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Clinical Trials

Clinical Trials. Phases of drug evaluation. Molecular Screening Pre-clinical studies Phase 1 Phase 2 Phase 3 Phase 4. Clinical trials. Stages of drug development. Preclinical studies Mutagenicity Acute toxicity Subacute toxicity Chronic toxicity Reproductive toxicity

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Clinical Trials

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  1. Clinical Trials

  2. Phases of drug evaluation • Molecular Screening • Pre-clinical studies • Phase 1 • Phase 2 • Phase 3 • Phase 4 Clinical trials

  3. Stages of drug development • Preclinical studies • Mutagenicity • Acute toxicity • Subacute toxicity • Chronic toxicity • Reproductive toxicity • Carcinogenicity • Efficacy • PK & PD • Clinical studies • Phase I • Phase Ia • Phase Ib • Phase II • Phase IIa • Phase IIb • Phase III • Phase IIIa • Phase IIIb • Phase IV Discovery • Computer modeling • Screening • Bioinformatics

  4. Need for preclinical study • Ethical aspects in using humans for studying an unknown drug (Nuremberg; 1947) • Objectives • Extensive Invitro and Invivo studies (Efficacy) • Short-term & long-term toxicity studies (Toxicity) • Finding molecular targets of drug action (Pharmacodynamics) • ADME studies (Pharmacokinetics)

  5. Limitations of Preclinical study • Time consuming (2-5 years) & expensive • Large number of animals needed • Target site/receptor absent in test species • Lack of available animal model(s) of disease • Extrapolation of data to humans not completely reliable • Rare adverse effects are unlikely to be detected

  6. Clinical Trials A clinical trial is an organized research conducted on human beings to investigate new methods of preventing, detecting, diagnosing, or treating an illness or disease. In some instances, clinical trials attempt to improve a patient’s quality of life.

  7. Phase1 trials • Phase I trials, sometimes called, “first in human” trials, • Conducted on relatively small groups (typically 10 to 30) • Healthy volunteers (except for oncology drugs or other potentially toxic compounds) • In specialized units, with 20 to 50 monitored beds

  8. Phase I • Phase I can be divided into 2 sub phases: • Phase Ia • Phase Ib

  9. Phase 1a • SAD - Single Ascending Dose studies • Maximum tolerated dose (MTD) is calculated. • Conducted in 6-8 groups with 3 to 6 individuals in each group. • Duration( a day to a week)

  10. Aims of phase1a trials • Safety( any serious adverse effect) • Tolerability (max. tolerated dose) • PK (dose response) • PD (pharmacology)

  11. Phase 1b • MAD - Multiple Ascending Dose studies • Better understand the pharmacokinetics/pharmacodynamics of the drug. • 8 individuals in 3 groups. • Dose range narrowed down

  12. Aims of phase1b trial • Safety • Tolerability on longer treatment duration with multiple doses.

  13. Prerequisites for phase 1 trials • Preclinical data.- Chemical and pharmaceutical information. Specific pharmacological action (dose- response relationship). • Regulatory approval • Clearance from ethics committee

  14. Prerequisites for phase 1 trials • Qualified investigator. • Lab. compliance with GLP • Specific protocol • Case Record Form- Data collection form • Informed consent

  15. Phase 2a clinical trial • 20 -30 patients • Relatively pure form of disease. • Duration – weeks to a few months. • Pilot trials to calculate dose range. • More PK information in disease condition • Preliminary evidences of efficacy

  16. Phase 2b of clinical trials • Aimed at elucidating dose response relationships. • Safety and, for the first time, efficacy, of the compound treating the disease or the condition for which it is intended. Parameters for efficacy measurement are defined.

  17. Phase2b cont’d • Drug-drug interactions are also studied carefully during Phase 2b • Identification of disease subtypes for which the drug is particularly effective/ ineffective. • Comparison with placebo.

  18. PHASE - III

  19. Phase-III Phase IIIb Phase IIIa

  20. Objectives Confirm the therapeutic effect. Less common side effects and adverse events. Establish dosage range and interval. Quantify specific side effects.

  21. Design Randomised,controlled trial. Usually multicentric study. Participants- 300-3000+

  22. Results It gives much information needed for package inserts and product labeling. Obtaining approval of authorities for marketing of drug.

  23. Phase-IIIb It’s started shortly before regulatory submission and is completed prior to product launch.

  24. Phase-IIIb Cost-effectiveness and efficacy. Develop information on use in special patient’s population. Strengthen the safety profile.

  25. PHASE IV

  26. Phase IV • If drug successfully passes through first 3 phases, it will usually be approved for use in general population.

  27. THEN WHYPHASE IV? • Mandated by regulatory authorities / undertaken by sponsors for competitive / other reasons. Main reasons: • More about the side effects and safety of the drug, • What will be the long term risks and benefits. • How well the drug works when it’s used more widely than in clinical trials. • Toxicity of already marketed drug.

  28. THEN WHYPHASE IV? • Safety Surveillance • Drug Effectiveness • Patient Satisfaction • Quality of Life • Outcomes Research • Cost Effectiveness • Pharmacoepidemiology

  29. TWO MAJOR DIVISIONS • PRUS – Post Registration Utilization Studies. • PMS - Post Marketing Surveillance.

  30. What it do? • Withdrawal / restriction of drug from market. • recent examples: Cervastatin- baycol & lipoboy Rofecoxib - vioxx

  31. HISTORY OF PMS • Thalidomide tragedy (1961)- seal limbs. • Chloramphenicol - aplastic anemia.

  32. To summarize

  33. Clinical Research:- Present scenario

  34. Clinical Research- Global Scenario • The global pharmaceutical market:-USD 427 billion • Research & Development:- USD 60-65 billion annually. • Clinical trials involve almost 70 % of time and money of new drug development. • Cost of conducting clinical trials for new drug is approximately between USD 200-250 million.

  35. Clinical Research-Indian Scenario • Mackinsey estimate, US and European pharmaceutical companies will spend almost US $1.5 billion/yr in India by 2010 and approximately 50,000 professionals are needed. • Started more courses in CR • Started pharmacovigilance system

  36. Why India? • Very large patient population/drug naïve patient’s • Low cost and fast • Trained doctors and paramedical professionals • Well equipped hospitals • Strong information technology infrastructure • Use of English as a primary business language

  37. Challenges of CR in India • Non-availability of ICH-GCP trained investigators and staff • Lack of data protection for the data generated in clinical trials. • Reliability and credibility of data generated. • Concerns over ethical issues in patient recruitment and conduct of trial. • Lack of validated equipments and accredited laboratories.

  38. Major players of clinical research • Sponsor • Contract Research Organization(CRO) • SMO • Regulatory authorities • Investigator and Site management team

  39. Types of clinical trials in India • CT for new drug-Phase 2 and Phase 3 • Phase 4 trials • Prevention studies • Quality of life studies • New combinations (Phase 3) • First time in India(Phase 3) • New diagnostic methods

  40. Job opportunities after pharmacy • CRA • Feasibility and site selection • Site initiation • Site management and monitoring • Site close out and Data retrieval • CRC • Getting informed consent • Filling CRF and trial related documentation • Adverse event reporting • Drug dispensing and maintaining drug accountability

  41. Job opportunities contd… • Regulatory affairs • Preparing regulatory documents for submission to different regulatory authorities like DCGI, USFDA, MOH etc. • Managing regulatory aspects of trial • Pharmacovigilance • AEs management and reporting to regulatory

  42. Job opportunities contd… • Data Management • CRF preparation, Data base preparation • Data entry • DCF Management • Data base locking • Medical Writing • Narrative writing • Report writing • Publication writing • BABE studies

  43. Courses in clinical research • Institute of clinical Research India(ICRI) • MSc in clinical research-2 years-(4.5 lacks fees) • Post graduate diploma in clinical research-1 year(1.2 lacks) • Amrita institute of medical science • Post graduate diploma in clinical research-1 year(2 lacks) • Apollo Hospitals • Fellowship in clinical research-6 month(Rs30,000)

  44. Pharmacovigilance • Symogen-Mumbai- 4 months course • Medical Writing • Certified program in healthcare and medical writing-Infocus, Hyderabad (15,000)

  45. Thank you

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