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Clinical Trials Scientific Aspects AND Legal & Procedural Aspects

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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  1. Clinical TrialsScientific AspectsANDLegal & Procedural Aspects M K Unnikrishnan [Aug 2006]

  2. 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

  3. 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,

  4. 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]

  5. 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]

  6. 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]

  7. 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

  8. 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]

  9. 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

  10. 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:

  11. 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]

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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,

  18. 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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