What is a Clinical Trial?
Clinical trials are research programs involving people who volunteer to test a new ‘treatment’. Clinical trials aim to find out whether medical, surgical or behavioral interventions work, and if they are safe and effective in management or prevention of disease.
The word intervention is a common term used for new or improved treatments, management programs, new detection or prevention methods.
To determine if the intervention treatment is effective, clinical trials compare two or more groups that receive different treatments.
The ICH document “General Considerations for Clinical Trials” is intended to:
a) describe internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal products.
b) facilitate the evaluation and acceptance of foreign clinical trial data by promoting a common understanding of general principles, general approaches and the definition of relevant terms.
c) present an overview of the ICH clinical safety and efficacy documents and
facilitate the user’s access to guidance pertinent to clinical trials within these
documents. The relevant ICH documents are listed in Annex 1.
d) provide a separate glossary of terms used in the ICH clinical safety and efficacy
related documents that pertain to clinical trials and indicate which documents
For the sake of brevity, the term “drug” has been used in this document. It should be
considered synonymous with “investigational (medicinal) product”, “medicinal
product” and “pharmaceutical” including vaccines and other biological products. The
principles established in this guideline may also be applied to other clinical
investigations (e.g. radiotherapy, psychotherapy, surgery, medical devices and
|Type of Study||The objective of the Study||Study Examples|
|Human Pharmacology||• Assess tolerance
• Define/describe PKand PD
• Explore drug metabolism and drug interactions
• Estimate activity
|• Dose-tolerance studies
• Single and multiple dose PK and/or PD studies
• Drug interaction studies
|• Explore use for the targeted indication
• Estimate dosage for subsequent studies
• Provide a basis for confirmatory study design, endpoints, methodologies
|• Earliest trials of relatively short duration in well- defined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures
• Dose-response exploration studies
• Establish safety profile
• Provide an adequate basis for assessing the benefit/risk relationship to support licensing
• Establish a dose-response relationship
|• Adequate, and well-controlled studies to establish the efficacy
• Randomized parallel dose-response studies
• Clinical safety studies
• Studies of mortality/ morbidity outcomes
• Large simple trials
• Comparative studies
|Therapeutic Use||• Refine understanding of benefit/risk relationship in general or special populations and/or environments
• Identify less common adverse reactions
• Refine dosing recommendation
|• Comparative effectiveness studies
• Studies of mortality/morbidity outcomes
• Studies of additional endpoints
• Large simple trials
• Pharmacoeconomic studies
Phase I (Most typical kind of study: Human Pharmacology)
Phase I starts with the initial administration of an investigational new drug into humans.
Although human pharmacology studies are typically identified with Phase I, they may also be indicated at other points in the development sequence. Studies in this phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteer subjects or certain types of patients, e.g. patients with mild hypertension. Drugs with significant potential toxicity, e.g. cytotoxic drugs, are usually studied in patients. Studies in this phase can be open, baseline controlled or may use randomization and blinding, to improve the validity of observations.
Studies conducted in Phase I typically involve one or a combination of the following aspects:
a) Estimation of Initial Safety and Tolerability
The initial and subsequent administration of an investigational new drug into humans is usually intended to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies typically include both single and multiple dose administration.
Characterization of a drug’s absorption, distribution, metabolism, and excretion continues throughout the development plan. Their preliminary characterization is an important goal of Phase I. Pharmacokinetics may be assessed via separate studies or as a part of efficacy, safety and tolerance studies. Pharmacokinetic studies are particularly important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites and potential drug-drug interactions. Some pharmacokinetic studies are commonly conducted in later phases to answer more specialised questions. For many orally administered drugs, especially modified release products, the study of food effects on bioavailability is important. Obtaining pharmacokinetic information in sub-populations such as patients with impaired elimination (renal or hepatic failure), the elderly, children, women and ethnic subgroups should be considered. Drug-drug interaction studies are important for many drugs; these are generally performed in phases beyond Phase I but studies in animals and in vitro studies of metabolism and potential interactions may lead to doing such studies earlier.
c) Assessment of Pharmacodynamics
Depending on the drug and the endpoint studied, pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted in healthy volunteer subjects or in patients with the target disease. In patients, if there is an appropriate measure, pharmacodynamic data can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimen in later studies.
d) Early Measurement of Drug Activity
Preliminary studies of the activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later phases but may be appropriate when the drug activity is readily measurable with a short duration of drug exposure in patients at this early stage.
Phase II (Most typical kind of study: Therapeutic Exploratory)
Phase II is usually considered to start with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients.
Initial therapeutic exploratory studies may use a variety of study designs, including concurrent controls and comparisons with baseline status. Subsequent trials are usually randomized and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication. Studies in Phase II are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population and are closely monitored.
An important goal for this phase is to determine the dose(s) and regimen for Phase III trials. Early studies in this phase often utilize dose escalation designs (see ICH E4) to give an early estimate of dose-response and later studies may confirm the dose-response relationship for the indication in question by using recognized parallel dose-response designs (could also be deferred to phase III). Confirmatory dose response studies may be conducted in Phase II or left for Phase III. Doses used in Phase II are usually but not always less than the highest doses used in Phase I.
Additional objectives of clinical trials conducted in Phase II may include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further study in Phase II or III. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials.
Phase III (Most typical kind of study: Therapeutic Confirmatory)
Phase III usually is considered, to begin with, the initiation of studies in which the primary objective is to demonstrate or confirm therapeutic benefit.
Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies are intended to provide an adequate basis for marketing approval. Studies in Phase III may also further explore the dose-response relationship, or explore the drug’s use in wider populations, in different stages of the disease, or in combination with another drug. For drugs intended to be administered for long periods, trials involving extended exposure to the drug are ordinarily conducted in Phase III, although they may be started in Phase II (see ICH E1). ICH E1 and ICH E7 describe the overall clinical safety database considerations for chronically administered drugs and drugs used in the elderly. These studies carried out in Phase III complete the information needed to support adequate instructions for use of the drug (official product information).
Phase IV (Variety of Studies: – Therapeutic Use)
Phase IV begins after drug approval. Therapeutic use studies go beyond the prior demonstration of the drug’s safety, efficacy and dose definition.
Studies in Phase IV are all studies (other than routine surveillance) performed after drug approval and related to the approved indication. They are studies that were not considered necessary for approval but are often important for optimizing the drug’s use. They may be of any type but should have valid scientific objectives. Commonly conducted studies include additional drug-drug interaction, dose-response or safety studies and studies designed to support use under the approved indication, e.g. mortality/morbidity studies, epidemiological studies.
Development of an application unrelated to the originally approved use
After initial approval, drug development may continue with studies of new or modified indications, new dosage regimens, new routes of administration or additional patient populations. If a new dose, formulation or combination is studied, additional human pharmacology studies may be indicated, necessitating a new development plan.
The need for some studies may be obviated by the availability of data from the original development plan or from therapeutic use.