For decades, developing a new CF treatment followed a familiar script. Patients in trials had progressive lung disease and few alternatives. Placebo-controlled studies were the standard. Improvement in lung function was how success was measured. That script no longer fits, and the European Medicines Agency has finally rewritten it.

The revised EMA guideline on the clinical investigation of medicinal products for CF is more than a technical update. It is an acknowledgement that the therapeutic landscape has fundamentally changed, and that the rules for developing future treatments need to change with it.

Two populations, two paths

The starting point of the revised guideline is a recognition that CF is no longer a single clinical reality. CFTR modulators have transformed the lives of many people with CF, stabilising lung disease, reducing hospitalisations and dramatically improving quality of life. But they have not reached everyone. Around ten percent of people with CF do not benefit from available modulators, and some cannot tolerate them. These two groups require different approaches to clinical development.

For people who benefit from modulators, the guideline makes clear that future research cannot simply interrupt an effective therapy to create a placebo arm. Instead, new medicines will be evaluated as add-on treatments or compared against existing active therapies. This is a significant shift in trial design, and it comes with its own challenge: when many participants already have relatively preserved lung function and fewer exacerbations, demonstrating meaningful additional benefit becomes harder. Traditional outcome measures become less sensitive, and more sophisticated approaches are needed.

For people who are not eligible for modulators or cannot tolerate them, the picture is very different. They are, in the words of the guideline, still living in “old-CF times,” facing high unmet medical needs with few effective options. Here, traditional trial designs including placebo or best supportive care comparisons remain appropriate, and the guideline explicitly supports the continued development of gene therapies, mRNA therapies and other CFTR-restoring technologies for this population.

Measuring success differently

One of the most important shifts in the revised guideline concerns how benefit is measured. For years, FEV1, the standard measure of lung function, was the primary endpoint in CF trials. It made sense when lung function was declining. It makes much less sense when many participants are already on effective treatment and their lung function is relatively well preserved.

The guideline therefore encourages broader use of more sensitive measures: the Lung Clearance Index (LCI), particularly in children; biological markers capable of demonstrating CFTR function restoration; and laboratory-based approaches such as theratyping and patient-derived organoids, especially for people with ultra-rare mutations. These tools may provide earlier evidence that a therapy is working, potentially reducing the need to wait years for long-term clinical outcomes to emerge.

The areas where work must continue

CFTR modulators have transformed care, but they have not made further innovation unnecessary. The revised guideline explicitly recognises a range of areas where active research remains essential: chronic bacterial infection, persistent inflammation, antimicrobial resistance, non-tuberculous mycobacterial infections, pulmonary exacerbations, and therapies for people who cannot tolerate current modulators. Modulators also change the lung environment in ways that require renewed evaluation of inhaled therapies and antibiotic delivery.

There is also a strong case for continued development of new CFTR modulators. Some people discontinue current treatments due to intolerance or adverse effects. And greater competition between modulators could meaningfully improve equitable access to treatment across European countries.

The patient perspective

The revised guideline is broadly welcomed by the CF community, but people with CF are clear about what they want to see in practice. More flexible eligibility criteria that allow a wider range of participants into trials. Greater acceptance of innovative study designs such as external control cohorts, hybrid control arms and adaptive trials. Meaningful involvement of patients who are transplant recipients, pregnant, have rare mutations, or are currently on modulators but may need alternatives in future.

Above all, people with CF ask that the outcomes measured in clinical trials reflect what matters in everyday life: quality of life, mental wellbeing, treatment burden, the ability to participate in education and employment, long-term independence. Biological markers and biomarkers are valuable, but they should complement, not replace, these patient-centred outcomes.

The community also calls for reducing the practical burden of trial participation: fewer hospital visits, more remote assessments, simpler procedures, and better integration of research into daily life. Trials that are easier to take part in are also more representative of the wider CF population, which benefits the quality of the science.

Looking ahead

The revised EMA guideline reflects the reality of where CF stands today: a condition that has entered a new era, but one where the work is far from done. Clinical development can no longer rely on a single model, because CF is no longer a single experience. The framework it provides — two pathways, smarter outcome measures, continued investment in unmet needs — is a foundation worth building on.

The objective of the guideline must remain the objective of the community: that every person with CF, whatever their mutation, whatever their response to existing treatments, wherever they live in Europe, can continue to benefit from scientific progress. That remains the standard against which this revision, and all future innovation, should be measured.