Dr. Sirisha1st year PG

CLINICAL TRIALS

DEFINITION• It is a prospective ethically designed investigation in human

subjects to discover/verify/compare the results of two or more

therapeutic measures /drugs.

•WHO definition: Prospectively assigned human participants to

one or more health related interventions to evaluate the effects

on health outcome.

DEFINITIONS

RANDOMIZATION:

Each study subject is randomly assigned to receive

either the study treatment or a control.

PLACEBO:

Pharmacologically inert substance given to please the

subjects

BLIND:

If the study is single blind, the subjects involved in the

study do not know which study treatment they receive.

If the study is double- blind, the researchers also do not

know which treatment is being given to any given subject.

This 'blinding' helps in preventing biases.

TYPES OF CLINICAL TRIALS

Treatment trials

Prevention trials

Diagnostic trials

Screening trials

Quality of life trials

DRUG DISCOVERY SOURCES

STAGES OF DRUG DISCOVERY

PRE-CLINICAL TRIALS

The testing on animals to expose the pharmacological profile

of a prospective drug is called pre-clinical trials.

The major kinds of information expected from preclinical

toxicity studies are

(1) acute toxicity—effects of large single doses; (LD50)

(2) Sub acute and chronic toxicity—effects of multiple doses,

which are especially important if the drug is intended for

prolonged use in humans

PRE-CLINICAL TRIALS

(3) effects on reproductive functions, including teratogenicity and

postnatal development;

(4) carcinogenicity;

(5) mutagenicity.

(6) Pharmaco dynamics

(7) Pharmaco kinetics

(8) Assessment of safety index

PRE-CLINICAL TRIALS

Tests:

Screening tests

Tests on isolated organs

Tests on bacterial culture

Tests on animal models of human diseases

Importance of pre clinical trials• Triparanol is a drug that lowers the concentration of cholesterol in

plasma.

• It was marketed in the USA in 1959. In 1962, the Food and Drug

Administration (FDA) received a tip-off and undertook an

unannounced inspection. This revealed that toxicology data

demonstrating cataract formation in rats and dogs had been

falsified.

• Triparanol was withdrawn, but some of the patients who had been

taking it for a year or longer also developed cataracts

ETHICSThe U.S. National Institutes of Health notes seven ethical

requirements that must be met before a clinical trial can begin.

These include

• social value,

• scientific validity,

• fair and objective selection of subjects,

• informed consent,

ETHICS

• favourable ratio of risks to benefits,

• approval and oversight by an independent/ institutional

review board (IRB),

• respect for human subjects.

LEGAL ISSUES

• Informed consent

• Institutional review board

•Medical insurance

• confidentiality

INFORMED CONSENT FORM

• Voluntary

• Explained in simple nontechnical, native language

• Comprehensive information regarding the trials like

• Benefit of new therapy over existing ones

• Alternative treatments available

• All possible adverse reactions

• Freedom to withdraw from the trial

Clinical trials must have

a) Good laboratory practice

b) Good clinical practice

c) Good manufacturing practice

d) Good documentation practice

e) Good regulatory practice

IND(Investigational New Drug)

The IND includes

(1) information on the composition and source of the drug

(2) manufacturing information,

(3) all data from animal studies,

(4) clinical plans and protocols,

(5) the names and credentials of physicians who will conduct

the clinical trials.

DRUG REGULATORY AGENCY

A clinical trial can begin only when drug regulatory authority

approves for the conduct

Ex: Food and drug administration(FDA)

Central Standard Drug Control Organization (CDSCO)

Drug Controller General of India(DCGI)

PHASE 0 / EXPLORATORY IND STUDIES• MICRODOSING:

Extremely low, nonpharmacologically active doses of a

drug are used to define the agent’s pharmacokinetic profile in

humans.

•DEFINITION:

Microdosing means use of ‘less than 1/100 of the dose

calculated to yield a pharmacological effect of the test substance

to a maximum dose of <100 micrograms and a maximum micro

dose of <30 nanomoles for protein products.

• FEATURES:

limited number of subjects(10-15)

limited dosing duration(<=7 days)

evaluates pharmacodynamic and pharmacokinetic properties

FEATURES MICRODOSING CONVENTIONAL

Time from preclinical to stage 1

6-8 months 12-18 months

Cost of early phase of drug development

US$ 0.3 -.0.5 million US$ 1.5-5.0 million

Amount of drug required <100 micrograms About 100 grams

Special requirements C14 labelled compound AMS

None required

Regulatory requirements Very few and limited Established firmly

Advantages:

• saves investment and resource utilization.

• less time.

• efficiency and success of successive trials can be improved.

•No adverse effects since the dose used has no pharmacological

action

• As per the regulatory requirement, animal studies, at least in one

species, are required to establish micro dose in humans, but at a

much reduced level.

Disadvantages:

• Drugs with non linear kinetics cannot be assessed Ex:warfarin

• False negative results can mislead (compound being rejected)

• No therapeutic or diagnostic conclusions can be made

• false positive results (compound acceptable based on micro

dose data but rejected subsequently when used in

pharmacological doses).

• Compound metabolism and solubility of compound.

Phase 1. Human pharmacology 20-50 subjects, open label, for 1 year

Healthy volunteers or volunteer patients, according to the class

of drug and its safety.

Objectives:

Pharmacokinetics (absorption, distribution, metabolism,

excretion).

Pharmacodynamics (biological effects)

tolerability, safety, efficacy.

Phase 2. Therapeutic exploration 50-300 subjects, open label, 2-3years

Patients.

Trials with inclusion and exclusion criteria

Primary and surrogate end points

Objectives:

Pharmacokinetics and pharmacodynamic dose-ranging

Therapeutic efficacy

• Phase 2a/ Early Phase

• 200 patients

• Single blind

• Potential therapeutic benefits

and side effects

• Phase 2b/ Late Phase

• 400 patients

•Double blind

• Potential therapeutic benefits

and side effects

Phase 3. Therapeutic confirmation

Randomised, double blind, multi-centric controlled trials; 250-

1000+

Cross over design

Patients

Objectives:

Efficacy on a substantial scale; safety;

comparision with existing drugs.

Drug interactions

Guidelines for use of drug

NEW DRUG APPLICATION• If phase 3 results meet expectations, application is made for

permission to market the new agent.

• Marketing approval requires submission of a New Drug

Application (NDA) to the DRA.

• The application contains, often in hundreds of volumes, full

reports of all preclinical and clinical data pertaining to the drug

under review, package inserts.

•median standard approval time was 12.9 months.

Phase 4. Therapeutic use

2000-10000+, post-licensing studies

Periodic Safety Update Report(PSUR)

Objectives:

Surveillance for safety and efficacy

uncommon and long term adverse effects

marketing studies

pharmacoeconomic studies.

additional indications

Phase 5. Therapeutic effectiveness

• The focus of Phase V studies, or "effectiveness" research, is

on determining whether "the therapeutic effect is realized in

day-to-day clinical practice".

• Generally, Phase V research is considered "field research" or

"community-based research" and is designed to test

generalization of the intervention to a larger sample and under

typical and somewhat variable clinical contexts.

PHASE 5

•A central question for Phase V research is whether the effects are

similar to those found in efficacy studies and to determine who

benefits from the treatment.

• It is during this phase of research that questions concerning the

cost-benefit ratio of the intervention can be addressed.

CRITICAL PATH INITIATIVE

• In 2004, a white paper, now known as the Critical Path Initiative

(CPI), is given by FDA that called attention to an alarming

decline in the number of innovative medical products being

submitted for FDA approval.

• This led to the new concept of adaptive phase clinical trials

ADAPTIVE PHASE CLINICAL TRIALS

• Study that includes a prospectively planned opportunity for

modification of one or more specified aspects of the study design

and hypotheses based on analysis of data (usually interim data)

from subjects in the study.

• The purpose is to make clinical trials more flexible, efficient

and fast. Due to the level of flexibility involved, these trial

designs are also termed as “flexible designs.”

NON INFERIORITY CLINICAL TRIALS

•Non-inferiority clinical trials aim to demonstrate that the test

product is no worse than the comparator by more than a

prespecified small amount. This amount is known as the non-

inferiority margin (M), or delta (Δ).

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