It has been an interesting few weeks. On 26th and 27th February, the results of the double-blind, placebo-controlled trial of GDNF in Parkinson’s and of the open-label extension study were published in Brain and Journal of Parkinson’s disease respectively. The following day the first part of a doublebill documentary on the trial was broadcast in the UK on BBC2. The following week the concluding part was also broadcast.
Between the papers and the documentary, the subject has been thoroughly examined and dissected. Discussion groups have been alive with interest, comment and interpretation. Many comments have been positive and congratulatory to the study participants, designers, scientists, documentary makers and the charities that funded the trial. Some comments have been negative, often expressing frustrations driven by the dichotomy between documentary title and final conclusions. Some thought that words like “miracle cure”, even when followed by a question mark, misled people over the content. If I’m honest, I would agree.
None of that should take away from the imagination of the scientists who devised this trial and from the naked courage of those who participated in the study. Let’s be under no illusions here – these men and women put their lives on the line by being part of the study. Alan Whone, the principal investigator, said as much at the beginning of the documentary. This was experimental surgery, an experimental method, and an experimental drug. The possibility of catastrophe was very real. And that’s not hyperbole. It’s fact.
Of course the documentary made much of the bravery of the participants (and rightly so, in my view), putting a human face on the raw numbers of science. Emotions ran high and low. A rollercoaster, if you must use that tired tabloid simile. And nowhere were the emotions more raw than in the sequence describing Tom’s death. Tragic – almost comically tragic – that the person so central to the instigation of the trial should be the only one unable to benefit. You could almost hear Tom laughing at the injustice of it.
So what are we left with? What is Tom’s legacy? If we strip away, for a moment, the human dimension and look simply at the numbers, what does the data show? Did GDNF work or did it not?
To answer that, you have to move away from the documentary and go to the papers themselves. The only piece of data presented as such in the documentary was the moment when Alan Whone revealed, in what was uncomfortably close to gameshow host mode, that the drug had failed to reach its primary endpoint.
But what does that mean?
To answer that question, you need to know a little bit about clinical trial design. Bear with me – I’ll try to keep this as short as possible.
Basically all clinical trials have what’s known as a primary endpoint. This is essentially a clinical measure chosen before the trial begins to determine efficacy over placebo. Depending on the nature of the trial, the primary endpoint can be one of many things. In some studies for instance, quality of life may be the main interest and a quality-of-life measure would therefore be chosen as the primary endpoint. In a cancer trial, the main interest might be duration of survival and an appropriate endpoint would be chosen to reflect that. But for trials of Parkinson’s drugs, the norm has been a measure called UPDRS (Universal Parkinson’s Disease Rating Scale) or at least the motor component of the scale.
The study investigators set themselves the target of a 20% improvement in “off” state motor UPDRS. GDNF failed to reach that target. Nor did it show any difference on secondary points. End of story. End of GDNF.
Hang on a moment. Not so fast. When you look at the post hoc analyses (the ones that weren’t included at the beginning), a rather different picture emerges. 43% of patients receiving GDNF showed clinically important motor improvement. None receiving placebo did. PET scans of patients receiving GDNF showed between 25% and hundred percent increased fluorodopa uptake in the putamen. Not one placebo patient showed a change.
These results are a little more difficult to reconcile with the failure to demonstrate effectiveness at the primary endpoint. But the rules of statistics are such that one needs to define one’s endpoints in advance of the trial not at the end. If the post hoc analyses had been included at the beginning, we might be talking about the data slightly differently. Imagine for instance if fluorodopa uptake had been chosen as a primary endpoint. The study would have been a triumph. They would be singing and dancing.
But that’s the cruel world of statistics. A beautiful hypothesis apparently slain by ugly fact. And of course you are welcome to believe that should you so wish. But I think you would be selling the study short if you did.
It is the easiest thing in the world to utter the standard scientific mantra that “further studies are required” before conclusions can be drawn. The general public, where science is concerned, is not fond of cliffhangers. I’m a patient and a scientist. As a patient, I want answers. As a scientist, I want to know that the answer is the correct one.
How do you marry up those two aspects? How do we blend the patient’s sense of urgency with the scientists need for accuracy? The longer you look at it the more obvious is the answer. You have to involve patients. Study designs have to reflect patient experience. And, more than that, that experience needs to be central not peripheral.
“GDNF works, I know it works” said Steven Gill “it’s just a matter of getting enough of it it in the right place”. We’ve learned a lot from this trial. And we owe a lot to the 41 souls who put their lives on the line in this trial.
To paraphrase Churchill “Never in the field of human neurosurgery has so much been owed by so many to so few”.