Rahil Khan ICRI Mumbai

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PHASE I AND PHASE II CLINICAL TRIALS OBJECTIVES AND STRATEGIES

Phase I

What is a safe dose to give for the NEW treatment and with what toxicities? the efficacy the IsIs the efficacy ofof the NEW treatment worthy NEW treatment worthy ofof direct comparison direct comparison toto STANDARD treatment STANDARD treatment ofof the day? the day? How does the NEW treatment compare to the STANDARD treatment of the day in terms of efficacy?

Toxicities

Phase II

Intermediate outcome of efficacy: Response

Phase III

Overall outcome of efficacy: Survival time

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Phase I Clinical Trials

PHASE I STUDIES

Definition: This may be defined as initial investigations in human. The subjects are usually healthy male adult volunteers.

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PHASE-I PREREQUISITES

PRE-CLINICAL STUDIES COMPLETED SINGLE DOSE TOXICITY STUDIES REPEATED DOSE SAFETY PHARMACOLOGY STUDIES LOCAL TOLERANCE STUDIES PHARMACOKINETIC STUDIES MUTAGENICITY STUDIES(INVITRO) CARCINOGENICITY STUDIES SELECTION OF DOSE

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AIMS OF PHASE I

Human tolerance Pharmacokinetics Pharmacodynamics Drug effects are determined by history,clinical examination,clinical

and laboratory examination

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AIMS Cont..

To assess the tolerability of drug Indicate MTD Determine the estimated therapeutic dose can be exceeded without ADR

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Determination of appropriate route

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SELECTION OF VOLUNTEERS

Volunteers male Age between 18-35 yrs 95% normal range 64% show one/more abnormal results

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PLAYERS IN PHASE-I

PARTICIPANTS(20-50)

HEALTHY VOLUNTEER SUBJECTS PATIENTS

PLACE

SPECIAL TESTING FACILITIES MONITORED CLOSELY

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PHYSICIAN

TRAINED INVESTIGATOR
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SELECTION Cont..

Clinical interpretation in relation to laboratory tests

Serological evidence of HEPATITIS,HIV

Ambulatory vital parameters ECG and BP

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SELECTION Cont.

Unusual to perform first studies in elderly

Greater risk of diseases

Women of child-bearing are underrepresented due to risk to fetus

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SELECTION Cont.

Exclusion criteria-Tricyclic antidepressant

Alcohol abuse( drugs of dependency)

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Cigarette smokers-nicotine Effect of smoking on hepatic drug metabolism

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SELECTION Cont.
Consumption of caffeine and caffeinated drinks

Dietary habits

Dose-lower than that shown to be

well tolerated in people with normal

enzyme activity
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INFORMED CONSENT

1
2 3 4
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Desirability of volunteers about precise nature of the study Responsibility of Investigator Purpose and description of study Tests to be performed before, during and after trial Possible risk and side effects to be informed Investigative procedures
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PLACE OF INVESTIGATION

No statutory regulations Voluntary inspection service and licensing of clinical drug research unit

becoming mandatory

Specialized units and experts

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All staff should be trained for

cardiopulmonary resuscitation
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PLACE Cont.

Nursing-care should be continuous

Certified labs with complete facilities like

hematology and chemical pathology

Advanced IT facility with access to validated data-base

Proximity to general hospital is great asset

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ETHICS COMMITTEE

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Research or independent ethics committee Constitution of ethics committeeICH Protect all the subjects from risk REC must be informed about additional emergency information which may affect ethics and safety of study Minimize the risks -

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OTHER ISSUES

Insurance and compensation Payment of volunteers Volunteer motivation- USA prison volunteer Concept of professional volunteers French National Insurance Number in France

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PROTOCOLS
Introduction Objectives and Purpose Study design Investigational product Selection and withdrawal of subjects Study procedures
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Protocols Cont.

Treatment programs Statistical considerations Ethics considerations Data handling and record keeping Confidentiality and publication policy

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References

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DESIGN OF STUDY

TYPES: Two stages,single rising dose and repeated administration Route of administration Blood sampling Placebo Investigation of efficacy

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ADVERSE EFFECTS

Toxic reactions is a challenge Prevent ADR Increase in Liver Trans-aminases is a commonest toxic effect ,exclude other causes Planning appropriate investigations

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ADVERSE EFFECTS
Type

and severity of harmful effects Within subjects comparison Risks associated Careful study design Database of potential pharmacological agents is desirable
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Phase II study

Proof of concept study Therapeutic exploratory trials in patients

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Phase 2 of clinical trials

Initial trials Limited number of patients Specific disease control or prophylaxis purpose

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Objectives of Phase II trial

Effects of the compound on physiological functions 2. Assessment of therapeutic or prophylactic activity and efficacy 3. Safe, tolerability and optimal dosage range of compound 4. Evaluation of the drug-emergent side-effects and toxicity 5. Choice of the best pharmaceutical formulation 6. Determine the mechanism of action 7. Pharmacokinetic behaviour and metabolism of the new investigational drug 26 5/28/2013 1.

SUBDIVISION OF PHASE II
A. Phase II a Pilot clinical trial B. Phase II b Pivotal clinical trial

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PHASE II a PILOT CLINICAL TRIAL

Feasibility trial Small scale Often unblind and open label Intended to provide experience to investigator

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PILOT CLINICAL TRIAL OBJECTIVES

1.

To confirm that trial medicine, procedure are safe, suitable, and operational. Dose range of new drug Initial efficacy evaluation of a new drug, or for new indication

2. 3.

4.

Determine the duration required

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PILOT CLINICAL TRIAL OBJECTIVE

5.

6.

7.

For evaluation of methodology Determination of availability of patient Exploration of ethical questions

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PHASE II b PIVOTAL CLINICAL TRIAL

Well planned, well controlled trial, in full scale Most rigorous demonstration of drug efficacy Conducted in units with specialist investigators with experience of particular indication Adequate investigational facilities to monitor safety and efficacy Doses are usually less than the highest doses used in phase I

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PHASE II b PIVOTAL CLINICAL TRIAL

Usually, only 3-4 centers are included

Normally, 10-12 patients should be studied at each dose-level

May or may not be randomized

Open or double blinded trial

Placebo or comparator controlled Further evaluation of safety, pharmacokinetic data
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Randomised Phase II Trial

Eligible Patients Randomised STANDARD Response Rate NEW1

NEW2

NEW3

Response Response Response Rate Rate Rate

0%
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Pick the winner

100%
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How do we go from Phase I to Phase II?

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How do we go from Phase I to Phase II?

1.

2.

3.
4. 5.

6.

Review your preclinical and Phase I data Decide on dose and schedule What indication(s) to study Select your trial design Select your endpoint(s)/outcome measure(s) Determine the sample size
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Choice of investigator

Qualifications of the scientist:

Enthusiasm and perseverence Originality-creativity, the spirit of invention, imagination, intuition, genius Intelligence logic, memory, experience, concentration, abstraction Ethics-honesty with self Technical skill Contact with people-understanding of self and others, compatibility, organization of teams, convincing others and listening to argument.
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Investigators meeting

Participants Contents

Introduction to study medication Protocol Study Endpoints Safety reporting New gadgets and technology GCP training CRF training Logistics for the trial

Event management
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DSMB

Data Safety Monitoring Board Members Meetings Charter Powers Communication Decision

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Conduct of trial

Trial initiation Monitoring Data management End of trial Data lock Statistical analysis Reports Publication Decision on planning phase III trial

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drug is effective if it fulfills by objective indices, its sponsors claims of prolonged life, improved physical condition, and safe if the drugs potential for inflicting death or physical injury is offset by the possibility of therapeutic benefit
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Thank you

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