Clinical Trial Design6:

The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design should include:

i. A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.

ii. A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.

iii. A description of the measures taken to minimize/avoid bias, including:

a. Randomization.

b. Blinding.

iv. A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labeling of the investigational product(s).

v. The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.

vi. A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.

vii. Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.

viii. Maintenance of trial treatment randomization codes and procedures for breaking codes.

Types of clinical trials[5,6:

Clinical trials are used to study many aspects of health care:-

a.      Prevention Trials:-It looks for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may be including medicines, vitamins, vaccines, minerals, or lifestyle changes.

b.      Screening Trials:-To test the best way to detect certain diseases or health conditions.

c.       Diagnostic Trials:-Conduct to find better tests or procedures for diagnosing a particular disease or condition.

d.      Treatment Trials:-To test experimental treatments, new combinations of drugs or new approaches to surgery or radiation therapy.

e.       Quality of Trials:-It is to explore ways to improve comfort and quality of life for individuals with a chronic illness.

Phases of clinical trials5,6,9,10:

Clinical trials involving new drugs are commonly classified into four phases. The development process will normally proceed through all four phases over many years. If the drug successfully passes through phases I, II and III, it will usually approve.

Pre-clinical study:

Preclinical studies involve in vitro (test tube) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug.
After a treatment is tested in the laboratory, it can go to human testing. There are four phases of human testing:

 Phase I: - (Human pharmacology)

It is the process of testing an investigational drug on a smaller number of subjects to establish that it is safe for use in humans.

  • Scope: A series of small tests to determine how healthy people (those without the condition or illness the drug will treat) react to and are affected by the treatment.

*  Subjects: Healthy volunteers who are not taking other medicines.

*  Number of volunteers: Less than 100.

*  Duration: Several months.

There are different kinds of phase I trials:-

Single Ascending Dose(SAD)

Single Ascending Dose studies are those in which small group of 3-6 patients receives

A small dose of the drug and observed for a specific period. If no adversed effects are observed, a new group of a patient is then given a higher dose,this is continued unit MTD (Maximum Tolerate Dose) is shown.

Multiple Ascending Dose(MAD)

MAD studies, in this a group of patients receives a low dose of drug than dose is subsequently escalated and sample is collected at various times.It is conducted for better understanding of the pharmacokinetic and pharmacodynamic of the drug.

The clinical pharmacokineticist on a drug development team does not simply analyse data at the end of the study. Typically, he or she is intimately involved in the design of the study, either making or contributing to the decision regarding the first dose to be given to humans, the dose escalation scheme, and potentially the decision to escalate doses. Often the pharmacokineticist will have to justify the sensitivity limits for the bioanalytical methods proposed for measuring drug concentrations in human plasma. To facilitate this, a thorough understanding of preclinical models for activity (including target drug concentrations), ADME data, pharmacokinetics and toxico­kinetics are required. This data can be characterized in the following ways:-

i] Useful Preclinical Pharmacology Data:

•      Does the proposed pharmacological mechanism suggest that there should be a direct correlation between drug concentration and phar­macological effect, or is the effect more likely to be indirect?

•    What is the IC50/EC50 needed to produce the desired effect?

•    What is the IC5o (/EC50 that produces a toxic effect?

•    Is there an in vitro/ex vivo correlation to the therapeutic or pharmaco­logical effect?

•    Is there a surrogate marker for the therapeutic effect and is it validated?

ii] Useful Pre-clinical Pharmacokinetics Data:-

•        Pharmacokinetics parameters from several species, especially species used for toxicology studies.

•         Probable site of absorption, and evidence of suitable absorption.

•         Routes of elimination, evidence of first-pass metabolism, nonlinear pharmacokinetics, and enzyme induction or inhibition.

•         Active/toxic metabolites, metabolic paths.

•         Probable isoenzymes involved in metabolizing from in vitro P-450 profiling, and uniqueness of metabolizing enzymes between two species.

•         Protein binding and evidence of saturable binding.

iii] Useful Preclinical Toxicology and Toxicokinetic Data:

•    Maximally tolerated dose and resulting plasma concentration in two species (rodent and nonrodent).

•    Dose and plasma concentrations that produced the first untoward effect.

•    Mechanism of toxic effect.

•    Toxicity profile and organs involved.

iv] Pharmacokinetic Evaluation:

Pharmacokinetic evaluation typically includes noncompartmenal analysis to characterise pharmacokinetics in term of AUG or clearance, Cmax, Tmax, Vd , and half-life .The high doses used in dose tolerance studies provide an unique opportunity to study linearity at concentrations   that might only occur through overdosing in the clinical setting. Because of the relatively small number of subjects per dose level and because most designs involve separate groups of subjects receiving each dose, intersubject variability may mask some deviations from linearity.

v] Pharmacodynamic Evaluation, Pharmacokinetic/Pharmacodynamic modeling:

             If the desired pharmacological effects are objective, quantitative, and the same as the therapeutic intent (e.g., increasing gastric pH to treat heartburn), then incorporating pharmacodynamic evaluations into Phase I studies can be extremely useful. If thera­peutic effects are indirect or subjective (e.g., treatment of schizophrenia), there might not be a pharmacodynamic marker for the desired therapeutic effect, or it may only be meaningful or measurable in patients with the disease of interest. The challenge of Phase I pharmacodynamic is to carefully select the drug effect that best represents the desired therapeutic response, and to develop methods to measure it reproducibly with minimum variance. If this can be done, Phase I studies offer excellent opportunities for pharmacokinetic/pharmacodynamic modeling. This modeling can be used to con­firm or validate preclinical pharmacokinetic/pharmacodynamic models over a wide range of doses. Areas of uncertainty in the preclinical model can be explored, and confirmation of whether the dose or concentration-effect relationship is direct or indirect may be established. As with pharmacokinetics, variability in pharmacodynamic should be assessed. Once validated in Phase I, the pharmacokinetic/pharmacodynamic model can be useful in extrapolating beyond existing data to maximize the chance that effective and safe dosage regimens can be introduced as early as possible in Phase II studies.