A consortium of 25 allergists and otorhinolaryngologists from five medical specialty societies in the United States has developed a guideline for designing clinical trials in the treatment of chronic rhinosinusitis.
Although the condition affects 30 million people nationwide, there has historically been a lack of consensus regarding its definition, and consensus is still lacking regarding standards of care for it. Therefore, according to the members of the consortium who produced the guidelines, a consensus regarding the design of clinical trials is an important next step to standardizing care.
The new guideline, Rhinosinusitis: Developing Guidance for Clinical Trials, consists of specific recommendations for such trials, and was published in November 2006 in both a supplement of the Journal of Allergy and Clinical Immunology (JACI) and Otolaryngology-Head and Neck Surgery (OTO-HNS).1,2 These are the official publications, respectively, of the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). The other participating societies in the consortium are the American Academy of Otolaryngic Allergy (AAOA), the American College of Allergy, Asthma and Immunology (ACAAI), and the American Rhinologic Society (ARS). This is the group’s second collaboration. The first document was published in December 2004, also concurrently JACI and OTO-HNS.
Acute and Chronic Disease Differentiated
The guideline makes separate recommendations for trials that focus on different subtypes of rhinosinusitis:
- Acute bacterial rhinosinusitis;
- Chronic rhinosinusitis, with or without nasal polyps; and
- Allergic fungal rhinosinusitis.
The goal … has been to provide researchers with the needed methodologies which will promote better clinical studies that can lead to improved patient care, corresponding author, Eli O. Meltzer, MD, said in a statement. He is the Co-Director of the Allergy and Asthma Medical Group and Research Center in San Diego, Calif.
The current publication reviews the FDA’s role in drug trials and offers guidelines for rhinosinusitis clinical trials of various modalities, including antimicrobials, anti-inflammatory agents, and treatments that are designed for symptom relief or the blockage of mediators that promote symptoms. The guidelines also include recommendations of scoring instruments for symptoms, radiographs, endoscopic testing, and quality of life, as well as techniques for quantifying microbiologic factors, assessing inflammatory indices, and statistically measuring outcomes. The guidelines also provide a list of the various components of a rhinosinusitis clinical trial, including the title of the trial, the study design, the objectives, and the safety assessments.
Two of the guideline participants, Dr. Meltzer and Bradley F. Marple, MD, commented in separate telephone interviews regarding the ways the guidelines will help researchers in rhinosinusitis.
New Treatment Modalities Needed
The diseases of the respiratory tract seem to be increasing across the world, and there is no magic potion to cure them, said Dr. Meltzer. Therefore, we need to develop new treatment modalities, pharmacologic, immunologic, surgical modalities, to improve people’s health.
Despite this urgent need, to date, there is no good road map to develop new treatments for sinus disease, he added. There has been guidance for clinical trial programs for rhinitis and asthma, but not for sinusitis. Therefore, thought leaders in allergy and in otolaryngology addressed the void in 2002 by forming the Rhinosinusitis Initiative, whose mission has been to develop better definitions and methodologies to document the efficacy of any intervention in rhinosinusitis, he said.
Most recent publications give guidance for specific methodologies regarding how to design trials in rhinosinusitis, he said. These range from inclusion criteria and exclusion criteria to ways for documenting how an intervention can be helpful and the magnitude of the benefit of the intervention.
The consortium considers the next important step to be the development by the Food and Drug Administration (FDA) of a clinical trial guidance for using the consortium’s guideline that is accepted by the research community and industry, he said.
Building on the Initiative’s History
Noting the importance of the history of the Rhinosinusitis Initiative, Dr. Marple, Professor and Vice-Chair of the Department of Otolaryngology at University of Texas Southwestern Medical School in Dallas, stressed that the most recent publication is the second part of a work in progress that is centered around improving our understanding of what underlies chronic rhinosinusitis and the therapies that would improve outcomes. He continued, The first document focused on defining the condition as a disease entity and identifying subsets within chronic rhinosinusitis. The second document recommends ways for evaluating different interventions for different subsets in an effort to best coordinate research efforts.
The Rhinosinusitis Initiative hopes that the guideline will help to standardize the approach by which these different interventions could be studied in different subsets, he said. The guideline consists of templates that are relatively versatile but revolve around a common theme: the type of intervention and the type of disease process.
Four Major Protocols
From this perspective, the Rhinosinusitis Initiative outlined four major protocol designs.
The first he described was the model for short-term therapeutic intervention for acute disease. In these settings, researchers would be utilizing a treatment algorithm that would be intended to shorten the duration of disease in people with acute rhinosinusitis. Antibiotics may may represent one intervention; symptom-relieving medications would represent another, Dr. Marple said. The point of this is to study the impact of a specific intervention upon a specific disease as measured by an objective outcome such as time to resolution of symptoms or differential improvement of CT findings.
The other three protocol designs are prevention of disease recurrence for chronic rhinosinusitis and short-term and long-term treatments for chronic disease.
These protocols were designed from a standpoint of guiding research, Dr. Marple said. The dilemma that we have in rhinosinusitis is one of a mosaic of treatments applied based on anecdotal evidence. No standardized, evidence-based algorithms exist. With this document, we’re trying to accelerate this process. At present, we have no clear understanding of the disease process that underlies chronic rhinosinusitis. We have no standardized treatment algorithms to apply to the disease process. The hope is that, as we collectively start producing more information, clinicians will be provided with treatments that have proven benefits.
Dr. Marple pointed out the irony of the need for such basic information for such a common disease. We’re still rather embryonic in our understanding of this disease process, he said. We all have an understanding of what chronic rhinosinusitis represents to our patients, but we’ve only had a standardized definition of the disease for the last four or five years. At present, there are a number of theories that attempt to explain the pathophysiology. Ideally, as data supporting some of these theories become more convincing, we would like a knowledge base to develop that would direct study of interventions that could improve outcomes for chronic rhinosinusitis in a consistent way. There’s so much to learn about this disease and the interventions that impact this disease.
Applying Scientific Rigor to Antibiotics
An example of an intervention method that could benefit from scientific rigor is the use of antibiotics, Dr. Marple said. This is the most common form of treatment for rhinosinusitis, but we have very little data to support that practice, he said. If you step back and look at the definition of rhinosinusitis, it is important to note that it’s an inflammatory disease process, so antibiotics may or may not have a role.
The Research Initiative, therefore, hopes to stop the paradigm of reacting to symptoms, he said. We hope that documents such as this can redirect energy into the development of evidence-based treatment options.
Therefore, otolaryngologists should view the guidelines as an effort to coordinate and guide research efforts to maximize information that we’re going to start collecting on this series of disease processes, he said. In chronic rhinosinusitis, when we talk about this being an inflammatory disease, we want to know which interventions will affect this disease process and which ones don’t.
The understanding that rhinosinusitis is an inflammatory disease, not necessarily an infectious one, opens up an entirely different way of looking at and studying the disease process, he said. In this way, one might think of chronic rhinosinusitis as comparable to asthma, whereas the acute rhinosinusitis might be more analogous to pneumonia. If you use that comparison, it is easy to see that antibiotics that are appropriate for acute disease may not always be the ideal treatment for chronic rhinosinusitis. This is an inflammatory disease, and we need to identify new forms of therapy. The new guidelines should help researchers help identify chronic rhinosinusitis therapies that are based on evidence from studies that are consistent in definitions, designs, and outcomes.
References
- Meltzer EO, Hamilos DO, Hadley JA, et al. Rhinosinusitis: Developing guidance for clinical trials. Otolaryngol Head Neck Surg 2006;135 (5Suppl):S31-S80, and J Allergy Clin Immunol 2006;118 (5 Suppl 1):S17-S61.
- Meltzer EO et al. Rhinosinusitis: Establishing definitions for clinical research and patient care. J Allergy Clin Immunol 2004;114:s155-s212.
©2007 The Triological Society