Fundamental Of Trial Design : Randomized Controlled Trials

INTRODUCTION

Randomized clinical trials are scientific investigations that examine and evaluate the safety and efficacy of new drugs or therapeutic procedures using human subjects. The results that these studies generate are considered to be the most valued data in the era of evidence-based medicine. Understanding the principles behind clinical trials enables an appreciation of the validity and reliability of their results.

What is a randomized clinical trial?

A clinical trial evaluates the effect of a new drug (or device or procedure) on human volunteers. These trials can be used to evaluate the safety of a new drug in healthy human volunteers, or to assess treatment benefits in patients with a specific disease. Clinical trials can compare a new drug against existing drugs or against dummy medications (placebo) or they may not have a comparison arm. A large proportion of clinical trials are sponsored by pharmaceutical or biotechnology companies who are developing the new drug, but some studies using older drugs in new disease areas are funded by health related government agencies, or through charitable grants.

In a randomized clinical trial, patients and trial personnel are deliberately kept unaware of which patient is on the new drug. This minimizes bias in the later evaluation so that the initial blind random allocation of patients to one or other treatment group is preserved throughout the trial. Clinical trials must be designed in an ethical manner so that patients are not denied the benefit of usual treatments. Patients must give their voluntary consent that they appreciate the purpose of the trial. Several key guidelines regarding the ethics, conduct, and reporting of clinical trials have been constructed to ensure that a patient’s rights and safety are not compromised by participating in clinical trials.

Are there different types of clinical trials?

Clinical trials vary depending on who is conducting the trial. Pharmaceutical companies typically conduct trials involving new drugs or established drugs in disease areas where their drug may gain a new license. Device manufacturers use trials to prove the safety and efficacy of their new device. Clinical trials conducted by clinical investigators unrelated to pharmaceutical companies might have other aims. They might use established or older drugs in new disease areas, often without commercial support, given that older drugs are

unlikely to generate much profit. Clinical investigators might also:

• look at the best way to give or withdraw drugs
• investigate the best duration of treatment to maximize outcome
• assess the benefits of prevention with vaccination or screening programs

Thus, different types of trials are needed to cover these needs; these can be classified under the following headings:

Phases:

The pharmaceutical industry has adopted a specific trial classification based on the four clinical phases of development of a particular drug (Phases I–IV). In Phase I, manufacturers usually test the effects of a new drug in healthy volunteers or patients unresponsive to usual therapies. They look at how the drug is handled in the human body (pharmacokinetics/pharmacodynamics), particularly with respect to the immediate short-term safety of higher doses. Clinical trials in Phase II examine dose–response curves in patients and what benefits might be seen in a small group of patients with a particular disease. In Phase III, a new drug is tested in a controlled fashion in a large patient population against a placebo or standard therapy. This is a key phase, where a drug will either make or break its reputation with respect to safety and efficacy before marketing begins. A positive study in Phase III is often known as a landmark study for a drug, through which it might gain a license to be prescribed for a specific disease. A study in Phase IV is often called a post-marketing study as the drug has already been granted regulatory approval/license. These studies are crucial for gathering additional safety information from a larger group of patients in order to understand the long-term safety of the drug and appreciate drug interactions.

Trial design:

Trials can be further classified by design. This classification is more descriptive in terms of how patients are randomized to treatment. The most common design is the parallel-group trial. Patients are randomized to the new treatment or to the standard treatment and followed-up to determine the effect of each treatment in parallel groups. Other trial designs include, amongst others, crossover trials, factorial trials, and cluster randomized trials.

Crossover trials randomize patients to different sequences of treatments, but all patients eventually get all treatments in varying order, i.e., the patient is his/her own control. Factorial trials assign patients to more than one treatment-comparison group. These are randomized in one trial at the same time, i.e., while drug A is being tested against placebo, patients are re-randomized to drug B or placebo, making four possible treatment combinations in total. Cluster randomized trials are performed when larger groups (e.g., patients of a single practitioner or hospital) are randomized instead of individual patients.


Number of centers:
Clinical trials can also be classified as single-center or multicenter studies according to the number of sites involved. While single-center studies are mainly used for Phase I and II studies, multicenter studies can be carried out at any stage of clinical development. Multicenter studies are necessary for two
major reasons:

• to evaluate a new medication or procedure more efficiently in terms of accruing sufficient subjects over a shorter period of time
• to provide a better basis for the subsequent generalization of the trial’s findings, i.e., the effects of the treatment are evaluated in many types of centers.