Clinical Trials Scientific Aspects AND Legal

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Clinical TrialsScientific AspectsANDLegal
Procedural Aspects

• M K Unnikrishnan Aug 2006

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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

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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,

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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

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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
• 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

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Cross over design

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

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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

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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

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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

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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

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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

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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

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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

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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

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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,

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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