The Journal of Allergy and Clinical Immunology: In Practice
RostrumThe Allergic Rhinitis and Its Impact on Asthma (ARIA) Approach of Value-Added Medicines: As-Needed Treatment in Allergic Rhinitis
Introduction
Allergic rhinitis (AR) is one of the most common chronic conditions in high-income settings, with a lifetime prevalence of up to 50% in some countries.1 It is a global health problem that causes major illness and disability worldwide.2 It affects social life, school, and work.3 Patients may also experience sleep disorders and emotional problems. The economic effect of AR is often underestimated, because indirect costs are substantial. The effects of AR on work productivity are estimated to cost between €30 billion and €50 billion per year in the European Union alone.3, 4, 5
Allergic rhinitis treatment is complex. Many treatments are available, including allergen avoidance, pharmacotherapy, and allergen immunotherapy.1,6, 7, 8 Medications are dispensed in oral and topical formulations. Many guidelines for AR are evidence-based8, 9, 10, 11 and have led to an improved understanding and management of AR. They all propose long-term continuous treatment. However, guidelines are mostly based on randomized controlled trials (RCTs), typically undertaken on highly-selected populations, often with limited or unclear generalizability to routine care contexts.12, 13, 14 Nonetheless, many patients are dissatisfied with their treatment, with symptoms remaining poorly controlled. Moreover, adherence to treatment is usually poor in AR, even when using mobile health (mHealth).15 Patients treat themselves according to the symptoms (irrespective of how they understand AR), and comedication use is driven by symptom severity.16 Many patients are on-demand (PRN) users, but guidelines have not yet approached this issue.
Large observational implementation studies are needed to triangulate RCTs. The former reflect real-world everyday use and practice more closely than RCTs in terms of the heterogeneous patient populations included, as well as the variety of medical interventions assessed.17 Observational studies with real-world data (RWD) examine the possible effect of a treatment on subjects when the investigator has no control over the experiment and cannot randomize subject allocation.18 However, they provide clinically relevant information that is complementary to insights gained from RCTs, because they assess implementation considerations in routine care.
In AR, there is an urgent need for change management.19 Novel treatment options are required and should consider unmet medical needs, demonstrating faster and more complete symptom control in direct comparison studies versus currently available first-line AR therapy. They should also show superior efficacy in patients, regardless of disease severity, and in those who present with a particularly bothersome or predominant symptom. The importance of mHealth needs to be stressed.20
Repurposing current medical options is another complementary strategy.21 The definition of repurposing is complex. Given the disparity and inconsistency of terminologies and classifications in the literature, a systematic review was carried out in 2013 to obtain a harmonized nomenclature for drug repositioning, reformulation, and combination cases.22 It was proposed that “The term repurposing includes all the re-development strategies based on the same chemical structure of the therapeutically active ingredient as in the original product.” Drug repurposing involves exploring new medical uses for existing drugs.23 Drug repurposing should be based on RCTs or RWD and provide the patient with effective and acceptable treatment. The model of AR has been used in this article. It includes results obtained using real-world evidence and combines RCTs, RWD, and chamber studies.24, 25, 26, 27 The Food and Drug Administration and the European Medicine Agency approved drug repurposing based on RWD (eg, palbociclib).28 However, RWD is better accepted by regulators in the United Kingdom and Canada than in certain other countries.
The purpose of this article is to argue that value-added medicines (VAMs), such as the PRN use of nasal sprays, may address unmet needs in rhinitis management.
Section snippets
Value-Added Medicines
Value-added medicines address different healthcare needs,29 including (1) innovation regarding existing molecules in the form of repurposing,30, 31, 32 reformulation, and combination of therapies; (2) improving patient adherence; (3) addressing problems related to polypharmacy; and (4) enhancing personalized healthcare services. Value-added medicines deliver relevant benefits for patients, healthcare professionals, and payers. Although most VAM solutions are based on generic medications, they
Unmet Needs in AR
Many patients are dissatisfied with their treatment because the symptoms are inadequately controlled, they do not want a lengthy treatment for a condition they perceive as nonthreatening, and/or they experience unacceptable side effects. Several unmet needs have been identified in AR.46,47 Real-world data offer new insights into the phenotypes and management of AR, which may enable a better understanding and mitigation of these unmet needs.48
Control and severity need to be better delineated.
Randomized controlled trials
Although large RCTs are not available, some studies have assessed the benefits of the PRN use of intranasal corticosteroids (INCSs) in AR.79 The first study was carried out in the 1990s. In 60 ragweed pollen–allergic patients with seasonal AR, the regular use of INCSs resulted in fewer symptoms and better quality of life compared with when the spray was taken only PRN.80 In the 2000s, PRN fluticasone propionate (FP) was found to be more effective than oral loratadine for controlling AR symptoms.
Repurposing asthma treatment
For the past 40 years,99 asthma management guidelines have recommended a stepwise approach based on the daily administration of controller medications (especially inhaled corticosteroids (ICSs) with or without long-acting ß-agonists [LABAs]), with the use of PRN rescue medication when needed (mostly short-acting β-agonists). In the 2000s, single maintenance and reliever therapy with the daily inhalation of ICS plus LABA, and the same medication for rescue, showed efficacy and safety.100
Conclusions
Value-added medicines address the following needs: (1) innovation regarding existing molecules in the form of repurposing therapies, (2) poor patient adherence, and (3) possible problems related to polypharmacy that are relevant to the proposal.
As proposed,49 patients consulting primary care physicians usually have uncontrolled symptoms despite using multiple medications. Real-life observational studies using mHealth have confirmed that adherence to treatment is a major issue because many
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Annex I: Summary of Product Characteristics
Barriers and facilitators of exploiting the potential of value-added medicines
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Conflicts of interest: J. Bousquet reports personal fees from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Purina, Sanofi-Aventis, Takeda, Teva, Uriach, and other from KYomed-Innov, outside the submitted work. I.J. Ansotegui reports personal fees from Roxall, UCB, Faes Farma, Sanofi, Bial, Abbott, Bayer, and Organon, outside the submitted work. S. Bosnic-Anticevich reports grants from Teva, personal fees from Teva, AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, and Mylan, outside the submitted work. L. Cecchi reports personal fees from Thermo Fisher, Sanofi, AstraZeneca, and Novartis, outside the submitted work. A.A. Cruz reports personal fees from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Sanofi, Novartis, Eurofarma, and Abdi-Ibrahim, outside the submitted work. S.D. Del Giacco reports grants and personal fees from AstraZeneca, GSK, and Novartis; and personal fees from Sanofi and Chiesi, outside the submitted work. J.A. Fonseca reports and is cofounder of a company that develops mHealth technologies. T. Haahtela reports receiving lecture fees from GSK, Orion Pharma, and Sanofi, outside the submitted work. J.C. Ivancevich reports personal fees from Laboratorios Casasco, Faes Farma, Abbott Ecuador, and Bago Bolivia, outside the submitted work. M. Jutel reports personal fees from ALK-Abello, Allergopharma, Stallergenes, Anergis, Allergy Therapeutics, Leti, and HAL, during the conduct of the study; and personal fees from GSK, Novartis, Teva, Takeda, and Chiesi, outside the submitted work. V. Kvedariene reports receiving support from Norameda and BerlinCHemie Menarini, which was to help LAAA (Lithuanian Allergy and Asthma Association) organise congresses, outside the submitted work. The author is the President of LAAA, but she did not receive personal fees. P. Kuna reports personal fees from Adamed, Berlin Chemie Menarini, Boehringer Ingelheim, AstraZeneca, Glenmark, Krka, Novartis, Polpharma, GSK, and Sanofi, outside the submitted work. D.E. Larenas-Linnemann reports personal fees from ALK, Allakos, Armstrong, AstraZeneca, Chiesi, DBV Technologies, Grunenthal, GSK, Mylan/Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Allakos, Gossamer, and Carnot; and grants from Sanofi, AstraZeneca, Lilly, Pfizer, Novartis, Circassia, UCB, GSK, and Purina Institute., outside the submitted work. B. Lipworth reports personal fees from Glenmark, grants and personal fees from Mylan, and grants from Sanofi and AstraZeneca during the conduct of the study; and is the son of a BJL employee of AstraZeneca. J. Mullol reports to be member of Advisory Boards from Sanofi-Genzyme, Regeneron, Novartis, AstraZeneca, and GSK; recieve research grants from Viatris and Noucor/Uriach Group; and personal fees from Mitsubishi-Tanabe, Menarini, UCB, AstraZeneca, GSK, Sanofi, and MSD, outside the submitted work. N.G. Papdopoulos reports receiving grants from Gerolymatos Int., Capricare, and Nutricia and advisories and/or honoraria for talks from ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GSK, HAL, Faes Farma, Medscape, Menarini, MSD, Mylan/Meda, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, and Takeda, outside the submitted work. B. Samoliński reports personal fees from Polpharma, Viatris, Teva, patient ombudsman, Polish Allergology Society; grants and personal fees from AstraZeneca; and grants from GSK, outside the submitted work. T. Zuberbier reports personal fees from AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Leti, Meda, Menarini, Merck, MSD, Pfizer, Sanofi, Stallergenes, Takeda, Teva, and UCB; grants and personal fees from Novartis; personal fees from Kryolan and L’Oréal, outside the submitted work; is affiliated with the World Health Organization Initiative "Allergic Rhinitis and Its Impact on Asthma," is a member of the board of the German Society for Allergy and Clinical Immunology, is board chairman of the European Centre for Allergy Research Foundation, is president of the Global Allergy and Asthma European Network, and is a member of the Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization. The rest of the authors declare that they have no relevant conflicts of interest.