New medicines are becoming increasingly complex to develop. As a result, clinical development is taking 25% longer and the chance of a new medicinal product getting market approval is half of what it was a decade ago. Much of this is reflected in the way clinical trials are performed, with a 10% annual increase in the number and variety of procedures required. Thus, the burden on investigators and trial sites is steadily becoming heavier.
In most aspects of our lives, the internet has enabled us to rapidly access information. In particular, smartphones allow us to search and retrieve almost any information that we need “on the fly.” We book our flights and hotels, make restaurant reservations and communicate with our families on our phones. Who uses, or even possesses, a telephone directory anymore?
However, a zombie-like relic of the telephone directory still lives on in clinical trials. It’s called the protocol, which:
- Is almost always a weighty document of perhaps 150 densely printed pages.
- Must only be used in its currently approved version, so it may need to be changed half a dozen times during the life of a trial. Each amendment must be approved for every individual site.
- Usually lives on a shelf in an office, often remote from where it is most needed in the clinical area in which its trial is being conducted.
- Is slow to search for information, especially if not immediately to hand. If it does have an electronic existence, it is usually as a PDF document which is hard to search in a hurry.
The protocol hasn’t changed in any significant way for 40 years. It is no surprise that about 35% of adverse findings of FDA inspections are related to non-compliance with the protocol. This is not a harmless zombie!
There are many examples to illustrate why printed protocols have outlived their utility.
For example, typical oncology sites outside of the major centers may run about a dozen different trials at one time. It is a big ask to expect an investigator to remember the detailed inclusion and exclusion criteria for each one when they sit in-clinic seeing their patients. Their time constraints mean that they have only a few minutes to consider whether any patient in particular might qualify for one of these trials. They are unlikely to rummage through a dozen protocols to check. They may refer to a “cheat sheet” with the criteria listed. Are they sure it’s from the current protocol version? It’s easier to procrastinate and move along to the next patient waiting in line outside their office. Another possible trial participant misses out.
Another example illustrates how adverse effects don’t respect office hours. Consider the following scenario. Its 8 p.m. on a Friday. A study coordinator in an Immuno-oncology study is about to sit down to dinner in a restaurant. A study participant phones urgently to report sudden onset bloody diarrhea and is desperate to know what to do. The protocol copy is two miles away. How will the coordinator instruct the participant exactly according to protocol? Do we expect them to recall precisely what the protocol says, or will they set off to consult it? Or will they just try to remember and hope that they are correct? It is vital that the right advice is given if the safety of the participant and the integrity of the trial are to be preserved.
To effectively deal with the many weaknesses of relying on printed protocols that live on office shelves, we need to bring the whole process into the 21st century. Just as we have with almost all ways that we seek and find information in every other aspect of our lives.
Do you have any other examples of how today’s paper protocol hinders clinical trial success? I’d like to hear them – you can email me at firstname.lastname@example.org.