Transcript Scientific Aspects of Clinical Trial

Clinical Trials
Scientific Aspects
AND
Legal & Procedural Aspects
M K Unnikrishnan [Aug 2006]
Scientific Aspects of Clinical Trial
Phases of Clinical Trial
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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
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Objectives
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Phase I
To assess a safe & tolerated dose
To see if pharmacokinetics differ much from animal to
man
To see if kinetics show proper absorption, bioavailability
To detect effects unrelated to the expected action
To detect any predictable toxicity
Inclusion criteria
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Healthy volunteers : Uniformity of subjects: age, sex,
nutritional status [Informed consent a must]
Exception: Patients only for toxic drugs Eg AntiHIV,
Anticancer
Exclusion criteria
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Women of child bearing age, children,
• 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]
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
• 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]
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Phase III
Large scale, Randomised, Controlled trials
Target population: 250 – 1000 patients
Performed by Clinicians in the hospital
Minimises errors of phases I and II
Methods
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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]
Cross over design
Group
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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
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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]
Clinical Trial: Legal & Procedural
aspects
Elements of a Clinical Trial
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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 :
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Pays for all expenses;
Appoints competent investigators,
Ships all drugs for the trial,
Files all papers to legal / regulatory authorities,
– [6] Regulatory Authorities:
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Legal authority on the outcomes of the trial
• Title & Abstract
• Introduction
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Clinical Trial Protocol
General statement of purpose
Complete Preclinical results on animal study
Clinical data if available
Time frame
• Goals: Primary & secondary objectives
• Study Design:
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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:
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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
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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