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 • 1960’s – 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 world’s top medicines were discovered and developed in UK • £9 million invested in UK R&D 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 1–2mm • 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-3 VEGFR-2 Proliferation, vascular permeability, migration, survival PlGF, placental growth factor VEGFR, vascular endothelial growth factor receptor

27. Monoclonal antibody 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. VEGFR-TKI Inhibition X X X X 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-3 VEGFR-2 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 ???