Lessons learnt: Pushing for submission - the red flag zone.

A sponsor, and sometimes site principle investigators (PI’s), are guilty of being impatient when it comes to study start up and wants to push startup activities and timelines to the max to make the next submission date. Why the rush? Every committee has set dates during a year when they sit to approve trials – if you miss this you will need to wait for the second round – this means a significant delay in study start, which means money.?Depending on when you started, you might only have one week or two to get everything ready to hit the “submit” button - a very tight timeline to meet for all the work that needs to be done.

This is what I call the “red flag zone”. One needs to take care in this “push for submission” to not sacrifice quality. Especially poor quality of your essential documents like your protocol and informed consent. These two documents are the main pillars of any study - the foundation that the study is built on - and if you do not take care to build a high quality, solid foundation your whole house can come tumbling down.

Let me share an example to explain. Sponsor was pushing us to meet the next available submission date which gave very little to no time to double check documents sent by sponsor for submission. In this instance you need to trust and assume a document, and specifically sponsor protocol and main study informed consent (ICF) were already quality checked on their side, as all you as a site have time for is to make it site specific??- you add your PI name, site address, ?emergency number , your local ethics and regulatory authority contact details and use your checklist to ensure?that all elements as required by ICH and SA GCP are more or less covered in the consent and push the submit button.

A few weeks later and the study is approved! The site initiation visit (SIV) was conducted, and we can start enrolling. But then you read the informed consent with a bit more care and discover a section, explaining one of the arms of the investigational product (IP), was missing from the information leaflet and is not lining up with the protocol!

What to do now? ?To have errors in your informed consent means a quality issue in your foundation. This has a domino effect - immediately a lot of stakeholders gets involved in communication and time and resources are turned away from recruiting and enrolling but rather used to focus to attend to the issue at hand.

There are two options:

a)???You continue to consent with the currently approved consent – but not having the correct info on it – now having to explain to the potential volunteer that details were omitted (not looking very professional on your very first meeting, does it?) Discuss it and add information by hand (?) to the informed consent as the participant needs to be offered a copy with all information on it (sign and date with an explanation of why you added information to an already approved ICF, by hand) and document in the source noted the discussion you had and explain why this was needed.

b)???You formally correct the document on your computer, update the version and date - discard the old version and continue with an unapproved version, while awaiting the approval, but at least the potential participant gets the correct info – making a note to file to explain why you are using a “not approved yet” ICF version.

We went for option A, as it was very clear in ICH GCP and the Ethics committee standard operating procedures (SOPs) that any revised written informed consent form, and written information should receive the ethics approval/favorable opinion in advance of use.

The next question popping to mind is:

a)???Do you continue screening and consenting participants on the approved (but wrong) ICF and in the discussion state upfront that we are consenting you on this version today and this is the missing information and errors (just that you are aware of our poor quality) but please continue to trust us and sign if you are still in agreement. (O, and by the way a week from now we will have the updated version and you will need to sign again), or

b)???Do you halt screening – (I am sure the sponsor and PI will choose this option, right?). In our case we have participants “lined up” as they hear about the study in the local clinics and due to their illness, they cannot “wait” for treatment so, when they come for informed consent to our site, they are already keen to learn more. We cannot tell them to wait a few days - we just awaiting on an updated document for them to sign – we cannot delay treatment - they will need to be send away - back to their clinic to start standard of care and they will be lost to the study and withheld the opportunity to take part.

So again – we decided to go with option A. The question we always ask is: what is the best for our participants? So, we will rather share an approved by ethics version and discuss the omitted info and make sure they are fully informed and consent them as they have already taken the time out to come to site.

Unfortunately, no matter what route we chose in this scenario we will have to take the time and resources again in a week or so to reconsent.

Let’s take a closer look at the domino effect, time and resources waisted due to one ICF error:

• Whose time is waisted? ?Regulatory staff, quality staff, sponsor staff, CRA, ethics committee administrator, ethics committee members, PI, site coordinator, participants. ?
• PI and site staff must adjust ICF discussions and documentation.
• Sponsor must draft an update to the ICF and update the version and date.
• Site needs to prepare and submit updated ICF for approval to IEC (at a cost).
• ICF is approved by IEC and now needs to be send for translation (yet another cost).
• A Note to file will need to be drawn up by PI to explain all of this for audit purposes and filed in the trial master files.
• All old versions of ICF needs to be discarded and one copy superseded in site file.
• New ICF needs to be implemented.
• All enrolled participants need to be reconsented.

This can turn into a one-month exercise with numerous role players involved. A lot of time, money, and resources unnecessarily waisted just because of this urge to submit in time. ?Should we have taken this month and add it to our start up planning and quality control activities - the error could most likely have been avoided and we would have ended up at the same timepoint but with a better, smoother, high-quality start to our study.

Karen Cloete