The Rise Of The Placebo Response In CNS Clinical Trials

There has been a lot of controversy recently about the rise of the Placebo response in recent Central Nervous System (CNS) clinical trials. Many of these trials failed to show statistically different responses between new treatments and Placebos. It seems that the Placebo Response in CNS trials has never been as high in the past and it is becoming more and more important.

Many people have tried to figure out why, some almost going to the extent of seeing some kind of mystical explanation to it. The most common and accepted explanation is to say that clinical investigators are becoming less and less experienced and are responsible for this. The theory is that if an investigator is too empathetic during a clinical trial, they might trigger a higher Placebo Response in the subject. In addition, if the investigator is not properly trained they might be responsible for inaccurate assessments.

I believe that the explanation is actually easier to figure out. As a clinical investigator myself, some might say that I am biased but I also believe myself to be more knowledgeable than mot people about this subject since I am writing about something I experience first hand.

It is my strong belief that the rise of the Placebo Response in recent CNS clinical trials is due to the rise of regulatory and legal pressure. Let me explain this. Pharmaceutical companies are responsible for the clinical trials that they conduct (investigators too of course). Regulatory agencies put a lot of pressure on Pharmaceutical Companies to prove the efficacy of their new treatments. Statistically speaking, if you want to prove the efficacy of a new agent, you have to conduct trials v. placebo and v. the most up-to-date treatment used in the same indication. In order to do so, subjects enrolled in clinical trials have to be "perfect" in the sense that the less concomitant medical condition and treatment they have the better. Following this logic, subjects enrolled in antidepressant trials seldom suffer from any other medical condition, they are not allowed to take other medicine for anxiety or sleeping disorder and most importantly they won't enter the trial if they have suicidal ideations.

This is where the explanation lies: the most severely depressed patients all have suicidal ideations, they all suffer from severe insomnia and anxiety that would require concomitant treatment. Therefore, they wouldn't be enrolled in CNS clinical trials. The only consequence to this is that only less severely depressed patients are enrolled in clinical trials and they are the ones that are the most likely to show Placebo response.

I understand that in order to statistically prove the efficacy of a new agent, it has to be taken by patients with no other concomitant medication. However, the reality is that enhancing to statistical "beauty" of a trial by not allowing concomitant medication leads to enrolling patients that are not heterogenous enough to differentiate the new agent from the Placebo.

In addition, pharmaceutical companies don't want investigators to enroll patients that are at suicidal risks because the legal consequences of a suicide would be devastating. Once again, I understand their reasons but the reality is that it leads to enrolling less severely depressed patients in CNS clinical trials, therefore leading to a higher rate of Placebo responders.

Authorities and Pharmaceutical Companies really need to consider this in the future before they start putting the blame on investigators that, on top of everything, are probably better trained than ever before. In essence, when pharmaceutical companies say that investigators are responsible for the rise of the Placebo Response, they are admitting that patients enrolled in their trials are very likely to show Placebo Response and it has been know for a very long time, that depressed patients very likely to react to external circumstances are usually the least severely depressed ones, hence proving my point!

Why The French System Is Doomed!

This blog was never supposed to be about politics but if you'll allow me, I'll make one exception with this post. Well, actually if there's anyone reading these lines besides me, feel free to let me know if this post is inappropriate!

Anyway, I really need to express my feelings about the way things are going in France and in particular, about how workers are being treated. France Telecom recently made the headlines because more than 20 of their employees committed suicide. This is, in my opinion, the tip of the iceberg. As a mental health professional, I see, everyday, people suffering from their working conditions and let me tell you, I've seen more and more of those patients in the last 3 years. It is therefore safe to assume that the increased impact of working conditions in France on mental health isn't related to the global financial crisis but, more likely, inherent to what I'm calling "The French System".

I'm sure that from a remote perspective, the French system seems appealing: 5 weeks of vacations, 4 weeks to compensate for the reduction in working hours, 35 working hour week, public health system of very high quality etc... It all looks good but in practice, it is failing and is doomed to bring my nation to its knees. Here's why:

We have a high level of unemployment here and this has been the case for a long time. So, someone wrongly thought that a good solution would be to make it unlawful to work more than 35 hours per week in order to create more jobs. Unfortunately, the cost of employing someone is so high in this country that this reduction in working hours only had a marginal effect on the unemployment rate. What it actually lead to is to make people do in 35 hours what they used to do in 39 hours and before 40 hours. So, people work less but when they work, they don't have a single second to themselves. They have to fulfill their goals no matter what. So basically, what happens is that they do in 35 hours what they were supposed to do in 40 hours but they are a lot more stressed and a lot more inclined to making errors.

And if this wasn't enough, everything now has to fit within procedures (and that word is probably the most popular in the 21st century... People keep creating procedures for the sake of creating procedures as if the world was suffering from Obsessive Compulsive Disorder...). So, if you could do something in 5 mns, you actually can't anymore because if some stupid jerk created a 2-hour long procedure to complete the task that you have at hand, you don't have any other choice than to comply!

Why were procedures created? My bet is that it originally aimed at ensuring quality of service and standardization. What it lead to is decreased quality and the feeling amongst workers that they are machines, incapable of making simple decisions, at least, in the eyes of their managers. Their basic existence and human qualities are denied in the working place. This leads to a great deal a frustration.

So, the 2 key factors: increased work load due to reduction in working hours and "proceduralization" lead to creating frustrated, stressed and unhappy workers. These workers, scared of losing their jobs, will stand this pressure for as long as they can... Until they can't deal with it anymore and end up being mentally sick (i.e. depressed). Some are on a sick leave for more than six months and many amongst those can't go back to work because the simple thought of it scares them to death. Some, of course, will never say a word until one day, they get to work in the morning, tie a rope around their neck and hang themselves.

I can't imagine that management isn't aware of this problem. And if they're not, how lousy managers they must be! It is my belief that managers are pushed to squeeze workers into being ever more productive because they are threatened in the same way by their hierarchy.

The French are supposed to be very productive but this fact doesn't take into account the amount of sick workers created by the system.

One last thing that I can't avoid to question: how can it be that people suffering from poor working conditions become sick and will in the end be paid by social security when they're on a sick leave or on a disability pension? This can only lead to increase the cost of the working force and create even more sick people which the state will have to look after!

It is my belief that this will lead to the failure of our system if nothing is done to change things. It is, of course, my personal opinion but as a mental health professional, I see sick people everyday and they all tell the same story whether they work in the private or public sector.

Anyone can notice the effects of what's going on: nothing works anymore in this country. Customer service is a joke (because customer service representatives suffer from I've just described. I don't blame them. They're just trying to cope with the system but in the end, they have so much to do that they're bound to make errors or overlook some tasks). "Proceduralization" makes it almost impossible to get anything done in a reasonable amount of time!

Now you might ask me: why did I write this blog entry when it is only related to France? Well, mostly, because I think we have already passed the point of no return where French has become an obsolete language and the failure of our system is inevitable.