Janyne AfsethResearch Network

ManagerScottish Cancer Research

Network

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

Patient

Behind the scenes Trial management

team

Statistician

Lab scientists

Regulation,

Management and approval

Clinic

Ethics Committees

Sponsors, Funding Sources

Regulatory Groups

Doctors, Nurses

NHS Laboratory Staff

Research study

Conducted in human volunteers

Designed to answer specific questions

Uses scientifically controlled methods

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)

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

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

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

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)

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

Phase I maximum tolerated dose Phase II determines drug

activity/response Phase III compared to standard

therapy Phase IV post marketing studies

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

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

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

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

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 •

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.

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

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

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

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

1940-50s the effect of mustard gas as therapeutic agent investigated.

50-60s combination chemotherapy Bone marrow transplant, hormonal

agents (Tamoxifen – 1970s) Biological agents

Allows selectivity with less toxicity As the understanding of how cancer cells

survive, thrive and spread can allow researchers to target these mechanisms.

Vascular Epithelial Growth Factor (VEGF) inhibitors• Avastin, Thalidomide

PARP inhibitors Epidermal Growth Factor Receptor

(EGFR) inhibitors• Herceptin, cetuximab, Iressa

Proteasome Inhibitors• velcade

• 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

Blood vascularendothelial cell

Proliferation, vascular permeability, migration, survival

PlGFVEGF-AVEGF-B

VEGF-AVEGF-CVEGF-D

VEGF-CVEGF-D

PlGF, placental growth factor VEGFR, vascular endothelial growth factor receptor

Lymphatic vascular

endothelial cell

VEGFR-2VEGFR-1 VEGFR-3

Anti-VEGF antibodies

Lymphatic vascular

endothelial cell

Blood vascularendothelial cell

VEGFR-1VEGFR-2

VEGFR-3

Monoclonal antibody

VEGF-B

VEGF-D

VEGF-A

VEGF-C

Ligands

Blood vascularendothelial cell

Angiogenesis

Lymphatic vascular

endothelial cell

VEGFR-2VEGFR-1 VEGFR-3

Lymphangiogenesis

VEGFR-TKIs VEGF-B

VEGF-D

VEGF-A

VEGF-C

Ligands

X X X

VEGFR-TKI

Inhibition X

VEGFR-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor

• 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

Patient advocate Patient educator Direct care provider Coordinator Administrator Data manager

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

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

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