CLINICAL TRIALS OF DRUGSDESIGN OF CLINICAL TRIALS

by

Mahender.k M.Pharm 1st yr,

(Pharmacology)

Srikrupa institute of pharmaceutical sciences

Velkatta,kondapak,medak. Andhra pradesh

Under the guidance of

Mr . CHIRANJIB BHATTACHARJEE M.Pharm (Ph.D)

DRUG DEVELOPMENT

Drug development is a term used to define the entire process of bringing a new drug or device to the market. It includes:

drug discovery product development pre-clinical research

(microorganisms/animals) clinical trials (on humans)

WHY ARE CLINICAL STUDIES PERFORMED?

No chemical can be certified as completely "safe". Every chemical is toxic at some dosage.

It is important to estimate the risk associated with exposure to the chemical under specified conditions by performing appropriate tests.

Clinical trials may be required before the national regulatory authority approves marketing of the drug or device, or a new dose of the drug, for use on patients.

WHEN IS CLINICAL TRIAL NECESSARY? Assess safety and efficacy of New Chemical

Entity Assess safety and effectiveness of a

different dose (e.g., 10 mg dose instead of 5 mg dose) Assess safety and efficacy of an already

marketed medication or device for a new indication i.e. a disease for which the drug is not specifically approved

To compare the effectiveness in patients with a specific disease of two or more already approved or common interventions for that disease

CORE COMPONENTS OF CLINICAL TRIALS Involve human subjects Move forward in time Most have a comparison CONTROL

group Must have method to measure

intervention Focus on unknowns: effect of medication Must be done before medication is part

of standard of care Conducted early in the development of

therapies

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TAKING PART IN RESEARCH STUDIES:QUESTIONS TO ASK

What is study about? What are the goals? Study sponsor? Participant input

into protocols? Inclusion criteria? Benefits & risks

Is there an incentive? How protected from

harm? What is required: #

study visit & what occurs?

What happens after study is over?

How results will be disseminated?

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CPARTICIPATION IN CLINICAL TRIALS

Why Some Participate: Give back to society Health care services Payment &

incentives Support Others??

Why Some Do Not? Mistrust of studies Do not want to be

“guinea pig” Do not meet criteria Cannot give up time

for study visits Barriers: long.,

distance

ETHICS OF CLINICAL TRIALS: PROTECTION OF PARTICIPANTS

3 ethical principles guide clinical research: Respect for Persons: Treatment of person

as autonomous. Beneficence: : potential conflict between

good of society vs. individual. Justice: Treatment of all fairly & all equally

share benefits & risks.

CLINICAL TRIALS

I. Phase I – Healthy VolunteersII. Phase II – Target Patient VolunteersIII. Phase III – Larger Number of PatientsIV. Phase IV – After marketing

PHASE 1

Phase 1 clinical trials are done to see if an experimental medication or treatment is safe.

After a treatment is tested in the lab or on animals, it enters a phase 1 clinical trial that is done with humans.

A phase 1 clinical trial usually involves only a small number of people to determine if a drug or treatment is safe, and to determine the best dose of a drug and how it should be given (whether orally or intravenously).

It includes: 1a.single ascending dose 1b.multiple ascending dose

SAD : Single Ascending Dose small groups of subjects are given a single

dose of the drug while they are observed and tested for a period of time.

If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose.

This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up

At this point the drug is said to have reached the Maximum tolerated dose (MTD).

MAD: Multiple Ascending Dose studies In these studies, a group of patients receives

multiple low doses of the drug Samples of blood and other fluids are collected

at various time points and analyzed to understand how the drug is processed within the body.

The dose is subsequently escalated for further groups, up to a predetermined level.

Parameters known by this Cmax Tmax T1/2 AUC Vd Cl MRT(Mean Residence Time)

PHASE2

Mainly used to study Safety efficacy and Dose fixing It includes Phase2a and Phase2b

Phase2a Single blind study Only 10-15 patients GO/NO GO concept i.e taking /not

taking of drugs It takes 9months-

2yrs.

Phase2b Double blind study 200-800 patients Similar to phase3 Determines dose

response relationship Conformation of clinic

dose and regimen. To find out exact

mechanism of action of individual drugs.

It takes 2-3 yrs.

PHASE 3

Deals mainly about pharmacoeconomics. Most of the ADR and D-D interactions are

studied. Combination testing of the drugs are carried

out at last stages of phase 3. In phase III, the drug is evaluated in much

larger numbers of patients—sometimes thousands—to further establish safety and efficacy.

Using information gathered in phases I and II, phase III trials are designed to minimize errors caused by placebo effects, variable course of the disease, etc.

Therefore, double-blind and crossover techniques are frequently used

Phase III studies can be difficult to design and execute and are usually expensive because of the large numbers of patients involved and the masses of data that must be collected and analyzed.

The investigators are usually specialists in the disease being treated.

Certain toxic effects—especially those caused by immunologic processes—may first become apparent in phase III.

PHASE IV

Phase IV trial is also known as Post Marketing Surveillance Trial.

Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for

1. competitive (finding a new market for the drug)

2. To check for drug interactions with other drugs

3. certain population groups such as pregnant women, who are unlikely to subject themselves to trials

• Careful and complete reporting of toxicity by physicians after marketing begins is very important.

• Low incidence drug effects will not generally be detected before phase 4 no matter how carefully the studies are executed.

• Phase 4 has no fixed duration.• Adverse effects detected by Phase IV trials

may result in withdrawal or restriction of a drug.

THE IMPACT OF STUDIESo Some clinical trials have been critical to

patient health & provision of health care.

Other clinical trials have not been as successful for a variety of reasons: Medications did not work as in

laboratory Loss to Follow-Up of too many patients Harmful substance Unethical & poorly conducted study

LIST OF WITHDRAWN DRUGS:

Rofecoxib (Vioxx) 2004 Withdrawn because of risk of myocardial infarction.

Thioridazine (Melleril) 2005 Withdrawn from U.K. market because of cardiotoxicity.

Pergolide (Permax) 2007 Voluntarily withdrawn in the U.S. because of the risk of heart valve damage. Still available elsewhere.

Cisapride (Propulsid) 2000s Withdrawn in many countries because of risk of cardiac arrhythmias.

Thalidomide 1950s–1960s Withdrawn because of risk of teratogenicity; returned to market for use in leprosy and multiple myeloma under FDA orphan drug rules.

RECENT DATA:

Drug : Teri flunomide {Aubajo}• Used in the treatment of multiple schlerosis

in adults causes the side effects like Nausea Dizziness Hair loss Abnormal liver tests Reserpidine like binding profile and

potential antipsychotic efficacy include ZIPRASIDONE,SERTINDOLE are removed recently from clinical trials due to cardiac depression.

CONCLUSIONS :

Clinical trials often yield important results that affect health and well being

Must follow guidelines & protocol Must ensure well-being of participant Clinical trials are susceptible to human

error either on part of investigator or patient

Research is soft science

THANK YOU