October 2003
The Future of Cancer Clinical Trials
This meeting arranged by ACDM, British Oncology Data Managers Association and The Institute of Clinical Research was held on June 10th, at the Thistle Hotel in Marble Arch.
The first speaker was Professor Karol Sikora who presented on the future of rational drug development. He discussed that the targets of drug design are now specific molecular targets like extracellular receptors or intracellular i.e. target genes. A large proportion of cancer drugs in development at present are targeting specific points in molecular pathways. He also proposed that the outcomes of phase 1 studies should be modified to determine the Maximum Efficacy dose instead of the Maximum Toxicity dose, and should also determine the PK and PD, and examine the molecular pathology.
He continued with a description of the use of biological markers (e.g. proteins, RNA in blood or urine) in drug development to measure the specific effect the study agent is having on the target pathway. The biological marker could become a surrogate endpoint of studies or even the new primary endpoint of the studies, replacing tumour response, which is the classical end point of these studies. Using such markers is non-invasive and also easy and cheap. They are biologically relevant and so can directly demonstrate disease activity. He predicted that in the future, the molecular abnormality of the cancer will become more important in influencing therapy choice and that disease control, not eradication of cancer, leading to life long patient treatment could become the norm.
The next speaker Professor Herbie Newell, followed on from this by elaborating upon Translational Research as a way of producing new anti-cancer drugs. By selecting specific targets in the molecular pathology of cancer, the results from basic lab studies can be translated into potential drugs. Molecular targets can be selected from pathways which normally result in the activation of oncogenes or inactivation of tumor suppression genes or cause angiogenesis or metastasis of the tumor cells. Preventing/blocking such pathways is the ultimate aim.
To demonstrate how translation research will provide new cancer drugs, Herbie picked some specific examples.
One of these was the development of the drug Herceptin/trastuzumab in breast cancer. The gene HER2 is overexpressed in certain phenotypes of breast cancer. This leads to an overexpression of growth receptors on the cell surface. Once the target had been identified antibodies were developed which bound to the growth receptor. The antibody with the most antagonistic properties was rhuMAB HER2 – which is the molecule currently being studied in patients with metastatic breast cancer overexpressing HER2 gene.
Translation research could also be used to individualise treatments specifically for the patient e.g. studies are being conducted in ovarian cancer to determine a dose for carboplatin based upon a patient's renal function not the body surface area.
He also pointed out that this type of research is more difficult to perform if there are no markers to assess how the target is being affected by the new treatment. For example, there is no biological marker to assess drugs that target a growing tumor's blood flow. The fast pace of the Human Genome project has benefited Translational research, leading to the production of new study agents that target molecular and cellular pathology of cancer.
The next speaker, Dr. Duncan Jodrell, concentrated on phase 1 studies in oncology. Unlike other therapeutic areas, oncology phase 1 trials are usually performed in patients and not healthy volunteers. This has benefits such as early identification of anti-tumor activity and improved quality of life as the relevant population is being tested. However there are also some disadvantages as the population is heterogeneous and patients are normally at the end of all other chemotherapy treatment.
The aim of phase 1 studies is to establish the MTD (maximum tolerated dose) and to determine and establish the toxicity profile of the study drug and to propose a safe dose for Phase II studies. He suggested that perhaps oncology studies should place less importance on finding the maximum toxicity of a study agent, as toxicity can be unrelated to efficacy and more emphasis placed on biological/mechanistic end points in order to determine dosing levels. This is becoming more relevant as more target-based drugs become available.
He suggested that we should also place more importance on investigating the pharmacokinetic and pharmacodynamic features of the study drug in a phase 1 study instead of just being a secondary objective of phase 1 studies.
He also discussed the use of accelerated dose escalation in phase 1 studies to reduce the numbers of patients receiving inactive doses.
Kevin Fishwick then spoke about the difficulties of data management in oncology trials. There are a number of unique problems associated with oncology trials including the toxic nature of the drugs, the unpredictable nature of the disease, efficacy assessments and long follow up periods. All lead to problems for the co-ordinators of such studies. The volume of data involved in cancer studies is huge, patients are seen by GP's, surgeons, oncologists, palliative care specialists and possibly others. Many tests and investigations take place leading to a huge quantity of data, which needs to be collected – often from different departments not located within the same hospital. All this data must be archived and stored and available for future queries on past studies.
These values cluster around the "People factor". We therefore concluded that the more "formal" quality models were not right for us at this time.
After lunch Darren Churchill presented on how e-case report forms can be used in cancer trials. Despite such trials being typically complex in design, EDC is now flexible enough to cope with this. The benefits of using EDC for the sponsor are clear:
Real time data
Ability to make quick decisions
If implemented correctly the training involved with this new technology can be minimal and the number of data queries will be fewer, resulting in reduced turn around time and workload at site.
Investigator input at the design stage of the eCRF was recommended.
Jean Mossman then discussed the patient's perspective of oncology trials.
She raised some interesting points for future trials including the view that patient's should have input into the study and CRF design, which is a novel approach to be considered. She felt that the factors a patient might consider of importance to their general well being, such as fatigue, are often not given serious consideration by investigators and trial designers.
The next speaker was Nancy Lester who spoke about the National Cancer Research Network, which was established by the Department of Health in 2001. It aims to co-ordinate and provide an infrastructure for oncology studies performed within the NHS. There are 34 Cancer research Networks across England and by appointing research staff this enables access to pharmacy, pathology, radiology and other areas, thus aiding the development of high quality research. Currently the Network has 130 open trials, but its future is dependent upon a good trials portfolio. It has been developing this by working closely with main cancer funders, NCRI clinical studies group and other such organisations.
The final speaker was Dr. Pablo Fernandez who discussed the challenges faced by Global Clinical trials. Many anti-cancer trials will be multinational and multi-centre.
The protocols and design of such studies should therefore take into account the differences between healthcare systems, medical practice and the availability of patient care across different countries and even across regions within those countries. Differences in language, regulatory requirements and economic diversity are also factors that should be considered.
A patient enrolment strategy should be developed and continually monitored and communication from sites, investigators and patient groups should be encouraged.
By using specialised study teams who are knowledgeable in the therapeutic area and experienced within the local country/region, these difficulties can be overcome. Strong project management and team communication are essential.
He concluded by emphasising the importance of live global development plans by applying continuous assessment and new knowledge to ongoing programmes, plus utilizing the outcomes and experiences of early trials.
The day was very enjoyable and informative. I would like to thank all the speakers and the event organisers.
Kelly Glasson
Data Analyst, PharmaNet Ltd