Finding a Better Way in Clinical Trials Fear about receiving the placebo is one of the biggest barriers to drug trial recriutment. In this article by Elly Earls in Pharma Technology Focus, Tom Isaacs comments on new trial designs which aim to reduce the number of people in the placebo groups. Concern about receiving the placebo is one of the biggest barriers to clinical trial recruitment. It’s just one factor that is leading more and more researchers to experiment with approaches to clinical trials that limit the number of patients in the placebo group. But could it be possible to do away with placebos entirely? Or are there certain scenarios where the baseline of data gained from patients that only receive sugar pills is absolutely necessary to statistically significant outcomes? A recent survey carried out by Parkinson’s Disease (PD) advocacy groups into the reasons behind the relatively low success rates of PD trials found that one of the top three barriers keeping PD sufferers from signing up to clinical trials was concern about receiving the placebo (38% of study subjects saw this as a principal barrier, compared to 56% who cited fears about potential adverse consequences or side effects and 53% who were mainly worried about disrupting their ongoing medical regime). And Parkinson’s isn’t the only condition where placebo fears affect recruitment rates. “There is always the fact that the patient would like to receive a treatment; that’s quite clear and understandable,” says Elisabetta Vaudano, principal scientific manager and coordinator of the Scientific Pillar at the Innovative Medicines Initiative (IMI). “Of course, it depends a lot on what procedures the patient has to undergo during the trial – for example if they have to do a lot of laborious testing and then on top of that they have a high chance they are only receiving placebo, clearly it can be particularly challenging.” Tom Isaacs, co-founder of The Cure Parkinson’s Trust and lead investigator of the recent survey into PD trials, agrees that psychological issues certainly come into play. “Imagine if you’ve been on a trial for two years and you’ve been feeling much better, and then they tell you at the end of the trial that you’ve been on a placebo all that time; it could be devastating.” Tom IsaacsTom adds that other factors that contribute to patients’ worries about receiving placebos, particularly during PD trials, include the inevitable upheaval in their medication regimes, as well as the fact that participating in one trial, even if you do only receive the placebo, may exclude you from others in the future. Of course, recruitment issues are not the only argument against the use of large placebo groups in clinical trials. They’re also very expensive, which is another reason why researchers are increasingly looking to limit the number of patients that don’t receive any potentially beneficial treatment. “There really is a tendency to try and minimise as much as possible the number of patients that are in the placebo group; it’s a general trend,” confirms Vaudano, who is currently involved in a €53m project at the IMI to pioneer new ways of studying drugs for Alzheimer's disease. During the study, there will be several treatment groups for different drugs but they will all share a single placebo group, shrinking the number of patients only receiving placebo to around 20% of the total cohort of patients, significantly less than the conventional 50-50 split. Correcting placebo use. So if the IMI team is already demonstrating that it could be possible to get the percentage of patients on placebo down to 20%, is it also conceivable that we could eventually do away with the placebo group altogether? It really does depend on the type of study. Trials for particular conditions, such as life-threatening cancers, never involve a placebo group. And it’s similar for conditions that already have a ‘standard of care’ that has been comprehensively studied and can be used as a baseline instead of the placebo. “In cancer, patients are normally provided with the ‘standard of care’; you never, never have clinical trials in oncology where you have patients that are given placebo, because this is considered unethical,” Vaudano explains. “Similarly, when you already have a trial that is advanced and you want to get some confirmational results or if you already have a range of drugs out there, then you don’t have a placebo simply because there are already treatments out there.”However, if you don’t already have some sort of baseline, the placebo group is absolutely crucial. “It would be a very difficult and challenging thing [to get rid of the placebo group entirely] in the types of trials we’re carrying out [in the IMI Alzheimer’s disease study], for example,” Vaudano says. “These trials are called proof of concept trials, which is the first type of trial you do with a drug on patients where you want to see if there is some effect. Now, if you don’t have a comparison with something, if you don’t have a baseline, then it’s not possible to do the comparison and your results won’t be valid. Indeed, those who receive the placebo are the most important group.”That said though, Tom Isaacs does think there is some merit to early trials that don’t have a placebo arm –open label trials – even if they don’t offer enough clinical evidence on their own to confirm whether or not a drug is effective. “Regardless of how anecdotal the evidence is in any trial, it’s still important. Why take the negative view when the positive view is equally valid? Evidence is anecdotal, yes, but don’t dismiss it – follow it up.” A great recent example is a small open label study of twelve patients, which studied the impact of an expensive cancer drug, nilotinib, on people with PD, and showed ‘fast improvement’ in the volunteers who were all at an advanced stage of illness. The results have been met with scepticism from many quarters, particularly as there is historically a big placebo effect with Parkinson’s open label trials. However, The Cure Parkinson’s Trust has already adopted a proactive and positive plan in the wake of these results to try and establish as quickly as possible whether the use of nilotinib in Parkinson’s can really change the course of the condition as dramatically as reported by those involved with the recent open label trial.As Tom Isaacs summarises: “At the moment, my opinion is that placebo syndrome is probably needed in later stage trials. But I think there needs to be a correction in the use of the placebo, a correction in the magnitude of how it’s used.” Patient-centred trials: the future. Vaudano is keen to stress that the industry is already heading in that direction, as well as trying to improve the experience for patients that are involved in any aspect of a clinical trial. “It’s important to say that in the space of doing better clinical trials, putting the patient at the centre is an area of very high attention at the moment - both from those who want to get the treatment to the patient quickly and also for commercial reasons, to reduce the cost,” she notes. There is also a bigger focus across the sector, she adds, on using data that has already been collected from other trials to make current trials more efficient, something else that can limit the number of patients needed for both the treatment and placebo group. For example, the IMI’s NEWMEDs programme, a collaborative project designed to find new methods for the development of drugs for schizophrenia and depression, recently released a paper revealing that early clinical trials of schizophrenia drugs could be made shorter and more efficient, dramatically reducing patients’ exposure to both the trial drug and the placebo, if more women and more people with certain types of symptoms and/or younger patients were recruited.“They found that by picking patients with the right characteristics you can make the trials shorter and use fewer people,” Vaudano remarks. “Obviously that brings down the cost and you don’t need to recruit as many patients.”“This whole idea is really in line with the overall goal that we have with the IMI - improving the overall drug development process to try and make it more efficient for everyone, including patients, but also the people who put the trials together,” she concludes. “There’s a lot of interest in this area at the moment.” This article was written by Elly Earls with contributions from Tom Isaacs (CPT President) and was published in the October 2015 edition of Pharma Technology Focus.