Clinical Trials

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Clinical Trials

• Janyne Afseth
• Research Network Manager
• Scottish Cancer Research Network

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Objectives

• Describe the drug development process
• Review the ethical framework that underpins
  clinical research
• Discuss current trends in cancer research and
  where we are going
• Discuss the role of the nurse in clinical trials

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Behind the scenes
Trial management team Statistician Lab scientists
Ethics Committees Sponsors, Funding
Sources Regulatory Groups
Patient
Regulation, Management and approval
Clinic
Doctors, Nurses NHS Laboratory Staff
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What is a Clinical Trial?

• Research study
• Conducted in human volunteers
• Designed to answer specific questions
• Uses scientifically controlled methods

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Why do Clinical Trials?

• Evaluate the efficacy of new drug therapies and
  drug side effects (combinations of drugs, new
  ways of giving treatment, new types of treatment)
• Evaluate the use and effectiveness of
  interventions, i.e.. surgical or diagnostic
  procedures (Scans, screening tests,surgical
  procedures)
• Evaluate programs of cancer prevention and
  control (vitamins,foods, drugs)
• Evaluate the psychological impact of treatment on
  patients (quality of life studies)

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Why is clinical research important?

• Quest to advance knowledge often benefits
  research subjects.
• Patients may directly benefit from advanced
  therapies or indirectly from the satisfaction of
  contributing to society
• Research benefits society as a whole
• Safe ways of new drug/novel agent development

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History of ClinicalTrials

• Lind (1747) comparative study using citrus in the
  treatment of scurvy (6 arms)
• 19th century utilized basic trial concepts in the
  development of of drugs and vaccines
• Early 20th century studies focused on the
  prophylaxis and treatment of infectious diseases
• 1948 first placebo, controlled randomised trial
• 1960s present over 50 new drugs have been
  developed for treatment of cancer

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Prospective randomised trials

• Gold standard for evaluating new practices and
  therapeutic agents in medicine
• The reason is that investigators could introduce
  bias and invalidate conclusions by the manner
  that they assigned patients to treatment groups

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Trial design

• Question to be answered needs to be defined
• Study endpoints
• Study then designed to test this hypothesis using
  statistical methods
• Investigators must evaluation also evaluate what
  is clinically significant (i.e likely to change
  practice)

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Protocols

• Ensure consistency
• Define a specific plan of action
• Contain the following elements
• Introduction
• Eligibility Criteria
• Schedule of events
• Toxicity evaluation/dose reduction
• Kinetic sampling information
• Drug storage and admixture information
• Evaluation of response/follow up

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Phases of New Drug Development

• Phase I maximum tolerated dose
• Phase II determines drug activity/response
• Phase III compared to standard therapy
• Phase IV post marketing studies

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Regulatory Agencies

• Medicines and Health Care Products Regulatory
  Agency (UK) (MHRA)/FDA (USA)
• Must give authorisation for trials
• Can inspect sites for compliance with research
  legislation
• Ultimately decide if the evidence for usage in an
  indication can be licensed

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MHRA

• 1948 NHS committee set up to look at limiting
  prescriptions
• 1960s Thalidomide sparked the formation of the
  Committee on the Safety of Drugs
• 1968 Medicines Act provided for a comprehensive
  system of licensing affecting manufacture, sale,
  supply and importation of medicinal products.
• MHRA also controls clinical trials, advertising,
  quality control, manufacture of unlicensed
  products and control of imports

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Codes of Conduct for Research Trials

• Nuremberg Code (1947) basic moral, ethical, and
  legal concepts for experimentation. Developed as
  a result of experiments done in the Nazi
  concentration camps.
• Helsinki Declaration (1964) Recommendations to
  guide the physician in biomedical research
  involving human subjects. Includes basic
  principles, medical research combined with
  professional care, and non-therapeutic biomedical
  research guidelines

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New Drug Development

• 10-12 years and 550 million to develop a new
  medicine
• 20 of worlds top medicines were discovered and
  developed in UK
• 9 million invested in UK RD daily
• -www.abpi.org.uk

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Who pays for Clinical Trials?

• Drug Companies
• 500 million annually
• International/national Trial Organizations
• EORTC
• NCRI
• Government Funding
• Medical research council (MRC)
• Department of Health (England)/CSO (Scotland)
• Cancer Charities
• Cancer Research UK (largest cancer research
  organisation outside US)
• The Leukaemia Research Fund
• 
  

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How can patients go onto trials

• All will have patient selection criteria
• Doctors and nurses identify patients through
  multidisciplinary meetings and by screening
  clinic lists
• Some patients will self refer
• Must pass all eligibility criteria to go on (i.e.
  bloods, scans etc.

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Advantages to Trial Participation

• New treatment may work, drug not available
  outside of trial
• Improving cancer treatment for other patients
• Close monitoring
• Patients treated in a centre where clinical
  trials are done do better than people with a
  similar stage and type of cancer

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Patients choose clinical trials because

• Altruism
• Family pressure
• Unwillingness to give up
• Hope of benefit
• Input into care
• They think the treatments may be better

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Patients chose not to participate

• Fear of being allocated to control group
• Too far to travel
• Desire to have Dr. choose treatment
• Guinea Pigs
• Complex Consent process
• Disliked focusing on disease

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Informed Consent

• Participation is voluntary
• No coercion or inducement
• Information verbally and in writing
• Time to consider
• Support and communication

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Clinical trials in Cancer

• 1940-50s the effect of mustard gas as therapeutic
  agent investigated.
• 50-60s combination chemotherapy
• Bone marrow transplant, hormonal agents
  (Tamoxifen 1970s)
• Biological agents

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New strategy - Molecular targeting

• Allows selectivity with less toxicity
• As the understanding of how cancer cells survive,
  thrive and spread can allow researchers to target
  these mechanisms.

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Targets of cancer cells under investigation

• Vascular Epithelial Growth Factor (VEGF)
  inhibitors
• Avastin, Thalidomide
• PARP inhibitors
• Epidermal Growth Factor Receptor (EGFR)
  inhibitors
• Herceptin, cetuximab, Iressa
• Proteasome Inhibitors
• velcade

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Angiogenesis

• Angiogenesis is the formation of new blood
  vessels from pre-existing vasculature
• Angiogenesis is highly dependent on the VEGF
  signalling pathway
• VEGFR-2 is the most important VEGF signalling
  pathway for angiogenesis
• VEGF is frequently overexpressed in cancer and is
  associated with poor prognosis
• Without a blood supply, tumours do not grow
  larger than 12mm
• As tumours grow they become hypoxic, which leads
  to the up-regulation of angiogenic factors such
  as VEGF
• Stimulates the production of new vasculature

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Activation of VEGF receptor signalling
VEGF-AVEGF-CVEGF-D
PlGFVEGF-AVEGF-B
VEGF-CVEGF-D
Blood vascularendothelial cell
Lymphatic vascularendothelial cell
VEGFR-1
VEGFR-2
VEGFR-3
Proliferation, vascular permeability, migration,
survival
PlGF, placental growth factor VEGFR, vascular
endothelial growth factor receptor
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Approaches to the inhibition of VEGF signalling
Ligands
VEGF-A
Anti-VEGF antibodies
VEGF-B
VEGF-C
VEGF-D
Blood vascularendothelial cell
Lymphatic vascularendothelial cell
VEGFR-1
VEGFR-2
VEGFR-3
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Approaches to the inhibition of VEGF signalling
Ligands
VEGFR-TKIs
VEGF-A
VEGF-B
VEGF-C
VEGF-D
Lymphatic vascularendothelial cell
Blood vascularendothelial cell
VEGFR-1
VEGFR-2
VEGFR-3
Angiogenesis
Lymphangiogenesis
VEGFR-TKI, vascular endothelial growth factor
receptor-tyrosine kinase inhibitor
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Inhibition of VEGF signalling

• Inhibiting VEGF signalling
• inhibits growth of new tumour vessels
• decreases vascular density, diameter and
  permeability
• may induce regression of recently developed
  tumour microvessels
• Therapeutic inhibition of tumour angiogenesis
  should be effective in a broad range of solid
  malignancies
• Target tissue is in direct contact with blood,
  facilitating drug delivery

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Support of the patient in Clinical Trials

• Patient advocate
• Patient educator
• Direct care provider
• Coordinator
• Administrator
• Data manager

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Implications of care for patients on trials

• The potential for unexpected side effects is high
  with the pattern not yet established
• Supportive care what works with chemotherapy
  may not be the same for newer agent
• Synergy of drugs is often unknown
• Information of to larger multidisciplinary team
  is essential
• Patient involvement and time commitment often may
  be much greater with the associated education
  needs

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Clinical Trials Improve Quality Care

• Scientific discovery
• New drug development
• Improved procedures
• Benefits to patients
• Economic development

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Any Questions

• ???