DRUG DISCOVERY AND CLINICAL EVALUATION OF NEW DRUGS

This presentation explains the stages of drug discovery and the clinical evaluation process.
It covers target identification, lead optimization, preclinical studies and the four phases of clinical trials, following BPharm syllabus.

1. Ms. FATHIMATH RAIHANA ASSISTANT PROFESSOR P A COLLEGE OF PHARMACY

2. A new drug may be identified by : Chemical modification of known drug. Random screenin g of natural or synthetic chemicals to detect the activity. Rational drug designing based on the chemical structure. After identification, Structure and purity determined by analyst. Screened for the presence of biological activities. Then subjected to preclinical evaluation.

3. Stages in new drug development : Synthesis or isolation of a compound Preclinical studies Scrutiny and grant of permission for clinical trials Pharmaceutical formulation, standardization of compound Clinical studies Review and grant of permission Post-marketing survelliance

4. Drug discovery : It is the process by which new drugs are identified, developed and brought into the market. Steps involved in drug discovery :

5. They can be from : i . Natural sources: Eg : Belladonna , Cinchona, Ephedra.. ii. Random or targeted chemical synthesis. Eg : Barbiturates, chlorpromazine…..

6. Rational approach : This depends of physiological, biochemical, pathological knowledge and identification of specific targets for drug action. Eg : Levodopa tried in parkinsonism as it is due to dopamine deficiency. ii. Molecular modelling : This involves protein chemistry and computer aided elucidation of three dimensional structure of key receptors,enzymes …. Eg : Designing of selective COX-2 inhibitors, by knowledge of COX-2 structure so that it fit only COX-2 active site.

7. iii. Combinatorial chemistry : It is a method in which chemical groups are combined in a random manner. Computerized analysis is required to identify those ‘hits’. iv. Biotechnology : Drugs are also produced from recombinant DNA technology. Eg : Human growth hormone, Insulin, interferons….

8. Preclinical toxicity testing is the process of checking if a potential of a drug is safe before it is tested in humans. Preclinical studies are done in animals and lab systems. Before undertaking the clinical trials, sufficient data about the drug must be obtained by testing it in animals. Selection of animals depend on the disease for which the drug is intended because we should be able to produce the disease in them. Animal studies generate pharmacodynamic , pharmacokinetic and toxicological data of the drug. PRECLINICAL EVALUATION :

9. 1. Screening tests 8 . Toxicity tests Preclinical studies:

10. Screening tests : These are done to indicate the presence or absence of a particular pharmacodynamics property. Eg : Analgesic activity 2. Tests on isolated organs, bacterial cultures : These are preliminary tests to detect specific gravity such as antihistaminic, vasodilator, antibacterial activity….

11. 3. Tests on animal models of human disease : Seizures in rat Experimental tuberculosis in mouse 4. Confirmatory tests and analogous activities : Compounds found active are taken up for detailed study. Eg : antipyretic and anti-inflammatory property in analgesics.

12. 5. Systemic pharmacology : Other than primary effects of drug are studied. The mechanism of action, side effects, drug interactins …… 6. Quantitative tests : Dose-response relationship, maximal effect… 7. Pharmacokinetics : Absorption, distribution, metabolism, excretion, volume of distribution….. are studies. 8. Toxicity tests

13. 8. Toxicity studies : Acute toxicity studies : It is a single dose test but now graded doses are also used. Objectives : To study the gross effects on behaviour. To study the lethal and toxic dose. Species : One rodent and one non-rodent is used .

14. Sex : Non-pregnant female animals are generally preferred. Route : The route intended for use in humans and other is preferred. Aministration : Single bolus. Observations : O bserved for 14 days and then sacrificed to see the pathological and histopathological changes. Dose : 5/50/300 and 2000mg/kg doses are used.

15. ii. Sub-acute toxicity studies : Objectives : To study the toxicity of target organ. To establish the maximum therapeutic dose. Species : One rodent and one non-rodent. Doses : Graded dose atleast 3. Duration : 14/18/90 or 180 days. Observations : O bserved for G ross changes and tests for organ function and microscopic changes. Liver kidney function tests Lipid profile Electrolyte levels

16. iii. Chronic toxicity studies : Animal : 2 species – one rodent and one non-rodent. Dose : daily for 6 months to 2 years. Three dose levels are used. Low dose – twice the expected therapeutic dose. No much toxicity. High dose – 10 times expected therapeutic dose. Third dose – between low and high doses. Mainly to study liver, kidney impairment, changes in BP, ECG, Study of organs, etc.

17. When the drug is found to be safe in animals, it is subjected to clinical trials in human beings after obtaining permission from regulatory agency. Good Clinical Practice : Certain regulatory guidelines are followed to ensure safety and transparency in the trial activities. They are provided by : ICH – International Conference on Harmonisation USFDA – United States Food and Drug Administration GCP – Good Clinical Practice of India WHO Ethical guidelines by – ICMR – Indian Council of Medical Research CLINICAL TRIALS :

18. Ethical clearance : After obtaining permission from regulatory authorities Permission should be obtained from Institutional Ethics Committee (IEC) or Institutional Review Board ( IRB). The IEC looks into the ethical aspects and ensures that the trial is conducted ethically and the rights of the participants are recorded.

19. Informed consent : For enrolling the trial, subject should be informed in detail about the trial including the risks and should be willingly participate in the study. He should sign the informed consent form and he can also withdraw at any time. This is to ensure that participants are in the study is not by force.

20. Preclinical animal studies Phase 0 Microdosing Phase I Safety Phase II Safety and efficacy Phase III Safety and efficacy FDA review and Approval Clinical Trials 10-15 people for < 7 days 20-50 healthy volunteers 100-300 patients 500-3000 patients 1-2 years

21. Preclinical Phase 0 20-50 participants Animals

22. PHASES OF CLINICAL TRIALS : Phase 0 : It is also called as microdosing . This is a recent approach in clinical trials to cut cost in drug development. It is conducted in small number of subjects; 10-15 for short durations, < 7days. Very small dose is used to evaluate the pharmacodynamics and pharmacokinetics. Analysis is done by accelerated mass spectroscopy, positron emission tomography. This phase doesn’t give safety and efficacy but gives an idea on ranking to take forward the drug development.

23. Phase I : Human pharmacology and safety It is conducted in 20-80 normal healthy volunteers. It is to establish the drug safety, to know the actions, determine pharmacokinetic property and to design safe dose. Phase II : Therapeutic exploration and dose ranging It is conducted in 100-500 patients. If phase I is successful, the compound undergoes Phase II. It is to establish efficacy, to detect any adverse effects, appropriate dose and detailed pharmacology of the compound .

24. Phase III : Therapeutic confirmation/comparison If phase II is safe, then undergoes phase III. Usually done in large number of patients around 500-3000 for short periods. It is done to establish the benefits of drug in the target disease, to identify the side effects, susceptibility to tolerance and to design ideal dosage regimen for different groups . Phase IV : Post-Marketing surveillance I t is a long-term safety and efficacy. They are done for systematic detection and evaluation of long-term safety of the drug. They are done by collection and evaluation of data by medical practitioners.