Clinical trials scientific aspects and legal procedural aspects
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Clinical Trials Scientific Aspects AND Legal & Procedural Aspects . M K Unnikrishnan [Aug 2006]. Scientific Aspects of Clinical Trial. Phases of Clinical Trial Phase I: First in man  safety Phase II: First in patient d ose, dosage form Phase III: Efficacy, ADRs

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Clinical Trials Scientific Aspects AND Legal & Procedural Aspects

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Clinical trials scientific aspects and legal procedural aspects

Clinical TrialsScientific AspectsANDLegal & Procedural Aspects

M K Unnikrishnan [Aug 2006]


Scientific aspects of clinical trial

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


Phase i

Phase I

  • Objectives

    • 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

    • Healthy volunteers : Uniformity of subjects: age, sex, nutritional status [Informed consent a must]

    • Exception: Patients only for toxic drugs Eg AntiHIV, Anticancer

  • Exclusion criteria

    • Women of child bearing age, children,


Phase i contd

Phase I contd

  • Methods:

    • 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

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]


Phase iii

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

    • 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

Cross over design

GroupWeek 1Week2Week3

IStandardPlaceboTest

IIPlaceboTestStandard

IIITestStandardPlacebo

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


Phase iv or post marketing surveillance

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

Clinical Trial: Legal & Procedural aspects

Elements of a Clinical Trial

  • 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

Participating Parties in Clinical Trial

  • Patient / Healthy volunteer

  • Clinical Pharmacologist, Clinical Investigator & team: [Qualified and competent]

  • Institution where trials are held : [Approval required]

  • Ethical Review Board or Institutional Ethical Committee:

  • Sponsor

  • Regulatory Authorities:


Functions of participating parties

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

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,

  • [6] Regulatory Authorities:

    • Legal authority on the outcomes of the trial


Clinical trial protocol

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

  • 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

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

Responsibilities of IEC

  • To protect the dignity, rights & well being of patients / volunteers

  • Ensure a competent review of the protocol

  • Advise on all aspects of welfare & safety

  • Ensure scientific soundness of the proposal


The composition of iec

The composition of IEC

1. Chairperson

2. 1-2 basic medical scientists.

3. 1-2 clinicians from various Institutes

4. One legal expert or retired judge

5. One social scientist / representative of NGO

6. One philosopher / ethicist / theologian

7. One lay person from the community

8. Member Secretary

  • Individuals from other institutions if required

  • Adequate representation of age, gender, community,


Problem areas

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


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