Clinical trials are stages of progressively larger clinical research on drug candidates on human participants, both healthy volunteers and patients. Their goal is to study the safety and efficacy of a prospective drug. Efficacy and safety play a paired but opposite relation in the sense that a drug may be approved if it is safe but not so effective, but it will almost always be rejected if it is effective but not so safe. Safety, again, depends on the target disease – what may be considered acceptable safety for a fatal disease like cancer may not be considered safe enough for a mild, not life-threatening disease.
Clinical trials occur in phases. There is a preclinical phase, where a drug may be tested in the laboratory, either by computer modelling or other non-live testing, or testing in vitro, that is, in a test tube or petri dish, or in vivo, that is, on live animals. This can often be the longest phase in the process. This process ends with the selection of a molecule or drug candidate, and the filing of an IND or Investigational New Drug application with the USFDA. The IND is used to seek permission from the FDA to test a promising new drug on humans. Once the IND is granted, phase 1 human clinical trial commences.
Only 10% of all drugs that begin a phase 1 clinical trial ever get approved.
The clinical trial protocol
A clinical trial protocol is like a master plan of a trial which determines who will participate, who will be excluded, procedures, dosages and study duration, key questions to be answered. The protocol is designed keeping participant safety in mind, and geared to answer specific research questions. Successive trial protocols are determined by results from previous trials. An example of this is an SPA, or a Special Protocol Assessment, which is a pre-determined results standard provided by the FDA to a trial sponsor in some circumstances. The SPA is often determined by previous trials, and makes it easier for the sponsor to conduct the phase 3 trial successfully. The study’s lead is called a principal investigator (PI).
A majority of US-based clinical trials are approved and monitored by an Institutional Review Board (IRB). The IRB is composed of sponsor-independent experts whose job, at every stage, is to determine whether the trial is safe and effective enough to be continued. The experts in an IRB could be physicians, statisticians, and members of the community. A trial that is being reviewed by an IRB is often considered a better-managed trial.
Phases of Trials
Phase I studies assess the safety of a drug, often in a small number of healthy volunteers (20 to 100) who are paid to participate in the study. The most important purpose of this trial is dose determination, which is done with a dose escalation study to determine precisely what dose of the drug is safe enough for human participants. Two other concepts are tied around the safety of drug dosage – pharmacokinetics and pharmacodynamics, defined respectively as what the drug does to the body and what the body does to the drug. Also called a drug’s pk/pd, the former tells us how the drug affects the body in terms of effects and side effects, and the latter tells us how the drug is absorbed, metabolised and excreted. About 70% of experimental drugs pass this phase of testing.
Phase II studies test the efficacy of a drug in a smaller group of patients numbering several hundreds. A properly conducted phase 2 trial should be randomized against bias, that is, it should have a drug arm and a control arm. The drug arm patients receive the drug being tested, while the control arm receives either a standard of care or SoC, or a placebo (an inactive product that resembles the test product, but without its treatment value). When available, using an SoC in a control arm is the preferred method not only because it is better comparison, but also because it is not ethical to give placebo to sick patients. Such a trial is called an Active Comparator study and clearly defines comparative efficacy and safety of two competing drugs. These studies are often blinded, meaning, at least one of the two groups, patients and researchers, do not know which arm received the experimental drug. If both groups are blinded, it is called a double blinded study. Blinding a study makes its results more independent of the “human factor” and is especially important in CNS and other psychological drugs. At the end of a trial, it is unblinded or unmasked to study patient responses against what drugs they were taking. About one-third of experimental drugs successfully complete both Phase I and Phase II studies.
Phase III studies involve doing a phase 2 trial in several hundred to several thousand patients. It must be randomized and blinded. This large-scale testing, which can last several years, provides the pharmaceutical company data to file an NDA, or New Drug Application, with the FDA. An NDA is approved or rejected in an FDA procedure called the PDUFA. If approved, a company can sell the drug in the market. 70% to 90% of drugs that enter Phase III studies successfully complete this phase of testing.
Phase IV studies, often called Post Marketing Surveillance Trials, are conducted after a drug has been approved for the market. The objective is to monitor the safety of the drug in thousands, sometimes millions of real-life users. Several other objectives could be there, including drug comparison studies between competing drugs, determine long-term effectiveness and cost-effectiveness. Sometimes, a phase 4 study may result in a drug being taken off the market altogether, or restrictions in use, called label restrictions or black box warnings, be put on the drug, depending on the assessed safety of the drug.
All clinical trials have participation guidelines or Inclusion/Exclusion Criteria. Factors that allow someone to participate in a clinical trial are “inclusion criteria.” Those that exclude or not allow participation are “exclusion criteria.” These criteria are based on factors such as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions.
A number of statistical concepts are used in assessing the outcome of clinical trials. Some of these are – null hypothesis, p-value, clinical significance and confidence interval. These concepts will be discussed in greater detail in future posts.