BRIEF REVIEW ON CLINICAL TRIALS

 

Phase II(Therapeutic exploratory trials):

The process of testing an investigational drug on a small number of subjects to show it is generally safe and effective in treating or preventing a specific condition or illness.

Scope: A limited number of studies that help establish the drug’s safety and effectiveness and identify its side effects.

· Subjects: Patients who have the condition or illness to be treated.

· Number of volunteers: Several hundred

· Duration: Several months to 2 years

· Goal: To establish how doctors should use the drug to treat patients with the specified condition or illness.

 Prerequisites for Phase II: Preclinical prerequisites for Phase II are similar for Phase I, but with an emphasis placed on understanding preclinical models for efficacy. It is not possible to formulate a checklist for preclinical work required to support Phase II. Drugs that are new but have a known mechanism of action that has been validated in humans may require only minimal preclinical work.  Drugs exploiting a known mechanism of action but with a new point of attack require more extensive pharmacological testing. New drugs with novel mechanisms of action will require extensive pre­clinical investigation. With truly innovative drugs based on new approaches, the validation of the preclinical model for efficacy will only come after the pivotal clinical studies. Therefore, it is vital that preclinical models provide pharmacody­namic measures that can also be applied in Phase II studies as markers of thera­peutic efficacy.

Study Design:
Phase II studies are often conducted under optimal experimental conditions, using a relatively homogeneous group of uncomplicated patients (no concomitant illness, medication, or organ dysfunction) and doses close to MTD. These studies are closely monitored and tend to be short term. The number of subjects is relatively small, usually involving only one or two hospitals. Phase IIb studies are larger, involving more centers and a more diverse patient population. Phase II studies are typically double blind and, when possible, are "controlled," i.e., involve comparisons to a placebo and/or standard therapy. Elements of study design are similar to phase I, but specifics will depend on the preclinical data and the pharmacokinetic, pharmacodynamic, and safety data obtained in Phase I, as well as the nature of the disease under investigation. If efficacy parameters are quantitative and objective, then one approach is to use a crossover design with the control agent(s) as treatment alternatives, if the disease has large natural interpatient variability (e.g., arthritis) or subjective efficacy parameters (e.g., schizophrenia), then parallel designs with separate patient groups on active, placebo, or comparator drugs are common.                                                                                                                                                       

Phase III (Therapeutic confirmatory trials):
The process of testing an investigational drug on a larger population of subjects to show that it is safe and effective in treating or preventing a specific condition or illness.

  • Scope:A large number of studies designed to establish a drug’s safety and effectiveness and to identify its side effects.
  • Subjects: Patients who have the condition or illness to be treated, who may have other illnesses, and who may be taking medications in addition to the investigational drug.
  • Number of volunteers: Several thousand.

· Duration: Several months to several years.

· Goal: To establish how doctors should use the drug to treat patients with the specified condition or illness.

 Population Pharmacokinetics:
To characterize the pharmacokinetics and pharmacodynamic variability of a drug adequately, it needs to be studies in a representative population using relatively large numbers of patients. Considering all the volunteers participating in clinical studies, patients in phase III studies are most representative of the populationintended for treatment. Additionally, the patient population in Phase III is generally larger and more heterogeneous than that encountered in Phase I and II, so it becomes possible to examine the effects of various patient characteristics (e.g. age, body size, renal function, concomitant medications). Therefore, the Phase III patient population is an ideal target for pharmacokinetic and pharmacodynamic scrutiny. However, there are many practical reasons intensive plasma sampling, like that employed to char­acterise pharmacokinetics in Phase I, is not possible in Phase III studies. Sparse sampling, i.e., one to six plasma samples per patient obtained over the entire course of the study, is usually possible. Through the techniques of population pharmaco­kinetics, particularly nonlinear mixed effects modeling, these data can be used to characterise pharmacokinetics, quantify variability, and examine its sources.

 Phase IV (Post marketing trials):
It is the process of testing an approved drug in order to determine additional information.

  • Scope: Multiple studies to determine how a drug compares with other drugs, to ascertain its safety in large number of patients and to identify its effects in patients with conditions that were excluded from phase III trials.
  • Subjects: Patients who have the condition or illness to be treated, who may have other illnesses, and who may be taking medications in addition to the study drug.
  • Number of volunteers: Several thousand.
  • Duration: Several months to several years.
  • Goal: To determine if the drug’s use can be broadened to include more patients and/or whether additional safety issues need to be addressed.

Phase II and Phase III both assess the safety and effectiveness of the investigational drug and often involve controlled studies in which the study drug is compared to a placebo (sugar pill) or to an existing drug. This comparison helps minimize bias in interpreting the study results. However, this does not mean that those in the placebo group never receive the investigational medication.

Phase III clinical trials are the most significant because they involve a large number of people who receive treatment for an extended period of time. The outcome of phase III trials provides the basis for FDA approval and establishes exactly how the drug is to be used.

Figure No.1 Schematic representation of new drug development, from drug discovery though clinical studies, NDA and post marketing activities.

Randomized trials2,7:
In a randomized trial, half the patients are chosen at random to get the treatment being tested. They are called the treatment group (or investigational group). In some studies, you will not know which group you are in. These are called blinded studies. 

· Single-blindstudy:-In this study, patients do not know whether they are in the treatment group or the control group.

· Double-blindstudy:-In this study, neither the patients nor their doctors know which group they are in.

   The purpose of blinded studies is to make sure the results are not biased by anyone's hopes for a certain treatment. Whichever group you are in, you will get the best care possible.

Clinical trials are designed to answer a specific question about a treatment, usuallythe safety and efficacy (how well it works under optimal conditions) of the treatment. Volunteers who meet specific criteria, including having the condition being studied, receive an explanation and, if they choose, join the trial. This informed consentprocess should include explaining the random treatment assignment as well as the risks and possible benefits of the trial and often includes a written form to document those issues and the volunteer’s consent. In a double-blind trial, neither the clinicians caring for the patients nor the participating volunteers know who has been assigned to the active treatment until the trial is concluded (unless a medical problem requires that the information be released before that). In a single-blindtrial, the investigators know the treatment assignments but the participants do not. Blinding procedures protect against the influence of bias(prejudice) for or against the treatment being studied.


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