Chest imaging in CF studies - Commentary

Abstract

Recently, the EMA concept paper on the need for revision of the “guideline on the clinical development of medicinal products for the treatment of cystic fibrosis” [[1]Concept paper on the need for revision of the guideline on the clinical development of medicinal products for the treatment of cystic fibrosis (CHMP/EWP/9147/08).http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/08/WC500211478.pdfGoogle Scholar] was put for public consultation. A revision of the current guideline is deemed necessary due to advances in the understanding of the pathophysiology and in the field of CF therapeutics with a shift from symptomatic treatment towards disease modifying approach. These advances render several elements of the guideline outdated. The clinical trial design, choice of comparator, duration, and endpoints in the existing guideline are no longer adequately covered for all clinical developments. Furthermore, novel treatments offer the prospect of early intervention to prevent the progression of the disease with clinical trials expected to be performed progressively in younger children. Most young children have well preserved lung function and normal anthropometric measurements. Thus, the clinical endpoints suitable for older children and adults would not be adequate. Current and future successes in the management of CF disease may further postpone the clinical manifestations of CF to older age groups, increasing the complexity around endpoints and effect size. A sensitive test of early CF lung disease reliably and reproducibly reflecting severity of lung disease and response to treatment is highly warranted. The review series on efficacy measures for clinical trials starting with reviews on physiologic endpoints [[2]Stanojevic S. Ratjen F. Physiologic endpoints for clinical studies for cystic fibrosis.J Cyst Fibros. 2016; 15: 416-423Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar] and biomarkers for cystic fibrosis drug development [[3]Muhlebach M.S. Clancy J.P. Heltshe S.L. Ziady A. Kelley T. Accurso F. et al.Biomarkers for cystic fibrosis drug development.J Cyst Fibros. 2016; 15: 714-723Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar] is therefore a timely initiative to summarise current evidence and to stimulate discussions among clinicians, regulators and patients and their families [[4]Flume P.A. VanDevanter D.R. Efficacy measures for clinical trials: a review series.J Cyst Fibros. 2016; 15: 415Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. The article in this issue “Chest Imaging in CF Studies: What counts, and can be counted” [[5]Szczesniak R. Turkovic L. Andrinopoulou E.R. Tiddens H.A.W.M. Chest imaging in CF studies: what counts, and can be counted.J Cyst Fibros. 2016; ([in this issue])PubMed Google Scholar] provides useful insight into the current state of knowledge as well as important statistical aspects for the utility of imaging markers, i.e. high resolution Chest Tomography (CT) and magnetic resonance imaging (MRI), as outcome measures for clinical studies. While the knowledgebase for the use of MRI is still in its infancy, it may emerge as useful radiation-free technique not only quantifying structural but also functional aspects of the CF lung. At present, CT is considered the most sensitive and accurate imaging modality to detect and monitor structural changes of early CF lung disease, and to be more sensitive and accurate than spirometry in the assessment of disease severity. While other lung function measurements such as the lung clearance index (LCI) have been reported to provide comparable sensitivity and accuracy to CT in the detection of CF lung disease in children older than 2 years of age, LCI may not be sensitive to mild structural abnormalities in infancy [[6]Ramsey K.A. Rosenow T. Turkovic L. Skoric B. Banton G. Adams A.M. et al.Lung clearance index and structural lung disease on computed tomography in early cystic fibrosis.Am J Respir Crit Care Med. 2016; 193: 60-67Crossref PubMed Scopus (129) Google Scholar]. However, before the use of CT scores can be recommended as outcome measures for clinical studies several challenges, particularly in but not restricted to very young children, have to be addressed [[7]Calder A.D. Bush A. Brody A.S. Owens C.M. Scoring of chest CT in children with cystic fibrosis: state of the art.Pediatr Radiol. 2014; 44: 1496-1506Crossref PubMed Scopus (47) Google Scholar]. The use of different CT modalities and scoring systems limits the comparability of CT results between studies. CT protocols, image quality and radiation dose usage differ largely among different CF centres [[8]Kuo W. Kemner-van de Corput M.P. Perez-Rovira A. de Bruijne M. Fajac I. Tiddens H.A. et al.Multicentre chest computed tomography standardisation in children and adolescents with cystic fibrosis: the way forward.Eur Respir J. 2016; 47: 1706-1717Crossref PubMed Scopus (30) Google Scholar]. In the absence of a universally agreed automated scoring system there is a need for either rigorous training of scorers or centralised scoring by highly trained scorers to ensure good reproducibility. Identification of very mild changes is prone to higher measurement bias and poor reproducibility. In addition, at present, the prognostic relevance of very mild bronchial dilatation in very young children is unclear. While bronchiectasis is defined as irreversible bronchial dilatation [[9]Hansell D.M. Bankier A.A. MacMahon H. et al.Fleischner society: glossary of terms for thoracic imaging.Radiology. 2008; 246: 697-722Crossref PubMed Scopus (2705) Google Scholar], mild bronchial dilatation has been reported to be reversible in some infants [[10]Mott L.S. Park J. Murray C.P. et al.Progression of early structural lung disease in young children with cystic fibrosis assessed using CT.Thorax. 2012; 67: 509-516Crossref PubMed Scopus (224) Google Scholar], raising the question, whether such finding should be scored as bronchiectasis. CT resolution may limit evaluation of small airways in infants and very young/small children. Even if standardisation and improvement in CT modalities enable acquisition of reproducible results in children, the clinical case definitions for bronchiectasis and other structural lung disease in children are not well established. The airway-artery ratio cut-off of 1 to define normal versus dilated bronchus might be too high for infants [[11]Thia L.P. Calder A. Stocks J. et al.Is chest CT useful in newborn screened infants with cystic fibrosis at 1 year of age?.Thorax. 2014 Apr; 69: 320-327Crossref PubMed Scopus (51) Google Scholar]. In multicomponent scores like PRAGMA CF [[12]Rosenow T. Oudraad M.C.J. Murray C.P. et al.PRAGMA-CF. a quantitative structural lung disease computed tomography outcome in young children with cystic fibrosis.Am J Respir Crit Care Med. 2015; 191: 1158-1165Crossref PubMed Scopus (161) Google Scholar], the weight of individual score components and their value for predicting long-term outcome is not known. Data on the power of CT to show response to treatment and changes over time are scarce and conflicting [[7]Calder A.D. Bush A. Brody A.S. Owens C.M. Scoring of chest CT in children with cystic fibrosis: state of the art.Pediatr Radiol. 2014; 44: 1496-1506Crossref PubMed Scopus (47) Google Scholar]. The time window for a repeat CT best suited to demonstrate changes in disease severity is unknown. Although radiation dose has been substantially reduced in new CT units, the radiation risk of repeat CT scans, particularly when started in infancy, cannot be disregarded. The review by Szczesniak summarises work currently undertaken in Australia, Europe and the US to address the manifold challenges and gives rise for optimism that CT markers could become a useful and accepted outcome measure reproducibly reflecting severity of lung disease and response to treatment. However, we are not there, yet. Regulatory authorities, beyond their role as gate keepers, have an important mandate as enablers in facilitating development and access to medicines. Many ongoing activities in EMA work towards achieving this objective. Especially the qualification of novel methodologies for medicine development is a platform created to enhance dialogue and data sharing between industry, academia, healthcare professionals, patients/carers and regulators on future plans to generate evidence (qualification advice), or to confirm adequacy of evidence (in the case of a qualification opinion), for the use of an innovative method in drug development. Several proposals for qualification of novel biomarkers or scores have been successfully concluded. A letter of support based on qualification advice may be issued by EMA as an option, when the novel methodology under evaluation cannot yet be qualified but is shown to be promising based on preliminary data [[13]EMA qualification of novel methodologies for medicine development.http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp&mid=WC0b01ac0580022bb0Google Scholar]. “May you live in interesting times” is purported to be the first of three Chinese curses of increasing severity, the other two being: “May you come to the attention of those in authority” and “May you find what you are looking for.” Let's not understand it as a curse but as an exciting opportunity and clear call to all stakeholders to work closely together and to join efforts in the development of safe, standardised scoring systems with high precision and accuracy that can be used as surrogate outcome measure for clinical studies. In the end the CF community may find what it is looking for, namely better medicines that address the primary defect in CF. The views presented in this correspondence are those of the authors and should not be understood or quoted as being made on behalf of the European Medicines Agency or its scientific Committees.