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MRC-NIHR Trials Methodology Research Partnership

24 Feb, 9 tweets, 8 min read

The fact that adaptive designs allow prespecified changes to be made to an ongoing trial based on interim results also creates the potential for biases to be introduced at different stages of the trial. #AdaptiveDesigns

This brings additional demands for transparency and adequate reporting of adaptive trials so that consumers of research findings can make informed judgements about the validity and trustworthiness of results. #AdaptiveDesigns

Inadequately reported adaptive trials that are difficult to interpret their results and reproduce methods, results, and inference. This can severely undermine public confidence in research findings to influence clinical practice resulting in research waste.

In addition, poorly reported adaptive trials are not useful for practical knowledge transfer which is essential for innovative and complex trial designs. #AdaptiveDesigns

@CONSORTing

#ADWG members in collaboration with industry, regulators, and @CONSORTing developed
a CONSORT Extension guidance to enhance the reporting of randomised trials that use an adaptive design. See details: bmcmedicine.biomedcentral.com/articles/10.11…

#AdaptiveDesigns

@bmj_latest

Resultant Adaptive designs CONSORT Extension (ACE) checklist and explanation & elaboration document is freely accessible
@bmj_latest: bmj.com/content/369/bm…

@CONSORTing: consort-statement.org/extensions/ove…

@BioMedCentral: trialsjournal.biomedcentral.com/articles/10.11…

@EQUATORNetwork: equator-network.org/reporting-guid…

Some researchers are already utilising the ACE guidance to improve transparency and reporting of their adaptive trials. For example, see this phase 2 group sequential trial that was stopped early for efficacy at the 2nd interim analysis: thelancet.com/journals/lanha…

#AdaptiveDesigns

@CONSORTing

To improve reporting of your adaptive trial, read the explanation & elaboration text, including examples in the ACE guidance. You can download the checklists here:

consort-statement.org/extensions/ove…

@CONSORTing #AdaptiveDesigns

@mdimairo

#Shoutout to many ACE contributors: @mdimairo @thomas_jaki @JMSWason @Ademander @ChristinaBYap @StevenJulious @Deborah_Ashby @FraKoenig @willmeurer @mattsydes @YJemiai @SofiaSVillar1 & others I've missed or who’re not on Twitter, as well as funders @MRCNIHRTMRP @NIHRresearch

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More from @MRCNIHRTMRP

MRC-NIHR Trials Methodology Research Partnership

@MRCNIHRTMRP

26 Feb

While platform trials are clearly more prominent in COVID-19 than they were before the pandemic, many other COVID-19 trials use adaptive features. Some examples to follow. #adaptivedesigns

(1/4)

@JMSWason

The MATIS trial (NCT04581954) is a multi-arm multi-stage trial with early stopping for lack of benefit which seeks to evaluate treatments to prevent more severe disease. @JMSWason

(2/4)

@recovery_rs

Similarly, the RECOVERY-Respiratory Support trial (ISRCTN16912075) seeks to identify optimal respiratory support using a multi-arm multi-stage structure. More details are here:

warwick.ac.uk/fac/sci/med/re…

@recovery_rs @WarwickCTU

(3/4)

Read 4 tweets

MRC-NIHR Trials Methodology Research Partnership

@MRCNIHRTMRP

26 Feb

A number of COVID-19 trials use a platform structure and we will look at a few examples in the later stages of development in this thread. #adaptivedesigns
(1/6)

@NIAIDNews

The first treatment to be shown to benefit COVID-19 patients was identified within the ACTT trial. The platform allows to stop the evaluation for benefit and lack thereof as well as adding additional treatments.

nejm.org/doi/full/10.10…

@NIAIDNews

@PeterHorby

The RECOVERY trial (recoverytrial.net) is with 38,000 patients to date the largest COVID trial. This has allowed several questions to be answered including dexamethasone as an effective treatment for severe disease.
@PeterHorby @MartinLandray @RichardHaynes3 (3/6)

Read 6 tweets

MRC-NIHR Trials Methodology Research Partnership

@MRCNIHRTMRP

26 Feb

Throughout this week we have made the case that adaptive designs can be useful to improve efficiency and discussed practical challenges. Two recent papers have made the case that trials that are adaptive can be particularly helpful in the of COVID-19. #adaptivedesigns (1/4)

Different types of adaptations and their utility for studies of COVID-19 treatments have been reviewed in

tandfonline.com/doi/full/10.10…
(2/4)

But the utility of adaptive designs is not limited to studies of COVID-19 treatments. They can also be useful for trials that are impacted by COVID-19 as argued here.

tandfonline.com/doi/full/10.10…
(3/4)

Read 4 tweets

MRC-NIHR Trials Methodology Research Partnership

@MRCNIHRTMRP

25 Feb

@thomas_jaki

The TAIloR trial (ISRCTN: 51069819) was a multi-arm multi-stage clinical trial that investigated the utility of different doses of telmisartan to reduce insulin resistance in HIV-positive individuals. @thomas_jaki (1/n).

The trial had one interim analysis during which doses that were deemed insufficiently promising were dropped from the study and in the study two of the initial three doses were dropped at this point. (2/n)

Due to the ability to eliminate insufficiently promising doses, fewer patients were exposed to doses that did not provide benefit to patients. (3/n)

Read 4 tweets

MRC-NIHR Trials Methodology Research Partnership

@MRCNIHRTMRP

25 Feb

The NOTACS trial (ISRCTN: 14092678) an adaptive, multicentre, parallel group, randomised controlled trial comparing the efficacy, cost-effectiveness and safety of 2 types of oxygen therapy in patients at high risk of post-operative pulmonary complication after cardiac surgery 1/n

@RoyalPapworth

The trial has an embedded interim sample size re-estimation, which is a type of adaptive trial design. This is joint work by @RoyalPapworth, @MRC_BSU (inc. @SofiaSVillar1, @SarahNDawson) (2/n)

After a pre-defined number of patients have been recruited and completed follow-up, we will use the data accumulated so far to re-estimate the nuisance parameters and use these to repeat the sample size calculation. (3/n)

Read 4 tweets

MRC-NIHR Trials Methodology Research Partnership

@MRCNIHRTMRP

24 Feb

Adaptive designs, and other innovative approaches, provide great benefits but are also more complex to run. In 2019, the Adaptive Designs Working Group started investigating what extra resource Clinical Trials Units (CTUs) might need to support #adaptivedesigns. (1/7)

@NIHRresearch

Funded by the @NIHRresearch @UKCTUNetwork CTU Support Fund and led by Newcastle CTU, the “Costing Adaptive Trials (CAT)’ project set about answering this question. Step 1 was a snazzy logo. (2/7)

We then did a mock costing exercise. Seven CTUs agreed to cost five trial scenarios - each based on a real trial. For each, we outlined a non-adaptive and adaptive version. CTUs returned the staff resource and other costs that they’d put in a funding application. (3/7)

Read 7 tweets

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