Clinical trial

Clinical Trials

Scientific AspectsAND

Legal & Procedural Aspects

ATHAR SHAMIMM.PHARM 2nd sem

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• Objectives1. 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, bioavailability4. To detect effects unrelated to the expected action5. 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• 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• 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 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• 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

Group Week 1 Week2 Week3I Standard Placebo TestII Placebo Test StandardIII Test Standard Placebo

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

New drug application

• The New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing.

• Goal of the NDA are to provide enough information to permit FDA reviewers to establish the following:

Cont…..

• Is the drug safe and effective in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks?

• Is the drug’s proposed labeling (package insert) appropriate, and what should it contain?

• Are the methods used in manufacturing (Good Manufacturing Practice, GMP) the drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity?

• Once approval of an NDA is obtained, the new drug can be legally marketed starting that day

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 • 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 Trial1. Patient / Healthy volunteer2. 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 :

– 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• 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 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– 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 IEC1. To protect the dignity, rights & well being of

patients / volunteers2. Ensure a competent review of the protocol3. Advise on all aspects of welfare & safety 4. Ensure scientific soundness of the proposal

The composition of IEC1. Chairperson 2. 1-2 basic medical scientists. 3. 1-2 clinicians from various Institutes4. One legal expert or retired judge5. One social scientist / representative of NGO 6. One philosopher / ethicist / theologian7. One lay person from the community8. 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

References

• Brunton L. J. et al., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed., 2006,Mc Graw Hill Publishers, pp 117-119

• Tripathi K.D., “Essentials of Medical Pharmacology” , 6th ed., 2008, Jaypee Publishers, pp 71-73, 77

• Ali Asgar et. al., “Clinical Trials and Health Care Policies”, 2005, Jamia Hamdard, pp 5-8, 22-25

• Rang H.P. et al., Rang & Dale’s Pharmacology, 6th ed., 2008, Churchill Livingstone, pp 92-95, 784-785

• http://clinicaltrials.gov/ct2/info/understand#Q01• http://en.wikipedia.org/wiki/Clinical_trial• http://cdsco.nic.in/html/schedule-y%20(amended%20version-2005)%20origina

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