Clinical trial

Stages in new drug development Stages

Durations

1) Synthesis / isolation of the compound

1-2 years

2) Preclinical studies: screening, evaluation, pharmacokinetic, and shortterm toxicity testing in animals.

2-4 years

3) Scrutiny and grant of permission for clinical trials

3 – 6 months

4) Pharmaceutical formulation, standardization of chemical / biological / immunoassay of the compound

0.5 – 1 year

5) Clinical studies, long-term animal toxicity testing.

3 – 10 years

6) Review and grant of marketing permission

0.5 – 2 years

7) Postmarketing surveillance

PRECLINICAL STUDIES After synthesizing / identifying a prospective compound, it is tested in animals to expose the whole pharmacological profile. Experiments are generally performed on a rodent (mouse, rat, guinea pig, hamster, rabbit) and then on larger animal (cat, dog, monkey). As the evaluation progresses, unfavourable compounds get rejected at each step. Types of test performed: Types of tests

Description

1) Screening test

Simple and rapidly performed tests to indicate presence or absence of a particular pharmacodynamic activity that is sought for.

2) Tests on isolated organs, bacterial cultures, etc

Preliminary tests to detect specific activity, such as vasodilator, antibacterial, antisecretory, antihistaminic

3) Tests on animal models of human disease

Such as genetically hypertensive rats, seizures in rats, experimental tuberculosis in mouse, induced diabetes in dog

4) General observational test

Before/after detecting useful activity in screening test, the drug is injected in tripling doses to small groups of mice which are observed for overt effects.

5) Confirmatory test and analogous activities

Compounds found active are taken up for detailed study by more elaborate tests which confirm and characterize the activity or other activity. Eg: antipyretic and anti-inflammatory activity of analgesic.

6) Mechanism of action

To find out the mechanism of action. Eg: whether the hypertensive drug is an α blocker/β blocker/ Calcium channel blocker/ ACEI etc

7) Systemic pharmacology

Study on the effects to the major organ systems eg CNS, cardiovascular, respiratory, renal, GIT, etc

8) Quantitative tests

The dose – response relationship, maximal effect and comparative efficacy with existing drugs is ascertained.

9) Pharmacokinetics

The absorption, tissue distribution, metabolism, excretion, volume of distribution, and half – life of the drug are quantified. To determine safety of the compound in at least 2 animal species – mostly rat/mouse and dog by oral and parental routes.

10) Toxicity tests

Toxicity tests Types of test

Description

Methods

1) Acute toxicity

The aim is to find out the acute lethal to 50% (LD50).

The study is done at least on two animal species and the drug is given in graded doses to several groups of animals by at least two routes, one of which should be proposed route to be used in human beings. Animals that are observed for overt effects and mortality for 1 – 3 days. The dose which kills 50% is calculated. Organ toxicity is examined by histopathology on all animals.

2) Subacute toxicity

The aim is to identify the target organ susceptible to drug toxicity.

Three doses are used on two animal species. The animals are maintained at maximum tolerated doses for a minimum period of four weeks to a maximum of three months as to allow for the development of pathological changes. Thereafter, the biochemical and haematological changes are evaluated. Finally, the animals are killed and subjected to histopathological examination. Animals are examined for overt effects, food intake, body weight, haematology, and organ toxicity.

3) Chronic toxicity

Important especially if the drug is intended for chronic use in human beings. Usually two animal species (one rodent and one non – rodent) are used. The duration of study may range from one to two years, the biochemical, haematological, and histopathological examination are undertaken.

The drug is given for 6 – 12 month. Study is done and animals are examined for overt effects, food intake, body weight, haematology, and organ toxicity.

4) Special long – term toxicity

Performed for only drugs which cross phase I clinical trials.

5) Reproduction

Studies are carried out on rats treated with the test drug before and after mating period. Effects of drugs on mating behaviour, fertility, parturition and lactation are noticed, including perinatal and postnatal effects if any.

Effects on spermatogenesis, ovulation, fertility, and developing foetus are studied.

6) Teratogenicity

Studies are carried out in two animal species to assess the effect of drugs on organogenesis.

The drug is given, after the mating, during the period of organogenesis. Foetus is then examined for any skeletal or visceral abnormality.

7) Mutagenicity

Ability of drug to induce genetic damage is assessed in bacteria (Ames test), mammalian cell cultures and in intact rodents.

8) Carcinogenicity

Drug is given for long term, even the whole life of the animal, and they are watched for development of tumours.

Clinical trials Under the ‘Good Clinical Practice’ (GCP), after been issued ‘investigational new drug (IND) licence, clinical trials in done under 4 phases. Phases

No of Subjects

Objectives

Conducted by

Methods

Phase I

20 – 50 normal volunteers

1. To determine whether humans and animals show significant pharmacokinetic differences. 2. To determine a safe and tolerated dose in human. 3. To determine the pharmacokinetics of the drug in humans so as to decide whether the deficiency in drug effects, if any, is a result of its lack of absorption or its faster elimination. 4. To detect any predictable toxicity.

Clinical pharmacologist

Done in a setting where all vital functions are monitored and emergency/ resuscitative facilities are available. Subjects are exposed to the drug one by one, starting with the lowest estimated dose and increasing stepwise to achieve effective dose. The trials are non – blind or open label, that means both investigator and subjects know what is given.

Phase II

100 – 300 patients suffering from the related diseases.

If phase I is successful, the phase II is done to establish efficacy, appropriate dose and detailed pharmacology of the chemical and to detect any adverse effects.

Clinical pharmacologists and clinical investigators.

In the early phase, a small number of patients (20 – 200) are studied in detail to observe the potential therapeutic benefits and side effects and dose range for more definitive therapeutic trials to be undertaken in the late phase. It is usually a single blind design where only the subject does not know whether he is taking an inert placebo or a positive control drug or the new drug.

*Clinical investigator – physicians who are trained as clinical investigators

The late phase, trials are conducted on a larger number of patients ( 50 – 300) in a controlled double blind manner, where both the investigator and subject are ignorant whether he is prescribing a placebo, or a positive control medicine or the new drug under trial. Carried out at 2 – 4 centres.

Phase III

250 – > 1000 selected patients.

If the phase II establishes that the drug is useful and generally safe, Phase III is done to establish the benefits of the drug in the target disease, to identify the latent side effects, susceptibility to tolerance and to design ideal dosage regimen for different groups of patients.

Clinical investigators

*Clinical investigator – physicians who are trained as clinical investigators.

Randomized double blind comparative trials conducted at many centres. Safety, tolerability and possible drug interactions are assessed on wider scale, while additional pharmacokinetic data is obtained. Double blind cross over are designed to minimise errors in the information gathered in phase I and II. Patient groups I II III

Medication given Week 1 Week 2 Week 3 Standard drug Placebo New drug Placebo New drug Standard drug New drug Standard drug Placebo

Indications are finalized and guidelines are formulated. A ‘new drug application’ (NDA) is submitted to the licencing authority, who will give the marketing permission and enter the market with ‘ New Drug Status’. Phase IV

2000 – 10, 000 patients.

Post-marketing surveillance. If Phase Medical III studies are satisfactory, the new practitioners. drug is marketed. Phase IV is done for systematic detection and evaluation of long – term safety and efficacy of the drug, rare side effects, and to identify other possible therapeutic uses, drug interaction and adverse effect.

After the drug has been marketed for general use, practising physicians are identified through whom data are collected on structured proforma about efficacy, acceptability and adverse effects of the drug. Patients treated in the normal course form the study population. Further therapeutic trials involving special group – children, elderly, pregnant/lactating women, patients with renal/hepatic disease, etc, may be undertaken at this stage. During the ‘New Drug Status’ period, the manufacturer is expected to report any new information about the drug concerning ite safety. The drug may remain in “New Drug Status’ for several years until the drug control authorities are confident for its release to unrestricted marketing.