Evolution of New Drugs

What are Clinical Trials ?

Research study in human subjects

which answer specific health questions

Carefully conducted trials are the safest

and fastest way to find treatments that

work in people.

THE SCIENCE OF CLINICAL TRIALS

Characterize the new drug by answering the following questions

Safety are the side effects acceptable?

Tolerability will the drug be taken?

Efficacy Can the drug work?

Development Phases
Discovery: (2 to 10 years) Preclinical Testing: Laboratory and animal testing Phase 1: 20 to 80 volunteers used to determine safety and dosage Phase 2: 100 to 300 volunteers; monitor for efficacy and side effects Phase 3: 1,000 to 5,000 volunteers; monitor for adverse reactions to long-term use FDA Review/Approval Postmarket Testing

Compound Success Rates by Stage:

5,000 to 10,000 Screened

250 enter Preclinical testing 5 enter Clinical testing:

1 FDA Approval

8 10 Years

12

14

16

THE CLINICAL TRIAL

Role of Industry in Bringing New Medicines to the Marketplace
To discover and develop innovative medicines To rapidly develop safe and effective medicines into useful therapeutic options To manufacture and distribute new medicines for the community . To ensure the new medicine does improve quality of life

The Clinical Trial

Good Clinical Science
+

Good Statistical Design

+

Good Ethical Conduct

+

Integrity & Quality

Phases of Clinical Trials

Phase I : First in man safety Phase II : First in patient dose, dosage form Phase III : Efficacy, ADRs Post marketing surveillance or Phase IV :

Evaluation in the real clinical setting

Phase I Clinical trial

Objectives To assess : ` Safe & tolerated dose ` If pharmacokinetics differ from animal to man `If kinetics show proper absorption bioavailability `To detect effects unrelated to the expected action ` To detect any predictable toxicity

Phase I Clinical trial

Inclusion criteria
Healthy volunteers Uniformity of subjects

age, sex, nutritional status

[Informed consent a must]

Exceptions: Patients only for toxic drugs Eg . Anti-HIV, Anticancer

Exclusion criteria
Women of child bearing age, children, elderly

Methods:

Phase I contd .....

First in Man : Small number of healthy volunteers ( 20 to 25 ) Start with a dose of about 1/10 to 1/5 tolerated animal dose Slowly increase the dose to find a safe tolerated dose If safe in a larger group of up to about 50 75 No blinding Performed by clinical pharmacologists Centre has emergency care & facility for kinetics study Performed in a single centre Takes 3 6 months [ 70% success rate]

Types of Phase II Studies

Phase II A Studies

Phase II B Studies

Therapeutic exploratory trials ( To explore therapeutic efficacy)

Phase II

First in patient [ different from healthy volunteer]

Early phase [20 200 patients with relevant disease] Therapeutic benefits & ADRs evaluated Establish a dose range to be used in late phase Single blind [Only patient knows] comparison with standard drug Late phase [ 50 500] Double blind Compared with a placebo or standard drug

Phase II

Expected outcomes Assesses efficacy against a defined therapeutic endpoint . Detailed P.kinetic & P.dynamic data Establishes a dose & a dosage form for future trials Takes 6 months to 2 years [ 35% success rate]

Phase III trials

Objective :
Generate robust and quality data Comparison with a standard treatment Advantages offered
Efficacy Safety Cost

Risk-benefit ratio

Phase III
Large scale, Randomised, Controlled trials Target population: 500 2000 patients Performed by Clinicians in the hospital Minimises errors of phases I and II Takes a long time: up to 5 years [25% success]

Phase III
Methods Multicentric Ensures geographic & ethnic variations Diff patient subgroups . 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

Phase IV or Post marketing Surveillance

Why it is needed
Generate robust data in large number of pts.
Safety Efficacy

Limited number of pts avl. for trials

Low pts. availability. Less pts. Volunteer

Cant subject large number to risks.

Phase IV or Post marketing Surveillance

Starts immediately after marketing Sponsors furnish periodic safety data ( Periodic safety update reports , PSURs ) PSURs submitted every 6 months for 2 years ;subsequently annually for 2 years. Helps to detect Rare ADRs Drug interactions Also new uses for drugs [Sometimes called Phase V]

Phase IV or Post marketing Surveillance

All serious ADRs reported within 15 days to regulatory authorities. Phase IV studies can result in

Withdrawal of new drugs. Reveal greater potential e.g. aspirin, metronidazole.

Basic objective is to gain safety data

Prevent ADRs e.g. use of antacids/antiulcer drug with NSAIDs).

CLINICAL TRIAL PHASES

PreClinic al testing Years 3.5 Phase I Phase II Phase III Regulat ory 2.5 12 Total Phase IV 1 2 3

Test Population

Laborator y& animal studies

File IND

20 to 80 Healthy volunteer s Determin e Safety And dosage

100 to 300 Patient volunteer s Evaluate Efficacy, look For side effects

1000 to 3000 Patient volunteers Verify Efficacy, Monitor adverse Reactions From long Term use

File NDA

Purpose

Assess safety & biological activity

Review process/ Approv al

Additio nal Post Marketi ng Testing Require d

Success Rate

5000 Compoun ds evaluated

1 approve d

Elements of Plan

Background pharmacology Phase 1 standard studies

Phase 2 dose-ranging studies

Phase 3 pivotal studies Drug-drug interaction Organ impairment PK, BA, metabolism Phase 3b and 4 studies Study outlines for individual studies Time for individual studies and whole plan Cost for individual studies and whole plan Discussion of issues, risks, alternatives

Decision-Making After the Trial

Did it work? How well did it work? NPV (Net Productive Value) Was the dose level about right? Higher than needed? Low? What side effects were observed?

Were side effects were dose limiting?

Does the risk/benefit ratio seem appropriate for the disease being studied? If risk/benefit in question, is there another candidate disease? Should the project be KILLED?

What if It didnt Work?

Was the drug absorbed? Did it get to the site of action? Was the dose/duration adequate Was half life long enough to impact the disease? Was duration of exposure long enough? Is there any reason why the target might not have responded?

PRINCIPLES OF CLINICAL RESEARCH

Systematic do everything the same way per the protocol Diligence attention to detail Practical good judgment, common sense Ethical behaviour always do the right thing Understand statistical issues and applications

Quality in clinical research may be defined as

Reliability and credibility of information

The output from the clinical research

process is information
Pooling of data in database

Trial protocol

Collection Of data

Analysis

Trial Report

The end product of clinical research

A product is an output from a process
The output from the clinical research

process is information

A Question

Collection & analysis of data

An Answer

5 STEPS IN CLINICAL RESEARCH PROCESS

Interpretation Documentation Implementation Strategic Planning Pre - Planning

Pre - Planning
Planning the Site & Investigators Planning Monitoring & QA team Planning contact point with regulatory Planning CRO

Planning who will analyze & interpret

generated data

Strategic Planning
Objectives of the study defined Time frames projection Estimation of required resources (investigational product, money & study personnel) IEC / IRB & Regulatory requirements studied Planning for supplies of IP(Investigational product

Planning lab where investigations to be done

Implementation
Monitoring team to be trained & organized Creating all essential documents (Detailed protocols, CRFs, Informed Consent Document, etc.) Finalizing Protocol with Investigator & team Submission of Protocol to regulatory agencies for approval Intiating the study after approval from regulatory & IEC / IRB

Documentation Data generated

Monitors supervise data

collected at timely
intervals

Interpretation

Collected information
organized, analyzed, interpreted & packaged for final presentation

Sponsor

Subjects

Investigator Team /Site

Clinical Trial
Regulatory Bodies Laboratory

IEC/IRB

Success of Clinical Trials depends on

Good information flow

Open communication Channel among participants

Keys to Administering Successful Trials

Plan, plan, plan-failing to plan is planning to fail
Define clear, concise, and complete objectives in the protocol Communicate with investigators as to their expectations and responsibilities Train all participants thoroughly in their expected activities and record keeping requirements Focus attention on regulatory & ethical requirements and issues

Keys to Administering Successful Trials (Contd.)

Maintain a good information exchange among the participants Follow up, follow up, follow up

Feedback, feedback, feedback

Document, document, document Better planning yields better tools, resulting in better research

 Any

Questions ?

Thank You