1. Clinical Trials Scientific Aspects AND Legal & 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 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 –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 GroupWeek 1Week2Week3 IStandardPlaceboTest IIPlaceboTestStandard IIITestStandardPlacebo * 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 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 :

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 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

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