The CONSORT2010 guidance is used globally when academics are writing papers on clinical trials, providing a checklist for researchers to ensure they report all the necessary details of protocols and results from late Phase clinical trials.
Dr Christina Yap, professor in clinical trials biostatistics at the Institute of Cancer Research in the Clinical Trials and Statistics Unit (ICR-CTSU), told the Clinical Trials Arena about how while she was working up a research paper in 2017 on a Phase I trial, she was searching on journal websites for guidance about what to include in her paper, she realised no such guidance existed.
As a result, Yap and her team at the ICR-CTSU led the DEFINE (DosE-FIndiNg Extensions) project in partnership with international experts.
The first document, CONSORT-DEFINE, builds on the CONsolidated Standards Of Reporting Trials (CONSORT) 2010 statement. The second, SPIRIT-DEFINE, expands on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement. Both papers have been published in the British Medical Journal.
Although SPIRIT and CONSORT represent opposite sides of the clinical research process – planning and reporting – they are strongly connected. The researchers therefore decided to develop both guideline extensions concurrently.
They followed the Enhancing QUAlity and Transparency of health Research (EQUATOR) Network’s methodological framework for guideline development. The finalised checklists include dosing strategies, prevention of harm, and adaptive design features, such as interim adaptations and underlying statistical methods. These items should help research teams provide a detailed elaboration of their trial designs and trial results for early-phase dose-finding trials in all clinical settings.
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Abigail Beaney (AB): What does the guidance touch upon to improve the planning and reporting of Phase I trials?
Dr Christina Yap (CY): There were a lot of items that were that were deemed very important for both protocol and reporting. One example is escalation and de-escalation strategy, questions such as how do you how do you decide when it’s safe to escalate?
It’s very straightforward, but it’s different designs and because of this, it also means that the de-escalation strategies are different as well so it has to be clearly specified. Questions such as, what is the rationale for the dosing that you are proposing? You obviously have a starting dose but what is the rationale for providing that starting dose? We were surprised because obviously, this is an important thing, that is not always explained.
We also examined other topics such as deciding on sample size and the justification for that. These are things that would always be reported in late phase trials and are in the CONSORT guidance, but they are not reported often in Phase I reporting. As a result, we felt it was crucial to compile this guidance, particularly after completing a methodological review of how good reporting is in both settings and protocols, when we realised that some of the key features which we thought would be so obvious to be reported were not there.
AB: How well has this guidance been accepted by the industry and how have you evaluated that?
CY: It’s hard to evaluate whether there will be an uptake until probably a few years down to see whether people have changed it. However, we received emails asking whether we could send the checklist before the guidance was published. If there’s a guideline to help you make sure that you have a better protocol and a better scientific paper, then surely that is a good thing. If nothing else, it at least helps that there is a baseline that you can use to make sure that you’ve got all the important bits that should be included. I think in general people will be happy with it, but I guess it’s the question of whether it adds additional work if companies already have their protocol template. Yes, it may be additional work to do but overall, it will improve the quality of your protocol or your paper.
AB: Given this is just guidance with no regulatory backing, how can you encourage sponsors to comply if there are no requirements to do so?
CY: It is difficult in terms of sponsors unless the funders are insistent on it. If it is charity or publicly funded and the funders endorse it then that helps. I also saw a World Health Organization (WHO) article about increasing transparency and enhancing reporting quality, and WHO specifically said to refer to established international guidelines to improve protocols. Also, the journals endorsing it will help. Once the journals are aware it’s very easy for them to then tell authors when they have not filled in the appropriate details.
AB: In October 2023, the European Medicines Agency (EMA) revised its transparency rules on publishing information about clinical trials submitted through the Clinical Trials Information System – how does this work alongside regulatory authorities?
CY: We followed the EMA guidance very closely because they have a lot of guidance. We also looked at the FDA and MHRA when we were thinking about what are the important bits that need to be included in a Phase I setting, first in human drug combination or any clinical development pathways.
I suspect that all the things that we’ve asked about what authors want to be included in the protocol would be very much aligned with what the regulators expect as well. We also had regulators who were part of our core co-authorship team, who have reviewed this thoroughly and the input has been helpful, coming from the FDA, the MHRA, and EMA perspective.
I think our guidance is very much in line with what you expect in a clinical trial protocol and because of what is eventually being reported within the scientific journals, it is a slightly condensed version of that. There has been a great push that when you publish your trial results you should include your protocol and it should be accessible.
This is a problem currently not a lot of protocols are accessible, which means that we publish trial results and only some of the journals make it mandatory that you insert your protocol. A lot of the Phase I protocols have been kept confidential, sometimes due to confidentiality reasons so they are not willing to share. I think there’s a great push and that’s part of what we are trying to say. Let’s make the protocol available and accessible with additional documents so people can understand your trial better.
AB: What do you hope will come as a result of releasing the guidance?
CY: My hope really is that journals will be actively adopting the guidelines but at the end of it, the responsibility is with each researcher, each of us. It’s our responsibility and we shouldn’t be neglecting that. If you are a researcher, you have spent the last 10 years from conception to delivery and it’s not been done well at the beginning then by the end, it is such a great research waste.
Having a checklist is there to help you, not hinder you. It’s there to really give you guidance on what’s really important. My hope is that people will just naturally do it, not because they’re asked to do it, but because they actually want to do it. If researchers act like that then it will that will really change the landscape of reporting in general, not just at Phase I but in general.