Title: Clinical Trials
1Clinical Trials
- Janyne Afseth
- Research Network Manager
- Scottish Cancer Research Network
2Objectives
- 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
3Behind 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
4What is a Clinical Trial?
- Research study
- Conducted in human volunteers
- Designed to answer specific questions
- Uses scientifically controlled methods
5Why 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)
6Why 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
7History 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
8Prospective 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
9Trial 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)
10Protocols
- 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
11Phases 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
12Regulatory 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
13MHRA
- 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
14Codes 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
15New 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
16Who 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
-
17How 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.
18Advantages 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
19Patients choose clinical trials because
- Altruism
- Family pressure
- Unwillingness to give up
- Hope of benefit
- Input into care
- They think the treatments may be better
20Patients 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
21Informed Consent
- Participation is voluntary
- No coercion or inducement
- Information verbally and in writing
- Time to consider
- Support and communication
22Clinical 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
23New 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.
24Targets 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
25Angiogenesis
- 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
26Activation 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
27Approaches 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
28Approaches 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
29Inhibition 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
30Support of the patient in Clinical Trials
- Patient advocate
- Patient educator
- Direct care provider
- Coordinator
- Administrator
- Data manager
31Implications 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
32Clinical Trials Improve Quality Care
- Scientific discovery
- New drug development
- Improved procedures
- Benefits to patients
- Economic development
33Any Questions