Clinical Trials - PowerPoint PPT Presentation

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Clinical Trials

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Janyne Afseth Research Network Manager Scottish Cancer Research Network * New blood vessel formation (angiogenesis) is highly dependent on VEGF (vascular endothelial ... – PowerPoint PPT presentation

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Title: Clinical Trials


1
Clinical Trials
  • Janyne Afseth
  • Research Network Manager
  • Scottish Cancer Research Network

2
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

3
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
4
What is a Clinical Trial?
  • Research study
  • Conducted in human volunteers
  • Designed to answer specific questions
  • Uses scientifically controlled methods

5
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)

6
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

7
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

8
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

9
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)

10
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

11
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

12
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

13
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

14
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

15
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

16
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


17
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.

18
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

19
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

20
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

21
Informed Consent
  • Participation is voluntary
  • No coercion or inducement
  • Information verbally and in writing
  • Time to consider
  • Support and communication

22
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

23
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.

24
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

25
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

26
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
27
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
28
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
29
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

30
Support of the patient in Clinical Trials
  • Patient advocate
  • Patient educator
  • Direct care provider
  • Coordinator
  • Administrator
  • Data manager

31
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

32
Clinical Trials Improve Quality Care
  • Scientific discovery
  • New drug development
  • Improved procedures
  • Benefits to patients
  • Economic development

33
Any Questions
  • ???
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