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We are grateful to Dr Wilkinson and Professor Woodcock for their comments on our paper.
A key topic raised is related to the assumptions on the timelines to transition to low-Global Warming Potential (GWP) propellants. As of today, several Companies have committed to substantial investments in metered dose inhalers (MDIs) with novel propellants (1-4), indicating developments are progressing fast to target market introduction over the next few years, with 2025 as suggested initial date, and roll-out across portfolios and geographies. Previous transition from CFC to HFC-containing MDIs represents a precedent experience that can be leveraged to ensure a faster process, also dictated by pressure imposed by evolving regulations of HFC use. The new lower global warming potential propellant used for the inhaler transition in this analysis, HFA-152a, has been under development by Koura for an extended period for use in MDIs for the treatment of respiratory disorders such as asthma and COPD (5). In 2020, Koura reported that the US FDA had approved clinical trials with HFA-152a (6) and that the medical-grade propellant has been subject to an extensive suite of inhalation safety testing (including a chronic two-year pre-clinical study). It is understood that this extensive program will be used to support the future commercial use of medical-grade HFA-152a, with the essential Drug Master File expected to be finalized in 2022 (7). We agree that, in addition, the necessary clinic...
A key topic raised is related to the assumptions on the timelines to transition to low-Global Warming Potential (GWP) propellants. As of today, several Companies have committed to substantial investments in metered dose inhalers (MDIs) with novel propellants (1-4), indicating developments are progressing fast to target market introduction over the next few years, with 2025 as suggested initial date, and roll-out across portfolios and geographies. Previous transition from CFC to HFC-containing MDIs represents a precedent experience that can be leveraged to ensure a faster process, also dictated by pressure imposed by evolving regulations of HFC use. The new lower global warming potential propellant used for the inhaler transition in this analysis, HFA-152a, has been under development by Koura for an extended period for use in MDIs for the treatment of respiratory disorders such as asthma and COPD (5). In 2020, Koura reported that the US FDA had approved clinical trials with HFA-152a (6) and that the medical-grade propellant has been subject to an extensive suite of inhalation safety testing (including a chronic two-year pre-clinical study). It is understood that this extensive program will be used to support the future commercial use of medical-grade HFA-152a, with the essential Drug Master File expected to be finalized in 2022 (7). We agree that, in addition, the necessary clinical evaluation, including appropriate safety and tolerability studies, are required. To that end, active and constructive dialogue has been ongoing for several years with international regulatory agencies, including in both Europe and the US, which have been convened both by those specific pharmaceutical companies committed to lower-GWP inhaler platforms, as well as by across-industry associations. Moreover, under the framework of that agency guidance on the scope and details of the required pre-registration clinical evidence, clinical programs are now underway led by a number of companies in collaboration with external clinical sites. Inevitably these lower-GWP programs are focused on the specific products for which specific companies have the access and rights to transition.
We would also like to point out that our study was intended as a model applied to five different European Countries, with data retrieved collectively from all the Countries involved, and was not focused on the UK. From a clinical perspective, the ultimate goal of performing these analyses is to highlight the possibility of reducing the climate impact of inhalers while maintaining access to the whole range of device options (including both DPIs and pMDIs) to allow optimal treatment personalization, very much in line with the UK approach which is clearly presented by Dr Wilkinson and Professor Woodcock.
We fully agree with the need to reduce carbon footprint by all possible means. Therefore, we deliberately tested different scenarios, including three different rates of switching from DPIs to pMDIs: one is the prolongation of the current trend and two have been called “forced” since they are based on an imposed deadline, which would fit with the definition of a forced strategy. We would of course not question a “clinical” switch based on the goals, outcomes and preferences of care-givers and patients. Modulating preferences through transparent and balanced scientific information is clearly also essential. Part of our paper includes a note regarding the potential risk to disease control that could occur should switching of inhalers be accelerated non-optimally (8). This has been included to encourage a wider approach whereby both benefits and risks of an inhaler change are considered; a holistic approach to patient management when targeting any intervention or change on environmental grounds.
As mentioned above, fighting impactful carbon footprints is absolutely needed and all efforts have to be applauded. It remains true that the contribution of MDIs to global greenhouse-gases (GHG) emissions is low: this suggests that efforts to decrease it should take the time required to do so robustly and safely without risking unwanted clinical consequences for patients; such consequences could happen if treatment options of value for some patients were made unavailable.
We agree that while development progresses, all efforts shall be made to minimize GHG emissions related with treatment of diseases of asthma and COPD. We agree that MART can help improving asthma control in some patients, although it may not be a universal solution: here again, personalization is key. We also agree that MART can be implemented with both DPIs and pMDIs, and this should be supported to allow appropriate personalization of device choice. Moreover, a multi-stakeholder approach including all contributors to the patient and inhaler journey should be encouraged, going beyond simply addressing the environmental impact of inhalers and concentrating on the wider challenge of reducing the carbon footprint of the sub-optimally controlled respiratory patient (9). Focusing solely on inhaler carbon footprint would truly represent a missed opportunity to improve respiratory disease management while simultaneously reducing the environmental impact.
Comments are made regarding the carbon footprint values which have been cited. Our model was built utilizing lifecycle analyses of carbon footprint data available (10-12) at the time of publication and in alternative estimates published elsewhere (13), matching the average values proposed. We welcome other sources of carbon footprint values based on recognized standards, in order to continue to develop in the future more accurate calculations, rather than relying on estimated values.
Regarding the point of the possible influence of conflicts of interest on the content of our paper. Some authors are indeed employed by Chiesi or by companies engaged by Chiesi to perform the analysis as experts in the field. Conversely, NR is an independent academic clinician and clinical researcher with fully transparent, balanced and exhaustively disclosed links of interest with many companies involved in the development of inhaled therapy for asthma and COPD deploying pMDIs, DPIs and SMIs. He contributed critically to the analysis plan, especially to the design of tested scenarios and data interpretation. As well, CS is a primary care based respiratory nurse, not an employee for Chiesi and who did not receive any payment for this work.
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10. Panigone S, Sandri F, Ferri R, et al. Environmental impact of inhalers for respiratory diseases: decreasing the carbon footprint while preserving patient-tailored treatment. BMJ Open Respir Res 2020;7:e000571. doi: 10.1136/bmjresp-2020-000571.
11. Janson C, Henderson R, Löfdahl M, et al. Carbon footprint impact of the choice of inhalers for asthma and COPD. Thorax 2019;0: 1–3.
12. Hänsel, M., Bambach, T. & Wachtel, H. Reduced Environmental Impact of the Reusable Respimat® Soft Mist™ Inhaler Compared with Pressurised Metered-Dose Inhalers. Adv Ther 36, 2487–2492 (2019). https://doi.org/10.1007/s12325-019-01028-y
13. Wilkinson AJK, Braggins R, Steinbach I, et al. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open 2019;9:e028763. doi: 10.1136/bmjopen-2018-028763.
We are strongly supportive of efforts to reduce the carbon footprint of inhalers. We believe this should be achieved by providing easily understood information to patients and health care workers to be able to make informed decisions about their inhaled treatments. Near term changes prioritising controller medication with the very large range of available Dry powder inhalers (DPIs) could reduce the carbon footprint by 90%, bringing the UK in line with the rest of Europe.
The paper is essentially written by Chiesi pharmaceuticals. We are concerned about potential bias in the paper arising from this conflict of interest. Chiesi are to be applauded for having committed substantial R&D to the development of metered dose inhalers (MDIs) containing a novel lower GWP propellant HFC-152a to replace high GWP 134a. They are one of only two companies who have announced a transition using HFC-152a for their large range of MDIs.(1,2) However, the paper contains a number of inaccuracies, and is over-optimistic on the timing and pace of transition.
The timelines for achieving a transition to HFC 152a pMDIs are unrealistic; the transition to HFA152a is likely to take far longer than described in the paper. So far, no safety or efficacy data is available for any inhaler containing HFC-152. No detail on requirements for HFC 152a inhalers has been published by the regulatory agencies, although it seems almost certain that long-term human safety data will be required.(3)...
The timelines for achieving a transition to HFC 152a pMDIs are unrealistic; the transition to HFA152a is likely to take far longer than described in the paper. So far, no safety or efficacy data is available for any inhaler containing HFC-152. No detail on requirements for HFC 152a inhalers has been published by the regulatory agencies, although it seems almost certain that long-term human safety data will be required.(3)
This makes a projected start date of 2025 extremely challenging for any HFC 152a pMDI. The best modelled scenario in the paper assumes an HFC 152a product will be available for every single pMDI product on the market within a 6 month period starting in 2025, and for the transition would be completed within just 2 years. The switch from CFC to HFC-containing MDIs took 20 years, and this 2-year transition period seems totally unrealistic. Other companies will also need time to reformulate, obtain regulatory approval, and launch ranges of MDIs around the world.
Continued pMDI use is compared with “forced switching” to DPIs/SMIs. This is a false premise - nobody is encouraging a “forced” switch or the removal of pMDIs as an option. This unfairly implies that efforts to cut the carbon footprint of therapy involve forcing patients onto inhaler devices they don’t want. On the contrary, in the UK the enforced switch has been in the opposite direction, and solely based on cost. In 2000, two-thirds of inhaled steroid inhalers were DPIs, but this has reduced to 9%, despite evidence that asthma control deteriorated and that multi-dose DPIs appear to be the devices most favoured by patients.(4)
NHS incentives only promote the use of DPIs where it is clinically appropriate, and they exist alongside incentives to improve care by cutting over-reliance on reliever inhalers and promoting adherence to maintenance therapy.(5) The NICE decision aid aims to inform patients about all aspects of inhaler use including their carbon footprint of therapy so they can make a fully informed decision.(6) A recent very large survey of asthma patients shows that they want their therapy to have a lower carbon footprint and most are willing to switch inhalers to achieve this.(7) Far from being a “forced switch”, current efforts involve working alongside patients to find the most convenient and preferred inhaler that patients can and will use, prioritising those with the lowest carbon footprint, and most important improving asthma control. Arguments about “forced switching” unhelpfully undermine these efforts.
The quoted carbon footprint figures used for propellant-free DPIs and SMIs inhalers are inaccurate and too high. A figure of 1.25kg is used for most DPIs, though it's unclear how this figure was reached. It was not the figure used in the reference.(8) There have been many life cycle analyses of non-propellant inhalers published recently, with carbon footprint varying from 0.19-0.9kg. For the Breezhaler, 0.75kg is used in the paper, though life-cycle analysis shows it has a carbon footprint of 0.19-0.38kg depending on how many days the device is re-used for.(9) The figures for soft mist inhalers assume these inhalers are never re-filled, even though refills are in common clinical use (in the UK at least) and can reduce the carbon footprint to as little as 0.225kg per 30 days. (10)
The article makes repeated references to the small contribution of pMDIs to global greenhouse gas emissions, implying that efforts to address this are unnecessary (at least until their own lower GWP inhalers are available!). pMDIs account for 13% of NHS carbon footprint related to the delivery of care,(4) and for a company like GSK around 45% - not at all trivial.(11) The climate crisis is such that all areas of society need to urgently do everything possible to minimise greenhouse gas emissions. A small contribution to the greatest threat to public health the world faces is highly valuable. Moreover, patients care about the carbon footprint of their treatment and most want to minimise its impact where possible.(7)
The article underestimates the impact of recycling by assuming only 25% of propellant is left within the inhaler. A previous national inhaler recycling scheme in the UK found far more wasteful use of MDIs in real-world practice, with 48% of doses remaining in MDIs (and higher rates of waste seen in MDIs that lack dose counters) but only 27% of doses remaining in DPIs (which all include dose counters).(12) The impact of incineration on the global warming potential of the propellant is also not clear from the paper. Nevertheless, the wasteful use of pMDIs potentially increases the positive impacts of recycling. This greater efficiency of DPI use in real-world practice is not factored into the overall analysis, potentially further biasing the conclusions in favour of pMDIs.
Asthma control across most European countries remains poor, with frequent over-reliance on reliever pMDIs. We agree that efforts to optimise asthma could significantly reduce greenhouse gas emissions, though reductions in the carbon footprint of care could be accelerated if this were instituted alongside prioritisation of DPIs. Most inhalers licensed for MART are DPIs, as are once-daily long-acting ICS/LABA combination inhalers. Greater use of these strategies could have a bigger impact than is shown in the paper if DPIs are prioritised simultaneously.(4) Similarly the carbon footprint of COPD could be improved by promoting smoking cessation, greater uptake of pulmonary rehabilitation, reducing unnecessary inhaled steroid use, and prioritisation of propellant-free inhalers.
The most problematic aspect of the analysis is the unrealistic assumption that an HFA152a inhaler will be available for every single class of drug therapy from 2025. We disagree with the implication that waiting for this novel propellant (whilst Chiesi maintain market dominance with a high GWP 134a MDI), is the best course of action. Whilst we strongly welcome efforts to cut the carbon footprint of pMDIs, there is no certainty that these propellants will be approved, and a complete transition to newer propellants could take decades. There are great opportunities available immediately to work alongside patients to improve care whilst simultaneously cutting the carbon footprint of therapy.
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5. NHS England. Annex B – Investment and Impact Fund: 2021/22 and 2022/23.
7. D’Ancona G, Cumella A, Renwick L, Walker S. The sustainability agenda and inhaled therapy: what do patients want? In: ERS International Conference. ; 2021.
8. Wilkinson AJK, Braggins R, Steinbach I, Smith J. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open. 2019;9(10):e028763. doi:10.1136/bmjopen-2018-028763.
9. Mezzi K. Carbon footprint impact of Breezhaler® dry powder inhaler: a life cycle assessment in the UK. IPCRG conference paper. Aug 2021 https://www.ipcrg.org/12368
10. Hänsel M, Bambach T, Wachtel H. Reduced environmental impact of the reusable Respimat® Soft mist™ inhaler compared with pressurised metered-dose inhalers. Adv Ther 2019;36:2487–92. doi: 10.1007/s12325-019- 01028-y.
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12. Wilkinson AJK, Anderson G. Sustainability in Inhaled Drug Delivery. Pharmaceut Med. 2020;34(3):191-199. doi:10.1007/s40290-020-00339-8.