Protocol or GCP Testing?

by Randall Westhead-Powell

I have always been interested in the focus of testing and certification in clinical trials. I have long had the opinion that there is too much emphasis on the stand-alone concept of GCP with a certain neglect for the, perhaps, equally important operational aspects of a clinical trial protocol. Do not get me wrong, I am not saying that GCP, the Declaration of Helsinki etc is not important, it is and is an integral part of my opinion piece here. A regular question: does it comply with GCP? as we know GCP is there to ensure the rights, safety and well-being of trial subjects are protected consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. Clearly intertwined with ensuring these principles are achieved is the execution of the protocol at site level. Just because an investigator, monitor, nurse etc has been involved in clinical trials before, (perhaps for a diverse range of sponsors) and has all the right GCP Certificates does this mean that they are well placed to work on the next trial. The next trial may have a completely different protocol, be in a different informed consent setting (e.g. emergency room), and be totally different from anything they have done before. To determine whether the available resource, investigators and monitors are “certified” to work on such a trial the first place we could turn to is ICH GCP itself.

According to ICH GCP “each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).”

ICH GCP goes on to say “The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).”

These two statements, in my opinion, focus on the general skill and experience of an individual. While this is essential there is an argument that says we need to define exactly what skill and experience is required to conduct the clinical trial in question. What is the minimum experience required to meet the requirements, well these will be clearly defined in terms of education/certification (e.g. qualified doctor/dentist for an investigator). In a practical sense it should be down to the sponsor to define the specific requirements of each individual role that will ensure that the protocol is followed and the trial delivered to the correct standard.

ICH GCP goes on to say that “The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.”

It could be considered that inherent to this statement is the fact that by signing the agreement

the investigator will comply with the protocol. This does not necessarily mean that the investigator fully understands the protocol or has been fully “trained” in the various aspects of it. Which brings me on to the next point, who “trains” the person who “trains” the investigator? Well the CRA/Monitor usually “trains” and “explains” to the investigator on behalf of the sponsor, but what does ICH GCP state about the Monitor?

Well, ICH GCP states that the SPONSOR should “obtain the investigator’s/institution’s agreement to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC”. This goes on to state that “Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).”

What does thoroughly familiar mean? Read the protocol once?, could pass a 50 question multiple choice open-book examination on the trial protocol? Well here is where my point comes to life. The monitor is responsible for (amongst other things)

1. Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
2. Ensuring that the investigator and the investigator’s trial staff are adequately informed about the trial.
3. Verifying that the investigator and the investigator’s trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.

The complexity of clinical trial protocols can be daunting, add on top of that the other aspects, e.g. data handling, data conventions, violations & deviations and you start to realise that a monitor cannot just walk straight onto a different trial and be effective, no matter how much experience, education, GCP Training and SOP Training that they have had. What they actually need is a thorough knowledge of a protocol and this thorough knowledge, in my opinion, should be subject to testing and sponsor certification in equal importance to any GCP and SOP Training. GCP and SOP Training cover the general setting, Protocol Testing would ensure that monitors know the important aspects of the trial and can therefore conduct their role correctly.

This then brings me back to the investigators. Should we formally test their knowledge of the protocol prior to them starting a study. Yes we train them, but sitting through “training” doesn’t mean they learn anything. Well perhaps this is a step too far as I can imagine the push-back that we’d get from asking investigators to sit yet another exam. However, if the monitors have a thorough insight into the protocol and have themselves demonstrated excellent understanding they should be able to engage in more substantial training and better identify knowledge and understanding gaps of the investigators and site staff.

I’ll conclude by referring to a previous article and a specific comment. The article I recommend you to read is What Makes a Good CRA/Monitor (click here)  and the comment from David (an investigator:

“I get scared when I know the protocol better than a monitor, because it means that if I don’t catch mistakes, the monitor won’t find them either.”

Randall Westhead-Powell

Project Manager, CRO Switzerland