Clinical development - Phases I to IV Clinical Trials

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  • Created by: LBCW0502
  • Created on: 15-01-20 16:45
What is a clinical trial?
A clinical trial is a carefully and ethically designed experiment with the aim of answering some precisely framed question. Well planned scientific experiment, includes all scientific aspects
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Why conduct clinical trials?
To assess the effectiveness and safety of a new treatment (medicine, surgical, device, psychological, physical) intervention
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What are the possible outcomes? (1)
Positive (new treatment is superior to standard treatment). Non-inferior (new treatment is equivalent to standard treatment, non-inferiority trial)
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What are the possible outcomes? (2)
Inconclusive trial (new treatment is neither clearly superior or nor clearly inferior to standard treatment). Negative (new treatment is inferior to standard treatment)
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Outline the history of the clinical trials (the drug development process) - 1
Ancient times - trial and error with plant extracts. Old testament – King Nebuchadnezzar 605-562BC -change of diet. Ambrose Pare (1537) - first clinical trial, concoction of turpentine, rose oil and egg yolk to treat wounds
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Outline the history of the clinical trials (the drug development process) - 2
James Lind (1747), introduced control groups, able to prove that citrus fruits in the diet could prevent scurvy. 1800s, placebo/dummy pill introduced. 1906 (FDA, prohibits misbranded/adulterated foods/drinks/drugs). 1923 - randomisation introduced
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Outline the history of the clinical trials (the drug development process) - 3
1930s - MRC set up therapeutic trials committee in UK, manage clinical trials on new medicines. 1938 - Federal Food, Drug and Cosmetic Act in USA (due to antifreeze in elixir of sulfanilamide/no safety/quality, start of animal studies
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Outline the history of the clinical trials (the drug development process) - 4
1944 - multi centre studies in USA, more statistical power, control of biological products/communicable diseases. 1947 - Nuremberg code, 10 points for protection of subjects/patients in clinical trials, introduced ethical principles
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Outline the history of the clinical trials (the drug development process) - 5
1948 - use of randomised double bind placebo controlled clinical trials. 1960/61 - thalidomide tragedy, caused pholcomelia. 1963 - Committee on Safety of Drugs. 1964 - Declaration of Helsinki (ethical codes)
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Outline the history of the clinical trials (the drug development process) - 6
1968 - Medicines Act UK, control therapeutic clinical trials. Directive 2001 - implement good clinical practice and good manufacturing practice. 2004 - Medicines for human use regulations. 2012 - human medicines regulations
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Outline the history of the clinical trials (the drug development process) - 7
2017 - EMEA guidance on first in human studies. Aim for 3Rs (reduce, replace and refine)
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What is a directive?
Directive – allows each member state to take contents of directive, interpret this and apply this to particular state
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What is a regulation?
Regulation – cannot be interpreted by member state
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Give examples of scientific advancement due to clinical trials (1)
Insulin for type I diabetes mellitus. Treatments/prevention of meningitis. Treatments for HIV. Treatments for invasive breast cancer (earlier diagnosis, awareness, screening, mammography
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Give examples of scientific advancement due to clinical trials (2)
Targeted use of endocrine/adjuvant therapies, trastuzumab, multi-disciplinary teams
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Outline the drug development process
Research (6.5 years), early development, clinical trials (7 years) phase I, phase II, phase III, towards full development, regulatory submission (1.5 years), launch, phase IV
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Describe features of the drug development process today (1)
New medicines have had a significant positive effect on human health. Desire for new more efficacious and safer drugs
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Describe features of the drug development process today (2)
Advances in molecular biology and biotechnology have led to - greater understanding of disease processes, discovery of exciting new classes of therapeutic agents, personalised medicine and the influence of genetics. Highly regulated environment
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Describe features of the drug development process today (3)
Safety, science, ethics. High cost industry. Research and development. Reimbursement vs cost effectiveness. Increased international harmonisation (ICH). Increased public awareness (high expectations for safety/efficacy, better outcomes for patients)
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What are the three factors considered for drug development?
Safety, quality data, efficiency
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State features of pre-clinical testing
Discovery, target optimisation, pharmacology, safety pharmacology, pharmacokinetics/toxicokinetics/ADME, acute toxicity, repeat dose toxicity, mutagenicity/genotoxicity, reproductive toxicity, carcinogenicity, juvenile toxicology
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State features of predicting from animal pharmacology and toxicology (1)
The fundamental tenet of testing drugs in animals is that such information helps to predict the efficacy and toxicity of drugs that are candidates for human use. Values of many tests unproven. Major interspecies variations
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State features of predicting from animal pharmacology and toxicology (2)
Animal studies don't necessarily predict what will happen in humans
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Describe features of phase 1 studies (1)
Initial exposure of humans to investigational drugs. Safety, tolerance, PK and PD. Exploratory but employs randomised placebo controlled study design. Subjects are healthy volunteers usually. Increased in more targeted medicines
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Describe features of phase 1 studies (2)
Monoclonal antibodies, advanced cell therapies. Usually single site. N = 40-100 subjects (not statistically powered). Usually conducted in hospitals and NIHR clinical research facilities
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Describe features of phase 1 studies (3)
Not looking for efficacy in phase 1 studies (not dosing for long enough). (Articles, incident report, cytokine storm, analgesics, anti-inflammatory drugs, EMA)
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Describe features of phase 2 studies (1)
Initial assessment in target (patient) population. Safety, tolerance, efficacy. Phase 2a (efficacy), phase 2b (effective dose range). Well controlled study designs in a narrowly defined patient population. Double blind, randomised, placebo controlled
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Describe features of phase 2 studies (2)
Market leader comparators included. Conducted in hospitals. Performed in more than one site. Statistically powered (N = 100-300). Identifies efficacious doses for later phase development
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Describe features of phase 3 studies (1)
Confirmation of effective doses from phase 2. Expanded tolerability profile. Collection of data from a more varied patient population, Determine overall risk/benefit profile. N = 1000-5000. Multi centre, international
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Describe features of phase 3 studies (2)
Carried out in hospitals, GP/equivalent sites. Double blond, randomised, fully controlled. Regarded as pivotal by regulatory authorities (subject to regulatory inspection). Next step - application for marketing approval
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Describe features of phase 4 studies (1)
Performed after marketing approval. Exposure of drug to wider population providing more safety an efficacy information. Different formulations, doses, new treatment uses, greater comparisons with other available treatments for the same condition
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Describe features of phase 4 studies (2)
Drug interactions in the wider population. Detection and definition of previously unknown or inadequately quantified adverse events and related risk factors. Expect reports of ADRs which were not seen in phases 2 and 3
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