spiral.imperial.ac.uk · web viewidentifying barriers to idiopathic pulmonary fibrosis treatment: a...

Identifying Barriers to Idiopathic Pulmonary Fibrosis Treatment: A Survey

of Patient and Physician Views

Toby M. Mahera, Jeffrey J. Swigrisb, Michael Kreuterc, Marlies Wijsenbeekd, Nicola Cassidye,

Lucy Irelandf, Judit Axmanng and Steven D. Nathanh

aInterstitial Lung Disease Unit, Royal Brompton Hospital and Imperial College London,

London, UK, E-mail: [email protected]; bNational Jewish Health, Denver, CO, USA, E-

mail: [email protected]; cCenter for Interstitial and Rare Lung Diseases, Pneumology and

Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, Member of the

German Center for Lung Research, Heidelberg, Germany, E-mail: [email protected]

heidelberg.de; dDepartment of Pulmonary Medicine, Erasmus University Medical Center,

Rotterdam, The Netherlands, E-mail: [email protected]; eIrish Lung

Fibrosis Association, Dublin, Ireland, E-mail: [email protected]; fHall and Partners,

London, UK, E-mail: [email protected]; gF. Hoffmann-La Roche, Ltd., Basel,

Switzerland, E-mail: [email protected]; hInova Fairfax Hospital, Falls Church, VA,

USA, E-mail: [email protected]

Corresponding/submitting author: Toby M. Maher, Fibrosis Research Group, Sir Alexander

Fleming Building, Imperial College London, London, SW7 2AZ, UK. Tel: +44 207 351 8951.

Fax: +44 207 679 6973. E-mail: [email protected]

Running title: Barriers to idiopathic pulmonary fibrosis treatment

Target journal: Respiration

Word count (no limit specified): 3891 (does not include quotes)

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Abstract [223/250 words]

Background: Antifibrotics are recommended for the treatment of individuals with idiopathic

pulmonary fibrosis (IPF) but treatment use remains at ~60%.

Objective: To investigate the views of individuals with IPF and pulmonologists on the diagnosis

and management of IPF to understand treatment patterns.

Methods: Interviews and/or online surveys were completed by patients and pulmonologists from

Canada, France, Germany, Italy, Spain, and the United Kingdom. Responses from physicians

were analyzed by time between diagnosis and treatment initiation in the majority of patients

with IPF (Group A, >4 months; Group B, ≤4 months). Statistical comparisons between

physicians were undertaken using z-tests, with p < 0.05 considered statistically significant.

Results: Physicians in Group A saw fewer patients, were less comfortable discussing IPF

prognosis with patients, and had less belief in the benefits of antifibrotic treatments compared

with physicians in Group B. These physicians’ attitudes contrasted with those of patients, who

wanted more information about IPF prognosis and pharmacological treatment options at

diagnosis and were more concerned about preventing disease progression than avoiding

medication side effects. Differences between countries were found regarding physicians’

comfort in discussing prognosis at diagnosis and access to care.

Conclusions: Several barriers to antifibrotic treatment, principally reflecting the differing views

and values of patients and physicians, were identified in this study, suggesting a need for better

patient–physician communication about pharmacological therapy for IPF.

Keywords (4/7): Idiopathic pulmonary fibrosis, Antifibrotic, Patient–physician communication,

Barriers to treatment

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Introduction

Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive, invariably fatal,

scarring lung disorder of unknown cause [1, 2] that significantly lowers quality of life [3] and

has a survival rate lower than that reported for many common cancers [2, 4-7]. The incidence,

prevalence, and number of deaths from IPF are currently increasing [8-10].

The clinical course of IPF is variable, and there is no good way to accurately predict

prognosis or directly assess treatment response in individual patients; all patients with IPF will

invariably experience lung-function decline at some point in their disease course [2, 11-13].

Currently there are two antifibrotic drugs, pirfenidone and nintedanib, approved for the

treatment of IPF; these therapies are recommended in universally accepted, international

treatment guidelines [14]. Recent evidence from post-hoc analyses supports early initiation of

antifibrotic therapy once patients are diagnosed with IPF to reduce loss of lung function and

slow disease progression [15-18]. However, despite the availability of effective treatments,

~40% of patients with a confirmed diagnosis of IPF do not receive treatment [19].

Here, we present results of qualitative and quantitative surveys of pulmonologists and

individuals with IPF that aimed to explore views on the diagnosis, treatment, and management

of IPF. We also sought to identify differences in behavior between pulmonologists who

commenced antifibrotic treatment ≤4 months after diagnosis and those who preferred to “watch

and wait”.

Methods

Design and Participants

Data for this study, comprising qualitative interviews and quantitative online questionnaires,

were collected from individuals with IPF (“patients”) and pulmonologists (“physicians”) from

Canada, France, Germany, Italy, Spain, and the United Kingdom (UK). Interviews and

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questionnaires were developed by Hall & Partners, an independent market research agency, on

behalf of F. Hoffmann-La Roche, Ltd. Participants were made aware that this study was

sponsored by a pharmaceutical company.

Between July 27 and September 16, 2016, 60-minute face-to-face interviews were

conducted with patients and physicians by professional market research moderators and were

supplemented by telephone interviews with physicians. Caregivers could participate in

interviews to support patients. Subsequently, patients and physicians participated in 20-minute

online surveys between September 23 and October 12, 2016. Different surveys were used by

patients and physicians (online suppl. files 1 and 2), and both surveys were provided in English,

French, German, Italian, and Spanish. Because surveys contained no identifying information,

there may have been overlap between those participating in face-to-face interviews and online

surveys.

Responses were collected from patients with IPF, and physicians who had consulted with

>5 patients with IPF within the previous 3 months and were responsible for initiation (or

recommending the initiation) of any approved drug treatment for IPF (for the face-to-face

interviews, physicians were required to be personally responsible for initiating treatment).

Patients were recruited via physician referrals, patient groups, or market research panels and

were eligible for inclusion if they had received pirfenidone and/or nintedanib, or had been

offered (but refused), treatment. Since prescription of antifibrotics is restricted to certain centers

in the UK and Italy, ≥50% of physicians in the UK and ≥67% of physicians in Italy were

required to work at centers authorized to prescribe antifibrotics for the online questionnaire;

these thresholds were selected based on previous research on the treatment of IPF. This

threshold was subsequently removed from the UK to allow a large enough sample of physicians

to be included in the study within the time that the survey was available. Physicians were

recruited from market research panels and were required to complete the surveys themselves.

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Patients and physicians received a small cash incentive for participation in the research (e.g., in

the UK, patients received £20 and physicians received £44; this value varied by country).

Statistical Analysis

Face-to-face interviews were recorded and transcribed, translated into English (if

applicable), and collated. Responses collected in online questionnaires were collated and

statistical analyses were performed by the research team at Hall & Partners using Askiaanalysis

(Askia, Paris, France).

Responses collected from physicians in the online questionnaires were split into two

groups: those who monitored ≥50% of patients for >4 months post-diagnosis before initiating an

antifibrotic (Group A) and those who initiated an antifibrotic within 4 months post-diagnosis in

the majority of patients (Group B). The 4-month threshold was based on observations from the

qualitative interviews indicating that physicians who tended to initiate treatment early would

either do so at diagnosis or at a follow-up appointment within 3 months of diagnosis, whereas

those who waited before initiating treatment would usually schedule a follow-up appointment

≥6 months post-diagnosis. Physician responses were also analyzed based on tertiles of their

caseloads (high, medium, or low) of patients with “mild” or “moderate” IPF (no definition of

“mild” or “moderate” IPF was provided and the assessment of disease severity was based solely

on the judgment of individual physicians). Statistical comparisons between physicians were

undertaken using z-tests, with p < 0.05 considered statistically significant.

Results

Physician Characteristics

Sixty-one physicians participated in face-to-face interviews and 287 completed online

questionnaires (online suppl. Table S1). The proportion of physicians who were authorized to

prescribe antifibrotics was 80% in the UK and 75% in Italy (this question was not asked in other

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countries, since they did not have the same restrictions on which centers could prescribe

antifibrotics). Of the physicians who completed online questionnaires, 46% were in Group A

and 54% were in Group B (online suppl. Table S1). The gender and age distributions of

physicians in Groups A and B were similar (Table 1).

Overall, 11% of physicians worked in specialist pulmonary centers or tertiary referral

centers for IPF; this did not differ significantly between Groups A and B (Table 1). The IPF

caseload was significantly lower for physicians in Group A than Group B (Table 1; means of

30.5 vs. 81.4 “mild” and 30.7 vs. 84.1 “moderate” patients per year for Group A vs. Group B).

Patient Characteristics

Sixty-eight patients participated in face-to-face interviews and 60 patients completed

online questionnaires (online suppl. Table S1). The mean age of patients who completed online

surveys was 64.6 (±9.0) years and 72% (43/60) were male. All patients had been treated with

pirfenidone (73% [44/60]), nintedanib (18% [11/60]), or both treatments sequentially

(pirfenidone then nintedanib; 8% [5/60]). At the time they completed the survey, 77% (46/60) of

patients were still taking treatment and 22% (13/60) had stopped treatment (one patient gave

his/her treatment status as “other”).

Physician Survey: Diagnosis

Topics physicians reported discussing at diagnosis are shown in Table 2. Significantly

more physicians with high caseloads discussed prognosis at diagnosis (60% [55/91]) than

physicians with low caseloads (44% [38/86]; p < 0.05). Topics discussed at diagnosis by country

are shown in online suppl. Table S2.

Only 28% of physicians “strongly agreed” or “agreed” that they were comfortable

discussing IPF prognosis (Table 2), with a significant difference between Groups A and B

(p < 0.05; Table 2). Similarly, there were differences at a country level (online suppl. Table S2).

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A considerable proportion of physicians (40%) avoided discussing typical prognosis or

life expectancy of IPF even when a patient asked about this, with more physicians in Group A

than Group B avoiding these questions from patients (Table 2). Some of the physicians who

participated in face-to-face interviews also expressed concerns with how to discuss prognosis

with patients:

Patient Survey: Diagnosis

Twenty-seven patients (45%) were informed of their diagnosis by a pulmonologist based

in a large teaching or specialist hospital; others were informed of their diagnosis by a

pulmonologist based in a local city/district hospital (28%) or office (15%), their general

practitioner (10%), or someone else (2%). The majority of patients had not heard of IPF when

they were diagnosed (77% [46/60]). Forty percent (24/60) of patients did not feel that they

received enough information from their physicians at diagnosis; 57% (34/60) remembered being

told that IPF is progressive, 43% (26/60) remembered a discussion on the impact IPF would

have on their lives (prognosis), and 43% (26/60) remembered being informed about treatment

options. Seventy percent (39/56) of patients received further information about IPF from their

physicians in later appointments, which took place at a mean (standard deviation) of 3.8 (7.6)

months after diagnosis (2.0 [1.6] months in patients treated within 4 months of diagnosis and 4.5

[8.8] months in patients treated >4 months after diagnosis).

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“My approach is not to confirm diagnosis but to think how do I let this patient know that this

[IPF] is a serious illness without scaring them?” (Physician – Canada)

“If you tell a patient or their family that you would rather wait [to start treatment] right after

you’ve told them that they have a fatal disease, they think you’re completely nuts [crazy].

Sometimes, I feel there is only little that can be done with the treatments but it is difficult not

to offer something.” (Physician – France)

Some patients/caregivers participating in face-to-face interviews expressed frustration

about the lack of information provided:

Most patients (93% [56/60]) preferred to receive information about IPF from their

physicians; however, 70% (42/60) of patients searched for further information themselves.

Google or other internet search engines (79% [41/52]) were most frequently used to look for

information about IPF; online patient forums (40% [21/52]), online information from patient

support or advocacy groups (42% [22/52]), and leaflets provided by the physician or hospital

(35% [18/52]) were also used.

Physician Survey: Treatment

Significantly fewer physicians in Group A than Group B agreed or strongly agreed with

statements supporting early initiation of antifibrotic therapy (Fig. 1). Differences in responses to

these questions were also observed at a country level (online suppl. Table S3). Overall, 23% of

physicians felt that side effects of pharmacological treatment were of more concern than risk of

IPF progression; significantly more physicians in Group A than Group B agreed or strongly

agreed with this statement (p < 0.05; Fig. 1).

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“They [physicians] should be a lot more honest… There is no point sugar-coating it. Even if

I was fearful of the truth, I would like to hear it… I get the impression that they [physicians]

never really know quite how to answer your question… They beat around the bush… They

don’t give any clear, honest, frank answers you can really understand.”

(Caregiver – France)

“I remember searching on the internet, and thinking, ‘I’ll probably be dead next week’. In

the beginning, because you know so very little, it can be very frightening. It was so

confusing.” (Patient – Canada)

Around 50% of physicians cited “stable” disease, “good” lung function, and/or

“asymptomatic” disease as reasons for not treating patients; significantly more physicians in

Group A than Group B gave these reasons (Fig. 2), and the majority of physicians in Canada

also gave these reasons for not treating patients (online suppl. Table S4).

Other reasons for not treating patients included patients having suspected IPF or an

unclear diagnosis, older age (as defined by the physician), comorbidities, cost of treatment or

lack of funding, and access restrictions (i.e., limitations on which patients could receive

treatment; Fig. 2); none of these differed significantly between Groups A and B. Access

restrictions were most frequently cited by physicians as a reason for not treating patients in the

UK and Canada (online suppl. Table S4).

Patient Survey: Treatment

Twenty-five patients (42%) reported that they were offered pharmacological treatment at

the same time as receiving their diagnosis. However, only 10% (6/60) of patients initiated

treatment when it was first offered. A further 25% (15/60) of patients initiated treatment within

4 months of it being offered. Most patients (72% [43/60]) reported that their physician made the

final decision on which treatment they received.

Some patients participating in face-to-face interviews wished that they had started

antifibrotic treatment earlier:

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Most patients (87% [52/60]) felt that slowing IPF progression with antifibrotics was

more important than potential side effects. Overall, 85% (51/60) of patients who received

antifibrotic therapy felt confident in managing those side effects, and most patients

(63% [38/60]) reported a “positive” or “very positive” experience of taking antifibrotics.

When asked what advice they would give to someone who had been recently diagnosed

with IPF, most patients advised ensuring that they are well informed about IPF, starting

treatment, and/or consulting an interstitial lung disease (ILD) specialist:

Discussion

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“They also said there were treatments that were not available in Spain yet. I even asked her

[the doctor] if we could get it, and she told us it was impossible… Those 2 years we were

missing [out on treatment]… We could do nothing about it, there were parameters [to

qualify for treatment].” (Patient – Spain)

“Above all, this abandonment we had for 3 months [until starting treatment], this worry, we

feel like we lost time.” (Patient – France)

“I don’t know why the treatment wasn’t started immediately, actually. It’s true that we didn’t

ask the question immediately, because we trust him [the doctor].” (Caregiver – France)

“Immediately consult a specialist who has a good knowledge of this disease.”

(Patient – Italy)

“Go to a specialist and to start the treatment immediately.” (Patient – Italy)

“I would advise them to go to the specialist to whom I went and to start treatment

immediately; I have waited too long.” (Patient – Italy)

"Listen to and ask questions of your doctor... Search out information about the disease and

how others have lived with the condition." (Patient – Canada)

The results of this study reveal several differences between physicians who initiated

antifibrotic therapy in the majority of their patients >4 months (Group A) and ≤4 months

(Group B) after diagnosis. They also highlight a disconnect between physician and patient views

regarding information provided at diagnosis and initiation of antifibrotic treatment.

Physicians in Group A were less likely to have high caseloads of patients that they

defined as having “mild” or “moderate” IPF, less comfortable discussing disease prognosis with

patients, and more likely to avoid this discussion altogether than physicians in Group B.

Furthermore, physicians in Group A were less likely to believe in the benefits of early treatment

in patients with less-advanced disease than physicians in Group B, and more likely to be

concerned about associated side effects. This is reflected in the finding that a higher proportion

of physicians in Group A than Group B cited “stable” disease, “good” lung function, and/or

“asymptomatic” disease as reasons not to treat “mild” IPF.

Overall, these results suggest that less experience in diagnosing and managing patients

with IPF and lack of confidence in the efficacy of antifibrotic treatments, particularly for

patients with less-advanced disease, might contribute to lower treatment rates of IPF.

Additionally, the concept of “stable disease” is a common belief amongst physicians and a

frequent reason for not treating IPF; it is possible that physicians in Group A were less

concerned about small declines in FVC and had limited access to high-resolution computed

tomography to further assess disease progression, but the results from this survey cannot

confirm this. Proponents of initiating antifibrotic therapy in all patients with IPF argue that

therapy is warranted because IPF causes progressive, irreversible lung damage and has a median

survival of approximately 3 years, and an individual’s disease course cannot be accurately

predicted [2, 11-13]. In support of this view, post-hoc analyses of CAPACITY [20] and the

extension study RECAP [21] comparing annual rate of lung-function decline in patients

randomized to pirfenidone or placebo in CAPACITY found that those who had pirfenidone

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treatment delayed (i.e., the placebo group) had a loss of lung function that was not recovered

when open-label pirfenidone was initiated in RECAP [18]. Furthermore, the efficacy of

antifibrotic treatment for reducing loss of lung function, regardless of baseline lung function, is

supported by clinical evidence [15-17, 22]. Moreover, half of the physicians surveyed cited

older age as a possible barrier to initiating antifibrotic treatment in patients. However, experts

believe that age alone should not hinder access to treatment if there are no contraindications

present [23-25], as is the case for lung cancer [26].

The patient surveys also revealed that, although physicians are still the main source of

trusted information for patients with IPF, many patients do not feel that they are provided with

enough information about the disease from their physicians. The resulting lack of access to

trustworthy information about IPF can be a source of distress for patients and their caregivers.

Of concern, there appeared to be a disconnect between the information physicians reported

providing and the information patients remember receiving. For example, 90% of physicians

said they gave patients information about treatment options, whereas only 43% of patients

remembered being told about IPF treatments. It is well known that some patients do not retain

all of the information in one consultation, particularly when bad news is being conveyed [27-

29]; thus, these findings emphasize the need for physicians to be able to communicate difficult

topics with empathy and to make sure that patients hear and understand them. Physician

education in communication skills should emphasize the importance of adjusting the amount,

timing, and format of information provided based on the needs and values of the individual

patient and their caregivers, and repeating important information at multiple visits. Physicians

may develop a partnership with their patients by providing comprehensive, effective, and timely

information. This promotes informed, shared decision making and enables patients with IPF to

have the best chance of adhering to pharmacological treatments by minimizing potential side

effects, as well as incorporating other interventions that may improve outcomes, such as

pulmonary rehabilitation [1, 30, 31].12

The majority of patients surveyed searched for more information on IPF online;

however, a recently published analysis found that online health information on IPF is frequently

incomplete, inaccurate, and outdated [32]. Results from other surveys suggest that the majority

of patients wanted to be provided with more information about IPF, including its progression

and treatment [33, 34]. The European IPF Patient Charter calls for “comprehensive and high-

quality information about IPF, including its treatment” to be made available to patients [35].

This is reiterated by Patient Charters from Ireland, the UK, and Canada [31, 36, 37].

Our results suggest a substantial disconnect between patients and physicians regarding

their general attitudes towards treatment. Patients were generally more concerned about slowing

IPF progression than medication side effects and most were confident that they could manage

the side effects. Furthermore, most patients would advise others newly diagnosed with IPF to

start treatment and/or see an ILD specialist, and some patients expressed frustration or distress

that their treatment was not initiated earlier. These views contrasted with the views of some

physicians, a large minority of whom were more concerned about antifibrotic drugs causing

problematic side effects for their patients than reducing IPF progression. The IPF international

treatment guidelines were updated in 2015 and were co-authored by 16 physicians, one scientist,

and one patient, with no ILD nurses or relatives of patients [14]. There is a need for greater

engagement with patients, their families, and patient organizations or advocacy groups when

preparing future guidelines or research study designs to ensure that patients’ needs, concerns,

wishes, and values are adequately and accurately captured.

The survey results also identified differences between countries regarding discussion of

prognosis and initiation of antifibrotic treatment. These differences could reflect the time that

antifibrotic therapy had been available locally (which differed between the countries surveyed),

cultural influences, regulatory policies, or various other reasons. Although physicians in Canada

were most likely to discuss prognosis and were more comfortable doing so than physicians from

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other countries, Canada also had the highest proportion of physicians in Group A, presumably

due to restrictions on drug reimbursement. Canada (and Spain) had access rules in place that

prevented treatment of patients with forced vital capacity (FVC) >80% predicted. Although

these rules were lifted in 2016, many physicians in these countries still cited access restrictions

as a barrier to treatment in this survey.

Physicians in the UK were least likely to discuss prognosis with patients and least

comfortable doing so. The UK also had the lowest proportion of physicians who believed in the

benefits of early use of antifibrotic treatment or the efficacy of antifibrotics in slowing IPF

progression. These results could be due to cultural differences in the UK compared with Canada

and the difference in time between the launch of antifibrotics in these countries. Additionally,

current National Institute for Health and Care Excellence (NICE) guidelines in the UK specify

that antifibrotic treatments should only be used in patients with FVC 50–80% [38, 39], thereby

excluding patients with limited lung-function impairment. This was reflected by the high

proportion of physicians in the UK citing access restrictions as a barrier.

There are a number of limitations to our study. Responses were all self-reported, and the

fidelity of responses (e.g., whether physicians actually waited >4 months to treat patients) was

not assessed. For example, designation of “mild” and “moderate” IPF were based solely on the

judgment of individual physicians, and it is unclear what disease parameters were used to define

these terms. In addition, physicians were not asked to provide detailed clinical characteristics or

demographics of their patients, rendering it difficult to draw comparisons. Furthermore, the

quantitative survey did not allow exploration of the reasoning or rationale behind the responses

provided, and may not have identified all reasons for delayed initiation of antifibrotic treatment.

Moreover, the physicians in Group A were not matched to physicians in Group B. However,

most physician characteristics were not significantly different between groups. Some physicians

included in the analysis (20–25% in the UK and Italy) were not authorized to prescribe

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antifibrotics, which may have affected their responses; however, this reflects treatment practice

in the UK and Italy, where the prescription of antifibrotics is limited to certain centers. Although

the restriction of antifibrotic prescription to certain centers is not an issue in countries besides

the UK and Italy, we cannot be certain that all physicians in these countries were authorized to

prescribe antifibrotics.

Furthermore, patients who completed the survey were not necessarily treated by

physicians who completed the survey; therefore, definitive conclusions regarding potential

disconnects between patients and physicians cannot be drawn from these results. Given that data

were anonymized from the interviews and surveys, it is impossible to know if patients or

physicians participated in both the interview and survey. It is also unclear whether the length of

time since patients had been diagnosed affected their responses, since this information was not

collected. No data were collected on the rate of disease progression or survival in patients

treated by physicians in Groups A or B, which prevents any direct conclusions to be drawn

regarding the effect of delaying initiation of antifibrotic treatment.

The results for subgroup analyses based on country should be considered with caution

due to the lower power of these data compared with the full data set. Additionally, a relatively

small number of patients were recruited to participate in the survey, and recruitment may have

been biased towards those who are more engaged with their care (e.g., patients recruited via

advocacy groups). All patients who participated in this survey had taken antifibrotic treatment;

thus, no data could be gained from patients who chose not to receive treatment or who were

never offered treatment. Excluding patients who had not been offered antifibrotic treatment may

have introduced bias into the responses, as we cannot rule out the possibility that these patients

represent a considerable proportion of patients with IPF.

Where patients were recruited by their physicians, there was a risk of selection bias.

There may have been selection bias towards patients who had taken pirfenidone, since the

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research was undertaken for F. Hoffmann-La Roche, Ltd. Also, recruiting via market research

panels and providing a cash incentive for completion of the survey may have biased

participation; however, it is an effective way to increase sample size in order to obtain

meaningful data from surveys [40].

In order to address these limitations in future studies, we would suggest conducting this

survey as part of a wider real-world study assessing the effect of timing of antifibrotic initiation

on IPF progression and survival. The survey could recruit physicians in Groups A and B plus a

representative sample of patients treated by physicians in each group within a certain time frame

to allow direct comparison of potential disconnects between physicians and patients. The patient

population should include patients who have not yet been offered treatment, patients who had

refused treatment, and more patients who had taken nintedanib. A definition of “mild” and

“moderate” IPF using lung-function parameters could be provided to physicians to homogenize

the responses. Additionally, a sample of patients and physicians completing the questionnaire

could be invited for face-to-face or telephone interviews to allow further exploration of the

responses given.

Conclusions

The results of this survey indicate that physicians who delay antifibrotic treatment see

fewer patients with IPF, find it more difficult to discuss prognosis with these patients, and have

less confidence in antifibrotic treatments and their value in treating patients with limited lung-

function impairment. The attitudes of physicians contrast with the views of patients, who are

more concerned about preventing disease progression than avoiding medication side effects and

want earlier treatment. Additionally, the survey identifies some key differences between

countries in terms of access to care, particularly related to prescribing/reimbursement

restrictions, which may prevent use of antifibrotic treatment in patients with limited lung-

function impairment.

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The results of this survey reinforce recommendations of the European IPF Patient

Charter and its call for comprehensive and high-quality information about IPF and equal access

to care [35]. We add to this a need for clearer IPF treatment guidelines and better physician

education, not only regarding the benefits of early treatment, but also in how to communicate

with patients and support them in making informed decisions about their care.

Acknowledgments

Medical writing support was provided by Rebekah Waters, PhD, on behalf of CMC AFFINITY,

a division of Complete Medical Communications, Ltd., Manchester, UK, funded by F.

Hoffmann-La Roche, Ltd. T.M. Maher is supported by an NIHR Clinician Scientist Fellowship

(NIHR Ref: CS-2013-13-017).

Ethics approval and consent to participate

Since no treatment was administered in this study, no ethical approval was required. Informed

consent was obtained from participants before they took part in the survey.

Financial Disclosure and Conflicts of Interest

T.M. Maher has received industry-academic research funding from GlaxoSmithKline R&D and

UCB. He has received consultancy or speakers’ fees from Apellis, AstraZeneca, aTyr Pharma,

Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, ProMetic,

Roche (and previously InterMune), and UCB. He is supported by an NIHR Clinician Scientist

Fellowship (NIHR Ref: CS-2013-13-017).

J.J. Swigris is a consultant for Boehringer Ingelheim and Roche-Genentech. He has received

research funding and is on the speaker bureau for both companies.

M. Kreuter and his institution have received compensation for speaker bureau and consultation

from Boehringer Ingelheim and InterMune/Roche, as well as unrestricted research grants from

both companies.17

M. Wijsenbeek has received speaker and consultation fees from Boehringer Ingelheim,

Galapagos, and InterMune/Roche, and unrestricted research grants from Boehringer Ingelheim

and InterMune/Roche. All fees and grants were paid to her institution.

N. Cassidy is a volunteer for the Irish Lung Fibrosis Association, which has received

unrestricted grants from Boehringer Ingelheim and Roche Products Ireland. Speaker fees from

Roche were paid to the Irish Lung Fibrosis Association.

L. Ireland is an employee of Hall & Partners, who receive funding from Roche for conducting

research surveys.

J. Axmann is an employee of F. Hoffmann-La Roche, Ltd.

S.D. Nathan is a consultant for Boehringer Ingelheim and Roche-Genentech. He has received

research funding and is on the speaker bureau for both companies.

Funding Sources

This study was sponsored by F. Hoffmann-La Roche, Ltd., which was involved in study design,

collection, analysis, and interpretation of the data.

Author Contributions

T.M. Maher, J.J. Swigris, M. Kreuter, M, Wijsenbeek, L. Ireland, J. Axmann, and S.D. Nathan

were involved in the design of this study and all authors were involved in the interpretation of

study results. L. Ireland co-ordinated a team of researchers from Hall & Partners in preparing

the online questionnaire and summarizing outcomes. All authors contributed to the manuscript

from the outset, and read and approved the final draft.

Online Supplementary Material

Online Supplementary File 1: Patient online questionnaire

Online Supplementary File 2: Physician online questionnaire

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Online Supplementary Table S1. Number of respondents taking part in face-to-face interviews

or online questionnaire, by country

Online Supplementary Table S2. Discussion of prognosis by physicians, by country

Online Supplementary Table S3. Physician attitudes to early treatment of patients with IPF, by

country

Online Supplementary Table S4. Reasons cited by physicians for not treating patients with

“mild” IPF, by country

19

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Glaspole I, Glassberg MK, Glasscock KF, King TE, Jr., Lancaster L, Lederer DJ, Lin Z,

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20 Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE,

Jr., Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM, CAPACITY Study

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randomised trials. Lancet 2011;377:1760-1769.

22

21 Lancaster LH, de Andrade J, Zibrak JD, Padilla ML, Albera C, Nathan SD, Wijsenbeek

MS, Stauffer JL, Kirchgaessler K-U, Costabel U: Pirfenidone safety and adverse event

management in idiopathic pulmonary fibrosis. Eur Respir Rev 2017;26:170057.

22 Brunnemer E, Walscher J, Tenenbaum S, Hausmanns J, Schulze K, Seiter M, Heussel

CP, Warth A, Herth FJF, Kreuter M: Real-World Experience with Nintedanib in Patients

with Idiopathic Pulmonary Fibrosis. Respiration 2018:DOI 10.1159/000485933.

23 European Medicines Agency. Summary of Product Characteristics - Esbriet

(pirfenidone). Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Product_Information/human/002154/WC500103049.pdf. Last update: 2017. Accessed:

March 27 2018.

24 European Medicines Agency. Summary of Product Characteristics - Ofev (nintedanib).

Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Product_Information/human/003821/WC500182474.pdf. Last update: 2017. Accessed:

March 27 2018.

25 Meyer KC, Danoff SK, Lancaster LH, Nathan SD: Management of Idiopathic

Pulmonary Fibrosis in the Elderly Patient: Addressing Key Questions. Chest

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26 Veluswamy RR, Levy B, Wisnivesky JP: Chemotherapy in elderly patients with

nonsmall cell lung cancer. Curr Opin Pulm Med 2016;22:336-343.

27 Richard C, Glaser E, Lussier MT: Communication and patient participation influencing

patient recall of treatment discussions. Health Expect 2017;20:760-770.

28 Sep MS, van Osch M, van Vliet LM, Smets EM, Bensing JM: The power of clinicians'

affective communication: how reassurance about non-abandonment can reduce patients'

physiological arousal and increase information recall in bad news consultations. An

experimental study using analogue patients. Patient Educ Couns 2014;95:45-52.

23

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003821/WC500182474.pdf




29 Kessels RP: Patients' memory for medical information. J R Soc Med 2003;96:219-222.

30 Costabel U, Bendstrup E, Cottin V, Dewint P, Egan JJ, Ferguson J, Groves R, Hellström

PM, Kreuter M, Maher TM, Molina-Molina M, Nordlind K, Sarafidis A, Vancheri C:

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management

of drug-related adverse events. Adv Ther 2014;31:375-391.

31 Irish Lung Fibrosis Association. National Patient Charter for Idiopathic Pulmonary

Fibrosis. Available at: http://www.ilfa.ie/docs/ILFA_CharterBooklet_lores.pdf. Last

update: 2015. Accessed: January 22 2018.

32 Fisher JH, O'Connor D, Flexman AM, Shapera S, Ryerson CJ: Accuracy and Reliability

of Internet Resources for Information on Idiopathic Pulmonary Fibrosis. Am J Respir

Crit Care Med 2016;194:218-225.

33 Boehringer Ingelheim. New survey reveals 9 out of 10 patients with IPF were happy

with how their doctor told them about their IPF diagnosis. Available at:

https://www.boehringer-ingelheim.com/sites/default/files/Infographics/Think%20of

%20Everything_IPF%20patient%20survey%20press%20release.pdf. Last update: 2016.

Accessed: January 19 2018.

34 van Manen MJ, Kreuter M, van den Blink B, Oltmanns U, Palmowski K, Brunnemer E,

Hummler S, Tak NC, van den Toorn L, Miedema J, Hoogsteden HC, Wijsenbeek MS:

What patients with pulmonary fibrosis and their partners think: a live, educative survey

in the Netherlands and Germany. ERJ Open Res 2017;3:00065-02016.

35 Bonella F, Wijsenbeek M, Molina-Molina M, Duck A, Mele R, Geissler K, Wuyts W:

European IPF Patient Charter: unmet needs and a call to action for healthcare

policymakers. Eur Respir J 2016;47:597-606.

36 British Lung Foundation. IPF Patient Charter. Available at:

https://www.blf.org.uk/sites/default/files/IPF-patient-charter-blf-2014.pdf. Last update:

2015. Accessed: January 19 2018.

24

https://www.blf.org.uk/sites/default/files/IPF-patient-charter-blf-2014.pdf

https://www.boehringer-ingelheim.com/sites/default/files/Infographics/Think%20of%20Everything_IPF%20patient%20survey%20press%20release.pdf

https://www.boehringer-ingelheim.com/sites/default/files/Infographics/Think%20of%20Everything_IPF%20patient%20survey%20press%20release.pdf

http://www.ilfa.ie/docs/ILFA_CharterBooklet_lores.pdf

37 Canadian Pulmonary Fibrosis Foundation. Toward Exceptional Care: A Canadian IPF

Patient Charter. Available at: http://cpff.ca/wp-content/uploads/2016/08/IPF-Patient-

Charter.pdf. Last update: 2016. Accessed: January 19 2018.

38 National Institute for Health and Care Excellence. Pirfenidone for treating idiopathic

pulmonary fibrosis: Technology appraisal guidance [TA282]. Available at:

https://www.nice.org.uk/guidance/TA282?UNLID=24856382920142610162. Last

update: 4/24/2013. Accessed: January 17 2018.

39 National Institute for Health and Care Excellence. Nintedanib for treating idiopathic

pulmonary fibrosis: Technology appraisal guidance [TA379]. Available at:

https://www.nice.org.uk/guidance/ta379. Last update: 2016. Accessed: January 19 2018.

40 Erwin WJ, Wheelright LA: Improving Mail Survey Response Rates Through the Use of

Monetary Incentive. J Ment Health Counseling 2002;24:247-255.

25

https://www.nice.org.uk/guidance/ta379

https://www.nice.org.uk/guidance/TA282?UNLID=24856382920142610162

http://cpff.ca/wp-content/uploads/2016/08/IPF-Patient-Charter.pdf

http://cpff.ca/wp-content/uploads/2016/08/IPF-Patient-Charter.pdf

Figure Legends

Fig. 1. Physician attitudes to early treatment of patients with IPF, by group.

* p < 0.05 in z-test. # Physicians who selected 6 or 7 on a 7-point Likert scale, ranging from 1 =

strongly disagree to 7 = strongly agree. ¶ Physicians who selected 1 or 2 on a 4-point Likert

scale, ranging from 1 = the risk of the patient suffering side effects that affect their quality of life

to 4 = the risk of the patient’s IPF progressing. + Physicians who monitored ≥50% of patients for

>4 months post-diagnosis before initiating an antifibrotic. § Physicians who initiated an

antifibrotic within 4 months post-diagnosis in the majority of patients. IPF, idiopathic

pulmonary fibrosis.

Fig. 2. Reasons cited by physicians for not treating patients with “mild” IPF#, by group.

* p < 0.05 in z-test. # IPF was defined as “mild” by physicians. ¶ Physicians who monitored

≥50% of patients for >4 months post-diagnosis before initiating an antifibrotic. + Physicians who

initiated an antifibrotic within 4 months post-diagnosis in the majority of patients. IPF,

idiopathic pulmonary fibrosis; NICE, National Institute for Health and Care Excellence.

26

Table 1. Physician demographics and characteristics

Total, n (%)

N = 287

Group A#, n (%)

N = 131

Group B¶, n (%)

N = 156

Gender

Male 218 (76) 102 (78) 116 (74)

Female 69 (24) 29 (22) 40 (26)

Age group+

<40 years of age 56 (20) 27 (21) 29 (19)

40–49 years of age 124 (43) 51 (39) 73 (47)

≥50 years of age 106 (37) 53 (40) 53 (34)

Primary practice type

Specialist pulmonary center/tertiary referral center for IPF§ 32 (11) 11 (8) 21 (13)

Large teaching/university hospital 109 (38) 43 (33) 66 (42)

Large trust/regional/community hospital 52 (18) 19 (15) 33 (21)

Medium-sized/district general hospital 30 (10) 22 (17)* 8 (5)

Small/local hospital 10 (3) 5 (4) 5 (3)

Private clinic/hospital 14 (5) 8 (6) 6 (4)27

Total, n (%)

N = 287

Group A#, n (%)

N = 131

Group B¶, n (%)

N = 156

Office##: solo 9 (3) 5 (4) 4 (3)

Office##: group practice, single speciality 13 (5) 5 (4) 8 (5)

Office##: group practice, multiple speciality 17 (6) 12 (9)* 5 (3)

Other 1 (0) 1 (1) 0

Caseload: “mild” patients¶¶

High 98 (34) 22 (17) 76 (49)*

Medium 97 (34) 58 (44)* 39 (25)

Low 92 (32) 51 (39)* 41 (26)

Caseload: “moderate” patients++

High 94 (33) 28 (21) 66 (42)*

Medium 101 (35) 45 (34) 56 (36)

Low 92 (32) 58 (44)* 34 (22)

* Had a significantly higher proportion of physicians with this response vs. the other group (p < 0.05). # Physicians who monitored ≥50% of

patients for >4 months post-diagnosis before initiating an antifibrotic. ¶ Physicians who initiated an antifibrotic within 4 months post-diagnosis in

28

the majority of patients. + One physician in Group B did not provide their age. § Specialist center was defined by physicians. ## Any practice based

outside the hospital or in a community setting. ¶¶ IPF was defined as “mild” by physicians, mean caseload in previous year: high = 133.7 patients,

medium = 28.7 patients, low = 9.4 patients. ++ IPF was defined as “moderate” by physicians, mean caseload in previous year: high = 141.4 patients,

medium = 18.9 patients, low = 8.8 patients. IPF, idiopathic pulmonary fibrosis.

29

Table 2. Discussion of prognosis by physicians, by group

Total,

n (%)

Group A#,

n (%)

Group B¶,

n (%)

What information do you typically communicate to your patients at diagnosis? N = 269 N = 122 N = 147

That the patient has IPF 250 (93) 116 (95) 134 (91)

The typical prognosis for IPF (or at least a clear indicator of how long the patient can expect to live) 144 (54) 58 (48) 86 (59)

How serious IPF is 185 (69) 90 (74) 95 (65)

What IPF is 250 (93) 117 (96) 133 (90)

That IPF is progressive 185 (69) 88 (72) 97 (66)

That IPF will progressively impact on the patient’s daily life (and quality of life) 187 (70) 82 (67) 105 (71)

Information about the treatment options for IPF 242 (90) 111 (91) 131 (89)

Please rate your level of comfort when discussing the typical prognosis for IPF (or at least a clear

indicator of how long the patient can expect to live)

N = 287 N = 131 N = 156

Extremely comfortable or comfortable+ 81 (28) 29 (22) 52 (33)*

30

Total,

n (%)

Group A#,

n (%)

Group B¶,

n (%)

If one of your IPF patients asks you about their prognosis (or how long they have left to live/words to

this effect), how do you typically answer?

N = 287 N = 131 N = 156

I give them the facts (including an idea of average prognosis and life expectancy for IPF patients

[3–5 years]) as part of the discussion

88 (31) 33 (25) 55 (35)

I give them an idea of what to expect, without giving hard facts 83 (29) 33 (25) 50 (32)

I prefer not to tell them anything on the fatality/prognosis of the disease as the prognosis and life

expectancy is unpredictable and can vary between IPF patients

48 (17) 33 (25)* 15 (10)

I reassure my patients that each patient is different so that I can monitor their symptoms/progression

for longer before having this conversation

68 (24) 32 (24) 36 (23)

* Had a significantly higher proportion of physicians with this response vs. the other group (p < 0.05). # Physicians who monitored ≥50% of

patients for >4 months post-diagnosis before initiating an antifibrotic. ¶ Physicians who initiated an antifibrotic within 4 months post-diagnosis in

the majority of patients. + Physicians who selected 6 or 7 on a 7-point Likert scale, ranging from 1 = strongly disagree to 7 = strongly agree. IPF,

idiopathic pulmonary fibrosis.

31

Fig. 1. Physician attitudes to early treatment of patients with IPF, by group.

* p < 0.05 in z-test. # Physicians who selected 6 or 7 on a 7-point Likert scale, ranging from 1 =

strongly disagree to 7 = strongly agree. ¶ Physicians who selected 1 or 2 on a 4-point Likert

scale, ranging from 1 = the risk of the patient suffering side effects that affect their quality of life

to 4 = the risk of the patient’s IPF progressing. + Physicians who monitored ≥50% of patients for

>4 months post-diagnosis before initiating an antifibrotic. § Physicians who initiated an

antifibrotic within 4 months post-diagnosis in the majority of patients. IPF, idiopathic

pulmonary fibrosis.

32

Fig. 2. Reasons cited by physicians for not treating patients with “mild” IPF#, by group.

* p < 0.05 in z-test. # IPF was defined as “mild” by physicians. ¶ Physicians who monitored

≥50% of patients for >4 months post-diagnosis before initiating an antifibrotic. + Physicians who

initiated an antifibrotic within 4 months post-diagnosis in the majority of patients. IPF,

idiopathic pulmonary fibrosis; NICE, National Institute for Health and Care Excellence.

33

Online Supplementary File 1. Patient online questionnaire

Screening section

I1. COUNTRY

In which country do you live?

Please select one answer only

France

Germany

UK

Italy

Spain

Canada

Other

S2. AGE

What is your age?

Please write your answer below

<NUMERICAL TEXT BOX>

S4a. TREATMENT EXPERIENCE

Have you ever taken any of the following treatment options for your Idiopathic Pulmonary

Fibrosis (IPF)?

Please select from the list below the treatment options you have taken for your IPF (please select

all that apply) or one of the other options that best describes why you have not taken any of

these treatment options

Esbriet (pirfenidone)

34

Ofev (nintedanib)

None of the above because I was offered them, but refused

None of the above for another reason (please specify)

I don't know

S4b. FIRST IPF TREATMENT

Which of the following Idiopathic Pulmonary Fibrosis (IPF) treatments did you receive first?


Esbriet (pirfenidone)

Ofev (nintedanib)

Section A – GENERAL ATTITUDES TO TREATMENT OF IPF

A1. INITIAL KNOWLEDGE AROUND IPF

Prior to being diagnosed with Idiopathic Pulmonary Fibrosis (IPF), how much information did

you know about it?

Please choose one answer from the list below

I had never heard of it

I had heard the name ‘Idiopathic Pulmonary Fibrosis (IPF)’, but nothing more

I had heard of IPF, but did not know anything about its treatment

I had heard of IPF and knew about the treatment options

A2. PROMPT TO SEEK TREATMENT

What prompted you to make the first appointment about your IPF symptoms with any doctor?

Please select all relevant answers from the list below

A cough that wouldn’t go away

35

Breathlessness when doing activities when previously doing those activities did not get

you out of breath

A family member/partner noticing symptoms and persuading you to go

Something else that you saw prompting you to go (please specify what)

Other (please specify)

My IPF was detected as part of tests for another condition/reason so I did not see a

doctor specifically for my IPF

A3. LENGTH OF TIME BETWEEN PRESENTATION AND DIAGNOSIS

How long after this first appointment to discuss your symptoms were you told about your IPF

diagnosis?


<NUMERICAL TEXT BOX> months later

Less than 1 month after

A4. DOCTOR RESPONSIBLE FOR DIAGNOSIS

What type of doctor told you of your IPF diagnosis?

Please choose an answer from the list below

An office-based Pulmonologist/Chest/Respiratory Specialist

A Pulmonologist/Chest/Respiratory Specialist in my local city/district hospital

A Pulmonologist/Chest/Respiratory Specialist in a large teaching/specialist hospital

My primary care physician (GP)


A5. INFORMATION COMMUNICATED AT DIAGNOSIS

In the appointment where you were told about your IPF diagnosis, what information was

discussed with you? 36


That you had IPF (i.e. your diagnosis)

A clear indicator of the impact the IPF could have on your life

How serious IPF is

What IPF is

That IPF is progressive

The treatment options for IPF


A6. FORMAT OF INFORMATION COMMUNICATED AT DIAGNOSIS

In what format was this information about your diagnosis/IPF communicated to you?


The doctor who told me my diagnosis talked through the information with me

A nurse from my doctor’s hospital/practice talked through the information with me

I was given leaflets to read

Websites were recommended to me (If so, which ones (please specify))


A7. PREFERRED FORMAT OF INFORMATION COMMUNICATED AT DIAGNOSIS

What is your preferred format for receiving information about your IPF?


From talking to my doctor (specialist)

From talking to a nurse from my doctor’s hospital/practice

Via reading leaflets

Via website searches/reading websites


37

A8. CLARITY OF INFORMATION PROVIDED AT DIAGNOSIS

In the appointment where you were told about your IPF diagnosis, how clear was the

information about IPF that your doctor told you/provided you with?

Please indicate how clear the information was on the scale below

1: It was extremely unclear

5: It was extremely clear

A9a. VOLUME OF INFORMATION PROVIDED

In the appointment where you learnt about your IPF diagnosis, were you provided with enough

information about IPF and what to expect?

Please select an answer from below

Yes

No

A9b. EXTRA INFORMATION REQUIRED

What extra information do you wish that you had received/been told when you learnt about your

IPF diagnosis?

Please write as full an answer as possible in the box below

<TEXT BOX>

A10. INFO SEEKING BEHAVIOUR

After the appointment where you learnt about your IPF diagnosis, did you look for further

information?

Please select all relevant answers from below

Yes, I did

Yes, my caregiver did38

Yes, a family member or friend (other than my caregiver) did

No

A11. INFO SEEKING BEHAVIOUR – INFO TYPES

After the appointment where you learnt about your IPF diagnosis, what information did

you/your caregiver/family member/friend look for?


More information about what IPF is

Information on the impact IPF has on patients’ lives

Information on IPF treatment

IPF patient testimonials

Information on IPF support groups

Information on hospitals/physicians who specialise in the management of IPF


A12. INFO SEEKING BEHAVIOUR – INFO SOURCES

After the appointment where you learnt about your IPF diagnosis, where did you/your

caregiver/family member/friend look for this information about IPF?


Google (or other internet search engines)

Facebook

Online patient forums

Face to face patient support groups

Leaflets from your hospital/physician

Online information provided by patient support/advocacy groups


39

A13. INFO SEEKING BEHAVIOUR – IMPACT

Did this information that you/your caregiver/family member/friend found make you feel more

confident in asking your doctor questions about your IPF?

Please select your answer below

Yes

Maybe

No

A14a. LATER INFORMATION PROVIDED

Earlier you answered questions about the information provided to you at the appointment where

you learnt of your IPF diagnosis.

Has your doctor provided you with more information about IPF or its treatment at any

appointments after the time that you learnt of your diagnosis?

Please select your answer below

Yes

Maybe (I am not certain)

No

A14b. INFORMATION COMMUNICATED LATER

What information did your doctor discuss with you at this later appointment (after your

diagnosis appointment)?


That you had IPF (i.e. your diagnosis)

A clear indicator of the impact the IPF could have on your life

40

How serious IPF is

What IPF is


The treatment options for IPF


A14c. TIMING OF EXTRA INFORMATION

What was the time gap between the appointment where you learnt of your diagnosis and the

appointment where your doctor gave you further information about your IPF?

Please write your answer in the box below

<TEXT BOX> months

Section B – CURRENT IPF TREATMENT AWARENESS AND USAGE

B1. LENGTH OF TIME BETWEEN DIAGNOSIS AND TREATMENTS OFFERED

How long after the appointment where you learnt of your IPF diagnosis did your doctor discuss

the treatment options available for your IPF?



At the same appointment (when I learnt about my diagnosis)

B2. TREATMENTS OFFERED AND TREATMENT INITIATED

How long after the appointment where you first discussed the treatment options available for

your IPF, did you start to receive your <pipe in answer to S4a/S4b>?



At the same appointment

41

B3a. INFORMATION ABOUT TREATMENT COMMUNICATED

What information did your doctor tell you about your treatment (in particular <pipe in answer to

S4a/S4b>) for your IPF when you first started taking it?


<TEXT BOX>

B3b. FEELINGS ABOUT THE TREATMENT

How did you feel about your treatment options (in particular Esbriet (pirfenidone) or Ofev

(nintedanib)) after this first discussion about IPF treatment?


<TEXT BOX>

B4. VOLUME OF INFORMATION PROVIDED

In the appointment where you learnt about the treatment options for IPF, were you provided

with enough information about these treatments to know what to expect?


Yes

No

B5a. DECISION MAKER

Who made the final decision of which IPF treatment you received?


You, the patient

Your caregiver

Your doctor (the chest/lungs specialist)

Your doctor (your GP/PCP)42


B5b. INFORMATION FOR DECISIONS

Which was the most important source of information for your decision on which IPF treatment

to receive?/to refuse IPF-approved treatment with either Esbriet (pirfenidone) or Ofev

(nintedanib)?


Your specialist doctor

A nurse from your doctors’ hospital/practice

Information that you have found from other information sources (e.g. website searches)

Information from a patient support/advocacy group


B5c. EFFICACY VS. SIDE EFFECTS

When doctors are considering how to treat IPF, two of the factors that they weigh up are how

well the treatments work vs. the side effects they may cause.

Using your experience of IPF, please can you rate which of the following is more important to

you?

Please use the slider below to indicate which is the more important of the two factors shown.

The further the slider is to one factor the more you believe that that factor is more important vs.

the other one shown.

1: The potential side effects that may happen

4: The potential ability for the treatment to slow down your IPF progression

B5d. QOL DEFINITION

43

When doctors are considering how to treat IPF, they often consider the impact the treatment

could have on patients’ day to day lives.

Please can you tell us the relative importance of the factors in the context of the impact that they

have on your day to day life?

Please allocate 100 points across the factors, giving the most points to the factor(s) you consider

most important.

Your symptoms

Your ability to live independently

Your ability to carry on your hobbies/interests

Potential treatment side effects

Your ability to maintain activities of daily living (e.g. cleaning, cooking)

B6. CONFIDENCE MANAGING SIDE EFFECTS

Based on the information that your doctor provided to you when you started on your IPF

treatment (Esbriet [pirfenidone] or Ofev [nintedanib]), did/do you feel confident in knowing

how to manage any side effects that you may experience from this treatment?


Yes

No

B7. EXPERIENCE WITH TREATMENT

On a scale of 1 to 5 where 1 = Very negative and 5 = Very positive, please rate your experience

of taking an IPF treatment.

Please note: by IPF treatment we are referring to Esbriet (pirfenidone) and Ofev (nintedanib)

Please use the slider scale

44

1: Very negative

5: Very positive

B8a. STOPPED TREATMENT

Earlier in the questionnaire you indicated that you have stopped taking an IPF treatment (Esbriet

[pirfenidone] or Ofev [nintedanib]). What actions, if any, did your doctor take prior to you

stopping this treatment?

Please select your answers from below

They provided advice/help on how to manage any side effects that you may have

experienced

They fully explained/talked through the benefits of staying on the IPF treatment

They provided help/support (e.g. treatment reminder service/recommended a reminder

app) to help you to remember when to take your treatment


They did not provide any support to encourage me to stay on these IPF treatments

B8b. ADVICE

Based on your experiences with IPF and IPF treatment, if you were to meet someone who had

just been diagnosed with IPF, what advice would you give them?


<TEXT BOX>

Section E: Demographics

E1. PRACTICE TYPE

Where do you see your chest/lung specialist doctor?

Please select the appropriate answer

45

In an out-patient clinic at a hospital

In a ward at a hospital

In an office-based practice


E2. GENDER

Are you …?


Male

Female

46

Online Supplementary File 2. Physician online questionnaire

I1. COUNTRY

In which country do you work?


France

Germany

UK

Italy

Spain

Canada

Other

S5. NUMBER OF IPF CONSULTATIONS

In the past 12 months approximately how many of your idiopathic pulmonary fibrosis patients

have you seen in consultation?

Please type your answer in the box below

<TEXT BOX> mild patients

<TEXT BOX> moderate patients

S6. TREATMENT APPROACH

When thinking of your newly diagnosed, mildly symptomatic IPF patients, using the scale

below, how would you describe your typical treatment approach?

By IPF approved treatments, we are referring to Esbriet (pirfenidone) and Ofev (nintedanib).

Please slide the marker to your answer.

Please select one answer below

47

I always initiate (or recommend initiation of) treatment with an IPF approved treatment

for all of the mildly symptomatic IPF patients I see within 4 months of diagnosis/as soon

as they qualify for treatment as per the NICE guidance

I initiate (or recommend initiation of) treatment with an IPF approved treatment for the

majority of the mildly symptomatic IPF patients I see within 4 months of diagnosis/as

soon as they qualify for treatment as per the NICE guidance

I initiate (or recommend initiation of) treatment with an IPF approved treatment for

approximately a half of the mildly symptomatic IPF patients I see within 4 months of

diagnosis/as soon as they qualify for treatment as per the NICE guidance

I like to monitor the progression of the IPF for the majority of the mildly symptomatic

IPF patients I see for at least 4 months post diagnosis (even if they qualify for treatment

as per the NICE guidance) before I initiate (or recommend initiation of) treatment with

an IPF approved treatment

I like to monitor the progression of the IPF for all of the mildly symptomatic IPF patients

I see for at least 4 months post diagnosis (even if they qualify for treatment as per the

NICE guidance) before I initiate (or recommend initiation of) treatment with an IPF

approved treatment

Section A – GENERAL ATTITUDES TO TREATMENT OF IPF

A1. PROFESSIONAL INTEREST & KNOWLEDGE AROUND IPF

On a scale of 1 to 7 where 1 = Strongly disagree and 7 = Strongly agree, please rate your level

of agreement with the following statements in relation to how well they describe your general

attitudes to IPF.

Please move the slider to the point on the scale to give your answer

I am less comfortable in treating IPF than other conditions that I manage

I believe I can make a big positive difference to my IPF patients’ life post diagnosis

48

IPF is serious condition with a worse prognosis compared to at least some forms of

metastatic lung cancer

o 1: Strongly disagree

o 7: Strongly agree

A2. ROLE IN IPF

Which of the following actions are you responsible for the IPF patients that you see?


Initiating investigations prior to diagnosis

Communicating the diagnosis to the patient

Confirming diagnosis

Taking part in a multi-disciplinary team to confirm diagnosis

Initiating treatment with an IPF approved treatment

Taking part in an MDT to recommend treatment

Referring a patient to a specialist center/MDT for IPF approved treatment

Managing patients once they have started on an IPF approved treatment

A3a. INFORMATION COMMUNICATED AT DIAGNOSIS

What information do you typically communicate to your patients at the following time points?


That the patient has IPF

The typical prognosis for IPF (or at least a clear indicator of how long the patient can

expect to live)

How serious IPF is

What IPF is


49

That IPF will progressively impact on the patient’s daily life (and quality of life)

Information about the treatment options for IPF

o At the appointment where you tell your IPF patients of their diagnosis

o At later follow up appointments when patients are showing signs of progression

A3b. COMFORT WITH COMMUNICATING IPF INFORMATION

On a scale of 1 to 7 where 1 = Extremely uncomfortable and 7 = Extremely comfortable, please

rate your level of comfort when discussing the following topics with your IPF patients:

Please move the slider to the point on the scale to give your answer

The typical prognosis for IPF (or at least a clear indicator of how long the patient can

expect to live)

The patient’s IPF disease scores/lung-function test results

What IPF is


The impact IPF will have on the patient’s daily life (and quality of life)

o 1: Extremely uncomfortable

o 7: Extremely comfortable

A4. APPROACH TO DIAGNOSIS CONVERSATION

In the appointment where you tell your IPF patients of their diagnosis, what is your approach to

discussing the diagnosis?

Please select your answer on the scale below the degree to which you tend towards either

approach

1: I keep the conversation short, to the point and based on the facts of their diagnosis e.g.

their test/scan results. I will then delay discussing any further details to later

appointments

50

5: I will spend as much time as the patient needs and answer all of their questions with as

much detail as I can. I will try to cover as much as possible in this appointment

A5. DIRECTNESS IN TALKING ABOUT PROGNOSIS

If one of your IPF patients asks you about their prognosis (or how long they have left to

live/words to this effect), how do you typically answer?


I give them the facts (including an idea of average prognosis and life expectancy for IPF

patients [3 – 5 years]) as part of the discussion

I give them an idea of what to expect, without giving hard facts

I prefer not to tell them anything on the fatality/prognosis of the disease as the prognosis

and life expectancy is unpredictable and can vary between IPF patients

I reassure my patients that each patient is different so that I can monitor their

symptoms/progression for longer before having this conversation

A6. LONGER PROGNOSIS PATIENT COHORT

In your experience, what proportion of IPF patients have…

Please type your answer in the boxes below.

A slow progressing form of the disease (i.e. IPF patients who do not lose more than 3%

in FVC over one year)

A fast progressing form of the disease (i.e. IPF patients who lose more than 10% in FVC

within 6 months)

Section B – CURRENT IPF TREATMENT AWARENESS AND USAGE

B1. BELIEFS ABOUT IPF TREATMENT

51

On a scale of 1 to 7 where 1 = Strongly disagree and 7 = Strongly agree, please rate your level

of agreement with the following statements in relation to how well they describe your attitudes

towards the treatment of IPF.

Please note: by IPF-approved treatments we are referring to Esbriet (pirfenidone) and Ofev

(nintedanib).

Please use the slider scale

IPF is a progressive disease thus it is imperative to start treatment upon diagnosis despite

no significant presence or escalation of symptoms

IPF-approved treatments offer significantly better long term outcomes or benefits for

patients vs. the other options I have available

I need to observe disease progression before initiating any IPF-approved treatment

Long-term outcomes in IPF are not necessarily affected by delaying treatment with IPF-

approved treatments

I always wait for a confirmed diagnosis before I initiate IPF treatment

IPF-approved treatments offer a risk:benefit ratio comparable to treatments for other

conditions I treat

IPF-approved treatments offer the same level of benefits to mild IPF patients as

moderate or severe IPF patients

My main focus is on improving or stabilising symptoms first before trying to stabilize

the disease as the patients’ QoL is most important

By starting IPF-approved treatments early, I have the best chance of maintaining

patients’ lung function at their current levels and hence quality of life for as long as

possible

IPF-approved treatments (e.g. Esbriet (pirfenidone) and Ofev (nintedanib)) significantly

slow the progression of IPF

52

o 1: Strongly disagree

o 7: Strongly agree

B2. PATIENT NUMBERS NOT RECEIVING AN IPF-APPROVED TREATMENT

Of the <pipe in answer to S5_1> mild and <pipe in answer to S5_2> moderate IPF patients that

you saw in the past year, what proportion did not receive either of the 2 drugs approved for the

treatment of IPF in the 4 months after diagnosis (e.g. pirfenidone or nintedanib).

Please type your answers in the boxes below

Patients with mild IPF not treated with an IPF approved treatment in first 4 months after

diagnosis: <TEXT BOX> %

Patients with moderate IPF not treated with an IPF approved treatment in first 4 months

after diagnosis: <TEXT BOX> %

B3a. REASON FOR USING NO PHARMACEUTICAL TREATMENT APPROACH

What are the relevant reasons why you do not initially prescribe any IPF- approved treatment

and just monitor for some of your mild IPF patients for at least the first 4 months post

diagnosis?

Please tick all relevant reasons in each column.

Stable Patient

Slow progressing IPF

Suspected/Unclear Diagnosis

New IPF diagnosis

Age/Old age

Risk of non compliance

Patient currently has a good quality of life

Patient currently has a good lung function

53

Few symptoms/Asymptomatic

Co-morbidities

Patient’s refusal not related to side effects

Patient’s worry about/refusal due to side effects

Drug intolerance

Benefits of drug not worth potential side effects

Want to monitor progression first

Treatment cost/lack of funding

Access restrictions (e.g. NICE guidance)

Available treatments have no effect on symptoms

B3b. STABLE PATIENT DEFINITION

You selected ‘stable patient’ as a reason to potentially delay initiating an IPF-approved

treatment.

How in practice, would you define a stable IPF patient?


<TEXT BOX>

B4. POINT OF INITIATION

At what point do you typically initiate/recommend the initiation of an IPF approved treatment

for your mild IPF patients?

Please include all of the relevant details, e.g. around FVC levels, Oxygen saturation levels, (or

changes in these levels), other disease measures, patient request and other factors.


<TEXT BOX>

54

B5. TREATMENT DECISION FACTORS

How important are the following factors when you are deciding whether to prescribe an

IPF-approved treatment to a mild IPF patient.

Please note: by IPF-approved treatments we are referring to Esbriet (pirfenidone) and Ofev

(nintedanib).


most important.

Patient’s current symptoms

Patient’s current quality of life

The need to prevent progression

Treatment side effect profile

The risk of prescribing treatment that is not required yet

Patient’s level of understanding about IPF and its treatment

Patient’s co-morbidities

Patient’s likelihood of being compliant

Patient’s lung function and other clinical scores

Patient’s CT-scan results (and how they have changed)

Patient’s wishes

Patient’s work status

B6a. QOL DEFINITION

We understand that one of the factors considered when deciding what to prescribe for your IPF

patients is their quality of life.

55

Using the same exercise again, please can you tell us the relative importance of the factors in the

context of assessing patients’ quality of life?


most important.

Patient’s symptoms

Patient’s ability to live independently

Patient’s ability to carry on their hobbies/interests

Treatment’s side effect profile

Maintenance of patient’s activities of daily living (e.g. cooking, cleaning and bathing)

Pill burden

Impact of patient’s co-morbidities

Patient’s psychological state

B6b. PATIENT REQUEST

How likely are you to initiate an IPF-approved treatment if an IPF confirmed patient (who is

currently IPF-approved treatment naïve), requested that you do?


Very unlikely

Very likely

B6c. RESPONSE TO PATIENT REQUEST RATIONALE

What is the reason behind your stated likelihood to initiate an IPF-approved treatment in

response to a request from an IPF confirmed patient?

56


<TEXT BOX>

B7. PATIENT PROFILE

Based on the following description, would you initiate (or recommend initiating) an IPF

approved treatment for this patient at the current appointment?

<Insert patient profile here>


Yes

No

B8. RISKS WEIGHED UP

Using the rating scale below, please indicate which of the following is more important to you,

when deciding whether to initiate an IPF approved treatment for your mild IPF patients?

Move the slider towards a factor to indicate how much more important it is to you than the other

factor

The risk of the patient suffering side effects that affect their quality of life

The risk of the patient’s IPF progressing

B9a. SIDE EFFECTS FREQUENCY

From what you have seen and read, what percentage of patients on the following treatments

suffer from side effects that could affect their quality of life?


Esbriet (pirfenidone): <TEXT BOX> %

Ofev (nintedanib): <TEXT BOX> %

B9b. SIDE EFFECTS FREQUENCY – SPECIFICS57

From what you have seen and read, what percentage of patients on the following treatments

suffer from the following specific side effects?


Photosensitivity in Esbriet (pirfenidone) patients: <TEXT BOX> %

Diarrhoea in Ofev (nintedanib) patients: <TEXT BOX> %

B10. DISCONNECT AROUND THEORY AND REALITY

Earlier in the survey, you agreed that IPF-approved treatments significantly slow disease

progression, however you see patients who have not started on an IPF-approved treatments in

the first 4 months post diagnosis. What causes this to happen?


<TEXT BOX>

B11. IMPACT OF FVC DROP OF 10%

Based on your knowledge of the data available, what impact does a drop of FVC of 10

percentage points (from a level around 80%) have on patient outcomes?


<TEXT BOX>

Section E: Demographics

E1. PRACTICE TYPE

Please indicate which of the following best describes your primary place of work?


58

Specialist Pulmonary center/tertiary referral center for IPF

Large teaching/university hospital

Large trust/regional/community hospital

Medium sized/district general hospital

Small/local hospital

Private clinic/hospital

Office - solo (By office-based, we are referring to any practice based outside the hospital

or in a community setting)

Office - group practice, single specialty (By office-based, we are referring to any

practice based outside the hospital or in a community setting)

Office - group practice, multiple specialty (By office-based, we are referring to any

practice based outside the hospital or in a community setting)


E2. GENDER

Are you …?


Male

Female

E3. AGE

Which of the following categories best describes your age?


20-29 years old

30-39 years old

59

40-49 years old

50-59 years old

60-69 years old

70 years old or older

Would rather not say

60

Online Supplementary Table S1. Number of respondents taking part in face-to-face interviews or online questionnaire, by country

Total, n Canada, n France, n Germany, n Italy, n Spain, n UK, n

Face-to-face interviews

Physicians 61 10 10 10 10 10 11

Patients 68 11 12 11 10 12 12

Online questionnaires

Physicians 287 30 50 51 52 54 50

Patients 60 10 10 10 10 10 10

Online questionnaires – physicians by group

Group A# 131 20 17 26 22 25 21

Group B¶ 156 10 33 25 30 29 29

# Physicians who monitored ≥50% of patients for >4 months post-diagnosis before initiating an antifibrotic. ¶ Physicians who initiated an

antifibrotic within 4 months post-diagnosis in the majority of patients.

61

Online Supplementary Table S2. Discussion of prognosis by physicians, by country

Total

n (%)

Canada

n (%)

France

n (%)

Germany

n (%)

Italy

n (%)

Spain

n (%)

UK

n (%)

What information do you typically communicate to your

patients at diagnosis?

N = 269 N = 30 N = 47 N = 47 N = 47 N = 50 N = 48

That the patient has IPF 250 (93) 29 (97) 41 (87) 42 (89) 46 (98) 46 (92) 46 (96)

The typical prognosis for IPF (or at least a clear

indicator of how long the patient can expect to live)

144 (54) 23 (77)* 20 (43) † 26 (55) 28 (60) 28 (56) 19 (40)†

How serious IPF is 185 (69) 27 (90)* 31 (66)† 37 (79) 30 (64)† 27 (54)† 33 (69)†

What IPF is 250 (93) 30 (100)* 45 (96)* 46 (98)* 36 (77)† 47 (94)* 46 (96)*

That IPF is progressive 185 (69) 26 (87)* 32 (68)* 35 (74)* 20 (43)† 36 (72)* 36 (75)*

That IPF will progressively impact on the patient’s

daily life (and quality of life)

187 (70) 22 (73) 31 (66) 35 (74) 35 (74) 33 (66) 31 (65)

Information about the treatment options for IPF 242 (90) 28 (93) 42 (89) 44 (94) 42 (89) 46 (92) 40 (83)

62

Total

n (%)

Canada

n (%)

France

n (%)

Germany

n (%)

Italy

n (%)

Spain

n (%)

UK

n (%)

Please rate your level of comfort when discussing the

typical prognosis for IPF (or at least a clear indicator of

how long the patient can expect to live)#

N = 287 N = 30 N = 50 N = 51 N = 52 N = 54 N = 50

Extremely comfortable or comfortable 81 (28) 12 (40)* 15 (30)* 21 (41)* 12 (23) 15 (28)* 6 (12)†

If one of your IPF patients asks you about their

prognosis (or how long they have left to live/words to

this effect), how do you typically answer?

N = 287 N = 30 N = 50 N = 51 N = 52 N = 54 N = 50

I give them the facts (including an idea of average

prognosis and life expectancy for IPF patients [3–5

years]) as part of the discussion

88 (31) 13 (43)* 15 (30) 15 (29) 13 (25) 12 (22)† 20 (40)

I give them an idea of what to expect, without giving

hard facts

83 (29) 10 (33) 15 (30) 17 (33) 11 (21) 18 (33) 12 (24)

I prefer not to tell them anything on the

fatality/prognosis of the disease as the prognosis and

life expectancy is unpredictable and can vary between

48 (17) 1 (3)† 13 (26) 17 (33)* 6 (12)† 5 (9)† 6 (12)†

63

Total

n (%)

Canada

n (%)

France

n (%)

Germany

n (%)

Italy

n (%)

Spain

n (%)

UK

n (%)

IPF patients

I reassure my patients that each patient is different so

that I can monitor their symptoms/progression for

longer before having this conversation

68 (24) 6 (20)† 7 (14)† 2 (4)† 22 (42)* 19 (35) 12 (24)

* Had a significantly higher proportion of physicians with this response than countries marked with a †; † had a significantly lower proportion of

physicians with this response than countries marked with an * (p < 0.05). # Physicians who selected 6 or 7 on a 7-point Likert scale, ranging from 1

= strongly disagree to 7 = strongly agree. IPF, idiopathic pulmonary fibrosis.

64

Online Supplementary Table S3. Physician attitudes to early treatment of patients with IPF, by country

Total

n (%)

Canada

n (%)

France

n (%)

Germany

n (%)

Italy

n (%)

Spain

n (%)

UK

n (%)

Physicians who agreed or strongly agreed# with the

following statements:

N = 287 N = 30 N = 50 N = 51 N = 52 N = 54 N = 50

I need to observe disease progression before

initiating any IPF-specific treatment

58 (20) 5 (17) 8 (16)† 17 (33)* 10 (19) 11 (20) 7 (14)†

By starting IPF-specific treatments early, I have the

best chance of maintaining patients’ lung function

at their current levels and hence quality of life for

as long as possible

119 (41) 14 (47) 20 (40) 27 (53)* 21 (40) 24 (44) 13 (26)†

IPF is a progressive disease thus it is imperative to

start treatment upon diagnosis despite no

significant presence or escalation of symptoms

105 (37) 10 (33) 13 (26) 23 (45)* 23 (44)* 26 (48)* 10 (20)†

IPF-specific treatments (e.g., pirfenidone and

nintedanib) significantly slow the progression of

121 (42) 12 (40) 23 (46)* 25 (49)* 26 (50)* 22 (41) 13 (26)†

65

Total

n (%)

Canada

n (%)

France

n (%)

Germany

n (%)

Italy

n (%)

Spain

n (%)

UK

n (%)

IPF

IPF-specific treatments offer the same level of

benefits to patients with “mild” IPF as those with

“moderate” or “severe” IPF

74 (26) 8 (27) 8 (16)† 22 (43)* 12 (23)† 12 (22)† 12 (24)†

Physicians who agreed or strongly agreed that the

risk of the patient suffering side effects that affect

their quality of life was more important in deciding

to initiate antifibrotic treatment compared with

the risk of the patient’s IPF progressing¶

67 (23) 1 (3)† 9 (18) 18 (35)* 14 (27)* 8 (15) 17 (34)*


physicians with this response than countries marked with an * (p < 0.05). # Physicians who selected 6 or 7 on a 7-point Likert scale, ranging from 1

= strongly disagree to 7 = strongly agree. ¶ Physicians who selected 1 or 2 on a 4-point Likert scale, ranging from 1 = the risk of the patient

suffering side effects that affect their quality of life to 4 = the risk of the patient’s IPF progressing. IPF, idiopathic pulmonary fibrosis.

66

Online Supplementary Table S4. Reasons cited by physicians for not treating patients with “mild”# IPF, by country

Total

n (%)

Canada

n (%)

France

n (%)

Germany

n (%)

Italy

n (%)

Spain

n (%)

UK

n (%)

What are the relevant reasons why you do not

initially prescribe any IPF-specific approved

treatment and just monitor some of your “mild” IPF

patients for at least the first 4 months post

diagnosis?

N = 216 N = 22 N = 41 N = 39 N = 39 N = 38 N = 37

IPF characteristics

Patient has stable disease 107 (50) 16 (73)* 22 (54) 21 (54) 13 (33)† 15 (39)† 20 (54)

Patient has a good quality of life 89 (41) 14 (64)* 15 (37)† 16 (41) 12 (31)† 17 (45) 15 (41)

Patient has good lung function 102 (47) 15 (68)* 22 (54) 19 (49) 13 (33)† 17 (45) 16 (43)

Patient is asymptomatic/has few symptoms 111 (51) 15 (68)* 20 (49) 23 (59)* 14 (36)† 19 (50) 20 (54)

IPF diagnosis is suspected or unclear 105 (49) 12 (55) 23 (56) 16 (41) 21 (54) 16 (42) 17 (46)

Patient risk factors

Patient is of an older age 115 (53) 13 (59)* 27 (66)* 17 (44) 24 (62)* 23 (61)* 11 (30)†

67

Total

n (%)

Canada

n (%)

France

n (%)

Germany

n (%)

Italy

n (%)

Spain

n (%)

UK

n (%)

Patient has comorbidities 88 (41) 12 (55)* 19 (46) 13 (33) 15 (38) 19 (50)* 10 (27)†

Patient choice

Risk of noncompliance with treatment regimen 47 (22) 3 (14) 14 (34)* 10 (26)* 8 (21) 9 (24) 3 (8)†

Patient worry about or refusal due to side effects 87 (40) 14 (64)* 19 (46) 15 (38) 13 (33)† 11 (29)† 15 (41)

Patient refusal not related to side effects 53 (25) 5 (23) 10 (24) 7 (18)† 16 (41)* 9 (24) 6 (16)†

Other

Cost of treatment or lack of funding 54 (25) 12 (55)* 6 (15)† 5 (13)† 8 (21) 14 (37)* 9 (24)

Access restrictions (e.g., NICE guidance) 56 (26) 10 (45)* 5 (12)† 2 (5)† 9 (23) 13 (34)* 17 (46)*


physicians with this response than countries marked with an * (p < 0.05). # IPF was defined as “mild” by physicians. IPF, idiopathic pulmonary

fibrosis; NICE, National Institute for Health and Care Excellence.

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