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Ann Am Thorac Soc
Ann Am Thorac Soc
AnnalsATS
Annals of the American Thoracic Society
2329-6933
2325-6621
American Thoracic Society

38935646
202401-115VP
10.1513/AnnalsATS.202401-115VP
Viewpoints
Climate Policy and Pediatric Asthma: How Transition to Nonhydrofluorocarbon Propellants Will Disproportionately Impact Children
https://orcid.org/0000-0002-9445-8148
Brennan Steven K. 1
Coates Anne C. 2
Laube Beth 3
Sadreameli S. Christy 3
1 Division of Pediatric Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri;
2 Division of Pediatric Pulmonology, Barbara Bush Children’s Hospital, Portland, Maine; and
3 Division of Pediatric Respiratory Sciences, Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
Correspondence and requests for reprints should be addressed to Steven K. Brennan, M.B. B.S., Division of Pediatric Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis, 660 S. Euclid Avenue, MSC 8116-43-14, St. Louis, MO 63110-1093. E-mail: skbrennan@wustl.edu.
1 9 2024
1 9 2024
1 9 2024
21 9 12421244
30 1 2024
21 6 2024
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern.
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pmc

In June 2023, GlaxoSmithKline, manufacturer of the pressurized metered dose inhaler (pMDI) Flovent (fluticasone propionate) hydrofluoroalkane (HFA; a type of hydrofluorocarbon [HFC]), notified the U.S. Food and Drug Administration (FDA) of its intent to discontinue the brand medication at the end of 2023. This appeared to be financially motivated because it coincided with the removal of a Medicaid rebate cap as part of the American Rescue Plan Act. Under this law, drug manufacturers must pay large penalties to Medicaid if they raise the price of their drug beyond inflation rates (1). A new authorized generic would not be impacted by pricing history.

As of early 2024, discontinuation of Flovent had caused a crisis in patients’ ability to access the alternative authorized generic drug and obtain insurance coverage for it. Losing access to this single critical medicine has significantly impacted treatment for patients with asthma and affords pediatric providers and health insurance plans the opportunity to reflect and prepare for the next major change in inhaled medication availability. In the coming years, the United States and Europe will gradually phase down HFC propellants used in pMDIs to help limit their impact on climate change.

Historical and Clinical Context

For decades, asthma control has been within reach for millions of children because of the availability of pMDIs. pMDIs contain a pressurized propellant and, when combined with a valved holding chamber, can be used by people of all ages. The propellant creates constant pressure within the canister such that the dose remains the same with each administration, even as the amount of drug in the canister decreases with subsequent actuations. In the 1970s, it was determined that the most commonly used propellants, chlorofluorocarbons (CFCs), were depleting the Earth’s protective ozone layer and increasing the ultraviolet radiation reaching our planet’s surface (2). In response, in 1988, the United States ratified the Montreal Protocol on Substances that Deplete the Ozone Layer and agreed to phase out CFC-containing products and other harmful aerosols by 2010 (2). This phase-out helped reduce the ozone hole. HFAs were developed in response to the CFC ban and incorporated into pMDIs (3). To sell pMDIs with new HFA propellants, manufacturers were required to submit new drug applications (NDA) to the FDA. Once approved, pMDIs containing HFCs could be sold under new patents at higher costs (4).

Climate Change and Transitioning to Non-HFC Propellants

Climate change is affecting children’s health. An example is the very high rates of emergency department use by children with asthma because of extreme heat, particulate pollution, and wildfire smoke during the summer of 2023 (5). Although HFCs have less of an impact on atmospheric ozone levels than CFCs, they affect Earth’s climate because of their high global warming potential (GWP) and extended atmospheric life. The two major HFC propellants in pMDIs, HFA 134a and HFA 227ea, remain in the atmosphere for 14 and 36 years, respectively (6), and absorb more heat than CO2, one of the most detrimental greenhouse gases. HFC 134a has a GWP of 1,430, meaning it absorbs 1,430 times more heat as the same mass of CO2 (7).

Refrigeration, air conditioning, fire suppression, and solvent industries are responsible for approximately 86% of global HFC emissions. pMDIs were responsible for 0.5% of U.S. HFC emissions in 2020 (4). In 2020, the U.S. Congress passed the American Innovation and Manufacturing Act (8) with the goals of phasing down the use of HFCs, managing current use, and moving toward alternatives with less GWP by 2047. The European Union (EU) is moving toward a complete phase-out of HFCs by 2050 together with management of the HFCs in pMDIs under a new quota system in the meantime (9).

Medical versus Environmental Impact: Dwindling pMDI Availability for Children

Although the American Innovation and Manufacturing Act allows HFC use in essential medications, this provision will expire in 2030 at the latest, when the phase-down will be complete (10). It is possible that the EU’s actions will impact the U.S. market sooner than 2030 if HFC manufacturers significantly scale down production. Without alternative propellants for pMDIs or newly designed delivery devices, asthma care for children will face major challenges. When young children lose access to pMDI-delivered steroids such as Flovent, this could increase the carbon footprint of children with asthma (11, 12) because of loss of asthma control and need for additional inhalations of short-acting β-agonist bronchodilator pMDIs.

Dry powder inhalers (DPIs) are an alternative to pMDIs because they do not contain a propellant. However, they are not suitable for anyone who cannot perform a forceful inhalation followed by a breathhold. Without enough force during inhalation, the drug will not exit the inhaler, leading to suboptimal dosing (13). This limitation affects individuals with neuromuscular disease, cognitive limitations, tracheostomies, and older adults with severe airflow obstruction (13). Children under the age of 4, and sometimes older, have difficulty generating adequate inhalation for DPIs (14). The Global Initiative for Asthma guidelines suggest that “DPIs are not suitable for most children aged ⩽5 years.” Switching from a pMDI to a DPI has also been associated with a decrease in lung function in older children with asthma (median age, 11 yr) (15).

The Centers for Disease Control and Prevention reports that 2.4 million children under age 12 years have asthma (16). DPIs are likely ineffective in a sizable portion of this group and in some children with other complex medical diseases. Limiting pMDI availability will have a significant impact on pediatric care in the United States.

The challenges posed by the abrupt discontinuation of Flovent should serve as a reflection point for prescribers, insurers, regulators, and the pharmaceutical industry on the importance of pMDIs for children. Many insurance companies have not covered the authorized generic version of Flovent HFA or an appropriate pMDI alternative, creating considerable difficulty for pediatricians to provide treatment. Although some payers have responded by adding the authorized generic version or another inhaled steroid to drug formularies for some ages, this has been inconsistent, and copays are often high. Many private and public payers do not include pMDIs in their formularies with appropriate age cutoffs for pediatric patients. In addition, equivalent medications (such as mometasone furoate) have dwindled in supply because of increased demand. It is evident that a clear transition plan is necessary to ensure that children retain access to pMDIs.

Regulatory and Drug Development Challenges

Similar to when the industry transitioned from CFC to HFC propellants, manufacturers may be required to submit NDAs for more climate-friendly propellants. This could result in lengthy reviews, delayed availability in the marketplace, and new patents with increased cost. There are two alternative propellant candidates being tested. Hydrofluroolefin-1234ze(E) is undergoing clinical trials, has a GWP of 1 (less than that of CO2), has an atmospheric half-life of 19 days, and may prove to be a viable alternative. Unfortunately, it is classified as a per- and polyfluoroalkyl substance, which may fall under a proposed ban by the EU on “forever chemicals.” Its breakdown product is trifluoroacetic acid, which does not degrade and accumulates in the environment (17, 18). The other propellant is HFC 152a, with an atmospheric half-life of 1.4 years and GWP of 124. Developing these new propellants and their delivery devices will include significant preclinical testing to determine toxicological profiles and effective dosing. They may not reach the market for a few years.

Future Directions

Solutions to the future availability of pMDI-delivered asthma medications for children are attainable but not simple. Although the threat of a permanently changed climate must be addressed, we recognize that pediatric use of pMDIs is a much smaller contributor to climate change than emissions from the refrigeration, air conditioning, and solvent industries and substantially improves the respiratory health of millions of children. For older children, switching to a DPI may be possible. Those who cannot perform the inhalation maneuvers required for DPIs will need access to pMDIs.

During the transition period to non-HFC, or alternatives to HFC, propellants, the FDA should consider the following policy changes:• Do not allow pharmaceutical companies to evade the Medicaid rebate cap that is part of the American Rescue Plan Act by calling a drug an “authorized generic.” Either the drug is a new drug that needs to undergo NDA testing, or it is a generic and should be covered by insurance providers.

• Reduce the years of patent protection for a brand drug and encourage more generic drug development to lower drug costs.

• Limit the total, or out-of-pocket, costs of drugs.

• Require payers to cover age-appropriate medications for children or anyone unable to perform the correct inhalation maneuvers for a DPI, whether a brand name or a generic.

• Do not permit insurance providers to require new provider authorizations for generics that are exactly the same as the brand drug.

With careful consideration of policies and solution-focused action from pediatric providers and industry partners, we can protect both the climate and a vulnerable population of children and adults who rely on pMDIs for asthma control.

Author disclosures are available with the text of this article at www.atsjournals.org.
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