AN INTRODUCTION

TO

CLINICAL PHARMACOLOGY

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 ?

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 RESPONSIBILITYDRUGS CAN DO GOOD

DRUGS CAN DO HARM

Whenever a drug is given a risk is taken

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

STEPS : DISCOVERY AND DEVELOPMENT OF DRUGSIdea or hypothesis

Design and synthesis of substances

Studies on tissues and whole animals- PRECLINICAL STUDIESStudies 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

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

PRECLINICAL STUDIES

Pharmacodynamics

Pharmacokinetics

Toxicology: acute, subacute and chronic

Special toxicology:

mutagenicity

carcinogenicity

teratogenicity

Phase I Phase IIExploratory

Phase IIIConfirmatory

Phase IVPMS

StudyPopulation

HealthyVolunteers

Patients Patients Patients

No. of pts. 20-50 50-300 250-1000 10000

Conductedby

Clin.Pharmacologist

ClinicalPharmac. &ClinicalInvestigator

ClinicalInvestigator

Doctors usingdrug

Objective PK Safety

PK Safety Efficacy/PD Dose Range

Efficacy Safety Comparison

with existingdrugs

Safety Drug use Comparison

with existingdrugs

Newindications

Bioavail. Bioequivalence

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

Protocol generation

Selection of investigator and sitesPermissions 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 authoritiesProceeding to the next step

STEPS TO CONDUCT A CLINICAL TRIAL

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

Common TermsReview 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

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

Pharmacologically inert substance (e.g., starch, sucrose)

Used to differentiate pharmacodynamic effects from psychological effects

Distinguish drug effects from fluctuations in the disease

Placebo

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

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.

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

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

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

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

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

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

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