1. AN INTRODUCTION TO CLINICAL PHARMACOLOGY

2. BEFORE STARTING DRUG THERAPY, DOCTORS CONSIDER  Whether intervention needed ?  Objective of treatment ?  Best suitable drug ?  How to monitor ?  How to administer ?  Side effects ?  When to discontinue ?  Risk benefit ratio ?

3. DRUG THERAPY involves a great deal more than matching the name of the drug to the name of the disease Requires:  Knowledge  Judgement  Skill and wisdom  A SENSE OF RESPONSIBILITY DRUGS CAN DO GOOD DRUGS CAN DO HARM Whenever a drug is given a risk is taken

4. Reduction of drug risk Better knowledge of drug and disease process: RESEARCH Site specific delivery and effect : Drug Delivery Systems INFORMED, CAREFUL AND RESPONSIBLE PRESCRIBING

5. STEPS : DISCOVERY AND DEVELOPMENT OF DRUGS Idea or hypothesis Design and synthesis of substances Studies on tissues and whole animals- PRECLINICAL STUDIES Studies in man- CLINICAL STUDIES (Phase I, II, III) Grant of an official licence to make therapeutic claims and to sell Post-licensing (marketing) Phase IV studies of safety and comparisons with other medicines From lab. to pharmacy : 9-12 years & crores of rupees

6. Bioequivalence Two pharmaceutically equivalent drug products are considered to be bioequivalent when the rates & extents of bioavailability of the active ingredient in the two products are not significantly different under suitable test conditions. For the products which are already available in the country, the companies conduct only bioequivalence studies to get drug license

7. PRECLINICAL STUDIES  Pharmacodynamics  Pharmacokinetics  Toxicology: acute, subacute and chronic  Special toxicology:  mutagenicity  carcinogenicity  teratogenicity

9. THERAPEUTIC / CLINICAL TRIAL It is a carefully, and ethically, designed experiment with the aim of answering some precisely framed question Aims:  Whether a treatment is of value  How great it’s value is/ comparisons  What is the best method of applying the treatment and dose  What are the disadvantages and dangers of the treatment

10. Protocol generation Selection of investigator and sites Permissions of drug regulatory authority and institutional ethics committee Initiating the trial: recruitment of subjects Monitoring and data collection Closing the trial Feeding the data in the computer Statistical analysis Report generation and submission to regulatory authorities Proceeding to the next step STEPS TO CONDUCT A CLINICAL TRIAL

11. Statistics, significance and “p” value: The probability (p) of incurring false positive results is expressed as significance Whenever this probability (of a false positive result) is less than 5 in 100 observations (p<0.05) it is said to have reached a level of significance When this probability is less than 1 in 1000 observations (p<0.001) it is said to be highly significant Common Terms

12. Review article : A review & analysis of available literature for a particular drug Prospective study : Ongoing study of patients receiving drug Retrospective study : Compilation & analysis of the records of the patients who were treated with the drug during a specific period

13. Meta analysis Collecting numerous trials in a systematic review and analysing the results by using appropriate statistical methods to assess benefits or risks that are sufficiently uncommon that an individual study lacks the power to detect them  Drawback : Publication bias

14.  Pharmacologically inert substance (e.g., starch, sucrose)  Used to differentiate pharmacodynamic effects from psychological effects  Distinguish drug effects from fluctuations in the disease Placebo

15. Open label trial When the patient as well as doctor is aware of the treatment given & there is no placebo arm E.g., Phase IV (Post-Marketing Surveillance) Drawbacks : –Doctor/ patient bias –For statistical significance, more pts. required

16. Blinding The purpose is to eliminate any bias in reporting of results Single blind trial : A blind trial is one in which the participant is not aware of which arm — experimental or control — of the clinical trial he or she is on Double-blind trial: A clinical trial in which neither the participants receiving the treatments nor the researchers administering the treatments are aware of which group is receiving the experimental treatment.

17. Randomization A process that reduces the likelihood of bias by assigning people to treatment groups by chance alone (randomly). When groups are created by random assignment, individual characteristics are less likely to make the results inaccurate

18. Control Group A group of clinical trial participants that receives the placebo (placebo controlled) or standard therapy (active control or parallel group) for a condition while another group is given the experimental treatment The control group serves as a measuring stick to gauge the effectiveness of the experimental treatment. It is possible to have a placebo group & parallel group compared with experimental drug in one trial

19. Cross-Over Study Patients 50 50 Drug A Drug B Wash-out Period/ No drug (e.g., 1-4 wks) Drug B Drug A Usually used in parallel group study, to reduce the likelihood of selection bias & to re-confirm drug effects

20. Cohort Follow up study of all the patients receiving a particular drug for estimation of incidence of adverse effects E.g., Phase IV (PMS) study Drawbacks : –Must have at least 10000 pts. –Can not discover rare events –Adverse event could be attributed to drug only if, it does not occur spontaneously in control group

21. Case-Control Study Follow up of a spontaneously occurring adverse event with a substantial no. of more patients & controls to establish the the drug as a cause of the adverse event Can discover rare drug-induced events Drawbacks –Difficult to establish appropriate control group –Can not establish incidence of adverse effect

22. Clinical Evidence Level Level Ia : Review (meta-analysis) of Randomized Placebo-Controlled Trials (RCTs) Level Ib : At least one RCT Level IIa : At least one placebo-controlled but non-randomized trial (CT) Level IIb : Well designed quasi-experimental study Level III : Comparative, Cohort, Case report, Case-series Level IV : Expert opinion (letter), Anecdotes

23. Statistical Tests Parametric : Quantitative analysis of objective parameters (blood pressure assessment) e.g., Student’s t-test (Paired/ Unpaired) Non-Parametric : Qualitative analysis of subjective parameters (pain assessment) e.g., Wlicoxon, Chi-square