Why Does It Take So Long?
In your mind, it’s a simple thing. Recruit a plentiful supply of willing PD patients, randomly assign them to the experimental drug or placebo and see if there’s a difference between them at the end. Why should it take so long?
The reasons are fairly dull, but of extreme importance because at the end of the experiment, you want results that stand up to scrutiny, that may influence clinical behavior and ultimately will make a difference to quality of life of PD patients.
You start with planning your team. In a trial of any size, this requires involving an approved Clinical Trials Unit. They will have great experience of trials, but may know next to nothing about Parkinson’s, nor will they have the same urgency that you have. The priority is for things to be done properly, not quickly. You’ll realize that you need a Project manager, a coordinator, a data manager, a statistician and more than a little help from your clinical friends and colleagues. You will discuss your plans and will be met with a series of potential “what if” questions regarding drug manufacturing, supply, labeling, storage, and dispensing all of which will have a cost attached. What if a batch of drug is not stored correctly e.g. refrigeration breakdown, and trial patients can’t access their drugs for a period of time?
Which patients will you recruit? Which will you exclude? You want the best chance of showing your drug helps, but you also want to know if it helps some people more than others. How will your patients be randomized? And what if the blind needs to be broken- daytime, night-times, weekends? Will you replace your recruited patients that drop-out? How will you know if your drug is doing more harm than good? You need to plan recruit enough people to answer your question, but then how many might dropout because their PD gets worse and the trips to their local centre become too difficult? Are they allowed to take regular PD meds? Are they allowed to change them if they need to? Should they come for their trial assessments without taking them? If so, for how long do they need to stop, and for which meds? Do you need to pay for Hotels/ taxis/ arrange wheelchairs? Even if your drug works, you won’t be able to show it unless your patients taking placebo stay motivated despite maybe correctly guessing that what they’re taking is of no benefit at all!
You’ll involve patient representatives in your decisions, and try and accommodate diverging opinions about what might be acceptable to a 45-year-old versus what might be acceptable to a 75-year-old. Are you going to max out the data you’ll collect, lots of scales, blood tests, spinal taps, scans, electronic devices- you risk patient fatigue if you over-burden people. You’ll also realize that the Institution that you work for is also a business, and needs to cover its own running costs/overheads, and it will want your project to contribute to these, with a bigger contribution according to the complexity of the project….the price of your project keeps going up.
When you finally have a realistic estimate of cost, you then have to get the funding. And there will be a repeat of the exercise you’ve just been through with the opposite set of priorities- your funder will scrutinize every decision with a view of keeping the costs down. Millions of pounds spent on PD, means less millions spent on Cancer, Heart disease, Alzheimer’s, HIV etc. There is no bottomless pit of research funding. You’ll remove the expensive scans, reduce the number of patient visits and hope you can still manage on a skeleton support staff, then if you’re lucky you’ll get the funds you need.
Even in investigator initiated trials, it’s likely you’ll need a commercial partner to manufacture and supply, drug and matched placebo. This means you’re entering an arena where legal contracts need to be prepared; lawyers will modify clear text into legal jargon and argue at length about intellectual property and responsibilities in the event of problems. All this while, your earlier costing estimates are at risk of becoming out of date. Your funder and commercial partner may have polarized views on your decisions- and neither will want to negotiate.
Finally, you have your funding in place and confirmed timelines to meet. How soon to advertise and employ the staff you’re going to need? Some of them will have nothing to do until you’ve got recruitment started! But nevertheless, you need a team to get all the paperwork in place, and you don’t want delays because necessary members of your team haven’t been appointed. A Protocol that everyone has signed up to, the Patient Information, the Consent form, the GP letter, all need to be approved by an ethics board and the Regulatory agencies to check that your plans are acceptable, robust and not exposing people to undue risk. This quality assurance process is vital so that we can believe the results we read in journals…
Your database and randomization system needs to be tried and tested, drug manufacturing needs to start, data monitors need to be assigned and steering committees and Data monitoring committees convened. You then get your permission to start contacting patients. Throughout all of this period you’ve tried to maintain patient interest in your trial, but its only at the end of this process that you can judge whether your original idea is still the best question to answer, and you keep your fingers crossed that it has enough shared enthusiasm to be delivered!
On that note, thanks for your understanding and unwavering support!
Tom Foltynie, PhD, MD, MRCP is a member of the WPC 2019 Program Committee and will be speaking at the 5th World Parkinson Congress in Kyoto, Japan. He currently serves as academic neurologist at the National Hospital for Neurology and Neurosurgery and the University College London (UCL) Institute of Neurology.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®