An Introduction to the Clinical Trial Process
Demystifying the Process of Participating in Medical Studies

Originally published in "Scleroderma Voice," 2004 #3

The Scleroderma Foundation receives questions on a daily basis from patients seeking answers to health issues. Although scleroderma is a highly individualized disease, we have found that some concerns are very common.

The focus of this article will be clinical trials.

There Are Now More Scleroderma-Related Studies Than Ever

Increasing interest from pharmaceutical and biotech companies in developing better treatments for the complications of scleroderma has created an environment in which a person with scleroderma may actually choose between trials to participate in. This has not previously been the case for scleroderma.

The increase in options has also caused confusion among those who may be eligible for participation, because the process can be daunting and confusing.

We hope that you find this section informative and that it clarifies any questions you may have regarding the clinical trial process.

However, we understand that individual circumstances are unique, and it is an extremely personal decision when one chooses to participate in a clinical trial.

It is also one that should be discussed in great detail with your healthcare provider, because everyone’s own unique health care history and circumstances should be considered.

We will start with an overview of the clinical trial process, and then answer some frequently asked questions.

An Introduction to the Clinical Trial Process

A clinical trial is a research study performed wth humans to determine if a new drug or therapy is both safe and effective for treating a disease or condition.

All clinical trials are based on a set of rules called a protocol. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study.

Clinical trials are carried out in steps called phases. Patients may be eligible for studies in different phases, depending on their general condition, the type and stage of their disease, and what therapy, if any, they have already had.

Trial participants are seen regularly by research staff to monitor their health and to determine the safety and effectiveness of their treatment.

On average, it takes 12 years for a drug to travel through the clinical testing phases to reach the patient population.

Approximately one in five drugs that enter clinical testing is ultimately approved for patient use.

The following is a description of each stage in the U.S. clinical trial process.

Pre-Clinical Testing

Before a drug can be tested in humans, pre-clinical testing is required. Laboratory studies are conducted to demonstrate safety in humans and the drug’s ability to fight against a targeted disease.

Pre-clinical research can take place in one or both of the follow-ing media:

• In vitro (Latin), meaning “in glass,” also known as bench research; or
• in vivo, meaning “in the living.” This research often occurs in rats and mice. Once the drug has been determined to have strong potential, it begins to be prepared for human delivery. Pre-clinical testing takes approximately three to four years.

Investigational New Drug Application (IND)

After completing pre-clinical testing, an Investigational New Drug application (IND) must be filed with the regulatory agency, the U.S. Food and Drug Administration (FDA).

The IND outlines the results of pre-clinical testing and clearly defines how future studies will be conducted.

The FDA has 30 days to review the IND. If they do not disapprove the IND within that time period, the drug can move on to a phase 1 trial where it can be tested in humans.

Phase 1

In a phase 1 clinical trial, the primary goal is to assess the drug’s safety.
For the first time, the drug is introduced to humans, with tests occurring in a small number of healthy volunteers (20 to 100).

The study is designed to determine how the human body reacts to the drug and, specifically, what side effects occur as dosage levels are increased.

This initial phase of testing typically takes several months to a year. About 70% of experimental drugs pass this initial phase.

Phase 2

Once a drug has been shown to be safe, it must be tested for effectiveness.

Most phase 2 studies are randomized trials. This means one group of patients will receive the experimental drug, while a second “control” group will receive a standard treatment or placebo (a substance containing no medication, to create a baseline against which to measure the effectiveness of the drug being tested).

Often these studies are “blinded”—neither the patients nor the researchers know who is getting the experimental drug. In this manner, the study can provide the pharmaceutical or biotechnology company and the regulatory agency comparative information about the relative safety and effectiveness of this new drug.

This second phase of testing may last from several months to two years, and involve up to several hundred patients. Only about 30% of experimental drugs successfully complete both phase 1 and phase 2 studies.

Phase 3

In a phase 3 study, a drug is tested in several hundred to several thousand patients. This large-scale testing allows the pharmaceutical or biotechnology company and the regulatory agency a more thorough understanding of the drug’s effectiveness, benefits, and the range of possible adverse reactions.

Most phase 3 studies are randomized and blinded trials.

Phase 3 studies typically last several years. Seventy to 90% of drugs that enter phase 3 studies successfully complete testing.

Once a phase 3 study is successfully completed, a company can request marketing approval for the drug from the U.S. Food and Drug Administration.

New Drug Application (NDA)/ Biologics License Application (BLA)
Once all three clinical trial phases are complete, and if the data demonstrates that the drug is safe and effective, a New Drug Application/Biologics License Application (NDA/BLA) is filed with the U.S. Food and Drug Administration (FDA).

This NDA/BLA must contain all of the scientific information compiled over the course of the trials.

The FDA is allowed at least six months to review the NDA/BLA. However, this review process can sometimes take up to two years, depending on the procedures set forth by a specific country.

Approval

Once the U.S. Food and Drug Administration approves the NDA/ BLA, the drug becomes available for physicians to prescribe.

Although the product is approved, it must continue to comply with regulatory requirements over time. For example, all cases of adverse events caused by the drug must be reported, and quality control standards must be met. In some cases, the regulatory agency will also require post-marketing studies to evaluate the long-term effects of the drug.

Post-Marketing Studies

Post-marketing studies, also called phase 4 studies, can have several objectives.

1. These studies are often performed in special patient populations not previously studied (for example, pediatric or geriatric).
2. The studies are often designed to monitor a drug’s long-term effectiveness and impact on a patient’s quality of life.
3. Many studies are designed to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies.

Frequently Asked Questions

• Why are clinical trials necessary?
  Clinical trials are necessary to make sure new treatments are safe and beneficial before they are widely distributed.
  
  They also help healthcare professionals determine what groups of people the new treatments are appropriate for, and what dosages are most effective.
• Are there different types of clinical trials?
  There are five different types of clinical trials, as listed below:

1. Treatment trials are designed to test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
2. Quality of life/supportive care trials explore ways to improve comfort and the quality of life for individuals with a chronic illness.
3. 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 methods may include medicines, vaccines, vitamins, minerals, or lifestyle changes.
4. Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
5. Screening trials test the best ways to detect certain diseases or health conditions.

• Who sponsors clinical trials?
  Clinical trials can be sponsored by government, industry, academic medical centers, foundations, or voluntary groups such as the Scleroderma Foundation.
• How are patients’ rights protected?
  Several important mechanisms protect participants during the clinical trial process:

1. The Informed Consent. This document is very detailed and can be long: it is not unusual for an informed consent to be 10–12 pages. The informed consent will include, but is not limited to, the following information:
   
   * Purpose of the trial.
   * Any procedures or tests that will be performed during the trial and how often they will be conducted.
   * Potential risks and benefits of participation.
   * The individual’s rights.
2. Strict review by the Office of Human Research Protections of the U.S. Department of Health.
3. Institutional review boards (IRBs) oversee studies. IRBs are made up of physicians, scientists, patient advocates, ethicists, and administrators. The IRB is responsible for reviewing study protocols before the study is launched, and then will closely monitor the trial after approval to ensure that participants are not exposed to unnecessary risk.

• Are there ever any reasons to discontinue a trial?
  A trial may be discontinued if evidence shows that the risks of a treatment are greater than any possible benefits; if participants are reporting unexpected or severe side effects; and if the experimental treatment is clearly less effective than the existing treatment.
• Are there benefits to participating in a clinical trial?
  Potential benefits include:
  • Patients will receive, at a minimum, the best standard treatment (if one exists).
  • If the new treatment or intervention is proven to work, participants may be among the first to benefit.
  • Patients have a chance to help others and improve patient care.
• Are there risks to participating in a clinical trial?
  Possible risks include:
  • New treatments or interventions under study are not always better than, or even as good as, standard care.
  • Even if a new treatment has benefits, it may not work for every patient.
  • Health insurance and managed care providers do not always cover clinical trials.
• Do many people take part in clinical trials?
  The short answer is, NO.
• What should I consider before participating in a study?
  Here are some things to think about or to discuss with your healthcare provider before enrolling in a trial.
  • Be as informed as possible about the clinical trial and be sure that you feel comfortable asking the members of the health care team questions.
  • What is the purpose of the study?
  • Who is going to be in the study?
  • Why do researchers believe that the new treatment being tested may be effective?
  • Has it been tested before?
  • What kinds of tests are involved?
  • How do the possible risks, side effects, and benefits in the study compare with my current treatment?
  • How might this trial affect my daily life?
  • How long will the trial last?
  • Will hospitalization be required?
  • Who will pay for the treatment?
  • Will I be reimbursed for other expenses?
  • What type of long-term follow-up care is part of this study?
  • How will I know the treatment is working?
  • Will the results of the trial be provided to me?
  • Who will be in charge of my care?
• What if I decide this is not right for me?
  Remember that clinical trial participants may leave a trial at any time.
  
  It is important to maintain an open dialogue with those in charge of your care during the trial. If you experience difficulties during the trial related to the therapy or the impact on your daily life, maintaining a continuous and open discussion could help to minimize or overcome these problems.
  
  If you decide to withdraw from a trial, please advise the research team of your withdrawal as well as the reasons for your departure.
• Where can I learn more about clinical trials that are currently enrolling?
  More information about ongoing clinical trials can be found on the following websites: