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![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](https://image.slidesharecdn.com/classclinicalpharmacology-151210104225/75/Class-clinical-pharmacology-13-2048.jpg)
![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]](https://image.slidesharecdn.com/classclinicalpharmacology-151210104225/75/Class-clinical-pharmacology-14-2048.jpg)
![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]](https://image.slidesharecdn.com/classclinicalpharmacology-151210104225/75/Class-clinical-pharmacology-15-2048.jpg)
Uploaded byRaghu Prasada
Class clinical pharmacology
This document discusses evidence-based medicine and the process of conducting clinical trials to evaluate new drugs. It describes how clinical trials progress from early phases evaluating safety and appropriate dosing to later phases assessing efficacy. Key aspects addressed include study design, informed consent, ethics review, and post-marketing surveillance. The goal of drug development is to demonstrate that a new medication has genuine clinical benefit compared to existing options and that its risks are closely monitored.
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- 1. Dr. RAGHU PRASADAM S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
- 2. Evidence-based medicine isthe systematic, scientific and explicit use of current best evidence in making decisions about the care of individual patients Therapeutic evaluation of drug Quantification of benefit Appropriate method-dosage, duration, patient selection Surveillance of adverse effects clinical trials cohort studies case control studies
- 4.
- 5. Cost vs HealthOutcomes Grid Effectiveness - Effectiveness + Costs - Costs + ? Useless Dominant re we ready to give up on effectiveness for lower costs?! Costs more but does less Costs more and does more Costs less but does more Costs less and does less
- 6. Based on: Appropriateness/Safety/Efficacy and cost Genuine indication Minimum number of drugs Inexpensive and appropriate formulation Preferably oral route – avoid injections Monitor adverse drug Event Patient education related to drugs and disease
- 7. Approval ofthe product, new drugs should be closely monitored for their clinical safety once they are marketed. The applicants shall furnish Periodic Safety Update Reports (PSURs) in order to- Report all the relevant new information from appropriate sources; Relate these data to patient exposure; Summarize the market authorization status in different countries and any significant variations related to safety; and Indicate whether changes should be made to produce information in order to optimize the use of the product.
- 8. Title & Abstract Introduction Generalstatement 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
- 9. Informed consent form: Voluntary Explainedin 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
- 10. 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
- 11. To protect thedignity, 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
- 12. It is aprospective ethically designed investigation in human subject to objectively discover/verify/ compare/ the results of two or more therapeutic measures(drugs) Preclincal studiesmicrodosing studies 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
- 13. Objectives To assess asafe & 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
- 14. 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]
- 15. 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]
- 18. Age: Pediatric,Geriatric Gender: Women Physiology:Pregnancy, Nursing Pathological states: renal failure, hepatic failure, cardiac failure, BMI: obese, lean Ethnicity/Race Vulnerability
- 19. Guidance for Industry,investigators and Reviewers; Exploratory IND Studies, Jan 2006,US FDA
- 20. Phase III A:up to NDA submission End of Phase III A studies must include special patient populations and pharmacoeconomic data collection At least one placebo controlled trial Phase III B: Ongoing at time of NDA submission Undertaken after NDA submission but before NCE is marketed New indications may be included New patient populations may be included Special features explored e.g. drug interactions 20PLS-2012
- 21. Objectives To assess overalland relative therapeutic value of the new drug Efficacy, Safety and Special Properties To determine optimal dosage schedule for use in General Practice The dosage schedule in C.T.’s should be as close as possible to its anticipated clinical use Data obtained is Major component of NDA submissions-Regulatory inputs are important i.e. what comparative drug to use Marketing Department inputs i.e. information on most widely Prescribed treatment 21PLS-2012
- 22. Large Sample Size:Multicentric, ↑Variability Fewer exclusion criteria (stable concomitant disease allowed) Longer duration of treatment: Weeks/Months Study design Parallel Cross over Investigator’s Brochure Study Protocol (Investigator’s meeting) All investigators agree to follow Case Record forms Same at all centers Study monitoring especially recruitment rate Study monitors Clinical research associates Drug supplies 22PLS-2012
- 23. After Marketing Permission (RealWorld Use of the New D Thousands/Lakhs of patients now use the drug G.P.’s, Little medical supervision Co morbidities/other drugs taken (Herbals) Non adherence to treatment rampant (> 50%) Long duration of treatment Self-medication rampant - Prescription drugs - OTC drugs PLS-2012 23
- 24. Phase IV C.T.:Special Characteristics 1. Very large sample size 2. No or little supervision: Physician shopping 3. Fewer data collected from each patient 4. Fewer Exclusions (Contraindications only) 5. Longer drug administrations 6. Expensive 7. Comorbidities and co-medications 8. Non adherence to treatment: Common 9. Self-medication common PLS-2012 24
- 25. To obtain informationon Unsupervised use of Registered Drug in the Community under daily routine conditions PMS: Legally fulfill this Regulatory Requirement Mandatory for Fast Track Approvals Does not influence diagnostic/therapeutic procedures of Participating physicians. Uses Specific Record Forms Enrolled patients are not subjected to any disadvantage or additional risk Data collected provides an unbiased picture of daily routine Use of drug, allowing Realistic assessment of Benefit-Risk ratios
- 26. 1. Comparative longterm Benefit-Risk assessment 2. Drug usage in the community 3. QOL Assessment 4. Dose-refinement 5. Rare ADR’s and long term safety 6. Benefit-Cost assessment 7. Improvement in Primary End-points of disease
- 27. 1. Spontaneous VoluntaryReporting 2. Case Control Studies 3. Intensive Hospital Monitoring 4. Prescription Event Monitoring 5. Literature Surveys 6. Prospective population based studies for rare ADR’s 7. Automated patient Data Banks (Useful for retrospective studies)
- 28. CDSCO, HQ National CoordinationCentre IPC Ghaziabad, UP Steering Committee Working Group Signal Review Panel CoreTraining Panel Quality Review Panel M O N A I D T R O R I N G IMMUNIZATION PROGRAMMES Pharmaceutical Industry ADRs originating in India PROFESSIONAL BODIES HOSPITALS MEDICAL COLLEGES Stakeholders Patients, Health Care Professionals, Pharma Industry CDSCO ZONAL/SUBZONAL OFFICES North Ghazi abad Chan digar h South Chenn ai,Hyd eraba d, Bangl ore East Kolkata West Mumb ai Ahma dabad 1 3 4 c A D E B PHARMACOVIGILANCE 28
- 29. It isthe pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse reaction with Pharmaceutical products. It is the study of the safety of marketed drugs under the practical conditions of clinical use in large communities It is concerned with the development of science and regulation in the area of drug safety.
- 32. Restrictive inclusion/exclusion criterialimits generalizability Conflict between results observed in controlled experiment versus use in real life Too expensive Single intervention, single-dose-though there is increasing use of factorial design Ethical considerations Bias in what interventions are studied and what studies are published Translation of large sample derived risks and outcomes to individual patients
- 33. 1. Not dependenton large resources or research infrastructure 2. Can be interesting, accessible and readily digestible for readers 3. Convey the ‘art’ of medicine 4. Not all research questions are amenable to RCT 5. An expedient way of communicating new ideas, syndromes, treatments and adverse reactions
- 34. “All substances arepoisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Paracelsus (1493-1541) THANKYOU Download slides from Authorstream/presentations/raghuprasada Slideshare/presentations/raghuprasada Youtube-raghuprasada