INTERIM ANALYSIS Frequently asked questions

EXPERTS-ALS is a Phase 2 experimental medicine platform designed to rapidly screen potential treatments for amyotrophic lateral sclerosis (ALS, the commonest form of motor neuron disease, MND). EXPERTS-ALS is not designed to determine whether a treatment improves symptoms, slows disability or extends survival. Its purpose is to identify treatments that show sufficient, compelling, evidence of biological activity to justify further testing in a larger Phase 3 clinical trial.

The EXPERTS-ALS platform can be used to prioritise the choice of drug according to signals of likely human benefit, which can be detected in small groups of participants. EXPERTS-ALS aims to:

• Screen potential treatments quickly

• Ensure the drugs with the highest chance of success go into the Phase 3 studies

• Minimise the number of participants treated with drugs which are unlikely to be effective by using interim analyses

Traditional drug-development programmes can require large numbers of participants and many years before an unpromising treatment is identified.

A biomarker-led interim analysis design allows EXPERTS-ALS to:

• identify unpromising treatments earlier;

• reduce unnecessary participant exposure to candidate drugs less likely to be effective;

• use research capacity and funding efficiently;

• investigate several treatments through a shared platform; and

• prioritise the strongest candidates for definitive Phase 3 evaluation.

An interim analysis is when the results are reviewed during a study whilst participants are still taking the study drugs. 

In EXPERTS-ALS, the interim analyses are looking at whether there is enough evidence of biological activity for a treatment to be justified to remain in the study for testing in new participants. This is assessed by measuring changes in serum neurofilament light chain (NfL), a biomarker associated with nerve-cell damage seen in MND. If the findings suggest that the treatment is unlikely to produce the required effect on NfL, the treatment will be stopped within the platform.

No. EXPERTS-ALS is not designed to establish clinical efficacy but can provide evidence to justify a further investigation.

Neurofilament light chain, usually shortened to NfL, is a protein released into the blood when nerve cells are damaged. Blood NfL levels can therefore provide information about the rate of neurodegeneration in MND.

EXPERTS-ALS uses changes in serum NfL as an early signal of whether a treatment may be affecting the underlying disease biology.

No. An overall reduction in NfL across the participants would provide very encouraging evidence of biological activity of that drug, but it would not prove clinical benefit.

A treatment showing such a promising NfL signal will need to be evaluated in a larger Phase III trial to establish whether it produces meaningful benefits for people living with MND.

Not necessarily. NfL is an important biomarker of disease activity in ALS, but it may not capture every potentially useful treatment effect. For example, a treatment might affect a biological pathway without producing the required change in NfL during the study period of EXPERTS-ALS. However, EXPERTS-ALS uses pre-agreed decision criteria so that treatment candidates can be assessed more efficiently and consistently, so that limited larger trial resources are focused on the most promising candidates.

The analysis is undertaken after the required number of participants in a treatment arm have completed sufficient follow-up and suitable NfL data are available.

The timing depends on recruitment, participant follow-up, sample processing, laboratory analysis and data-quality checks. The statistical team must confirm that the required data are complete and suitable before the analysis begins.

The analysis primarily considers the change in serum NfL from baseline to the relevant follow-up time points, particularly weeks 18 and 24.

The analysis follows the pre-specified statistical analysis plan. Safety, treatment exposure, participant retention, missing data and data quality are also reviewed when interpreting the findings.

The analysis is conducted by the trial’s statistical team in accordance with an externally and independently-approved statistical analysis plan. Results are reviewed through the appropriate EXPERTS-ALS governance and independent oversight processes before a recommendation or decision is confirmed.

This helps ensure that decisions are scientifically robust and are not based on an informal interpretation of the results.

The outcome may support a decision to:

• stop further recruitment to the treatment arm (for futility);

• continue the arm to gather additional evidence to come to a decision;

• prioritise the treatment for further development, potentially including a Phase 3 trial;

• undertake further analysis where permitted by the statistical plan.

Further recruitment to that arm will stop. Participants already receiving the treatment would be informed and managed in accordance with the trial protocol, regulatory approvals and advice from the study team.

Other treatment arms within the EXPERTS-ALS platform can continue because each treatment is assessed separately.

If the independent oversight committee recommends that a treatment continues in EXPERTS-ALS, it means that the treatment has met the pre-specified threshold for remaining scientifically promising. It does not mean that the treatment has been proven clinically effective.

The next step might involve collecting further evidence, continuing within the platform or developing a larger Phase 3 clinical trial.

Individual biomarker results from research trials are not used to make clinical decisions. Clinical trials are designed to answer research questions at a group level rather than provide conclusions about individual participants. Sharing individual results prior to the end of a study can introduce bias and compromise the reliability of the data.

The study team will communicate overall study findings when these have been appropriately reviewed and are ready for release.

No. Nor does it mean that it has caused you any harm.

The interim analysis looks at results across the whole study population and cannot determine whether an individual participant benefited from taking part.

Clinical trials are designed to answer research questions at a group level rather than provide conclusions about individual participants. If you have questions about your own health or ongoing care, you should speak with your study team or treating clinician.

Many people living with MND choose to take part in research because it helps improve understanding of the disease and supports the development of future treatments.

Every study is different, with its own aims, potential benefits and risks. If you are interested in participating in further research, speak with your MND clinical team, who can advise whether there are studies that may be appropriate for you.

If your question relates to your own treatment or medical care, you should contact your treating clinician or specialist MND team.

If your question relates to your participation in the EXPERTS-ALS study, you can also contact your local study team using the contact details provided in your participant information.