Clinical Trials

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Clinical Trials
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What are clinical trials?

• Research studies involving people
• Try to answer scientific questions and find
  better ways to prevent, diagnose, or treat
  diseases
• Used to determine if drug treatments are safe and
  effective
• Carefully conducted clinical trials are the
  safest and quickest way to find treatments that
  work

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Types of clinical trials

• Prevention trials
• Screening trials
• Diagnostic trials
• Treatment trials
• Quality-of-life studies/supportive care studies
• Genetics studies

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Drug development

• From traditional remedies
• aspirin
• penicillin
• Small changes to existing drugs
• combining existing pain relievers
• ampicillin
• Rational design of synthetic compounds
• proton pump inhibitors
• tamoxifen
• viagra

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Drug development

• Rational design of synthetic compounds
• desired effect identified eg block cell receptor
• compound identified which exerts desired effect
• improve compound activity
• In vitro testing
• test active compound against the target cell
• provides evidence on beneficial/harmful effects
• very simplistic, target organs/tissues are made
  up of multiple cell types
• Organ culture is where small pieces from whole
  organs are grown is useful for the testing of new
  drugs

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Pre-clinical testing animal testing

• Pharmacology testing
• effects of drug on all major systems
• absorption/metabolism/distribution/excretion data
• plasma levels, half life, measurement of
  metabolites
• Toxicology testing
• acute toxicity (single dose)
• short term toxicity (daily dosing for 2 wks - 3
  mths)
• potential to affect reproduction, cause cancer

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Pre-clinical testing

• ED50 - Effective Dose 50 is the amount of the
  drug required to produce a specified effect in
  50 of an animal population
• LD50 - Lethal Dose 50 is the amount of the drug
  required to cause death in 50 of an animal
  population

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Clinical trial protocol

• A recipe or blueprint
• Strict scientific guidelines
• Purpose of study
• How many people will participate
• Who is eligible to participate
• How the study will be carried out
• What information will be gathered about
  participants
• Endpoints

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Before you begin testing..

• Any clinical trial with a medicinal product must
  apply for a Clinical Trial Authorisation (CTA).
• Tires to make sure that a drug is at the right
  stage for testing in humans

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Clinical Trial Phases

• Phase I trials
• Use healthy volunteers
• How does the agent affect the human body?
• Drug absorption, metabolism and excretion
• Preferred method of administration
• What dosage is safe?

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Clinical Trial Phases

• Phase II trials
• Use target patient group
• Volunteers should be representative of those who
  will be likely to benefit form the disease
• No pregnant women
• Does the drug on have a beneficial effect on the
  disease
• Determine therapeutic dosage range
• Usually placebo controlled
• Conducted by experts in the particular disease

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Clinical Trial Phases

• Phase III trials
• Get all the data needed for regulatory agencies
• Often multi-centred, multi national
• More varied patient than phase II
• Long term safety is evaluated
• Is the new drug better than the standard?
• Participants have an equal chance to be assigned
  to one of two or more groups

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Randomised controlled trials (RCTs)

• gold standard
• Doctors have no say in who gets put in which
  group to reduce bias
• bias is something that could favour/promote one
  treatment over another give misleading results
• volunteers randomly assigned to new treatment or
  to best existing (or placebo if no current
  treatment available)
• Why is randomization important?
• So all groups are as alike as possible
• Provides best way to prove the effectiveness of a
  new drug

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What is a placebo?

• an inactive pill, identical in appearance to the
  treatment pill, given to the control group in a
  study
• used to control for the placebo effect
• due to a belief in the treatments and believes
  in the treatment

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Randomized trials
2000 patients 1000 male 1000 female
Placebo 200M 200F
Standard treatment 200M 200F
New drug dose 1 200M 200F
New drug dose 2 200M 200F
New drug dose 3 200M 200F
Sample collection and analysis
RESULT??
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Blinding

• Trials are blinded if the patients does not know
  what they are getting
• Single-blind - patient doesnt know but doctor
  does
• Double blind neither patient or doctor know
  best design (reduces bias)

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Participants in Clinical Trials

• Protocol sets out who can participate
• Use inclusion/exclusion criteria
• Factors that allow people in are the inclusion
  criteria (eg maybe study only for women)
• Factors that are used to reject people are the
  exclusion criteria (eg may be too old, history of
  illness)
• Some trials want only healthy people, some what
  only people with specific diseases (eg to test
  treatment for bowel cancer)

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During the trial

• Clinical trial team includes doctors, nurses,
  scientists, statisticians etc
• Meet volunteers explain study
• Check volunteers health
• Randomly assigned to group (by statistician)
• Given instructions for participating
• Monitored regularly

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Ethical research

• Ethical moral, right, principled
• Unethical experiments carried out by the Nazis on
  prisoners
• Some Nazi doctors tried in 1946 at Nuremberg
• Led to the Nuremberg Code first ethics code
• Set out 10 points for legitimate human
  experiments
• Led to the Declaration of Helsinki in 1964
• One key principal is informed consent
• The doctor should obtain the patients freely
  given informed consent, preferably in writing

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Patient protection

• There have, unfortunately, been past abuses in
  patient protection
• in the UK too
• Research governance regulations have been
  introduced to ensure that people are told about
  the benefits, risks, and purpose of research
  before they agree to participate and that all
  information and samples collected are treated
  properly

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How are patients rights protected?

• Ethical approval must be obtained
• Informed consent must be obtained
• Investigator must explain
• Purpose
• Procedures
• Risks and potential benefits
• Individual rights
• Ensure that risks are minimized
• Ensure data integrity/confidentiality
• Stop a trial if safety concerns arise
• Volunteer can withdraw at any stage

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Clinical trial the results

• Endpoints are used to test a trials success
• Ideally, use a hard endpoint cure from
  disease/survival
• Not always possible because of time
• Use surrogate endpoints eg in HIV we could use
  the number of CD4 cells or viral activity
• Statisticians key in analysing the results is
  test A better than B.
• Only then is study unblinded to tell what is A
  and B?

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Drug licensing

• Applications submitted by drug company to the
  Medicines Control Agency's (MCA)
• The MCA carries out pre-marketing assessment of
  the medicine's safety, quality and efficacy,
  examining all the research and test results in
  detail, before a decision is made on whether the
  product should be granted a marketing
  authorization.

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Research Governance
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What is Research Governance?

• control framework for all health and social care
  research within the NHS
• It applies to all research involving the NHS
  whether involving patients, patient records,
  patient tissues, blood samples, questionnaires,
  interviews etc

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Why do we need Research Governance?

• To ensure the public have confidence in research
  in the NHS.
• To make sure the research is
• High scientific quality
• Ethical
• Financially transparent
• Well-monitored
• Who checks?
• Government inspectors can audit a clinical trial
  at any stage

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Roles and Responsibilities

• Principal Investigator (PI)
• Sponsor - Hospital, University, Research Centre
• Monitor
• Auditor
• Funder Charity/Government/Pharmaceutical
  Industry
• Research Team

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What happens in an audit?

• Altnagelvin Trust Audits a trial on lipid
  lowering
• PI meets with auditor to give overview of project
• Auditor goes through documents to check for
• Compliance with protocol
• Evidence of scientific review
• Ethical approvals present
• Managerial approvals present
• Honorary contracts in place for research staff
• Informed consent for all participants
• Financial clarity
• Evidence of research team meetings

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Why has this all happened?

• Need to make sure that all research is following
  the law for clinical trials
• The law began with an EU Directive 2001/20/EC
• EU Directives set outcomes to be achieved each
  member State can implement how they wish
• The Directive has been implemented into UK law
  and it is this law that must now be followed
• Statutory Instrument 2004/1031 The Medicines for
  Human Use (Clinical Trials) Regulations 2004.

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Extra information

• http//www.clinicaltrials.gov/
• http//www.bbc.co.uk/science/hottopics/animalexper
  iments/
• http//www.mca.gov.uk/
• http//www.schoolscience.co.uk/content/index.asp