Cystic Fibrosis: EMA Considers Revisions to Guidance for Developing New Drugs

Regulatory NewsRegulatory News | 01 August 2016 |  By 

As the knowledge of the genetic principles and other recent developments in the field of cystic fibrosis (CF) has provided more insight into the pathophysiology of the disease, the European Medicines Agency (EMA) on Monday announced its intention to update certain outdated elements in its guidance.


CF is an autosomal recessive disorder caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR). More than 2,000 mutations in the CFTR gene have been identified for CF, though only very few have been characterized in terms of the defect they cause or in terms of whether they are disease-causing.

When the current EMA guideline for developing new CF drugs was adopted in 2009, medicinal products were developed for either the management of the pulmonary disease or the pancreatic exocrine insufficiency associated with CF. As a result, the current guideline is mainly focused on these clinical situations and should be updated, EMA says.

“A number of CFTR modulators are currently either under development or have been recently authorized. This has represented a shift in the therapeutic understanding of CF treatment from the symptomatic treatment towards a disease modifying approach,” the agency adds.

And although the progress in the management of CF has improved considerably, with patients living longer than in the past, these positive effects also raise the expectations for future treatments and add to the challenge of using historical controls or published literature for estimating the benefits of new treatments.

Potential Updates

The clinical trial design, choice of comparator, duration and endpoints in the existing guideline “may not be adequately covered for all clinical developments,” EMA says, noting that such new treatments offer the prospect of early intervention to prevent the progression of the disease, which means clinical trials are expected to be performed progressively in younger children.

However, no reference is made in the current guideline to clinical endpoints that would be relevant to this young population, EMA says, adding that there is also no detailed discussion of the potential for extrapolation between different age groups.

“The understanding of the CFTR mutations is critical for the design and the development of target therapies for CF. However, sufficient guidance is not provided in the current guideline. Given that the CF phenotype is highly heterogeneous, it is relevant for an adequate interpretation of efficacy and safety data that the patient populations are well characterised in terms of disease characteristics and prior CF related morbidity and concomitant medications,” EMA says.

Meanwhile, biomarkers are only described in a “very general way,” EMA says, despite several biomarkers having been identified or under assessment that could become useful to individualize treatment or to assess therapeutic effects, which merits more detailed discussion.

What New Guidance Should Address

EMA has identified the following that would need to be addressed in the revised guideline:

  • The scope needs to be widened to cover newer drug classes and mechanisms of action.
  • Potential study designs, use of comparators (placebo, active), biomarkers and endpoints considering recent clinical trial experience, regulatory assessments and scientific advice procedures will be discussed.
  • Definition of pulmonary exacerbation will be updated in line with recent scientific discussions.
  • There is a need to improve quality of the baseline data to be collected for CF patients as this is essential for a robust efficacy assessment.

In addition, EMA says the following items will be discussed in the guideline as part of baseline data: CFTR-mutations, concomitant medications, age at diagnosis, prior pulmonary disease, prior gastrointestinal disease and CF-related comorbidities.

And since it is virtually impossible to study all of the CFTR genetic mutations in clinical trials, EMA says the appropriateness of extrapolating data across different mutations within a certain class needs to be discussed in the revised guideline. Comments can be submitted through 31 October 2016.

Concept paper on the need for revision of the guideline on the clinical development of medicinal products for the treatment of cystic fibrosis


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