Everybody has heard of research and that without it we cannot make progress but exactly what is it and how does it work? Here the charity’s Scientific Director, Dr David Flavell answers this question and explains exactly why research is absolutely vital to improving existing treatments and in devising new ones for leukaemia and other cancers.
Put simply, research by definition is the process by which new facts are discovered about anything. This new information can then be put to good use for improving something that already exists by understanding it better or even to invent something that is entirely new. This is exactly the approach that Leukaemia Busters funded scientists have always adopted in pursuit of their potentially lifesaving research and it is the approach that has been proven time after time as the most effective way to conduct medical research that leads eventually to clinical improvements.
Research is not an activity conducted by researchers working in isolation, it is a process that involves the sharing of new information with other scientists worldwide, usually through the publication of scientific papers but also through specialized scientific and medical conferences and through personal contacts and collaborations between different laboratories with common interests. Research networks can grow as agglomerations of multiple bodies of research scientists often scattered around the globe who pursue a shared research interest together, with each contributing their own particular skills and know-how to the group. This is often termed the multidisciplinary approach and has an real accelerating effect on what is possible. Whilst such large bodies of collaborating networks of scientists can reach a critical mass for making discoveries this is not to underestimate the value of the individual or small teams of researchers who make valuable contributions to the body of knowledge that can then be drawn on by others.
In a nutshell there are basically three types of research in medicine each seamlessly integrating with each other to achieve the right outcomes at improving patient.
Basic Discovery Research
Basic or discovery research is laboratory based and is designed to uncover new facts about fundamental biological processes relevant to a particular disease. This type of research doesn’t always have an obvious immediate practical application. However, it is often the case that discoveries made this way are found to have an important practical value, many years into the future. Scientists who work in translational research (see below) are always on the lookout for basic discoveries made previously by others that they see can likely be turned into something of practical value either in the diagnosis, therapy or general care of patients.
But how does the discovery research process work? It begins with an observation that raises an unanswered question. A simple example would be something like this – some types of cancer cells grow in the laboratory more quickly than others and the research scientist asks the question “why?” The researcher may then do some online research searching the scientific literature and talking to other colleagues to find out which genes have been discovered that might account for such a difference in growth rates. The scientist will then create a hypothesis that speculates which gene or set of genes might be responsible and why. They then devise experiments that are designed to “test” their hypothesis and to prove if it is correct or not. If it is correct then this leads to further experiments to investigate things in more depth. If experiments prove their hypothesis wrong then it’s back to the drawing board, the hypothesis will be discarded and the researcher will have to look at other explanations and construct an alternative hypothesis that can be tested once again. The process continues and eventually the true facts emerge through an iterative process of hypothesis testing that is aptly named hypothesis led research. This is at the heart of all basic discovery research.
Translational Research
Translational research is really a direct extension of basic research that is focused on taking and developing results that look promising as being of practical application for patients. Scientists and institutes often work on basic and translational research in parallel. The secret of successful translational research is to be able to identify those discoveries that are most likely to be developed into something of practical value for patients. Once this has been identified it is the job of the translational research scientist to think of ways in which the discovery can be practically applied and to conduct experiments that demonstrate this. Such an example might be the further development of an antibody discovered through basic research that laboratory and animal experiments have shown to have positive therapeutic effects.
Clinical Research
Ultimately it is the intention of all research to be of direct benefit for cancer and leukaemia patients. This is achieved through meticulous clinical studies in the form of clinical trials that carefully test in real world patients whether a new treatment is both safe and effective against the cancer in question. The clinical trial process to approve a new drug can take many years and is expensive but it is currently the only assured way of knowing that a drug is safe and of any potential therapeutic value against the cancer in question. Formal clinical trials are complex undertakings and are carried out under a strict protocol that requires a multidisciplinary approach involving teams including specialised nurses, laboratory staff, pharmacists, statisticians, research managers and physicians to name but some.
Clinical trials can be broken down into four distinct phases.
Phase I
A phase I trial marks the very beginning of a long process that leads eventually to a new drug being approved for general use in patients with a specific disease. Phase I clinical trials in cancer usually involve a relatively small number of patients, maybe 20 -30 at most. The primary purpose is to evaluate the safety of the drug by administering increasing doses of the drug to cohorts of usually three patients and then escalating the dose for subsequent cohorts according to a strict mathematical formula. Patients are monitored very carefully for adverse effects or toxicities that are thought to be due to the drug until a dose level called the maximum tolerated dose (MTD) is reached where certain side effects of a given intensity are seen. The MTD is taken as being the starting dose for a follow-on Phase II clinical trial.
Phase II
Having established the safe dose to use in Phase I, a Phase II trial is designed to establish an estimate of the response rate using the drug at the MTD. Again, this usually involves a relatively small number of 20-30 patients. If this trial demonstrates that 20 percent or more of patients show a response to the drug without any serious side effects then the trial may progress to Phase III (see below)If any unexpected side effects arise in these Phase II patients or of there are no therapeutic results, then the Phase I trial may be repeated to re-evaluate the MTD, or the development of the drug may be discontinued.
Phase III
If all goes well in the Phase II trial and responses are seen without serious side effects, then large numbers of patients, that can number up to several hundred, are recruited into a Phase III trial and treated at the MTD dose. This is to get a more accurate evaluation of the response of the cancer to the new drug and is often called the pivotal trial. If the response rate is shown to be good without any serious side effects, then the drug can proceed to a Phase IV trial or trials.
Phase IV
The Phase IV trial usually involves large numbers of patients and is intended to compare the new drug against existing best current treatments or alternatively to incorporate the new drug into existing established drug cocktails (regimens) to determine whether adding the new drug to existing treatments improves the therapeutic effect for patients. These types of advanced trial are usually done on what is called a “double blind” basis to avoid any bias in the interpretation of results. Patients are split into two groups, one that receives the existing best current treatment plus a placebo (a dummy drug) and the other that receives the same existing best current treatment plus the new drug. Neither the patient nor treating physicians know who is receiving which treatment to avoid any bias in the observed outcomes. Groups of patients in Phase IV studies need to be large so an accurate statistical analysis can be undertaken to say definitively whether the drug is genuinely active.
At Leukaemia Busters we have always adhered to all these best practice principles that drive good meaningful research. It has been proven many times over that doing so leads to discoveries of real practical value for patients and is the best route to progress through so called evidence-based research in medicine.
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