any phase of a trial. It is not uncommon for the subjects in a clinical trial to be very similar related to both their diagnosis(es) and their overall health. This similarity among subjects helps to ensure that any noted progress is related to treatment and not to initial differences in their health.

Phases of Clinical Trials

The clinical trial portion of the treatment production process is extensive. It involves at least four phases. Each phase is necessary to ensure both the safety of the trial subjects (and future patients) and to yield accurate results. At times phases may occur concurrently, but none of phases 1-4 may be skipped.

Phase Zero:

Some clinical trials choose to include this phase and some do not. If included, this is the first trial done on human subjects. The subject group is very small (<10-15) and a sub-therapeutic dose of the drug is given. The goal in this phase is to determine how the body responds to and processes the drug or treatment. Phase zero is often skipped for phase one.

Phase One:

If phase zero does not occur, phase one trials are the first time a drug is tested on human subjects. Typically, this phase involves a small group of patients (15-30) and lasts for several months to a year. The goal of this phase is to determine the best dose of the drug that results in the fewest side effects. This is achieved through the practice of dose-ranging, in which different doses of the treatment are tested against each other to see which yields the best results or is the least harmful to the subjects. At times, subjects will see positive health results in this stage, but that is not the goal. If the treatment is shown to be safe, the trial can proceed to the next phase.

Phase Two:

Phase two trials have two goals – continue to assess safety while also addressing treatment efficacy. They are performed on larger groups of subjects (100-300) and typically last a couple of years. Often, the treatment is tested among subjects with a very specific diagnosis. Phase two may include two groups (called trial arms) of subjects that receive different treatments. It is also not uncommon for phase two trials to test different combinations of treatments. If the phase two trial shows that the treatment is both safe and likely to work, the trial can proceed to a phase three trial.

Phase Three:

In phase three clinical trials, the new treatment is compared to the existing standard treatment. The goal of these trials is to determine the side effects of each treatment as well as which treatment is more therapeutic (effectiveness). If not already present, a physician joins the clinical researcher on the subject monitoring team. The subject group is large (300+) and these trials often take several years. Frequently, these trials utilize randomization, a process in which subjects are randomly placed into different trial arms. When done by a computer, randomization helps prevent selection bias and accidental bias. The subjects in the trial do not know what trial arm they are in until the trial is over.

Phase three trials have 2+ trial arms. One arm receives the standard treatment (or a placebo), while the other arm(s) receive the new treatment. Subjects are monitored closely in phase three trials. Trials may be stopped early if side effects of the new treatment are too severe or if one arm is seeing much better results. Typically, treatment needs to be studied in a phase three trial (sometimes twice) before being approved for general public use by the FDA. If the FDA approves a new treatment, a provider may prescribe it.

Phase Four:

Phase four trials are meant to test new treatments that have been approved by the FDA. They are often referred to as a postmarketing surveillance trial or a confirmatory trial. The goal of these trials is surveillance (pharamacovigilance), as teams continue to spend many years gathering research on rare and long lasting side effects and treatment safety. The subject groups of phase four trials are the largest (often thousands). Personal providers prescribe the subjects the same therapeutic dose of the treatment. The large number of subjects and the longer time frame helps ensure that any rare or long-term side effects will be discovered. Phase four trials may also help determine how helpful the new treatment is in combination with other existing treatments.

Many treatments never make it to phase three or four clinical trials. Subject safety, adverse side effects, and poor effectiveness are just a few of the many reasons a treatment fails during the clinical research process. However, should a treatment adequately and safely survive all the phases of clinical trials, it has the power to change tomorrows’ standard of care.

Laura Mansfield

Master of Healthcare Administration (MHA) | Sacred Heart University

Associate’s Degree of Nursing (ADN) | North Seattle Community College

Bachelor of Business Administration (B.B.A.), Marketing, Sales | University of Washington (Seattle)

October 2019

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