Clinical studies & Pharmacovigilance
Clinical studies & Pharmacovigilance
Content
• Stages of clinical studies
• Pharmacodynamic studies
• Toxicity studies
• Assessment of safety index
At the end of this lecture, student will be able to
• Explain the stages of clinical studies
• Describe Post marketing studies
• Discuss the assessment of safety index
Clinical Studies
Clinical trial is a systemic research of investigating the safety and efficacy of a new drug in human subjects
• Establishing new drugs
• comparing with standard treatments trying in different population
• To study the pharmacological properties of drugs i.e. pharmacokinetic & pharmacodynemic
• To study toxicological properties of drugs
• It represent the scientific way to test individual agents to ensure safety & effectiveness, as well as compare two or more methods.
• It can give information about appropriate route & frequency of administration of drug in human.
Phases of clinical trial
Phase 0
• Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the U.S. Food and Drug Administration’s (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies
• Also known as human microdosing studies
• Administration of single sub-therapeutic dose of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the drug’s :
ü pharmacokinetics (how the body processes the drug)
ü pharmacodynamics (how the drug works in the body)
It gives no data on safety/efficacy, as the dose is too low to cause any therapeutic effect
Phase-1
• First time testing
• In a small group of 20-100
• Duration : 6-9 months
Purpose
• To evaluate safety & tolerability with the initial administration of investigational new drug into human.
• Conducted in healthy volunteers
• Drugs with significant potential toxicity e.g. Cytotoxic drugs are usually studies.
Studies conducted in phase-1, usually intended to involve one or a combination of following objectives:
• Maximum tolerated dose: to determine the tolerability of the dose range expected to be needed, nature of adverse reaction that can be expectd, in this included both single & multiple dose
• Pharmacokinetics : i.e. characterization of drug’s absorption, disteibution, metabolism, excretion
• Pharmacodynamics: depending on the drug & endpoint studies, studies related to drug blood levels may be conducted into healthy patient or patient with target disease
Phase-2 Therapeutic exploratory trials
Tested in large group of people
• 100-300
Duration
• 6 month to 3 year
Purpose is to further evaluate
• Effectiveness of a drug for a particular indication in patients with the condition under study to determine the common short term side effects & risk associated with the drug.
• Additional objectives of phase 2 studies can include evaluation of potential study endpoints, therapeutic regimens for further study
Classification
• Phase IIA - to assess dosing requirements (how much drug should be given)
• Phase IIB - to study efficacy (how well the drug works at the prescribed dose)
Phase 3 Therapeutic confirmatory trial
Objective
ü to gather additional information about efficacy and safety to evaluate overall benefit-risk ratio of the drug
Sample size
• several hundred to several thousand(1000 to 3000/more)
• Duration : 1 to 4 year
Design
• randomized controlled multicenter (can be multinational also)trials
• sometimes crossover design is also used
Phase-4 Post marketing trial
• Post marketing trial are studies performed after drug approval
• These trials go beyond the prior demonstration of drug’s safety, efficacy.
• These trials may not be considered necessary at the time of new drug approval but may be required by licensing authority for optimizing drug’s use
• Certain rare ADRs/low frequency effects not manifest in earlier clinical trials because of small study population
• To study increase in frequency or severity of known adverse reactions as population of users expand after drug approval.
• Study population in clinical trial not always representative of normal clinical practices i.e. age, gender, race etc
• To study modifiers of efficacy-concurrent drugs, disease severity, pregnancy, lactation, renal impairment etc.
• To compare the incidence of ADRs in humans treated and not treated with the drug
• Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses.
Post marketing surveillance
After the approval of the product, new drugs should be closely monitored for their clinical safety once they are in marketed, as per revised Schedule Y, the applicant is required Periodic Safety Update Report(PSURs) every 6 months for the first 2 years after approval of drug.
Structure of PSURs:
• Title page(applicant name data of approval etc)
• Introduction
• Current worldwide market authorization status
• Update of actions taken for safety reasons
• Changes to reference safety reasons
• Estimated patient exposure
• Presentation of individual case history
• Studies
• Other information
• Overall safety evaluation
• Conclusion
• appendix
Phase 5
• new uses for drugs
Summary
• Clinical trials are experiments or observations done in clinical research
• Such prospective biomedical or behavioural research studies on human participants are designed to answer specific questions about biomedical or behavioural interventions, including new treatments
• Clinical trials generate data on safety and efficacy
• They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought.
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