Required steps• Clinical protocol preparation• Informed consent• Approval of the ethical committee

Phase IPhase I

Healthy volunteers

Objectives:1 - To identify a safe & tolerated dose (MTD)2 - To compare PK profile in man versus animal/s3 - To see if compound show proper absorption, bioavailability4 -To detect effects unrelated to the expected action5 -To detect any predictable toxicity

Methods: 1. Inclusion criteria

• Healthy volunteers : Uniformity of subjects: age, sex, nutritional status Exception: Patients only for toxic drugs Eg AntiHIV, Anticancer

2. Exclusion criteria– Pregnant women

3. First in a small group of 20 to 25• Start with a dose of about 1/100 NOAEL animal dose• Slowly increase the dose to find safe tolerated dose (stop at 1/5

animal NOAEL)• If safe in a larger group of up to about 50 –75

4. No blinding5. Performed by clinical pharmacologists 6. Centre has emergency care & facility for kinetics study7. Performed in a single centre8. Takes 3 – 6 months

Phase IPhase I

Phase IIA and BObjectives

• Detailed PK & PD in patients• Establish doses for future Ph III trials• Efficacy against a defined therapeutic endpoint • Therapeutic benefits

MethodsFirst in patient Performed by Clinicians in the hospital Few centres

IIA [20 – 200 patients with relevant disease]PK in patients: Establish a dose range to be used in late phaseMaximum tolerated dose and Safety e AEsMethod: same as phase I

IIB patients [ 50 – 500]Double blindCompared with a placebo or standard drug

Takes 6 months to 2 years (35% of success)

Proof of concept (POC)

• May be considered as Phase IIA or IIB or can occur sometime between Phase IIA and Phase IIB

• Decision based on studies specifically chosen to demonstrate or “prove” the drug will be efficacious and safe in Phase III

• These studies are mainly of two types:– Target engagement

– Effect on disease biomarkers

Proof of Concept (PoC)

Phase I Phase IIA Phase IIB PhIII

Target engagement biomarker

In vivo receptor occupancy in human:- PET technology

Is the most selective and sensitive (pico- to nanomolar range) method for measuring receptor density and interactions in vivo. Very important tool for translation from preclinical to clinical research

- In vivo radioligand binding- Ex vivo radioligand binding

PETPOSITRON EMISSION TOMOGRAPHY

NK1 receptor engagement by Aprepitant

Binding of PET tracer to NK1 receptors in man

Blockade of NK1 receptorsafter aprepitant dosing

Low High

Tracer Binding

(Hargreaves J Clin Psych 63: (suppl 11): 18-24, 2003)

40 mg 125 mg375 mg

Aprepitant Plasma Concentration (ng/mL)

Bra

in N

K1

Rec

epto

r O

ccu

pan

cy (

%)

0102030405060708090

100

0 1 10 100 1000 10000

BIOMARKER

Characteristics of a “good” biomarker:Characteristics of a “good” biomarker:

-- Biological feasibilityBiological feasibility

-- Dose-related response to interventionDose-related response to intervention

-- Easy to measureEasy to measure

-- Reproducible, specific and sensitive with Reproducible, specific and sensitive with high high predictive valuepredictive value

-- Acceptable by expertsAcceptable by experts

-- Acceptable by Regulatory AuthoritiesAcceptable by Regulatory Authorities

The ideal biomarker

Disease Clinical Endpoint

Treatment

Biomarker

Biomarker

BiomarkerB

A

C

Inappropriate biomarkersA - Unrelated to mechanism that leads to clinical outcomeB - Linked to clinical outcome via a pathway not affected by treatment

Ideal biomarkerC - Treatment Intervention acts through pathway affecting clinicalendpoint through the surrogate

Phase III: establishing the therapeutic valueObjectives

• Confirm doses and efficacy established in Phase II

• Verify possible interaction with other drugs in a large population of patients• Identify possible patient subpopulations • Compare effect with that of drugs in the market

Methods

- Performed by Clinicians in the hospital

- Large scale (500 – 2000 patients)

- Multicentric Ensures geographic & ethnic variations

- Diff patient subgroups Eg pediatric, geriatric, renal impaired

- Randomised allocation of test drug /placebo / standard drug

- Double blinded

- Cross over design

- Vigilant recording of all adverse drug reactions

- Rigorous statistical evaluation of all clinical data

• Takes a long time: up to 5 years [25% success]

Classics

A B

Randomization

Compare Outcome

Advantages

- Minimization of bias

- Blind or double blind

- Suitable for comparisons

Issues- Half of the patients do not get the treatment

- High number of patients to minimize outliers

- Time and resource consuming

Cross over

A B

Randomization

A B

Compare Outcome

Advantages- Minimization of bias- Blind or double blind- Suitable for comparisons

Issues- High number of patients to minimize outliers

- Time and resource consuming

- Potential risk of sinergy between treatment

Randomized

Types of clinical trials

Registration• Each state has his own regulatory agency and rules may

different from state to state

• Efficacy and safety are the major concerns

• Data and protocols are carefully analyzed

• Support documentation could be cumbersome: 50-400 volumes (30,000-150,000 pages)

• The process require a continuous dialogue between regulatory agency and pharmaceutical company

• If the drug is approved it will be labelled for a single indication

Phase IV:Marketing e post-marketing surveillance

• Adequate commercialization of the product

• Explore the possibility to use the drug for additional therapeutic indications

• Enlarge the knwoledge about the potential side effects

• Evaluate the ratio between benefit and ling term adverse effects.

P2Y12 antagonists on the market and in clinical trials

Novel P2Y12 antagonists under development, have a faster onset of action, as well as more potent, and less variable, inhibition of platelet function ex vivo.

Two currently FDA-approved P2Y12 antagonists: ticlopidine and clopidogrel are thienopyridines. The active compound is a metabolite of this thienopyridine and is an irreversible inhibitor.

Compassioned used

• The term "compassionate use" refers to the treatment of a seriously ill patient using a new, unapproved drug

• Requirements:

– Drugs that have shown activity in phase III– No other treatments are available– Simplified protocols– It is necessary the informed consent

Abbreviated new drug application

This procedure is applicable only for very seriuos pathology

It is applied to molecules that could represent a significant improvement other existing therapy.

To have access to this procedure there are two major requirements:

- Safety of the patient is guarantee by the use of the drug in controlled condition

- There are compelling laboratory data indicating a clear efficacy