Clinical Trials in a Nut Shell

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Clinical Trials
Scientific Aspects AND Legal & Procedural Aspects

Scientific Aspects of Clinical Trial

Phases of Clinical Trial
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

Objectives

Phase I

1. To assess a safe & tolerated dose 2. To see if pharmacokinetics differ much from animal to man 3. To see if kinetics show proper absorption, bioavailability 4. To detect effects unrelated to the expected action 5. To detect any predictable toxicity

Inclusion criteria
Healthy volunteers : Uniformity of subjects: age, sex, nutritional status [Informed consent a must] Exception: Patients only for toxic drugs Eg AntiHIV, Anticancer Women of child bearing age, children,

Exclusion criteria

 Methods:

Phase I contd

First in Man : Small number of healthy volunteers First in a small group of 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]

 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

Phase II

Late phase [ 50 500]

Double blind Compared with a placebo or standard drug

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]

Large scale, Randomised, Controlled trials Target population: 250 1000 patients Performed by Clinicians in the hospital Minimises errors of phases I and II Methods
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

Phase III

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

Cross over design

Group I II III Week 1 Standard Placebo Test Week2 Placebo Test Standard Week3 Test Standard Placebo

* A wash out period of a week between two weeks of therapy

Phase IV or Post marketing Surveillance

No fixed duration / patient population Starts immediately after marketing Report all ADRs Helps to detect
rare ADRs Drug interactions Also new uses for drugs [Sometimes called Phase V]

Elements of a Clinical Trial

Clinical Trial: Legal & Procedural aspects

Aim or objective Protocol : study design Ethics committee clearance Regulatory approval whenever required Informed consent Implementation of protocol Collection of data Compilation of data, analysis and interpretation Report writing

Participating Parties in Clinical Trial

1. Patient / Healthy volunteer 2. Clinical Pharmacologist, Clinical Investigator & team: [Qualified and competent] 3. Institution where trials are held : [Approval required] 4. Ethical Review Board or Institutional Ethical Committee: 5. Sponsor 6. Regulatory Authorities:

Functions of participating parties

[1] Patient / Healthy volunteer : Subject of the trial [2] Clinical Pharmacologist, Clinical Investigator & team:
Conducts the clinical trial; reports all adverse events

[3] Institution where trials are held :

Provides all facilities [Approval required]

Functions of parties contd.

[4] Ethical Review Board or Institutional Ethical Committee:
Supervises and monitors every step; Safeguard the welfare and the rights of the participants

[5] Sponsor :
Pays for all expenses; Appoints competent investigators, Ships all drugs for the trial, Files all papers to legal / regulatory authorities,
Legal authority on the outcomes of the trial

[6] Regulatory Authorities:

Clinical Trial Protocol

Title & Abstract Introduction
General statement of purpose Complete Preclinical results on animal study Clinical data if available Time frame Goals: Primary & secondary objectives

Study Design:
Type of study Recruitment criteria : Exclusion & Inclusion criteria Randomisation criteria and Sample size Duration of study

Data Analysis:
Case report forms, Statistical Analysis, Bibliography

Informed Consent
Informed consent form:
Voluntary Explained in simple nontechnical language Translated in the native language of the subject Comprehensive information regarding the trials
Benefit of new therapy over existing ones Alternative treatments available

All possible adverse reactions Freedom to withdraw from the trial

at any time, without giving any reason

Institutional Ethical Committee

Independent Competent 5 7 members; 5 required for quorum. Member Sec from same Institution Others: A mix of medical non-medical, scientific & non-scientific including lay public Multidisciplinary & Multisectorial

Responsibilities of IEC
1. To protect the dignity, rights & well being of patients / volunteers 2. Ensure a competent review of the protocol 3. Advise on all aspects of welfare & safety 4. Ensure scientific soundness of the proposal

The composition of IEC

1. 2. 3. 4. 5. 6. 7. 8. Chairperson 1-2 basic medical scientists. 1-2 clinicians from various Institutes One legal expert or retired judge One social scientist / representative of NGO One philosopher / ethicist / theologian One lay person from the community Member Secretary

Individuals from other institutions if required Adequate representation of age, gender, community,

Problem areas
Compensation in drug related injuries
Mild and Severe

Patient Rights
Confidentiality of data Right to withdraw

Collection procedures & amount of biological material taken Compensation & Insurance claims Sending bio-material abroad Selection of Patients