Informatics Question of the Week: Clinical Research

Hey guys, welcome to this week’s clinical informatics question of the week. This week’s topic – clinical research.

Clinical research is scientific research involving humans with the goal to determine the safety and effectiveness of pharmaceuticals, medical devices, treatments, and diagnostic products intended for human use. Data and evidence found from clinical research trials and experiments is used to establish treatment for various diseases and disorders.

Clinical trials in clinical research are divided into three phases: preclinical, phase 0, phases I-V. Each phase increases the number of human subjects as well as varies the level of doses.

• Preclinical research includes in vitro (performed with cells or biological molecules studied outside their normal biological context) and in vivo (clinical studies on animals, but not humans) studies, in the process of which various dosages are studied in order to get preliminary data about the studied drug’s pharmaceutical properties, toxicity, pharmacokinetics and the metabolism.

Preclinical research allows pharmaceutical companies to figure out whether the drug should be further studied or not. Studies involving humans can be started only when the data obtained as a result of preclinical studies show that the drug may be effective and is safe enough to be taken by humans.

• Phase 0. This phase studies the pharmacodynamics as well as pharmacokinetics of the studied drug. The dosage of the drug cannot exceed half of the therapeutic dosage. The most common study size during this phase is around ten participants.  This phase has the status of high responsibility – first-in-human trials.

Due to its low dosage,  Phase 0 does not offer any valuable data about the drug’s safety or effectiveness, as low dosages do not present any therapeutic effect. Therefore, this phase only provides go/no-go decisions for the following stage.

• Phase I. Phase I studies usually involve from 20 to 100 healthy volunteers. It sometimes happens that the high toxicity of the drug (for example, drugs to treat oncological diseases and HIV/AIDS) makes it unethical to test such a drug on healthy volunteers, in which case those with the studied disease will make up the study’s participants.

During the Phase I such criteria as the drug’s absorption, breakdown, metabolism, excretion as well as the preferable form of application and the safe level of dosage are studied. The purpose of the Phase I is to find out whether the drug is safe enough for the further studies of its efficiency.

• Phase II. Having studied the pharmacodynamics and pharmacokinetics as well as the safety of the tested drug during the Phase I, the company starts the Phase II studies involving a larger amount of subjects (from 100 to 500 humans).

The essence of this phase is to determine the level of dosages as well as the dosage regimen for the Phase III. The dosage of the drug taken by Phase II subjects is usually lower than the highest dosages given to subjects during the Phase I.

• Phase III is randomized controlled multi-central studies involving larger amount of subjects (from 300 to over 3,000 depending on the disease). Phase III studies are planned in such a way to confirm the safety and effectiveness of the drug that were determined during the Phase II. The Phase III studies: the effect’s dependence on the dosage of the drug, the drug’s effectiveness for diseases of various severity as well as the drug’s ability to be combined with other drugs.
• Phase IV includes studies of the drug after it has been registered with the data confirmed so far. Phase IV studies are studies that were not required to register the drug, but are required to optimize its further use.
• Phase V. This phase analyses the collected data and integrates the data into medical practice.

Question

What is the main difference between Phase 0 and Phase I?

1. The amount of money paid to subjects;
2. The effectiveness of the studied drug;
3. Phase 0 dosage is two times lower than Phase I dosage;
4. Phase 0 and Phase I differ only in the amount of subjects involved.

Answer and explanation

The correct answer is c) Phase 0 dosage is two times lower than Phase I dosage.

Phase 0 is an introductory study, during which the dosage is lowered by two times compared to its therapeutic dosage in order to avoid any potential side effects.

References and Recommended Reading

Designing Clinical Research.

By Stephen B. Hulley, Steven R. Cummings, Warren S. Browner, Deborah G. Grady, Thomas B. Newman

What Makes Clinical Research Ethical?

By Ezekiel J. Emanuel, MD, PhD; David Wendler, PhD; Christine Grady, PhD