**14.3. Molecular markers in drug development**

*In vitro* predictive efficacy and toxico-genomics should be carried out after phase 1 clinical trials in order to validate the results of the phase 1 clinical trials. This is achieved by using animal cell lines in which gene expression profiling and patterns of protein production are used to identity candidate biomarkers for the disease. The utilization of markers that are associated with the disease or those that indicate a known response to a therapeutic interven‐ tion or reflect a clinical outcome may yield information on efficacy or toxicity of a test drug. An example of a biological readout that has traditionally been used to determine efficacy during the treatment of diabetics is the determination of glucose in the urine of a diabetic patient. Reliable and specific biomarkers that act as predictors of efficacy or long-term toxicity are useful because they reduce the time, size and cost of clinical trials.

#### **14.4. Phase II clinical trials**

contained only once in each row and column and the order of treatment is different in each group (Table 3).The presence of other diseases or risk factors should be taken into consideration

> **Group Treatment** 1 A B C D 2 C D A B 3 D C B A 4 B A D C

**Table 3.** A random number table array for assignment of various treatment regimes to various groups of patients in

This approach eliminates systematic variation between groups since the patients are allocated at random order to group 1, 2, 3, or 4. A code list should be drawn up so that the main investigators may be kept blind to the treatment an individual is receiving but also so that it is possible to know the treatment by breaking the code. Coding should be such that when broken, it does not yield information about the treatments other patients are getting. The treatment information about all the patients should be left to one person preferably the

Blinding is a design which does not allow the investigator to know what treatment the patient is receiving. The purpose of blinding is to eliminate bias in reporting the outcome of the treatment since if an investigator knows what treatment the patient is taking, he/she may in some way influence a measurement or an outcome thus shifting the outcome in one direction or another consciously or unconsciously. The ideal trial should be double blind where neither the investigator nor the patient knows what treatment the patient is taking. Placebos or dummies are used in order to achieve blindness. The placebos should match the active treatment as closely as possible in terms of size, shape, color, texture, weight, taste and smell

Clinical trial should be carried out in a defined centre so as to minimize variations in the popula‐ tion and in the investigators techniques. This also avoids problems of data collection, communi‐ cation and follows up. Multi-centre trials may become necessary when studying a rare disease hence scarcity of patients or when the effect being investigated is small one e.g. when one is

Clinical trials designed to evaluate efficacy of new drugs should always be prospective i.e. the characteristics of the population to be studied should be identified before the study begins. For example, if one randomized all patients with heart failure to treatment with either digoxin or a new drug X and then studied the outcome over six months that would be a prospective

looking out for an interaction effect between a major condition and a minor condition.

clinical trials

502 Drug Discovery

**Blindness**

pharmacist or trial co-ordinator.

with the active formulation. **Number of testing centers**

i.e. need for careful selection and assignment of patients to each of the study groups.

These are studies that recruit willing and informed patients and are designed to assess long term safety, refine pharmacokinetic data, determine optimal dose. The purpose of phase II studies is to determine efficacy. Typically, phase II trials require 100-150 subjects and take 9-12 months. An assessment of no effect or no worthwhile effect of a given drug demonstrates that it is futile to proceed with further clinical testing of the drug. It is therefore important to minimize type I errors or false negatives in the study design in order to minimize the risk of discontinuing a potentially effective drug. The data from well designed phase I and phase II trials are therefore critical in planning the subsequent trials. The phase III trials are large trials intended to determine whether a treatment is effective and to establish safety data.

Phase II clinical trials include inert placebos as negative controls and older active drugs as positive controls alongside the investigative compound. These studies are done in special clinical centers such as University Hospitals. A broader range of toxicities may be detected at this phase.
