CANCER NEW DRUG TRIALS AND THE COMMITTEE
For most modern trials, there will be a committee (usually called the Independent Data Monitoring Committee, IDMC, or Data and Safety Monitoring Committee, DSMC) set up to independently monitor the results as they accrue. This is in place to protect patients primarily – if there are unforeseen toxicity problems, for example, the trial may be stopped early. Later on in the trial, the IDMC can end the study if the predefined endpoints are met early. This allows early dissemination of the data and allows other patients access to the drug earlier. Conversely, the IDMC can also determine that the trial is never likely to show significant differences and stop the trial early on grounds of futility.
Endpoints in trials are controversial. Trials are expensive, often $100 million plus, and hence drug companies want them to be as small and quick as possible. Conversely, regulators want the most reliable outcome measures and hence longer follow-up periods or larger sample sizes. Society at large has needs somewhere in between. We all want better medicines, and if we’ve got cancer, we want them now. Equally, we want them to be safe. Also, the larger and longer the trial, the more the drug company has to charge for the drug in order to pay back the higher development costs for a more detailed discussion of this issue. As health budgets grow, so the pressure to reduce drug costs rises, making the availability of new drugs increasingly restricted for cancer patients in poorer economies. As a way out of these conflicting tensions, increasingly, researchers are looking for what is called ‘surrogate’ endpoints. The aim is to pick an early endpoint that will accurately predict the final outcome of the trial. The response rate in a phase 2 trial is an example of a surrogate endpoint used to select a drug for phase 3 study. The problem is that the correlation between response rate and the sort of endpoints regulators require, such as improved survival, is not sufficiently good to allow a high response rate in phase 2 to lead directly to a licence. The same will generally apply to comparisons of the response rates in randomized trials.
In order to get away from using survival-based comparisons, which clearly take a long time, investigators must show that some earlier measure reliably predicts the final outcome. An example of such a measure is the ‘time to progression’ mentioned above. This is the time taken for the tumour to grow or spread by pre-specified amounts and is commonly used as a registration trial endpoint in early breast cancer. In some disease settings, for example, PSA in prostate cancer, the candidate marker is unreliable, and drugs in prostate cancer are still currently stuck with needing to show improved survival to get a licence. In prostate cancer, studies are currently evaluating a novel method of response which is counting the number of circulating tumour cells. Typically, these are present in tiny numbers – around 5 per 7.5 millilitres of blood is the key cut-off level – a very tiny number of needles in a massive haystack of tens of millions of blood cells. If validated, such a test could greatly accelerate the pace of cancer drug development in diseases like prostate cancer currently stuck with overall survival endpoints. As shorter trials are cheaper, it could also reduce the price of the drug when licensed.