**14.2. Study design of phase I trials**

For clinical trials to have validity they must be based on a sound statistical basis. Some of the of the criteria that must be met include;

#### **Randomization**

**The reproductive performance**

**Carcinogenicity studies**

500 Drug Discovery

**Mutagenicity studies**

**Investigative toxicology**

basis of patient response to a drug.

who will conduct the clinical trials.

**14.1. Phase I clinical trials**

future research.

of safer drugs.

These are measurements intended to determine the effects of the drug agents on; mating behaviour, reproduction, parturition, progeny birth defects, and postnatal development.

These studies are required to determine the effects of prolonged usage of the drug under

These studies look at the genetic stability and mutations of bacterial or mammalian cells in culture. These studies are at the academic research level and are intended to provide data for

The main purpose of toxicology is to discover the pathways that are involved in toxic action. It includes studies on mechanisms of toxic action of drugs which may lead to the development

Toxicity testing is time consuming and expensive and may require two to five years to collect

The safety or efficacy of a drug must be thoroughly understood before the drug is ad‐ ministered to any group of individuals. Therefore regulations governing the develop‐ ment of new drugs have evolved to assure safety and efficacy of new medications. The clinical trials during drug development and post marketing experience form the scientific

Once a drug is judged ready to be studied in humans, a notice of clinical investigational exemption for a new drug (IND) must be filled with the government body concerned with the regulation and registration of drugs. The IND includes manufacturing information, all data from animal studies, clinical plans and protocols and the names and credentials of physicians

The main goal in phase I is to determine whether test animals and humans show signifi‐ cant different responses to the drug and to establish limits of the safe clinical dosage range. The measurements carried out in phase I include, the rate of absorption, t1/2 and

and analyze data before the drug can be considered ready for testing in humans.

Extrapolation of toxicity data from animals to humans may not be completely reliable.

investigation. They involve hematological and histological autopsy analysis.

**14. Evaluation of new drugs and drug approval process**

Large numbers of animals are needed to obtain valid preclinical data.

Randomization is a design which ensures that there is no bias in allocation of treatments among the different groups. The purpose of randomization is to minimize the possibility that an observed treatment effect is due to inherent differences between groups. Randomization eliminates bias by avoiding recruiting patients who have a particular characteristic to one group and not the other e.g. only women/men and smokers/alcoholics. Randomization should not be carried out until immediately before treatment. The delay allows a patient to have second thoughts about taking part or the investigator to have to re-consider about admitting patients to the study. Simple methods of randomization can be designed using published tables of random numbers, where treatments are in a form of a square in which each treatment is


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

trial. In case of control study the outcome is first identified and then comparisons are made retrospectively between the characteristics of patients who did or did not have the outcome. Such a study for instance has shown that oral anticoagulants can reduce incidences of reinfarction in patients who have already had a myocardial infarction. The case control studies may be carried out some time, after the introduction of a drug therapy in order to get some idea of its place in the overall management of the disease since the results of a case control

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*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

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

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

The drug is evaluated in a much larger number of patients (thousands) to further establish safety and efficacy. Phase III trials are performed in settings similar to those anticipated for the ultimate use of the drug. After successful phase III trials, the next step is the application for review of the new drug to seek approval to use the drug for clinical management of the

intended to determine whether a treatment is effective and to establish safety data.

study may prompt formal prospective trials in order to confirm original findings.

are useful because they reduce the time, size and cost of clinical trials.

**14.3. Molecular markers in drug development**

**14.4. Phase II clinical trials**

this phase.

disease condition.

**14.5. Phase III clinical trials**

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

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 pharmacist or trial co-ordinator.
